WorldWideScience

Sample records for eurisol target design

  1. EURISOL-DS Multi-MW Target: Design of the EURISOL Liquid metal loop

    CERN Document Server

    K. Samec (PSI)

    A Mercury loop capable of evacuating 2.7 MW of the 4 MW deposited in the Eurisol liquid metal neutron spallation target is described in the present design study.The study takes into account the effects on the loop of temperature, pressure, irradiation, liquid metal corrosion, including both steady state operations and normal transients. Accidental conditions are only briefly alluded to in the form of a description of the protection barriers and envisaged mitigation strategies.

  2. ENGINEERING DESIGN OF THE EURISOL MULTI-MW SPALLATION TARGET

    CERN Document Server

    Adonai Herrera-Martinez*, Yacine Kadi, Morteza Ashrafi-Nik, Karel Samec, Janis Freibergs, Ernests Platacis

    The European Isotope Separation On-Line Radioactive Ion Beam project (EURISOL) is set to design the ‘next-generation’ European Isotope Separation On-Line (ISOL) Radioactive Ion Beam (RIB) facility. It will extend and amplify current research on nuclear physics, nuclear astrophysics and fundamental interactions beyond the year 2010. In EURISOL, four target stations are foreseen, three direct targets of approximately 100 kW of beam power and one multi-MW target assembly, all driven by a high-power particle accelerator. In this high power target station, high-intensity RIBs of neutron-rich isotopes will be obtained by inducing fission in several actinide targets surrounding a liquid metal spallation neutron source. This article summarises the work carried out within Task 2 of the EURISOL Design Study, with special attention to the coupled neutronics of the mercury proton-to-neutron converter and the fission targets. The overall performance of the facility, which will sustain fast neutron fluxes of the order ...

  3. Engineering design of the EURISOL multi-MW spallation target

    CERN Document Server

    Herrera-Martínez, A; Ashrafi-Nik, M; Samec, K; Freibergs, J; Platacis, E

    2007-01-01

    The European Isotope Separation On-Line Radioactive Ion Beam project (EURISOL) is set to design the 'next-generation' European Isotope Separation On-Line (ISOL) Radioactive Ion Beam (RIB) facility. It will extend and amplify current research on nuclear physics, nuclear astrophysics and fundamental interactions beyond the year 2010. In EURISOL, four target stations are foreseen, three direct targets of approximately 100 kW of beam power and one multi-MW target assembly, all driven by a high-power particle accelerator. In this high power target station, high-intensity RIBs of neutron-rich isotopes will be obtained by inducing fission in several actinide targets surrounding a liquid metal spallation neutron source. This article summarises the work carried out within Task 2 of the EURISOL Design Study, with special attention to the coupled neutronics of the mercury proton-to-neutron converter and the fission targets. The overall performance of the facility, which will sustain fast neutron fluxes of the order of 1...

  4. Driver beam-led EURISOL target design constraints

    CERN Document Server

    Noah, Etam; Catherall, Richard; Kadi, Yacine; Kharoua, Cyril; Lettry, Jacques

    2008-01-01

    The EURISOL (European Isotope Separation Online) Design Study is addressing new high power target design challenges. A three-step method [1] was proposed to split the high power linac proton driver beam into one $H^{-}$ branch for the 4 $MW_{b}$ [2] mercury target that produces radioactive ion beams (RIB) via spallation neutroninduced fission in a secondary actinide target and three 100 $kW_{b}$ $H^{+}$ branches for the direct targets producing RIBs via fragmentation and spallation reactions. This scheme minimises transient thermo-mechanical stresses on targets and preserves the cw nature of the driver beam in the four branches. The heat load for oxides, carbides, refractory metal foils and liquid metals is driven by the incident proton driver beam while for actinides, exothermic fission reactions are an additional contribution. This paper discusses the constraints that are specific to each class of material and the target design strategies.

  5. EURISOL High Power Targets

    CERN Document Server

    Kadi, Y; Lindroos, M; Ridikas, D; Stora, T; Tecchio, L; CERN. Geneva. BE Department

    2009-01-01

    Modern Nuclear Physics requires access to higher yields of rare isotopes, that relies on further development of the In-flight and Isotope Separation On-Line (ISOL) production methods. The limits of the In-Flight method will be applied via the next generation facilities FAIR in Germany, RIKEN in Japan and RIBF in the USA. The ISOL method will be explored at facilities including ISAC-TRIUMF in Canada, SPIRAL-2 in France, SPES in Italy, ISOLDE at CERN and eventually at the very ambitious multi-MW EURISOL facility. ISOL and in-flight facilities are complementary entities. While in-flight facilities excel in the production of very short lived radioisotopes independently of their chemical nature, ISOL facilities provide high Radioisotope Beam (RIB) intensities and excellent beam quality for 70 elements. Both production schemes are opening vast and rich fields of nuclear physics research. In this article we will introduce the targets planned for the EURISOL facility and highlight some of the technical and safety cha...

  6. Design of the EURISOL multi-MW target assembly radiation and safety issues

    CERN Document Server

    Felcini, Marta; Kadi, Yacine; Otto, Thomas; Tecchio, L

    2006-01-01

    The multi-MW target proposed for the EURISOL facility will be based on fission of uranium (or thorium) compounds to produce rare isotopes far from stability. A two-step process is used for the isotope production. First, neutrons are generated in a liquid mercury target, irradiated by the 1 GeV proton or deuteron beam, provided by the EURISOL linac driver. Then, the neutrons induce fission in a surrounding assembly of uranium carbide. R&D projects on several aspects of the target assembly are ongoing. Key criteria for the target design are a maximum beam power capability of 4 MW, a remote handling system with minimum downtime and maximum reliability, as well as radiation safety, minimization of hazards and the classification of the facility. In the framework of the ongoing radiation characterization and safety studies, radiation transport simulations have been performed to calculate the prompt radiation dose in the target and surrounding materials, as well as to determine shielding material and angle-depen...

  7. FISSION TARGET DESIGN AND INTEGRATION OF NEUTRON CONVERTER FOR EURISOL-DS PROJECT

    CERN Document Server

    J. Bermudez, O. Alyakrinskiy, M. Barbui, F. Negoita, L. Serbina, L.B. Tecchio, E. Udup

    A study of a new fission target for EURISOL-DS is presented with a detailed description of the target. Calculations of several configurations were done using Monte Carlo code FLUKA aimed to obtaining 1015 fissions/s on single target. In Eurisol, neutrons inducing the fission reactions are produced by a proton beam 1GeV-4mA interacting with a mercury converter. The target configuration was customized to gain fission yield from the large amount of low energy neutrons produced by the Hg converter. To this purpose, the fissile material is composed by discs of 238-Uranium carbide enriched with 15 g of 235-U. Studies of several geometries were done in order to define the shape and composition of uranium target, taking into account the mechanical and space constraints

  8. Design of a compact high-power neutron source—The EURISOL converter target

    Science.gov (United States)

    Samec, K.; Milenković, R. Ž.; Dementjevs, S.; Ashrafi-Nik, M.; Kalt, A.

    2009-07-01

    The EURISOL project, a multi-lateral initiative supported by the EU, aims to develop a facility to achieve high yields of isotopes in radioactive beams and extend the variety of these isotopes towards more exotic types. The neutron source at the heart of the projected facility is designed to generate isotopes by fissioning uranium carbide (UC) targets arranged around a 4 MW neutron source. For reasons of efficiency, it is essential that the neutron source be as compact as possible, to avoid losing neutrons by absorption whilst maximising the escaping neutron flux, thus increasing the number of fissions in the UC targets. The resulting configuration presents a challenge in terms of absorbing heat deposition rates of up to 8 kW/cm3 in the neutron source; it has led to the selection of liquid metal for the target material. The current paper presents the design of a compact high-power liquid-metal neutron source comprising a specially optimised beam window concept. The design is based on two-dimensional (2D) and three-dimensional (3D) computational fluid dynamics (CFD) numerical simulations for thermal hydraulics and hydraulic aspects, as well as finite-element method (FEM) for assessing thermo-mechanical stability. The resulting optimised design was validated by a dedicated hydraulic test under realistic flow conditions. A full-scale mock-up was built at the Paul Scherrer Institute (PSI) and was tested at the Institute of Physics of the University of Latvia (IPUL).

  9. Design of a compact high-power neutron source-The EURISOL converter target

    Energy Technology Data Exchange (ETDEWEB)

    Samec, K. [Paul Scherrer Institut, Villigen, 5232 Villigen (Switzerland)], E-mail: karel.samec@psi.ch; Milenkovic, R.Z.; Dementjevs, S.; Ashrafi-Nik, M.; Kalt, A. [Paul Scherrer Institut, Villigen, 5232 Villigen (Switzerland)

    2009-07-21

    The EURISOL project, a multi-lateral initiative supported by the EU, aims to develop a facility to achieve high yields of isotopes in radioactive beams and extend the variety of these isotopes towards more exotic types. The neutron source at the heart of the projected facility is designed to generate isotopes by fissioning uranium carbide (UC) targets arranged around a 4 MW neutron source. For reasons of efficiency, it is essential that the neutron source be as compact as possible, to avoid losing neutrons by absorption whilst maximising the escaping neutron flux, thus increasing the number of fissions in the UC targets. The resulting configuration presents a challenge in terms of absorbing heat deposition rates of up to 8 kW/cm{sup 3} in the neutron source; it has led to the selection of liquid metal for the target material. The current paper presents the design of a compact high-power liquid-metal neutron source comprising a specially optimised beam window concept. The design is based on two-dimensional (2D) and three-dimensional (3D) computational fluid dynamics (CFD) numerical simulations for thermal hydraulics and hydraulic aspects, as well as finite-element method (FEM) for assessing thermo-mechanical stability. The resulting optimised design was validated by a dedicated hydraulic test under realistic flow conditions. A full-scale mock-up was built at the Paul Scherrer Institute (PSI) and was tested at the Institute of Physics of the University of Latvia (IPUL)

  10. EURISOL Multi-MW Target: Preliminary Study

    CERN Document Server

    A.Herrera-Martínez and Y.Kadi

    This technical note summarises the design calculations performed within Task #2 of the EURopean Isotope Separation On-Line Radioactive Ion Beam Facility Design Study (EURISOL DS).A preliminary study was carried out in order to determine the optimum value of relevant parameters in the target design. Different scenarios were simulated using the Monte Carlo code FLUKA. Namely, sensitivity studies were performed to assess the impact of the projectile particle energy on the neutronics and energy deposition in the spallation target. The optimum target dimension was also studied for every case as well as the proper target material for the liquid metal proton-to-neutron converter, since mercury and lead-bismuth eutectic are reasonable options. The effect of the beam width on the power densities was also evaluated, taking into account the geometrical limitations of the facility. Finally, a comparison between protons and deuterons as primary particles was performed, acknowledging the limitations of using FLUKA for thes...

  11. EURISOL 100 kW Target Stations Operation and Implications for its Proton Driver Beam

    CERN Document Server

    Noah, Etam; Lettry, Jacques; Lindroos, Mats; Stora, Thierry

    EURISOL, the next European radioactive ion beam (RIB) facility calls for the development of target and ion source assemblies to dissipate deposited heat and to extract and ionize isotopes of interest efficiently. The EURISOL 100 kW direct targets should be designed for a goal lifetime of up to three weeks. Target operation from the moment it is installed on a target station until its exhaustion involves several phases with specific proton beam intensity requirements. This paper discusses operation of the 100 kW targets within the ongoing EURISOL Design Study, with an emphasis on the requirements for the proton driver beam.

  12. EURISOL Multimegawatt Target Unit - MAFF Configuration: Dosimetry and Activation Studies

    CERN Document Server

    Luis, R; Kadi, Y; Tecchio, L; Kharoua, C; Vaz, P; Ene, D; David, J C; Goncalves, I F; Rocca, R; Romanets, Y; Negoita, F

    2011-01-01

    The EURopean Isotope Separation On-Line Radioactive Ion Beam (EURISOL) project aims at building a facility to produce radioactive ion beams with intensities two to three orders of magnitude higher than those presently available. A 4-MW (1-GeV, 4-mA) proton beam hits a liquid mercury converter, generating, by spallation reactions, high neutron fluxes that induce fission in surrounding fissile targets. In this work, Monte Carlo calculations of dose rate and activation were carried out to identify the necessary shielding and access restrictions for each section of the facility, including maintenance, storage, and remote control spaces. These calculations allowed an optimization of the materials chosen for the assembly, based on the radioprotection issues, while taking into account the desired performance of the system. The results of the design studies indicate that the intended performance parameters (namely neutron fluxes, fission rates, and easy fission target manipulation) of the EURISOL multimegawatt target...

  13. EURISOL-DS MULTI-MW TARGET ISSUES: BEAM WINDOW AND TRANSVERSE FILM TARGET

    CERN Document Server

    Adonai Herrera-Martínez, Yacine Kadi

    The analysis of the EURISOL-DS Multi_MW target precise geometry (Fig.1) has proved that large fission yields can be achieved with a 4 MW, providing a technically feasible design to evacuate the power deposited in the liquid mercury. Different designs for the mercury flow have been proposed, which maintain its temperature below the boiling point with moderate flow speeds (maximum 4 m/s).

  14. The EURISOL Multi Megawatt Target Station, a liquid metal target for a High Power spallation source.

    CERN Document Server

    Kharoua, C; Blumenfeld, L; Milenkovich, R; Wagner, W; Thomsen, K; Dementjevs, S; Platacis, E; Kravalis, K; Zik, A

    The European Isotope Separation On-Line Radioactive Ion Beam Facility (EURISOL) is set to be the ‘next-generation’ European Isotope Separation On-Line (ISOL) Radioactive Ion Beam (RIB) facility. It will extend and amplify current research in nuclear physics, nuclear astrophysics and fundamental interactions beyond the year 2013.In EURISOL, four target stations are foreseen, three direct targets of approximately 100 kW of beam power and one multi-MW liquid metal proton-to-neutron converter, all driven by a high-power particle accelerator. In the aforementioned multi-MW target assembly, high-intensity RIBs of neutron-rich isotopes will be obtained by inducing fission in several actinide targets surrounding a liquid metal spallation neutron source.This presentation summarises the work carried out for the Multi Megawatt target station of the EURISOL Design Study with particular attention to the coupled neutronic of the liquid converter and the overall performance of the facility, which will sustain fast neutr...

  15. EURISOL-DS Multi-MW Target: Cost Analysis for a Proposed Development Phase

    CERN Document Server

    Karel, Samec; Kadi, Yacine; Noah, Etam; Lettry, Jacques; Wagner, Werner; Thomsen, Knud; Patorski, Jacek; Dementevjs, Sergej; Zik, Anatoli; Platacis, Erik

    The EURISOL Design Study has reached final completion and the three institutes, CERN, IPUL and PSI, participating in the development of the Multi-Megawatt target station have met the objective of a reliable, affordable and credible design. The costs involved in the full development of such a target are forecast to reach 200 million €, approximately 15% of the total costs of the EURISOL facility.A breakdown of the costs is presented as well as an outline of future possible R&D efforts aimed at improving reliability and safety of the facility. Another important goal of the proposed R&D is to minimise development risk by focusing resources, early on in the project, on areas identified as presenting a particular risk. An example clearly identified in the study would be the conditioning of the contaminated Mercury, both during the lifetime of the facility and after decommissioning.

  16. EURISOL-DS Multi-MW Target Preliminary Study of the Thermal Behaviour of the fission target inspired by the MAFF project

    CERN Document Server

    Cyril Kharoua, Yacine Kadi

    This technical note summarises the design calculations performed within Task #2 of the European Isotope Separation On-Line Radioactive Ion Beam Facility Design Study (EURISOL-DS) [1] for the thermal behaviour of the fission target. A preliminary study was carried out in order to determine the heat deposition within the fissile material and estimate the temperature raise.

  17. EURISOL-DS Multi-MW Target: Thermal Behaviour of the fission target disk arrangement inspired by the MAFF project

    CERN Document Server

    Cyril Kharoua, Yacine Kadi and the EURISOL-DS Task#2 collaboration

    This technical note summarises the design calculations performed within Task #2 of the European Isotope Separation On-Line Radioactive Ion Beam Facility Design Study (EURISOL-DS) [1] for the thermal behaviour of the fission target.A preliminary study was carried out in order to determine the heat deposition within the fissile material and estimate the temperature rise. This new solution takes into account the problems related to effusion/diffusion of radioactive isotopes inside a thick target. To enhance the extraction rates and the thermal behaviour it is proposed to study a solution where the fissile material is split into an arrangement of disks.

  18. Mercury purification in the megawatt liquid metal spallation target of EURISOL-DS

    CERN Document Server

    Neuhausen, Joerg; Eller, Martin; Schumann, Dorothea; Eichler, Bernd; Horn, Susanne

    High power spallation targets are going to be used extensively in future research and technical facilities such as spallation neutron sources, neutrino factories, radioactive beam facilities or accelerator driven systems for the transmutation of long-lived nuclear waste. Within EURISOL-DS, a 4 MW liquid metal spallation target is designed to provide neutrons for a fission target, where neutron rich radionuclides will be produced. For the spallation target, mercury is planned to be used as target material. A large amount of radionuclides ranging from atomic number Z=1 to 81 will be produced in the liquid metal during long term irradiation. It is planned to remove those radionuclides by chemical or physicochemical methods to reduce its radioactivity. For the development of a purification procedure, knowledge about the chemical state of the different elements present in the mixture is required. We present a general concept of applicable separation techniques in a target system and show some results of experiment...

  19. EURISOL-DS Multi-MW Target: Cavitations detection by the a Laser Doppler Vibrometer

    CERN Document Server

    Cyril Kharoua, Yacine Kadi, Jacques Lettry, Laure Blumenfeld, Karel Samec (CERN)Knud Thomsen, Sergej Dementevjs, Rade Milenkovich (PSI)Anatoli Zik, Erik Platacis (IPUL)

    This technical note summarises the innovative measurement devices used within Task #2 of the European Isotope Separation On-Line Radioactive Ion Beam Facility Design Study (EURISOL-DS) to detect the occurrence of cavitation in liquid metal flowing inside the CGS target mock-up.During the METEX hydraulic experiment carried out at IPUL (Institute of Physics of the University of Latvia), a Laser Doppler Vibrometer was used to characterize the wall vibrations of the beam window at different flow regimes. A series of tests proved the high sensitivity of the LDV to detect the occurrence of cavitation in the liquid metal flowing inside the target. In this context, a dedicated test procedure was developed to establish the validity of using LDV for detecting the onset of cavitation.

  20. EURISOL Multi-MW Target: First thermal-hydraulic studies for the EURISOL high-power liquid-metal target using Computational Fluid Dynamics

    CERN Document Server

    Trevor V. Dury

    A scoping study of a mercury target for the Multi-Megawatt Proton-to-Neutron Converter of theEURISOL Project has been made at PSI using the Computational Fluid Dynamics (CFD) codeCFX-4. A mesh model of a horizontal target with forced circulation was used which had beenoriginally proposed for the European Spallation Source (ESS). The heat deposition profilewhich was applied produced a total of 4 MW of heat in the fluid and 13.4 kW in the window,

  1. EURISOL-DS Multi-MW Target Preliminary Study of the Liquid Metal Proton-to-Neutron Converter

    CERN Document Server

    Herrera-Martínez, A; CERN. Geneva. AB Department

    2006-01-01

    This technical note summarises the design calculations performed within Task #2 of the European Isotope Separation On-Line Radioactive Ion Beam Facility Design Study (EURISOL-DS) [1]. A preliminary study was carried out in order to determine the optimum value of relevant parameters in the target design. Different scenarios were simulated using the Monte Carlo code FLUKA [2]. Namely, sensitivity studies were performed to assess the impact of the projectile particle energy on the neutronics and energy deposition in the spallation target. The optimal target dimensions were also studied for every case as well as the proper target material for the liquid metal proton-to-neutron converter, since mercury and lead-bismuth eutectic are reasonable options. The effect of the beam width on the power densities was also evaluated, taking into account the geometrical limitations of the facility. Finally, a comparison between protons and deuterons as primary particles was performed, acknowledging the limitations of using FLU...

  2. In-target rare nuclei production rates with EURISOL single-stage configuration

    CERN Document Server

    Chabod, S P; Ene, D; Doré, D; Blideanu, V; David, J.-Ch; Ridikas, D

    2010-01-01

    We conducted calculations of exotic nuclei production rates for 320 configurations of EURISOL (European Isotope Separation On-Line Radioactive Ion Beam Facility) direct spallation targets. The nuclei yields were evaluated using neutron generation-transport codes, completed with evolution calculations to account for nuclei decays and low energy neutron interactions. The yields were optimized for 11 selected elements (Li, Be, Ne, Mg, Ar, Ni, Ga, Kr, Sn, Hg, Fr) and 23 of their isotopes, as function of the target compositions and geometries as well as the incident proton beam energies. For the considered elements, we evaluated the yield distributions as functions of the charge and mass numbers using two different spallation models.

  3. Innovative Waste Management in the Mercury Loop of the EURISOL Multi-MW Converter Target

    CERN Document Server

    PSI: Jörg Neuhausen, Dorothea Schumann, Rugard Dressler, Susanne Horn, Sabrina Lüthi, Stephan Heinitz, Suresh ChirikiCERN: Thierry Stora, Martin Eller

    The choice of mercury as target material imposes various questions concerning the safe operation of such a system that are related to the physical and chemical properties of the target material itself and the nuclear reaction products produced within the target during its life time of several decades. Therefore, a subtask was created within the EURISOL-DS project that is concerned with studying an innovative waste management for the generated radioactivity by chemical means. Such a study strongly depends on the radioactive inventory and its distribution throughout the target and loop system. Radioactive inventory calculations were performed within task 5 [6]. The distribution of nuclear reaction products and their chemical state that can be expected within the target and loop system is one of the topics covered in this report. Based on the results obtained by theoretical studies as well as laboratory scale experiments, the feasibility of waste reduction using chemical methods, both conventional (e.g. leaching...

  4. EURISOL-DS Multi-MW Target Unit: Neutronics and shielding performance, dose rate and material activation calculations for the MAFF configuration

    CERN Document Server

    Luis, R; Goncalves, I. F; Vaz, P; Kadi, Y; Kharoua, C; Rocca, R; Tecchio, L; Negoita, F; Ene, D; David, J.C

    One of the EURISOL-DS (The EURopean Isotope Separation On-Line Radioactive Ion Beam – Design Study) objectives is to provide a safe and reliable facility layout meeting the following operational parameters:1.

  5. EURISOL-DS Multi-MW Target: Study of the WTF Liquid Metal Proton-to-Neutron Converter

    CERN Document Server

    Cyril Kharoua, Yacine Kadi (CERN)Erik Platacis, Kalvis Kravalis (IPUL)

    This technical note summarises the design calculations and experiments performed within Task #2 of the European Isotope Separation On-Line Radioactive Ion Beam Facility Design Study (EURISOL-DS) for the WTF (Windowless Transverse Film) mercury converter.A preliminary study was carried out in order to determine the heat deposition within the mercury and estimate the flow velocity needed in the film. The geometry used is based on previous analysis simulated using the Monte Carlo code FLUKA.Many experiments have been performed at IPUL to optimise an inlet nozzle capable to create a stable film. The experimental program followed to design the film former will be detailed in this report.The results of these calculations are addressing the baseline parameters. Particularly, a 1 GeV proton beam with a sigma ~2 mm Gaussian distribution impacting on a 4x30x40cm long target. The very high power density requires about 5m/s velocity in the region where the heat deposition is maximum.

  6. Detailed thermal stress analysis of EURISOL Fission target-First concept

    CERN Document Server

    Emeric Brun

    A first concept for the fission boxes of the planned EURISOL facility is analysed from a thermal and structural point of view. The fission boxes in this facility consists in stacks of uranium carbide sheets surrounded by tantalum blanket which are all cooled through radiative heat exchange with a convectively cooled outer stainless steel container.

  7. EURISOL-DS Multi-MW Target Preliminary Study of the WTF(Windowless Transverse Film) Liquid Metal Proton-to-Neutron Converter

    CERN Document Server

    Cyril Kharoua, Yacine Kadi, Karel Samec, Roberto Rocca

    This technical note summarises the design calculations performed within Task #2 of the European Isotope Separation On-Line Radioactive Ion Beam Facility Design Study (EURISOL-DS) [1] for the WTF (Windowless Transverse Film) mercury converter. A preliminary study was carried out in order to determine the heat deposition within the mercury and estimate the mercury velocity needed in the film. The geometry used is based on previous analysis simulated using the Monte Carlo code FLUKA [2]. The results of these calculations show the baseline parameters, which will be used for the detailed design. Particularly, with a 1 GeV proton beam with a ~2 mm Gaussian distribution on a 4x30x40cm long target and with a 5m/s velocity at the peak power density region seems a suitable solution.

  8. Eurisol-DS Multi MW Target Preliminary Study of the Windlowless Transverse Film (WTF) Liquid Metal Proton-to Neutron Converter

    CERN Document Server

    Kadi, Y; Rocca, R; Samec, K

    2008-01-01

    This technical note summarises the design calculations performed within Task#2 of the European Isotope Separation On-Line Radioactive Ion Beam Facility Design Study (EURISOL-DS) for the WTF (Windowless Transverse Film) mercur converter. A preliminary study was carried out in order to determine the heat deposition within the mercury and estimate the mercury velocity needed in the film. The geometry used is based on previous analysis simulated using the Monte Carlo code FLUKA. The results of these calculations show the baseline parameters, which will be used for the detailed design. Particularly, with a 1 GeV proton beam with a $\\sigma$ ~2 mm Gaussian distribution on a 4x30x40cm long target and with a 5m/s velocity at the peak power density region seems a suitable solution.

  9. EURISOL-DS Multi-MWatt Hg Target: Neutron flux and fission rate calculations for the MAFF configuration

    CERN Document Server

    Romanets, Y; Vaz, P; Herrera-Martinez, A; Kadi, Y; Kharoua, C; Lettry, J; Lindroos, M

    The EURISOL (The EURopean Isotope Separation On-Line Radioactive Ion Beam) project aims at producing high intensity radioactive ion beams produced by neutron induced fission on a fissile target (235U) surrounding a liquid mercury converter. A proton beam of 1 GeV and 4 MW impinges on the Hg converter generating by spallation reactions high neutron fluxes. In this work the state-of-the-art Monte Carlo codes MCNPX and FLUKA were used to assess the neutronics performance of the system which geometry, inspired from the MAFF concept, allows a versatile manipulation of the fission targets. The objective of the study was to optimize the geometry of the system and the materials used in the fuel and reflector elements of the system, in order to achieve the highest possible fission rate.

  10. Development of the EURISOL Multi-Megawatt Target Station (2005-2009): Executive Summary

    CERN Document Server

    Karel Samec et al. (CERN, IPUL, ITN and PSI)

    Advances in nano-technology, bio-technology, nuclear medicine and the fundamental sciences require a facility to continue improving current capabilities in Europe beyond the year 2010. European competitiveness could benefit greatly from a unique research facility, flexible enough to satisfy users from many different fields of science and technology. The facility would be a valuable asset enabling economies of scale and giving Europe access to cutting-edge technology at the heart of future technological advances of major economic importance. Specialised facilities already operating at full capacity such as SINQ in Switzerland, ILL in France, have demonstrated the benefits of bringing together users from different scientific backgrounds and different countries. Such a research policy may be reinforced by the improved performance and greater reach of the EURISOL project which is aimed at a larger research community. Beneficiaries include the medical sciences such as oncology, medical imagery or studies of protei...

  11. EURISOL-DS multi-MW target unit: Neutronics performance and shielding assessment, dose rate and material activation calculations for the MAFF configuration

    CERN Document Server

    Romanets, Y; Kadi, Y; Luis, R; Goncalves, I F; Tecchio, L; Kharoua, C; Vaz, P; Ene, D; David, J C; Rocca, R; Negoita, F

    2010-01-01

    One of the objectives of the EURISOL (EURopean Isotope Separation On-Line Radioactive Ion Beam) Design Study consisted of providing a safe and reliable facility layout and design for the following operational parameters and characteristics: (a) a 4 MW proton beam of 1 GeV energy impinging on a mercury target (the converter); (b) high neutron fluxes (similar to 3 x 10(16) neutrons/s) generated by spallation reactions of the protons impinging in the converter and (c) fission rate on fissile U-235 targets in excess of 10(15) fissions/s. In this work, the state-of-the-art Monte Carlo codes MCNPX (Pelowitz, 2005) and FLUKA (Vlachoudis, 2009; Ferrari et al., 2008) were used to characterize the neutronics performance and to perform the shielding assessment (Herrera-Martinez and Kadi, 2006; Cornell, 2003) of the EURISOLTarget Unit and to provide estimations of dose rate and activation of different components, in view of the radiation safety assessment of the facility. Dosimetry and activation calculations were perfor...

  12. Radiation safety with high power operation of EURISOL

    CERN Document Server

    Ridikas, D

    2007-01-01

    The European Community has launched the design study for a next generation RIB facility able to increase by a few orders of magnitude, the exotic beam intensity and availability in Europe. Forty institutes and laboratories within Europe, North America and Asia are taking part in this consortium, named EURISOL DS project (European Isotope Separation On Line Design Study). In EURISOL, four target stations are foreseen, three direct targets of approximately 100 kW of beam power and one multi-MW (MMW) target assembly, all driven by a high-power particle accelerator. In this MMW station, high-intensity RIBs of neutron-rich isotopes will be obtained by inducing fission in several actinide targets surrounding a liquid metal spallation neutron source. The envisaged increase in RIB intensities at EURISOL means a drastic increase of the radioactive inventory and corresponding radioprotection related issues. Safety aspects of the future RIB production targets (aiming at a few ~1015 fissions/s) will become decisive in li...

  13. Beam dynamics studies on the EURISOL driver accelerator

    CERN Document Server

    Facco, A; Paparella, R; Zenere, D; Biarrotte, J. L; Bousson, S; Ponton, A; Berkovits, D; Rodnizki, J; Duperrier, R; Uriot, D; Zvyagintsev, V

    A 1 GeV, 5 mA cw superconducting proton/H- linac, with the capability of supplying cw primary beam to up to four targets simultaneously by means of a new beam splitting scheme, is under study in the framework of the EURISOL DS project which aims to produce an engineering-oriented design of a next generation European Radioactive beam facility. The EURISOL driver accelerator would be able to accelerate also a 100 μA, 3He beam up to 2.2 GeV, and a 5 mA deuteron beam up to 264 MeV. The linac characteristics and the status of the beam dynamics studies will be presented.

  14. EURISOL Multi-MW Target: Investigation of the hydrodynamics of liquid metal (Hg) jet

    CERN Document Server

    Freibergs, J

    In order to develop a windowless target it is necessary to investigate the hydrodynamics of liquid metal (Hg) jet. On the basis of the schematic layout of a high-power target module presented in Ref. [2], and the parameters of the windowless target (speed of the mercury jet up to 30 m/s, diameter of jet 10-20 mm and length of jet about 1 m), a first estimation of the parameters of the main components of a Hg-loop has been obtained by the Institute of Physics, University of Latvia. A preliminary engineering design of a functional Hg-loop to be constructed soon is also proposed. A simplified water stand has been developed with the ability of testing different Hg-nozzle configurations. The tests carried out showed that the kinetic energy of the jet is so high that the coaxial water flow at contact point is transformed into small bubbles (spray). The characteristics of the jet were shown to depend on the pressure of the stand.

  15. Status of ionization by radial electron neat adaptation ion source research and development for SPIRAL2 and EURISOL-DS

    CERN Document Server

    Lau, C; Cheikh-Mhamed, M; 10.1063/1.2834316

    2008-01-01

    To take up the most challenging issue of supplying plasma ion source able to produce radioactive beams under extreme SPIRAL-2 and EURISOL irradiation conditions, an R&D program has been initiated to work out IRENA (Ionization by Radial Electrons Neat Adaptation) ion source. Using EBGP (Electron Beam Generated Plasma) concept, the ion source is specifically adapted for thick target and intense irradiation. A validation prototype has been designed, constructed and tested. Results obtained will be presented and commented and IRENA potential discussed, particularly in the framework of the multi-megawatts EURISOL.

  16. Feasibility of High Power Refractory Metal Foil-Targets for EURISOL

    CERN Document Server

    R. Wilfinger, J. Lettry and the EURISOL Task 3 Workgroup

    Radioisotopes are produced by the ISOL method in thick targets. In existing ISOL facilities, only small yields have been obtained for short-lived nuclei close to the driplines due to the radioactive decay during the diffusion, effusion and ionization processes. An increase of the proton beam current increases the production rate, which is directly proportional to the primary proton flux. But at the same time, the power deposition inside the target is also increased proportional to the primary proton flux...

  17. Benchmark calculations on residue production within the EURISOL DS project; Part I: thin targets

    CERN Document Server

    David, J.C; Boudard, A; Doré, D; Leray, S; Rapp, B; Ridikas, D; Thiollière, N

    Report on benchmark calculations on residue production in thin targets. Calculations were performed using MCNPX 2.5.0 coupled to a selection of reaction models. The results were compared to nuclide production cross-sections measured in GSI in inverse kinematics

  18. Benchmark calculations on residue production within the EURISOL DS project; Part II: thick targets

    CERN Document Server

    David, J.-C; Boudard, A; Doré, D; Leray, S; Rapp, B; Ridikas, D; Thiollière, N

    Benchmark calculations on residue production using MCNPX 2.5.0. Calculations were compared to mass-distribution data for 5 different elements measured at ISOLDE, and to specific activities of 28 radionuclides in different places along the thick target measured in Dubna.

  19. EURISOL-DS Multi-MW Target: Experimental program associated to validation of CFD simulations of the mercury loop

    CERN Document Server

    Blumenfeld, Laure; Kadi, Yacine; Samec, Karel; Lindroos, Mats

    At the core of the Eurisol project facility, the neutron source produces spallation neutrons from a proton beam impacting dense liquid. The liquid circulates at high speed inside the source, a closed vessel with beam windows.This technical note summarises the needed of the hydraulic METEX 1 and METEX 2 data tests to contribute to validate CFD turbulent simulation of liquid metal with the LES model and FEM structural model as well as a-dimensional analysis of Laser Dopplet Velocimetry for cavitation measurements.

  20. Engineering design and construction of a function Hg – loop & Contribution of IPUL in windowless Hg-target feasibility studies

    CERN Document Server

    J. Freibergs, E. Platacis, K. Kravalis, A. Ziks&I.Platnieks

    Within EURISOL – DS, a liquid metal /LM/ spallation target with a power of several Megawatt is designed to provide neutrons to a fission target. The target station that allows the full intensity of a 4 MW proton beam to be used for RIB production will require new advanced technology. It is a critical component of EURISOL.For a power density above 103 MW/m3 the windowless, free-surface, molten LM-jet is proposed as a target since it avoids the very serious lifetime – shortening damage caused by the power proton beam in any system

  1. The multi megawatt target station integration of the MAFF/PIAFE fission target design

    CERN Document Server

    Kharoua, C; Herrera-Martinez, A; Lettry, J; Ashrafi-Nik, M; Groeschel, F; Samec, K; Zanini, L; Alyakriskiy, O; Barbui, M; Tecchio, Luigi; Freibergs, J; Gross, M; Nebel, F; Thirolf, P; Negoita, F; Serbina, L; Romanets, Y; Vaz, P; Lindroos, M; Kadi, Y

    The European Isotope Separation On-Line Radioactive Ion Beam Facility (EURISOL) is set to be the ‘next-generation’ European Isotope Separation On-Line (ISOL) Radioactive Ion Beam (RIB) facility. It will extend and amplify current research on nuclear physics, nuclear astrophysics and fundamental interactions beyond the year 2010.In EURISOL, four target stations are foreseen, three direct targets of approximately 100 kW of beam power and one multi-MW liquid metal proton-to-neutron converter, all driven by a high-power particle accelerator. In the aforementioned multi-MW target assembly, high-intensity RIBs of neutron-rich isotopes will be obtained by inducing fission in several actinide targets surrounding a liquid metal spallation neutron source.This article summarises the work carried out within Task 2 of the EURISOL Design Study, with special attention to the coupled neutronics of the liquid converter and fission target (MAFF/PIAFE design like) and the overall performance of the facility, which will sust...

  2. High Power CW Superconducting Linacs for EURISOL and XADS

    CERN Document Server

    Biarrotte, J L

    2004-01-01

    A multi-MW superconducting proton linac is proposed as the baseline solution for the EURISOL and the XADS driver accelerators. In the EURISOL project, which studies the design of the next-generation European ISOL facility, it is used to produce both neutron-deficient and neutron-rich exotic nuclei far from the valley of stability. In the PDS-XADS project, which aims to the demonstration of the feasibility of an ADS system for nuclear waste transmutation, it is used to produce the neutron flux required by the associated sub-critical reactor. In this paper, we report the main results and conclusions reached within these preliminary design studies. A special emphasis is given on the on-going and future R&D to be done to accomplish the demonstration of the full technology.

  3. EURISOL-DS Multi-MW Target-Comparative Neutronic Performance of the Baseline-Configuration vs. the Hg-Jet Option

    CERN Document Server

    Adonai Herrera-Martínez, Yacine Kadi,and the EURISOL-DS Task#2 collaboration

    This technical report summarises the comparative study between several design options for the Multi-MW target station performed within Task #2 of the European Isotope Separation On-Line Radioactive Ion Beam Facility Design Study.

  4. The Eurisol report. A feasibility study for a European isotope-separation-on-line radioactive ion beam facility

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2003-12-01

    The Eurisol project aims at a preliminary design study of the next-generation European isotope separation on-line (ISOL) radioactive ion beam (RIB) facility. In this document, the scientific case of high-intensity RIBs using the ISOL method is first summarised, more details being given in appendix A. It includes: 1) the study of atomic nuclei under extreme and so-far unexplored conditions of composition (i.e. as a function of the numbers of protons and neutrons, or the so-called isospin), rotational angular velocity (or spin), density and temperature, 2) the investigation of the nucleosynthesis of heavy elements in the Universe, an important part of nuclear astrophysics, 3) a study of the properties of the fundamental interactions which govern the properties of the universe, and in particular of the violation of some of their symmetries, 4) potential applications of RIBs in solid-state physics and in nuclear medicine, for example, where completely new fields could be opened up by the availability of high-intensity RIBs produced by the ISOL method. The proposed Eurisol facility is then presented, with particular emphasis on its main components: the driver accelerator, the target/ion-source assembly, the mass-selection system and post-accelerator, and the required scientific instrumentation. Special details of these components are given in appendices B to E, respectively. The estimates of the costs of the Eurisol, construction and running costs, have been performed in as much details as is presently possible. The total capital cost (installation manpower cost included) of the project is estimated to be of the order of 630 million Euros within 20%. In general, experience has shown that operational costs per annum for large accelerator facilities are about 10% of the capital cost. (A.C.)

  5. Evaluation of charge breeding options for EURISOL

    CERN Document Server

    Delahaye, P; Lamy, T; Marie-Jeanne, M; Kester, O; Wenander, F

    2010-01-01

    A comprehensive study of charge breeding techniques for the most ambitious ISOL-facility project, EURISOL, is presented here. It is based on results obtained during the past years at CERN-ISOLDE and LPSC Grenoble with charge breeders of both ECR and EBIS types.

  6. EURISOL-DS METEX: CERN SAFETY COMMISSION RECOMMENDATIONS

    CERN Document Server

    J.Gulley (CERN: SC/GS)

    Following a request from M. Lindroos (CERN, AB Department) a visit to the EURISOL mercury target experiment atIPUL (Institute of Physics of University of Latvia) outside Riga in Latvia was organized for 17th September 2008 with J.Gulley (CERN Safety Commission, chemical safety expert) accompanied by K. Samec (CERN, AB Department) and K.Thomsen (Paul Scherrer Institute, PSI). The aim of the visit was to provide general recommendations to IPUL on healthand safety issues related to the use of mercury, with the objective being to reduce exposure to acceptable levels, sofar as is reasonably practicable. An in‐depth process safety study using a systematic risk assessment/hazardidentification technique was outside the scope of the study.

  7. EURISOL MERCURY TARGET EXPERIMENT: CERN SAFETY REPORT

    CERN Document Server

    J. Gulley (CERN SC/GS)

    Report on a visit to the mercury-handling lab at IPUL. The aim was to provide recommendations to IPUL on general health and safety issues relatring to the handling of mercury, the objective being to reduce exposure to acceptable levels, so far as is reasonably practical.

  8. Multi-MW target station: Beam Window Issues and Transverse Film Target

    CERN Document Server

    Herrera-Martinez, A

    The analysis of the EURISOL-DS Multi_MW target precise geometry has proved that large fission yields can be achieved with a 4 MW, providing a technically feasible design to evacuate the power deposited in the liquid mercury. Different designs for the mercury flow have been proposed, which maintain its temperature below the boiling point with moderate flow speeds (maximum 4 m/s).

  9. Implementing Target Value Design.

    Science.gov (United States)

    Alves, Thais da C L; Lichtig, Will; Rybkowski, Zofia K

    2017-04-01

    An alternative to the traditional way of designing projects is the process of target value design (TVD), which takes different departure points to start the design process. The TVD process starts with the client defining an allowable cost that needs to be met by the design and construction teams. An expected cost in the TVD process is defined through multiple interactions between multiple stakeholders who define wishes and others who define ways of achieving these wishes. Finally, a target cost is defined based on the expected profit the design and construction teams are expecting to make. TVD follows a series of continuous improvement efforts aimed at reaching the desired goals for the project and its associated target value cost. The process takes advantage of rapid cycles of suggestions, analyses, and implementation that starts with the definition of value for the client. In the traditional design process, the goal is to identify user preferences and find solutions that meet the needs of the client's expressed preferences. In the lean design process, the goal is to educate users about their values and advocate for a better facility over the long run; this way owners can help contractors and designers to identify better solutions. This article aims to inform the healthcare community about tools and techniques commonly used during the TVD process and how they can be used to educate and support project participants in developing better solutions to meet their needs now as well as in the future.

  10. Measurement and analysis of turbulent liquid metal flow in a high-power spallation neutron source-EURISOL

    CERN Document Server

    Samec, K; Blumenfeld, L; Kharoua, C; Dementjevs, S; Milenkovic, R Z

    2011-01-01

    The European Isotope Separation On-Line (EURISOL) design study completed in 2009 examined means of producing exotic nuclei for fundamental research. One of the critical components identified in the study was a high-power neutron spallation source in which a target material is impacted by a proton beam producing neutrons by a process known as spallation. Due to the high heat power deposition, liquid metal, in this case mercury, is the only viable choice as target material. Complex issues arise from the use of liquid metal. It is characterised by an unusually low Prandtl number and a higher thermal expansivity than conventional fluids. The turbulence structure in LM is thereby affected and still an object of intense research, hampered in part by measurement difficulties. The use of Computational Fluid Dynamics (CFD) allowed a satisfactory design for the neutron source to be found rapidly with little iteration. However it was feared that the development of the boundary layer and associated turbulence would not b...

  11. Segmented Target Design

    Science.gov (United States)

    Merhi, Abdul Rahman; Frank, Nathan; Gueye, Paul; Thoennessen, Michael; MoNA Collaboration

    2013-10-01

    A proposed segmented target would improve decay energy measurements of neutron-unbound nuclei. Experiments like this have been performed at the National Superconducting Cyclotron Laboratory (NSCL) located at Michigan State University. Many different nuclei are produced in such experiments, some of which immediately decay into a charged particle and neutron. The charged particles are bent by a large magnet and measured by a suite of charged particle detectors. The neutrons are measured by the Modular Neutron Array (MoNA) and Large Multi-Institutional Scintillation Array (LISA). With the current target setup, a nucleus in a neutron-unbound state is produced with a radioactive beam impinged upon a beryllium target. The resolution of these measurements is very dependent on the target thickness since the nuclear interaction point is unknown. In a segmented target using alternating layers of silicon detectors and Be-targets, the Be-target in which the nuclear reaction takes place would be determined. Thus the experimental resolution would improve. This poster will describe the improvement over the current target along with the status of the design. Work supported by Augustana College and the National Science Foundation grant #0969173.

  12. BEAM DYNAMICS SIMULATIONS OF SARAF ACCELERATOR INCLUDING ERROR PROPAGATION AND IMPLICATIONS FOR THE EURISOL DRIVER

    CERN Document Server

    J. Rodnizki, D. Berkovits, K. Lavie, I. Mardor, A. Shor and Y. Yanay (Soreq NRC, Yavne), K. Dunkel, C. Piel (ACCEL, Bergisch Gladbach), A. Facco (INFN/LNL, Legnaro, Padova), V. Zviagintsev (TRIUMF, Vancouver)

    AbstractBeam dynamics simulations of SARAF (Soreq Applied Research Accelerator Facility) superconducting RF linear accelerator have been performed in order to establish the accelerator design. The multi-particle simulation includes 3D realistic electromagnetic field distributions, space charge forces and fabrication, misalignment and operation errors. A 4 mA proton or deuteron beam is accelerated up to 40 MeV with a moderated rms emittance growth and a high real-estate gradient of 2 MeV/m. An envelope of 40,000 macro-particles is kept under a radius of 1.1 cm, well below the beam pipe bore radius. The accelerator design of SARAF is proposed as an injector for the EURISOL driver accelerator. The Accel 176 MHZ β0=0.09 and β0=0.15 HWR lattice was extended to 90 MeV based on the LNL 352 MHZ β0=0.31 HWR. The matching between both lattices ensures smooth transition and the possibility to extend the accelerator to the required EURISOL ion energy.

  13. EURISOL-DS METEX: Post-processing of the experimental data: Test matrix, Pre-calculations, Data Recording and Mining, Statistical and Advance Data Analysis

    CERN Document Server

    R. Milenkovic and S. DemetjevsE. Manfrin, F. Barbagallo, S. Joray, J. Patorski, F. Groeschel

    At its first stage, the hydraulic and structural test of the EURISOL target mock-up, named METEX1 (MErcury Target EXperiment 1), accompanied by extended thermal-hydraulic and structural computational studies, have been carefully planned and prepared at PSI (PaulScherrer Institut). The experiment will be performed by PSI on the adopted IPUL-loop in June, 2008 at IPUL, Riga, Latvia.The main objective of this document is to give a brief overview of the following: the test matrixaccompanied by computational results, the procedures and methods, which are to be used fordata acquisition, signal post-processing and validation of the computational methods.

  14. Studies on the benefit of extended capabilities of the driver accelerator for EURISOL

    CERN Document Server

    Schmidt, K.-H; Lukic, S; Ricciardi, M. V; Veselsky, M

    Possibilities are studied for the optimization of EURISOL rare nuclide yields in specific regions of the nuclear chart by building the driver accelerator in a way that enables accelerating several additional beam species, to specific energies, besides the baseline 1 GeV proton beam. Nuclide production rates with these driver beams are compared to the production rates expected with the 1 GeV proton beam in the direct-production and the high-power-converter scenarios. Arguments are presented to show that several additional driver-beam scenarios could provide substantial benefit for the production of nuclides in specific regions of the nuclear chart. The quantitative values in this report are preliminary in the sense that they depend on assumptions on the values of some key parameters which are subject to technical development, e.g. maximum beam intensities or limits on the target heat load. The different scenarios are compared from the aspect of nuclide yields. The arguments presented here, when complemented by...

  15. Prospects for advanced electron cyclotron resonance and electron beam ion source charge breeding methods for EURISOL.

    Science.gov (United States)

    Delahaye, P; Galata, A; Angot, J; Ban, G; Celona, L; Choinski, J; Gmaj, P; Jakubowski, A; Jardin, P; Kalvas, T; Koivisto, H; Kolhinen, V; Lamy, T; Lunney, D; Maunoury, L; Porcellato, A M; Prete, G F; Steckiewicz, O; Sortais, P; Thuillier, T; Tarvainen, O; Traykov, E; Varenne, F; Wenander, F

    2012-02-01

    As the most ambitious concept of isotope separation on line (ISOL) facility, EURISOL aims at producing unprecedented intensities of post-accelerated radioactive isotopes. Charge breeding, which transforms the charge state of radioactive beams from 1+ to an n+ charge state prior to post-acceleration, is a key technology which has to overcome the following challenges: high charge states for high energies, efficiency, rapidity and purity. On the roadmap to EURISOL, a dedicated R&D is being undertaken to push forward the frontiers of the present state-of-the-art techniques which use either electron cyclotron resonance or electron beam ion sources. We describe here the guidelines of this R&D.

  16. Bioengineering Strategies for Designing Targeted Cancer Therapies

    Science.gov (United States)

    Wen, Xuejun

    2014-01-01

    The goals of bioengineering strategies for targeted cancer therapies are (1) to deliver a high dose of an anticancer drug directly to a cancer tumor, (2) to enhance drug uptake by malignant cells, and (3) to minimize drug uptake by nonmalignant cells. Effective cancer-targeting therapies will require both passive- and active targeting strategies and a thorough understanding of physiologic barriers to targeted drug delivery. Designing a targeted therapy includes the selection and optimization of a nanoparticle delivery vehicle for passive accumulation in tumors, a targeting moiety for active receptor-mediated uptake, and stimuli-responsive polymers for control of drug release. The future direction of cancer targeting is a combinatorial approach, in which targeting therapies are designed to use multiple targeting strategies. The combinatorial approach will enable combination therapy for delivery of multiple drugs and dual ligand targeting to improve targeting specificity. Targeted cancer treatments in development and the new combinatorial approaches show promise for improving targeted anticancer drug delivery and improving treatment outcomes. PMID:23768509

  17. Design of the Target Fabrication Tritium Laboratory

    Energy Technology Data Exchange (ETDEWEB)

    Sherohman, J.W.; Roberts, D.H.; Levine, B.H.

    1982-05-05

    The design of the Target Fabrication Tritium Laboratory for deuterium-tritium fuel processing for laser fusion targets has been accomplished with the intent of providing redundant safeguard systems. The design of the tritium laboratory is based on a combination of tritium handling techniques that are currently used by experienced laboratories. A description of the laboratory in terms of its interrelated processing systems is presented to provide an understanding of the design features for safe operation.

  18. Technical Design Report, Second Target Station

    Energy Technology Data Exchange (ETDEWEB)

    Galambos, John D. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Anderson, David E. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Bechtol, D. [HDR, Inc., Chattanooga, TN (United States); Bethea, Katie L. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Brown, N. [Barge Waggoner Sumner & Cannon, Inc., Nashville, TN (United States); Carden, W. F. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Chae, Steven M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Clark, A. [Barge Waggoner Sumner & Cannon, Inc., Nashville, TN (United States); Counce, Deborah M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Craft, K. [Barge Waggoner Sumner & Cannon, Inc., Nashville, TN (United States); Crofford, Mark T. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Collins, Richard M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Cousineau, Sarah M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Curry, Douglas E. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Cutler, Roy I. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Dayton, Michael J. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Dean, Robert A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Deibele, Craig E. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Doleans, Marc [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Dye, T. [HDR, Inc., Chattanooga, TN (United States); Eason, Bob H. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Eckroth, James A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Fincrock, C. [HDR, Inc., Chattanooga, TN (United States); Fritts, S. [Barge Waggoner Sumner & Cannon, Inc., Nashville, TN (United States); Gallmeier, Franz X. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Gawne, Ken R. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Hartman, Steven M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Herwig, Kenneth W. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Hess, S. [HDR, Inc., Chattanooga, TN (United States); Holmes, Jeffrey A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Horak, Charlie M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Howell, Matthew P. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Iverson, Erik B. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Jacobs, Lorelei L. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Jones, Larry C. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Johnson, B. [HDR, Inc., Chattanooga, TN (United States); Johnson, S. [HDR, Inc., Chattanooga, TN (United States); Kasemir, Kay [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Kim, Sang-Ho [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Laughon, Gregory J. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Lu, W. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Mahoney, Kelly L. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Mammosser, John [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); McManamy, T. [McManamy Consulting, Inc., Knoxville, TN (United States); Michilini, M. [HDR, Inc., Chattanooga, TN (United States); Middendorf, Mark E. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); O' Neal, Ed [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Nemec, B. [Barge Waggoner Sumner & Cannon, Inc., Nashville, TN (United States); Peters, Roy Cecil [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Plum, Michael A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Reagan, G. [Barge Waggoner Sumner & Cannon, Inc., Nashville, TN (United States); Remec, Igor [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Rennich, Mark J. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Riemer, Bernie [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Saethre, Robert B. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Schubert, James Phillip [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Shishlo, Andrei P. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Smith, C. Craig [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Strong, William Herb [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Tallant, Kathie M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Tennant, David Alan [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Thibadeau, Barbara M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Trumble, S. [HDR, Inc., Chattanooga, TN (United States); Trotter, Steven M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Wang, Z. [Institute of Modern Physics (IMP), Chinese Academy of Sciences (China); Webb, Steven B. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Williams, Derrick C. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); White, Karen S. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Zhao, Jinkui [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2015-01-01

    The Second Target Station (STS) is a proposed upgrade for SNS. It includes a doubling of the accelerator power and an additional instrument hall. The new instrument hall will receive a 467 kW 10 Hz beam. The parameters and preliminary design aspects of the STS are presented for the accelerator, target systems, instrument hall, instruments and civil construction aspects.

  19. Development of a liquid Pb-Bi target for high-power ISOL facilities

    Energy Technology Data Exchange (ETDEWEB)

    Houngbo, D., E-mail: dhoungbo@sckcen.be [Belgian Nuclear Research Centre (SCK-CEN), Boeretang 200, B-2400 Mol (Belgium); Department of Flow, Heat and Combustion Mechanics, Ghent University (UGent), St.-Pietersnieuwstraat 41, B-9000 Gent (Belgium); Bernardes, A.P. [CERN, 1211 Geneva 23 (Switzerland); David, J.C. [CEA/Saclay, 91191 Gif-sur-Yvette cedex (France); Delonca, M. [CERN, 1211 Geneva 23 (Switzerland); IRTES-M3M & IRTES-LERMPS, Université de Technologie de Belfort-Montbeliard, 90010 Belfort Cedex (France); Kravalis, K. [Institute of Physics of University of Latvia (IPUL), 32 Miera iela, Salaspils LV-2169 (Latvia); Lahiri, S. [Saha Institute of Nuclear Physics 1/AF Bidhannagar, Kolkata 700064 (India); Losito, R.; Maglioni, C. [CERN, 1211 Geneva 23 (Switzerland); Marchix, A. [CEA/Saclay, 91191 Gif-sur-Yvette cedex (France); Mendonca, T.M. [CERN, 1211 Geneva 23 (Switzerland); Popescu, L. [Belgian Nuclear Research Centre (SCK-CEN), Boeretang 200, B-2400 Mol (Belgium); Schumann, D. [Paul Scherrer Institute (PSI), 5232 Villigen PSI (Switzerland); Schuurmans, P. [Belgian Nuclear Research Centre (SCK-CEN), Boeretang 200, B-2400 Mol (Belgium); Stora, T.; Vollaire, J. [CERN, 1211 Geneva 23 (Switzerland); Vierendeels, J. [Department of Flow, Heat and Combustion Mechanics, Ghent University (UGent), St.-Pietersnieuwstraat 41, B-9000 Gent (Belgium)

    2016-06-01

    This paper describes some R&D activities conducted in support of the design and safe operation of a high-power liquid Pb-Bi target within the LIEBE (Liquid Eutectic Lead Bismuth Loop Target for EURISOL) project. The target material is lead bismuth eutectic (LBE) which also acts as a primary coolant. As a consequence of interaction of the highly pulsed 1.4-GeV protons at ISOLDE with the target, heat powers of the order of 2 GW would be instantaneously deposited in the target during a bunch. Considerable R&D effort is thus required to demonstrate its continued coolability and structural integrity. This paper mainly reports on the conjugate flow (CFD) and heat deposition (Monte Carlo) calculations, not accounting for Fluid–Structure Interactions.

  20. Design of the LBNF Beamline Target Station

    Energy Technology Data Exchange (ETDEWEB)

    Tariq, S. [Fermilab; Ammigan, K. [Fermilab; Anderson, K.; ; Buccellato, S. A. [Fermilab; Crowley, C. F. [Fermilab; Hartsell, B. D. [Fermilab; Hurh, P. [Fermilab; Hylen, J. [Fermilab; Kasper, P. [Fermilab; Krafczyk, G. E. [Fermilab; Lee, A. [Fermilab; Lundberg, B. [Fermilab; Reitzner, S. D. [Fermilab; Sidorov, V. [Fermilab; Stefanik, A. M. [Fermilab; Tropin, I. S. [Fermilab; Vaziri, K. [Fermilab; Williams, K. [Fermilab; Zwaska, R. M. [Fermilab; Densham, C. [RAL, Didcot

    2016-10-01

    The Long Baseline Neutrino Facility (LBNF) project will build a beamline located at Fermilab to create and aim an intense neutrino beam of appropriate energy range toward the DUNE detectors at the SURF facility in Lead, South Dakota. Neutrino production starts in the Target Station, which consists of a solid target, magnetic focusing horns, and the associated sub-systems and shielding infrastructure. Protons hit the target producing mesons which are then focused by the horns into a helium-filled decay pipe where they decay into muons and neutrinos. The target and horns are encased in actively cooled steel and concrete shielding in a chamber called the target chase. The reference design chase is filled with air, but nitrogen and helium are being evaluated as alternatives. A replaceable beam window separates the decay pipe from the target chase. The facility is designed for initial operation at 1.2 MW, with the ability to upgrade to 2.4 MW, and is taking advantage of the experience gained by operating Fermilab’s NuMI facility. We discuss here the design status, associated challenges, and ongoing R&D and physics-driven component optimization of the Target Station.

  1. 29 mm Diameter Test Target Design Report

    Energy Technology Data Exchange (ETDEWEB)

    Woloshun, Keith Albert [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Dale, Gregory E. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Olivas, Eric Richard [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Naranjo, Angela Carol [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Romero, Frank Patrick [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-08-15

    The Northstar target for Mo99 production is made up of Mo100 disks in a stack separated by coolant gaps for helium flow. A number of targets have been tested at ANL for both production of Mo99 and for thermal-hydraulic performance. These have all been with a 12 mm diameter target, even while the production goals have increased the diameter to now 29 mm. A 29 mm diameter target has been designed that is consistent with the ANL beam capabilities and the capabilities of the helium circulation system currently in use at ANL. This target is designed for 500 μA at 35 MeV electrons. While the plant design calls for 42 MeV, the chosen design point is more favorable and higher power given the limits of the ANL accelerator. The intended beam spot size is 12 mm FWHM, but the thermal analysis presented herein conservatively assumed a 10 mm FWHM beam, which results in a 44% higher beam current density at beam center.

  2. Test of a High Power Target Design

    CERN Multimedia

    2002-01-01

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

  3. Designed nucleases for targeted genome editing.

    Science.gov (United States)

    Lee, Junwon; Chung, Jae-Hee; Kim, Ho Min; Kim, Dong-Wook; Kim, Hyongbum

    2016-02-01

    Targeted genome-editing technology using designed nucleases has been evolving rapidly, and its applications are widely expanding in research, medicine and biotechnology. Using this genome-modifying technology, researchers can precisely and efficiently insert, remove or change specific sequences in various cultured cells, micro-organisms, animals and plants. This genome editing is based on the generation of double-strand breaks (DSBs), repair of which modifies the genome through nonhomologous end-joining (NHEJ) or homology-directed repair (HDR). In addition, designed nickase-induced generation of single-strand breaks can also lead to precise genome editing through HDR, albeit at relatively lower efficiencies than that induced by nucleases. Three kinds of designed nucleases have been used for targeted DSB formation: zinc-finger nucleases, transcription activator-like effector nucleases, and RNA-guided engineered nucleases derived from the bacterial clustered regularly interspaced short palindromic repeat (CRISPR)-Cas (CRISPR-associated) system. A growing number of researchers are using genome-editing technologies, which have become more accessible and affordable since the discovery and adaptation of CRISPR-Cas9. Here, the repair mechanism and outcomes of DSBs are reviewed and the three types of designed nucleases are discussed with the hope that such understanding will facilitate applications to genome editing. © 2015 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

  4. Estimator design for re-entry targets.

    Science.gov (United States)

    Huang, Chun-Wei; Lin, Chun-Liang; Lin, Yu-Ping

    2014-03-01

    This study proposes a trajectory estimation scheme for tactical ballistic missiles (TBMs). Target information acquired from the ground-based radar system is investigated by incorporating input estimation (IE) and extended Kalman filtering techniques. In addition to estimate the missile's position and velocity, our special focus is put on the estimation of the TBMs evasive acceleration and ballistic coefficient. In the demonstrative example, radar measurement errors are served as specifications while characterizing the acquirable zone of the ground-based radar system. Effect of the proposed design is fully verified by examining the estimation performance. © 2013 ISA Published by ISA All rights reserved.

  5. Targeted proteins for diabetes drug design

    Science.gov (United States)

    Doan Trang Nguyen, Ngoc; Thi Le, Ly

    2012-03-01

    Type 2 diabetes mellitus is a common metabolism disorder characterized by high glucose in the bloodstream, especially in the case of insulin resistance and relative insulin deficiency. Nowadays, it is very common in middle-aged people and involves such dangerous symptoms as increasing risk of stroke, obesity and heart failure. In Vietnam, besides the common treatment of insulin injection, some herbal medication is used but no unified optimum remedy for the disease yet exists and there is no production of antidiabetic drugs in the domestic market yet. In the development of nanomedicine at the present time, drug design is considered as an innovative tool for researchers to study the mechanisms of diseases at the molecular level. The aim of this article is to review some common protein targets involved in type 2 diabetes, offering a new idea for designing new drug candidates to produce antidiabetic drugs against type 2 diabetes for Vietnamese people.

  6. EURISOL Desktop Assistant Toolkit (EDAT): A modeling, simulation and visualization support to the preliminary radiological assessment of RIB projects

    Science.gov (United States)

    Vamanu, D.; Vamanu, B.; Acasandrei, V.; Maceika, E.; Plukis, A.

    2010-04-01

    The paper describes an approach taken within the EURISOL-DS project (European Isotope Separation Online Radioactive Ion Beam Facility) to a number of safety and radioprotection issues raised by the advent of radioactive ion beam facilities in the cutting edge area of particle accelerators. The ensuing solution emerged from a collaborative effort of the investigating team-in-charge, affiliated with the Horia Hulubei National Institute of Physics and Nuclear Engineering in Bucharest, with expert colleagues at the Physics Institute in Vilnius, and at CERN, within the participation in the EURISOL-DS project, Sub-Task B: Radiation, Activation, Shielding and Doses of the Safety and Radioprotection, Task 5. The work was primarily geared towards the identification of knowledge and data in line with validated, accepted and nationally/internationally recommended methods and models of radiological assessment applied within the nuclear power fuel cycle, deemed to be suitable for assessing health and environmental impact of accelerator operations as well. As a result, a computer software platform code-named “EURISOL Desktop Assistant Toolkit” was developed. The software is, inter alia, capable to assess radiation doses from pure or isotopically mixed open or shielded point sources; emergency response-relevant doses; critical group doses via complex pathways, including the air, the water, and the food chain and derived release limits for the normal, routine operations of nuclear facilities. Dedicated data libraries and GIS (Geographic Information System) facilities assist the input/output operations.

  7. Design of the LBNF Beamline Target Station

    OpenAIRE

    Tariq, S.; Ammigan, K.; Anderson, K.; Buccellato, S. A.; Crowley, C. F.; Hartsell, B. D.; Hurh, P.; Hylen, J.; Kasper, P.; Krafczyk, G. E.; Lee, A.; Lundberg, B.; Marchionni, A; Mokhov, N. V.; Moore, C. D.

    2016-01-01

    The Long Baseline Neutrino Facility (LBNF) project will build a beamline located at Fermilab to create and aim an intense neutrino beam of appropriate energy range toward the DUNE detectors at the SURF facility in Lead, South Dakota. Neutrino production starts in the Target Station, which consists of a solid target, magnetic focusing horns, and the associated sub-systems and shielding infrastructure. Protons hit the target producing mesons which are then focused by the horns into a helium-fil...

  8. 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...

  9. Design of the Next Generation Spallation Target

    Energy Technology Data Exchange (ETDEWEB)

    Ferres, Laurent [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-06-13

    The purpose of this summary is to detail the studies that enable new nuclear physics experiments currently limited by neutron intensity or energy resolution available at LANSCE. The target is being redesigned so that the Flight Paths (FP) in the upper tier provide a higher intensity in the epithermal and medium energy ranges.

  10. 'EURISOL Desktop Assistant Toolkit' (EDAT): a modeling, simulation and visualization support to the preliminary radiological assessment of RIB projects

    CERN Document Server

    Vamanu, D; Acasandrei, V; Plukis, A; Maceika, E

    The paper describes an approach taken within EURISOL-DS project (European Isotope Separation On-Line Radioactive Ion Beam Facility) to a number of safety and radioprotection issues raised by the advent of radioactive ion beam facilities in the cutting edge area of particle accelerators. The ensuing solution emerged from a collaborative effort of the investigating team-in-charge, affiliated with ‘Horia Hulubei’ National Institute of Physics and Nuclear Engineering in Bucharest, with expert colleagues at the Physics Institute in Vilnius, and at CERN.

  11. Designing high power targets with computational fluid dynamics (CFD)

    Energy Technology Data Exchange (ETDEWEB)

    Covrig, Silviu D. [JLAB

    2013-11-01

    High power liquid hydrogen (LH2) targets, up to 850 W, have been widely used at Jefferson Lab for the 6 GeV physics program. The typical luminosity loss of a 20 cm long LH2 target was 20% for a beam current of 100 {micro}A rastered on a square of side 2 mm on the target. The 35 cm long, 2500 W LH2 target for the Qweak experiment had a luminosity loss of 0.8% at 180 {micro}A beam rastered on a square of side 4 mm at the target. The Qweak target was the highest power liquid hydrogen target in the world and with the lowest noise figure. The Qweak target was the first one designed with CFD at Jefferson Lab. A CFD facility is being established at Jefferson Lab to design, build and test a new generation of low noise high power targets.

  12. Designing high power targets with computational fluid dynamics (CFD)

    Energy Technology Data Exchange (ETDEWEB)

    Covrig, S. D. [Thomas Jefferson National Laboratory, Newport News, VA 23606 (United States)

    2013-11-07

    High power liquid hydrogen (LH2) targets, up to 850 W, have been widely used at Jefferson Lab for the 6 GeV physics program. The typical luminosity loss of a 20 cm long LH2 target was 20% for a beam current of 100 μA rastered on a square of side 2 mm on the target. The 35 cm long, 2500 W LH2 target for the Qweak experiment had a luminosity loss of 0.8% at 180 μA beam rastered on a square of side 4 mm at the target. The Qweak target was the highest power liquid hydrogen target in the world and with the lowest noise figure. The Qweak target was the first one designed with CFD at Jefferson Lab. A CFD facility is being established at Jefferson Lab to design, build and test a new generation of low noise high power targets.

  13. Subcellular targeting strategies for drug design and delivery.

    Science.gov (United States)

    Rajendran, Lawrence; Knölker, Hans-Joachim; Simons, Kai

    2010-01-01

    Many drug targets are localized to particular subcellular compartments, yet current drug design strategies are focused on bioavailability and tissue targeting and rarely address drug delivery to specific intracellular compartments. Insights into how the cell traffics its constituents to these different cellular locations could improve drug design. In this Review, we explore the fundamentals of membrane trafficking and subcellular organization, as well as strategies used by pathogens to appropriate these mechanisms and the implications for drug design and delivery.

  14. Ignition target design for the National Ignition Facility

    Energy Technology Data Exchange (ETDEWEB)

    Haan, S.W.; Pollaine, S.M.; Lindl, J.D. [Los Alamos National Laboratory, NM (United States)] [and others

    1996-06-01

    The goal of inertial confinement fusion (ICF) is to produce significant thermonuclear burn from a target driven with a laser or ion beam. To achieve that goal, the national ICF Program has proposed a laser capable of producing ignition and intermediate gain. The facility is called the National Ignition Facility (NIF). This article describes ignition targets designed for the NIF and their modeling. Although the baseline NIF target design, described herein, is indirect drive, the facility will also be capable of doing direct-drive ignition targets - currently being developed at the University of Rochester.

  15. Adaptive Waveform Design for Cognitive Radar in Multiple Targets Situations

    Directory of Open Access Journals (Sweden)

    Xiaowen Zhang

    2018-02-01

    Full Text Available In this paper, the problem of cognitive radar (CR waveform optimization design for target detection and estimation in multiple extended targets situations is investigated. This problem is analyzed in signal-dependent interference, as well as additive channel noise for extended targets with unknown target impulse response (TIR. To address this problem, an improved algorithm is employed for target detection by maximizing the detection probability of the received echo on the promise of ensuring the TIR estimation precision. In this algorithm, an additional weight vector is introduced to achieve a trade-off among different targets. Both the estimate of TIR and transmit waveform can be updated at each step based on the previous step. Under the same constraint on waveform energy and bandwidth, the information theoretical approach is also considered. In addition, the relationship between the waveforms that are designed based on the two criteria is discussed. Unlike most existing works that only consider single target with temporally correlated characteristics, waveform design for multiple extended targets is considered in this method. Simulation results demonstrate that compared with linear frequency modulated (LFM signal, waveforms designed based on maximum detection probability and maximum mutual information (MI criteria can make radar echoes contain more multiple-target information and improve radar performance as a result.

  16. Design of the next generation target at Lujan center, LANSCE.

    Energy Technology Data Exchange (ETDEWEB)

    Ferres, Laurent [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-07-27

    This is a presentation given at Los Alamos National Laboratory (LANL) on the design of the next generation target at Lujan center, LANSCE. The motivation for this design is to enable new nuclear physics experiments (defense program applications (DANCE)) that are currently limited by neutron intensity or energy resolution available at LANSCE. The target is being redesigned so that the Flight Paths in the upper tier provide a higher intensity in the epithermal and medium energy ranges.

  17. Target and PADC Track Detectors for Rare Isotope Studies

    Directory of Open Access Journals (Sweden)

    J. Bermudez

    2011-01-01

    Full Text Available A higher yield of rare isotope production methods, for example, isotope separation on-line (ISOL, is expected to be developed for the EURISOL facility. In this paper as a part of the ongoing project, high power-target assembly and passive detector inclusion are given. Theoretical calculations of several configurations were done using Monte Carlo code FLUKA aimed to produce 1015 fiss/s on LEU-Cx target. The proposed radioactive ion beam (RIB production relies on a high-power (4 MW multibody target; a complete target design is given. Additionally we explore the possibility to employ PADC passive detector as a complementary system for RIB characterization, since these already demonstrated their importance in nuclear interactions phenomenology. In fact, information and recording rare and complex reaction product or short-lived isotope detection is obtained in an integral form through latent track formation. Some technical details on track formation and PADC detector etching conditions complete this study.

  18. Designing allosteric peptide ligands targeting a globular protein.

    Science.gov (United States)

    Selz, Karen A; Samoylova, Tatiana I; Samoylov, Alexandre M; Vodyanoy, Vitaly J; Mandell, Arnold J

    2007-01-01

    Patented signal analytic algorithms applied to hydrophobically transformed, numerical amino acid sequences have previously been used to design short, protein-targeted, L or D retro-inverso peptides. These peptides have demonstrated allosteric and/or indirect agonist effects on a variety of G-protein and tyrosine kinase coupled membrane receptors with 30% to over 80% hit rates. Here we extend these approaches to a globular protein target. We designed eight peptide ligands targeting an ELISA antibody responsive protein, beta-galactosidase, betaGAL. Three of the eight 14mer peptides allosterically activated betaGAL with ELISA methodology. Using Bayesian statistics, this 38% hit rate would have occurred 2 x 10(-9) by chance. These peptides demonstrated binding site competitive or noncompetitive interactions, suggesting allosteric site multiplicity with respect to their betaGAL binding-mediated ELISA signal. Kinetic studies demonstrated the temperature dependence of the betaGAL peptide binding functions. Using the van't Hoff relation, we found evidence for enthalpy-entropy compensation. This relation is often found for hydrophobic interactions in aqueous media, and is consistent with the postulated hydrophobic series encoding underlying our protein-targeted, peptide design methods. It appears that our algorithmic, hydrophobic autocovariance eigenvector template approach to the design of allosteric peptides targeting membrane receptors may also be applicable to the design of peptide ligands targeting nonmembrane involved globular proteins. Copyright 2006 Wiley Periodicals, Inc.

  19. LBNF 1.2 MW Target: Conceptual Design & Fabrication

    Energy Technology Data Exchange (ETDEWEB)

    Crowley, C. [Fermilab; Ammigan, K. [Fermilab; Anderson, K. [Fermilab; Hartsell, B. [Fermilab; Hurh, P. [Fermilab; Hylen, J. [Fermilab; Zwaska, R. [Fermilab

    2015-06-01

    Fermilab’s Long-Baseline Neutrino Facility (LBNF) will utilize a modified design based on the NuMI low energy target that is reconfigured to accommodate beam operation at 1.2 MW. Achieving this power with a graphite target material and ancillary systems originally rated for 400 kW requires several design changes and R&D efforts related to material bonding and electrical isolation. Target cooling, structural design, and fabrication techniques must address higher stresses and heat loads that will be present during 1.2 MW operation, as the assembly will be subject to cyclic loads and thermal expansion. Mitigations must be balanced against compromises in neutrino yield. Beam monitoring and subsystem instrumentation will be updated and added to ensure confidence in target positioning and monitoring. Remote connection to the target hall support structure must provide for the eventual upgrade to a 2.4 MW target design, without producing excessive radioactive waste or unreasonable exposure to technicians during reconfiguration. Current designs and assembly layouts will be presented, in addition to current findings on processes and possibilities for prototype and final assembly fabrication.

  20. LBNF 1.2 MW TARGET: CONCEPTUAL DESIGN & FABRICATION

    Energy Technology Data Exchange (ETDEWEB)

    Crowley, Cory F. [Fermilab; Ammigan, K. [Fermilab; Anderson, K. [Fermilab; Hartsell, B. [Fermilab; Hurh, P. [Fermilab; Hylen, J. [Fermilab; Zwaska, R. [Fermilab

    2015-06-29

    Fermilab’s Long-Baseline Neutrino Facility (LBNF) will utilize a modified design based on the NuMI low energy target that is reconfigured to accommodate beam operation at 1.2 MW. Achieving this power with a graphite target material and ancillary systems originally rated for 400 kW requires several design changes and R&D efforts related to material bonding and electrical isolation. Target cooling, structural design, and fabrication techniques must address higher stresses and heat loads that will be present during 1.2 MW operation, as the assembly will be subject to cyclic loads and thermal expansion. Mitigations must be balanced against compromises in neutrino yield. Beam monitoring and subsystem instrumentation will be updated and added to ensure confidence in target positioning and monitoring. Remote connection to the target hall support structure must provide for the eventual upgrade to a 2.4 MW target design, without producing excessive radioactive waste or unreasonable exposure to technicians during reconfiguration. Current designs and assembly layouts will be presented, in addition to current findings on processes and possibilities for prototype and final assembly fabrication.

  1. Design of a covert RFID tag network for target discovery and target information routing.

    Science.gov (United States)

    Pan, Qihe; Narayanan, Ram M

    2011-01-01

    Radio frequency identification (RFID) tags are small electronic devices working in the radio frequency range. They use wireless radio communications to automatically identify objects or people without the need for line-of-sight or contact, and are widely used in inventory tracking, object location, environmental monitoring. This paper presents a design of a covert RFID tag network for target discovery and target information routing. In the design, a static or very slowly moving target in the field of RFID tags transmits a distinct pseudo-noise signal, and the RFID tags in the network collect the target information and route it to the command center. A map of each RFID tag's location is saved at command center, which can determine where a RFID tag is located based on each RFID tag's ID. We propose the target information collection method with target association and clustering, and we also propose the information routing algorithm within the RFID tag network. The design and operation of the proposed algorithms are illustrated through examples. Simulation results demonstrate the effectiveness of the design.

  2. Baseline Design of a Solid Neutron Converter Driven by 160 MeV Protons

    CERN Document Server

    Herrera-Martínez, A

    2006-01-01

    The European Isotope Separation On-Line Radioactive Ion Beam Facility Design Study (EURISOL DS) aims at the design of several spallation and fission targets for the production of radioactive isotopes. Namely, direct targets, where high-energy protons interact directly with the fission targets, as well as the design of a Multi-MW proton-to-neutron converter coupled with a fission target. For the later, several options have been proposed, including the use of a relatively low energy (in the hundreds of MeV) high intensity proton beam. In this scope, the neutronic characteristics of a tantalum n-converter/fission-target system have been established (although not yet optimised) for a reference proton energy of 160 MeV. A set of simulations has been carried out for different design requirements and different characteristics of the proton beam. An extensive comparison of the main physical parameters has also been carried out, in order to allow the optimal engineering design of the whole target station.

  3. Quantifying design trade-offs of beryllium targets on NIF

    Science.gov (United States)

    Yi, S. A.; Zylstra, A. B.; Kline, J. L.; Loomis, E. N.; Kyrala, G. A.; Shah, R. C.; Perry, T. S.; Kanzleiter, R. J.; Batha, S. H.; MacLaren, S. A.; Ralph, J. E.; Masse, L. P.; Salmonson, J. D.; Tipton, R. E.; Callahan, D. A.; Hurricane, O. A.

    2017-10-01

    An important determinant of target performance is implosion kinetic energy, which scales with the capsule size. The maximum achievable performance for a given laser is thus related to the largest capsule that can be imploded symmetrically, constrained by drive uniformity. A limiting factor for symmetric radiation drive is the ratio of hohlraum to capsule radii, or case-to-capsule ratio (CCR). For a fixed laser energy, a larger hohlraum allows for driving bigger capsules symmetrically at the cost of reduced peak radiation temperature (Tr). Beryllium ablators may thus allow for unique target design trade-offs due to their higher ablation efficiency at lower Tr. By utilizing larger hohlraum sizes than most modern NIF designs, beryllium capsules thus have the potential to operate in unique regions of the target design parameter space. We present design simulations of beryllium targets with a large CCR = 4.3 3.7 . These are scaled surrogates of large hohlraum low Tr beryllium targets, with the goal of quantifying symmetry tunability as a function of CCR. This work performed under the auspices of the U.S. DOE by LANL under contract DE-AC52- 06NA25396, and by LLNL under Contract DE-AC52-07NA27344.

  4. Designing to target cost: one approach to design/construction integration

    DEFF Research Database (Denmark)

    Jørgensen, Bo

    2005-01-01

    One approach to a more integrated construction delivery process is the concept of ‘designing to target cost’ of which the first examples of application within a lean construction framework have recently been seen. This paper introduces the main principles of the design to target cost method...... and discusses the applicability of this approach to construction. The low degree of organizational and technical continuity from one construction project to the next limits the applicability of the design for target cost approach when compared to its origin in product development of mass manufactured artefacts....... It can be argued that design to target cost may also provide a frame for developing the supply chain towards better coordination and collaboration. Thus methods of design to target cost may serve to facilitate the development of a more integrated supply chain....

  5. Target value design: applications to newborn intensive care units.

    Science.gov (United States)

    Rybkowski, Zofia K; Shepley, Mardelle McCuskey; Ballard, H Glenn

    2012-01-01

    There is a need for greater understanding of the health impact of various design elements in neonatal intensive care units (NICUs) as well as cost-benefit information to make informed decisions about the long-term value of design decisions. This is particularly evident when design teams are considering the transition from open-bay NICUs to single-family-room (SFR) units. This paper introduces the guiding principles behind target value design (TVD)-a price-led design methodology that is gaining acceptance in healthcare facility design within the Lean construction methodology. The paper also discusses the role that set-based design plays in TVD and its application to NICUs.

  6. Anti-malarial Drug Design by Targeting Apicoplasts: New Perspectives

    Directory of Open Access Journals (Sweden)

    Avinaba Mukherjee

    2016-03-01

    Full Text Available Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the ‘apicoplast’, which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle’s function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug

  7. Oak Ridge Spallation Neutron Source (ORSNS) target station design integration

    Energy Technology Data Exchange (ETDEWEB)

    McManamy, T.; Booth, R.; Cleaves, J.; Gabriel, T. [and others

    1996-06-01

    The conceptual design for a 1- to 3-MW short pulse spallation source with a liquid mercury target has been started recently. The design tools and methods being developed to define requirements, integrate the work, and provide early cost guidance will be presented with a summary of the current target station design status. The initial design point was selected with performance and cost estimate projections by a systems code. This code was developed recently using cost estimates from the Brookhaven Pulsed Spallation Neutron Source study and experience from the Advanced Neutron Source Project`s conceptual design. It will be updated and improved as the design develops. Performance was characterized by a simplified figure of merit based on a ratio of neutron production to costs. A work breakdown structure was developed, with simplified systems diagrams used to define interfaces and system responsibilities. A risk assessment method was used to identify potential problems, to identify required research and development (R&D), and to aid contingency development. Preliminary 3-D models of the target station are being used to develop remote maintenance concepts and to estimate costs.

  8. Massively parallel de novo protein design for targeted therapeutics

    Science.gov (United States)

    Chevalier, Aaron; Silva, Daniel-Adriano; Rocklin, Gabriel J.; Hicks, Derrick R.; Vergara, Renan; Murapa, Patience; Bernard, Steffen M.; Zhang, Lu; Lam, Kwok-Ho; Yao, Guorui; Bahl, Christopher D.; Miyashita, Shin-Ichiro; Goreshnik, Inna; Fuller, James T.; Koday, Merika T.; Jenkins, Cody M.; Colvin, Tom; Carter, Lauren; Bohn, Alan; Bryan, Cassie M.; Fernández-Velasco, D. Alejandro; Stewart, Lance; Dong, Min; Huang, Xuhui; Jin, Rongsheng; Wilson, Ian A.; Fuller, Deborah H.; Baker, David

    2017-10-01

    De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37–43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing.

  9. Massively parallel de novo protein design for targeted therapeutics

    KAUST Repository

    Chevalier, Aaron

    2017-09-26

    De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37-43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing.

  10. Design and Validation of the APT Target/Blanket System

    Science.gov (United States)

    Waters, L. S.

    1998-04-01

    The Accelerator Production of Tritium (APT) project is now under development as part of DOE's dual track strategy for the replenishment of the nation's tritium supply. APT produces tritium through the He^3(n,p)t reaction, with neutrons generated in a tungsten spallation target and moderated in a surrounding lead blanket filled with He^3 gas tubes. A 100 mA, 1.7 GeV linac provides source protons for the target, and a separate tritium extraction facility continually processes the helium gas stream. Within APT, the Target/Blanket and Materials Engineering Development and Demonstration Project has primary responsibility for validating the neutronics performance of the Target/Blanket system, and for addressing materials issues for all of APT. The APT target design and T/B & Materials ED&D activities will be briefly reviewed, with special emphasis placed on activities leading to the development and validation of radiation transport codes and nuclear data used in the APT design. These include the evolution of the MCNPX simulation code, as well as theoretical work and cross section measurements now underway to support high energy nuclear data library evaluations. Large scale benchmarking measurements completed or planned at LANSCE, the Brookhaven AGS, and Saturne will also be discussed.

  11. HIE-ISOLDE: Baseline Design of a Solid Neutron Converter Driven by 160 MeV Protons

    CERN Document Server

    Kadi, Yacine

    The European Isotope Separation On-Line Radioactive Ion Beam Facility Design Study (EURISOL DS) aims at the design of several spallation and fission targets for the production of radioactive isotopes. Namely, direct targets, where high-energy protons interact directly with the fission targets, as well as the design of a Multi-MW proton-to-neutron converter coupled with a fission target. For the later, several options have been proposed, including the use of a relatively low energy (in the hundreds of MeV) high intensity proton beam. In this scope, the neutronic characteristics of a tantalum n-converter/fission-target system have been established (although not yet optimised) for a reference proton energy of 160 MeV. A set of simulations has been carried out for different design requirements and different characteristics of the proton beam. An extensive comparison of the main physical parameters has also been carried out, in order to allow the optimal engineering design of the whole target station.

  12. Some Aspects on Filter Design for Target Tracking

    Directory of Open Access Journals (Sweden)

    Bertil Ekstrand

    2012-01-01

    Full Text Available Tracking filter design is discussed. It is argued that the basis of the present stochastic paradigm is questionable. White process noise is not adequate as a model for target manoeuvring, stochastic least-square optimality is not relevant or required in practice, the fact that requirements are necessary for design is ignored, and root mean square (RMS errors are insufficient as performance measure. It is argued that there is no process noise and that the covariance of the assumed process noise contains the design parameters. Focus is on the basic tracking filter, the Kalman filter, which is convenient for clarity and simplicity, but the arguments and conclusions are relevant in general. For design the possibility of an observer transfer function approach is pointed out. The issues can also be considered as a consequence of the fact that there is a difference between estimation and design. The - filter is used for illustration.

  13. Selection and trajectory design to mission secondary targets

    Science.gov (United States)

    Victorino Sarli, Bruno; Kawakatsu, Yasuhiro

    2017-02-01

    Recently, with new trajectory design techniques and use of low-thrust propulsion systems, missions have become more efficient and cheaper with respect to propellant. As a way to increase the mission's value and scientific return, secondary targets close to the main trajectory are often added with a small change in the transfer trajectory. As a result of their large number, importance and facility to perform a flyby, asteroids are commonly used as such targets. This work uses the Primer Vector theory to define the direction and magnitude of the thrust for a minimum fuel consumption problem. The design of a low-thrust trajectory with a midcourse asteroid flyby is not only challenging for the low-thrust problem solution, but also with respect to the selection of a target and its flyby point. Currently more than 700,000 minor bodies have been identified, which generates a very large number of possible flyby points. This work uses a combination of reachability, reference orbit, and linear theory to select appropriate candidates, drastically reducing the simulation time, to be later included in the main trajectory and optimized. Two test cases are presented using the aforementioned selection process and optimization to add and design a secondary flyby to a mission with the primary objective of 3200 Phaethon flyby and 25143 Itokawa rendezvous.

  14. Target Station Design for the Mu2e Experiment

    Energy Technology Data Exchange (ETDEWEB)

    Pronskikh, Vitaly [Fermilab; Ambrosio, Giorgio [Fermilab; Campbell, Michael [Fermilab; Coleman, Richard [Fermilab; Ginther, George [Fermilab; Kashikhin, Vadim [Fermilab; Krempetz, Kurt [Fermilab; Lamm, Michael [Fermilab; Lee, Ang [Fermilab; Leveling, Anthony [Fermilab; Mokhov, Nikolai [Fermilab; Nagaslaev, Vladimir [Fermilab; Stefanik, Andrew [Fermilab; Striganov, Sergei [Fermilab; Werkema, Steven [Fermilab; Bartoszek, Larry [Technicare; Densham, Chris [Rutherford; Loveridge, Peter [Rutherford; Lynch, Kevin [BMCC, New York; Popp, James [BMCC, New York

    2014-07-01

    The Mu2e experiment at Fermilab is devoted to search for the conversion of a negative muon into an electron in the field of a nucleus without emission of neutrinos. One of the main parts of the Mu2e experimental setup is its Target Station in which negative pions are generated in interactions of the 8-GeV primary proton beam with a tungsten target. A large-aperture 5-T superconducting production solenoid (PS) enhances pion collection, and an S-shaped transport solenoid (TS) delivers muons and pions to the Mu2e detector. The heat and radiation shield (HRS) protects the PS and the first TS coils. A beam dump absorbs the spent beam. In order for the PS superconducting magnet to operate reliably the sophisticated HRS was designed and optimized for performance and cost. The beam dump was designed to absorb the spent beam and maintaining its temperature and air activation in the hall at the allowable level. Comprehensive MARS15 simulations have been carried out to optimize all the parts while maximizing muon yield. Results of simulations of critical radiation quantities and their implications on the overall Target Station design and integration will be reported.

  15. Design of peptide-targeted liposomes containing nucleic acids.

    Science.gov (United States)

    Santos, Adriana O; da Silva, Lígia C Gomes; Bimbo, Luís M; de Lima, Maria C Pedroso; Simões, Sérgio; Moreira, João N

    2010-03-01

    Anticancer systemic gene silencing therapy has been so far limited by the inexistence of adequate carrier systems that ultimately provide an efficient intracellular delivery into target tumor cells. In this respect, one promising strategy involves the covalent attachment of internalizing-targeting ligands at the extremity of PEG chains grafted onto liposomes. Therefore, the present work aims at designing targeted liposomes containing nucleic acids, with small size, high encapsulation efficiency and able to be actively internalized by SCLC cells, using a hexapeptide (antagonist G) as a targeting ligand. For this purpose, the effect of the liposomal preparation method, loading material (ODN versus siRNA) and peptide-coupling procedure (direct coupling versus post-insertion) on each of the above-mentioned parameters was assessed. Post-insertion of DSPE-PEG-antagonist G conjugates into preformed liposomes herein named as stabilized lipid particles, resulted in targeted vesicles with a mean size of about 130 nm, encapsulation efficiency close to 100%, and a loading capacity of approximately 5 nmol siRNA/mumol of total lipid. In addition, the developed targeted vesicles showed increased internalization in SCLC cells, as well as in other tumor cells and HMEC-1 microvascular endothelial cells. The improved cellular association, however, did not correlate with enhanced downregulation of the target protein (Bcl-2) in SCLC cells. These results indicate that additional improvements need to be performed in the future, namely by ameliorating the access of the nucleic acids to the cytoplasm of the tumor cells following receptor-mediated endocytosis. Copyright 2009 Elsevier B.V. All rights reserved.

  16. Design, Operations, and Safety Report for the MERIT Target System

    Energy Technology Data Exchange (ETDEWEB)

    Graves, Van B [ORNL; Spampinato, Philip Thomas [ORNL

    2007-09-01

    The Mercury Intense Target Project (MERIT) is a proof-of-principal experiment to determine the feasibility of using a free-jet of Hg as a spallation target in a Neutrino Factory or a Muon Collider facility. The 1-cm-diameter, 20-m/sec jet will be generated inside a 15-Tesla magnetic field, and high-speed optical diagnostics will be used to photograph the interaction between the Hg jet and a 24-GeV proton beam.The experiment is scheduled to be conducted at CERN in 2007. ORNL is responsible for the design, fabrication, and testing of a system to deliver the Hg jet within the confines of the 15-cm magnet bore. This report documents the functional and safety requirements of the Hg system along with descriptions of its interfaces to the other experimental equipment.

  17. Survey design for precise fire management conservation targets.

    Science.gov (United States)

    Sitters, Holly; Di Stefano, Julian; Wills, Timothy; Swan, Matthew; York, Alan

    2017-09-12

    Common goals of ecological fire management are to sustain biodiversity and minimize extinction risk. A novel approach to achieving these goals determines the relative proportions of vegetation growth stages (equivalent to successional stages, which are categorical representations of time since fire) that maximize a biodiversity index. The method combines data describing species abundances in each growth stage with numerical optimization to define an optimal growth-stage structure which provides a conservation-based operational target for managers. However, conservation targets derived from growth-stage optimization are likely to depend critically on choices regarding input data. There is growing interest in use of growth-stage optimization as a basis for fire management, thus understanding of how input data influence the outputs is crucial. Simulated datasets provide a flexible platform for systematically varying aspects of survey design and species inclusions. We used artificial data with known properties, and a case-study dataset from southeastern Australia, to examine the influence of (i) survey design (total number of sites, and their distribution among growth stages) and (ii) species inclusions (total number of species and their level of specialization) on the precision of conservation targets. Based on our findings, we recommend that survey designs for precise estimates would ideally involve at least 80 sites, and include at least 80 species. Greater numbers of sites and species will yield increasingly reliable results, but fewer might be sufficient in some circumstances. An even distribution of sites among growth stages was less important than the total number of sites, and omission of species is unlikely to have a major influence on results as long as several species specialize on each growth stage. We highlight the importance of examining the responses of individual species to growth stage before feeding survey data into the growth-stage optimization black

  18. Application of analytical target cascading method in multidisciplinary design optimization of ship conceptual design

    Directory of Open Access Journals (Sweden)

    WANG Jian

    2017-10-01

    Full Text Available [Objectives] Ship conceptual design requires the coordination of many different disciplines for comprehensive optimization, which presents a complicated system design problem affecting several fields of technology. However, the development of overall ship design is relatively slow compared with other subjects. [Methods] The decomposition and coordination strategy of ship design is presented, and the analytical target cascading (ATC method is applied to the multidisciplinary design optimization of the conceptual design phase of ships on this basis. A tank ship example covering the 5 disciplines of buoyancy and stability, rapidity, maneuverability, capacity and economy is established to illustrate the analysis process in the present study. [Results] The results demonstrate the stability, convergence and validity of the ATC method in dealing with the complex coupling effect occurring in ship conceptual design.[Conclusions] The proposed method provides an effective basis for optimization of ship conceptual design.

  19. Enzyme Tunnels and Gates As Relevant Targets in Drug Design.

    Science.gov (United States)

    Marques, Sergio M; Daniel, Lukas; Buryska, Tomas; Prokop, Zbynek; Brezovsky, Jan; Damborsky, Jiri

    2017-09-01

    Many enzymes contain tunnels and gates that are essential to their function. Gates reversibly switch between open and closed conformations and thereby control the traffic of small molecules-substrates, products, ions, and solvent molecules-into and out of the enzyme's structure via molecular tunnels. Many transient tunnels and gates undoubtedly remain to be identified, and their functional roles and utility as potential drug targets have received comparatively little attention. Here, we describe a set of general concepts relating to the structural properties, function, and classification of these interesting structural features. In addition, we highlight the potential of enzyme tunnels and gates as targets for the binding of small molecules. The different types of binding that are possible and the potential pharmacological benefits of such targeting are discussed. Twelve examples of ligands bound to the tunnels and/or gates of clinically relevant enzymes are used to illustrate the different binding modes and to explain some new strategies for drug design. Such strategies could potentially help to overcome some of the problems facing medicinal chemists and lead to the discovery of more effective drugs. © 2016 Wiley Periodicals, Inc.

  20. High Power Molten Targets for Radioactive Ion Beam Production: from Particle Physics to Medical Applications

    CERN Document Server

    De Melo Mendonca, T M

    2014-01-01

    Megawatt-class molten targets, combining high material densities and good heat transfer properties are being considered for neutron spallation sources, neutrino physics facilities and radioactive ion beam production. For this last category of facilities, in order to cope with the limitation of long diffusion times affecting the extraction of short-lived isotopes, a lead-bismuth eutectic (LBE) target loop equipped with a diffusion chamber has been proposed and tested offline during the EURISOL design study. To validate the concept, a molten LBE loop is now in the design phase and will be prototyped and tested on-line at CERN-ISOLDE. This concept was further extended to an alternative route to produce 1013 18Ne/s for the Beta Beams, where a molten salt loop would be irradiated with 7 mA, 160 MeV proton beam. Some elements of the concept have been tested by using a molten fluoride salt static unit at CERNISOLDE. The investigation of the release and production of neon isotopes allowed the measurement of the diffu...

  1. Mock Target Window OTR and IR Design and Testing

    Energy Technology Data Exchange (ETDEWEB)

    Wass, Alexander Joseph [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-09-19

    In order to fully verify temperature measurements made on the target window using infrared (IR) optical non-contact methods, actual comparative measurements are made with a real beam distribution as the heat source using Argonne National Laboratory’s (ANL) 35 MeV electron accelerator. Using Monte Carlo N-Particle (MCNP) simulations and thermal Finite Element Analysis (FEA), a cooled mock target window with thermocouple implants is designed to be used in such a test to achieve window temperatures up to 700°C. An uncoated and blackcoated mock window is designed to enhance the IR temperature measurements and verify optical transmitted radiation (OTR) imagery. This allows us to fully verify and characterize our temperature accuracy with our current IR camera method and any future method we may wish to explore using actual production conditions. This test also provides us with valuable conclusions/concerns regarding the calibration method we developed using our IR test stand at TA-53 in MPF-14.

  2. Target design for materials processing very far from equilibrium

    Science.gov (United States)

    Barnard, John J.; Schenkel, Thomas

    2016-10-01

    Local heating and electronic excitations can trigger phase transitions or novel material states that can be stabilized by rapid quenching. An example on the few nanometer scale are phase transitions induced by the passage of swift heavy ions in solids where nitrogen-vacancy color centers form locally in diamonds when ions heat the diamond matrix to warm dense matter conditions at 0.5 eV. We optimize mask geometries for target materials such as silicon and diamond to induce phase transitions by intense ion pulses (e. g. from NDCX-II or from laser-plasma acceleration). The goal is to rapidly heat a solid target volumetrically and to trigger a phase transition or local lattice reconstruction followed by rapid cooling. The stabilized phase can then be studied ex situ. We performed HYDRA simulations that calculate peak temperatures for a series of excitation conditions and cooling rates of crystal targets with micro-structured masks. A simple analytical model, that includes ion heating and radial, diffusive cooling, was developed that agrees closely with the HYDRA simulations. The model gives scaling laws that can guide the design of targets over a wide range of parameters including those for NDCX-II and the proposed BELLA-i. This work was performed under the auspices of the U.S. DOE under contracts DE-AC52-07NA27344 (LLNL), DE-AC02-05CH11231 (LBNL) and was supported by the US DOE Office of Science, Fusion Energy Sciences. LLNL-ABS-697271.

  3. Modern Prodrug Design for Targeted Oral Drug Delivery

    Directory of Open Access Journals (Sweden)

    Arik Dahan

    2014-10-01

    Full Text Available The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug approach in particular. While the traditional prodrug approach was aimed at altering various physiochemical parameters, e.g., lipophilicity and charge state, the modern approach to prodrug design considers molecular/cellular factors, e.g., membrane influx/efflux transporters and cellular protein expression and distribution. This novel targeted-prodrug approach is aimed to exploit carrier-mediated transport for enhanced intestinal permeability, as well as specific enzymes to promote activation of the prodrug and liberation of the free parent drug. The purpose of this article is to provide a concise overview of this modern prodrug approach, with useful successful examples for its utilization. In the past the prodrug approach used to be viewed as a last option strategy, after all other possible solutions were exhausted; nowadays this is no longer the case, and in fact, the prodrug approach should be considered already in the very earliest development stages. Indeed, the prodrug approach becomes more and more popular and successful. A mechanistic prodrug design that aims to allow intestinal permeability by specific transporters, as well as activation by specific enzymes, may greatly improve the prodrug efficiency, and allow for novel oral treatment options.

  4. Design study of ITER-like divertor target for DEMO

    Energy Technology Data Exchange (ETDEWEB)

    Crescenzi, Fabio, E-mail: fabio.crescenzi@enea.it [ENEA, Unità Tecnica Fusione, ENEA C. R. Frascati, via E. Fermi 45, 00044 Frascati (Roma) (Italy); Bachmann, C. [EFDA, Power Plant Physics and Technology, Boltzmannstraße 2, 85748 Garching (Germany); Richou, M. [CEA, IRFM, F-13108 Saint Paul Lez Durance (France); Roccella, S.; Visca, E. [ENEA, Unità Tecnica Fusione, ENEA C. R. Frascati, via E. Fermi 45, 00044 Frascati (Roma) (Italy); You, J.-H. [Max-Planck-Institut für Plasmaphysik, Boltzmannstr. 2, 85748 Garching (Germany)

    2015-10-15

    Highlights: • ‘DEMO’ is a near-term Power Plant Conceptual Study (PPCS). • The ITER-like design concept represents a promising solution also for DEMO plasma facing units. • The optimization of PFUs aims to enhance the thermo-mechanical behaviour of the component. • The optimized geometry was evaluated by ITER SDC-IC criteria and in terms of low cycle fatigue (LCF). - Abstract: A near-term water-cooled target solution has to be evaluated together with the required technologies and its power exhaust limit under ‘DEMO’ conditions. The ITER-like design concept based on the mono-block technology using W as armour material and the CuCrZr-IG as structural material with an interlayer of pure copper represents a promising solution also for DEMO. This work reports the design study of an “optimized” ITER-like Water Cooled Divertor able to withstand a heat flux of 10 MW m{sup −2}, as requested for DEMO operating conditions. The optimization of plasma facing unit (PFU) aims to enhance the thermo-mechanical behaviour of the component by varying some geometrical parameters (monoblock size, interlayer thickness and, tube diameter and thickness). The optimization was performed by means of the multi-variable optimization algorithms using the FEM code ANSYS. The coolant hydraulic conditions (inlet pressure, temperature and velocity) were fixed for simplicity. This study is based on elastic analysis and 3 dimensional modelling. The resulting optimized geometry was evaluated on the basis of the ITER SDC-IC criteria and in terms of low cycle fatigue (LCF). The margin to the critical heat flux (CHF) was also estimated. Further design study (taking into account the effect of neutron radiation on the material properties) together with mock-up fabrication and high-heat-flux (HHF) tests are foreseen in next work programmes.

  5. Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Luc Calvin Owono Owono

    2013-01-01

    Full Text Available We design here new nanomolar antituberculotics, inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt, by means of structure-based molecular design. 3D models of TMPKmt-inhibitor complexes have been prepared from the crystal structure of TMPKmt cocrystallized with the natural substrate deoxythymidine monophosphate (dTMP (1GSI for a training set of 15 thymidine analogues (TMDs with known activity to prepare a QSAR model of interaction establishing a correlation between the free energy of complexation and the biological activity. Subsequent validation of the predictability of the model has been performed with a 3D QSAR pharmacophore generation. The structural information derived from the model served to design new subnanomolar thymidine analogues. From molecular modeling investigations, the agreement between free energy of complexation (ΔΔGcom and Ki values explains 94% of the TMPKmt inhibition (pKi=-0.2924ΔΔGcom+3.234;R2=0.94 by variation of the computed ΔΔGcom and 92% for the pharmacophore (PH4 model (pKi=1.0206×pKipred-0.0832,  R2=0.92. The analysis of contributions from active site residues suggested substitution at the 5-position of pyrimidine ring and various groups at the 5′-position of the ribose. The best inhibitor reached a predicted Ki of 0.155 nM. The computational approach through the combined use of molecular modeling and PH4 pharmacophore is helpful in targeted drug design, providing valuable information for the synthesis and prediction of activity of novel antituberculotic agents.

  6. Designer interface peptide grafts target estrogen receptor alpha dimerization

    Energy Technology Data Exchange (ETDEWEB)

    Chakraborty, S. [Laboratory of Computational Biophysics & Bioengineering, Department of Physics, Tougaloo College, Tougaloo, MS 39174 (United States); Asare, B.K. [Department of Pharmacology and Toxicology, University of Buffalo, Buffalo, NY 14214 (United States); Biswas, P.K., E-mail: pbiswas@tougaloo.edu [Laboratory of Computational Biophysics & Bioengineering, Department of Physics, Tougaloo College, Tougaloo, MS 39174 (United States); Rajnarayanan, R.V., E-mail: rajendra@buffalo.edu [Department of Pharmacology and Toxicology, University of Buffalo, Buffalo, NY 14214 (United States)

    2016-09-09

    The nuclear transcription factor estrogen receptor alpha (ERα), triggered by its cognate ligand estrogen, regulates a variety of cellular signaling events. ERα is expressed in 70% of breast cancers and is a widely validated target for anti-breast cancer drug discovery. Administration of anti-estrogen to block estrogen receptor activation is still a viable anti-breast cancer treatment option but anti-estrogen resistance has been a significant bottle-neck. Dimerization of estrogen receptor is required for ER activation. Blocking ERα dimerization is therefore a complementary and alternative strategy to combat anti-estrogen resistance. Dimer interface peptide “I-box” derived from ER residues 503–518 specifically blocks ER dimerization. Recently using a comprehensive molecular simulation we studied the interaction dynamics of ERα LBDs in a homo-dimer. Based on this study, we identified three interface recognition peptide motifs LDKITDT (ERα residues 479–485), LQQQHQRLAQ (residues 497–506), and LSHIRHMSNK (residues 511–520) and reported the suitability of using LQQQHQRLAQ (ER 497–506) as a template to design inhibitors of ERα dimerization. Stability and self-aggregation of peptide based therapeutics poses a significant bottle-neck to proceed further. In this study utilizing peptide grafted to preserve their pharmacophoric recognition motif and assessed their stability and potential to block ERα mediated activity in silico and in vitro. The Grafted peptides blocked ERα mediated cell proliferation and viability of breast cancer cells but did not alter their apoptotic fate. We believe the structural clues identified in this study can be used to identify novel peptidometics and small molecules that specifically target ER dimer interface generating a new breed of anti-cancer agents. - Highlights: • Designer peptide grafts retain core molecular recognition motif during MD simulations. • Designer peptide grafts with Poly-ALA helix form stable

  7. Colocated MIMO Radar: Beamforming, Waveform design, and Target Parameter Estimation

    KAUST Repository

    Jardak, Seifallah

    2014-04-01

    Thanks to its improved capabilities, the Multiple Input Multiple Output (MIMO) radar is attracting the attention of researchers and practitioners alike. Because it transmits orthogonal or partially correlated waveforms, this emerging technology outperformed the phased array radar by providing better parametric identifiability, achieving higher spatial resolution, and designing complex beampatterns. To avoid jamming and enhance the signal to noise ratio, it is often interesting to maximize the transmitted power in a given region of interest and minimize it elsewhere. This problem is known as the transmit beampattern design and is usually tackled as a two-step process: a transmit covariance matrix is firstly designed by minimizing a convex optimization problem, which is then used to generate practical waveforms. In this work, we propose simple novel methods to generate correlated waveforms using finite alphabet constant and non-constant-envelope symbols. To generate finite alphabet waveforms, the proposed method maps easily generated Gaussian random variables onto the phase-shift-keying, pulse-amplitude, and quadrature-amplitude modulation schemes. For such mapping, the probability density function of Gaussian random variables is divided into M regions, where M is the number of alphabets in the corresponding modulation scheme. By exploiting the mapping function, the relationship between the cross-correlation of Gaussian and finite alphabet symbols is derived. The second part of this thesis covers the topic of target parameter estimation. To determine the reflection coefficient, spatial location, and Doppler shift of a target, maximum likelihood estimation yields the best performance. However, it requires a two dimensional search problem. Therefore, its computational complexity is prohibitively high. So, we proposed a reduced complexity and optimum performance algorithm which allows the two dimensional fast Fourier transform to jointly estimate the spatial location

  8. Designing block copolymer architectures for targeted membrane performance

    KAUST Repository

    Dorin, Rachel Mika

    2014-01-01

    Using a combination of block copolymer self-assembly and non-solvent induced phase separation, isoporous ultrafiltration membranes were fabricated from four poly(isoprene-b-styrene-b-4-vinylpyridine) triblock terpolymers with similar block volume fractions but varying in total molar mass from 43 kg/mol to 115 kg/mol to systematically study the effect of polymer size on membrane structure. Small-angle X-ray scattering was used to probe terpolymer solution structure in the dope. All four triblocks displayed solution scattering patterns consistent with a body-centered cubic morphology. After membrane formation, structures were characterized using a combination of scanning electron microscopy and filtration performance tests. Membrane pore densities that ranged from 4.53 × 1014 to 1.48 × 1015 pores/m 2 were observed, which are the highest pore densities yet reported for membranes using self-assembly and non-solvent induced phase separation. Hydraulic permeabilities ranging from 24 to 850 L m-2 h-1 bar-1 and pore diameters ranging from 7 to 36 nm were determined from permeation and rejection experiments. Both the hydraulic permeability and pore size increased with increasing molar mass of the parent terpolymer. The combination of polymer characterization and membrane transport tests described here demonstrates the ability to rationally design macromolecular structures to target specific performance characteristics in block copolymer derived ultrafiltration membranes. © 2013 Elsevier Ltd. All rights reserved.

  9. Tailoring nanoparticle designs to target cancer based on tumor pathophysiology

    Science.gov (United States)

    Sykes, Edward A.; Dai, Qin; Sarsons, Christopher D.; Chen, Juan; Rocheleau, Jonathan V.; Hwang, David M.; Zheng, Gang; Cramb, David T.; Rinker, Kristina D.; Chan, Warren C. W.

    2016-03-01

    Nanoparticles can provide significant improvements in the diagnosis and treatment of cancer. How nanoparticle size, shape, and surface chemistry can affect their accumulation, retention, and penetration in tumors remains heavily investigated, because such findings provide guiding principles for engineering optimal nanosystems for tumor targeting. Currently, the experimental focus has been on particle design and not the biological system. Here, we varied tumor volume to determine whether cancer pathophysiology can influence tumor accumulation and penetration of different sized nanoparticles. Monte Carlo simulations were also used to model the process of nanoparticle accumulation. We discovered that changes in pathophysiology associated with tumor volume can selectively change tumor uptake of nanoparticles of varying size. We further determine that nanoparticle retention within tumors depends on the frequency of interaction of particles with the perivascular extracellular matrix for smaller nanoparticles, whereas transport of larger nanomaterials is dominated by Brownian motion. These results reveal that nanoparticles can potentially be personalized according to a patient's disease state to achieve optimal diagnostic and therapeutic outcomes.

  10. Criteria for selection of target materials and design of high-efficiency-release targets for radioactive ion beam generation

    CERN Document Server

    Alton, G D; Liu, Y

    1999-01-01

    In this report, we define criteria for choosing target materials and for designing, mechanically stable, short-diffusion-length, highly permeable targets for generation of high-intensity radioactive ion beams (RIBs) for use at nuclear physics and astrophysics research facilities based on the ISOL principle. In addition, lists of refractory target materials are provided and examples are given of a number of successful targets, based on these criteria, that have been fabricated and tested for use at the Holifield Radioactive Ion Beam Facility (HRIBF).

  11. APT target/blanket design and thermal hydraulics

    Energy Technology Data Exchange (ETDEWEB)

    Cappiello, M.; Pitcher, E.; Pasamehmetoglu, K.

    1999-04-01

    The Accelerator Production of Tritium (APT) Target/Blanket (T/B) system is comprised of an assembly of tritium producing modules supported by control, heat removal, shielding and retargeting systems. The T/B assembly produces tritium using a high-energy proton beam, a tungsten/lead spallation neutron source and {sup 3}He gas as the tritium producing feedstock. For the nominal production mode, protons are accelerated to an energy of 1030 MeV at a current of 100 mA and are directed onto the T/B assembly. The protons are expanded using a raster/expansion system to illuminate a 0.19m by 1.9m beam spot on the front face of a centrally located tungsten neutron source. A surrounding lead blanket produces additional neutrons from scattered high-energy particles. The tungsten neutron source consists of nested, Inconel-718 clad tungsten cylinders assembled in horizontal Inconel-718 tubes. Each tube contains up to 6 cylinders with annular flow channel gaps of 0.102 cm. These horizontal tubes are manifolded into larger diameter vertical inlet and outlet pipes, which provide coolant. The horizontal and vertical tubes make up a structure similar to that of rungs on a ladder. The entire tungsten neutron source consists of 11 such ladders separated into two modules, one containing five ladders and the other six. Ladders are separated by a 0.3 m void region to increase nucleon leakage. The peak thermal-hydraulic conditions in the tungsten neutron source occur in the second ladder from the front. Because tungsten neutron source design has a significant number of parallel flow channels, the limiting thermal-hydraulic parameter is the onset of significant void (OSV) rather than critical heat flux (CHF). A blanket region surrounds the tungsten neutron source. The lateral blanket region is approximately 120 cm thick and 400 cm high. Blanket material consists of lead, {sup 3}He gas, aluminum, and light-water coolant. The blanket region is subdivided into rows based on the local power

  12. Muon-catalyzed fusion experiment target and detector system. Preliminary design report

    Energy Technology Data Exchange (ETDEWEB)

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

    1982-03-01

    We present detailed plans for the target and particle detector systems for the muon-catalyzed fusion experiment. Requirements imposed on the target vessel by experimental conditions and safety considerations are delineated. Preliminary designs for the target vessel capsule and secondary containment vessel have been developed which meet these requirements. In addition, the particle detection system is outlined, including associated fast electronics and on-line data acquisition. Computer programs developed to study the target and detector system designs are described.

  13. Novel target design for enhanced laser driven proton acceleration

    Directory of Open Access Journals (Sweden)

    Malay Dalui

    2017-09-01

    Full Text Available We demonstrate a simple method of preparing structured target for enhanced laser-driven proton acceleration under target-normal-sheath-acceleration scheme. A few layers of genetically modified, clinically grown micron sized E. Coli bacteria cell coated on a thin metal foil has resulted in an increase in the maximum proton energy by about 1.5 times and the total proton yield is enhanced by approximately 25 times compared to an unstructured reference foil at a laser intensity of 1019 W/cm2. Particle-in-cell simulations on the system shows that the structures on the target-foil facilitates anharmonic resonance, contributing to enhanced hot electron production which leads to stronger accelerating field. The effect is observed to grow as the number of structures is increased in the focal area of the laser pulse.

  14. Novel target design for enhanced laser driven proton acceleration

    Science.gov (United States)

    Dalui, Malay; Kundu, M.; Tata, Sheroy; Lad, Amit D.; Jha, J.; Ray, Krishanu; Krishnamurthy, M.

    2017-09-01

    We demonstrate a simple method of preparing structured target for enhanced laser-driven proton acceleration under target-normal-sheath-acceleration scheme. A few layers of genetically modified, clinically grown micron sized E. Coli bacteria cell coated on a thin metal foil has resulted in an increase in the maximum proton energy by about 1.5 times and the total proton yield is enhanced by approximately 25 times compared to an unstructured reference foil at a laser intensity of 1019 W/cm2. Particle-in-cell simulations on the system shows that the structures on the target-foil facilitates anharmonic resonance, contributing to enhanced hot electron production which leads to stronger accelerating field. The effect is observed to grow as the number of structures is increased in the focal area of the laser pulse.

  15. Design of targeting ligands in medicinal inorganic chemistry.

    Science.gov (United States)

    Storr, Tim; Thompson, Katherine H; Orvig, Chris

    2006-06-01

    This tutorial review will highlight recent advances in medicinal inorganic chemistry pertaining to the use of multifunctional ligands for enhanced effect. Ligands that adequately bind metal ions and also include specific targeting features are gaining in popularity due to their ability to enhance the efficacy of less complicated metal-based agents. Moving beyond the traditional view of ligands modifying reactivity, stabilizing specific oxidation states, and contributing to substitution inertness, we will discuss recent work involving metal complexes with multifunctional ligands that target specific tissues, membrane receptors, or endogenous molecules, including enzymes.

  16. MEGAPIE spallation target: Design, manufacturing and preliminary tests of the first pro-typical spallation target for future ADS

    Energy Technology Data Exchange (ETDEWEB)

    Latge, Ch.; Laffont, G. [CEA Cadarache, 13108 Saint Paul Lez Durance Cedex (France); Groeschel, F.; Thomsen, K.; Wagner, W. [Paul Scherrer Institut (PSI), 5232 Villigen PSI (Switzerland); Agostini, P. [Centro Ricerche ENEA - Brasimone, c.p. no.1 - 40035 Castiglione dei Pepoli (Italy); Dierckx, M. [SCK-CEN, Boeretang 200, BR1 Building, B-2400 Mol (Belgium); Fazio, C. [Forschungszentrum Karlsruhe, Hermann-von-Helmholtz-Platz, 1, 76344 Eggenstein-Leopoldshafen (Germany); Kirchner, T. [SUBATECH, Ecole des Mines de Nantes, 4 rue Alfred Kastler, La Chantrerie - BP 20722, 44307 Nantes cedex (France); Kurata, Y. [JAERI, Meijiyasuda-seimei Kahiwa Fames, 14-1 Suehiro-cho, Kashiwa-shi, Chiba-ken 277-0842 (Japan); Song, T. [Korea Atomic Energy Research Institute, PO Box 7, Daedok Science Town, Daejun 302-353 (Korea, Republic of); Woloshun, K. [DOE-LANL, Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM 87545 (United States)

    2006-07-01

    Partitioning and Transmutation (P and T) techniques could contribute to reduce the radioactive inventory and its associated radiotoxicity. Sub-critical Accelerator Driven Systems (ADS) are potential candidates as dedicated transmutation systems, and thus their development is a relevant R and D topic in Europe. Following a first phase focused on the understanding of the basic principles of ADS (e.g. the programme MUSE), the R and D has been streamlined and focused on practical demonstration key issues. These demonstrations cover high intensity proton accelerators (beam current in the range 1 to 20 mA), spallation targets of high power and their effective coupling with a subcritical core. Presently there is general consensus that up to 1 MW of beam power solid targets are feasible from a heat removal point of view. For higher power levels liquid metal targets are the option of choice because of their higher heat removal capability, higher spallation material density in the volume and lower specific radioactivity, Therefore, a key experiment in the ADS road map, the Megawatt Pilot Experiment (MEGAPIE) (1 MW) was initiated in 1999 in order to design and build a liquid lead-bismuth spallation target, then to operate it into the Swiss spallation neutron facility SINQ at Paul Scherrer Institute (PSI). It has to be equipped to provide the largest possible amount of scientific and technical information without jeopardizing its safe operation. The minimum design service life has been fixed at 1 year (6000 mAh). Whereas the interest of the partner institutes is driven by the development needs of ADS, PSI interest lies also in the potential use of a LM target as a SINQ standard target providing a higher neutron flux than the current solid targets. Calculations of the radial distribution of the undisturbed thermal neutron flux for the LBE target in comparison to the former Zircaloy and current steel-clad solid lead target were done with different nuclear codes; nevertheless

  17. Advances in target design and fabrication for experiments on NIF

    Directory of Open Access Journals (Sweden)

    Obrey K.

    2013-11-01

    Full Text Available The ability to build target platforms for National Ignition Facility (NIF is a key feature in LANL's (Los Alamos National Laboratory Target Fabrication Program. We recently built and manufactured the first LANL targets to be fielded on NIF in March 2011. Experiments on NIF require precision component manufacturing and accurate knowledge of the materials used in the targets. The characterization of foams and aerogels, the Be ignition capsule, and machining unique components are of main material focus. One important characterization metric the physics' have determined is that the knowledge of density gradients in foams is important. We are making strides in not only locating these density gradients in aerogels and foams as a result of how they are manufactured and machined but also quantifying the density within the foam using 3D confocal micro x-ray fluorescence (μXRF imaging and 3D x-ray computed tomography (CT imaging. In addition, collaborative efforts between General Atomics (GA and LANL in the characterization of the NIF Ignition beryllium capsule have shown that the copper in the capsule migrates radially from the capsule center.

  18. 1L Mark-IV Target Design Review

    Energy Technology Data Exchange (ETDEWEB)

    Koehler, Paul E. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-11-16

    This presentation includes General Design Considerations; Current (Mark-III) Lower Tier; Mark-III Upper Tier; Performance Metrics; General Improvements for Material Science; General Improvements for Nuclear Science; Improving FOM for Nuclear Science; General Design Considerations Summary; Design Optimization Studies; Expected Mark-IV Performance: Material Science; Expected Mark-IV Performance: Nuclear Science (Disk); Mark IV Enables Much Wider Range of Nuclear-Science FOM Gains than Mark III; Mark-IV Performance Summary; Rod or Disk? Center or Real FOV?; and Project Cost and Schedule.

  19. Optimization of Neutrino Rates from the EURISOL Beta-Beam Accelerator Complex

    CERN Document Server

    Wildner, E; Emelianenko, N; Fabich, A; Hancock, S; Lindroos, M

    2007-01-01

    The beta beam concept for the production of intense (anti-)neutrino beams is now well established. A baseline design has recently been published for a beta-beam facility at CERN. It has the virtue of respecting the known limitations of the CERN PS and SPS synchrotrons, but falls short of delivering the requested annual rate of neutrinos. We report on a first analysis to increase the rate using the baseline ions of 6He and 18 Ne. A powerful method to understand the functional dependence of the many parameters that influence the figure of merit for a given facility is available with modern analytical calculation software. The method requires that a symbolic analytical description is produced of the full accelerator chain. Such a description has been made using Mathematica for the proposed beta beam facility at CERN. The direct access from Mathematica to an ORACLE database for reading basic design parameters and re-injecting derived parameters for completion of the parameter list is both convenient and efficient...

  20. Secretases as targets for drug design in Alzheimer's disease

    NARCIS (Netherlands)

    Hendriksen, JVRB; Nottet, HSLM; Smits, HA; Smits, H.J.

    Alzheimer's disease accounts for the majority of dementia in the elderly. Worldwide, approximately 20 million people are suffering from this devastating disease, with no effective treatment currently available. For efficient drug design, it is important to identify the molecular mechanisms

  1. Change in design targets for building energy towards smart cities

    DEFF Research Database (Denmark)

    Heller, Alfred; Gianniou, Panagiota; Katsigiannis, Emmanouil

    2014-01-01

    Designing cities from an overall energy optimization system point of view, demands changes in engineering procedures. Traditionally the design was driven independently between the involved domains and energy system components. By modelling the whole energy system in one, it is expected that there......Designing cities from an overall energy optimization system point of view, demands changes in engineering procedures. Traditionally the design was driven independently between the involved domains and energy system components. By modelling the whole energy system in one, it is expected...... so is, to move demands from high demand periods to low demand periods and hereby to avoid “peak” demands. This is called “flexibility” within the terminology of “smart grids”. In early solutions the search was for energy capacities within the domain of the electrical grid, hence car batteries where...

  2. Design of a cone target for fast ignition

    Directory of Open Access Journals (Sweden)

    Sunahara Atsushi

    2013-11-01

    Full Text Available We propose a new type of target for the fast ignition of inertial confinement fusion. Pre-formed plasma inside a cone target can significantly reduce the energy coupling efficiency from the ultra-high intense short-pulse laser to the imploded core plasma. Also, in order to protect the tip of the cone and reduce generation of pre-formed plasma, we propose pointed shaped cone target. In our estimation, the shock traveling time can be delayed 20–30 ps by lower-Z material with larger areal density compared to the conventional gold flat tip. Also, the jet flow can sweep the blow-off plasma from the tip of the cone, and the implosion performance is not drastically affected by the existence of pointed tip. In addition, the self-generated magnetic field is generated along the boundary of cone tip and surrounding CD or DT plasma. This magnetic field can confine fast electrons and focus to the implosion core plasma. Resultant heating efficiency is improved by 30% compared to that with conventional gold flat tip.

  3. Rational design of non-resistant targeted cancer therapies

    Science.gov (United States)

    Martínez-Jiménez, Francisco; Overington, John P.; Al-Lazikani, Bissan; Marti-Renom, Marc A.

    2017-01-01

    Drug resistance is one of the major problems in targeted cancer therapy. A major cause of resistance is changes in the amino acids that form the drug-target binding site. Despite of the numerous efforts made to individually understand and overcome these mutations, there is a lack of comprehensive analysis of the mutational landscape that can prospectively estimate drug-resistance mutations. Here we describe and computationally validate a framework that combines the cancer-specific likelihood with the resistance impact to enable the detection of single point mutations with the highest chance to be responsible of resistance to a particular targeted cancer therapy. Moreover, for these treatment-threatening mutations, the model proposes alternative therapies overcoming the resistance. We exemplified the applicability of the model using EGFR-gefitinib treatment for Lung Adenocarcinoma (LUAD) and Lung Squamous Cell Cancer (LSCC) and the ERK2-VTX11e treatment for melanoma and colorectal cancer. Our model correctly identified the phenotype known resistance mutations, including the classic EGFR-T790M and the ERK2-P58L/S/T mutations. Moreover, the model predicted new previously undescribed mutations as potentially responsible of drug resistance. Finally, we provided a map of the predicted sensitivity of alternative ERK2 and EGFR inhibitors, with a particular highlight of two molecules with a low predicted resistance impact. PMID:28436422

  4. Computational Design of a Krueger Flap Targeting Conventional Slat Aerodynamics

    Science.gov (United States)

    Akaydin, H. Dogus; Housman, Jeffrey A.; Kiris, Cetin C.; Bahr, Christopher J.; Hutcheson, Florence V.

    2016-01-01

    In this study, we demonstrate the design of a Krueger flap as a substitute for a conventional slat in a high-lift system. This notional design, with the objective of matching equivalent-mission performance on aircraft approach, was required for a comparative aeroacoustic study with computational and experimental components. We generated a family of high-lift systems with Krueger flaps based on a set of design parameters. Then, we evaluated the high-lift systems using steady 2D RANS simulations to find a good match for the conventional slat, based on total lift coefficients in free-air. Finally, we evaluated the mean aerodynamics of the high-lift systems with Krueger flap and conventional slat as they were installed in an open-jet wind tunnel flow. The surface pressures predicted with the simulations agreed well with experimental results.

  5. TRPV1: A Target for Rational Drug Design

    Directory of Open Access Journals (Sweden)

    Vincenzo Carnevale

    2016-08-01

    Full Text Available Transient Receptor Potential Vanilloid 1 (TRPV1 is a non-selective, Ca2+ permeable cation channel activated by noxious heat, and chemical ligands, such as capsaicin and resiniferatoxin (RTX. Many compounds have been developed that either activate or inhibit TRPV1, but none of them are in routine clinical practice. This review will discuss the rationale for antagonists and agonists of TRPV1 for pain relief and other conditions, and strategies to develop new, better drugs to target this ion channel, using the newly available high-resolution structures.

  6. Design and implementation of location-based wireless targeted advertising

    Science.gov (United States)

    Li, Benjamin; Xu, Deyin

    2001-10-01

    As advertisements are time and location sensitive, a challenge for wireless marketing is to have advertisements delivered when and where they are most convenient. In this paper we introduce a two-stage auction model for location-based wireless targeted advertising. This system extends the notion of location-based service by using location information to target advertising, and does so specifically by enabling advertisers to specify their preferences and bid for advertisement delivery, where those preferences are then used in a subsequent automated auction of actual deliveries to wireless data users. The automated auction in the second stage is especially effective because it can use information about the individual user profile data, including customer relationship management system contents as well as location from the wireless system's location management service, including potentially location history such as current trajectory from recent history and longer-term historical trip records for that user. Through two-stage auction, real-time bidding by advertisers and matching ads contents to mobile users help advertising information reach maximal value.

  7. In silico design of targeted SRM-based experiments

    Directory of Open Access Journals (Sweden)

    Nahnsen Sven

    2012-11-01

    Full Text Available Abstract Selected reaction monitoring (SRM-based proteomics approaches enable highly sensitive and reproducible assays for profiling of thousands of peptides in one experiment. The development of such assays involves the determination of retention time, detectability and fragmentation properties of peptides, followed by an optimal selection of transitions. If those properties have to be identified experimentally, the assay development becomes a time-consuming task. We introduce a computational framework for the optimal selection of transitions for a given set of proteins based on their sequence information alone or in conjunction with already existing transition databases. The presented method enables the rapid and fully automated initial development of assays for targeted proteomics. We introduce the relevant methods, report and discuss a step-wise and generic protocol and we also show that we can reach an ad hoc coverage of 80 % of the targeted proteins. The presented algorithmic procedure is implemented in the open-source software package OpenMS/TOPP.

  8. Lumican Peptides: Rational Design Targeting ALK5/TGFBRI

    Science.gov (United States)

    Gesteira, Tarsis Ferreira; Coulson-Thomas, Vivien J.; Yuan, Yong; Zhang, Jianhua; Nader, Helena B.; Kao, Winston W.-Y.

    2017-02-01

    Lumican, a small leucine rich proteoglycan (SLRP), is a component of extracellular matrix which also functions as a matrikine regulating multiple cell activities. In the cornea, lumican maintains corneal transparency by regulating collagen fibrillogenesis, promoting corneal epithelial wound healing, regulating gene expression and maintaining corneal homeostasis. We have recently shown that a peptide designed from the 13 C-terminal amino acids of lumican (LumC13) binds to ALK5/TGFBR1 (type1 receptor of TGFβ) to promote wound healing. Herein we evaluate the mechanism by which this synthetic C-terminal amphiphilic peptide (LumC13), binds to ALK5. These studies clearly reveal that LumC13-ALK5 form a stable complex. In order to determine the minimal amino acids required for the formation of a stable lumican/ALK5 complex derivatives of LumC13 were designed and their binding to ALK5 investigated in silico. These LumC13 derivatives were tested both in vitro and in vivo to evaluate their ability to promote corneal epithelial cell migration and corneal wound healing, respectively. These validations add to the therapeutic value of LumC13 (Lumikine) and aid its clinical relevance of promoting the healing of corneal epithelium debridement. Moreover, our data validates the efficacy of our computational approach to design active peptides based on interactions of receptor and chemokine/ligand.

  9. Rational design of chemical genetic probes of RNA function and lead therapeutics targeting repeating transcripts.

    Science.gov (United States)

    Disney, Matthew D

    2013-12-01

    RNA is an important yet vastly underexploited target for small molecule chemical probes or lead therapeutics. Small molecules have been used successfully to modulate the function of the bacterial ribosome, viral RNAs and riboswitches. These RNAs are either highly expressed or can be targeted using substrate mimicry, a mainstay in the design of enzyme inhibitors. However, most cellular RNAs are neither highly expressed nor have a lead small molecule inhibitor, a significant challenge for drug discovery efforts. Herein, I describe the design of small molecules targeting expanded repeating transcripts that cause myotonic muscular dystrophy (DM). These test cases illustrate the challenges of designing small molecules that target RNA and the advantages of targeting repeating transcripts. Lastly, I discuss how small molecules might be more advantageous than oligonucleotides for targeting RNA. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Rational Vehicle Design Ensures Targeted Cutaneous Steroid Delivery.

    Science.gov (United States)

    Kircik, Leon; Okumu, Franklin; Kandavilli, Sateesh; Sugarman, Jeffrey

    2017-02-01

    Objective: To design a topical vehicle that provided the optimal balance of betamethasone dipropionate penetration and retention in the skin, with minimal systemic absorption. Design: Six test formulations of betamethasone dipropionate 0.05% in vehicles contained the following penetration enhancers: elaidyl alcohol (Formulation-1), hexanol (Formulation-2), dodecanol (Formulation-3), octadecanol (Formulation-4), docosanol (Formulation-5), or oleyl alcohol (Formulation-6). Test agents were applied to human cadaver skin in static Franz-cell chambers containing receptor fluid. Measurements: Betamethasone absorption into the receptor fluid was measured over 24 hours. The distribution of betamethasone and its metabolites in the stratum corneum, epidermis, and dermis was analyzed using LC-MS/MS. The formulation with the optimal balance of penetration, permeation, retention, and minimal absorption was selected for a similar study comparing its penetration and absorption versus several commercially available betamethasone formulations. Results: Formulation-3 resulted in the highest retention of betamethasone in the skin as well as the highest steroid levels in the receptor fluid at 12 and 24 hours. Formulation-6 had the second highest retention of betamethasone in total skin, with relatively low absorption into the receptor fluid. All other variants had both lower steroid retention in the skin and lower absorption into the receptor fluid, with the exception of Formulation-2 which had higher absorption at 24 hours. Formulation-6/DFD-01 was selected for further development. Comparison of Formulation-6/DFD-01 with commercially available formulations of betamethasone dipropionate showed it had the highest steroid levels in the epidermis and dermis combined, with relatively low levels in the receptor fluid. Conclusion: Formulation-6/DFD-01 had the optimal balance of betamethasone retention in the skin, with low systemic absorption. This designed vehicle ensured retention of the

  11. Targeting Fold Stiffness to Design Enhanced Origami Structures

    Science.gov (United States)

    Buskohl, Philip; Bazzan, Giorgio; Abbott, Andrew; Durstock, Michael; Vaia, Richard

    2014-03-01

    Structures with adaptive geometry are increasingly of interest for actuation, sensing and packaging applications. Origami structures, by definition, can ``shape-shift'' between multiple geometric configurations that are predefined by a pattern of folds. Plastic deformation and local failure at the fold lines transform an originally homogenous material into a grid with locally tailored mechanical properties that bias the response of the overall structure to external loading. Typically, origami structures focus on uniformly stiff fold lines with rigid facets. In this study, we discuss how localized variations in stiffness can influence global properties, including energy budget to transition from flat to folded structure, the preferred path through configuration space, and the final mechanical response of the folded architecture. A simple, bi-stable origami fold pattern is laser machined into polypropylene sheets of different compliance and the critical load of the transition is measured. We model the structure as a truss with bar elongation, folding, and facet bending in order to predict ways to enhance or mitigate the critical load. Targeting local folding properties to modify global performance directly extends to the analysis of more complex architectures.

  12. Study of a New Target Design with an Additional Horn for NuMI Beam

    OpenAIRE

    Jyoti, Tripathi

    2017-01-01

    This paper describes the simulation studies done for the standard NOvA target and the proposed new minimal NOvA target design, in forward and reverse horn current for studying the neutrino and antineutrino event yield and the background contamination at the near and far detector. The standard NOvA target is segmented into 48 graphite segments (fins) with two magnetic horns, Horn 1 placed at MCZERO and Horn 2 placed at 19.18 m from MCZERO. The new minimal target design has 24 graphite fins ext...

  13. Sustainable Process Design under uncertainty analysis: targeting environmental indicators

    DEFF Research Database (Denmark)

    L. Gargalo, Carina; Gani, Rafiqul

    2015-01-01

    This study focuses on uncertainty analysis of environmental indicators used to support sustainable process design efforts. To this end, the Life Cycle Assessment methodology is extended with a comprehensive uncertainty analysis to propagate the uncertainties in input LCA data to the environmental...... indicators. The resulting uncertainties in the environmental indicators are then represented by empirical cumulative distribution function, which provides a probabilistic basis for the interpretation of the indicators. In order to highlight the main features of the extended LCA, the production of biodiesel...... from algae biomass is used as a case study. The results indicate there are considerable uncertainties in the calculated environmental indicators as revealed by CDFs. The underlying sources of these uncertainties are indeed the significant variation in the databases used for the LCA analysis...

  14. Designing decision support tools for targeted N-regulation

    DEFF Research Database (Denmark)

    Christensen, Andreas Aagaard; Piil, Kristoffer; Andersen, Peter Stubkjær

    2017-01-01

    , storing, editing, displaying and modelling landscape scale farming practices and associated emission consequences was developed. The tool was designed to integrate locally held knowledge with national scale datasets in live scenario situations through the implementation of a flexible, uniform and editable...... data model for land use data – the dNmark landscape model. Based on input data which is corrected and edited by workshop participants, the tool estimates the effect of potential land use scenarios on nutrient emissions. The tool was tested in 5 scenario workshops in case areas in Denmark in 2016...... integrated datasets can be stored and used to model environmental effects of current and possible land use patterns? (3) In what way data and estimates of consequences of land use changes are best made available in decision making processes? To address these questions this study reports on ongoing work...

  15. Dead-blow hammer design applied to a calibration target mechanism to dampen excessive rebound

    Science.gov (United States)

    Lim, Brian Y.

    1991-01-01

    An existing rotary electromagnetic driver was specified to be used to deploy and restow a blackbody calibration target inside of a spacecraft infrared science instrument. However, this target was much more massive than any other previously inherited design applications. The target experienced unacceptable bounce when reaching its stops. Without any design modification, the momentum generated by the driver caused the target to bounce back to its starting position. Initially, elastomeric dampers were used between the driver and the target. However, this design could not prevent the bounce, and it compromised the positional accuracy of the calibration target. A design that successfully met all the requirements incorporated a sealed pocket 85 percent full of 0.75 mm diameter stainless steel balls in the back of the target to provide the effect of a dead-blow hammer. The energy dissipation resulting from the collision of balls in the pocket successfully dampened the excess momentum generated during the target deployment. The disastrous effects of new requirements on a design with a successful flight history, the modifications that were necessary to make the device work, and the tests performed to verify its functionality are described.

  16. Strategies for Designing and Monitoring Malaria Vaccines Targeting Diverse Antigens

    Science.gov (United States)

    Barry, Alyssa E.; Arnott, Alicia

    2014-01-01

    After more than 50 years of intensive research and development, only one malaria vaccine candidate, “RTS,S,” has progressed to Phase 3 clinical trials. Despite only partial efficacy, this candidate is now forecast to become the first licensed malaria vaccine. Hence, more efficacious second-generation malaria vaccines that can significantly reduce transmission are urgently needed. This review will focus on a major obstacle hindering development of effective malaria vaccines: parasite antigenic diversity. Despite extensive genetic diversity in leading candidate antigens, vaccines have been and continue to be formulated using recombinant antigens representing only one or two strains. These vaccine strains represent only a small fraction of the diversity circulating in natural parasite populations, leading to escape of non-vaccine strains and challenging investigators’ abilities to measure strain-specific efficacy in vaccine trials. Novel strategies are needed to overcome antigenic diversity in order for vaccine development to succeed. Many studies have now cataloged the global diversity of leading Plasmodium falciparum and Plasmodium vivax vaccine antigens. In this review, we describe how population genetic approaches can be applied to this rich data source to predict the alleles that best represent antigenic diversity, polymorphisms that contribute to it, and to identify key polymorphisms associated with antigenic escape. We also suggest an approach to summarize the known global diversity of a given antigen to predict antigenic diversity, how to select variants that best represent the strains circulating in natural parasite populations and how to investigate the strain-specific efficacy of vaccine trials. Use of these strategies in the design and monitoring of vaccine trials will not only shed light on the contribution of genetic diversity to the antigenic diversity of malaria, but will also maximize the potential of future malaria vaccine candidates. PMID

  17. Strategies for designing and monitoring malaria vaccines targeting diverse antigens

    Directory of Open Access Journals (Sweden)

    Alyssa E Barry

    2014-07-01

    Full Text Available After more than 50 years of intensive research and development, only one malaria vaccine candidate, RTS,S, has progressed to Phase 3 clinical trials. Despite only partial efficacy, this candidate is now forecast to become the first licensed malaria vaccine. Hence, more efficacious second-generation malaria vaccines that can significantly reduce transmission are urgently needed. This review will focus on a major obstacle hindering development of effective malaria vaccines: parasite antigenic diversity. Despite extensive genetic diversity in leading candidate antigens, vaccines have been and continue to be formulated using recombinant antigens representing only one or two strains. These vaccine strains represent only a small fraction of the diversity circulating in natural parasite populations, leading to escape of non-vaccine strains and challenging investigators’ abilities to measure strain-specific efficacy in vaccine trials. Novel strategies are needed to overcome antigenic diversity in order for vaccine development to succeed. Many studies have now catalogued the global diversity of leading Plasmodium falciparum and Plasmodium vivax vaccine antigens. In this review, we describe how population genetic approaches can be applied to this rich data source to predict the alleles that best represent antigenic diversity, polymorphisms that contribute to it, and to identify key polymorphisms associated with antigenic escape. We also suggest an approach to summarise the known global diversity of a given antigen to predict antigenic diversity, how to select variants that best represent the strains circulating in natural parasite populations and how to investigate the strain-specific efficacy of vaccine trials. Use of these strategies in the design and monitoring of vaccine trials will not only shed light on the contribution of genetic diversity to the antigenic diversity of malaria, but will also maximise the potential of future malaria vaccine

  18. Computational design of high efficiency release targets for use at ISOL facilities

    CERN Document Server

    Liu, Y

    1999-01-01

    This report describes efforts made at the Oak Ridge National Laboratory to design high-efficiency-release targets that simultaneously incorporate the short diffusion lengths, high permeabilities, controllable temperatures, and heat-removal properties required for the generation of useful radioactive ion beam (RIB) intensities for nuclear physics and astrophysics research using the isotope separation on-line (ISOL) technique. Short diffusion lengths are achieved either by using thin fibrous target materials or by coating thin layers of selected target material onto low-density carbon fibers such as reticulated-vitreous-carbon fiber (RVCF) or carbon-bonded-carbon fiber (CBCF) to form highly permeable composite target matrices. Computational studies that simulate the generation and removal of primary beam deposited heat from target materials have been conducted to optimize the design of target/heat-sink systems for generating RIBs. The results derived from diffusion release-rate simulation studies for selected t...

  19. Computer Aided Drug Design for Multi-Target Drug Design: SAR /QSAR, Molecular Docking and Pharmacophore Methods.

    Science.gov (United States)

    Abdolmaleki, Azizeh; Ghasemi, Jahan B; Ghasemi, Fatemeh

    2017-01-01

    Multi-target drugs against particular multiple targets get better protection, resistance profiles and curative influence by cooperative rules of a key beneficial target with resistance behavior and compensatory elements. Computational techniques can assist us in the efforts to design novel drugs (ligands) with a preferred bioactivity outline and alternative bioactive molecules at an early stage. A number of in silico methods have been explored extensively in order to facilitate the investigation of individual target agents and to propose a selective drug. A different, progressively more significant field which is used to predict the bioactivity of chemical compounds is the data mining method. Some of the previously mentioned methods have been investigated for multi-target drug design (MTDD) to find drug leads interact simultaneously with multiple targets. Several cheminformatics methods and structure-based approaches try to extract information from units working cooperatively in a biomolecular system to fulfill their task. To dominate the difficulties of the experimental specification of ligand-target structures, rational methods, namely molecular docking, SAR and QSAR are vital substitutes to obtain knowledge for each structure in atomic insight. These procedures are logically successful for the prediction of binding affinity and have shown promising potential in facilitating MTDD. Here, we review some of the important features of the multi-target therapeutics discoveries using the computational approach, highlighting the SAR, QSAR, docking and pharmacophore methods to discover interactions between drug-target that could be leveraged for curative benefits. A summary of each, followed by examples of its applications in drug design has been provided. Computational efficiency of each method has been represented according to its main strengths and limitations. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  20. Target design considerations for high specific activity [{sup 11}C]O{sub 2}

    Energy Technology Data Exchange (ETDEWEB)

    Ferrieri, R.A.; Alexoff, D.L.; Schlyer, D.J.; McDonald, K.; Wolf, A.P.

    1993-12-31

    In the routine preparation of {sup 11}C-labeled compounds through N-[{sup 11}C]-methylation using [{sup 11}C]H{sub 3}I, total masses are always higher than synthesis mass contribution, suggesting that the target system contributes carrier carbon to the final product mass. This conclusion prompted this evaluation of target materials and target design for [{sup 11}C]O{sub 2} production. Ultimately, one is faced with the sprospect of compromising between [{sup 11}C]O{sub 2} specific activity and the amount that can be extracted from the target after a reasonable irradiation time.

  1. Magnet Design for the ISIS Second Target Station Proton Beam Line

    CERN Document Server

    Thomas, Chris; Jago, Stephen

    2005-01-01

    The ISIS facility, based at the Rutherford Appleton Laboratory in the UK, is an intense source of neutrons and muons for condensed matter research. The accelerator facility delivers an 800 MeV proton beam of 2.5x1013 protons per pulse at 50 Hz to the present target station. As part of a facility upgrade, it is planned to share the source with a second, 10 Hz, target station. The beam line supplying this target will extract from the existing target station beam line. Electromagnetic Finite Element Modelling techniques have been used to design the magnets required to meet the specified beam line optics. Kicker, septum, dipole, quadrupole, and steering magnets are covered. The magnet design process, involving 2D and 3D modelling, the calculation of ideal shims and chamfers, choice of steel, design of conducting coils, handling of heating issues and eddy current effects, is discussed.

  2. Design and construction of the cluster-jet target for PANDA

    Energy Technology Data Exchange (ETDEWEB)

    Hergemoeller, Ann-Katrin; Bonaventura, Daniel; Grieser, Silke; Hetz, Benjamin; Hordt, Fabian; Koehler, Esperanza; Taeschner, Alexander; Khoukaz, Alfons [Institut fuer Kernphysik, Westfaelische Wilhelms-Universitaet Muenster, 48149 Muenster (Germany)

    2015-07-01

    Cluster-jet targets are highly suited as internal targets for storage ring experiments. Hence, the first target to be operated at the PANDA experiment at the future accelerator center FAIR will be a cluster-jet target. In such a target the cluster beam itself is formed due to the expansion of pre-cooled gases within a Laval nozzle. Afterwards an orifice, the skimmer, separates the cluster beam from the residual gas and a second orifice, the collimator, defines its final size and shape. A prototype for the cluster-jet target for PANDA has already been built up in full PANDA geometry at the University of Muenster and operates successfully for years. In combination with a nozzle tilting system allowing for an adjustment of the nozzle system relative to the experimental setup, the prototype provides a target thickness of more than 2 x 10{sup 15} atoms/cm{sup 2}. Based on the results of the performance of this prototype, the final cluster-jet target source was designed and constructed in Muenster as well. In this presentation an overview of the cluster-jet target design, various special features and first performance results are presented and discussed.

  3. Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site

    Energy Technology Data Exchange (ETDEWEB)

    Strauch, Eva-Maria; Bernard, Steffen M.; La, David; Bohn, Alan J.; Lee, Peter S.; Anderson, Caitlin E.; Nieusma, Travis; Holstein, Carly A.; Garcia, Natalie K.; Hooper, Kathryn A.; Ravichandran, Rashmi; Nelson, Jorgen W.; Sheffler, William; Bloom, Jesse D.; Lee, Kelly K.; Ward, Andrew B.; Yager, Paul; Fuller, Deborah H.; Wilson, Ian A.; Baker , David (UWASH); (Scripps); (FHCRC)

    2017-06-12

    Many viral surface glycoproteins and cell surface receptors are homo-oligomers1, 2, 3, 4, and thus can potentially be targeted by geometrically matched homo-oligomers that engage all subunits simultaneously to attain high avidity and/or lock subunits together. The adaptive immune system cannot generally employ this strategy since the individual antibody binding sites are not arranged with appropriate geometry to simultaneously engage multiple sites in a single target homo-oligomer. We describe a general strategy for the computational design of homo-oligomeric protein assemblies with binding functionality precisely matched to homo-oligomeric target sites5, 6, 7, 8. In the first step, a small protein is designed that binds a single site on the target. In the second step, the designed protein is assembled into a homo-oligomer such that the designed binding sites are aligned with the target sites. We use this approach to design high-avidity trimeric proteins that bind influenza A hemagglutinin (HA) at its conserved receptor binding site. The designed trimers can both capture and detect HA in a paper-based diagnostic format, neutralizes influenza in cell culture, and completely protects mice when given as a single dose 24 h before or after challenge with influenza.

  4. Analysis of the thermomechanical behavior of the IFMIF bayonet target assembly under design loading scenarios

    Energy Technology Data Exchange (ETDEWEB)

    Bernardi, D., E-mail: davide.bernardi@enea.it [ENEA Brasimone, Camugnano, BO (Italy); Arena, P.; Bongiovì, G.; Di Maio, P.A. [Dipartimento di Energia, Ingegneria dell’Informazione e Modelli Matematici, Università di Palermo, Viale delle Scienze, Palermo (Italy); Frisoni, M. [ENEA Bologna, Via Martiri di Monte Sole 4, Bologna (Italy); Miccichè, G.; Serra, M. [ENEA Brasimone, Camugnano, BO (Italy)

    2015-10-15

    In the framework of the IFMIF Engineering Validation and Engineering Design Activities (IFMIF/EVEDA) phase, ENEA is responsible for the design of the European concept of the IFMIF lithium target system which foresees the possibility to periodically replace only the most irradiated and thus critical component (i.e., the backplate) while continuing to operate the rest of the target for a longer period (the so-called bayonet backplate concept). In this work, the results of the steady state thermomechanical analysis of the IFMIF bayonet target assembly under two different design loading scenarios (a “hot” scenario and a “cold” scenario) are briefly reported highlighting the relevant indications obtained with respect to the fulfillment of the design requirements. In particular, the analyses have shown that in the hot scenario the temperatures reached in the target assembly are within the material acceptable limits while in the cold scenario transition below the ductile to brittle transition temperature (DBTT) cannot be excluded. Moreover, results indicate that the contact between backplate and high flux test module is avoided and that the overall structural integrity of the system is assured in both scenarios. However, stress linearization analysis reveals that ITER Structural Design Criteria for In-vessel Components (SDC-IC) design rules are not always met along the selected paths at backplate middle plane section in the hot scenario, thus suggesting the need of a revision of the backplate design or a change of the operating conditions.

  5. Radar Constant-Modulus Waveform Design with Prior Information of the Extended Target and Clutter.

    Science.gov (United States)

    Yue, Wenzhen; Zhang, Yan; Liu, Yimin; Xie, Jingwen

    2016-06-17

    Radar waveform design is of great importance for radar system performances and has drawn considerable attention recently. Constant modulus is an important waveform design consideration, both from the point of view of hardware realization and to allow for full utilization of the transmitter's power. In this paper, we consider the problem of constant-modulus waveform design for extended target detection with prior information about the extended target and clutter. At first, we propose an arbitrary-phase unimodular waveform design method via joint transmitter-receiver optimization. We exploit a semi-definite relaxation technique to transform an intractable non-convex problem into a convex problem, which can then be efficiently solved. Furthermore, quadrature phase shift keying waveform is designed, which is easier to implement than arbitrary-phase waveforms. Numerical results demonstrate the effectiveness of the proposed methods.

  6. Radar Constant-Modulus Waveform Design with Prior Information of the Extended Target and Clutter

    Directory of Open Access Journals (Sweden)

    Wenzhen Yue

    2016-06-01

    Full Text Available Radar waveform design is of great importance for radar system performances and has drawn considerable attention recently. Constant modulus is an important waveform design consideration, both from the point of view of hardware realization and to allow for full utilization of the transmitter’s power. In this paper, we consider the problem of constant-modulus waveform design for extended target detection with prior information about the extended target and clutter. At first, we propose an arbitrary-phase unimodular waveform design method via joint transmitter-receiver optimization. We exploit a semi-definite relaxation technique to transform an intractable non-convex problem into a convex problem, which can then be efficiently solved. Furthermore, quadrature phase shift keying waveform is designed, which is easier to implement than arbitrary-phase waveforms. Numerical results demonstrate the effectiveness of the proposed methods.

  7. Current infrared target acquisition approach for military sensor design and wargaming

    Science.gov (United States)

    Driggers, Ronald G.; Jacobs, Eddie L.; Vollmerhausen, Richard H.; O'Kane, Barbara; Self, Mid; Moyer, Steve; Hixson, Jonathan G.; Page, Gary; Krapels, Keith; Dixon, David; Kistner, Regina; Mazz, John

    2006-05-01

    The U.S. Army's infrared target acquisition models have been used for many years by the military sensor community, and there have been significant improvements to these models over the past few years. Significant improvements are the Target Task Performance (TTP) metric for all imaging sensors, the ACQUIRE-LC approach for low contrast infrared targets, and the development of discrimination criteria for the urban environment. This paper is intended to provide an overview of the current infrared target acquisition modeling approach. This paper will discuss recent advances and changes to the models and methodologies used to: (1) design and compare sensors, (2) predict expected target acquisition performance in the field, (3) predict target detection performance for combat simulations, (4) measure and characterize human operator performance in an operational environment (field performance), and (5) relate the models to target acquisition tasks and address targets that are relevant to urban operations. Finally, we present a catalog of discrimination criteria, characteristic dimensions, and target contrasts.

  8. Designing nanoconjugates to effectively target pancreatic cancer cells in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Jameel Ahmad Khan

    Full Text Available Pancreatic cancer is the fourth leading cause of cancer related deaths in America. Monoclonal antibodies are a viable treatment option for inhibiting cancer growth. Tumor specific drug delivery could be achieved utilizing these monoclonal antibodies as targeting agents. This type of designer therapeutic is evolving and with the use of gold nanoparticles it is a promising approach to selectively deliver chemotherapeutics to malignant cells. Gold nanoparticles (GNPs are showing extreme promise in current medicinal research. GNPs have been shown to non-invasively kill tumor cells by hyperthermia using radiofrequency. They have also been implemented as early detection agents due to their unique X-ray contrast properties; success was revealed with clear delineation of blood capillaries in a preclinical model by CT (computer tomography. The fundamental parameters for intelligent design of nanoconjugates are on the forefront. The goal of this study is to define the necessary design parameters to successfully target pancreatic cancer cells.The nanoconjugates described in this study were characterized with various physico-chemical techniques. We demonstrate that the number of cetuximab molecules (targeting agent on a GNP, the hydrodynamic size of the nanoconjugates, available reactive surface area and the ability of the nanoconjugates to sequester EGFR (epidermal growth factor receptor, all play critical roles in effectively targeting tumor cells in vitro and in vivo in an orthotopic model of pancreatic cancer.Our results suggest the specific targeting of tumor cells depends on a number of crucial components 1 targeting agent to nanoparticle ratio 2 availability of reactive surface area on the nanoparticle 3 ability of the nanoconjugate to bind the target and 4 hydrodynamic diameter of the nanoconjugate. We believe this study will help define the design parameters for formulating better strategies for specifically targeting tumors with nanoparticle

  9. Design, Synthesis, and Some Aspects of the Biological Activity of Mitochondria-Targeted Antioxidants.

    Science.gov (United States)

    Korshunova, G A; Shishkina, A V; Skulachev, M V

    2017-07-01

    This review summarizes for the first time data on the design and synthesis of biologically active compounds of a new generation - mitochondria-targeted antioxidants, which are natural (or synthetic) p-benzoquinones conjugated via a lipophilic linker with (triphenyl)phosphonium or ammonium cations with delocalized charge. It also describes the synthesis of mitochondria-targeted antioxidants - uncouplers of oxidative phosphorylation - based on fluorescent dyes.

  10. Flowing lead spallation target design for use in an ADTT experimental facility located at LAMPF

    Science.gov (United States)

    Beard, C. A.; Bracht, R. R.; Buksa, J. J.; Chaves, W.; DeVolder, B. G.; O'Brien, H.; Park, J. J.; Parker, R. B.; Pillai, C.; Potter, R. C.; Reid, R. S.; Trujillo, D. A.; Vela, O. A.; Venneri, F.; Weinacht, D. J.; Wender, S. A.; Wilson, W. B.; Woloshun, K. A.

    1995-09-01

    A conceptual design has been initiated for a flowing lead spallation target for use in an ADTT experimental facility located at LAMPF. The lead is contained using Nb-1Zr as the structural material. This material was selected based on its favorable material properties as well as its compatibility with the flowing lead. Heat deposited in the lead and the Nb-1Zr container by the 800-MeV, 1-mA beam is removed by the flowing lead and transferred to helium via a conventional heat exchanger. The neutronic, thermal hydraulic, and stress characteristics of the system have been determined. In addition, a module to control the thaw and freeze of the lead has been developed and incorporated into the target system design. The entire primary target system (spallation target, thaw/freeze system, and intermediate heat exchanger) has been designed to be built as a contained module to allow easy insertion into an experimental ADTT blanket assembly and to provide multiple levels of containment for the lead. For the 800-MeV LAMPF beam, the target delivers a source of approximately 18 neutrons/proton. A total of 540 kW are deposited in the target. The lead temperature ranges from 400 to 500 C. The peak structural heating occurs at the beam interface, and the target is designed to maximize cooling at this point. An innovative thin-window structure has been incorporated that allows direct, convective cooling of the window by the inlet flowing lead. Safe and reliable operation of the target has been maximized through simple, robust engineering.

  11. Methods to enable the design of bioactive small molecules targeting RNA.

    Science.gov (United States)

    Disney, Matthew D; Yildirim, Ilyas; Childs-Disney, Jessica L

    2014-02-21

    RNA is an immensely important target for small molecule therapeutics or chemical probes of function. However, methods that identify, annotate, and optimize RNA-small molecule interactions that could enable the design of compounds that modulate RNA function are in their infancies. This review describes recent approaches that have been developed to understand and optimize RNA motif-small molecule interactions, including structure-activity relationships through sequencing (StARTS), quantitative structure-activity relationships (QSAR), chemical similarity searching, structure-based design and docking, and molecular dynamics (MD) simulations. Case studies described include the design of small molecules targeting RNA expansions, the bacterial A-site, viral RNAs, and telomerase RNA. These approaches can be combined to afford a synergistic method to exploit the myriad of RNA targets in the transcriptome.

  12. Customer Focused Product Design Using Integrated Model of Target Costing, Quality Function Deployment and Value Engineering

    Directory of Open Access Journals (Sweden)

    Hossein Rezaei Dolatabadi

    2013-01-01

    Full Text Available Target costing by integrating customer requirements, technical attributes and cost information into the product design phase and eliminating the non-value added functions, plays a vital role in different phases of the product life cycle. Quality Function Deployment (QFD and Value Engineering (VE are two techniques which can be used for applying target costing, successfully. The purpose of this paper is to propose an integrated model of target costing, QFD and VE to explore the role of target costing in managing product costs while promoting quality specifications meeting customers’ needs. F indings indicate that the integration of target costing, QFD and VE is an essential technique in managing the costs of production process. Findings also imply that integration of the three techniques provides a competitive cost advantage to companies.

  13. CFD Analysis and Design of Detailed Target Configurations for an Accelerator-Driven Subcritical System

    Energy Technology Data Exchange (ETDEWEB)

    Kraus, Adam; Merzari, Elia; Sofu, Tanju; Zhong, Zhaopeng; Gohar, Yousry

    2016-08-01

    High-fidelity analysis has been utilized in the design of beam target options for an accelerator driven subcritical system. Designs featuring stacks of plates with square cross section have been investigated for both tungsten and uranium target materials. The presented work includes the first thermal-hydraulic simulations of the full, detailed target geometry. The innovative target cooling manifold design features many regions with complex flow features, including 90 bends and merging jets, which necessitate three-dimensional fluid simulations. These were performed using the commercial computational fluid dynamics code STAR-CCM+. Conjugate heat transfer was modeled between the plates, cladding, manifold structure, and fluid. Steady-state simulations were performed but lacked good residual convergence. Unsteady simulations were then performed, which converged well and demonstrated that flow instability existed in the lower portion of the manifold. It was established that the flow instability had little effect on the peak plate temperatures, which were well below the melting point. The estimated plate surface temperatures and target region pressure were shown to provide sufficient margin to subcooled boiling for standard operating conditions. This demonstrated the safety of both potential target configurations during normal operation.

  14. Design and Certification of Targets for Drop Tests at the NTRC Packaging Research Facility

    Energy Technology Data Exchange (ETDEWEB)

    Ludwig, S.B.

    2003-06-05

    This report provides documentation of the design and certification of drop pad (targets) at the National Transportation Research Center (NTRC) Packaging Research Facility(PRF). Based on the evaluation performed, it has been demonstrated that the small (interior) drop pad (target) meets the regulatory definition of a flat, essentially unyielding, horizontal surface for packages weighing up to 3,150 lb (1,432 kg). The large (exterior) drop pad (target) meets the regulatory definition of a flat, essentially unyielding, horizontal surface for packages weighing up to 28,184 lb (12,811 kg).

  15. Secondary structure in the target as a confounding factor in synthetic oligomer microarray design

    Directory of Open Access Journals (Sweden)

    Gibas Cynthia J

    2005-03-01

    Full Text Available Abstract Background Secondary structure in the target is a property not usually considered in software applications for design of optimal custom oligonucleotide probes. It is frequently assumed that eliminating self-complementarity, or screening for secondary structure in the probe, is sufficient to avoid interference with hybridization by stable secondary structures in the probe binding site. Prediction and thermodynamic analysis of secondary structure formation in a genome-wide set of transcripts from Brucella suis 1330 demonstrates that the properties of the target molecule have the potential to strongly influence the rate and extent of hybridization between transcript and tethered oligonucleotide probe in a microarray experiment. Results Despite the relatively high hybridization temperatures and 1M monovalent salt imposed in the modeling process to approximate hybridization conditions used in the laboratory, we find that parts of the target molecules are likely to be inaccessible to intermolecular hybridization due to the formation of stable intramolecular secondary structure. For example, at 65°C, 28 ± 7% of the average cDNA target sequence is predicted to be inaccessible to hybridization. We also analyzed the specific binding sites of a set of 70mer probes previously designed for Brucella using a freely available oligo design software package. 21 ± 13% of the nucleotides in each probe binding site are within a double-stranded structure in over half of the folds predicted for the cDNA target at 65°C. The intramolecular structures formed are more stable and extensive when an RNA target is modeled rather than cDNA. When random shearing of the target is modeled for fragments of 200, 100 and 50 nt, an overall destabilization of secondary structure is predicted, but shearing does not eliminate secondary structure. Conclusion Secondary structure in the target is pervasive, and a significant fraction of the target is found in double stranded

  16. Block design enhances classification of 3D reach targets from electroencephalographic signals.

    Science.gov (United States)

    Sosnik, Ronen; Tadipatri, Vijay Aditya; Tewfik, Ahmed H; Pellizzer, Giuseppe

    2016-08-04

    To date, decoding accuracy of actual or imagined pointing movements to targets in 3D space from electroencephalographic (EEG) signals has remained modest. The reason may pertain to the fact that these movements activate essentially the same neural networks. In this study, we aimed at testing whether repetitive pointing movements to each of the targets promotes the development of segregated neural patterns, resulting in enhanced decoding accuracy. Six human subjects generated slow or fast repetitive pointing movements with their right dominant arm to one of five targets distributed in 3D space, followed by repetitive imagery of movements to the same target or to a different target. Nine naive subjects generated both repetitive and non-repetitive slow actual movements to each of the five targets to test the effect of block design on decoding accuracy. In order to assure that base line drift and low frequency motion artifacts do not contaminate the data, the data were high-pass filtered in 4-30Hz, leaving out the delta and gamma band. For the repetitive trials, the model decoded target location with 81% accuracy, which is significantly higher than chance level. The average decoding rate of target location was only 30% for the non-repetitive trials, which is not significantly different than chance level. A subset of electrodes, mainly over the contralateral sensorimotor areas, was found to provide most of the discriminative features for all tested conditions. Time proximity between trained and tested blocks was found to enhance decoding accuracy of target location both by target non-specific and specific mechanisms. Our findings suggest that movement repetition promotes the development of distinct neural patterns, presumably by the formation of target-specific kinesthetic memory. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  17. From drug target to leads--sketching a physicochemical pathway for lead molecule design in silico.

    Science.gov (United States)

    Shaikh, S A; Jain, T; Sandhu, G; Latha, N; Jayaram, B

    2007-01-01

    The discovery of new pharmaceuticals via computer modeling is one of the key challenges in modern medicine. The advent of global networks of genomic, proteomic and metabolomic endeavors is ushering in an increasing number of novel and clinically important targets for screening. Computational methods are anticipated to play a pivotal role in exploiting the structural and functional information to understand specific molecular recognition events of the target macromolecule with candidate hits leading ultimately to the design of improved leads for the target. In this review, we sketch a system independent, comprehensive physicochemical pathway for lead molecule design focusing on the emerging in silico trends and techniques. We survey strategies for the generation of candidate molecules, docking them with the target and ranking them based on binding affinities. We present a molecular level treatment for distinguishing affinity from specificity of a ligand for a given target. We also discuss the significant aspects of drug absorption, distribution, metabolism, excretion and toxicity (ADMET) and highlight improved protocols required for higher quality and throughput of in silico methods employed at early stages of discovery. We present a realization of the various stages in the pathway proposed with select examples from the literature and from our own research to demonstrate the way in which an iterative process of computer design and validation can aid in developing potent leads. The review thus summarizes recent advances and presents a viewpoint on improvements envisioned in the years to come for automated computer aided lead molecule discovery.

  18. Reduced cost design of liquid lithium target for international fusion material irradiation facility (IFMIF)

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, Hiroo; Ida, Mizuho; Sugimoto, Masayoshi; Takeuchi, Hiroshi [Department of Fussion Engineering Research, Naka Fusion Research Establishment, Japan Atomic Energy Research Institute, Tokai, Ibaraki (Japan); Yutani, Toshiaki [Toshiba Corp., Tokyo (Japan)

    2001-01-01

    The International Fusion Materials Irradiation Facility (IFMIF) is being jointly planned to provide an accelerator-based D-Li neutron source to produce intense high energy neutrons (2 MW/m{sup 2}) up to 200 dpa and a sufficient irradiation volume (500 cm{sup 3}) for testing the candidate materials and components up to about a full lifetime of their anticipated use in ITER and DEMO. To realize such a condition, 40 MeV deuteron beam with a current of 250 mA is injected into high speed liquid lithium flow with a speed of 20 m/s. Following Conceptual Design Activity (1995-1998), a design study with focus on cost reduction without changing its original mission has been done in 1999. The following major changes to the CAD target design have been considered in the study and included in the new design: i) number of the Li target has been changed from 2 to 1, ii) spare of impurity traps of the Li loop was removed although the spare will be stored in a laboratory for quick exchange, iii) building volume was reduced via design changes in lithium loop length. This paper describes the reduced cost design of the lithium target system and recent status of Key Element Technology activities. (author)

  19. Design and Experimental Validation of Small Activating RNAs Targeting an Exogenous Promoter in Human Cells.

    Science.gov (United States)

    Harris, Edouard A; Buzina, Alla; Moffat, Jason; McMillen, David R

    2017-04-21

    It is increasingly practical to co-opt many native cellular components into use as elements of synthetic biological systems. We present the design and experimental investigation of the first exogenous genetic construct to be successfully targeted by RNA activation, a phenomenon whereby small double-stranded RNAs increase gene expression from sequence-similar promoters by a mechanism thought to be related to that of RNA interference. Our selection of activating RNA candidates was informed by a custom-written computer program designed to choose target sites in the promoter of interest according to a set of empirical optimality criteria drawn from prior research. Activating RNA candidates were assessed for activity against two exogenously derived target promoters, with successful candidates being subjected to further rounds of validation as a precaution against potential off-target effects. A genetic platform was assembled that allowed activating RNA candidates to be simultaneously screened both for positive activity on the target reporter gene and for possible nonspecific effects on cell metabolism. Several candidate sequences were tested to appraise the utility of this platform, with the most successful achieving a moderate activation level with minimal off-target effects.

  20. Modifications to risk-targeted seismic design maps for subduction and near-fault hazards

    Science.gov (United States)

    Liel, Abbie B.; Luco, Nicolas; Raghunandan, Meera; Champion, C.; Haukaas, Terje

    2015-01-01

    ASCE 7-10 introduced new seismic design maps that define risk-targeted ground motions such that buildings designed according to these maps will have 1% chance of collapse in 50 years. These maps were developed by iterative risk calculation, wherein a generic building collapse fragility curve is convolved with the U.S. Geological Survey hazard curve until target risk criteria are met. Recent research shows that this current approach may be unconservative at locations where the tectonic environment is much different than that used to develop the generic fragility curve. This study illustrates how risk-targeted ground motions at selected sites would change if generic building fragility curve and hazard assessment were modified to account for seismic risk from subduction earthquakes and near-fault pulses. The paper also explores the difficulties in implementing these changes.

  1. MetCap: a bioinformatics probe design pipeline for large-scale targeted metagenomics.

    Science.gov (United States)

    Kushwaha, Sandeep K; Manoharan, Lokeshwaran; Meerupati, Tejashwari; Hedlund, Katarina; Ahrén, Dag

    2015-02-28

    Massive sequencing of genes from different environments has evolved metagenomics as central to enhancing the understanding of the wide diversity of micro-organisms and their roles in driving ecological processes. Reduced cost and high throughput sequencing has made large-scale projects achievable to a wider group of researchers, though complete metagenome sequencing is still a daunting task in terms of sequencing as well as the downstream bioinformatics analyses. Alternative approaches such as targeted amplicon sequencing requires custom PCR primer generation, and is not scalable to thousands of genes or gene families. In this study, we are presenting a web-based tool called MetCap that circumvents the limitations of amplicon sequencing of multiple genes by designing probes that are suitable for large-scale targeted metagenomics sequencing studies. MetCap provides a novel approach to target thousands of genes and genomic regions that could be used in targeted metagenomics studies. Automatic analysis of user-defined sequences is performed, and probes specifically designed for metagenome studies are generated. To illustrate the advantage of a targeted metagenome approach, we have generated more than 400,000 probes that match more than 300,000 [corrected] publicly available sequences related to carbon degradation, and used these probes for target sequencing in a soil metagenome study. The results show high enrichment of target genes and a successful capturing of the majority of gene families. MetCap is freely available to users from: http://soilecology.biol.lu.se/metcap/ . MetCap is facilitating probe-based target enrichment as an easy and efficient alternative tool compared to complex primer-based enrichment for large-scale investigations of metagenomes. Our results have shown efficient large-scale target enrichment through MetCap-designed probes for a soil metagenome. The web service is suitable for any targeted metagenomics project that aims to study several genes

  2. Evaluation design for a complex intervention program targeting loneliness in non-institutionalized elderly Dutch people

    NARCIS (Netherlands)

    Vlaming, de R.; Haveman-Nies, A.; Veer, van 't P.; Groot, de C.P.G.M.

    2010-01-01

    Background - The aim of this paper is to provide the rationale for an evaluation design for a complex intervention program targeting loneliness among non-institutionalized elderly people in a Dutch community. Complex public health interventions characteristically use the combined approach of

  3. From laptop to benchtop to bedside: structure-based drug design on protein targets.

    Science.gov (United States)

    Chen, Lu; Morrow, John K; Tran, Hoang T; Phatak, Sharangdhar S; Du-Cuny, Lei; Zhang, Shuxing

    2012-01-01

    As an important aspect of computer-aided drug design, structure-based drug design brought a new horizon to pharmaceutical development. This in silico method permeates all aspects of drug discovery today, including lead identification, lead optimization, ADMET prediction and drug repurposing. Structure-based drug design has resulted in fruitful successes drug discovery targeting proteinligand and protein-protein interactions. Meanwhile, challenges, noted by low accuracy and combinatoric issues, may also cause failures. In this review, state-of-the-art techniques for protein modeling (e.g. structure prediction, modeling protein flexibility, etc.), hit identification/ optimization (e.g. molecular docking, focused library design, fragment-based design, molecular dynamic, etc.), and polypharmacology design will be discussed. We will explore how structure-based techniques can facilitate the drug discovery process and interplay with other experimental approaches.

  4. From laptop to benchtop to bedside: Structure-based Drug Design on Protein Targets

    Science.gov (United States)

    Chen, Lu; Morrow, John K.; Tran, Hoang T.; Phatak, Sharangdhar S.; Du-Cuny, Lei; Zhang, Shuxing

    2013-01-01

    As an important aspect of computer-aided drug design, structure-based drug design brought a new horizon to pharmaceutical development. This in silico method permeates all aspects of drug discovery today, including lead identification, lead optimization, ADMET prediction and drug repurposing. Structure-based drug design has resulted in fruitful successes drug discovery targeting protein-ligand and protein-protein interactions. Meanwhile, challenges, noted by low accuracy and combinatoric issues, may also cause failures. In this review, state-of-the-art techniques for protein modeling (e.g. structure prediction, modeling protein flexibility, etc.), hit identification/optimization (e.g. molecular docking, focused library design, fragment-based design, molecular dynamic, etc.), and polypharmacology design will be discussed. We will explore how structure-based techniques can facilitate the drug discovery process and interplay with other experimental approaches. PMID:22316152

  5. Targeting the SUMO E2 conjugating enzyme Ubc9 interaction for anti-cancer drug design.

    Science.gov (United States)

    Duan, Xinyuan; Trent, John O; Ye, Hong

    2009-01-01

    Sumoylation has been implicated in a variety of cancers, suggesting that sumoylation manipulation could be one approach for regulating tumorgenesis. Ubc9 exerts a central function for the sumoylation pathway, interacting with almost all the partners required for sumoylation. The high-resolution structure available for Ubc9 as well as the recent determination of more interacting partner complex structures makes rational drug design that target Ubc9 possible. Structure-based virtual drug screening has been used increasingly as the first step of drug design to select potential lead templates. This review analyzes all the interfaces between Ubc9 and its binding partners while also highlighting the possible targeting sites on Ubc9 best suited for virtual screening and drug design.

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

    Science.gov (United States)

    Macfarlane, Joseph; Golovkin, Igor; Sebald, James

    2017-10-01

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

  7. Adaptable setups for magnetic drug targeting in human muscular arteries: Design and implementation

    Science.gov (United States)

    Hajiaghajani, Amirhossein; Hashemi, Soheil; Abdolali, Ali

    2017-09-01

    Magnetic drug targeting has been used to steer magnetic therapeutic agents and has received much attention for capillaries and human brain arteries. In this paper, we focus on noninvasive targeting of nanoparticles in muscular arteries, in where the vessel diameter and blood flow are much challengingly higher than brain capillaries. We aim to design a low intensity magnetic field which avoids potential side effects on blood cells while steers particles with high targeting rate. The setup design procedure is considerably flexible to be used in a wide variety of large vessels. Using particle tracing, a new method is proposed to connect the geometry of the vessel under the action of targeting to the required magnetic force. Specifications of the coil which is placed outside the body are derived based on this required force. Mutual effects of coil dimensions on the produced magnetic force are elaborated and summarized in a design flowchart to be used for arbitrary muscular vessel sizes. The performance of the optimized coil is validated by in vitro experiments and it is shown that particles are steered with the average efficiency of 80.2% for various conditions.

  8. In Silico Design of Novel Anticoagulant Peptides targeting Blood Coagulation Factor VIIa.

    Science.gov (United States)

    Al-Amri, Manal S Q; Alrasadi, Khalid; Bayoumi, Riad; Banerjee, Yajnavalka

    2011-02-01

    The coagulation cascade initiated during vascular injury prevents bleeding. Unwanted clot formation is however detrimental and requires the use of anticoagulants for prophylaxis and treatment. Anticoagulants targeting a specific step or an enzyme in the clotting process are most preferred as they minimise disadvantageous side-effects. A principal step in the discovery of novel anticoagulants encompasses the in silico design of potential leads. This study depicts the in silico design of peptide anticoagulants targeting coagulation factor VIIa. APPLYING THE PROLINE BRACKET RULE AND USING VARIOUS BIOINFORMATICS TOOLS: the basic alignment search tool (BLAST) of National Center for Biotechnology Information; the T-coffee module provided by European Molecular Biology Laboratory-European Bioinformatics Institute, and several modules available on the ExPASy server, we designed five bivalent chimeric anticoagulants targeting factor VIIa, using factor VIIa inhibitors - hemextin A from Hemachatus haemachatus (African Ringhals cobra) venom and factor VIIa exosite-inhibitor peptide as templates. Six peptides were derived from hemextin A, which were concomitantly fused with factor VIIa exosite-inhibitor peptide intermediated by a polyalanine spacer, and analysed for structural stability using the SWISS-MODEL software developed at the Swiss Institute of Bioinformatics and WebLab ViewerPro (Version 4.2). Twelve chimeric peptides were obtained; only five exhibited stable structures in silico. The five peptides obtained are probable anticoagulant leads that should be further evaluated using suitable in vitro and in vivo assays. Further, this study shows how simple web-based modules can be used for the rational design of probable leads targeting specific physiological molecular targets.

  9. Design of the Fifth-Generation Target-Moderator-Reflector-Shield Assembly

    Energy Technology Data Exchange (ETDEWEB)

    Nowicki, Suzanne Florence [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Mocko, Michal [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2015-11-16

    The facilities at the Los Alamos Neutron Science Center are described first. The target is being redesigned so that the Flight Paths (FP) in the upper tier provide a higher intensity in the epithermal and medium energy range. It is found that a 3-piece design looks promising: intensity in epithermal and medium energy range in upper tier is an order of magnitude higher than current Mark III, and intensity in the thermal energy range is higher in the lower tier than current Mark III. Time emission spectra show a bump due to the scattering of fast neutrons. Other investigations such as the addition of wings around the upper target will be conducted.

  10. Numerical investigation of performance of some designs of heavy ion thermonuclear fusion target

    Energy Technology Data Exchange (ETDEWEB)

    Vatulin, V.V. [Russian Federal Nucl. Centre, Arzamas (Russian Federation). Inst. of Exp. Phys.; Voronin, B.L. [Russian Federal Nucl. Centre, Arzamas (Russian Federation). Inst. of Exp. Phys.; Zagrafov, V.G. [Russian Federal Nucl. Centre, Arzamas (Russian Federation). Inst. of Exp. Phys.; Remizov, G.N. [Russian Federal Nucl. Centre, Arzamas (Russian Federation). Inst. of Exp. Phys.; Skidan, G.I. [Russian Federal Nucl. Centre, Arzamas (Russian Federation). Inst. of Exp. Phys.; Skrypnik, S.I. [Russian Federal Nucl. Centre, Arzamas (Russian Federation). Inst. of Exp. Phys.

    1996-11-01

    At present one of the main problems to be solved in heavy ion inertial fusion is the development of an operative design for a target compatible with the beam geometries by a driver. This report presents the research results obtained so far on the target parameters with a cylindrical chamber and converters mounted on the lateral surface of the chamber walls. The cited results were obtained by numerical simulation of X-ray generation in heavy ion flux irradiation, X-ray radiation propagation in the hohlraum volume and gas dynamic processes with 2D and 3D mathematical codes developed at VNIIEF. (orig.)

  11. Validation of a New Design of Tellurium Dioxide-Irradiated Target

    Directory of Open Access Journals (Sweden)

    Aziz Fllaoui

    2016-10-01

    Full Text Available Production of iodine-131 by neutron activation of tellurium in tellurium dioxide (TeO2 material requires a target that meets the safety requirements. In a radiopharmaceutical production unit, a new lid for a can was designed, which permits tight sealing of the target by using tungsten inert gas welding. The leakage rate of all prepared targets was assessed using a helium mass spectrometer. The accepted leakage rate is ≤ 10−4 mbr.L/s, according to the approved safety report related to iodine-131 production in the TRIGA Mark II research reactor (TRIGA: Training, Research, Isotopes, General Atomics. To confirm the resistance of the new design to the irradiation conditions in the TRIGA Mark II research reactor's central thimble, a study of heat effect on the sealed targets for 7 hours in an oven was conducted and the leakage rates were evaluated. The results show that the tightness of the targets is ensured up to 600°C with the appearance of deformations on lids beyond 450°C. The study of heat transfer through the target was conducted by adopting a one-dimensional approximation, under consideration of the three transfer modes—convection, conduction, and radiation. The quantities of heat generated by gamma and neutron heating were calculated by a validated computational model for the neutronic simulation of the TRIGA Mark II research reactor using the Monte Carlo N-Particle transport code. Using the heat transfer equations according to the three modes of heat transfer, the thermal study of I-131 production by irradiation of the target in the central thimble showed that the temperatures of materials do not exceed the corresponding melting points. To validate this new design, several targets have been irradiated in the central thimble according to a preplanned irradiation program, going from 4 hours of irradiation at a power level of 0.5 MW up to 35 hours (7 h/d for 5 days a week at 1.5 MW. The results show that the irradiated targets are

  12. Design of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10.

    Science.gov (United States)

    Yang, Wang-Yong; Gao, Rui; Southern, Mark; Sarkar, Partha S; Disney, Matthew D

    2016-06-01

    RNA is an important target for chemical probes of function and lead therapeutics; however, it is difficult to target with small molecules. One approach to tackle this problem is to identify compounds that target RNA structures and utilize them to multivalently target RNA. Here we show that small molecules can be identified to selectively bind RNA base pairs by probing a library of RNA-focused small molecules. A small molecule that selectively binds AU base pairs informed design of a dimeric compound (2AU-2) that targets the pathogenic RNA, expanded r(AUUCU) repeats, that causes spinocerebellar ataxia type 10 (SCA10) in patient-derived cells. Indeed, 2AU-2 (50 nM) ameliorates various aspects of SCA10 pathology including improvement of mitochondrial dysfunction, reduced activation of caspase 3, and reduction of nuclear foci. These studies provide a first-in-class chemical probe to study SCA10 RNA toxicity and potentially define broadly applicable compounds targeting RNA AU base pairs in cells.

  13. Package design and nutritional profile of foods targeted at children in supermarkets in Montevideo, Uruguay

    Directory of Open Access Journals (Sweden)

    Ana Giménez

    Full Text Available Abstract: Marketing of unhealthy products has been identified as one of the main characteristics of the food environment that negatively affects children’s eating patterns. Restrictions on advertising of unhealthy foods to children have already been imposed in different countries. However, marketing strategies are not limited to broadcast and digital advertising, but also include package design. In this context, the current study aimed to describe the food products targeted at children and sold in supermarkets in Montevideo, Uruguay, in terms of package design and nutrient profile. Two supermarkets in Montevideo were selected for data collection. In each supermarket, all products targeted at children were identified. Products were analyzed in terms of package design and nutritional profile, considering the Pan American Health Organization Nutrient Profile Model. A total of 180 unique products were identified, which included a wide range of product categories. The great majority of the products corresponded to ultra-processed products with excessive amounts of sodium, free sugars, total fat, saturated fat, and/or trans fat, which are not recommended for frequent consumption. Several marketing strategies were identified in the design of packages to attract children’s attention and drive their preferences. The most common strategies were the inclusion of cartoon characters, bright colors, childish lettering, and a wide range of claims related to health and nutrition, as well as the products’ sensory and hedonic characteristics. The study’s findings provide additional evidence on the need to regulate packaging of products targeted at children.

  14. Design of an ignition target for the laser megajoule, mitigating parametric instabilities

    Science.gov (United States)

    Laffite, S.; Loiseau, P.

    2010-10-01

    Laser plasma interaction (LPI) is a critical issue in ignition target design. Based on both scaling laws and two-dimensional calculations, this article describes how we can constrain a laser megajoule (LMJ) [J. Ebrardt and J. M. Chaput, J. Phys.: Conf. Ser. 112, 032005 (2008)] target design by mitigating LPI. An ignition indirect drive target has been designed for the 2/3 LMJ step. It requires 0.9 MJ and 260 TW of laser energy and power, to achieve a temperature of 300 eV in a rugby-shaped Hohlraum and give a yield of about 20 MJ. The study focuses on the analysis of linear gain for stimulated Raman and Brillouin scatterings. Enlarging the focal spot is an obvious way to reduce linear gains. We show that this reduction is nonlinear with the focal spot size. For relatively small focal spot area, linear gains are significantly reduced by enlarging the focal spot. However, there is no benefit in too large focal spots because of necessary larger laser entrance holes, which require more laser energy. Furthermore, this leads to the existence, for a given design, of a minimum value for linear gains for which we cannot go below.

  15. Designing Multi-Targeted Therapeutics for the Treatment of Alzheimer's Disease.

    Science.gov (United States)

    Orhan, Ilkay Erdogan; Senol, F Sezer

    2016-01-01

    Due to multi-faceted pathology of AD; no drug can seize the progress of the disease, whereas only the symptomatic treatment is available at the moment. Several drug classes to treat AD are available in clinical use, AChEIs being the most prescribed. In addition to AChEIs, secretase enzymes and iron chelators have turned out to be the focus of research and the popular targets in drug discovery against AD. The latest approaches such as immunotherapy, multi-targeted drug ligand design, AChE inhibitors, antioxidants, metal chelators, monoamine oxidase (MAO) inhibitors, antiinflammatory drugs, and N-methyl-D-aspartate (NMDA) inhibitors are currently in use to cure this disease to some extent. But, there is a certain need to develop new drugs to fight with AD, particularly acting on multi-targets or with dual mechanisms of action. In this review, a particular emphasis will be focused on multitargets aiming at AD to design new drug molecules with respect to treatment strategies and preventive measures. Since the underlying pathogenesis of AD is complicated and still under investigation, the attempts to design highly selective and potent agents to treat AD are quite intensively continuing. In this respect, designing novel drugs with dual/multi-acting mechanisms seems to be more rational.

  16. Package design and nutritional profile of foods targeted at children in supermarkets in Montevideo, Uruguay.

    Science.gov (United States)

    Giménez, Ana; Saldamando, Luis de; Curutchet, María Rosa; Ares, Gastón

    2017-06-12

    Marketing of unhealthy products has been identified as one of the main characteristics of the food environment that negatively affects children's eating patterns. Restrictions on advertising of unhealthy foods to children have already been imposed in different countries. However, marketing strategies are not limited to broadcast and digital advertising, but also include package design. In this context, the current study aimed to describe the food products targeted at children and sold in supermarkets in Montevideo, Uruguay, in terms of package design and nutrient profile. Two supermarkets in Montevideo were selected for data collection. In each supermarket, all products targeted at children were identified. Products were analyzed in terms of package design and nutritional profile, considering the Pan American Health Organization Nutrient Profile Model. A total of 180 unique products were identified, which included a wide range of product categories. The great majority of the products corresponded to ultra-processed products with excessive amounts of sodium, free sugars, total fat, saturated fat, and/or trans fat, which are not recommended for frequent consumption. Several marketing strategies were identified in the design of packages to attract children's attention and drive their preferences. The most common strategies were the inclusion of cartoon characters, bright colors, childish lettering, and a wide range of claims related to health and nutrition, as well as the products' sensory and hedonic characteristics. The study's findings provide additional evidence on the need to regulate packaging of products targeted at children.

  17. Critical Density Target Design for Ion Acceleration on the T-Cubed Laser

    Science.gov (United States)

    Kordell, Peter; Campbell, Paul; Maksimchuk, Anatoly; Willingale, Louise; Krushelnick, Karl

    2016-10-01

    The interaction of an intense laser pulse with a critical density target can form a high Mach number electrostatic shock. Recent experiments on CO2 lasers have demonstrated that such shocks can be used to produce directional, quasi-monoenergetic proton beams. PIC simulations indicate that the our single pulse system, the T-Cubed laser (1.053 μm, 6J in 400fs), is both capable of both producing these shocks and accelerating protons to MeV energies. Shock formation and propagation with our system has challenging target peak density and density gradient requirements. We present our target design, an interferometric characterization of its density profile and preliminary experiments on T-Cubed.

  18. Single freeform surface design for prescribed input wavefront and target irradiance.

    Science.gov (United States)

    Bösel, Christoph; Gross, Herbert

    2017-09-01

    In beam shaping applications, the minimization of the number of necessary optical elements for the beam shaping process can benefit the compactness of the optical system and reduce its cost. The single freeform surface design for input wavefronts, which are neither planar nor spherical, is therefore of interest. In this work, the design of single freeform surfaces for a given zero-étendue source and complex target irradiances is investigated. Hence, not only collimated input beams or point sources are assumed. Instead, a predefined input ray direction vector field and irradiance distribution on a source plane, which has to be redistributed by a single freeform surface to give the predefined target irradiance, is considered. To solve this design problem, a partial differential equation (PDE) or PDE system, respectively, for the unknown surface and its corresponding ray mapping is derived from energy conservation and the ray-tracing equations. In contrast to former PDE formulations of the single freeform design problem, the derived PDE of Monge-Ampère type is formulated for general zero-étendue sources in Cartesian coordinates. The PDE system is discretized with finite differences, and the resulting nonlinear equation system is solved by a root-finding algorithm. The basis of the efficient solution of the PDE system builds the introduction of an initial iterate construction approach for a given input direction vector field, which uses optimal mass transport with a quadratic cost function. After a detailed description of the numerical algorithm, the efficiency of the design method is demonstrated by applying it to several design examples. This includes the redistribution of a collimated input beam beyond the paraxial approximation, the shaping of point source radiation, and the shaping of an astigmatic input wavefront into a complex target irradiance distribution.

  19. Thermal-hydraulic design concept of the solid-target system of spallation neutron source

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, F.; Hibiki, T.; Saito, Y.; Takeda, T.; Mishima, K. [Kyoto Univ., Research Reactor Institute (Japan)

    2001-07-01

    In relation to thermal-hydraulic design of the N-Arena solid-target system of the JHF project, heat transfer experiments were performed to obtain experimental data systematically on heat transfer coefficient and CHF for vertical upward and horizontal flows in a thin rectangular channel simulating a coolant channel of the proposed spallation neutron source. Thermal-hydraulic correlations which can be used for design calculations were proposed based on the obtained data. Finally tentative results of feasibility study on maximum beam power which could be attained with a solid target were presented. The result indicated that the condition for the onset of nucleate boiling is the most significant limiting factor to the maximum beam power. (author)

  20. Data driven polypharmacological drug design for lung cancer: analyses for targeting ALK, MET, and EGFR

    DEFF Research Database (Denmark)

    Narayanan, Dilip; Gani, Osman ABSM; Gruber, Franz XE

    2017-01-01

    Drug design of protein kinase inhibitors is now greatly enabled by thousands of publicly available X-ray structures, extensive ligand binding data, and optimized scaffolds coming off patent. The extensive data begin to enable design against a spectrum of targets (polypharmacology); however......, the data also reveal heterogeneities of structure, subtleties of chemical interactions, and apparent inconsistencies between diverse data types. As a result, incorporation of all relevant data requires expert choices to combine computational and informatics methods, along with human insight. Here we...

  1. Design and Implementation of the Automated Rendezvous Targeting Algorithms for Orion

    Science.gov (United States)

    DSouza, Christopher; Weeks, Michael

    2010-01-01

    The Orion vehicle will be designed to perform several rendezvous missions: rendezvous with the ISS in Low Earth Orbit (LEO), rendezvous with the EDS/Altair in LEO, a contingency rendezvous with the ascent stage of the Altair in Low Lunar Orbit (LLO) and a contingency rendezvous in LLO with the ascent and descent stage in the case of an aborted lunar landing. Therefore, it is not difficult to realize that each of these scenarios imposes different operational, timing, and performance constraints on the GNC system. To this end, a suite of on-board guidance and targeting algorithms have been designed to meet the requirement to perform the rendezvous independent of communications with the ground. This capability is particularly relevant for the lunar missions, some of which may occur on the far side of the moon. This paper will describe these algorithms which are designed to be structured and arranged in such a way so as to be flexible and able to safely perform a wide variety of rendezvous trajectories. The goal of the algorithms is not to merely fly one specific type of canned rendezvous profile. Conversely, it was designed from the start to be general enough such that any type of trajectory profile can be flown.(i.e. a coelliptic profile, a stable orbit rendezvous profile, and a expedited LLO rendezvous profile, etc) all using the same rendezvous suite of algorithms. Each of these profiles makes use of maneuver types which have been designed with dual goals of robustness and performance. They are designed to converge quickly under dispersed conditions and they are designed to perform many of the functions performed on the ground today. The targeting algorithms consist of a phasing maneuver (NC), an altitude adjust maneuver (NH), and plane change maneuver (NPC), a coelliptic maneuver (NSR), a Lambert targeted maneuver, and several multiple-burn targeted maneuvers which combine one of more of these algorithms. The derivation and implementation of each of these

  2. Design of PSIRA with focusing lens concentrating picosecond impulse on biological target.

    Science.gov (United States)

    Petrishia, A; Sasikala, M

    2016-03-04

    The Prolate Spheroidal Impulse Radiating Antenna (PSIRA) is used to radiate very fast pulses in a narrow beam with low dispersion and high field amplitude. The PSIRA is suitable to apply fast, intense pulses without direct contact, for skin cancer treatment. In this proposed work, SWB (Slanted Wire Biconical), EPH (Elliptical Profile Horn), TSVS (Tapered Slot Vivaldi Shape) and Tapered Arm Conical Plate (TACP) feed antenna configurations for Prolate Spheroidal Reflector (PSR) are explored to enhance spatial resolution on biological targets. The feed antenna is placed at the first focal point and the target is located at the second focal point of the PSR. Next, the near field focusing lens is designed to enhance the amplitude and the resolution of the wave incident at the second focus. A 10 layer Log periodic lens system is placed before the target to reduce the spot size of the focused field on the target. The delivery of subnanosecond pulses using reflector in conjunction with and without Log periodic lens system on the biological target is compared for all feed antenna configurations. Tapered Arm Conical Plate (TACP) fed PSR with the 10 layer Log periodic lens system greatly reduces the spot size to 0.75 cm along lateral direction and 1.5 cm along axial direction. The enhancement in spatial resolution is very suitable to reduce the damage to healthy tissues during cancer treatment.

  3. Rationally designed small molecules targeting the RNA that causes myotonic dystrophy type 1 are potently bioactive.

    Science.gov (United States)

    Childs-Disney, Jessica L; Hoskins, Jason; Rzuczek, Suzanne G; Thornton, Charles A; Disney, Matthew D

    2012-05-18

    RNA is an important drug target, but it is difficult to design or discover small molecules that modulate RNA function. In the present study, we report that rationally designed, modularly assembled small molecules that bind the RNA that causes myotonic dystrophy type 1 (DM1) are potently bioactive in cell culture models. DM1 is caused when an expansion of r(CUG) repeats, or r(CUG)(exp), is present in the 3' untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) mRNA. r(CUG)(exp) folds into a hairpin with regularly repeating 5'CUG/3'GUC motifs and sequesters muscleblind-like 1 protein (MBNL1). A variety of defects are associated with DM1, including (i) formation of nuclear foci, (ii) decreased translation of DMPK mRNA due to its nuclear retention, and (iii) pre-mRNA splicing defects due to inactivation of MBNL1, which controls the alternative splicing of various pre-mRNAs. Previously, modularly assembled ligands targeting r(CUG)(exp) were designed using information in an RNA motif-ligand database. These studies showed that a bis-benzimidazole (H) binds the 5'CUG/3'GUC motif in r(CUG)(exp.) Therefore, we designed multivalent ligands to bind simultaneously multiple copies of this motif in r(CUG)(exp). Herein, we report that the designed compounds improve DM1-associated defects including improvement of translational and pre-mRNA splicing defects and the disruption of nuclear foci. These studies may establish a foundation to exploit other RNA targets in genomic sequence.

  4. Mandatory Targets and Environmental Performance: An Analysis Based on Regression Discontinuity Design

    Directory of Open Access Journals (Sweden)

    Xiao Tang

    2016-09-01

    Full Text Available It is a critical question for environmental governance to examine whether the administrative award and punishment measures are effective in promoting environmental governance performance. Choosing the implementation of a mandatory target system (MTS as the subject, this paper employs a fixed-effect panel data model and regression discontinuity design to test whether the MTS has improved the environmental governance performance of local governments in China. The results of this research demonstrate that the MTS has a positive effect on environmental performance, however the regression discontinuity design illustrates that the reward and punishment measures in the MTS have no significant effects on the provincial environmental performance. The results of this research provide a reasonable explanation to the existing gaps among the studies on the effectiveness of the MTS. This study has profound policy implications for the design and implementation of the environmental governance system in China.

  5. Metabolic engineering of an industrial polyoxin producer for the targeted overproduction of designer nucleoside antibiotics.

    Science.gov (United States)

    Qi, Jianzhao; Liu, Jin; Wan, Dan; Cai, You-Sheng; Wang, Yinghu; Li, Shunying; Wu, Pan; Feng, Xuan; Qiu, Guofu; Yang, Sheng-Ping; Chen, Wenqing; Deng, Zixin

    2015-09-01

    Polyoxin and nikkomycin are naturally occurring peptidyl nucleoside antibiotics with potent antifungal bioactivity. Both exhibit similar structural features, having a nucleoside skeleton and one or two peptidyl moieties. Combining the refactoring of the polyoxin producer Streptomyces aureochromogenes with import of the hydroxypyridylhomothreonine pathway of nikkomycin allows the targeted production of three designer nucleoside antibiotics designated as nikkoxin E, F, and G. These structures were determined by NMR and/or high resolution mass spectrometry. Remarkably, the introduction of an extra copy of the nikS gene encoding an ATP-dependent ligase significantly enhanced the production of the designer antibiotics. Moreover, all three nikkoxins displayed improved bioactivity against several pathogenic fungi as compared with the naturally-occurring antibiotics. These data provide a feasible model for high efficiency generation of nucleoside antibiotics related to polyoxins and nikkomycins in a polyoxin cell factory via synthetic biology strategy. © 2015 Wiley Periodicals, Inc.

  6. Design Optimisation of a High Intensity Beam Facility and Feasibility Experiment of a Solid Fragmented Target

    CERN Document Server

    Charitonidis, Nikolaos; Rivkin, Leonid

    2014-06-13

    The present PhD thesis describes the design, execution and results of the HRMT-10 experiment performed at the HiRadMat facility of the CERN/SPS complex. The first part of the thesis covers the design optimization studies of the HiRadMat facility, focusing in particular on the radiation protection issues. A detailed Monte-Carlo model of the facility has been developed and validated through comparison with measurements. A very satisfactory agreement between the simulation and the experimental data is observed. In the second part of this thesis, a novel feasibility experiment of a fragmented solid target for a future Neutrino Factory or a Super Beam facility, able to support high beam powers ( 1 MW) is presented in detail. A solid granular target has been proposed as an interesting alternative to an open Hg jet target, presently considered as the baseline for such facilities, but posing considerable technical challenges. The HRMT-10 experiment seeks to address the lack of experimental data of the feasibility of...

  7. Design specification for the European Spallation Source neutron generating target element

    Energy Technology Data Exchange (ETDEWEB)

    Aguilar, A. [Consorcio ESS-BILBAO. Parque Tecnológico Bizkaia. Poligono Ugaldeguren III, Pol. A, 7B, 48170 Zamudio (Spain); Sordo, F., E-mail: fernando.sordo@essbilbao.org [Consorcio ESS-BILBAO. Parque Tecnológico Bizkaia. Poligono Ugaldeguren III, Pol. A, 7B, 48170 Zamudio (Spain); Instituto de Fusión Nuclear, José Gutiérrez Abascal, 2, 28006 Madrid (Spain); Mora, T. [Consorcio ESS-BILBAO. Parque Tecnológico Bizkaia. Poligono Ugaldeguren III, Pol. A, 7B, 48170 Zamudio (Spain); Mena, L. [Consorcio ESS-BILBAO. Parque Tecnológico Bizkaia. Poligono Ugaldeguren III, Pol. A, 7B, 48170 Zamudio (Spain); Instituto de Fusión Nuclear, José Gutiérrez Abascal, 2, 28006 Madrid (Spain); Mancisidor, M.; Aguilar, J.; Bakedano, G.; Herranz, I.; Luna, P. [Consorcio ESS-BILBAO. Parque Tecnológico Bizkaia. Poligono Ugaldeguren III, Pol. A, 7B, 48170 Zamudio (Spain); Magan, M.; Vivanco, R. [Consorcio ESS-BILBAO. Parque Tecnológico Bizkaia. Poligono Ugaldeguren III, Pol. A, 7B, 48170 Zamudio (Spain); Instituto de Fusión Nuclear, José Gutiérrez Abascal, 2, 28006 Madrid (Spain); Jimenez-Villacorta, F. [Consorcio ESS-BILBAO. Parque Tecnológico Bizkaia. Poligono Ugaldeguren III, Pol. A, 7B, 48170 Zamudio (Spain); Sjogreen, K.; Oden, U. [European Spallation Source ERIC, P.O Box 176, SE-221 00 Lund (Sweden); Perlado, J.M. [Instituto de Fusión Nuclear, José Gutiérrez Abascal, 2, 28006 Madrid (Spain); and others

    2017-06-01

    The paper addresses some of the most relevant issues concerning the thermal hydraulics and radiation damage of the neutron generation target to be built at the European Spallation Source as recently approved after a critical design review. The target unit consists of a set of Tungsten blocks placed inside a wheel of 2.5 m diameter which rotates at some 0.5 Hz in order to distribute the heat generated from incoming protons which reach the target in the radial direction. The spallation material elements are composed of an array of Tungsten pieces which rest on a rotating steel support (the cassette) and are distributed in a cross-flow configuration. The thermal, mechanical and radiation effects resulting from the impact of a 2 GeV proton pulse are analysed in detail as well as an evaluation of the inventory of spallation products. The current design is found to conform to specifications and found to be robust enough to deal with several accident scenarios.

  8. A Rapid Python-Based Methodology for Target-Focused Combinatorial Library Design.

    Science.gov (United States)

    Li, Shiliang; Song, Yuwei; Liu, Xiaofeng; Li, Honglin

    2016-01-01

    The chemical space is so vast that only a small portion of it has been examined. As a complementary approach to systematically probe the chemical space, virtual combinatorial library design has extended enormous impacts on generating novel and diverse structures for drug discovery. Despite the favorable contributions, high attrition rates in drug development that mainly resulted from lack of efficacy and side effects make it increasingly challenging to discover good chemical starting points. In most cases, focused libraries, which are restricted to particular regions of the chemical space, are deftly exploited to maximize hit rate and improve efficiency at the beginning of the drug discovery and drug development pipeline. This paper presented a valid methodology for fast target-focused combinatorial library design in both reaction-based and production-based ways with the library creating rates of approximately 70,000 molecules per second. Simple, quick and convenient operating procedures are the specific features of the method. SHAFTS, a hybrid 3D similarity calculation software, was embedded to help refine the size of the libraries and improve hit rates. Two target-focused (p38-focused and COX2-focused) libraries were constructed efficiently in this study. This rapid library enumeration method is portable and applicable to any other targets for good chemical starting points identification collaborated with either structure-based or ligand-based virtual screening.

  9. Development of TMTP-1 targeted designer biopolymers for gene delivery to prostate cancer.

    Science.gov (United States)

    McBride, John W; Massey, Ashley S; McCaffrey, J; McCrudden, Cian M; Coulter, Jonathan A; Dunne, Nicholas J; Robson, Tracy; McCarthy, Helen O

    2016-03-16

    Designer biopolymers (DBPs) represent state of the art genetically engineered biomacromolecules designed to condense plasmid DNA, and overcome intra- and extra- cellular barriers to gene delivery. Three DBPs were synthesized, each with the tumor molecular targeting peptide-1 (TMTP-1) motif to specifically target metastases. Each DBP was complexed with a pEGFP-N1 reporter plasmid to permit physiochemical and biological assay analysis. Results indicated that two of the biopolymers (RMHT and RM3GT) effectively condensed pEGFP-N1 into cationic nanoparticles <100 nm and were capable of transfecting PC-3 metastatic prostate cancer cells. Conversely the anionic RMGT DBP nanoparticles could not transfect PC-3 cells. RMHT and RM3GT nanoparticles were stable in the presence of serum and protected the cargo from degradation. Additionally it was concluded that cell viability could recover post-transfection with these DBPs, which were less toxic than the commercially available transfection reagent Lipofectamine(®) 2000. With both DBPs, a higher transfection efficacy was observed in PC-3 cells than in the moderately metastatic, DU145, and normal, PNT2-C2, cell lines. Blocking of the TMTP-1 receptors inhibited gene transfer indicating internalization via this receptor. In conclusion RMHT and RM3GT are fully functional DBPs that address major obstacles to gene delivery and target metastatic cells expressing the TMTP-1 receptor. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Injector design for liner-on-target gas-puff experiments

    Science.gov (United States)

    Valenzuela, J. C.; Krasheninnikov, I.; Conti, F.; Wessel, F.; Fadeev, V.; Narkis, J.; Ross, M. P.; Rahman, H. U.; Ruskov, E.; Beg, F. N.

    2017-11-01

    We present the design of a gas-puff injector for liner-on-target experiments. The injector is composed of an annular high atomic number (e.g., Ar and Kr) gas and an on-axis plasma gun that delivers an ionized deuterium target. The annular supersonic nozzle injector has been studied using Computational Fluid Dynamics (CFD) simulations to produce a highly collimated (M > 5), ˜1 cm radius gas profile that satisfies the theoretical requirement for best performance on ˜1-MA current generators. The CFD simulations allowed us to study output density profiles as a function of the nozzle shape, gas pressure, and gas composition. We have performed line-integrated density measurements using a continuous wave (CW) He-Ne laser to characterize the liner gas density. The measurements agree well with the CFD values. We have used a simple snowplow model to study the plasma sheath acceleration in a coaxial plasma gun to help us properly design the target injector.

  11. Customizable de novo design strategies for DOCK: Application to HIVgp41 and other therapeutic targets.

    Science.gov (United States)

    Allen, William J; Fochtman, Brian C; Balius, Trent E; Rizzo, Robert C

    2017-11-15

    De novo design can be used to explore vast areas of chemical space in computational lead discovery. As a complement to virtual screening, from-scratch construction of molecules is not limited to compounds in pre-existing vendor catalogs. Here, we present an iterative fragment growth method, integrated into the program DOCK, in which new molecules are built using rules for allowable connections based on known molecules. The method leverages DOCK's advanced scoring and pruning approaches and users can define very specific criteria in terms of properties or features to customize growth toward a particular region of chemical space. The code was validated using three increasingly difficult classes of calculations: (1) Rebuilding known X-ray ligands taken from 663 complexes using only their component parts (focused libraries), (2) construction of new ligands in 57 drug target sites using a library derived from ∼13M drug-like compounds (generic libraries), and (3) application to a challenging protein-protein interface on the viral drug target HIVgp41. The computational testing confirms that the de novo DOCK routines are robust and working as envisioned, and the compelling results highlight the potential utility for designing new molecules against a wide variety of important protein targets. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  12. GLRS-R 2-colour retroreflector target design and predicted performance

    Science.gov (United States)

    Lund, Glenn

    1993-01-01

    This paper reports on the retroreflector ground-target design for the GLRS-R spaceborne dual-wavelength laser ranging system. The described passive design flows down from the requirements of high station autonomy, high global FOV (up to 60 degrees zenith angle), little or no multiple pulse returns, and adequate optical cross section for most ranging geometries. The proposed solution makes use of 5 hollow cube-corner retroreflectors of which one points to the zenith and the remaining four are inclined from the vertical at uniform azimuthal spacings. The need for fairly large (is approximately 10 cm) retroreflectors is expected (within turbulence limitations) to generate quite narrow diffraction lobes, thus placing non-trivial requirements on the vectorial accuracy of velocity aberration corrections. A good compromise solution is found by appropriately spoiling just one of the retroreflector dihedral angles from 90 degrees, thus generating two symmetrically oriented diffraction lobes in the return beam. The required spoil angles are found to have little dependence on ground target latitude. Various link budget analyses are presented, showing the influence of such factors as point-ahead optimization, turbulence, ranging angle, atmospheric visibility and ground target thermal deformations.

  13. [siRNAs with high specificity to the target: a systematic design by CRM algorithm].

    Science.gov (United States)

    Alsheddi, T; Vasin, L; Meduri, R; Randhawa, M; Glazko, G; Baranova, A

    2008-01-01

    'Off-target' silencing effect hinders the development of siRNA-based therapeutic and research applications. Common solution to this problem is an employment of the BLAST that may miss significant alignments or an exhaustive Smith-Waterman algorithm that is very time-consuming. We have developed a Comprehensive Redundancy Minimizer (CRM) approach for mapping all unique sequences ("targets") 9-to-15 nt in size within large sets of sequences (e.g. transcriptomes). CRM outputs a list of potential siRNA candidates for every transcript of the particular species. These candidates could be further analyzed by traditional "set-of-rules" types of siRNA designing tools. For human, 91% of transcripts are covered by candidate siRNAs with kernel targets of N = 15. We tested our approach on the collection of previously described experimentally assessed siRNAs and found that the correlation between efficacy and presence in CRM-approved set is significant (r = 0.215, p-value = 0.0001). An interactive database that contains a precompiled set of all human siRNA candidates with minimized redundancy is available at http://129.174.194.243. Application of the CRM-based filtering minimizes potential "off-target" silencing effects and could improve routine siRNA applications.

  14. Conceptual design of the beryllium rotating target for the ESS-Bilbao facility

    Energy Technology Data Exchange (ETDEWEB)

    Terrón, S., E-mail: santiago.terron@essbilbao.org [ESS-Bilbao, Parque Tecnológico Bizkaia, Laida Bidea, Edificio 207 B Planta Baja. 48160 Derio (Spain); Instituto de Fusión Nuclear - UPM, ETS Ingenieros Industriales, C José Gutiérrez Abascal, 2, 28006 Madrid (Spain); Sordo, F.; Magán, M.; Ghiglino, A.; Martínez, F.; Vicente, P.J. de; Vivanco, R. [ESS-Bilbao, Parque Tecnológico Bizkaia, Laida Bidea, Edificio 207 B Planta Baja. 48160 Derio (Spain); Instituto de Fusión Nuclear - UPM, ETS Ingenieros Industriales, C José Gutiérrez Abascal, 2, 28006 Madrid (Spain); Thomsen, K. [Paul Scherrer Institut, 5232 Villigen PSI (Switzerland); Perlado, J.M. [Instituto de Fusión Nuclear - UPM, ETS Ingenieros Industriales, C José Gutiérrez Abascal, 2, 28006 Madrid (Spain); Bermejo, F.J. [Instituto de Estructura de la Materia, IEM-CSIC, Consejo Superior de Investigaciones Científicas, Serrano 123, 28006 Madrid (Spain); ESS-Bilbao, Parque Tecnológico Bizkaia, Laida Bidea, Edificio 207 B Planta Baja. 48160 Derio (Spain); Abánades, A. [Instituto de Fusión Nuclear - UPM, ETS Ingenieros Industriales, C José Gutiérrez Abascal, 2, 28006 Madrid (Spain)

    2013-10-01

    The ESS-Bilbao facility, hosted by the University of the Basque Country (UPV/EHU), envisages the operation of a high-current proton accelerator delivering beams with energies up to 50 MeV. The time-averaged proton current will be 2.25 mA, delivered by 1.5 ms proton pulses with a repetition rate of 20 Hz. This beam will feed a neutron source based upon the Be (p,n) reaction, which will enable the provision of relevant neutron experimentation capabilities. The neutron source baseline concept consists in a rotating beryllium target cooled by water. The target structure will comprise a rotatable disk made of 6061-T6 aluminium alloy holding 20 beryllium plates. Heat dissipation from the target relies upon a distribution of coolant-flow channels. The practical implementation of such a concept is here described with emphasis put on the beryllium plates thermo-mechanical optimization, the chosen coolant distribution system as well as the mechanical behavior of the assembly. -- Highlights: • The conceptual design of ESS-Bilbao neutron production target has been carried out. • This device is a rotating disk holding Be elements cooled by water. • Thermo-mechanical and lifespan behavior of the Be elements have been analyzed. • Disk structure ensures coolability and a proper mechanical behavior of the assembly.

  15. Ionic Channels as Targets for Drug Design: A Review on Computational Methods

    Directory of Open Access Journals (Sweden)

    José Manuel González-Ros

    2011-12-01

    Full Text Available Ion channels are involved in a broad range of physiological and pathological processes. The implications of ion channels in a variety of diseases, including diabetes, epilepsy, hypertension, cancer and even chronic pain, have signaled them as pivotal drug targets. Thus far, drugs targeting ion channels were developed without detailed knowledge of the molecular interactions between the lead compounds and the target channels. In recent years, however, the emergence of high-resolution structures for a plethora of ion channels paves the way for computer-assisted drug design. Currently, available functional and structural data provide an attractive platform to generate models that combine substrate-based and protein-based approaches. In silico approaches include homology modeling, quantitative structure-activity relationships, virtual ligand screening, similarity and pharmacophore searching, data mining, and data analysis tools. These strategies have been frequently used in the discovery and optimization of novel molecules with enhanced affinity and specificity for the selected therapeutic targets. In this review we summarize recent applications of in silico methods that are being used for the development of ion channel drugs.

  16. Identification of novel cancer therapeutic targets using a designed and pooled shRNA library screen

    Science.gov (United States)

    Oliver, David; Ji, Hao; Liu, Piaomu; Gasparian, Alexander; Gardiner, Ellen; Lee, Samuel; Zenteno, Adrian; Perinskaya, Lillian O.; Chen, Mengqian; Buckhaults, Phillip; Broude, Eugenia; Wyatt, Michael D.; Valafar, Homayoun; Peña, Edsel; Shtutman, Michael

    2017-01-01

    Targeted cancer therapeutics aim to exploit tumor-specific, genetic vulnerabilities specifically affecting neoplastic cells without similarly affecting normal cells. Here we performed sequencing-based screening of an shRNA library on a panel of cancer cells of different origins as well as normal cells. The shRNA library was designed to target a subset of genes previously identified using a whole genome screening approach. This focused shRNA library was infected into cells followed by analysis of enrichment and depletion of the shRNAs over the course of cell proliferation. We developed a bootstrap likelihood ratio test for the interpretation of the effects of multiple shRNAs over multiple cell line passages. Our analysis identified 44 genes whose depletion preferentially inhibited the growth of cancer cells. Among these genes ribosomal protein RPL35A, putative RNA helicase DDX24, and coatomer complex I (COPI) subunit ARCN1 most significantly inhibited growth of multiple cancer cell lines without affecting normal cell growth and survival. Further investigation revealed that the growth inhibition caused by DDX24 depletion is independent of p53 status underlining its value as a drug target. Overall, our study establishes a new approach for the analysis of proliferation-based shRNA selection strategies and identifies new targets for the development of cancer therapeutics. PMID:28223711

  17. SU-E-T-244: Designing Low-Z Targets To Enhance Surface Dose: A Monte Carlo Simulation

    Energy Technology Data Exchange (ETDEWEB)

    Kelly, R [Nova Scotia Cancer Centre, Halifax, NS (Canada); Robar, J [Capital District Health Authority, Halifax, NS (Canada); Parsons, D [Dalhousie University, Halifax, Nova Scotia (Canada)

    2015-06-15

    Purpose: Recent developments in The Varian Truebeam linac platform allows for the introduction of low-Z targets into the beam line for the imaging purposes. We have proposed using a low-Z target for radiation therapy purposes to enhance the surface dose during radiation treatment. The target arm of the Varian Truebeam accelerator consists of multiple targets with are linearly translated into the beam line. We have designed two Low-Z targets made of carbon: 1) a step target consisting of three steps of 15%, 30% and 60% CSDA range for 2.5 MeV electrons Figure 1a; 2) and a ramp target, an incline plane 2cm long with thicknesses ranging from 0% to 60% CSDA range, Figure 1b. The purpose of this work will determine the spectral characteristics of these target designs and determine if they have practical clinical applications for enhancing surface dose. Methods: To calculate the spectral characteristics of these targets, a standard Monte Carlo model of a Varian Clinac accelerator was used. Simulations were performed with a carbon step target, and a carbon ramp target, located at the same position as the electron foil in the rotating carousel. Simulations were carried out using a 2.5 MeV electron beam. Results: The step target design produced spectral characteristics which were similar to spectral model using a single disk target of the same thickness. The ramp target provides a means to have positional variation of the spectral components of the beam, however, the electron component as 60% CSDA us much broader than the step target. Conclusion: The carbon step-target provides a spectral distribution which is similar to a carbon disk of comparable thickness. The spectral distribution from the ramp-target can be modified as a function of position to provide a wide range of low energy electrons for surface dose enhancement.

  18. Design of a modular protein-based MRI contrast agent for targeted application.

    Directory of Open Access Journals (Sweden)

    Daniel Grum

    Full Text Available Magnetic resonance imaging (MRI offers a non-radioactive alternative for the non-invasive detection of tumours. Low molecular weight MRI contrast agents currently in clinical use suffer either from a lack of specificity for tumour tissue or from low relaxivity and thus low contrast amplification. In this study, we present the newly designed two domain fusion protein Zarvin, which is able to bind to therapeutic IgG antibodies suitable for targeting, while facilitating contrast enhancement through high affinity binding sites for Gd(3+. We show that the Zarvin fold is stable under serum conditions, specifically targets a cancer cell-line when bound to the Cetuximab IgG, and allows for imaging with high relaxivity, a property that would be advantageous for the detection of small tumours and metastases at 1.5 or 3 T.

  19. Design of a Potent CB1 Receptor Antagonist Series: Potential Scaffold for Peripherally-Targeted Agents.

    Science.gov (United States)

    Dow, Robert L; Carpino, Philip A; Gautreau, Denise; Hadcock, John R; Iredale, Philip A; Kelly-Sullivan, Dawn; Lizano, Jeffrey S; O'Connor, Rebecca E; Schneider, Steven R; Scott, Dennis O; Ward, Karen M

    2012-05-10

    Antagonism of cannabinoid-1 (CB1) receptor signaling has been demonstrated to inhibit feeding behaviors in humans, but CB1-mediated central nervous system (CNS) side effects have halted the marketing and further development of the lead drugs against this target. However, peripherally restricted CB1 receptor antagonists may hold potential for providing the desired efficacy with reduced CNS side effect profiles. In this report we detail the discovery and structure-activity-relationship analysis of a novel bicyclic scaffold (3) that exhibits potent CB1 receptor antagonism and oral activity in preclinical feeding models. Optimization of physical properties has led to the identification of analogues which are predicted to have reduced CNS exposure and could serve as a starting point for the design of peripherally targeted CB1 receptor antagonists.

  20. Design and synthesis of tumor-targeting theranostic drug conjugates for SPECT and PET imaging studies.

    Science.gov (United States)

    Wang, Tao; Vineberg, Jacob G; Honda, Tadashi; Ojima, Iwao

    2017-12-11

    Theranostics will play a significant role in the next-generation chemotherapy. Two novel tumor-targeting theranostic drug conjugates, bearing imaging arms, were designed and synthesized. These theranostic conjugates consist of biotin as the tumor-targeting moiety, a second generation taxoid, SB-T-1214, as a potent anticancer drug, and two different imaging arms for capturing 99mTc for SPECT (single photon emission computed tomography) and 64Cu for PET (positron emission tomography). To explore the best reaction conditions for capturing radionuclides and work out the chemistry directly applicable to "hot" nuclides, cold chemistry was investigated to capture 185Re(I) and 63Cu(II) species as surrogates for 99mTc and 64Cu, respectively. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Design and development of receptor-avid peptide conjugates for in-vivo targeting of cancer

    Science.gov (United States)

    Volkert, Wynn A.; Hoffman, Timothy J.

    1999-07-01

    Radiometallated peptides that exhibit high specificity for cognate receptors over expressed on cancer cells offer important potential as site-directed diagnostic and therapeutic radiopharmaceutical. The formation of effective radioactive drugs for specific in vivo targeting of cancerous tumors is being facilitated by the integration of novel chelation strategies and receptor-avid derivatives. Significant efforts are being made to design Technetium-99m labeled for diagnostic imaging of cancerous tumors for use in conjunction with Single Photon Emission Tomography instrumentation in nuclear medicine. Receptor avid radiopharmaceutical are also being developed that utilize other radionuclides for imaging and therapeutic applications. Despite the technological challenges that must be overcome, radiolabeled receptor avid peptide conjugates are providing promising site-directed targeting agents for the assessment and treatment of cancerous tumors in humans.

  2. Sequence-based design of bioactive small molecules that target precursor microRNAs.

    Science.gov (United States)

    Velagapudi, Sai Pradeep; Gallo, Steven M; Disney, Matthew D

    2014-04-01

    Oligonucleotides are designed to target RNA using base pairing rules, but they can be hampered by poor cellular delivery and nonspecific stimulation of the immune system. Small molecules are preferred as lead drugs or probes but cannot be designed from sequence. Herein, we describe an approach termed Inforna that designs lead small molecules for RNA from solely sequence. Inforna was applied to all human microRNA hairpin precursors, and it identified bioactive small molecules that inhibit biogenesis by binding nuclease-processing sites (44% hit rate). Among 27 lead interactions, the most avid interaction is between a benzimidazole (1) and precursor microRNA-96. Compound 1 selectively inhibits biogenesis of microRNA-96, upregulating a protein target (FOXO1) and inducing apoptosis in cancer cells. Apoptosis is ablated when FOXO1 mRNA expression is knocked down by an siRNA, validating compound selectivity. Markedly, microRNA profiling shows that 1 only affects microRNA-96 biogenesis and is at least as selective as an oligonucleotide.

  3. Design upgrade of the ISOLDE target unit for HIE-ISOLDE

    Energy Technology Data Exchange (ETDEWEB)

    Montaño, J., E-mail: Jacobo.Montano@cern.ch [CERN, ISOLDE, CH-1211 Geneva 23 (Switzerland); Giles, T. [CERN, ISOLDE, CH-1211 Geneva 23 (Switzerland); Gottberg, A. [CERN, ISOLDE, CH-1211 Geneva 23 (Switzerland); Instituto de Estructura de la Materia, CSIC, 28006 Madrid (Spain)

    2013-12-15

    Highlights: • Requirements for a new target-source system for the radioactive facility HIE-ISOLDE. • For the upgraded facility a higher radiation field will be present. • The new design has to take into account the radiation field of the upgraded facility. -- Abstract: The High Intensity and Energy HIE-ISOLDE project is a major upgrade of the existing ISOLDE and REX-ISOLDE facilities with the objective of increasing the energy and the intensity of the delivered radioactive ion beams (RIB) [1]. In order to accommodate the future increase of primary beam intensity delivered by the new LINAC4 H{sup −} driver to the Proton Synchrotron Booster (PSB) [2] and from this to ISOLDE, a major study is being carried out to upgrade the existing designs of the ISOLDE target and its supporting infrastructure. In particular, the extraction optics plays an important role in the initial beam transport and the quality of the beam supplied to the mass separators. Important factors include the emittance of the beam and the beam profile to avoid beam losses. A new double electrode extraction system has been developed for simplifying and improving the interface between the target unit and the frontend (target coupling table). Numerical and experimental studies have been performed in order to define the new extraction geometry, and the coupling table has been adapted to keep the compatibility. An alternative heating system is under study. An electron bombardment heating system is being developed as an option for avoiding the employment of big cross section cables. The results of these studies and the mechanical models developed are presented and discussed.

  4. Thermal-hydraulic design of tungsten rod bundles for the APT 3He neutron spallation target

    Science.gov (United States)

    Willcutt, Gordon J. E.

    1995-01-01

    A preconceptual design has been developed for the 3He Target/Blanket System for the Accelerator Production of Tritium Project. The design use tungsten wire-wrapped rods to produce neutrons when the rods are struck by a proton beam. The rods are contained in bundles inside hexagonal Inconel ducts and cooled by D2O. Rod bundles are grouped in patterns in the proton beam inside a chamber filled with 3He that is transmuted to tritium by the neutrons coming from the tungsten rods. Additional 3He is transmuted in a blanket region surrounding the helium chamber. This paper describes the initial thermal-hydraulic design and testing that has been completed to confirm the designed calculations for pressure drop through the bundle and heat transfer in the bundle. Heat transfer tests were run to verify steady-state operation. These tests were followed by increasing power until nucleate boiling occurs to determine operating margins. Changes that improve the initial design are described.

  5. Design of a channel board used in an electronic warfare target simulator

    OpenAIRE

    Andersson, Peter

    2006-01-01

    A channel board was designed for a DRFM circuit. The DRFM is implemented in a Virtex-4 FPGA from Xilinx. In the future a similar channel board is intended to be used for target echo generation in ELSI which is an electronic warfare simulator at Saab Bofors Dynamics in Linköping. Besides the DRFM circuit the channel board consists of analog-to-digital converters, digital-to-analog converters, Ethernet plug-in board with a microcontroller, voltage regulators, FPGA configuration memory, voltage ...

  6. 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)

  7. Integrin αvβ3 targeting activity study of different retro-inverso sequences of RGD and their potentiality in the designing of tumor targeting peptides.

    Science.gov (United States)

    Liu, Yayuan; Mei, Ling; Yu, Qianwen; Zhang, Qianyu; Gao, Huile; Zhang, Zhirong; He, Qin

    2015-12-01

    Retro-inverso peptide represented the isomer of a parent peptide in which the direction of the sequence was reversed and the chirality of each amino acid residue was inverted. Generally, retro-inverso peptides possessed equal or even higher activities compared to the original peptide. RGD was a commonly used ligand for tumor and vascular targeting due to its affinity to integrin αvβ3 receptors. The biological activity study of the isomers of RGD would indeed provide useful suggestions for the design of tumor targeting peptides. Therefore, the tumor targeting activities of octa-arginine which was modified with different retro-inverso sequences of RGD peptide were investigated in this study. Three different tandem peptides (R8-GDGR, R8-GdGr and R8-GdGR) were designed on the basis of R8-GRGD. The tumor targeting activities of these tandem peptides were evaluated both in vitro and in vivo. Finally, R8-GdGR displayed selective binding affinity to integrin αvβ3 at the cellular level, and exhibited efficient tumor homing and penetrating capabilities in vivo. Meanwhile, R8-GdGR also showed stronger neovessel targeting ability compared to the others. In conclusion, all the results demonstrated that dGR possessed similar biological activity to RGD and was a potential ligand for further designing of tumor targeting peptides.

  8. Rational Design of Small Molecules Targeting Oncogenic Noncoding RNAs from Sequence.

    Science.gov (United States)

    Disney, Matthew D; Angelbello, Alicia J

    2016-12-20

    The discovery of RNA catalysis in the 1980s and the dissemination of the human genome sequence at the start of this century inspired investigations of the regulatory roles of noncoding RNAs in biology. In fact, the Encyclopedia of DNA Elements (ENCODE) project has shown that only 1-2% of the human genome encodes protein, yet 75% is transcribed into RNA. Functional studies both preceding and following the ENCODE project have shown that these noncoding RNAs have important roles in regulating gene expression, developmental timing, and other critical functions. RNA's diverse roles are often a consequence of the various folds that it adopts. The single-stranded nature of the biopolymer enables it to adopt intramolecular folds with noncanonical pairings to lower its free energy. These folds can be scaffolds to bind proteins or to form frameworks to interact with other RNAs. Not surprisingly, dysregulation of certain noncoding RNAs has been shown to be causative of disease. Given this as the background, it is easy to see why it would be useful to develop methods that target RNA and manipulate its biology in rational and predictable ways. The antisense approach has afforded strategies to target RNAs via Watson-Crick base pairing and has typically focused on targeting partially unstructured regions of RNA. Small molecule strategies to target RNA would be desirable not only because compounds could be lead optimized via medicinal chemistry but also because structured regions within an RNA of interest could be targeted to directly interfere with RNA folds that contribute to disease. Additionally, small molecules have historically been the most successful drug candidates. Until recently, the ability to design small molecules that target non-ribosomal RNAs has been elusive, creating the perception that they are "undruggable". In this Account, approaches to demystify targeting RNA with small molecules are described. Rather than bulk screening for compounds that bind to singular

  9. Design of reversible, cysteine-targeted Michael acceptors guided by kinetic and computational analysis.

    Science.gov (United States)

    Krishnan, Shyam; Miller, Rand M; Tian, Boxue; Mullins, R Dyche; Jacobson, Matthew P; Taunton, Jack

    2014-09-10

    Electrophilic probes that covalently modify a cysteine thiol often show enhanced pharmacological potency and selectivity. Although reversible Michael acceptors have been reported, the structural requirements for reversibility are poorly understood. Here, we report a novel class of acrylonitrile-based Michael acceptors, activated by aryl or heteroaryl electron-withdrawing groups. We demonstrate that thiol adducts of these acrylonitriles undergo β-elimination at rates that span more than 3 orders of magnitude. These rates correlate inversely with the computed proton affinity of the corresponding carbanions, enabling the intrinsic reversibility of the thiol-Michael reaction to be tuned in a predictable manner. We apply these principles to the design of new reversible covalent kinase inhibitors with improved properties. A cocrystal structure of one such inhibitor reveals specific noncovalent interactions between the 1,2,4-triazole activating group and the kinase. Our experimental and computational study enables the design of new Michael acceptors, expanding the palette of reversible, cysteine-targeted electrophiles.

  10. Image-Forming System Design of Dynamic Targets Based on Reflecting Mirror Splicing

    Directory of Open Access Journals (Sweden)

    Zhu Hong Mei

    2016-01-01

    Full Text Available In this paper, the author designed an area-scan CCD reflecting mirror splicing image-forming system with area-scan CCD ICX415AL as its transducer module and this system can be used for tracking dynamic targets. By analyzing the theory of vignetting generating, the author made mathematic model of vignetting and confirmed the splicing and overlapping pixel number of the optical system. What’s more, the sequential circuit and driving power circuit of ICX415AL was designed and the correlated noise in video signals was strained with CDS technology. Therefore, the signal-to-noise ratio (SNR of the system was elevated. With FPGA as its core controlling module, this system postponed the splicing image-forming system to a period during which a line of CCD data are read, thus the need of real-time tracking was completely met.

  11. Saturn Designs for Small Proton-Backlighter Targets at the National Ignition Facility

    Science.gov (United States)

    Craxton, R. S.; Garcia, E. M.; Browning, L. T.; Le Pape, S.; Park, H.-S.; Li, C. K.; Zylstra, A. B.

    2017-10-01

    Small exploding-pusher capsules with D3He fill are ideal sources for high-resolution proton radiography for many high-energy-density experiments at the National Ignition Facility (NIF). However, the laser energy that can be delivered to these capsules is currently limited by the need to minimize laser blowby-unabsorbed laser light passing by the target into opposing beam ports with the potential of damaging laser optics. This issue arises because it is logistically convenient to leave the indirect-drive phase plates in place. Saturn targets, in which the capsule is surrounded by a toroidal plastic ring, promise to remove the energy limitation by blocking blowby light, permitting a brighter proton source. A design has been developed using the 2-D hydrodynamics code SAGE for a ring that can be used to block the laser blowby for target diameters from 440 to 866 μm and drive beams from any of the NIF quads. Full-power NIF beams can be safely used. This material is based upon work supported by the Department of Energy National Nuclear Security Administration under Award Number DE-NA0001944.

  12. Design upgrade of the ISOLDE target unit for HIE-ISOLDE

    CERN Document Server

    Montano, J; Gottberg, A

    2013-01-01

    The High Intensity and Energy HIE-ISOLDE project is a major upgrade of the existing ISOLDE and REX-ISOLDE facilities with the objective of increasing the energy and the intensity of the delivered radioactive ion beams (RIB) {[}1]. In order to accommodate the future increase of primary beam intensity delivered by the new LINAC4 H- driver to the Proton Synchrotron Booster (PSB) {[}2] and from this to ISOLDE, a major study is being carried out to upgrade the existing designs of the ISOLDE target and its supporting infrastructure. In particular, the extraction optics plays an important role in the initial beam transport and the quality of the beam supplied to the mass separators. Important factors include the emittance of the beam and the beam profile to avoid beam losses. A new double electrode extraction system has been developed for simplifying and improving the interface between the target unit and the frontend (target coupling table). Numerical and experimental studies have been performed in order to define ...

  13. Design Analysis of SNS Target StationBiological Shielding Monoligh with Proton Power Uprate

    Energy Technology Data Exchange (ETDEWEB)

    Bekar, Kursat B. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Ibrahim, Ahmad M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2017-05-01

    This report documents the analysis of the dose rate in the experiment area outside the Spallation Neutron Source (SNS) target station shielding monolith with proton beam energy of 1.3 GeV. The analysis implemented a coupled three dimensional (3D)/two dimensional (2D) approach that used both the Monte Carlo N-Particle Extended (MCNPX) 3D Monte Carlo code and the Discrete Ordinates Transport (DORT) two dimensional deterministic code. The analysis with proton beam energy of 1.3 GeV showed that the dose rate in continuously occupied areas on the lateral surface outside the SNS target station shielding monolith is less than 0.25 mrem/h, which complies with the SNS facility design objective. However, the methods and codes used in this analysis are out of date and unsupported, and the 2D approximation of the target shielding monolith does not accurately represent the geometry. We recommend that this analysis is updated with modern codes and libraries such as ADVANTG or SHIFT. These codes have demonstrated very high efficiency in performing full 3D radiation shielding analyses of similar and even more difficult problems.

  14. Design and production of color calibration targets for digital input devices

    Science.gov (United States)

    Wen, ChaoHua; Lee, Jyh-Jiun

    2000-06-01

    This paper presents the design and production of calibration targets for digital input color devices. By experimentally determined gamut of surface color, this study redesigns the aim values based on ISO/FDIS 12641 and to meet process specifications of Noritsu QSS23-HRCRT photographic printer with silver halide photography. The calibration target includes four components: a set of 144 color patches (3 levels in lightness and 4 levels in chroma at 12 different hue angles) within printing gamut, a neutral scale containing 22 steps based on visual perception, a set of C- M-Y-K-R-G-B dye scales showing characteristics of photographic materials, and a series of facial colors ranked by red. This research will describe the meaning of each element, the use of colorimetric mapping to CIELCH for each element, the conversion of these patch into a RGB-mode electronic image file, and how to control the processing of color photographic materials. And we proposed an approach of dynamic subgroup linear interpolation to achieve high process quality of manufacturing calibration targets and cost-down. Finally, statistic results revealed that 99% of the patches are within 10 delta Eab of the aim values specified in this study from long-term test and 99% of the patches in the manufacturing batch are within 5 delta Eab of the mean values from short-term test.

  15. Rational Design of a Transferrin-Binding Peptide Sequence Tailored to Targeted Nanoparticle Internalization.

    Science.gov (United States)

    Santi, Melissa; Maccari, Giuseppe; Mereghetti, Paolo; Voliani, Valerio; Rocchiccioli, Silvia; Ucciferri, Nadia; Luin, Stefano; Signore, Giovanni

    2017-02-15

    The transferrin receptor (TfR) is a promising target in cancer therapy owing to its overexpression in most solid tumors and on the blood-brain barrier. Nanostructures chemically derivatized with transferrin are employed in TfR targeting but often lose their functionality upon injection in the bloodstream. As an alternative strategy, we rationally designed a peptide coating able to bind transferrin on suitable pockets not involved in binding to TfR or iron by using an iterative multiscale-modeling approach coupled with quantitative structure-activity and relationship (QSAR) analysis and evolutionary algorithms. We tested that selected sequences have low aspecific protein adsorption and high binding energy toward transferrin, and one of them is efficiently internalized in cells with a transferrin-dependent pathway. Furthermore, it promotes transferrin-mediated endocytosis of gold nanoparticles by modifying their protein corona and promoting oriented adsorption of transferrin. This strategy leads to highly effective nanostructures, potentially useful in diagnostic and therapeutic applications, which exploit (and do not suffer) the protein solvation for achieving a better targeting.

  16. Designed Amino Acid Feed in Improvement of Production and Quality Targets of a Therapeutic Monoclonal Antibody.

    Directory of Open Access Journals (Sweden)

    Fatemeh Torkashvand

    Full Text Available Cell culture feeds optimization is a critical step in process development of pharmaceutical recombinant protein production. Amino acids are the basic supplements of mammalian cell culture feeds with known effect on their growth promotion and productivity. In this study, we reported the implementation of the Plackett-Burman (PB multifactorial design to screen the effects of amino acids on the growth promotion and productivity of a Chinese hamster ovary DG-44 (CHO-DG44 cell line producing bevacizumab. After this screening, the amino acid combinations were optimized by the response surface methodology (RSM to determine the most effective concentration in feeds. Through this strategy, the final monoclonal antibody (mAb titre was enhanced by 70%, compared to the control group. For this particular cell line, aspartic acid, glutamic acid, arginine and glycine had the highest positive effects on the final mAb titre. Simultaneously, the impact of the designed amino acid feed on some critical quality attributes of bevacizumab was examined in the group with highest productivity. The product was analysed for N-glycan profiles, charge variant distribution, and low molecular weight forms. The results showed that the target product quality has been improved using this feeding strategy. It was shown how this strategy could significantly diminish the time and number of experiments in identifying the most effective amino acids and related concentrations in target product enhancement. This model could be successfully applied to other components of culture media and feeds.

  17. Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor-Binding Site.

    Science.gov (United States)

    Kanekiyo, Masaru; Bu, Wei; Joyce, M Gordon; Meng, Geng; Whittle, James R R; Baxa, Ulrich; Yamamoto, Takuya; Narpala, Sandeep; Todd, John-Paul; Rao, Srinivas S; McDermott, Adrian B; Koup, Richard A; Rossmann, Michael G; Mascola, John R; Graham, Barney S; Cohen, Jeffrey I; Nabel, Gary J

    2015-08-27

    Epstein-Barr virus (EBV) represents a major global health problem. Though it is associated with infectious mononucleosis and ∼200,000 cancers annually worldwide, a vaccine is not available. The major target of immunity is EBV glycoprotein 350/220 (gp350) that mediates attachment to B cells through complement receptor 2 (CR2/CD21). Here, we created self-assembling nanoparticles that displayed different domains of gp350 in a symmetric array. By focusing presentation of the CR2-binding domain on nanoparticles, potent neutralizing antibodies were elicited in mice and non-human primates. The structurally designed nanoparticle vaccine increased neutralization 10- to 100-fold compared to soluble gp350 by targeting a functionally conserved site of vulnerability, improving vaccine-induced protection in a mouse model. This rational approach to EBV vaccine design elicited potent neutralizing antibody responses by arrayed presentation of a conserved viral entry domain, a strategy that can be applied to other viruses. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. In silico design, synthesis, and screening of novel deoxyhypusine synthase inhibitors targeting HIV-1 replication.

    Science.gov (United States)

    Schroeder, Marcus; Kolodzik, Adrian; Pfaff, Katharina; Priyadarshini, Poornima; Krepstakies, Marcel; Hauber, Joachim; Rarey, Matthias; Meier, Chris

    2014-05-01

    The human enzyme deoxyhypusine synthase (DHS) is an important host cell factor that participates in the post-translational hypusine modification of eukaryotic initiation factor 5A (eIF-5A). Hypusine-modified eIF-5A plays a role in a number of diseases, including HIV infection/AIDS. Thus, DHS represents a novel and attractive drug target. So far, four crystal structures are available, and various substances have been tested for inhibition of human DHS. Among these inhibitors, N-1-guanyl-1,7-diaminoheptane (GC7) has been co-crystallized in the active site of DHS. However, despite its potency, GC7 is not selective enough to be used in drug applications. Therefore, new compounds that target DHS are needed. Herein we report the in silico design, chemical synthesis, and biological evaluation of new DHS inhibitors. One of these inhibitors showed dose-dependent inhibition of DHS in vitro, as well as suppression of HIV replication in cell cultures. Furthermore, the compound exhibited no cytotoxic effects at active concentrations. Thus, this designed compound demonstrated proof of principle and represents a promising starting point for the development of new drug candidates to specifically interfere with DHS activity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. MIDAS: a practical Bayesian design for platform trials with molecularly targeted agents.

    Science.gov (United States)

    Yuan, Ying; Guo, Beibei; Munsell, Mark; Lu, Karen; Jazaeri, Amir

    2016-09-30

    Recent success of immunotherapy and other targeted therapies in cancer treatment has led to an unprecedented surge in the number of novel therapeutic agents that need to be evaluated in clinical trials. Traditional phase II clinical trial designs were developed for evaluating one candidate treatment at a time and thus not efficient for this task. We propose a Bayesian phase II platform design, the multi-candidate iterative design with adaptive selection (MIDAS), which allows investigators to continuously screen a large number of candidate agents in an efficient and seamless fashion. MIDAS consists of one control arm, which contains a standard therapy as the control, and several experimental arms, which contain the experimental agents. Patients are adaptively randomized to the control and experimental agents based on their estimated efficacy. During the trial, we adaptively drop inefficacious or overly toxic agents and 'graduate' the promising agents from the trial to the next stage of development. Whenever an experimental agent graduates or is dropped, the corresponding arm opens immediately for testing the next available new agent. Simulation studies show that MIDAS substantially outperforms the conventional approach. The proposed design yields a significantly higher probability for identifying the promising agents and dropping the futile agents. In addition, MIDAS requires only one master protocol, which streamlines trial conduct and substantially decreases the overhead burden. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  20. GADIS: Algorithm for designing sequences to achieve target secondary structure profiles of intrinsically disordered proteins.

    Science.gov (United States)

    Harmon, Tyler S; Crabtree, Michael D; Shammas, Sarah L; Posey, Ammon E; Clarke, Jane; Pappu, Rohit V

    2016-09-01

    Many intrinsically disordered proteins (IDPs) participate in coupled folding and binding reactions and form alpha helical structures in their bound complexes. Alanine, glycine, or proline scanning mutagenesis approaches are often used to dissect the contributions of intrinsic helicities to coupled folding and binding. These experiments can yield confounding results because the mutagenesis strategy changes the amino acid compositions of IDPs. Therefore, an important next step in mutagenesis-based approaches to mechanistic studies of coupled folding and binding is the design of sequences that satisfy three major constraints. These are (i) achieving a target intrinsic alpha helicity profile; (ii) fixing the positions of residues corresponding to the binding interface; and (iii) maintaining the native amino acid composition. Here, we report the development of a G: enetic A: lgorithm for D: esign of I: ntrinsic secondary S: tructure (GADIS) for designing sequences that satisfy the specified constraints. We describe the algorithm and present results to demonstrate the applicability of GADIS by designing sequence variants of the intrinsically disordered PUMA system that undergoes coupled folding and binding to Mcl-1. Our sequence designs span a range of intrinsic helicity profiles. The predicted variations in sequence-encoded mean helicities are tested against experimental measurements. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  1. Targeted repression of AXIN2 and MYC gene expression using designer TALEs

    Energy Technology Data Exchange (ETDEWEB)

    Rennoll, Sherri A.; Scott, Samantha A.; Yochum, Gregory S., E-mail: gsy3@psu.edu

    2014-04-18

    Highlights: • We designed TALE–SID fusion proteins to target AXIN2 and MYC. • TALE–SIDs bound the chromosomal AXIN2 and MYC genes and repressed their expression. • TALE–SIDs repress β-catenin{sup S45F}-dependent AXIN2 and MYC transcription. - Abstract: Designer TALEs (dTALEs) are chimeric transcription factors that can be engineered to regulate gene expression in mammalian cells. Whether dTALEs can block gene transcription downstream of signal transduction cascades, however, has yet to be fully explored. Here we tested whether dTALEs can be used to target genes whose expression is controlled by Wnt/β-catenin signaling. TALE DNA binding domains were engineered to recognize sequences adjacent to Wnt responsive enhancer elements (WREs) that control expression of axis inhibition protein 2 (AXIN2) and c-MYC (MYC). These custom DNA binding domains were linked to the mSin3A interaction domain (SID) to generate TALE–SID chimeric repressors. The TALE–SIDs repressed luciferase reporter activity, bound their genomic target sites, and repressed AXIN2 and MYC expression in HEK293 cells. We generated a novel HEK293 cell line to determine whether the TALE–SIDs could function downstream of oncogenic Wnt/β-catenin signaling. Treating these cells with doxycycline and tamoxifen stimulates nuclear accumulation of a stabilized form of β-catenin found in a subset of colorectal cancers. The TALE–SIDs repressed AXIN2 and MYC expression in these cells, which suggests that dTALEs could offer an effective therapeutic strategy for the treatment of colorectal cancer.

  2. An integrated in silico approach to design specific inhibitors targeting human poly(a-specific ribonuclease.

    Directory of Open Access Journals (Sweden)

    Dimitrios Vlachakis

    Full Text Available Poly(A-specific ribonuclease (PARN is an exoribonuclease/deadenylase that degrades 3'-end poly(A tails in almost all eukaryotic organisms. Much of the biochemical and structural information on PARN comes from the human enzyme. However, the existence of PARN all along the eukaryotic evolutionary ladder requires further and thorough investigation. Although the complete structure of the full-length human PARN, as well as several aspects of the catalytic mechanism still remain elusive, many previous studies indicate that PARN can be used as potent and promising anti-cancer target. In the present study, we attempt to complement the existing structural information on PARN with in-depth bioinformatics analyses, in order to get a hologram of the molecular evolution of PARNs active site. In an effort to draw an outline, which allows specific drug design targeting PARN, an unequivocally specific platform was designed for the development of selective modulators focusing on the unique structural and catalytic features of the enzyme. Extensive phylogenetic analysis based on all the publicly available genomes indicated a broad distribution for PARN across eukaryotic species and revealed structurally important amino acids which could be assigned as potentially strong contributors to the regulation of the catalytic mechanism of PARN. Based on the above, we propose a comprehensive in silico model for the PARN's catalytic mechanism and moreover, we developed a 3D pharmacophore model, which was subsequently used for the introduction of DNP-poly(A amphipathic substrate analog as a potential inhibitor of PARN. Indeed, biochemical analysis revealed that DNP-poly(A inhibits PARN competitively. Our approach provides an efficient integrated platform for the rational design of pharmacophore models as well as novel modulators of PARN with therapeutic potential.

  3. Target dIsease-Guided placEbo-contRolled (TIGER) design: a novel method for clinical trials of acupuncture

    National Research Council Canada - National Science Library

    Zheng, Wenke; Wang, Hui; Zhang, Li; Bian, Zhaoxiang; Shang, Hongcai

    2013-01-01

    .... Guided by evidence-based medicine (EBM) theories, we have made an initial attempt to establish a set of control methods for use in acupuncture studies, which is named the target disease-guided placebo-controlled (TIGER) design...

  4. 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

  5. Defilade, Stationary Target and Moving Target Embankment, Low Water Crossing, and Course Road Designs for Soil Loss Prevention

    National Research Council Canada - National Science Library

    Svendsen, Niels G; Kalita, Prasanta K; Gebhart, Dick L; Denight, Michael L

    2006-01-01

    ... for military training requirements. This report proposes several new range structure designs to begin the iterative process of developing new range edifices that reduce soil loss, control erosion, promote sustainability, and enhance training...

  6. Small UAS Analysis of Laser Designation and Search and Target Acquisition Capabilities in an Urban Environment

    National Research Council Canada - National Science Library

    Harclerode, Eric

    2008-01-01

    Conclusions: -Small UAS has extreme difficulty lasing moving targets in high density urban environments -Lasing moving targets in medium density terrain is possible but not certain -Lasing of stationary targets...

  7. Design of short external guide sequences (EGSs) for cleavage of target molecules with RNase P.

    Science.gov (United States)

    Werner, M; Rosa, E; George, S T

    1997-01-01

    The minimal substrate for human RNase P consists of the 5' leader sequence, aminoacyl acceptor stem, T-stem and T-loop of tRNA. The sequences corresponding to the D-stem, anticodon stem and loop and variable loop are replaced by a bulge which can be as small as 1 nt, but requires > 4 nt for optimal cleavage by RNase P. We found that a trans construct in which the T loop is opened between G57 and A58 (tRNA numbering system) is still processed by RNase P. The strand that is cleaved can be considered the target RNA while the other strand serves as an External Guide Sequence (EGS). We were also able to delete the nucleotides corresponding to nt 58 to 60 in the T-loop without affecting cleavage of the substrate. We propose that the sequence UUCG or UUCA (nucleotide 55 to 57 in the T-loop) positioned 3' to a double helical region of 12 to 13 basepairs containing a bulge of > 4 nt can form a structure that is recognized by human RNase P. The four nucleotides UUCR probably form a structure that resembles the uridine turn in the Tloop of tRNA. Since recognition by RNase P seems to be independent of the helical sequence, we suggest that this motif can be used for targeting RNA molecules for EGS-directed cleavage by RNase P. Based on these results, several 13-mer EGSs targeted to the 2.1 Kb surface antigen mRNA of hepatitis B virus (HBV) were designed and tested using a co-transcriptional cleavage assay with a 2.1 Kb HBV transcript. Some of these were capable of inducing cleavage of the HBV RNA by RNase P. The use of such small EGSs for the inactivation of various genes will be discussed.

  8. Circular revisit orbits design for responsive mission over a single target

    Science.gov (United States)

    Li, Taibo; Xiang, Junhua; Wang, Zhaokui; Zhang, Yulin

    2016-10-01

    The responsive orbits play a key role in addressing the mission of Operationally Responsive Space (ORS) because of their capabilities. These capabilities are usually focused on supporting specific targets as opposed to providing global coverage. One subtype of responsive orbits is repeat coverage orbit which is nearly circular in most remote sensing applications. This paper deals with a special kind of repeating ground track orbit, referred to as circular revisit orbit. Different from traditional repeat coverage orbits, a satellite on circular revisit orbit can visit a target site at both the ascending and descending stages in one revisit cycle. This typology of trajectory allows a halving of the traditional revisit time and does a favor to get useful information for responsive applications. However the previous reported numerical methods in some references often cost lots of computation or fail to obtain such orbits. To overcome this difficulty, an analytical method to determine the existence conditions of the solutions to revisit orbits is presented in this paper. To this end, the mathematical model of circular revisit orbit is established under the central gravity model and the J2 perturbation. A constraint function of the circular revisit orbit is introduced, and the monotonicity of that function has been studied. The existent conditions and the number of such orbits are naturally worked out. Taking the launch cost into consideration, optimal design model of circular revisit orbit is established to achieve a best orbit which visits a target twice a day in the morning and in the afternoon respectively for several days. The result shows that it is effective to apply circular revisit orbits in responsive application such as reconnoiter of natural disaster.

  9. Modern dose-finding designs for cancer phase I trials drug combinations and molecularly targeted agents

    CERN Document Server

    Hirakawa, Akihiro; Daimon, Takashi; Matsui, Shigeyuki

    2018-01-01

    This book deals with advanced methods for adaptive phase I dose-finding clinical trials for combination of two agents and molecularly targeted agents (MTAs) in oncology. It provides not only methodological aspects of the dose-finding methods, but also software implementations and practical considerations in applying these complex methods to real cancer clinical trials. Thus, the book aims to furnish researchers in biostatistics and statistical science with a good summary of recent developments of adaptive dose-finding methods as well as providing practitioners in biostatistics and clinical investigators with advanced materials for designing, conducting, monitoring, and analyzing adaptive dose-finding trials. The topics in the book are mainly related to cancer clinical trials, but many of those topics are potentially applicable or can be extended to trials for other diseases. The focus is mainly on model-based dose-finding methods for two kinds of phase I trials. One is clinical trials with combinations of tw...

  10. A real-time brain-machine interface combining motor target and trajectory intent using an optimal feedback control design.

    Science.gov (United States)

    Shanechi, Maryam M; Williams, Ziv M; Wornell, Gregory W; Hu, Rollin C; Powers, Marissa; Brown, Emery N

    2013-01-01

    Real-time brain-machine interfaces (BMI) have focused on either estimating the continuous movement trajectory or target intent. However, natural movement often incorporates both. Additionally, BMIs can be modeled as a feedback control system in which the subject modulates the neural activity to move the prosthetic device towards a desired target while receiving real-time sensory feedback of the state of the movement. We develop a novel real-time BMI using an optimal feedback control design that jointly estimates the movement target and trajectory of monkeys in two stages. First, the target is decoded from neural spiking activity before movement initiation. Second, the trajectory is decoded by combining the decoded target with the peri-movement spiking activity using an optimal feedback control design. This design exploits a recursive Bayesian decoder that uses an optimal feedback control model of the sensorimotor system to take into account the intended target location and the sensory feedback in its trajectory estimation from spiking activity. The real-time BMI processes the spiking activity directly using point process modeling. We implement the BMI in experiments consisting of an instructed-delay center-out task in which monkeys are presented with a target location on the screen during a delay period and then have to move a cursor to it without touching the incorrect targets. We show that the two-stage BMI performs more accurately than either stage alone. Correct target prediction can compensate for inaccurate trajectory estimation and vice versa. The optimal feedback control design also results in trajectories that are smoother and have lower estimation error. The two-stage decoder also performs better than linear regression approaches in offline cross-validation analyses. Our results demonstrate the advantage of a BMI design that jointly estimates the target and trajectory of movement and more closely mimics the sensorimotor control system.

  11. A real-time brain-machine interface combining motor target and trajectory intent using an optimal feedback control design.

    Directory of Open Access Journals (Sweden)

    Maryam M Shanechi

    Full Text Available Real-time brain-machine interfaces (BMI have focused on either estimating the continuous movement trajectory or target intent. However, natural movement often incorporates both. Additionally, BMIs can be modeled as a feedback control system in which the subject modulates the neural activity to move the prosthetic device towards a desired target while receiving real-time sensory feedback of the state of the movement. We develop a novel real-time BMI using an optimal feedback control design that jointly estimates the movement target and trajectory of monkeys in two stages. First, the target is decoded from neural spiking activity before movement initiation. Second, the trajectory is decoded by combining the decoded target with the peri-movement spiking activity using an optimal feedback control design. This design exploits a recursive Bayesian decoder that uses an optimal feedback control model of the sensorimotor system to take into account the intended target location and the sensory feedback in its trajectory estimation from spiking activity. The real-time BMI processes the spiking activity directly using point process modeling. We implement the BMI in experiments consisting of an instructed-delay center-out task in which monkeys are presented with a target location on the screen during a delay period and then have to move a cursor to it without touching the incorrect targets. We show that the two-stage BMI performs more accurately than either stage alone. Correct target prediction can compensate for inaccurate trajectory estimation and vice versa. The optimal feedback control design also results in trajectories that are smoother and have lower estimation error. The two-stage decoder also performs better than linear regression approaches in offline cross-validation analyses. Our results demonstrate the advantage of a BMI design that jointly estimates the target and trajectory of movement and more closely mimics the sensorimotor control system.

  12. Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria

    Science.gov (United States)

    Inaoka, Daniel Ken; Shiba, Tomoo; Sato, Dan; Balogun, Emmanuel Oluwadare; Sasaki, Tsuyoshi; Nagahama, Madoka; Oda, Masatsugu; Matsuoka, Shigeru; Ohmori, Junko; Honma, Teruki; Inoue, Masayuki; Kita, Kiyoshi; Harada, Shigeharu

    2015-01-01

    Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major pathway of energy metabolism for adaptation to a hypoxic environment not only in parasitic organisms, but also in some types of human cancer cells. Thus, enzymes of the pathway are potential targets for chemotherapy. We found that flutolanil is an excellent inhibitor for A. suum complex II (IC50 = 0.058 μM) but less effectively inhibits homologous porcine complex II (IC50 = 45.9 μM). In order to account for the specificity of flutolanil to A. suum complex II from the standpoint of structural biology, we determined the crystal structures of A. suum and porcine complex IIs binding flutolanil and its derivative compounds. The structures clearly demonstrated key interactions responsible for its high specificity to A. suum complex II and enabled us to find analogue compounds, which surpass flutolanil in both potency and specificity to A. suum complex II. Structures of complex IIs binding these compounds will be helpful to accelerate structure-based drug design targeted for complex IIs. PMID:26198225

  13. Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria

    Directory of Open Access Journals (Sweden)

    Daniel Ken Inaoka

    2015-07-01

    Full Text Available Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major pathway of energy metabolism for adaptation to a hypoxic environment not only in parasitic organisms, but also in some types of human cancer cells. Thus, enzymes of the pathway are potential targets for chemotherapy. We found that flutolanil is an excellent inhibitor for A. suum complex II (IC50 = 0.058 μM but less effectively inhibits homologous porcine complex II (IC50 = 45.9 μM. In order to account for the specificity of flutolanil to A. suum complex II from the standpoint of structural biology, we determined the crystal structures of A. suum and porcine complex IIs binding flutolanil and its derivative compounds. The structures clearly demonstrated key interactions responsible for its high specificity to A. suum complex II and enabled us to find analogue compounds, which surpass flutolanil in both potency and specificity to A. suum complex II. Structures of complex IIs binding these compounds will be helpful to accelerate structure-based drug design targeted for complex IIs.

  14. Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria.

    Science.gov (United States)

    Inaoka, Daniel Ken; Shiba, Tomoo; Sato, Dan; Balogun, Emmanuel Oluwadare; Sasaki, Tsuyoshi; Nagahama, Madoka; Oda, Masatsugu; Matsuoka, Shigeru; Ohmori, Junko; Honma, Teruki; Inoue, Masayuki; Kita, Kiyoshi; Harada, Shigeharu

    2015-07-07

    Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major pathway of energy metabolism for adaptation to a hypoxic environment not only in parasitic organisms, but also in some types of human cancer cells. Thus, enzymes of the pathway are potential targets for chemotherapy. We found that flutolanil is an excellent inhibitor for A. suum complex II (IC50 = 0.058 μM) but less effectively inhibits homologous porcine complex II (IC50 = 45.9 μM). In order to account for the specificity of flutolanil to A. suum complex II from the standpoint of structural biology, we determined the crystal structures of A. suum and porcine complex IIs binding flutolanil and its derivative compounds. The structures clearly demonstrated key interactions responsible for its high specificity to A. suum complex II and enabled us to find analogue compounds, which surpass flutolanil in both potency and specificity to A. suum complex II. Structures of complex IIs binding these compounds will be helpful to accelerate structure-based drug design targeted for complex IIs.

  15. Design of a novel curcumin-soybean phosphatidylcholine complex-based targeted drug delivery systems.

    Science.gov (United States)

    Xie, Jiajiang; Li, Yanxiu; Song, Liang; Pan, Zhou; Ye, Shefang; Hou, Zhenqing

    2017-11-01

    Recently, the global trend in the field of nanomedicine has been toward the design of combination of nature active constituents and phospholipid (PC) to form a therapeutic drug-phospholipid complex. As a particular amphiphilic molecular complex, it can be a unique bridge of traditional dosage-form and novel drug delivery system. In thisarticle, on the basis of drug-phospholipid complex technique and self-assembly technique, we chose a pharmacologically safe and low toxic drug curcumin (CUR) to increase drug-loading ability, achieve controlled/sustained drug release and improve anticancer activity. A novel CUR-soybean phosphatidylcholine (SPC) complex and CUR-SPC complex self-assembled nanoparticles (CUR-SPC NPs) were prepared by a co-solvent method and a nanoprecipitation method. DSPE-PEG-FA was further functionalized on the surface of PEG-CUR-SPC NPs (designed as FA-PEG-CUR-SPC NPs) to specifically increase cellular uptake and targetability. The FA-PEG-CUR-SPC NPs showed a spherical shape, a mean diameter of about 180 nm, an excellent physiological stability and pH-triggered drug release. The drug entrapment efficiency and drug-loading content was up to 92.5 and 16.3%, respectively. In vitro cellular uptake and cytotoxicity studies demonstrated that FA-PEG-CUR-SPC NPs and CUR-SPC NPs presented significantly stronger cellular uptake efficacy and anticancer activity against HeLa cells and Caco-2 cells compared to free CUR, CUR-SPC NPs and PEG-CUR-SPC NPs. More importantly, FA-PEG-CUR-SPC NPs showed the prolonged systemic circulation lifetime and enhanced tumor accumulation compared with free CUR and PEG-CUR-SPC NPs. These results suggest that the FA targeted PEGylated CUR-SPC complex self-assembled NPs might be a promising candidate in cancer therapy.

  16. In Silico Design and Experimental Validation of siRNAs Targeting Conserved Regions of Multiple Hepatitis C Virus Genotypes.

    Science.gov (United States)

    ElHefnawi, Mahmoud; Kim, TaeKyu; Kamar, Mona A; Min, Saehong; Hassan, Nafisa M; El-Ahwany, Eman; Kim, Heeyoung; Zada, Suher; Amer, Marwa; Windisch, Marc P

    2016-01-01

    RNA interference (RNAi) is a post-transcriptional gene silencing mechanism that mediates the sequence-specific degradation of targeted RNA and thus provides a tremendous opportunity for development of oligonucleotide-based drugs. Here, we report on the design and validation of small interfering RNAs (siRNAs) targeting highly conserved regions of the hepatitis C virus (HCV) genome. To aim for therapeutic applications by optimizing the RNAi efficacy and reducing potential side effects, we considered different factors such as target RNA variations, thermodynamics and accessibility of the siRNA and target RNA, and off-target effects. This aim was achieved using an in silico design and selection protocol complemented by an automated MysiRNA-Designer pipeline. The protocol included the design and filtration of siRNAs targeting highly conserved and accessible regions within the HCV internal ribosome entry site, and adjacent core sequences of the viral genome with high-ranking efficacy scores. Off-target analysis excluded siRNAs with potential binding to human mRNAs. Under this strict selection process, two siRNAs (HCV353 and HCV258) were selected based on their predicted high specificity and potency. These siRNAs were tested for antiviral efficacy in HCV genotype 1 and 2 replicon cell lines. Both in silico-designed siRNAs efficiently inhibited HCV RNA replication, even at low concentrations and for short exposure times (24h); they also exceeded the antiviral potencies of reference siRNAs targeting HCV. Furthermore, HCV353 and HCV258 siRNAs also inhibited replication of patient-derived HCV genotype 4 isolates in infected Huh-7 cells. Prolonged treatment of HCV replicon cells with HCV353 did not result in the appearance of escape mutant viruses. Taken together, these results reveal the accuracy and strength of our integrated siRNA design and selection protocols. These protocols could be used to design highly potent and specific RNAi-based therapeutic oligonucleotide

  17. Soft computing model for optimized siRNA design by identifying off target possibilities using artificial neural network model.

    Science.gov (United States)

    Murali, Reena; John, Philips George; Peter S, David

    2015-05-15

    The ability of small interfering RNA (siRNA) to do posttranscriptional gene regulation by knocking down targeted genes is an important research topic in functional genomics, biomedical research and in cancer therapeutics. Many tools had been developed to design exogenous siRNA with high experimental inhibition. Even though considerable amount of work has been done in designing exogenous siRNA, design of effective siRNA sequences is still a challenging work because the target mRNAs must be selected such that their corresponding siRNAs are likely to be efficient against that target and unlikely to accidentally silence other transcripts due to sequence similarity. In some cases, siRNAs may tolerate mismatches with the target mRNA, but knockdown of genes other than the intended target could make serious consequences. Hence to design siRNAs, two important concepts must be considered: the ability in knocking down target genes and the off target possibility on any nontarget genes. So before doing gene silencing by siRNAs, it is essential to analyze their off target effects in addition to their inhibition efficacy against a particular target. Only a few methods have been developed by considering both efficacy and off target possibility of siRNA against a gene. In this paper we present a new design of neural network model with whole stacking energy (ΔG) that enables to identify the efficacy and off target effect of siRNAs against target genes. The tool lists all siRNAs against a particular target with their inhibition efficacy and number of matches or sequence similarity with other genes in the database. We could achieve an excellent performance of Pearson Correlation Coefficient (R=0. 74) and Area Under Curve (AUC=0.906) when the threshold of whole stacking energy is ≥-34.6 kcal/mol. To the best of the author's knowledge, this is one of the best score while considering the "combined efficacy and off target possibility" of siRNA for silencing a gene. The proposed model

  18. Report on the R&D of Uranium Carbide targets by the PLOG collaboration at PNPI-Gatchina

    CERN Document Server

    A.E. Barzakh, D.V. Fedorov, A.M. Ionan, V.S. Ivanov, M.P. Levchenko, K.A. Mezilev, F.V. Moroz, S.Yu. Orlov, V.N. Panteleev, Yu.M. Volkov,O. Alyakrinskiy, A. Andrighetto, A. Lanchais, G. Lhersonneau*, V. Rizzi, L. Stroe#, L.B. Tecchio,O. Bajeat, M. Cheikh Mhamed, S. Essabaa, C. Lau, B. Roussière,M. Dubois, C. Eléon, G. Gaubert, P. Jardin, N. Lecesne, R. Leroy, J.Y. Pacquet, M. -G. Saint Laurent, A.C.C. Villari.

    The aim of this report is to summarize the experimental results of the R&D program on Uranium Carbide targets for Radioactive Ion Beam (RIB) production performed at the Petersburg Nuclear Physics Institute (PNPI) of Gatchina (Russia). The targets have been irradiated with 1 GeV protons delivered by the Synchrocyclotron and the measurements were carried out at the IRIS isotope separator on-line. Different compositions of Uranium Carbide targets as well as different kinds of ion sources have been tested in order to evaluate efficiency and release times of the reaction products. The report includes the results of experiments performed in the period of time going from November 2001 up to March 2006. This R&D program was performed in the framework of the collaboration with the EURISOL, SPES and SPIRAL-2 projects and ISTC program.

  19. Rational Design of Iron Oxide Nanoparticles as Targeted Nanomedicines for Cancer Therapy

    Science.gov (United States)

    Kievit, Forrest M.

    2011-07-01

    Nanotechnology provides a flexible platform for the development of effective therapeutic nanomaterials that can interact specifically with a target in a biological system and provoke a desired biological response. Of the nanomaterials studied, superparamagnetic iron oxide nanoparticles (SPIONs) have emerged as one of top candidates for cancer therapy due to their intrinsic superparamagnetism that enables non-invasive magnetic resonance imaging (MRI) and biodegradability favorable for in vivo application. This dissertation is aimed at development of SPION-based nanomedicines to overcome the current limitations in cancer therapy. These limitations include non-specificity of therapy which can harm healthy tissue, the difficulty in delivering nucleic acids for gene therapy, the formation of drug resistance, and the inability to detect and treat micrometastases. First, a SPION-based non-viral gene delivery vehicle was developed through functionalization of the SPION core with a co-polymer designed to provide stable binding of DNA and low toxicity which showed excellent gene delivery in vitro and in vivo. This SPION-based non-viral gene delivery vehicle was then activated with a targeting agent to improve gene delivery throughout a xenograft tumor of brain cancer. It was found that targeting did not promote the accumulation of SPIONs at the tumor site, but rather improved the distribution of SPIONs throughout the tumor so a higher proportion of cells received treatment. Next, the high surface area of SPIONs was utilized for loading large amounts of drug which was shown to overcome the multidrug resistance acquired by many cancer cells. Drug bound to SPIONs showed significantly higher multidrug resistant cell uptake as compared to free drug which translated into improved cell kill. Also, an antibody activated SPION was developed and was shown to be able to target micrometastases in a transgenic animal model of metastatic breast cancer. These SPION-based nanomedicines

  20. K-targeted metabolomic analysis extends chemical subtraction to DESIGNER extracts: selective depletion of extracts of hops (Humulus lupulus).

    Science.gov (United States)

    Ramos Alvarenga, René F; Friesen, J Brent; Nikolić, Dejan; Simmler, Charlotte; Napolitano, José G; van Breemen, Richard; Lankin, David C; McAlpine, James B; Pauli, Guido F; Chen, Shao-Nong

    2014-12-26

    This study introduces a flexible and compound targeted approach to Deplete and Enrich Select Ingredients to Generate Normalized Extract Resources, generating DESIGNER extracts, by means of chemical subtraction or augmentation of metabolites. Targeting metabolites based on their liquid-liquid partition coefficients (K values), K targeting uses countercurrent separation methodology to remove single or multiple compounds from a chemically complex mixture, according to the following equation: DESIGNER extract = total extract ± target compound(s). Expanding the scope of the recently reported depletion of extracts by immunoaffinity or solid phase liquid chromatography, the present approach allows a more flexible, single- or multi-targeted removal of constituents from complex extracts such as botanicals. Chemical subtraction enables both chemical and biological characterization, including detection of synergism/antagonism by both the subtracted targets and the remaining metabolite mixture, as well as definition of the residual complexity of all fractions. The feasibility of the DESIGNER concept is shown by K-targeted subtraction of four bioactive prenylated phenols, isoxanthohumol (1), 8-prenylnaringenin (2), 6-prenylnaringenin (3), and xanthohumol (4), from a standardized hops (Humulus lupulus L.) extract using specific solvent systems. Conversely, adding K-targeted isolates allows enrichment of the original extract and hence provides an augmented DESIGNER material. Multiple countercurrent separation steps were used to purify each of the four compounds, and four DESIGNER extracts with varying depletions were prepared. The DESIGNER approach innovates the characterization of chemically complex extracts through integration of enabling technologies such as countercurrent separation, K-by-bioactivity, the residual complexity concepts, as well as quantitative analysis by (1)H NMR, LC-MS, and HiFSA-based NMR fingerprinting.

  1. Perspectives on the design of clinical trials combining transarterial chemoembolization and molecular targeted therapy.

    Science.gov (United States)

    Hsu, Chiun; Po-Ching-Liang; Morita, Satoshi; Hu, Fu-Chang; Cheng, Ann-Lii

    2012-11-01

    Transarterial chemoembolization (TACE) moderately prolongs the survival of patients with intermediate-stage hepatocellular carcinoma. Molecular targeted therapy (MTT) may improve the efficacy of TACE. However, the findings of clinical trials evaluating the efficacy of a combination of TACE and MTT are conflicting. We hypothesized that this disparity can be prevented using alternative study designs. In this review, we classify the pertinent issues of study designs into five domains: primary endpoints, patients, TACE procedures, timing of randomization, and drug administration. Furthermore, we discuss the methods for increasing the success rate by minimizing potentially confounding factors within these five domains. Transarterial chemoembolization (TACE) is the current standard therapy for patients with Barcelona Clinic Liver Cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC) [1, 2, 3]. The survival benefit of TACE is supported by the results of meta-analysis of clinical trials comparing TACE with other conservative treatments in patients with inoperable HCC [4]. The results showed that the median survival of patients improved from approximately 16 to 20 months following TACE [4, 5]. Although advances in TACE techniques and the use of new embolization agents may improve the efficacy of TACE [6, 7], other approaches are needed to further improve the outcome in HCC patients treated using TACE. Molecular targeted therapy (MTT) has improved the survival of patients with advanced-stage HCC [5, 8]. Therefore, combining MTT and TACE may additionally improve the survival in patients with intermediate-stage HCC. Many molecular targeted agents (MTA) are currently undergoing evaluation in randomized trials (table 1). However, the designs of these trials differ significantly. The results of two trials combining sorafenib and TACE were recently reported. Both trials failed to demonstrate a therapeutic benefit of the combination therapy for time to tumor progression

  2. Conceptual Biorefinery Design and Research Targeted for 2022: Hydrothermal Liquefacation Processing of Wet Waste to Fuels

    Energy Technology Data Exchange (ETDEWEB)

    Snowden-Swan, Lesley J. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Zhu, Yunhua [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Bearden, Mark D. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Seiple, Timothy E. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Jones, Susanne B. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Schmidt, Andrew J. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Billing, Justin M. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Hallen, Richard T. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Hart, Todd R. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Liu, Jian [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Albrecht, Karl O. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Fox, Samuel P. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Maupin, Gary D. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Elliott, Douglas C. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2017-12-28

    represents a goal case for the pathway, targeting performance that is anticipated to be achievable by 2022 with further research and development. The year 2022 is BETO’s target year for verification of hydrocarbon biofuel pathways. As this analysis represents a goal case, assumed values of several design parameters represent improvements in the technology relative to what has currently been demonstrated in the laboratory. While HTL is fairly well developed and may therefore be ready for commercialization prior to 2022, there are specific advancements addressed in this analysis that are necessary to enhance performance compared to what has been demonstrated to date. In addition, an important aspect to the pathway is the upgrading of biocrude to fuel blendstock, an area that has received much less attention and requires significant research to validate the goal case performance parameters. The estimated plant gate minimum fuel selling price for fuel blendstock from sludge HTL and upgrading is $3.46/gasoline gallon equivalent (gge). This price is within the tolerance (+$0.49/gge) of BETO’s $3/gge programmatic cost target and illustrates that fuel blendstocks generated from HTL of sludge and centralized biocrude upgrading have the potential to be competitive with fossil fuels. This analysis illustrates the feasibility of HTL for point-of-generation conversion of waste feedstock at a scale 1/20th that of the standard lignocellulosic biorefinery scale typically used in BETO design cases. The relevance of this work reaches beyond wastewater treatment sludge to lay the groundwork for application to other distributed wet wastes and blends that together represent a significant resource of underutilized biomass.

  3. Design and Demonstration of a Material-Plasma Exposure Target Station for Neutron Irradiated Samples

    Energy Technology Data Exchange (ETDEWEB)

    Rapp, Juergen [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Aaron, A. M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Bell, Gary L. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Burgess, Thomas W. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Ellis, Ronald James [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Giuliano, D. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Howard, R. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Kiggans, James O. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Lessard, Timothy L. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Ohriner, Evan Keith [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Perkins, Dale E. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Varma, Venugopal Koikal [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2015-10-20

    Fusion energy is the most promising energy source for the future, and one of the most important problems to be solved progressing to a commercial fusion reactor is the identification of plasma-facing materials compatible with the extreme conditions in the fusion reactor environment. The development of plasma–material interaction (PMI) science and the technology of plasma-facing components are key elements in the development of the next step fusion device in the United States, the so-called Fusion Nuclear Science Facility (FNSF). All of these PMI issues and the uncertain impact of the 14-MeV neutron irradiation have been identified in numerous expert panel reports to the fusion community. The 2007 Greenwald report classifies reactor plasma-facing materials (PFCs) and materials as the only Tier 1 issues, requiring a “. . . major extrapolation from the current state of knowledge, need for qualitative improvements and substantial development for both the short and long term.” The Greenwald report goes on to list 19 gaps in understanding and performance related to the plasma–material interface for the technology facilities needed for DEMO-oriented R&D and DEMO itself. Of the 15 major gaps, six (G7, G9, G10, G12, G13) can possibly be addressed with ORNL’s proposal of an advanced Material Plasma Exposure eXperiment. Establishing this mid-scale plasma materials test facility at ORNL is a key element in ORNL’s strategy to secure a leadership role for decades of fusion R&D. That is to say, our end goal is to bring the “signature facility” FNSF home to ORNL. This project is related to the pre-conceptual design of an innovative target station for a future Material–Plasma Exposure eXperiment (MPEX). The target station will be designed to expose candidate fusion reactor plasma-facing materials and components (PFMs and PFCs) to conditions anticipated in fusion reactors, where PFCs will be exposed to dense high-temperature hydrogen plasmas providing steady

  4. Molecular Design of Bisphosphonate-Modified Proteins for Efficient Bone Targeting In Vivo.

    Directory of Open Access Journals (Sweden)

    Hidemasa Katsumi

    Full Text Available To establish a rational molecular design for bisphosphonate (BP-modified proteins for efficient bone targeting, a pharmacokinetic study was performed using a series of alendronate (ALN, a nitrogen-containing BP, modified proteins with various molecular weights and varying degrees of modification. Four proteins with different molecular weight-yeast glutathione reductase (GR; MW: 112,000 Da, bovine serum albumin (BSA; MW: 67,000 Da, recombinant human superoxide dismutase (SOD; MW: 32,000 Da, and chicken egg white lysozyme (LZM; MW: 14,000 Da-were modified with ALN to obtain ALN-modified proteins. Pharmacokinetic analysis of the tissue distribution of the ALN-modified and unmodified proteins was performed after radiolabeling them with indium-111 (111In by using a bifunctional chelating agent. Calculation of tissue uptake clearances revealed that the bone uptake clearances of 111In-ALN-modified proteins were proportional to the degree of ALN modification. 111In-GR-ALN and BSA-ALN, the two high-molecular-weight proteins, efficiently accumulated in bones, regardless of the degree of ALN modification. Approximately 36 and 34% of the dose, respectively, was calculated to be delivered to the bones. In contrast, the maximum amounts taken up by bone were 18 and 13% of the dose for 111In-SOD-ALN(32 and LZM-ALN(9, respectively, because of their high renal clearance. 111In-SOD modified with both polyethylene glycol (PEG and ALN (111In-PEG-SOD-ALN was efficiently delivered to the bone. Approximately 36% of the dose was estimated to be delivered to the bones. In an experimental bone metastasis mouse model, treatment with PEG-SOD-ALN significantly reduced the number of tumor cells in the bone of the mice. These results indicate that the combination of PEG and ALN modification is a promising approach for efficient bone targeting of proteins with a high total-body clearance.

  5. Conceptual design of the handling and storage system of the spent target vessel for neutron scattering facility 2

    Energy Technology Data Exchange (ETDEWEB)

    Adachi, Junichi; Kaminaga, Masanori; Sasaki, Shinobu; Haga, Katsuhiro; Aso, Tomokazu; Kinoshita, Hidetaka; Hino, Ryutaro [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment

    2002-01-01

    In designing the neutron scattering facility, a spent target vessel should be replaced with remote handling devices in order to protect radioactive exposure, since it would be highly activated through the high energy neutron irradiation caused by the spallation reaction between mercury of the target material and the MW-class proton beam. In the storage of the spent target vessel, it is necessary to consider decay heat of the target vessel and mercury contamination caused by vaporization of the residual mercury in the vessel. A conceptual design has been carried out to establish basic concept and to clarify its specification of main equipments on handling and storage systems for the spent target vessel. This report presents the basic concept and a system plot plan based on latest design works of remote handling devices such as a spent target vessel storage cask and a target vessel exchange trolley, which aim at reasonability and simplification. In addition, storage systems for the spent moderator vessel, the spent proton beam window and the spent reflector vessel are also investigated based on the plot plan. (author)

  6. Examination of CRISPR/Cas9 design tools and the effect of target site accessibility on Cas9 activity.

    Science.gov (United States)

    Lee, Ciaran M; Davis, Timothy H; Bao, Gang

    2017-03-16

    What is the topic of this review? In this review, we analyse the performance of recently described tools for CRISPR/Cas9 guide RNA design, in particular, design tools that predict CRISPR/Cas9 activity. What advances does it highlight? Recently, many tools designed to predict CRISPR/Cas9 activity have been reported. However, the majority of these tools lack experimental validation. Our analyses indicate that these tools have poor predictive power. Our preliminary results suggest that target site accessibility should be considered in order to develop better guide RNA design tools with improved predictive power. The recent adaptation of the clustered regulatory interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system for targeted genome engineering has led to its widespread application in many fields worldwide. In order to gain a better understanding of the design rules of CRISPR/Cas9 systems, several groups have carried out large library-based screens leading to some insight into sequence preferences among highly active target sites. To facilitate CRISPR/Cas9 design, these studies have spawned a plethora of guide RNA (gRNA) design tools with algorithms based solely on direct or indirect sequence features. Here, we demonstrate that the predictive power of these tools is poor, suggesting that sequence features alone cannot accurately inform the cutting efficiency of a particular CRISPR/Cas9 gRNA design. Furthermore, we demonstrate that DNA target site accessibility influences the activity of CRISPR/Cas9. With further optimization, we hypothesize that it will be possible to increase the predictive power of gRNA design tools by including both sequence and target site accessibility metrics. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

  7. FEA Analysis of AP-0 Target Hall Collection Lens (Current Design)

    Energy Technology Data Exchange (ETDEWEB)

    Hurh, P.G.; Tang, Z.

    2001-06-22

    The AP-0 Target Hall Collection Lens is a pulsed device which focuses anti-protons just downstream of the Target. Since the angles at which the anti-protons depart the Target can be quite large, a very high focusing strength is required to maximize anti-proton capture into the downstream Debuncher Ring. The current design of the Collection Lens was designed to operate with a focusing gradient of 1,000 T/m. However, multiple failures of early devices resulted in lowering the normal operating gradient to about 750 T/m. At this gradient, the Lens design fares much better, lasting several million pulses, but ultimately still fails. A Finite Element Analysis (FEA) has been performed on this Collection Lens design to help determine the cause and/or nature of the failures. The Collection Lens magnetic field is created by passing high current through a central conductor cylinder. A uniform current distribution through the cylinder will create a tangential or azimuthal magnetic field that varies linearly from zero at the center of the cylinder to a maximum at the outer surface of the cylinder. Anti-proton particles passing through this cylinder (along the longitudinal direction) will see an inward focusing kick back toward the center of the cylinder proportional to the magnetic field strength. For the current Lens design a gradient of 1,000 T/m requires a current of about 580,000 amps. Since the DC power and cooling requirements would be prohibitive, the Lens is operated in a pulsed mode. Each pulse is half sine wave in shape with a pulse duration of about 350 microseconds. Because of the skin effect, the most uniform current density actually occurs about two-thirds of the way through the pulse. This means that the maximum current of the pulse is actually higher than that required in the DC case (about 670,000 amps). Since the beam must pass through the central conductor cylinder it must be made of a conducting material that is also very 'transparent' to the beam

  8. Mucoadhesive microemulsion of ibuprofen: design and evaluation for brain targeting efficiency through intranasal route

    Directory of Open Access Journals (Sweden)

    Surjyanarayan Mandal

    2015-09-01

    Full Text Available This study aimed at designing mucoadhesive microemulsion gel to enhance the brain uptake of Ibuprofen through intranasal route. Ibuprofen loaded mucoadhesive microemulsion (MMEI was developed by incorporating polycarbophil as mucoadhesive polymer into Capmul MCM based optimal microemulsion (MEI and was subjected to characterization, stability, mucoadhesion and naso-ciliotoxicity study. Brain uptake of ibuprofen via nasal route was studied by performing biodistribution study in Swiss albino rats. MEI was found to be transparent, stable and non ciliotoxic with 66.29 ± 4.15 nm, -20.9 ± 3.98 mV and 98.66 ± 1.01% as average globule size, zeta potential and drug content respectively. Transmission Electron Microscopy (TEM study revealed the narrow globule size distribution of MEI. Following single intranasal administration of MMEI and MEI at a dose of 2.86 mg/kg, uptake of ibuprofen in the olfactory bulb was around 3.0 and 1.7 folds compared with intravenous injection of ibuprofen solution (IDS. The ratios of AUC in brain tissues to that in plasma obtained after nasal administration of MMEI were significantly higher than those after intravenous administration of IDS. Findings of the present investigation revealed that the developed mucoadhesive microemulsion gel could be a promising approach for brain targeting of ibuprofen through intranasal route.

  9. Structure-Based Design of Scaffolds Targeting PDE10A by INPHARMA-NMR.

    Science.gov (United States)

    Codutti, Luca; Grimaldi, Manuela; Carlomagno, Teresa

    2017-06-26

    Phosphodiesterases (PDE) hydrolyze both cyclic AMP and GMP (cAMP/cGMP) and are responsible for the regulation of their levels in a multitude of cellular functions. PDE10A is expressed in the brain and is a validated target for both schizophrenia and Huntington disease. Here, we address the identification of novel chemical scaffolds that may bind PDE10A via structure-based drug design. For this task, we use INPHARMA, an NMR-based method that measures protein-mediated interligand NOEs between pairs of weakly, competitively binding ligands. INPHARMA is applied to a combination of four chemically diverse PDE10A binding fragments, with the aim of merging their pharmacophoric features into a larger, tighter binding molecule. All four ligands bind the PDE10A cAMP binding domain with affinity in the micromolar range. The application of INPHARMA to identify the correct docking poses of these ligands is challenging due to the nature of the binding pocket and the high content of water-mediated intermolecular contacts. Nevertheless, ensemble docking in the presence of conserved water molecules generates docking poses that are in agreement with all sets of INPHARMA data. These poses are used to build a pharmacophore model with which we search the ZINC database.

  10. Designing Efficient Double RNA trans-Splicing Molecules for Targeted RNA Repair

    Directory of Open Access Journals (Sweden)

    Clemens Hüttner

    2016-09-01

    Full Text Available RNA trans-splicing is a promising tool for mRNA modification in a diversity of genetic disorders. In particular, the substitution of internal exons of a gene by combining 3′ and 5′ RNA trans-splicing seems to be an elegant way to modify especially large pre-mRNAs. Here we discuss a robust method for designing double RNA trans-splicing molecules (dRTM. We demonstrate how the technique can be implemented in an endogenous setting, using COL7A1, the gene encoding type VII collagen, as a target. An RTM screening system was developed with the aim of testing the replacement of two internal COL7A1 exons, harbouring a homozygous mutation, with the wild-type version. The most efficient RTMs from a pool of randomly generated variants were selected via our fluorescence-based screening system and adapted for use in an in vitro disease model system. Transduction of type VII collagen-deficient keratinocytes with the selected dRTM led to accurate replacement of two internal COL7A1 exons resulting in a restored wild-type RNA sequence. This is the first study demonstrating specific exon replacement by double RNA trans-splicing within an endogenous transcript in cultured cells, corroborating the utility of this technology for mRNA repair in a variety of genetic disorders.

  11. Target/Blanket Design for the Accelerator Production of Tritium Plant

    Energy Technology Data Exchange (ETDEWEB)

    Cappiello, M. W.

    1997-12-31

    The Accelerator Production of Tritium Target/Blanket (T/B) system is comprised of the T/B assembly and the attendant heat removal systems. The T/B assembly produces tritium using a high energy proton beam, and a spallation neutron source. The supporting heat removal systems safely remove the heat deposited by the proton beam during both normal and off-normal conditions. All systems reside within the T/B building, which is located at the end of a linear accelerator. Protons are accelerated to an energy of 1700 MeV at a current of 100 mA and are directed onto the T/B assembly. The protons interact with tungsten and lead nuclei to produce neutrons through the process of nuclear spallation. Neutron capture in {sup 3}He gas produces tritium which is removed on a continual basis in an adjacent Tritium Separation Facility (TSF). The T/B assembly is modular to allow for replacement of spent components and minimization of waste. Systems and components are designed with safety as a primary consideration to minimize risk to the workers and the public.

  12. Evaluating protein-protein interaction (PPI) networks for diseases pathway, target discovery, and drug-design using 'in silico pharmacology'.

    Science.gov (United States)

    Chakraborty, Chiranjib; Doss C, George Priya; Chen, Luonan; Zhu, Hailong

    2014-01-01

    In silico pharmacology is a promising field in the current state-of drug discovery. This area exploits "protein-protein Interaction (PPI) network analysis for drug discovery using the drug "target class". To document the current status, we have discussed in this article how this an integrated system of PPI networks contribute to understand the disease pathways, present state-of-the-art drug target discovery and drug discovery process. This review article enhances our knowledge on conventional drug discovery and current drug discovery using in silico techniques, best "target class", universal architecture of PPI networks, the present scenario of disease pathways and protein-protein interaction networks as well as the method to comprehend the PPI networks. Taken all together, ultimately a snapshot has been discussed to be familiar with how PPI network architecture can used to validate a drug target. At the conclusion, we have illustrated the future directions of PPI in target discovery and drug-design.

  13. Design, Synthesis, and Evaluation of Near Infrared Fluorescent Multimeric RGD Peptides for Targeting Tumors

    Science.gov (United States)

    Ye, Yunpeng; Bloch, Sharon; Xu, Baogang; Achilefu, Samuel

    2008-01-01

    Molecular interactions between RGD peptides and integrins are known to mediate many biological and pathological processes. This has led to an increased interest in the development of RGD compounds with high affinity and improved selectivity for integrin receptors. In this study, we synthesized and evaluated a series of multimeric RGD compounds constructed on a dicarboxylic acid-containing near infrared (NIR) fluorescent dye (cypate) for tumor targeting. An array of NIR fluorescent RGD compounds were prepared efficiently, including an RGD monomer (cypate-(RGD)2-NH2), two RGD dimers (cypate-(RGD)2-NH2 and cypate-(RGD-NH2)2), a trimer (cypate-(RGD)3-NH2), two tetramers (cypate-(RGD)4-NH2 and cypate-[(RGD)2-NH2]2), a hexamer (cypate-[(RGD)3-NH2]2), and an octamer (cypate-[(RGD)4-NH2]2). The binding affinity of the multimeric RGD compounds for αvβ3 integrin receptor (ABIR) showed a remarkable increase relative to the monomer cypate-RGD-NH2. Generally, the divalent linear arrays of the multimeric RGD units bound the ABIR with slightly higher affinity than their monovalent analogues. These results suggest that the receptor binding affinity was not only dependent on the number of RGD moieties but also on the spatial alignments of the pendant peptides. Internalization of the compounds by ABIR-positive tumor cells (A549) was monitored by NIR fluorescence microscopy. The data showed that endocytosis of the octameric RGD derivative was significantly higher by comparison to other compounds in this study. In vivo noninvasive optical imaging and biodistribution data showed that the compounds were retained in A549 tumor tissue. These results clearly demonstrated that an array of simple RGD tripeptides on a NIR fluorescent dye core can be recognized by ABIR. Optimization of the spatial alignment of the RGD moieties through careful molecular design and library construction could induce multivalent ligand-receptor interactions useful for in vivo tumor imaging and tumor-targeted

  14. OptMAVEn--a new framework for the de novo design of antibody variable region models targeting specific antigen epitopes.

    Directory of Open Access Journals (Sweden)

    Tong Li

    Full Text Available Antibody-based therapeutics provides novel and efficacious treatments for a number of diseases. Traditional experimental approaches for designing therapeutic antibodies rely on raising antibodies against a target antigen in an immunized animal or directed evolution of antibodies with low affinity for the desired antigen. However, these methods remain time consuming, cannot target a specific epitope and do not lead to broad design principles informing other studies. Computational design methods can overcome some of these limitations by using biophysics models to rationally select antibody parts that maximize affinity for a target antigen epitope. This has been addressed to some extend by OptCDR for the design of complementary determining regions. Here, we extend this earlier contribution by addressing the de novo design of a model of the entire antibody variable region against a given antigen epitope while safeguarding for immunogenicity (Optimal Method for Antibody Variable region Engineering, OptMAVEn. OptMAVEn simulates in silico the in vivo steps of antibody generation and evolution, and is capable of capturing the critical structural features responsible for affinity maturation of antibodies. In addition, a humanization procedure was developed and incorporated into OptMAVEn to minimize the potential immunogenicity of the designed antibody models. As case studies, OptMAVEn was applied to design models of neutralizing antibodies targeting influenza hemagglutinin and HIV gp120. For both HA and gp120, novel computational antibody models with numerous interactions with their target epitopes were generated. The observed rates of mutations and types of amino acid changes during in silico affinity maturation are consistent with what has been observed during in vivo affinity maturation. The results demonstrate that OptMAVEn can efficiently generate diverse computational antibody models with both optimized binding affinity to antigens and reduced

  15. CRISPRdirect: software for designing CRISPR/Cas guide RNA with reduced off-target sites.

    Science.gov (United States)

    Naito, Yuki; Hino, Kimihiro; Bono, Hidemasa; Ui-Tei, Kumiko

    2015-04-01

    CRISPRdirect is a simple and functional web server for selecting rational CRISPR/Cas targets from an input sequence. The CRISPR/Cas system is a promising technique for genome engineering which allows target-specific cleavage of genomic DNA guided by Cas9 nuclease in complex with a guide RNA (gRNA), that complementarily binds to a ∼ 20 nt targeted sequence. The target sequence requirements are twofold. First, the 5'-NGG protospacer adjacent motif (PAM) sequence must be located adjacent to the target sequence. Second, the target sequence should be specific within the entire genome in order to avoid off-target editing. CRISPRdirect enables users to easily select rational target sequences with minimized off-target sites by performing exhaustive searches against genomic sequences. The server currently incorporates the genomic sequences of human, mouse, rat, marmoset, pig, chicken, frog, zebrafish, Ciona, fruit fly, silkworm, Caenorhabditis elegans, Arabidopsis, rice, Sorghum and budding yeast. Freely available at http://crispr.dbcls.jp/. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press.

  16. High Bandwidth, Multi-Purpose Passive Radar Receiver Design For Aerospace and Geoscience Targets

    Science.gov (United States)

    Vertatschitsch, Laura

    Passive radar permits inexpensive and stealthy detection and tracking of aerospace and geoscience targets. Transmitters of opportunity such as commercial FM broadcast, DTV broadcast, and cell phone towers are already illuminating many populated areas with continuous power. Passive radar receivers can be located at a distance from the transmitter, and can sense this direct transmission as well as any reflections from ground clutter, aircraft, ionospheric turbulence and meteor trails. The 100% duty cycle allows for long coherent integration, increasing the sensitivity of these instruments greatly. Traditional radar receivers employ analog front end downconverters to translate the radio frequency spectrum to an intermediate frequency (IF) for sampling and signal processing. Such downconverters limit the spectrum available for study, and can introduce nonlinearities which limit the detectability of weak signals in the presence of strong signals. With suitably fast digitizers one can bypass the downconversion stage completely. Very fast digitizers may have relatively few bits, but precision is recovered in subsequent signal processing. We present a new passive radar receiver designed to utilize a broad spectrum of commercial transmitters without the use of a front end analog downconverter. The receiver centers around a Reconfigurable Open Architecture Computing Hardware (ROACH) board developed by the Collaboration for Astronomy Signal Processing and Electronics Research (CASPER) group. Fast sampling rates (8-bit samples as fast as 3 GSps) combined with 640 multiply/addition operations on the Virtex-5 FPGA centered on the ROACH allows for coherent processing of broad spectrum and dynamic decision-making on one device all while sharing a single front end, putting this device on the cutting edge of wideband receiver technology. The radar is also designed to support mobile operation. It fits within a 19'' rack, it is equipped with solid state hard drives, and can run off an

  17. In Silico Design and Experimental Validation of siRNAs Targeting Conserved Regions of Multiple Hepatitis C Virus Genotypes.

    Directory of Open Access Journals (Sweden)

    Mahmoud ElHefnawi

    Full Text Available RNA interference (RNAi is a post-transcriptional gene silencing mechanism that mediates the sequence-specific degradation of targeted RNA and thus provides a tremendous opportunity for development of oligonucleotide-based drugs. Here, we report on the design and validation of small interfering RNAs (siRNAs targeting highly conserved regions of the hepatitis C virus (HCV genome. To aim for therapeutic applications by optimizing the RNAi efficacy and reducing potential side effects, we considered different factors such as target RNA variations, thermodynamics and accessibility of the siRNA and target RNA, and off-target effects. This aim was achieved using an in silico design and selection protocol complemented by an automated MysiRNA-Designer pipeline. The protocol included the design and filtration of siRNAs targeting highly conserved and accessible regions within the HCV internal ribosome entry site, and adjacent core sequences of the viral genome with high-ranking efficacy scores. Off-target analysis excluded siRNAs with potential binding to human mRNAs. Under this strict selection process, two siRNAs (HCV353 and HCV258 were selected based on their predicted high specificity and potency. These siRNAs were tested for antiviral efficacy in HCV genotype 1 and 2 replicon cell lines. Both in silico-designed siRNAs efficiently inhibited HCV RNA replication, even at low concentrations and for short exposure times (24h; they also exceeded the antiviral potencies of reference siRNAs targeting HCV. Furthermore, HCV353 and HCV258 siRNAs also inhibited replication of patient-derived HCV genotype 4 isolates in infected Huh-7 cells. Prolonged treatment of HCV replicon cells with HCV353 did not result in the appearance of escape mutant viruses. Taken together, these results reveal the accuracy and strength of our integrated siRNA design and selection protocols. These protocols could be used to design highly potent and specific RNAi-based therapeutic

  18. Multifunctional gold nanoparticles for targeted imaging of angiotensin converting enzyme design, characterization, and application

    Science.gov (United States)

    Ghann, William Emmanuel

    agent could ultimately be used to monitor the levels of this biomarker in people predisposed to cardiovascular diseases due to genetic biases. It is anticipated that the targeted gold nanoparticle system could be applied in the design of similar multifunctional nanoparticles through the use of other disease-specific imaging nanoprobes.

  19. Impact of first-principles properties of deuterium–tritium on inertial confinement fusion target designs

    Energy Technology Data Exchange (ETDEWEB)

    Hu, S. X., E-mail: shu@lle.rochester.edu; Goncharov, V. N.; Boehly, T. R.; McCrory, R. L.; Skupsky, S. [Laboratory for Laser Energetics, University of Rochester, 250 East River Road, Rochester, New York 14623-1299 (United States); Collins, L. A.; Kress, J. D. [Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545 (United States); Militzer, B. [Department of Earth and Planetary Science and Department of Astronomy, University of California, Berkeley, California 94720 (United States)

    2015-05-15

    -based properties of DT are essential for designing ICF ignition targets. Future work on first-principles studies of ICF ablator materials is also discussed.

  20. Use of designer nucleases for targeted gene and genome editing in plants.

    Science.gov (United States)

    Weeks, Donald P; Spalding, Martin H; Yang, Bing

    2016-02-01

    The ability to efficiently inactivate or replace genes in model organisms allowed a rapid expansion of our understanding of many of the genetic, biochemical, molecular and cellular mechanisms that support life. With the advent of new techniques for manipulating genes and genomes that are applicable not only to single-celled organisms, but also to more complex organisms such as animals and plants, the speed with which scientists and biotechnologists can expand fundamental knowledge and apply that knowledge to improvements in medicine, industry and agriculture is set to expand in an exponential fashion. At the heart of these advancements will be the use of gene editing tools such as zinc finger nucleases, modified meganucleases, hybrid DNA/RNA oligonucleotides, TAL effector nucleases and modified CRISPR/Cas9. Each of these tools has the ability to precisely target one specific DNA sequence within a genome and (except for DNA/RNA oligonucleotides) to create a double-stranded DNA break. DNA repair to such breaks sometimes leads to gene knockouts or gene replacement by homologous recombination if exogenously supplied homologous DNA fragments are made available. Genome rearrangements are also possible to engineer. Creation and use of such genome rearrangements, gene knockouts and gene replacements by the plant science community is gaining significant momentum. To document some of this progress and to explore the technology's longer term potential, this review highlights present and future uses of designer nucleases to greatly expedite research with model plant systems and to engineer genes and genomes in major and minor crop species for enhanced food production. © 2015 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

  1. Design and optimisation of the positron production chain for CLIC from the target to the damping ring

    Science.gov (United States)

    Bayar, C.; Ciftci, A. K.; Doebert, S.; Latina, A.

    2017-10-01

    The CLIC Positron source has been designed to produce non-polarised positron beams using a hybrid target composed of a crystal followed by an amorphous target. After production, positrons are captured and accelerated to 200 MeV in the pre-injector linac and subsequently accelerated further up to 2.86 GeV in the injector linac. At this point they enter the pre-damping ring and afterwards the main damping ring to obtain the necessary beam quality for a linear collider. In this study, we have designed and optimised the beam transport and acceleration from the target to the pre-damping ring which has a limiting transverse and longitudinal acceptance. The goal of the study was to maximise the positron yield accepted by the pre-damping ring.

  2. Design, synthesis and evaluation of seleno-dihydropyrimidinones as potential multi-targeted therapeutics for Alzheimer's disease.

    Science.gov (United States)

    Canto, Rômulo F S; Barbosa, Flavio A R; Nascimento, Vanessa; de Oliveira, Aldo S; Brighente, Inês M C; Braga, Antonio Luiz

    2014-06-07

    In this paper we report the design, synthesis and evaluation of a series of seleno-dihydropyrimidinones as potential multi-targeted therapeutics for Alzheimer's disease. The compounds show excellent results as acetylcholinesterase inhibitors, being as active as the standard drug. All these compounds also show very good antioxidant activity through different mechanisms of action.

  3. Design and synthesis of a novel inhibitor of T. Viride chitinase through an in silico target fishing protocol.

    Science.gov (United States)

    Maccari, Giorgio; Deodato, Davide; Fiorucci, Diego; Orofino, Francesco; Truglio, Giuseppina I; Pasero, Carolina; Martini, Riccardo; De Luca, Filomena; Docquier, Jean-Denis; Botta, Maurizio

    2017-08-01

    In the last ten years, we identified and developed a new therapeutic class of antifungal agents, the macrocyclic amidinoureas. These compounds are active against several Candida species, including clinical isolates resistant to currently available antifungal drugs. The mode of action of these molecules is still unknown. In this work, we developed an in-silico target fishing procedure to identify a possible target for this class of compounds based on shape similarity, inverse docking procedure and consensus score rank-by-rank. Chitinase enzyme emerged as possible target. To confirm this hypothesis a novel macrocyclic derivative has been produced, specifically designed to increase the inhibition of the chitinase. Biological evaluation highlights a stronger enzymatic inhibition for the new derivative, while its antifungal activity drops probably because of pharmacokinetic issues. Collectively, our data suggest that chitinase represent at least one of the main target of macrocyclic amidinoureas. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. A rail system for circular synthetic aperture sonar imaging and acoustic target strength measurements: design/operation/preliminary results.

    Science.gov (United States)

    Kennedy, J L; Marston, T M; Lee, K; Lopes, J L; Lim, R

    2014-01-01

    A 22 m diameter circular rail, outfitted with a mobile sonar tower trolley, was designed, fabricated, instrumented with underwater acoustic transducers, and assembled on a 1.5 m thick sand layer at the bottom of a large freshwater pool to carry out sonar design and target scattering response studies. The mobile sonar tower translates along the rail via a drive motor controlled by customized LabVIEW software. The rail system is modular and assembly consists of separately deploying eight circular arc sections, measuring a nominal center radius of 11 m and 8.64 m arc length each, and having divers connect them together in the underwater environment. The system enables full scale measurements on targets of interest with 0.1° angular resolution over a complete 360° aperture, without disrupting target setup, and affording a level of control over target environment conditions and noise sources unachievable in standard field measurements. In recent use, the mobile cart carrying an instrumented sonar tower was translated along the rail in 720 equal position increments and acoustic backscatter data were acquired at each position. In addition, this system can accommodate both broadband monostatic and bistatic scattering measurements on targets of interest, allowing capture of target signature phenomena under diverse configurations to address current scientific and technical issues encountered in mine countermeasure and unexploded ordnance applications. In the work discussed here, the circular rail apparatus is used for acoustic backscatter testing, but this system also has the capacity to facilitate the acquisition of magnetic and optical sensor data from targets of interest. A brief description of the system design and operation will be presented along with preliminary processed results for data acquired from acoustic measurements conducted at the Naval Surface Warfare Center, Panama City Division Test Pond Facility. [Work Supported by the U.S. Office of Naval Research and

  5. Ultra-intense laser interaction with specially-designed targets as a source of energetic protons

    Science.gov (United States)

    Psikal, J.; Matys, M.

    2017-05-01

    In this contribution, we discuss the optimization of laser driven proton acceleration efficiency by nanostructured targets, interpret the experimental results showing the manipulation of proton beam profiles by nanosctructured rear surface of the targets and investigate the acceleration of protons from hydrogen solid ribbon by PW-class lasers, with the help of multidimensional particle-in-cell simulations. Microstructured hollow targets are proposed to enhance the absorption of the laser pulse energy while keeping the target thickness to minimum, which is both favorable for enhanced efficiency of the acceleration of protons. Thin targets with grating structures of various configurations on their rear sides stretch the proton beams in the perpendicular direction to the grating orientation due to transverse electric fields generated inside the target grooves and can reduce the proton beam divergence in the parallel direction to the grating due to a lower density of the stretched beam compared with flat foils. Finally, it is shown that when multiPW laser pulse interacts with hydrogen solid ribbon, hole boring radiation pressure acceleration (RPA) dominates over the target normal sheath acceleration (TNSA).

  6. Atomic Beam Merging and Suppression of Alkali Contaminants in Multi Body High Power Targets: Design and Test of Target and Ion Source Prototypes at ISOLDE

    CERN Document Server

    Bouquerel, Elian J A; Lettry, J; Stora, T

    2009-01-01

    The next generation of high power ISOL-facilities will deliver intense and pure radioactive ion beams. Two key issues of developments mandatory for the forthcoming generation of ISOL target-ion source units are assessed and demonstrated in this thesis. The design and production of target and ion-source prototypes is described and dedicated measurements at ISOLDE-CERN of their radioisotope yields are analyzed. The purity of short lived or rare radioisotopes suffer from isobaric contaminants, notably alkalis which are highly volatile and easily ionized elements. Therefore, relying on their chemical nature, temperature controlled transfer lines were equipped with a tube of quartz that aimed at trapping these unwanted elements before they reached the ion source. The successful application yields high alkali-suppression factors for several elements (ie: 80, 82mRb, 126, 142Cs, 8Li, 46K, 25Na, 114In, 77Ga, 95, 96Sr) for quartz temperatures between 300ºC and 1100ºC. The enthalpies of adsorption on quartz were measu...

  7. Generation of Parametric Equivalent-Area Targets for Design of Low-Boom Supersonic Concepts

    Science.gov (United States)

    Li, Wu; Shields, Elwood

    2011-01-01

    A tool with an Excel visual interface is developed to generate equivalent-area (A(sub e)) targets that satisfy the volume constraints for a low-boom supersonic configuration. The new parametric Ae target explorer allows users to interactively study the tradeoffs between the aircraft volume constraints and the low-boom characteristics (e.g., loudness) of the ground signature. Moreover, numerical optimization can be used to generate the optimal A(sub e) target for given A(sub e) volume constraints. A case study is used to demonstrate how a generated low-boom Ae target can be matched by a supersonic configuration that includes a fuselage, wing, nacelle, pylon, aft pod, horizontal tail, and vertical tail. The low-boom configuration is verified by sonic-boom analysis with an off-body pressure distribution at three body lengths below the configuration

  8. Target, purging magnet and electron collector design for scanned high-energy photon beams

    Energy Technology Data Exchange (ETDEWEB)

    Svensson, Roger; Aasell, Mats; Naefstadius, Peder; Brahme, Anders [Department of Medical Radiation Physics, Karolinska Institutet and Stockholm University, PO Box 260, S-171 76 Stockholm (Sweden)

    1998-05-01

    A new method for producing very narrow and intense 50 MV bremsstrahlung beams with a half-width as low as 35 mm at a distance of 1 m from the target is presented. Such a beam is well suited for intensity modulation using scanned photon beams. An algorithm has been developed to minimize the width of the bremsstrahlung beam generated in a multilayer target by varying the individual layer thicknesses and atomic numbers under given constraints on the total target thickness and the mean energy of the transmitted electrons. Under such constraints the narrowest possible bremsstrahlung beam is obtained with a target composed of layers of monotonically increasing atomic number starting with the lowest possible value at the entrance side where the electrons impinge. It is also shown that the narrowest photon beam profile is associated with the highest possible forward photon yield. To be able to use the optimized target clinically it is desirable to be able to collect and stop all the electrons that are transmitted through the target. The electrons are most efficiently collected if they are kept close together, i.e. by minimizing the multiple scatter of the electrons and consequently the half-width of the generated bremsstrahlung beam. This is achieved by a thin low-atomic-number target. A dedicated electron stopper has been developed and integrated with the purging magnet. When the electron stopper is combined with a purging magnet, a primary photon collimator and a multileaf collimator, almost all of the transmitted electrons and their associated bremsstrahlung contamination can effectively be collected. The narrow photon beams from thin low-atomic-number targets have the additional advantage of producing the hardest and most penetrative photon spectrum possible, which is ideal for treating large deep-seated tumours. (author)

  9. A Bombesin-Shepherdin Radioconjugate Designed for Combined Extra- and Intracellular Targeting

    Directory of Open Access Journals (Sweden)

    Christiane A. Fischer

    2014-05-01

    Full Text Available Radiolabeled peptides which target tumor-specific membrane structures of cancer cells represent a promising class of targeted radiopharmaceuticals for the diagnosis and therapy of cancer. A potential drawback of a number of reported radiopeptides is the rapid washout of a substantial fraction of the initially delivered radioactivity from cancer cells and tumors. This renders the initial targeting effort in part futile and results in a lower imaging quality and efficacy of the radiotracer than achievable. We are investigating the combination of internalizing radiopeptides with molecular entities specific for an intracellular target. By enabling intracellular interactions of the radioconjugate, we aim at reducing/decelerating the externalization of radioactivity from cancer cells. Using the “click-to-chelate” approach, the 99mTc-tricarbonyl core as a reporter probe for single-photon emission computed tomography (SPECT was combined with the binding sequence of bombesin for extracellular targeting of the gastrin-releasing peptide receptor (GRP-r and peptidic inhibitors of the cytosolic heat shock 90 protein (Hsp90 for intracellular targeting. Receptor-specific uptake of the multifunctional radioconjugate could be confirmed, however, the cellular washout of radioactivity was not improved. We assume that either endosomal trapping or lysosomal degradation of the radioconjugate is accountable for these observations.

  10. Learning from structure-based drug design and new antivirals targeting the ribonucleoprotein complex for the treatment of influenza.

    Science.gov (United States)

    Monod, Alexandre; Swale, Christopher; Tarus, Bogdan; Tissot, Alice; Delmas, Bernard; Ruigrok, Rob Wh; Crépin, Thibaut; Slama-Schwok, Anny

    2015-04-01

    Influenza viruses are a threat to human health. There are presently only two methods for treating influenza: vaccines, which require yearly updates, and two classes of antivirals that suffer with the problem of resistance by current human influenza viruses; this is especially the case with amantadine and rimantadine. Consequently, there is an urgent need for the development of new antivirals with new mechanisms of action. In this review, the authors focus on viral protein domains, their associated activity and their inhibition by small molecules defined by a structure-based design with a special emphasis on the ribonucleoprotein complex and its inhibitors. Several new classes of antiviral candidates targeting viral replication through individual domains of the polymerase and the nucleoprotein (NP) have been developed through structure-based design. To date, the antivirals targeting neuraminidase are by far the most developed and potent. Antiviral candidates targeting the NP and polymerase domains are in the pipeline but their pharmacokinetics needs further studies. The recently published structures of the polymerase expand the possibilities for development of new antivirals. Combination therapies targeting conserved viral targets and new cellular proteins or exploiting drug promiscuity hold promises to fight against the emergence of resistance.

  11. Comparative Evaluation of Several Gene Targets for Designing a Multiplex-PCR for an Early Diagnosis of Extrapulmonary Tuberculosis.

    Science.gov (United States)

    Raj, Ankush; Singh, Netrapal; Gupta, Krishna B; Chaudhary, Dhruva; Yadav, Aparna; Chaudhary, Anil; Agarwal, Kshitij; Varma-Basil, Mandira; Prasad, Rajendra; Khuller, Gopal K; Mehta, Promod K

    2016-01-01

    Diagnosis of extrapulmonary tuberculosis (EPTB) poses serious challenges. A careful selection of appropriate gene targets is essential for designing a multiplex-polymerase chain reaction (M-PCR) assay. We compared several gene targets of Mycobacterium tuberculosis, including IS6110, devR, and genes encoding MPB-64 (mpb64), 38kDa (pstS1), 65kDa (hsp65), 30kDa (fbpB), ESAT-6 (esat6), and CFP-10 (cfp10) proteins, using PCR assays on 105 EPTB specimens. From these data, we chose the two best gene targets to design an M-PCR. Among all gene targets tested, mpb64 showed the highest sensitivity (84% in confirmed cases and 77.5% in clinically suspected cases), followed by IS6110, hsp65, 38kDa, 30kDa, esat6, cfp10, and devR. We used mpb64+IS6110 for designing an M-PCR assay. Our M-PCR assay demonstrated a high sensitivity of 96% in confirmed EPTB cases and 88.75% in clinically suspected EPTB cases with a high specificity of 100%, taking clinical diagnosis as the gold standard. These M-PCR results along with the clinical findings may facilitate an early diagnosis of EPTB patients and clinical management of disease.

  12. 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.

  13. Advanced Targeting Cost Function Design for Evolutionary Optimization of Control of Logistic Equation

    Science.gov (United States)

    Senkerik, Roman; Zelinka, Ivan; Davendra, Donald; Oplatkova, Zuzana

    2010-06-01

    This research deals with the optimization of the control of chaos by means of evolutionary algorithms. This work is aimed on an explanation of how to use evolutionary algorithms (EAs) and how to properly define the advanced targeting cost function (CF) securing very fast and precise stabilization of desired state for any initial conditions. As a model of deterministic chaotic system, the one dimensional Logistic equation was used. The evolutionary algorithm Self-Organizing Migrating Algorithm (SOMA) was used in four versions. For each version, repeated simulations were conducted to outline the effectiveness and robustness of used method and targeting CF.

  14. Requirements for design of accelerator, beam transport, and target in a study of thermonuclear reaction cross section

    Energy Technology Data Exchange (ETDEWEB)

    Itahashi, T.; Takahisa, K.; Fujiwara, M.; Toki, H.; Ejiri, H. [Osaka Univ., Ibaraki (Japan). Research Center for Nuclear Physics; Ohsumi, H.; Komori, M.

    1997-03-01

    A compact accelerator with high current ion source, low energy beam transport elements and windowless gas target was designed to investigate the thermonuclear reaction cross section. The idea of this project focused on the cross section measurement of the fusion reaction data {sup 3}He+{sup 3}He-{sup 4}He+p+p at 25keV. The system will be installed in Otoh Cosmo Observatory (1270m.w.e.) to get rid of the huge cosmic and environmental background. It consists of NANOGUN ECR ion source, focusing elements made of permanent magnets window less {sup 3}He gas target and/or He{sup 3} plasma target and detector telescopes with low noise and low background. Requirements for these were discussed technically and various ideas were proposed. (author)

  15. 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.

  16. Structure-based drug design approach to target toll-like receptor ...

    African Journals Online (AJOL)

    unregulated innate immune responses can lead to autoimmune disorders, in which the body attacks itself, causing organ damages [27]. In humans, various families of TLRs have been identified and due to their importance in defense against pathogens, they have been viewed as potential drug targets in the treatment of.

  17. Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor-Binding Site

    National Research Council Canada - National Science Library

    Kanekiyo, Masaru; Bu, Wei; Joyce, M. Gordon; Meng, Geng; Whittle, James R.R; Baxa, Ulrich; Yamamoto, Takuya; Narpala, Sandeep; Todd, John-Paul; Rao, Srinivas S; McDermott, Adrian B; Koup, Richard A; Rossmann, Michael G; Mascola, John R; Graham, Barney S; Cohen, Jeffrey I; Nabel, Gary J

    2015-01-01

    ... a vaccine have focused on the viral major envelope glycoprotein 350/220 (gp350), because it represents a principal target of neutralizing antibodies in naturally infected individuals ( Hoffman et al., 1980; Thorley-Lawson and Geilinger, 1980; Thorley-Lawson and Poodry, 1982 ). Prototype gp350-based vaccines have induced protective immunity a...

  18. Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis.

    Directory of Open Access Journals (Sweden)

    Bálint Mészáros

    2011-07-01

    Full Text Available Lengthy co-evolution of Homo sapiens and Mycobacterium tuberculosis, the main causative agent of tuberculosis, resulted in a dramatically successful pathogen species that presents considerable challenge for modern medicine. The continuous and ever increasing appearance of multi-drug resistant mycobacteria necessitates the identification of novel drug targets and drugs with new mechanisms of action. However, further insights are needed to establish automated protocols for target selection based on the available complete genome sequences. In the present study, we perform complete proteome level comparisons between M. tuberculosis, mycobacteria, other prokaryotes and available eukaryotes based on protein domains, local sequence similarities and protein disorder. We show that the enrichment of certain domains in the genome can indicate an important function specific to M. tuberculosis. We identified two families, termed pkn and PE/PPE that stand out in this respect. The common property of these two protein families is a complex domain organization that combines species-specific regions, commonly occurring domains and disordered segments. Besides highlighting promising novel drug target candidates in M. tuberculosis, the presented analysis can also be viewed as a general protocol to identify proteins involved in species-specific functions in a given organism. We conclude that target selection protocols should be extended to include proteins with complex domain architectures instead of focusing on sequentially unique and essential proteins only.

  19. 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.

  20. The DESI Experiment Part I: Science,Targeting, and Survey Design

    Energy Technology Data Exchange (ETDEWEB)

    Aghamousa, Amir; et al.

    2016-10-31

    DESI (Dark Energy Spectroscopic Instrument) is a Stage IV ground-based dark energy experiment that will study baryon acoustic oscillations (BAO) and the growth of structure through redshift-space distortions with a wide-area galaxy and quasar redshift survey. To trace the underlying dark matter distribution, spectroscopic targets will be selected in four classes from imaging data. We will measure luminous red galaxies up to $z=1.0$. To probe the Universe out to even higher redshift, DESI will target bright [O II] emission line galaxies up to $z=1.7$. Quasars will be targeted both as direct tracers of the underlying dark matter distribution and, at higher redshifts ($ 2.1 < z < 3.5$), for the Ly-$\\alpha$ forest absorption features in their spectra, which will be used to trace the distribution of neutral hydrogen. When moonlight prevents efficient observations of the faint targets of the baseline survey, DESI will conduct a magnitude-limited Bright Galaxy Survey comprising approximately 10 million galaxies with a median $z\\approx 0.2$. In total, more than 30 million galaxy and quasar redshifts will be obtained to measure the BAO feature and determine the matter power spectrum, including redshift space distortions.

  1. Optimizations of siRNA design for the activation of gene transcription by targeting the TATA-box motif.

    Directory of Open Access Journals (Sweden)

    Miaomiao Fan

    Full Text Available Small interfering RNAs (siRNAs are widely used to repress gene expression by targeting mRNAs. Some reports reveal that siRNAs can also activate or inhibit gene expression through targeting the gene promoters. Our group has found that microRNAs (miRNAs could activate gene transcription via interaction with the TATA-box motif in gene promoters. To investigate whether siRNA targeting the same region could upregulate the promoter activity, we test the activating efficiency of siRNAs targeting the TATA-box motif of 16 genes and perform a systematic analysis to identify the common features of the functional siRNAs for effective activation of gene promoters. Further, we try various modifications to improve the activating efficiency of siRNAs and find that it is quite useful to design the promoter-targeting activating siRNA by following several rules such as (a complementary to the TATA-box-centered region; (b UA usage at the first two bases of the antisense strand; (c twenty-three nucleotides (nts in length; (d 2'-O-Methyl (2'-OMe modification at the 3' terminus of the antisense strand; (e avoiding mismatches at the 3' end of the antisense strand. The optimized activating siRNAs potently enhance the expression of interleukin-2 (IL-2 gene in human and mouse primary CD4+ T cells with a long-time effect. Taken together, our study provides a guideline for rational design the promoter-targeting siRNA to sequence-specifically enhance gene expression.

  2. Optimizations of SiRNA Design for the Activation of Gene Transcription by Targeting the TATA-Box Motif

    Science.gov (United States)

    Huang, Zhuoqiong; Liu, Jun; Guo, Xuemin; Zhang, Hui; Luo, Haihua

    2014-01-01

    Small interfering RNAs (siRNAs) are widely used to repress gene expression by targeting mRNAs. Some reports reveal that siRNAs can also activate or inhibit gene expression through targeting the gene promoters. Our group has found that microRNAs (miRNAs) could activate gene transcription via interaction with the TATA-box motif in gene promoters. To investigate whether siRNA targeting the same region could upregulate the promoter activity, we test the activating efficiency of siRNAs targeting the TATA-box motif of 16 genes and perform a systematic analysis to identify the common features of the functional siRNAs for effective activation of gene promoters. Further, we try various modifications to improve the activating efficiency of siRNAs and find that it is quite useful to design the promoter-targeting activating siRNA by following several rules such as (a) complementary to the TATA-box-centered region; (b) UA usage at the first two bases of the antisense strand; (c) twenty-three nucleotides (nts) in length; (d) 2′-O-Methyl (2′-OMe) modification at the 3′ terminus of the antisense strand; (e) avoiding mismatches at the 3′ end of the antisense strand. The optimized activating siRNAs potently enhance the expression of interleukin-2 (IL-2) gene in human and mouse primary CD4+ T cells with a long-time effect. Taken together, our study provides a guideline for rational design the promoter-targeting siRNA to sequence-specifically enhance gene expression. PMID:25250958

  3. Design and test of a 434 MHz multi-channel amplifier system for targeted hyperthermia applicators

    NARCIS (Netherlands)

    Bakker, J. F.; Paulides, M. M.; Westra, A. H.; Schippers, H.; Van Rhoon, G. C.

    2010-01-01

    Purpose: For our head-and-neck hyperthermia ( HT) applicator, an amplifier system with full amplitude and phase-control to deliver the radio-frequency signals, was not available. We therefore designed and tested a 433.92 MHz multi-channel amplifier system. System description: The design consists of

  4. Design of Experiments for Model Calibration of Multi-Physics Systems with Targeted Events of Interest

    Science.gov (United States)

    2017-03-01

    than calibration. The area of the design of validation tests will be a subject of future research . Figure 4. Flowchart of the process of... Validation Tests Find max Utest geometry or ntest = 1 ntest = ntest+1 Define design space (candidate geometries and instrumentation locations... research , the maximum expected information gain is used to determine which wind tunnel specimen geometry, instrumentation locations, and observables

  5. Target Group Characteristics: Are Perceptional Modality Preferences Relevant for Instructional Material Design?

    Science.gov (United States)

    Jaspers, Fons

    1992-01-01

    Discussion of instructional materials design highlights perceptional modality preferences. Research on perception is reviewed; preferences for audio versus video, verbal versus pictorial, and listening versus reading are described; learning styles are considered; and theoretical and practical implications for audiovisual designers are suggested.…

  6. 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.

  7. Separation of on-target efficacy from adverse effects through rational design of a bitopic adenosine receptor agonist.

    Science.gov (United States)

    Valant, Celine; May, Lauren T; Aurelio, Luigi; Chuo, Chung Hui; White, Paul J; Baltos, Jo-Anne; Sexton, Patrick M; Scammells, Peter J; Christopoulos, Arthur

    2014-03-25

    The concepts of allosteric modulation and biased agonism are revolutionizing modern approaches to drug discovery, particularly in the field of G protein-coupled receptors (GPCRs). Both phenomena exploit topographically distinct binding sites to promote unique GPCR conformations that can lead to different patterns of cellular responsiveness. The adenosine A1 GPCR (A1AR) is a major therapeutic target for cardioprotection, but current agents acting on the receptor are clinically limited for this indication because of on-target bradycardia as a serious adverse effect. In the current study, we have rationally designed a novel A1AR ligand (VCP746)--a hybrid molecule comprising adenosine linked to a positive allosteric modulator--specifically to engender biased signaling at the A1AR. We validate that the interaction of VCP746 with the A1AR is consistent with a bitopic mode of receptor engagement (i.e., concomitant association with orthosteric and allosteric sites) and that the compound displays biased agonism relative to prototypical A1AR ligands. Importantly, we also show that the unique pharmacology of VCP746 is (patho)physiologically relevant, because the compound protects against ischemic insult in native A1AR-expressing cardiomyoblasts and cardiomyocytes but does not affect rat atrial heart rate. Thus, this study provides proof of concept that bitopic ligands can be designed as biased agonists to promote on-target efficacy without on-target side effects.

  8. A PC-based imaging system for the Naval Postgraduate School Infrared Search and Target Designation (NPS-IRSTD) system.

    OpenAIRE

    Engel, Raymond Charles

    1989-01-01

    Approved for public release; distribution is unlimited A system to display images from data generated by the Naval Postgraduate School Infrared Search and Target Designation (NPS-IRSTD) system (modified AN/SAR-8 ADM) was developed using an Intel 80386 CPU based desktop computer as the base platform. This computer was enhanced with a Metrabyte PDMA-16 Input/output board to facilitate data transfers and a Data Translation DT2861 framegrabber board for image processing. Images are displayed...

  9. Design, construction and performance evaluation of the target tissue thickness measurement system in intraoperative radiotherapy for breast cancer

    Science.gov (United States)

    Yazdani, Mohammad Reza; Setayeshi, Saeed; Arabalibeik, Hossein; Akbari, Mohammad Esmaeil

    2017-05-01

    Intraoperative electron radiation therapy (IOERT), which uses electron beams for irradiating the target directly during the surgery, has the advantage of delivering a homogeneous dose to a controlled layer of tissue. Since the dose falls off quickly below the target thickness, the underlying normal tissues are spared. In selecting the appropriate electron energy, the accuracy of the target tissue thickness measurement is critical. In contrast to other procedures applied in IOERT, the routine measurement method is considered to be completely traditional and approximate. In this work, a novel mechanism is proposed for measuring the target tissue thickness with an acceptable level of accuracy. An electronic system has been designed and manufactured with the capability of measuring the tissue thickness based on the recorded electron density under the target. The results indicated the possibility of thickness measurement with a maximum error of 2 mm for 91.35% of data. Aside from system limitation in estimating the thickness of 5 mm phantom, for 88.94% of data, maximum error is 1 mm.

  10. Design, construction and performance evaluation of the target tissue thickness measurement system in intraoperative radiotherapy for breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yazdani, Mohammad Reza, E-mail: myazdani@aut.ac.ir [Faculty of Energy Engineering and Physics, Amirkabir University of Technology, Tehran (Iran, Islamic Republic of); Setayeshi, Saeed, E-mail: setayesh@aut.ac.ir [Faculty of Energy Engineering and Physics, Amirkabir University of Technology, Tehran (Iran, Islamic Republic of); Arabalibeik, Hossein, E-mail: arabalibeik@tums.ac.ir [Research Center for Biomedical Technology and Robotics (RCBTR), Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Akbari, Mohammad Esmaeil [Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran (Iran, Islamic Republic of)

    2017-05-21

    Intraoperative electron radiation therapy (IOERT), which uses electron beams for irradiating the target directly during the surgery, has the advantage of delivering a homogeneous dose to a controlled layer of tissue. Since the dose falls off quickly below the target thickness, the underlying normal tissues are spared. In selecting the appropriate electron energy, the accuracy of the target tissue thickness measurement is critical. In contrast to other procedures applied in IOERT, the routine measurement method is considered to be completely traditional and approximate. In this work, a novel mechanism is proposed for measuring the target tissue thickness with an acceptable level of accuracy. An electronic system has been designed and manufactured with the capability of measuring the tissue thickness based on the recorded electron density under the target. The results indicated the possibility of thickness measurement with a maximum error of 2 mm for 91.35% of data. Aside from system limitation in estimating the thickness of 5 mm phantom, for 88.94% of data, maximum error is 1 mm.

  11. Design and In Vivo Characterization of Immunoconjugates Targeting HIV gp160

    Science.gov (United States)

    Song, Kejing; Maresh, Grace A.; Frank, Anderson; Worthylake, David; Chung, Hye-Kyung; Polacino, Patricia; Hamer, Dean H.; Coyne, Cody P.; Rosenblum, Michael G.; Marks, John W.; Chen, Gang; Weiss, Deborah; Ghetie, Victor; Vitetta, Ellen S.; Robinson, James E.; Hu, Shiu-Lok

    2016-01-01

    ABSTRACT The envelope (Env) glycoprotein of HIV is expressed on the surface of productively infected cells and can be used as a target for cytotoxic immunoconjugates (ICs), in which cell-killing moieties, including toxins, drugs, or radionuclides, are chemically or genetically linked to monoclonal antibodies (MAbs) or other targeting ligands. Such ICs could be used to eliminate persistent reservoirs of HIV infection. We have found that MAbs which bind to the external loop of gp41, e.g., MAb 7B2, make highly effective ICs, particularly when used in combination with soluble CD4. We evaluated the toxicity, immunogenicity, and efficacy of the ICs targeted with 7B2 in mice and in simian-human immunodeficiency virus-infected macaques. In the macaques, we tested immunotoxins (ITs), consisting of protein toxins bound to the targeting agent. ITs were well tolerated and initially efficacious but were ultimately limited by their immunogenicity. In an effort to decrease immunogenicity, we tested different toxic moieties, including recombinant toxins, cytotoxic drugs, and tubulin inhibitors. ICs containing deglycosylated ricin A chain prepared from ricin toxin extracted from castor beans were the most effective in killing HIV-infected cells. Having identified immunogenicity as a major concern, we show that conjugation of IT to polyethylene glycol limits immunogenicity. These studies demonstrate that cytotoxic ICs can target virus-infected cells in vivo but also highlight potential problems to be addressed. IMPORTANCE It is not yet possible to cure HIV infection. Even after years of fully effective antiviral therapy, a persistent reservoir of virus-infected cells remains. Here we propose that a targeted conjugate consisting of an anti-HIV antibody bound to a toxic moiety could function to kill the HIV-infected cells that constitute this reservoir. We tested this approach in HIV-infected cells grown in the lab and in animal infections. Our studies demonstrated that these

  12. A Flexible System Level Design Methodology Targeting Run-Time Reconfigurable FPGAs

    Directory of Open Access Journals (Sweden)

    Dominique Houzet

    2008-03-01

    Full Text Available Reconfigurable computing is certainly one of the most important emerging research topics on digital processing architectures over the last few years. The introduction of run-time reconfiguration (RTR on FPGAs requires appropriate design flows and methodologies to fully exploit this new functionality. For that purpose, we present an automatic design generation methodology for heterogeneous architectures based on DSPs and FPGAs that ease and speed RTR implementation. We focus on how to take into account specificities of partially reconfigurable components from a high-level specification during the design generation steps. This method automatically generates designs for both fixed and partially reconfigurable parts of an FPGA with automatic management of the reconfiguration process. Furthermore, this automatic design generation enables a reconfiguration prefetching technique to minimize reconfiguration latency and buffer-merging techniques to minimize memory requirements of the generated design. This concept has been applied to different wireless access schemes, based on a combination of OFDM and CDMA techniques. This implementation example illustrates the benefits of the proposed design methodology.

  13. A Flexible System Level Design Methodology Targeting Run-Time Reconfigurable FPGAs

    Directory of Open Access Journals (Sweden)

    Houzet Dominique

    2007-01-01

    Full Text Available Abstract Reconfigurable computing is certainly one of the most important emerging research topics on digital processing architectures over the last few years. The introduction of run-time reconfiguration (RTR on FPGAs requires appropriate design flows and methodologies to fully exploit this new functionality. For that purpose, we present an automatic design generation methodology for heterogeneous architectures based on DSPs and FPGAs that ease and speed RTR implementation. We focus on how to take into account specificities of partially reconfigurable components from a high-level specification during the design generation steps. This method automatically generates designs for both fixed and partially reconfigurable parts of an FPGA with automatic management of the reconfiguration process. Furthermore, this automatic design generation enables a reconfiguration prefetching technique to minimize reconfiguration latency and buffer-merging techniques to minimize memory requirements of the generated design. This concept has been applied to different wireless access schemes, based on a combination of OFDM and CDMA techniques. This implementation example illustrates the benefits of the proposed design methodology.

  14. Validation of a Computer Code for Use in the Mechanical Design of Spallation Neutron Targets

    CERN Document Server

    Montanez, P A

    2000-01-01

    The present work concentrates on comparing a numerical code and a closed-form analytic solution for determining transient stress waves generated by an impinging, high-intensity proton pulse onto a perfectly elastic solid cylindrical target. The comparison of the two methods serves both to benchmark the physics and numerical methods of the codes, and to verify them against analytic expressions that can be established for calculating the response of the target for simple cases of loading and geometry. Additionally, the comparison elucidated the effects of approximations used in the computation of the analytic results. Two load cases have been investigated: (1) an instantaneously uniform thermal loading along the central core, and (2) a ramped and uniform thermal load applied along the central core. In addition, the influence of the approximations applied to the accurate analytic forms has been elucidated. By validating these analytical results, the closed-form solution may be confidently used to "bound" the sol...

  15. Conceptual Design of Target Assembly System for Boron Neutron Capture Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Kye, Y. U.; Shin, S. G. [POSTECH, Pohang (Korea, Republic of); Namkung, W.; Cho, M. H. [Pohang Accelerator Laboratory, Pohang (Korea, Republic of); Bae, Y. S. [National Fusion Research Institute, Daejeon (Korea, Republic of)

    2016-05-15

    There are many type of accelerator based BNCT. Cyclotron based proton beam is high energy. But it has weakness about low current, severe target damage, and radioactivity problem. This research would be treat by LINAC based proton beam because LINAC based proton beam has high current and low energy. These point are possible to reduce treatment time. Therefore, patients don't have to irradiate at normal cell by neutron beam. Monte Carlo and thermal hydraulics simulation were conducted as neutron flux after moderator assembly, temperature distribution of beryllium target. General consensus is that an epithermal neutron fluence of about 1 x 10{sup 13} /cm{sup 2} is required for successful Neutron Capture Therapy (NCT). If epithermal neutron flux is 1 x 10{sup 10} /cm{sup 2}· sec, the neutron irradiation time would be necessary about 3 hours for therapy.

  16. The DESI Experiment Part I: Science,Targeting, and Survey Design

    OpenAIRE

    DESI Collaboration; Aghamousa, Amir; Aguilar, Jessica; Ahlen, Steve; Alam, Shadab; Allen, Lori E.; Prieto, Carlos Allende; Annis, James; Bailey, Stephen; Balland, Christophe; Ballester, Otger; Baltay, Charles; Beaufore, Lucas; Bebek, Chris; Beers, Timothy C.

    2016-01-01

    DESI (Dark Energy Spectroscopic Instrument) is a Stage IV ground-based dark energy experiment that will study baryon acoustic oscillations (BAO) and the growth of structure through redshift-space distortions with a wide-area galaxy and quasar redshift survey. To trace the underlying dark matter distribution, spectroscopic targets will be selected in four classes from imaging data. We will measure luminous red galaxies up to $z=1.0$. To probe the Universe out to even higher redshift, DESI will...

  17. Crystallation, X-Ray Structure Determination and Structure-Based Drug Design for Targeted Malarial Enzymes

    National Research Council Canada - National Science Library

    DeLucas, Lawrence

    1997-01-01

    .... This structure is currently being used for designing lead inhibitors. We have also purified PFPK-DHPS bifunctional enzyme for structure analysis and are presently screening for crystallization conditions...

  18. Targeting a heterologous protein to multiple plant organelles via rationally designed 5? mRNA tags

    NARCIS (Netherlands)

    Voges, M.J.; Silver, P.A.; Way, J.C.; Mattozzi, M.D.

    2013-01-01

    Background Plant bioengineers require simple genetic devices for predictable localization of heterologous proteins to multiple subcellular compartments. Results We designed novel hybrid signal sequences for multiple-compartment localization and characterize their function when fused to GFP in

  19. Non-equilibrium model for solute transport in differently designed biofilters targeting agricultural drainage water

    DEFF Research Database (Denmark)

    Pugliese, Lorenzo; Bruun, Jacob; Kjaergaard, Charlotte

    2017-01-01

    Biogeochemical processes in subsurface flow constructed wetlands are influenced by flow direction, degree of saturation and influent loading position. This study presents a simulation tool, which aims to predict the performance of the unit and improve the design. The model was developed using...... the HYDRUS program, calibrated and verified on previously measured bromide (Br-) pulse tracer tests. Three different hydraulic designs (Horizontal (HF), Vertical upward (VF-up), Vertical downward (VF-down) and two different flow rates: Low (L), and High (H)) were investigated. The model simulated well the Br......- transport behaviour and the results underline the importance of the hydraulic design. Calibrated model parameters (longitudinal dispersivity, immobile liquid phase, mass transfer coefficient) showed a common trend for all the designs, for increasing flow rates within the investigated range. The VF...

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

    Energy Technology Data Exchange (ETDEWEB)

    Ferres, Laurent [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); National Graduate School of Engineering and Research Center (ENSICAEN), Caen (France)

    2016-08-03

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

  1. Design of a predictive targeting error simulator for MRI-guided prostate biopsy

    Science.gov (United States)

    Avni, Shachar; Vikal, Siddharth; Fichtinger, Gabor

    2010-02-01

    Multi-parametric MRI is a new imaging modality superior in quality to Ultrasound (US) which is currently used in standard prostate biopsy procedures. Surface-based registration of the pre-operative and intra-operative prostate volumes is a simple alternative to side-step the challenges involved with deformable registration. However, segmentation errors inevitably introduced during prostate contouring spoil the registration and biopsy targeting accuracies. For the crucial purpose of validating this procedure, we introduce a fully interactive and customizable simulator which determines the resulting targeting errors of simulated registrations between prostate volumes given user-provided parameters for organ deformation, segmentation, and targeting. We present the workflow executed by the simulator in detail and discuss the parameters involved. We also present a segmentation error introduction algorithm, based on polar curves and natural cubic spline interpolation, which introduces statistically realistic contouring errors. One simulation, including all I/O and preparation for rendering, takes approximately 1 minute and 40 seconds to complete on a system with 3 GB of RAM and four Intel Core 2 Quad CPUs each with a speed of 2.40 GHz. Preliminary results of our simulation suggest the maximum tolerable segmentation error given the presence of a 5.0 mm wide small tumor is between 4-5 mm. We intend to validate these results via clinical trials as part of our ongoing work.

  2. Designing calcium phosphate-based bifunctional nanocapsules with bone-targeting properties

    Energy Technology Data Exchange (ETDEWEB)

    Khung, Yit-Lung; Bastari, Kelsen; Cho, Xing Ling; Yee, Wu Aik; Loo, Say Chye Joachim, E-mail: joachimloo@ntu.edu.sg [Nanyang Technological University, School of Materials Science and Engineering (Singapore)

    2012-06-15

    Using sodium dodecyl sulphate micelles as template, hollow-cored calcium phosphate nanocapsules were produced. The surfaces of the nanocapsule were subsequently silanised by a polyethylene glycol (PEG)-based silane with an N-hydroxysuccinimide ester end groups which permits for further attachment with bisphosphonates (BP). Characterisations of these nanocapsules were investigated using Field Emission Scanning Electron Microscopy (FESEM), Transmission Electron Microscopy, Fourier Transform Infra-Red Spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy and Dynamic Light Scattering. To further validate the bone-targeting potential, dentine discs were incubated with these functionalised nanocapsules. FESEM analysis showed that these surface-modified nanocapsules would bind strongly to dentine surfaces compared to non-functionalised nanocapsules. We envisage that respective components would give this construct a bifunctional attribute, whereby (1) the shell of the calcium phosphate nanocapsule would serve as biocompatible coating aiding in gradual osteoconduction, while (2) surface BP moieties, acting as targeting ligands, would provide the bone-targeting potential of these calcium phosphate nanocapsules.

  3. Drug design with Cdc7 kinase: a potential novel cancer therapy target

    Directory of Open Access Journals (Sweden)

    Masaaki Sawa

    2008-11-01

    Full Text Available Masaaki Sawa1, Hisao Masai21Carna Biosciences, Inc., Kobe, Japan; 2Genome Dynamics Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, JapanAbstract: Identification of novel molecular targets is critical in development of new and efficient cancer therapies. Kinases are one of the most common drug targets with a potential for cancer therapy. Cell cycle progression is regulated by a number of kinases, some of which are being developed to treat cancer. Cdc7 is a serine-threonine kinase originally discovered in budding yeast, which has been shown to be necessary to initiate the S phase. Inhibition of Cdc7 in cancer cells retards the progression of the S phase, accumulates DNA damage, and induces p53-independent cell death, but the same treatment in normal cells does not significantly affect viability. Low-molecular-weight compounds that inhibit Cdc7 kinase with an IC50 of less than 10 nM have been identified, and shown to be effective in the inhibition of tumor growth in animal models. Thus Cdc7 kinase can be recognized as a novel molecular target for cancer therapy.Keywords: Cdc7 kinase, cell cycle, replication fork, genome stability, DNA damages, ATP-binding pocket, kinase inhibitor

  4. Conceptual Design of Targeted Scrum: Applying Mission Command to Agile Software Development

    Science.gov (United States)

    2014-06-01

    on design. Drury et al. (2012) report that many of the decisions made during Scrum planning were more tactical in nature (i.e., which tasks to...Coram, R. (2002). Boyd: The fighter pilot who changed the art of war. Boston, MA: Little, Brown and Company. Drury , M., Conboy, K., & Power, K. (2012...responsiveness (Hochmüller, 2011) (Hoda et al., 2010) • Lack of design focus → Planning decisions more tactical than strategic ( Drury et al., 2012

  5. Implementation of a target volume design function for intrafractional range variation in a particle beam treatment planning system.

    Science.gov (United States)

    Mori, S; Inaniwa, T; Miki, K; Shirai, T; Noda, K

    2014-11-01

    Treatment planning for charged particle therapy in the thoracic and abdominal regions should take account of range uncertainty due to intrafractional motion. Here, we developed a design tool (4Dtool) for the target volume [field-specific target volume (FTV)], which accounts for this uncertainty using four-dimensional CT (4DCT). Target and normal tissue contours were input manually into a treatment planning system (TPS). These data were transferred to the 4Dtool via the picture archiving and communication system (PACS). Contours at the reference phase were propagated to other phases by deformable image registration. FTV was calculated using 4DCT on the 4Dtool. The TPS displays FTV contours using digital imaging and communications in medicine files imported from the PACS. These treatment parameters on the CT image at the reference phase were then used for dose calculation on the TPS. The tool was tested in single clinical case randomly selected from patients treated at our centre for lung cancer. In this clinical case, calculation of dose distribution with the 4Dtool resulted in the successful delivery of carbon-ion beam at the reference phase of 95% of the prescribed dose to the clinical target volume (CTV). Application to the other phases also provided sufficient dose to the CTV. The 4Dtool software allows the design of the target volume with consideration to intrafractional range variation and is now in routine clinical use at our institution. Our alternative technique represents a practical approach to four-dimensional treatment planning within the current state of charged particle therapy.

  6. Nonlocal heat transport and improved target design for x-ray heating studies at x-ray free electron lasers

    Science.gov (United States)

    Hoidn, Oliver; Seidler, Gerald T.

    2018-01-01

    The extremely high-power densities and short durations of single pulses of x-ray free electron lasers (XFELs) have opened new opportunities in atomic physics, where complex excitation-relaxation chains allow for high ionization states in atomic and molecular systems, and in dense plasma physics, where XFEL heating of solid-density targets can create unique dense states of matter having temperatures on the order of the Fermi energy. We focus here on the latter phenomena, with special emphasis on the problem of optimum target design to achieve high x-ray heating into the warm dense matter (WDM) state. We report fully three-dimensional simulations of the incident x-ray pulse and the resulting multielectron relaxation cascade to model the spatial energy density deposition in multicomponent targets, with particular focus on the effects of nonlocal heat transport due to the motion of high energy photoelectrons and Auger electrons. We find that nanoscale high-Z /low-Z multicomponent targets can give much improved energy density deposition in lower-Z materials, with enhancements reaching a factor of 100. This has three important benefits. First, it greatly enlarges the thermodynamic parameter space in XFEL x-ray heating studies of lower-Z materials. Second, it allows the use of higher probe photon energies, enabling higher-information content x-ray diffraction (XRD) measurements such as in two-color XFEL operations. Third, while this is merely one step toward optimization of x-ray heating target design, the demonstration of the importance of nonlocal heat transport establishes important common ground between XFEL-based x-ray heating studies and more traditional laser plasma methods.

  7. The Impact of Targeted Data Collection on Nonresponse Bias in an Establishment Survey: A Simulation Study of Adaptive Survey Design

    Directory of Open Access Journals (Sweden)

    McCarthy Jaki

    2017-09-01

    Full Text Available Nonresponse rates have been growing over time leading to concerns about survey data quality. Adaptive designs seek to allocate scarce resources by targeting specific subsets of sampled units for additional effort or a different recruitment protocol. In order to be effective in reducing nonresponse, the identified subsets of the sample need two key features: 1 their probabilities of response can be impacted by changing design features, and 2 once they have responded, this can have an impact on estimates after adjustment. The National Agricultural Statistics Service (NASS is investigating the use of adaptive design techniques in the Crops Acreage, Production, and Stocks Survey (Crops APS. The Crops APS is a survey of establishments which vary in size and, hence, in their potential impact on estimates. In order to identify subgroups for targeted designs, we conducted a simulation study that used Census of Agriculture (COA data as proxies for similar survey items. Different patterns of nonresponse were simulated to identify subgroups that may reduce estimated nonresponse bias when their response propensities are changed.

  8. Angular Phenozaxine Ethers as Potent Multi-microbial Targets Inhibitors: Design, Synthesis, and Molecular Docking Studies

    Directory of Open Access Journals (Sweden)

    Mercy A. Ezeokonkwo

    2017-11-01

    Full Text Available The reaction of diaza-5H-benzo[a]phenoxazin-5-one and 5H-benzo[a]phenoxazin-5-one with various phenols catalyzed by Pd/t-BuXPhos/K3PO4 system gave previously unknown ether derivatives (7a–f and 8a–f in good yields. UV-visible, FTIR, and 1H NMR data were used to confirm structures of the synthesized compounds. The parent compounds and the derivatives were screened in-silico for their drug-likeness and binding affinities to the microbial targets through molecular docking. Molinspiration software and AutoDock were used for the drug-likeness and docking studies, respectively. All the synthesized compounds showed strong drug-likeness. They also showed excellent binding affinities with glucosamine-6-phosphate synthase (2VF5, AmpC beta-lactamase (1KE4, and Lanosterol-14α-demethylase (3JUV, with compound 7e having the highest binding energies −9.5, −9.3, and −9.3 kcal/mol, respectively. These were found to be higher than the binding energies of the standard drugs. The binding energies of ciprofloxacin with 2VF5 and 1KE4 were −7.8 and −7.5 kcal/mol, respectively, while that of ketoconazole with 3JUV was −8.6 kcal/mol. The study showed that the synthesized compounds have multi-target inhibitory effects and can be very useful in multi-drug resistance cases. A 2D quantitative structural activity relationship (QSAR model against target Glucosamine-6-phosphate synthase (2VF5 was developed using partial least squares regression (PLS with good internal prediction (R2 = 0.7400 and external prediction (R2_ predicted = 0.5475 via Molecular Operating Environment (2014.

  9. Targeting CYP51 for drug design by the contributions of molecular modeling.

    Science.gov (United States)

    Rabelo, Vitor W; Santos, Taísa F; Terra, Luciana; Santana, Marcos V; Castro, Helena C; Rodrigues, Carlos R; Abreu, Paula A

    2017-02-01

    CYP51 is an enzyme of sterol biosynthesis pathway present in animals, plants, protozoa and fungi. This enzyme is described as an important drug target that is still of interest. Therefore, in this work, we reviewed the structure and function of CYP51 and explored the molecular modeling approaches for the development of new antifungal and antiprotozoans that target this enzyme. Crystallographic structures of CYP51 of some organisms have already been described in the literature, which enable the construction of homology models of other organisms' enzymes and molecular docking studies of new ligands. The binding mode and interactions of some new series of azoles with antifungal or antiprotozoan activities has been studied and showed important residues of the active site. Molecular modeling is an important tool to be explored for the discovery and optimization of CYP51 inhibitors with better activities, pharmacokinetics, and toxicological profiles. © 2016 Société Française de Pharmacologie et de Thérapeutique.

  10. Enhancing Shared Decision Making Through Carefully Designed Interventions That Target Patient And Provider Behavior

    NARCIS (Netherlands)

    Tai-Seale, M.; Elwyn, G.; Wilson, C.J.; Stults, C.; Dillon, E.C.; Li, M.; Chuang, J.; Meehan, A.; Frosch, D.L.

    2016-01-01

    Patient-provider communication and shared decision making are essential for primary care delivery and are vital contributors to patient experience and health outcomes. To alleviate communication shortfalls, we designed a novel, multidimensional intervention aimed at nudging both patients and primary

  11. Design Guidelines for the Development of Digital Nutrigenomics Learning Material for Heterogeneous Target Groups

    Science.gov (United States)

    Busstra, Maria C.; Hartog, Rob; Kersten, Sander; Muller, Michael

    2007-01-01

    Nutritional genomics, or nutrigenomics, can be considered as the combination of molecular nutrition and genomics. Students who attend courses in nutrigenomics differ with respect to their prior knowledge. This study describes digital nutrigenomics learning material suitable for students from various backgrounds and provides design guidelines for…

  12. Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies.

    Science.gov (United States)

    Bononi, Angela; Napolitano, Andrea; Pass, Harvey I; Yang, Haining; Carbone, Michele

    2015-10-01

    Malignant mesothelioma is an aggressive cancer whose pathogenesis is causally linked to occupational exposure to asbestos. Familial clusters of mesotheliomas have been observed in settings of genetic predisposition. Mesothelioma incidence is anticipated to increase worldwide in the next two decades. Novel treatments are needed, as current treatment modalities may improve the quality of life, but have shown modest effects in improving overall survival. Increasing knowledge on the molecular characteristics of mesothelioma has led to the development of novel potential therapeutic strategies, including: molecular targeted approaches, that is the inhibition of vascular endothelial growth factor with bevacizumab; immunotherapy with chimeric monoclonal antibody, immunotoxin, antibody drug conjugate, vaccine and viruses; inhibition of asbestos-induced inflammation, that is aspirin inhibition of HMGB1 activity may decrease or delay mesothelioma onset and/or growth. We elaborate on the rationale behind new therapeutic strategies, and summarize available preclinical and clinical results, as well as efforts still ongoing.

  13. Rational design of drug-like compounds targeting Mycobacterium marinum MelF protein.

    Directory of Open Access Journals (Sweden)

    Renu Dharra

    Full Text Available The mycobacterial mel2 locus (mycobacterial enhanced infection locus, Rv1936-1941 is Mycobacterium marinum and M. tuberculosis specific, which can withstand reactive oxygen species (ROS and reactive nitrogen species (RNS induced stress. A library of over a million compounds was screened using in silico virtual ligand screening (VLS to identify inhibitors against the modeled structure of MelF protein expressed by melF of mel2 locus so that M. marinum's ability to withstand ROS/RNS stress could be reduced. The top ranked 1000 compounds were further screened to identify 178 compounds to maximize the scaffold diversity by manually evaluating the interaction of each compound with the target site. M. marinum melF was cloned, expressed and purified as maltose binding protein (MBP-tagged recombinant protein in Escherichia coli. After establishing the flavin dependent oxidoreductase activity of MelF (~ 84 kDa, the inhibitors were screened for the inhibition of enzyme activity of whole cell lysate (WCL and the purified MelF. Amongst these, 16 compounds could significantly inhibit the enzyme activity of purified MelF. For the six best inhibitory compounds, the minimal inhibitory concentration (MIC was determined to be 3.4-19.4 μM and 13.5-38.8 μM for M. marinum and M. tuberculosis, respectively. Similarly, the minimal bactericidal concentration (MBC was determined to be 6.8-38.8 μM and 27-38.8 μM against M. marinum and M. tuberculosis, respectively. One compound each in combination with isoniazid (INH also showed synergistic inhibitory effect against M. marinum and M. tuberculosis with no cytotoxicity in HeLa cells. Interestingly, these inhibitors did not display any non-specific protein-structure destabilizing effect. Such inhibitors targeting the anti-ROS/RNS machinery may facilitate the efficient killing of replicating and nonreplicating mycobacteria inside the host cells.

  14. Selection of design and determination of quality targets for vs6 pump stages

    Science.gov (United States)

    Tverdokhleb, I.; Yelin, A.

    2017-08-01

    A comparative analysis of VS6 pump type in the range of specific speed nq = 25...55 was carried out basing on information about analogous pumps produced by the world’s leading manufacturers. The focus was made on mass-dimensional characteristics of the pump stages. It was found that rational design of a diffuser with radial vanes provides lower material consumption at similar hydraulic characteristics compared to using a semi-axial vanes diffuser in the stage.

  15. Design of a liquid metal target loop for a high power spallation

    CERN Document Server

    Andreas Vetter (PSI)

    Diplomarbeit zur Erlangung des Grades Diplom-IngenieurTechnische Universität BerlinThis thesis shows the lay-out of the liquid metal loop, which is designed to evacuate 3.0 MW of thermal power. It describes the function and sizing of the piping and components. The thesis deals with the choice of the pump, the expansion tank/gas separator and the heat exchanger using water as cooling fluid as well as instrumentation.

  16. A Value Analysis of Lean Processes in Target Value Design and Integrated Project Delivery.

    Science.gov (United States)

    Nanda, Upali; K Rybkowski, Zofia; Pati, Sipra; Nejati, Adeleh

    2017-04-01

    To investigate what key stakeholders consider to be the advantages and the opportunities for improvement in using lean thinking and tools in the integrated project delivery (IPD) process. A detailed literature review was followed by case study of a Lean-IPD project. Interviews with members of the project leadership team, focus groups with the integrated team as well as the design team, and an online survey of all stakeholders were conducted. Statistical analysis and thematic content analysis were used to analyze the data, followed by a plus-delta analysis. (1) Learning is a large, implicit benefit of Lean-IPD that is not currently captured by any success metric; (2) the cardboard mock-up was the most successful lean strategy; (3) although a collaborative project, the level of influence of different stakeholder groups was perceived to be different by different stakeholders; (4) overall, Lean-IPD was rated as better than traditional design-bid-build methods; and (5) opportunities for improvement reported were increase in accurate cost estimating, more efficient use of time, perception of imbalance of control/influence, and need for facilitation (which represents different points of view). While lean tools and an IPD method are preferred to traditional design-bid-build methods, the perception of different stakeholders varies and more work needs to be done to allow a truly shared decision-making model. Learning was identified as one of the biggest advantages.

  17. Low Density Supersonic Decelerator Flight Dynamics Test-1 Flight Design and Targeting

    Science.gov (United States)

    Ivanov, Mark

    2015-01-01

    NASA's Low Density Supersonic Decelerator (LDSD) program was established to identify, develop, and eventually qualify to Test [i.e. Technology] Readiness Level (TRL) - 6 aerodynamic decelerators for eventual use on Mars. Through comprehensive Mars application studies, two distinct Supersonic Inflatable Aerodynamic Decelerator (SIAD) designs were chosen that afforded the optimum balance of benefit, cost, and development risk. In addition, a Supersonic Disk Sail (SSDS) parachute design was chosen that satisfied the same criteria. The final phase of the multi-tiered qualification process involves Earth Supersonic Flight Dynamics Tests (SFDTs) within environmental conditions similar to those that would be experienced during a Mars Entry, Descent, and Landing (EDL) mission. The first of these flight tests (i.e. SFDT-1) was completed on June 28, 2014 with two more tests scheduled for the summer of 2015 and 2016, respectively. The basic flight design for all the SFDT flights is for the SFDT test vehicle to be ferried to a float altitude of 120 kilo-feet by a 34 thousand cubic feet (Mcf) heavy lift helium balloon. Once float altitude is reached, the test vehicle is released from the balloon, spun-up for stability, and accelerated to supersonic speeds using a Star48 solid rocket motor. After burnout of the Star48 motor the vehicle decelerates to pre-flight selected test conditions for the deployment of the SIAD system. After further deceleration with the SIAD deployed, the SSDS parachute is then deployed stressing the performance of the parachute in the wake of the SIAD augmented blunt body. The test vehicle/SIAD/parachute system then descends to splashdown in the Pacific Ocean for eventual recovery. This paper will discuss the development of both the test vehicle and the trajectory sequence including design trade-offs resulting from the interaction of both engineering efforts. In addition, the SFDT-1 nominal trajectory design and associated sensitivities will be discussed

  18. Interface design principles for usable decision support: a targeted review of best practices for clinical prescribing interventions.

    Science.gov (United States)

    Horsky, Jan; Schiff, Gordon D; Johnston, Douglas; Mercincavage, Lauren; Bell, Douglas; Middleton, Blackford

    2012-12-01

    Developing effective clinical decision support (CDS) systems for the highly complex and dynamic domain of clinical medicine is a serious challenge for designers. Poor usability is one of the core barriers to adoption and a deterrent to its routine use. We reviewed reports describing system implementation efforts and collected best available design conventions, procedures, practices and lessons learned in order to provide developers a short compendium of design goals and recommended principles. This targeted review is focused on CDS related to medication prescribing. Published reports suggest that important principles include consistency of design concepts across networked systems, use of appropriate visual representation of clinical data, use of controlled terminology, presenting advice at the time and place of decision making and matching the most appropriate CDS interventions to clinical goals. Specificity and contextual relevance can be increased by periodic review of trigger rules, analysis of performance logs and maintenance of accurate allergy, problem and medication lists in health records in order to help avoid excessive alerting. Developers need to adopt design practices that include user-centered, iterative design and common standards based on human-computer interaction (HCI) research methods rooted in ethnography and cognitive science. Suggestions outlined in this report may help clarify the goals of optimal CDS design but larger national initiatives are needed for systematic application of human factors in health information technology (HIT) development. Appropriate design strategies are essential for developing meaningful decision support systems that meet the grand challenges of high-quality healthcare. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Design of an EGFR-targeting toxin for photochemical delivery: in vitro and in vivo selectivity and efficacy.

    Science.gov (United States)

    Berstad, M B; Cheung, L H; Berg, K; Peng, Q; Fremstedal, A S V; Patzke, S; Rosenblum, M G; Weyergang, A

    2015-10-29

    The number of epidermal growth factor receptor (EGFR)-targeting drugs in the development for cancer treatment is continuously increasing. Currently used EGFR-targeted monoclonal antibodies and tyrosine kinase inhibitors have specific limitations related to toxicity and development of resistance, and there is a need for alternative treatment strategies to maximize the clinical potential of EGFR as a molecular target. This study describes the design and production of a novel EGFR-targeted fusion protein, rGel/EGF, composed of the recombinant plant toxin gelonin and EGF. rGel/EGF was custom-made for administration by photochemical internalization (PCI), a clinically tested modality for cytosolic release of macromolecular therapeutics. rGel/EGF lacks efficient mechanisms for endosomal escape and is therefore minimally toxic as monotherapy. However, PCI induces selective and efficient cytosolic release of rGel/EGF in EGFR-expressing target cells by light-directed activation of photosensitizers accumulated selectively in tumor tissue. PCI of rGel/EGF was shown to be highly effective against EGFR-expressing cell lines, including head and neck squamous cell carcinoma (HNSCC) cell lines resistant to cetuximab (Erbitux). Apoptosis, necrosis and autophagy were identified as mechanisms of action following PCI of rGel/EGF in vitro. PCI of rGel/EGF was further shown as a highly tumor-specific and potent modality in vivo, with growth inhibitory effects demonstrated on A-431 squamous cell carcinoma (SCC) xenografts and reduction of tumor perfusion and necrosis induction in SCC-026 HNSCC tumors. Considering the small amount of rGel/EGF injected per animal (0.1 mg/kg), the presented in vivo results are highly promising and warrant optimization and production of rGel/EGF for further preclinical evaluation with PCI.

  20. Design, synthesis and biological activity of a targeted library of potential tryptase inhibitors.

    Science.gov (United States)

    García, Mónica; del Rio, Xavier; Silvestre, Sandra; Rubiralta, Mario; Lozoya, Estrella; Segarra, Victor; Fernández, Dolors; Miralpeix, Montserrat; Aparici, Mònica; Diez, Anna

    2004-06-07

    We have designed, synthesized, and tested two small collections of potential tryptase inhibitors. The first library consists of diversely N-substituted 3-aminopiperidin-2-ones 6, and the second (compounds 7) was prepared by dimerising compounds 6 through the 3-amino function using diverse carbon chains. We have established efficient routes for obtaining 6 both in solution and on solid supports. We have also compared the dimerisation on-resin and in solution. Four of the compounds showed a high degree of tryptase inhibition at 1 microM, but none surpassed the tryptase inhibition activity of BABIM.

  1. Design of HIV Protease Inhibitors Targeting Protein Backbone: An Effective Strategy for Combating Drug Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Ghosh, Arun K.; Chapsal, Bruno D.; Weber, Irene T.; Mitsuya, Hiroaki (GSU); (Kumamoto Univ., Japan); (Purdue)

    2008-06-03

    The discovery of human immunodeficiency virus (HIV) protease inhibitors (PIs) and their utilization in highly active antiretroviral therapy (HAART) have been a major turning point in the management of HIV/acquired immune-deficiency syndrome (AIDS). However, despite the successes in disease management and the decrease of HIV/AIDS-related mortality, several drawbacks continue to hamper first-generation protease inhibitor therapies. The rapid emergence of drug resistance has become the most urgent concern because it renders current treatments ineffective and therefore compels the scientific community to continue efforts in the design of inhibitors that can efficiently combat drug resistance.

  2. Plant-Scale Concentration Column Designs for SHINE Target Solution Utilizing AG 1 Anion Exchange Resin

    Energy Technology Data Exchange (ETDEWEB)

    Stepinski, Dominique C. [Argonne National Lab. (ANL), Argonne, IL (United States); Vandegrift, G. F. [Argonne National Lab. (ANL), Argonne, IL (United States)

    2015-09-30

    Argonne is assisting SHINE Medical Technologies (SHINE) in their efforts to develop SHINE, an accelerator-driven process that will utilize a uranyl-sulfate solution for the production of fission product Mo-99. An integral part of the process is the development of a column for the separation and recovery of Mo-99, followed by a concentration column to reduce the product volume from 15-25 L to <1 L. Argonne has collected data from batch studies and breakthrough column experiments to utilize the VERSE (Versatile Reaction Separation) simulation program (Purdue University) to design plant-scale product recovery and concentration processes.

  3. Rational design of bioactive, modularly assembled aminoglycosides targeting the RNA that causes myotonic dystrophy type 1.

    Science.gov (United States)

    Childs-Disney, Jessica L; Parkesh, Raman; Nakamori, Masayuki; Thornton, Charles A; Disney, Matthew D

    2012-12-21

    Myotonic dystrophy type 1 (DM1) is caused when an expanded r(CUG) repeat (r(CUG)(exp)) binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1) as well as other proteins. Previously, we reported that modularly assembled small molecules displaying a 6'-N-5-hexynoate kanamycin A RNA-binding module (K) on a peptoid backbone potently inhibit the binding of MBNL1 to r(CUG)(exp). However, these parent compounds are not appreciably active in cell-based models of DM1. The lack of potency was traced to suboptimal cellular permeability and localization. To improve these properties, second-generation compounds that are conjugated to a d-Arg(9) molecular transporter were synthesized. These modified compounds enter cells in higher concentrations than the parent compounds and are efficacious in cell-based DM1 model systems at low micromolar concentrations. In particular, they improve three defects that are the hallmarks of DM1: a translational defect due to nuclear retention of transcripts containing r(CUG)(exp); pre-mRNA splicing defects due to inactivation of MBNL1; and the formation of nuclear foci. The best compound in cell-based studies was tested in a mouse model of DM1. Modest improvement of pre-mRNA splicing defects was observed. These studies suggest that a modular assembly approach can afford bioactive compounds that target RNA.

  4. Designing Novel Nanoformulations Targeting Glutamate Transporter Excitatory Amino Acid Transporter 2: Implications in Treating Drug Addiction.

    Science.gov (United States)

    Rao, Pss; Yallapu, Murali M; Sari, Youssef; Fisher, Paul B; Kumar, Santosh

    Chronic drug abuse is associated with elevated extracellular glutamate concentration in the brain reward regions. Deficit of glutamate clearance has been identified as a contributing factor that leads to enhanced glutamate concentration following extended drug abuse. Importantly, normalization of glutamate level through induction of glutamate transporter 1 (GLT1)/ excitatory amino acid transporter 2 (EAAT2) expression has been described in several in vivo studies. GLT1 upregulators including ceftriaxone, a beta-lactam antibiotic, have been effective in attenuating drug-seeking and drug-consumption behavior in rodent models. However, potential obstacles toward clinical translation of GLT1 (EAAT2) upregulators as treatment for drug addiction might include poor gastrointestinal absorption, serious peripheral adverse effects, and/or suboptimal CNS concentrations. Given the growing success of nanotechnology in targeting CNS ailments, nanoformulating known GLT1 (EAAT2) upregulators for selective uptake across the blood brain barrier presents an ideal therapeutic approach for treating drug addiction. In this review, we summarize the results obtained with promising GLT1 (EAAT2) inducing compounds in animal models recapitulating drug addiction. Additionally, the various nanoformulations that can be employed for selectively increasing the CNS bioavailability of GLT1 (EAAT2) upregulators are discussed. Finally, the applicability of GLT1 (EAAT2) induction via central delivery of drug-loaded nanoformulations is described.

  5. Structure-Based Drug Design Targeting a Subunit Interaction of Influenza Virus RNA Polymerase

    Science.gov (United States)

    Sugiyama, Kanako; Obayashi, Eiji; Yoshida, Hisashi; Park, Sam-Yong

    Influenza A virus is a major human and animal pathogen with the potential to cause catastrophic loss of life. Influenza virus reproduces rapidly, mutates frequently, and occasionally crosses species barriers. The recent emergence of swine-origin influenza H1N1 and avian influenza related to highly pathogenic forms of the human virus has highlighted the urgent need for new effective treatments. Here, we describe two crystal structures of complexes made by fragments of PA and PB1, and PB1 and PB2. These novel interfaces are surprisingly small, yet they play a crucial role in regulating the 250 kDa polymerase complex, and are completely conserved among swine, avian and human influenza viruses. Given their importance to viral replication and strict conservation, the PA/PB1 and PB1/PB2 interfaces appear to be promising targets for novel anti-influenza drugs of use against all strains of influenza A virus. It is hoped that the structures presented here will assist the search for such compounds.

  6. Structure-based drug design targeting the cell membrane receptor GPBAR1: exploiting the bile acid scaffold towards selective agonism

    Science.gov (United States)

    di Leva, Francesco Saverio; Festa, Carmen; Renga, Barbara; Sepe, Valentina; Novellino, Ettore; Fiorucci, Stefano; Zampella, Angela; Limongelli, Vittorio

    2015-11-01

    Bile acids can regulate nutrient metabolism through the activation of the cell membrane receptor GPBAR1 and the nuclear receptor FXR. Developing an exogenous control over these receptors represents an attractive strategy for the treatment of enterohepatic and metabolic disorders. A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors. On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding. Here, taking advantage of our knowledge of the two targets, we have identified through a rational drug design study a series of amine lithocholic acid derivatives as selective GPBAR1 agonists. The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.

  7. Design of a TOF-SANS instrument for the proposed long-wavelength target station at the spallation neutron source

    CERN Document Server

    Littrell, K C; Carpenter, J M; Seeger, P A

    2002-01-01

    We have designed a versatile high-data-rate SANS instrument (broad-range intense multipurpose SANS (BRIMS)) for the proposed long-wavelength target station at the SNS using the Los Alamos NISP Monte Carlo simulation package. BRIMS is designed to produce data spanning a Q range from 0.0025 to 0.7 A sup - sup 1 in a single measurement by simultaneously using neutrons with wavelengths from 1 to 14.5 A in a time-of-flight mode. The effects of various collimation choices, including multiple confocal pinhole apertures, on count rate, resolution, and Q range have been characterized with simulations using spherical particle and delta-function scatterers. We compare the anticipated performance of BRIMS with that of the premier reactor-based SANS instrument, D22, at ILL. (orig.)

  8. Selective CFAE targeting for atrial fibrillation study (SELECT AF): clinical rationale, design, and implementation.

    Science.gov (United States)

    Verma, Atul; Sanders, Prashanthan; Macle, Laurent; Champagne, Jean; Nair, Girish M; Calkins, Hugh; Wilber, David J

    2011-05-01

    Adjuvant ablation of complex fractionated atrial electrograms (CFAE) in addition to pulmonary vein isolation (PVI) likely improves procedural outcome compared to PVI alone, particularly in patients with persistent atrial fibrillation (AF). However, CFAE regions can be extensive, occasionally requiring a large amount of extra ablation. Some CFAE regions may also represent passive wavefront collision and may not require ablation. Thus, there is interest in identifying more selective CFAE sites that are critical to AF perpetuation, minimizing the amount of adjuvant ablation that must be performed. The SELECT AF study is a prospective, multicenter, randomized trial comparing a strategy of PVI plus generalized CFAE ablation versus a strategy of PVI plus selective CFAE ablation, focusing on regions of continuous electrical activity (CEA). The primary efficacy endpoint is freedom from atrial arrhythmia at 1 year and the primary safety endpoint is total radiofrequency (RF) delivery time per procedure. Patients undergoing a first time ablation procedure for symptomatic persistent AF will be included. Patients with permanent AF or with left atrial size ≥55 mm will be excluded. Patients will all receive PVI at the time of their ablation, but will be randomized 1:1 to receive adjuvant CFAE ablation using the traditional "generalized" approach, or a "selective" approach targeting only CEA regions. Both strategies will be guided by automated mapping algorithms. This study will enroll a minimum of 80 evaluable subjects; 40 in each randomization group. SELECT AF is a randomized trial in patients with persistent AF to evaluate the efficacy of selective versus generalized CFAE ablation in addition to traditional PVI. © 2010 Wiley Periodicals, Inc.

  9. Graphene stirrer with designed movements: Targeting on environmental remediation and supercapacitor applications

    Directory of Open Access Journals (Sweden)

    Yang Huang

    2018-01-01

    Full Text Available Beyond the traditional focus on improvements in mechanical, electronic and absorption properties, controllability, actuation, and dynamic response of monoliths have received increasing attentions for practical applications. However, most of them could only realize simple response to constant conditions (e.g. a stationary magnetic field while carrying out humdrum motions. By controlling distribution of metal organic framework obtained carbon-enriched Fe3O4 nanoparticles in self-assembly reduced graphene oxide (RGO monoliths, we could achieve two distinctive RGO–Fe3O4 stirrers that could dynamically respond to the rapidly changing magnetic field while executing designed movements precisely: rotating with lying down posture or standing straight posture. These stirrers can not only be applied in environmental remediation (e.g. suction skimmer, but also be recycled as electrode active materials for supercapacitors after fulfilling their destiny, realizing transformation of trash to treasure, which will inspire other dynamically responsive monoliths for various applications.

  10. Activation pathway of Src kinase reveals intermediate states as targets for drug design

    Science.gov (United States)

    Shukla, Diwakar; Meng, Yilin; Roux, Benoît; Pande, Vijay S.

    2014-03-01

    Unregulated activation of Src kinases leads to aberrant signalling, uncontrolled growth and differentiation of cancerous cells. Reaching a complete mechanistic understanding of large-scale conformational transformations underlying the activation of kinases could greatly help in the development of therapeutic drugs for the treatment of these pathologies. In principle, the nature of conformational transition could be modelled in silico via atomistic molecular dynamics simulations, although this is very challenging because of the long activation timescales. Here we employ a computational paradigm that couples transition pathway techniques and Markov state model-based massively distributed simulations for mapping the conformational landscape of c-src tyrosine kinase. The computations provide the thermodynamics and kinetics of kinase activation for the first time, and help identify key structural intermediates. Furthermore, the presence of a novel allosteric site in an intermediate state of c-src that could be potentially used for drug design is predicted.

  11. Design, synthesis and biological evaluation for docetaxel-loaded brain targeting liposome with "lock-in" function.

    Science.gov (United States)

    Li, Xiaocen; Qu, Boyi; Jin, Xiuxiu; Hai, Li; Wu, Yong

    2013-12-09

    Abstract Background: Glucose-modified liposome showed a good brain-targeting ability. However, bidirectional transport of glucose transporter-1 (GLUT1) might reversely pump drugs out of the brain before releasing from the liposomes. Purpose: To overcome the bidirectional delivery of GLUT1, the thiamine disulfide system (TDS), with ability of "lock-in", was introduced and a new ligand, L-TDS-G, was designed and synthesized. Methods: The liposome was prepared and characterized for particle size, zeta potential, surface morphological property, encapsulation efficiency and release profile. C6 glioma cells were used as an in vitro model to access the cellular uptake abilities and cytotoxicity of the liposomes. Competition assay was performed to validate the GLUT1-mediated transport mechanism. Furthermore, the brain targeting abilities of the liposomes were evaluated through in vivo. Results: The preliminary evaluation in vivo demonstrated that L-TDS-G-coated liposome has an improved targeting ability and significantly increased the area under the concentration-time of docetaxel in brain as compared to naked docetaxel, non-coated and L-G coated liposomes. The relative uptake efficiency and concentration efficiency were enhanced by 3.82- and 4.99-fold compared to that of naked docetaxel, respectively. Conclusion: The results of this study indicated that L-TDS-G-coated liposome is a promising drug delivery system to enhance the brain concentrations of chemotherapeutic agents.

  12. Design choices made by target users for a pay-for-performance program in primary care: an action research approach

    Directory of Open Access Journals (Sweden)

    Kirschner Kirsten

    2012-03-01

    Full Text Available Abstract Background International interest in pay-for-performance (P4P initiatives to improve quality of health care is growing. Current programs vary in the methods of performance measurement, appraisal and reimbursement. One may assume that involvement of health care professionals in the goal setting and methods of quality measurement and subsequent payment schemes may enhance their commitment to and motivation for P4P programs and therefore the impact of these programs. We developed a P4P program in which the target users were involved in decisions about the P4P methods. Methods For the development of the P4P program a framework was used which distinguished three main components: performance measurement, appraisal and reimbursement. Based on this framework design choices were discussed in two panels of target users using an adapted Delphi procedure. The target users were 65 general practices and two health insurance companies in the South of the Netherlands. Results Performance measurement was linked to the Dutch accreditation program based on three domains (clinical care, practice management and patient experience. The general practice was chosen as unit of assessment. Relative standards were set at the 25th percentile of group performance. The incentive for clinical care was set twice as high as the one for practice management and patient experience. Quality scores were to be calculated separately for all three domains, and for both the quality level and the improvement of performance. The incentive for quality level was set thrice as high as the one for the improvement of performance. For reimbursement, quality scores were divided into seven levels. A practice with a quality score in the lowest group was not supposed to receive a bonus. The additional payment grew proportionally for each extra group. The bonus aimed at was on average 5% to 10% of the practice income. Conclusions Designing a P4P program for primary care with involvement of

  13. In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis.

    Directory of Open Access Journals (Sweden)

    Antony M Latham

    Full Text Available Protein kinases play a central role in tumor progression, regulating fundamental processes such as angiogenesis, proliferation and metastasis. Such enzymes are an increasingly important class of drug target with small molecule kinase inhibitors being a major focus in drug development. However, balancing drug specificity and efficacy is problematic with off-target effects and toxicity issues.We have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2 and cyclin-dependent kinase 1 (CDK1. This compound acts by simultaneously inhibiting pro-angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A-mediated signaling response and CDK1-mediated mitotic entry elicits anti-angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis.We deduce that JK-31 reduces the growth of both human endothelial cells and human breast cancer cells in vitro. This novel synthetic molecule has broad implications for development of similar multi-kinase inhibitors with anti-angiogenic and anti-cancer properties. In silico design is an attractive and innovative method to aid such drug discovery.

  14. In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis.

    Science.gov (United States)

    Latham, Antony M; Kankanala, Jayakanth; Fearnley, Gareth W; Gage, Matthew C; Kearney, Mark T; Homer-Vanniasinkam, Shervanthi; Wheatcroft, Stephen B; Fishwick, Colin W G; Ponnambalam, Sreenivasan

    2014-01-01

    Protein kinases play a central role in tumor progression, regulating fundamental processes such as angiogenesis, proliferation and metastasis. Such enzymes are an increasingly important class of drug target with small molecule kinase inhibitors being a major focus in drug development. However, balancing drug specificity and efficacy is problematic with off-target effects and toxicity issues. We have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 1 (CDK1). This compound acts by simultaneously inhibiting pro-angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A)-mediated signaling response and CDK1-mediated mitotic entry elicits anti-angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis. We deduce that JK-31 reduces the growth of both human endothelial cells and human breast cancer cells in vitro. This novel synthetic molecule has broad implications for development of similar multi-kinase inhibitors with anti-angiogenic and anti-cancer properties. In silico design is an attractive and innovative method to aid such drug discovery.

  15. Design, synthesis, and testing of multivalent compounds targeted to melanocortin receptors

    Science.gov (United States)

    Dehigaspitiya, Dilani Chathurika

    Our focus is on developing non-invasive molecular imaging reagents, which target human cancers that presently are difficult to detect, such as melanoma. We wish to apply the multivalency concept to differentiate between healthy cells and melanoma cells. Melanoma cells are known to over-express alpha melanocyte stimulating hormone receptors. A successful multivalent construct should show greater avidity towards melanoma cells than healthy cells due to the synergistic effects arising from multivalency. Both oligomeric and shorter linear constructs bearing the minimum active sequence of melanocyte stimulating hormone, His-DPhe-Arg-Trp-NH2(MSH4), which binds with low micromolar affinity to alpha melanocyte stimulating hormone receptors, were synthesized. Binding affinities of these constructs were evaluated in a competitive binding assay by competing with labeled ligands, Eu-DTPA-PEGO-MSH7 and/or Eu-DTPA-PEGO-NDP-alpha-MSH on the engineered cell line HEK293 CCK2R/hMC4R, which is genetically modified to over-express both the cholecystokinin 2 receptor (CCK2R) and human melanocortin 4 receptor (hMC4R). The oligomers were rapidly assembled using microwave-assisted copper catalyzed azide-alkyne cycloaddition between a dialkyne derivative of MSH4 and a diazide derivative of (Pro-Gly)3 as co-monomers. Three oligomer mixtures were further analyzed based on their degree of oligomerization and the route by which the MSH4 monomers were oligomerized, protected vs deprotected. Completive binding assay against Eu-DTPA-PEGO-MSH7 showed only a statistical enhancement of binding when calculated based on the total MSH4 concentration. However, when the calculation of avidity is based on an estimation of the particles numbers, there was a seven times enhancement of binding compared to a monovalent MSH4 control. The shorter linear multivalent MSH4 constructs were synthesized using ethylene glycol, glycerol, and mannitol as core scaffolds with maximum inter-ligand distances ranging from 27

  16. Design and performance of a clean and economic power supply targeting energy independence and operative security

    Energy Technology Data Exchange (ETDEWEB)

    Mushtaha, Mohammed

    2012-07-01

    Stand alone wind-diesel power systems address the major issues for the supply of remotely located consumers or the provision of enhanced energy independence. The specific configuration considered here comprises a prior wind turbine driven induction generator and a supplementary synchronous generator driven by a combustion engine, the latter caring for frequency control and reactive power balance. An accumulator-bank and a hydrogen storage path consisting of an electrolyzer and a hydrogen storage tank are added as short-term and long-term storage devices - respectively - in order to adjust volatile wind generation and varying load demand. The hydrogen re-conversion to electricity is achieved by design of the drive of the synchronous generator as a dual-fuel engine, fed with stored hydrogen primarily, and with diesel oil in case of the rare event of hydrogen storage emptiness. An elementary waste heat recovery from engine cooling water and from exhaust gases makes the system even more energy efficient and environment friendly. For proper sizing of the particular system components under minimization of the life cycle cost - which are composed of the initial installation cost, the replacement cost, the operation and maintenance cost as well as the remaining fuel cost - the meta-heuristic computational method of Particle Swarm Optimization (PSO) was applied. The crucial task of intelligently managing the energy storage strategy depending on their actual states of charge and the current excess power under a given load profile was solved by a fuzzy system and a subsequent time scheduler, the latter providing definite set-point steps for definite periods of time to the electrolyzer in order to achieve smooth and conservative operation. The concrete design and performance of the proposed system structure is shown with the two relevant application examples of independent electricity supply of the main hospital in Gaza-Strip, Palestine, and a remotely located dairy farm. For

  17. Horses for Courses: Moving India towards Universal Health Coverage through Targeted Policy Design.

    Science.gov (United States)

    Maurya, Dayashankar; Virani, Altaf; Rajasulochana, S

    2017-12-01

    The debate on how India's health system should move towards universal health coverage was (meant to be) put to rest by the recent National Health Policy 2017. However, the new policy is silent about tackling bottlenecks mentioned in the said policy proposal. It aims to provide universal access to free primary care by strengthening the public system, and to secondary and tertiary care through strategic purchasing from the private sector, to overcome deficiencies in public provisioning in the short run. Yet, in doing so, it ignores critical factors needed to replicate successful models of public healthcare delivery from certain states that it hopes to emulate. The policy also overestimates the capacity of the public sector and downplays the challenges observed in purchasing secondary care. Drawing from literature in policy design, we emphasize that primary, secondary and tertiary care have distinct characteristics, and their provision requires separate approaches or policy tools depending on the context. Public provisioning, contract purchasing and insurance mechanisms are different policy tools that have to be matched with the context and characteristics of the policy arena. Given the current challenges of India's health system, we argue that tertiary care services are most suitable for insurance-based purchasing, while the public sector should concentrate on building the required capacities to dominate the provisioning of secondary care and fill gaps in primary care delivery, for India to achieve its universal coverage ambitions.

  18. Targeted inhibition of oncogenic miR-21 maturation with designed RNA-binding proteins.

    Science.gov (United States)

    Chen, Yu; Yang, Fan; Zubovic, Lorena; Pavelitz, Tom; Yang, Wen; Godin, Katherine; Walker, Matthew; Zheng, Suxin; Macchi, Paolo; Varani, Gabriele

    2016-09-01

    The RNA recognition motif (RRM) is the largest family of eukaryotic RNA-binding proteins. Engineered RRMs with well-defined specificity would provide valuable tools and an exacting test of the current understanding of specificity. We have redesigned the specificity of an RRM using rational methods and demonstrated retargeting of its activity in cells. We engineered the conserved RRM of human Rbfox proteins to specifically bind to the terminal loop of a microRNA precursor (pre-miR-21) with high affinity and inhibit its processing by Drosha and Dicer. We further engineered Giardia Dicer by replacing its PAZ domain with the designed RRM. The reprogrammed enzyme degrades pre-miR-21 specifically in vitro and suppresses mature miR-21 levels in cells, which results in increased expression of the tumor suppressor PDCD4 and significantly decreased viability for cancer cells. The results demonstrate the feasibility of rationally engineering the sequence-specificity of RRMs and of using this ubiquitous platform for diverse biological applications.

  19. Production yields of noble-gas isotopes from ISOLDE UC$_{x}$/graphite targets

    CERN Document Server

    Bergmann, U C; Catherall, R; Cederkäll, J; Diget, C A; Fraile-Prieto, L M; Franchoo, S; Fynbo, H O U; Gausemel, H; Georg, U; Giles, T; Hagebø, E; Jeppesen, H B; Jonsson, O C; Köster, U; Lettry, Jacques; Nilsson, T; Peräjärvi, K; Ravn, H L; Riisager, K; Weissman, L; Äystö, J

    2003-01-01

    Yields of He, Ne, Ar, Kr and Xe isotopic chains were measured from UC$_{x}$/graphite and ThC$_{x}$/graphite targets at the PSB-ISOLDE facility at CERN using isobaric selectivity achieved by the combination of a plasma-discharge ion source with a water-cooled transfer line. %The measured half-lives allowed %to calculate the decay losses of neutron-rich isotopes in the %target and ion-source system, and thus to obtain information on the in-target %productions from the measured yields. The delay times measured for a UC$_x$/graphite target allow for an extrapolation to the expected yields of very neutron-rich noble gas isotopes, in particular for the ``NuPECC reference elements'' Ar and Kr, at the next-generation radioactive ion-beam facility EURISOL. \\end{abstract} \\begin{keyword} % keywords here, in the form: keyword \\sep keyword radioactive ion beams \\sep release \\sep ion yields \\sep ISOL (Isotope Separation On-Line) \\sep uranium and thorium carbide targets. % PACS codes here, in the form: \\PACS code \\sep code...

  20. A new drug design targeting the adenosinergic system for Huntington's disease.

    Directory of Open Access Journals (Sweden)

    Nai-Kuei Huang

    Full Text Available BACKGROUND: Huntington's disease (HD is a neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt gene. The expanded CAG repeats are translated into polyglutamine (polyQ, causing aberrant functions as well as aggregate formation of mutant Htt. Effective treatments for HD are yet to be developed. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report a novel dual-function compound, N(6-(4-hydroxybenzyladenine riboside (designated T1-11 which activates the A(2AR and a major adenosine transporter (ENT1. T1-11 was originally isolated from a Chinese medicinal herb. Molecular modeling analyses showed that T1-11 binds to the adenosine pockets of the A(2AR and ENT1. Introduction of T1-11 into the striatum significantly enhanced the level of striatal adenosine as determined by a microdialysis technique, demonstrating that T1-11 inhibited adenosine uptake in vivo. A single intraperitoneal injection of T1-11 in wildtype mice, but not in A(2AR knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A(2AR in vivo. Most importantly, addition of T1-11 (0.05 mg/ml to the drinking water of a transgenic mouse model of HD (R6/2 ameliorated the progressive deterioration in motor coordination, reduced the formation of striatal Htt aggregates, elevated proteasome activity, and increased the level of an important neurotrophic factor (brain derived neurotrophic factor in the brain. These results demonstrate the therapeutic potential of T1-11 for treating HD. CONCLUSIONS/SIGNIFICANCE: The dual functions of T1-11 enable T1-11 to effectively activate the adenosinergic system and subsequently delay the progression of HD. This is a novel therapeutic strategy for HD. Similar dual-function drugs aimed at a particular neurotransmitter system as proposed herein may be applicable to other neurotransmitter systems (e.g., the dopamine receptor/dopamine transporter and the serotonin receptor

  1. 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.

  2. Design and development of a multifunctional nano carrier system for imaging, drug delivery, and cell targeting in cancer research

    Science.gov (United States)

    Cho, Hoon-Sung

    There has been an increasing need in the last decade for early diagnosis and treatment of cancer prior to the tumor mass becoming evident as anatomical anomaly. A major challenge in cancer diagnosis is to distinguish cancer cells from the surrounding, normal tissue. For early cancer diagnosis and treatment, a nano carrier system was designed and developed with key components uniquely structured according to biomedical and clinical requirements: targeting, drug storage capabilities, fluorescent emissions near the infrared range for in vivo imaging, and magnetic hyperthermia. For in vivo imaging, quantum dots with emissions near infrared range (˜800 nm) were conjugated onto the surface of carbon nanotubes and nanospheres consisting of a spherical polystyrene matrix (˜100 nm) and high fraction of superparamagnetic Fe3O4 nanoparticles (˜10 nm) embedded. The QDs on these nano carriers exhibited intense visible emissions using fluorescent spectroscopy and successfully facilitated in vivo soft tissue imaging in mice. For drug storage, the chemotherapeutic agent, paclitaxel (PTX) was loaded onto the surfaces of these nano-carriers by using a layer of biodegradable poly(lactic-co-glycolic acid) (PLGA). A cell-based cytotoxicity assay was employed to verify successful loading of pharmacologically active drug, PTX. Cell viability of human, metastatic PC3mm2 prostate cancer cells was assessed in the presence and absence of various nano-carrier populations using the MTT assay. For hyperthermia, Fe3O 4 nanoparticles were conjugated onto the surfaces of carbon nanotubes (CNT) and embedded into the nanospheres. Magnetization measurements showed nearly reversible hysteresis curves from the Fe3O4-conjugated CNTs and the magnetic nanospheres (MNS). Application of an alternating electromagnetic field effectively induced heating the solution of the Fe3O 4-conjugated CNTs and the magnetic nanospheres (MNS) into temperature ranges (up to 55ºC) suitable for therapeutic hyperthermia

  3. Design and evaluation of novel pH-sensitive ureido-conjugated chitosan/TPP nanoparticles targeted to Helicobacter pylori.

    Science.gov (United States)

    Jing, Zi-Wei; Jia, Yi-Yang; Wan, Ning; Luo, Min; Huan, Meng-Lei; Kang, Tai-Bin; Zhou, Si-Yuan; Zhang, Bang-Le

    2016-04-01

    The covalently modified ureido-conjugated chitosan/TPP multifunctional nanoparticles have been developed as targeted nanomedicine delivery system for eradication of Helicobacter pylori. H. pylori can specifically express the urea transport protein on its membrane to transport urea into cytoplasm for urease to produce ammonia, which protects the bacterium in the acid milieu of stomach. The clinical applicability of topical antimicrobial agent is needed to eradicate H. pylori in the infected fundal area. In this study, we designed and synthesized two ureido-conjugated chitosan derivatives UCCs-1 and UCCs-2 for preparation of multifunctional nanoparticles. The process was optimized in order to prepare UCCs/TPP nanoparticles for encapsulation of amoxicillin. The results showed that the amoxicillin-UCCs/TPP nanoparticles exhibited favorable pH-sensitive characteristics, which could procrastinate the release of amoxicillin at gastric acids and enable the drug to deliver and target to H. pylori at its survival region effectively. Compared with unmodified amoxicillin-chitosan/TPP nanoparticles, a more specific and effective H. pylori growth inhibition was observed for amoxicillin-UCCs/TPP nanoparticles. Drug uptake analysis tested by flow cytometry and confocal laser scanning microscopy verified that the uptake of FITC-UCCs-2/TPP nanoparticles was associated with urea transport protein on the membrane of H. pylori and reduced with the addition of urea as competitive transport substrate. These findings suggest that the multifunctional amoxicillin-loaded nanoparticles have great potential for effective therapy of H. pylori infection. They may also serve as pharmacologically effective nanocarriers for oral targeted delivery of other therapeutic drugs to treat H. pylori. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation.

    Science.gov (United States)

    Bochicchio, Anna; Jordaan, Sandra; Losasso, Valeria; Chetty, Shivan; Perera, Rodrigo Casasnovas; Ippoliti, Emiliano; Barth, Stefan; Carloni, Paolo

    2017-02-17

    Targeted human cytolytic fusion proteins (hCFPs) are humanized immunotoxins for selective treatment of different diseases including cancer. They are composed of a ligand specifically binding to target cells genetically linked to a human apoptosis-inducing enzyme. hCFPs target cancer cells via an antibody or derivative (scFv) specifically binding to e.g., tumor associated antigens (TAAs). After internalization and translocation of the enzyme from endocytosed endosomes, the human enzymes introduced into the cytosol are efficiently inducing apoptosis. Under in vivo conditions such enzymes are subject to tight regulation by native inhibitors in order to prevent inappropriate induction of cell death in healthy cells. Tumor cells are known to upregulate these inhibitors as a survival mechanism resulting in escape of malignant cells from elimination by immune effector cells. Cytosolic inhibitors of Granzyme B and Angiogenin (Serpin P9 and RNH1, respectively), reduce the efficacy of hCFPs with these enzymes as effector domains, requiring detrimentally high doses in order to saturate inhibitor binding and rescue cytolytic activity. Variants of Granzyme B and Angiogenin might feature reduced affinity for their respective inhibitors, while retaining or even enhancing their catalytic activity. A powerful tool to design hCFPs mutants with improved potency is given by in silico methods. These include molecular dynamics (MD) simulations and enhanced sampling methods (ESM). MD and ESM allow predicting the enzyme-protein inhibitor binding stability and the associated conformational changes, provided that structural information is available. Such "high-resolution" detailed description enables the elucidation of interaction domains and the identification of sites where particular point mutations may modify those interactions. This review discusses recent advances in the use of MD and ESM for hCFP development from the viewpoints of scientists involved in both fields.

  5. Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation

    Directory of Open Access Journals (Sweden)

    Anna Bochicchio

    2017-02-01

    Full Text Available Targeted human cytolytic fusion proteins (hCFPs are humanized immunotoxins for selective treatment of different diseases including cancer. They are composed of a ligand specifically binding to target cells genetically linked to a human apoptosis-inducing enzyme. hCFPs target cancer cells via an antibody or derivative (scFv specifically binding to e.g., tumor associated antigens (TAAs. After internalization and translocation of the enzyme from endocytosed endosomes, the human enzymes introduced into the cytosol are efficiently inducing apoptosis. Under in vivo conditions such enzymes are subject to tight regulation by native inhibitors in order to prevent inappropriate induction of cell death in healthy cells. Tumor cells are known to upregulate these inhibitors as a survival mechanism resulting in escape of malignant cells from elimination by immune effector cells. Cytosolic inhibitors of Granzyme B and Angiogenin (Serpin P9 and RNH1, respectively, reduce the efficacy of hCFPs with these enzymes as effector domains, requiring detrimentally high doses in order to saturate inhibitor binding and rescue cytolytic activity. Variants of Granzyme B and Angiogenin might feature reduced affinity for their respective inhibitors, while retaining or even enhancing their catalytic activity. A powerful tool to design hCFPs mutants with improved potency is given by in silico methods. These include molecular dynamics (MD simulations and enhanced sampling methods (ESM. MD and ESM allow predicting the enzyme-protein inhibitor binding stability and the associated conformational changes, provided that structural information is available. Such “high-resolution” detailed description enables the elucidation of interaction domains and the identification of sites where particular point mutations may modify those interactions. This review discusses recent advances in the use of MD and ESM for hCFP development from the viewpoints of scientists involved in both fields.

  6. Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation

    Science.gov (United States)

    Bochicchio, Anna; Jordaan, Sandra; Losasso, Valeria; Chetty, Shivan; Casasnovas Perera, Rodrigo; Ippoliti, Emiliano; Barth, Stefan; Carloni, Paolo

    2017-01-01

    Targeted human cytolytic fusion proteins (hCFPs) are humanized immunotoxins for selective treatment of different diseases including cancer. They are composed of a ligand specifically binding to target cells genetically linked to a human apoptosis-inducing enzyme. hCFPs target cancer cells via an antibody or derivative (scFv) specifically binding to e.g., tumor associated antigens (TAAs). After internalization and translocation of the enzyme from endocytosed endosomes, the human enzymes introduced into the cytosol are efficiently inducing apoptosis. Under in vivo conditions such enzymes are subject to tight regulation by native inhibitors in order to prevent inappropriate induction of cell death in healthy cells. Tumor cells are known to up-regulate these inhibitors as a survival mechanism resulting in escape of malignant cells from elimination by immune effector cells. Cytosolic inhibitors of Granzyme B and Angiogenin (Serpin P9 and RNH1, respectively), reduce the efficacy of hCFPs with these enzymes as effector domains, requiring detrimentally high doses in order to saturate inhibitor binding and rescue cytolytic activity. Variants of Granzyme B and Angiogenin might feature reduced affinity for their respective inhibitors, while retaining or even enhancing their catalytic activity. A powerful tool to design hCFPs mutants with improved potency is given by in silico methods. These include molecular dynamics (MD) simulations and enhanced sampling methods (ESM). MD and ESM allow predicting the enzyme-protein inhibitor binding stability and the associated conformational changes, provided that structural information is available. Such “high-resolution” detailed description enables the elucidation of interaction domains and the identification of sites where particular point mutations may modify those interactions. This review discusses recent advances in the use of MD and ESM for hCFP development from the viewpoints of scientists involved in both fields. PMID

  7. Design, synthesis and biological evaluation of brain targeting l-ascorbic acid prodrugs of ibuprofen with "lock-in" function.

    Science.gov (United States)

    Zhao, Yi; Qu, Boyi; Wu, Xueying; Li, Xiaocen; Liu, Qingqing; Jin, Xiuxiu; Guo, Li; Hai, Li; Wu, Yong

    2014-07-23

    A novel brain targeting l-ascorbic acid derivatives with "lock-in" function were designed and synthesized as prodrugs to achieve the effective delivery of ibuprofen to brain by glucose transporter 1 (GLUT1) and the Na(+)-dependent vitamin C transporter SVCT2. Ibuprofen-loaded four prodrugs were tested in the animals. Results from the in vivo distribution study after i.v. administration of these four prodrugs and naked ibuprofen indicated that four prodrugs exhibited excellent transport ability across the BBB and significantly increased the level of ibuprofen in brain. Among them, prodrugs 4 showed higher brain concentration. Both biodistribution data and pharmacokinetic parameters suggested that l-ascorbic acid thiamine disulfide delivery system was a promising carrier to enhance CNS drug's delivery ability into brain. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  8. Recommendations for the design of laboratory studies on non-target arthropods for risk assessment of genetically engineered plants.

    Science.gov (United States)

    Romeis, Jörg; Hellmich, Richard L; Candolfi, Marco P; Carstens, Keri; De Schrijver, Adinda; Gatehouse, Angharad M R; Herman, Rod A; Huesing, Joseph E; McLean, Morven A; Raybould, Alan; Shelton, Anthony M; Waggoner, Annabel

    2011-02-01

    This paper provides recommendations on experimental design for early-tier laboratory studies used in risk assessments to evaluate potential adverse impacts of arthropod-resistant genetically engineered (GE) plants on non-target arthropods (NTAs). While we rely heavily on the currently used proteins from Bacillus thuringiensis (Bt) in this discussion, the concepts apply to other arthropod-active proteins. A risk may exist if the newly acquired trait of the GE plant has adverse effects on NTAs when they are exposed to the arthropod-active protein. Typically, the risk assessment follows a tiered approach that starts with laboratory studies under worst-case exposure conditions; such studies have a high ability to detect adverse effects on non-target species. Clear guidance on how such data are produced in laboratory studies assists the product developers and risk assessors. The studies should be reproducible and test clearly defined risk hypotheses. These properties contribute to the robustness of, and confidence in, environmental risk assessments for GE plants. Data from NTA studies, collected during the analysis phase of an environmental risk assessment, are critical to the outcome of the assessment and ultimately the decision taken by regulatory authorities on the release of a GE plant. Confidence in the results of early-tier laboratory studies is a precondition for the acceptance of data across regulatory jurisdictions and should encourage agencies to share useful information and thus avoid redundant testing.

  9. In silico design of fragment-based drug targeting host processing α-glucosidase i for dengue fever

    Science.gov (United States)

    Toepak, E. P.; Tambunan, U. S. F.

    2017-02-01

    Dengue is a major health problem in the tropical and sub-tropical regions. The development of antiviral that targeting dengue’s host enzyme can be more effective and efficient treatment than the viral enzyme. Host enzyme processing α-glucosidase I has an important role in the maturation process of dengue virus envelope glycoprotein. The inhibition of processing α-glucosidase I can become a promising target for dengue fever treatment. The antiviral approach using in silico fragment-based drug design can generate drug candidates with high binding affinity. In this research, 198.621 compounds were obtained from ZINC15 Biogenic Database. These compounds were screened to find the favorable fragments according to Rules of Three and pharmacological properties. The screening fragments were docked into the active site of processing α-glucosidase I. The potential fragment candidates from the molecular docking simulation were linked with castanospermine (CAST) to generate ligands with a better binding affinity. The Analysis of ligand - enzyme interaction showed ligands with code LRS 22, 28, and 47 have the better binding free energy than the standard ligand. Ligand LRS 28 (N-2-4-methyl-5-((1S,3S,6S,7R,8R,8aR)-1,6,7,8-tetrahydroxyoctahydroindolizin-3-yl) pentyl) indolin-1-yl) propionamide) itself among the other ligands has the lowest binding free energy. Pharmacological properties prediction also showed the ligands LRS 22, 28, and 47 can be promising as the dengue fever drug candidates.

  10. In Silico Designing and Analysis of Inhibitors against Target Protein Identified through Host-Pathogen Protein Interactions in Malaria

    Directory of Open Access Journals (Sweden)

    Monika Samant

    2016-01-01

    Full Text Available Malaria, a life-threatening blood disease, has been a major concern in the field of healthcare. One of the severe forms of malaria is caused by the parasite Plasmodium falciparum which is initiated through protein interactions of pathogen with the host proteins. It is essential to analyse the protein-protein interactions among the host and pathogen for better understanding of the process and characterizing specific molecular mechanisms involved in pathogen persistence and survival. In this study, a complete protein-protein interaction network of human host and Plasmodium falciparum has been generated by integration of the experimental data and computationally predicting interactions using the interolog method. The interacting proteins were filtered according to their biological significance and functional roles. α-tubulin was identified as a potential protein target and inhibitors were designed against it by modification of amiprophos methyl. Docking and binding affinity analysis showed two modified inhibitors exhibiting better docking scores of −10.5 kcal/mol and −10.43 kcal/mol and an improved binding affinity of −83.80 kJ/mol and −98.16 kJ/mol with the target. These inhibitors can further be tested and validated in vivo for their properties as an antimalarial drug.

  11. Folate-conjugated pH-responsive nanocarrier designed for active tumor targeting and controlled release of doxorubicin

    Science.gov (United States)

    Wei, Lulu; Lu, Beibei; Cui, Lin; Peng, Xueying; Wu, Jianning; Li, Deqiang; Liu, Zhiyong; Guo, Xuhong

    2017-12-01

    A novel type of amphiphilic pH-responsive folate-poly(ɛ-caprolactone)- block-poly(2-hydroxyethylmethacrylate)- co-poly(2-(dimethylamino)-ethylmethacrylate) (FA-PCL- b-P(HEMA- co-DMAEMA)) (MFP) block copolymers were designed and synthesized via atom transfer radical polymerization (ATRP) and ring opening polymerization (ROP) techniques. The molecular structures of the copolymers were confirmed with 1H NMR, FTIR and GPC measurements. The critical micelle concentration (CMC) of MFP in aqueous solution was extremely low (about 6.54 mg/L). The in vitro release behavior of DOX-loaded micelles was significantly accelerated when the pH value of solution decreased from 7.4 to 5.0. In vitro antitumor efficiency was evaluated by incubating DOX-loaded micelles with Hela cells. The results demonstrated that this copolymer possessed excellent biocompatibility, and FA-decorated micelles MFP showed higher cellular uptake than those micelles without the FA moiety, indicating their unique targetability. These folate-conjugated biodegradable micelles are highly promising for targeted cancer chemothe-rapy.

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

    Science.gov (United States)

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

    2015-11-01

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

  13. Folate-conjugated pH-responsive nanocarrier designed for active tumor targeting and controlled release of doxorubicin

    Science.gov (United States)

    Wei, Lulu; Lu, Beibei; Cui, Lin; Peng, Xueying; Wu, Jianning; Li, Deqiang; Liu, Zhiyong; Guo, Xuhong

    2017-11-01

    A novel type of amphiphilic pH-responsive folate-poly(ɛ-caprolactone)-block-poly(2-hydroxyethylmethacrylate)-co-poly(2-(dimethylamino)-ethylmethacrylate) (FA-PCL-b-P(HEMA-co-DMAEMA)) (MFP) block copolymers were designed and synthesized via atom transfer radical polymerization (ATRP) and ring opening polymerization (ROP) techniques. The molecular structures of the copolymers were confirmed with 1H NMR, FTIR and GPC measurements. The critical micelle concentration (CMC) of MFP in aqueous solution was extremely low (about 6.54 mg/L). The in vitro release behavior of DOX-loaded micelles was significantly accelerated when the pH value of solution decreased from 7.4 to 5.0. In vitro antitumor efficiency was evaluated by incubating DOXloaded micelles with Hela cells. The results demonstrated that this copolymer possessed excellent biocompatibility, and FA-decorated micelles MFP showed higher cellular uptake than those micelles without the FA moiety, indicating their unique targetability. These folate-conjugated biodegradable micelles are highly promising for targeted cancer chemothe-rapy.

  14. Designing inhibitors of cytochrome c/cardiolipin peroxidase complexes: mitochondria-targeted imidazole-substituted fatty acids.

    Science.gov (United States)

    Jiang, Jianfei; Bakan, Ahmet; Kapralov, Alexandr A; Silva, K Ishara; Huang, Zhentai; Amoscato, Andrew A; Peterson, James; Garapati, Venkata Krishna; Saxena, Sunil; Bayir, Hülya; Atkinson, Jeffrey; Bahar, Ivet; Kagan, Valerian E

    2014-06-01

    Mitochondria have emerged as the major regulatory platform responsible for the coordination of numerous metabolic reactions as well as cell death processes, whereby the execution of intrinsic apoptosis includes the production of reactive oxygen species fueling oxidation of cardiolipin (CL) catalyzed by cytochrome (Cyt) c. As this oxidation occurs within the peroxidase complex of Cyt c with CL, the latter represents a promising target for the discovery and design of drugs with antiapoptotic mechanisms of action. In this work, we designed and synthesized a new group of mitochondria-targeted imidazole-substituted analogs of stearic acid TPP-n-ISAs with various positions of the attached imidazole group on the fatty acid (n = 6, 8, 10, 13, and 14). By using a combination of absorption spectroscopy and EPR protocols (continuous wave electron paramagnetic resonance and electron spin echo envelope modulation) we demonstrated that TPP-n-ISAs indeed were able to potently suppress CL-induced structural rearrangements in Cyt c, paving the way to its peroxidase competence. TPP-n-ISA analogs preserved the low-spin hexa-coordinated heme-iron state in Cyt c/CL complexes whereby TPP-6-ISA displayed a significantly more effective preservation pattern than TPP-14-ISA. Elucidation of these intermolecular stabilization mechanisms of Cyt c identified TPP-6-ISA as an effective inhibitor of the peroxidase function of Cyt c/CL complexes with a significant antiapoptotic potential realized in mouse embryonic cells exposed to ionizing irradiation. These experimental findings were detailed and supported by all-atom molecular dynamics simulations. Based on the experimental data and computation predictions, we identified TPP-6-ISA as a candidate drug with optimized antiapoptotic potency. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Rational-differential design of highly specific glycomimetic ligands: Targeting DC-SIGN and excluding Langerin recognition.

    Science.gov (United States)

    Porkolab, Vanessa; Chabrol, Eric; Varga, Norbert; Ordanini, Stefania; Sutkeviciute, Ieva; Thépaut, Michel; Garcia-Jiménez, Maria José; Girard, Eric; Nieto, Pedro M; Bernardi, Anna; Fieschi, Franck

    2017-12-22

    At the surface of dendritic cells, C-type lectin receptors (CLRs) allow the recognition of carbohydrate-based PAMPS or DAMPS (pathogen- or danger-associated molecular patterns respectively) and promote immune response regulation. However, some CLRs are hijacked by viral and bacterial pathogens. Thus, the design of ligands able to target specifically one CLR, to either modulate a immune response or to inhibit a given infection mechanism, has a great potential value in therapeutic design. A case study is the selective blocking of DC-SIGN, involved notably in HIV trans-infection of T lymphocytes, without interfering with Langerin-mediated HIV clearance. This is a challenging task due to their overlapping carbohydrate specificity. Towards the rational design of DC-SIGN selective ligands, we performed a comparative affinity study between DC-SIGN and Langerin with natural ligands. We found that GlcNAc is recognized by both CLRs, however, selective sulfatations are shown to increase the selectivity in favour of Langerin. With the combination of site-directed mutagenesis and X-ray structural analysis of Langerin/GlcNS6S complex, we highlighted that 6-sulfatation of the carbohydrate ligand induced Langerin specificity. Additionally, the K313 residue from Langerin was identified as a critical feature of its binding site. Using a rational and a differential approach in the study of CLR binding sites, we designed, synthetized and characterized a new glycomimetic which is highly specific for DC-SIGN vs Langerin. STD NMR, SPR and ITC characterizations show that compound 7 conserved the overall binding mode of the natural disaccharide while possessing an improved affinity and a strict specificity for DC-SIGN.

  16. Design of Novel Chemotherapeutic Agents Targeting Checkpoint Kinase 1 Using 3D-QSAR Modeling and Molecular Docking Methods.

    Science.gov (United States)

    Balupuri, Anand; Balasubramanian, Pavithra K; Cho, Seung J

    2016-01-01

    Checkpoint kinase 1 (Chk1) has emerged as a potential therapeutic target for design and development of novel anticancer drugs. Herein, we have performed three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking analyses on a series of diazacarbazoles to design potent Chk1 inhibitors. 3D-QSAR models were developed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Docking studies were performed using AutoDock. The best CoMFA and CoMSIA models exhibited cross-validated correlation coefficient (q2) values of 0.631 and 0.585, and non-cross-validated correlation coefficient (r2) values of 0.933 and 0.900, respectively. CoMFA and CoMSIA models showed reasonable external predictabilities (r2 pred) of 0.672 and 0.513, respectively. A satisfactory performance in the various internal and external validation techniques indicated the reliability and robustness of the best model. Docking studies were performed to explore the binding mode of inhibitors inside the active site of Chk1. Molecular docking revealed that hydrogen bond interactions with Lys38, Glu85 and Cys87 are essential for Chk1 inhibitory activity. The binding interaction patterns observed during docking studies were complementary to 3D-QSAR results. Information obtained from the contour map analysis was utilized to design novel potent Chk1 inhibitors. Their activities and binding affinities were predicted using the derived model and docking studies. Designed inhibitors were proposed as potential candidates for experimental synthesis.

  17. siDirect 2.0: updated software for designing functional siRNA with reduced seed-dependent off-target effect

    Directory of Open Access Journals (Sweden)

    Morishita Shinichi

    2009-11-01

    Full Text Available Abstract Background RNA interference (RNAi, mediated by 21-nucleotide (nt-length small interfering RNAs (siRNAs, is a powerful tool not only for studying gene function but also for therapeutic applications. RNAi, requiring perfect complementarity between the siRNA guide strand and the target mRNA, was believed to be extremely specific. However, a recent growing body of evidence has suggested that siRNA could down-regulate unintended genes whose transcripts possess complementarity to the 7-nt siRNA seed region. This off-target gene silencing may often provide incongruous results obtained from knockdown experiments, leading to misinterpretation. Thus, an efficient algorithm for designing functional siRNAs with minimal off-target effect based on the mechanistic features is considered of value. Results We present siDirect 2.0, an update of our web-based software siDirect, which provides functional and off-target minimized siRNA design for mammalian RNAi. The previous version of our software designed functional siRNAs by considering the relationship between siRNA sequence and RNAi activity, and provided them along with the enumeration of potential off-target gene candidates by using a fast and sensitive homology search algorithm. In the new version, the siRNA design algorithm is extensively updated to eliminate off-target effects by reflecting our recent finding that the capability of siRNA to induce off-target effect is highly correlated to the thermodynamic stability, or the melting temperature (Tm, of the seed-target duplex, which is formed between the nucleotides positioned at 2-8 from the 5' end of the siRNA guide strand and its target mRNA. Selection of siRNAs with lower seed-target duplex stabilities (benchmark Tm Conclusion siDirect 2.0 provides functional, target-specific siRNA design with the updated algorithm which significantly reduces off-target silencing. When the candidate functional siRNAs could form seed-target duplexes with Tm

  18. Design of a TOF-SANS instrument for the proposed long wavelength target station at the spallation neutron source

    Energy Technology Data Exchange (ETDEWEB)

    Thiyagarajan, P.; Littrell, K. [Intense Pulsed Neutron Source, Argonne National Laboratory, IL (United States); Seeger, P.A.

    2001-03-01

    We have designed a versatile high-throughput SANS instrument [Broad Range Intense Multipurpose SANS (BRIMS)] for the proposed Long Wavelength Target Station at the SNS by using acceptance diagrams and the Los Alamos NISP Monte Carlo simulation package. This instrument has been fully optimized to take advantage of the 10 Hz source frequency (broad wavelength bandwidth) and the cold neutron spectrum from a tall coupled solid methane moderator (12 cm x 20 cm). BRIMS has been designed to produce data in a Q range spanning from 0.0025 to 0.7 A{sup -1} in a single measurement by simultaneously using neutrons with wavelengths ranging from 1 to 14.5 A in a time of flight mode. A supermirror guide and bender assembly is employed to separate and redirect the useful portion of the neutron spectrum with {lambda}>1 A, by 2.3deg away from the direct beam containing high energy neutrons and {gamma} rays. The effects of various collimation choices on count rate, resolution and Q{sub min} have been characterized using spherical particle and delta function scatterers. The overall performance of BRIMS has been compared with that of the best existing reactor-based SANS instrument D22 at ILL. (author)

  19. Design of a TOF-SANS instrument for the proposed Long Wavelength Target Station at the Spallation Neutron Source.

    Energy Technology Data Exchange (ETDEWEB)

    Thiyagarajan, P.; Littrell, K.; Seeger, P. A.

    2000-11-28

    We have designed a versatile high-throughput SANS instrument [Broad Range Intense Multipurpose SANS (BRIMS)] for the proposed Long Wavelength Target Station at the SNS by using acceptance diagrams and the Los Alamos NISP Monte Carlo simulation package. This instrument has been fully optimized to take advantage of the 10 Hz source frequency (broad wavelength bandwidth) and the cold neutron spectrum from a tall coupled solid methane moderator (12 cm x 20 cm). BRIMS has been designed to produce data in a Q range spanning from 0.001 to 0.7 {angstrom}{sup {minus}1} in a single measurement by simultaneously using neutrons with wavelengths ranging from 1 to 14.5 {angstrom} in a time of flight mode. A supermirror guide and bender assembly is employed to separate and redirect the useful portion of the neutron spectrum with {lambda} > 1 {angstrom}, by 2.3{degree} away from the direct beam containing high energy neutrons and {gamma} rays. The effects of the supermirror coating of the guide, the location of the bender assembly with respect to the source, the bend angle, and various collimation choices on the flux, resolution and Q{sub min} have been characterized using spherical particle and delta function scatterers. The overall performance of BRIMS has been compared with that of the best existing reactor-based SANS instrument D22 at ILL.

  20. Population Connectivity Measures of Fishery-Targeted Coral Reef Species to Inform Marine Reserve Network Design in Fiji.

    Science.gov (United States)

    Eastwood, Erin K; López, Elora H; Drew, Joshua A

    2016-01-25

    Coral reef fish serve as food sources to coastal communities worldwide, yet are vulnerable to mounting anthropogenic pressures like overfishing and climate change. Marine reserve networks have become important tools for mitigating these pressures, and one of the most critical factors in determining their spatial design is the degree of connectivity among different populations of species prioritized for protection. To help inform the spatial design of an expanded reserve network in Fiji, we used rapidly evolving mitochondrial genes to investigate connectivity patterns of three coral reef species targeted by fisheries in Fiji: Epinephelus merra (Serranidae), Halichoeres trimaculatus (Labridae), and Holothuria atra (Holothuriidae). The two fish species, E. merra and Ha. trimaculatus, exhibited low genetic structuring and high amounts of gene flow, whereas the sea cucumber Ho. atra displayed high genetic partitioning and predominantly westward gene flow. The idiosyncratic patterns observed among these species indicate that patterns of connectivity in Fiji are likely determined by a combination of oceanographic and ecological characteristics. Our data indicate that in the cases of species with high connectivity, other factors such as representation or political availability may dictate where reserves are placed. In low connectivity species, ensuring upstream and downstream connections is critical.

  1. A systematic approach to identify novel cancer drug targets using machine learning, inhibitor design and high-throughput screening

    OpenAIRE

    Jeon, Jouhyun; Nim, Satra; Teyra, Joan; Datti, Alessandro; Wrana, Jeffrey L.; Sidhu, Sachdev S.; Moffat, Jason; Kim, Philip M.

    2014-01-01

    We present an integrated approach that predicts and validates novel anti-cancer drug targets. We first built a classifier that integrates a variety of genomic and systematic datasets to prioritize drug targets specific for breast, pancreatic and ovarian cancer. We then devised strategies to inhibit these anti-cancer drug targets and selected a set of targets that are amenable to inhibition by small molecules, antibodies and synthetic peptides. We validated the predicted drug targets by showin...

  2. K-Targeted Metabolomic Analysis Extends Chemical Subtraction to DESIGNER Extracts: Selective Depletion of Extracts of Hops (Humulus lupulus)⊥

    Science.gov (United States)

    2015-01-01

    This study introduces a flexible and compound targeted approach to Deplete and Enrich Select Ingredients to Generate Normalized Extract Resources, generating DESIGNER extracts, by means of chemical subtraction or augmentation of metabolites. Targeting metabolites based on their liquid–liquid partition coefficients (K values), K targeting uses countercurrent separation methodology to remove single or multiple compounds from a chemically complex mixture, according to the following equation: DESIGNER extract = total extract ± target compound(s). Expanding the scope of the recently reported depletion of extracts by immunoaffinity or solid phase liquid chromatography, the present approach allows a more flexible, single- or multi-targeted removal of constituents from complex extracts such as botanicals. Chemical subtraction enables both chemical and biological characterization, including detection of synergism/antagonism by both the subtracted targets and the remaining metabolite mixture, as well as definition of the residual complexity of all fractions. The feasibility of the DESIGNER concept is shown by K-targeted subtraction of four bioactive prenylated phenols, isoxanthohumol (1), 8-prenylnaringenin (2), 6-prenylnaringenin (3), and xanthohumol (4), from a standardized hops (Humulus lupulus L.) extract using specific solvent systems. Conversely, adding K-targeted isolates allows enrichment of the original extract and hence provides an augmented DESIGNER material. Multiple countercurrent separation steps were used to purify each of the four compounds, and four DESIGNER extracts with varying depletions were prepared. The DESIGNER approach innovates the characterization of chemically complex extracts through integration of enabling technologies such as countercurrent separation, K-by-bioactivity, the residual complexity concepts, as well as quantitative analysis by 1H NMR, LC-MS, and HiFSA-based NMR fingerprinting. PMID:25437744

  3. Double-shell target design for the NIF: Noncryogenic ignition and nonlinear mix studies for Stockpile Stewardship

    Energy Technology Data Exchange (ETDEWEB)

    Amendt, P

    2004-02-10

    Double-shell ignition is complementary to the baseline approach by virtue of not requiring: (1) cryogenic preparation and fielding, (2) high-contrast pulse-shaping for shock-timing, and (3) demanding x-ray flux symmetry control. The use of simpler low-contrast pulse-shaping potentially allows more benign hohlraum conditions by reducing the risk of laser backscatter. In addition, the associated higher laser fluence threshold for optics damage initiation allows the possibility of more routine high-fluence shots with 2{omega} on the NIF. Based on LDRD-sponsored research in FY01-03 on NIF double-shell ignition target designs, the feasibility of this approach was advanced through both a highly successful implosion campaign on the Omega laser facility and a variety of design improvements for mitigating instability. The double-shell implosion campaign on Omega achieved the important milestone of repeatably demonstrating dominant primary (2.45 MeV) neutron production from the mix-susceptible compressional phase of a double-shell implosion, using fall-line design optimization and exacting fabrication standards. Showing effective control of fuel-pusher mix during final compression is an essential element for achieving ignition. In our studies to control mix by reducing hydrodynamic instability a new pathway for destructive Rayleigh-Taylor growth on the outer surface of the inner shell at ignition scales was identified. However, highly resolved multi-mode simulations showed that with use of a graded dopant in the inner shell and material-matching with an exterior metallic foam, this instability was significantly reduced. In addition, the resulting density-gradient stabilization was seen to quench small-wavelength growth, thereby avoiding the computationally challenging turbulent regime. A major goal of future research for realizing double-shell ignition on the NIF is experimental validation of this instability mitigation approach using the Omega laser facility.

  4. Design of immuno-enzymosomes with maximum enzyme targeting capability : effect of the enzyme density on the enzyme targeting capability and cell binding properties

    NARCIS (Netherlands)

    Fonseca, MJ; Haisma, HJ; Klaasen, S; Vingerhoeds, MH; Storm, G

    1999-01-01

    Immuno-enzymosomes have been proposed for the targeting of enzymes to cancer cells to achieve site specific activation of anticancer prodrugs. Previously, we reported that the enzyme beta-glucuronidase (GUS), capable of activating anthracycline-glucuronide prodrugs, can be coupled to the surface of

  5. An iterative and targeted sampling design informed by habitat suitability models for detecting focal plant species over extensive areas.

    Science.gov (United States)

    Wang, Ophelia; Zachmann, Luke J; Sesnie, Steven E; Olsson, Aaryn D; Dickson, Brett G

    2014-01-01

    Prioritizing areas for management of non-native invasive plants is critical, as invasive plants can negatively impact plant community structure. Extensive and multi-jurisdictional inventories are essential to prioritize actions aimed at mitigating the impact of invasions and changes in disturbance regimes. However, previous work devoted little effort to devising sampling methods sufficient to assess the scope of multi-jurisdictional invasion over extensive areas. Here we describe a large-scale sampling design that used species occurrence data, habitat suitability models, and iterative and targeted sampling efforts to sample five species and satisfy two key management objectives: 1) detecting non-native invasive plants across previously unsampled gradients, and 2) characterizing the distribution of non-native invasive plants at landscape to regional scales. Habitat suitability models of five species were based on occurrence records and predictor variables derived from topography, precipitation, and remotely sensed data. We stratified and established field sampling locations according to predicted habitat suitability and phenological, substrate, and logistical constraints. Across previously unvisited areas, we detected at least one of our focal species on 77% of plots. In turn, we used detections from 2011 to improve habitat suitability models and sampling efforts in 2012, as well as additional spatial constraints to increase detections. These modifications resulted in a 96% detection rate at plots. The range of habitat suitability values that identified highly and less suitable habitats and their environmental conditions corresponded to field detections with mixed levels of agreement. Our study demonstrated that an iterative and targeted sampling framework can address sampling bias, reduce time costs, and increase detections. Other studies can extend the sampling framework to develop methods in other ecosystems to provide detection data. The sampling methods

  6. An iterative and targeted sampling design informed by habitat suitability models for detecting focal plant species over extensive areas.

    Directory of Open Access Journals (Sweden)

    Ophelia Wang

    Full Text Available Prioritizing areas for management of non-native invasive plants is critical, as invasive plants can negatively impact plant community structure. Extensive and multi-jurisdictional inventories are essential to prioritize actions aimed at mitigating the impact of invasions and changes in disturbance regimes. However, previous work devoted little effort to devising sampling methods sufficient to assess the scope of multi-jurisdictional invasion over extensive areas. Here we describe a large-scale sampling design that used species occurrence data, habitat suitability models, and iterative and targeted sampling efforts to sample five species and satisfy two key management objectives: 1 detecting non-native invasive plants across previously unsampled gradients, and 2 characterizing the distribution of non-native invasive plants at landscape to regional scales. Habitat suitability models of five species were based on occurrence records and predictor variables derived from topography, precipitation, and remotely sensed data. We stratified and established field sampling locations according to predicted habitat suitability and phenological, substrate, and logistical constraints. Across previously unvisited areas, we detected at least one of our focal species on 77% of plots. In turn, we used detections from 2011 to improve habitat suitability models and sampling efforts in 2012, as well as additional spatial constraints to increase detections. These modifications resulted in a 96% detection rate at plots. The range of habitat suitability values that identified highly and less suitable habitats and their environmental conditions corresponded to field detections with mixed levels of agreement. Our study demonstrated that an iterative and targeted sampling framework can address sampling bias, reduce time costs, and increase detections. Other studies can extend the sampling framework to develop methods in other ecosystems to provide detection data. The

  7. Design and construction of multifunctional hyperbranched polymers coated magnetite nanoparticles for both targeting magnetic resonance imaging and cancer therapy.

    Science.gov (United States)

    Mashhadi Malekzadeh, Asemeh; Ramazani, Ali; Tabatabaei Rezaei, Seyed Jamal; Niknejad, Hassan

    2017-03-15

    Magnetic drug targeting is a drug delivery strategy that can be used to improve the therapeutic efficiency on tumor cells and reduce the side effects on normal cells and tissues. The aim in this study is designing a novel multifunctional drug delivery system based on superparamagnetic nanoparticles for cancer therapy. Magnetic nanoparticles were synthesized by coprecipitation of iron oxide followed by coating with poly citric acid (PCA) dendritic macromolecules via bulk polymerization strategy. It was further surface-functionalized with poly(ethylene glycol) (PEG) and then to achieve tumor cell targeting property, folic acid was further incorporated to the surface of prepared carriers via a facile coupling reaction between the hydroxyl end group of the PEG and the carboxyl group of folic acid. The so prepared nanocarriers (Fe3O4@PCA-PEG-FA) were characterized by X-ray diffraction, TEM, TGA, FT-IR, DLS and VSM techniques. The room temperature VSM measurements showed that magnetic particles were superparamagnetic. Transmission electron microscopy and dynamic light scattering were also performed which revealed that size of nanocarriers was lying in the range of 10-49nm. Quercetin loading and release profiles of prepared nanocarriers showed that up to 83% of loaded drug was released in 250h. Fluorescent microscopy showed that the cellular uptake by folate receptor-overexpressing HeLa cells of the quercetin-loaded Fe3O4@PCA-PEG-FA nanoparticles was higher than that of non-folate conjugated nanoparticles. Thus, folate conjugation significantly increased nanoparticle cytotoxicity. Also, T2-weighted MRI images of Fe3O4@PCA-PEG-FA nanoparticles showed that the magnetic resonance signal is enhanced significantly with increasing nanoparticle concentration in water and they also served as MRI contrast agents with relaxivities of 3.4mM-1s-1 (r1) and 99.8mM-1s-1 (r2). The results indicate that this multifunctional nanocarrier is a significant breakthrough in developing a drug

  8. Design, synthesis, and validation of a β-turn mimetic library targeting protein-protein and peptide-receptor interactions.

    Science.gov (United States)

    Whitby, Landon R; Ando, Yoshio; Setola, Vincent; Vogt, Peter K; Roth, Bryan L; Boger, Dale L

    2011-07-06

    The design and synthesis of a β-turn mimetic library as a key component of a small-molecule library targeting the major recognition motifs involved in protein-protein interactions is described. Analysis of a geometric characterization of 10,245 β-turns in the protein data bank (PDB) suggested that trans-pyrrolidine-3,4-dicarboxamide could serve as an effective and synthetically accessible library template. This was confirmed by initially screening select compounds against a series of peptide-activated GPCRs that recognize a β-turn structure in their endogenous ligands. This validation study was highlighted by identification of both nonbasic and basic small molecules with high affinities (K(i) = 390 and 23 nM, respectively) for the κ-opioid receptor (KOR). Consistent with the screening capabilities of collaborators and following the design validation, the complete library was assembled as 210 mixtures of 20 compounds, providing a total of 4200 compounds designed to mimic all possible permutations of 3 of the 4 residues in a naturally occurring β-turn. Unique to the design and because of the C(2) symmetry of the template, a typical 20 × 20 × 20-mix (8000 compounds prepared as 400 mixtures of 20 compounds) needed to represent 20 variations in the side chains of three amino acid residues reduces to a 210 × 20-mix, thereby simplifying the library synthesis and subsequent screening. The library was prepared using a solution-phase synthetic protocol with liquid-liquid or liquid-solid extractions for purification and conducted on a scale that insures its long-term availability for screening campaigns. Screening the library against the human opioid receptors (KOR, MOR, and DOR) identified not only the activity of library members expected to mimic the opioid receptor peptide ligands but also additional side-chain combinations that provided enhanced receptor binding selectivities (>100-fold) and affinities (as low as K(i) = 80 nM for KOR). A key insight to emerge from

  9. Implementation of treat-to-target in rheumatoid arthritis through a Learning Collaborative: Rationale and design of the TRACTION trial.

    Science.gov (United States)

    Solomon, Daniel H; Lee, Sara B; Zak, Agnes; Corrigan, Cassandra; Agosti, Jenifer; Bitton, Asaf; Harrold, Leslie; Losina, Elena; Lu, Bing; Pincus, Ted; Radner, Helga; Smolen, Josef; Katz, Jeffrey N; Fraenkel, Liana

    2016-08-01

    Treat-to-target (TTT) is a recommended strategy in the management of rheumatoid arthritis (RA), but various data sources suggest that its uptake in routine care in the US is suboptimal. Herein, we describe the design of a randomized controlled trial of a Learning Collaborative to facilitate implementation of TTT. We recruited 11 rheumatology sites from across the US and randomized them into the following two groups: one received the Learning Collaborative intervention in Phase 1 (month 1-9) and the second formed a wait-list control group to receive the intervention in Phase 2 (months 10-18). The Learning Collaborative intervention was designed using the Model for Improvement, consisting of a Change Package with corresponding principles and action phases. Phase 1 intervention practices had nine learning sessions, collaborated using a web-based tool, and shared results of plan-do-study-act cycles and monthly improvement metrics collected at each practice. The wait-list control group sites had no intervention during Phase 1. The primary trial outcome is the implementation of TTT as measured by chart review, comparing the differences from baseline to end of Phase 1, between intervention and control sites. All intervention sites remained engaged in the Learning Collaborative throughout Phase 1, with a total of 38 providers participating. The primary trial outcome measures are currently being collected by the study team through medical record review. If the Learning Collaborative is an effective means for improving implementation of TTT, this strategy could serve as a way of implementing disseminating TTT more widely. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Bioinformatics and rational drug design: tools for discovery and better understanding of biological targets and mode of action of drugs.

    Science.gov (United States)

    Thibaut, U

    2002-01-01

    With the advent of modern high throughput technologies in both genomics and biological screening, and at the same time the enormous advances in computer technology, it is now feasible to use these tools in rational approaches in the search for new medicines. The role of bioinformatics in the search for new medicines is discussed. Discussion of the author's own work on bioinformatics in drug research in future perspective. The emerging discipline of Bioinformatics plays a central role in the concert of technologies of the 'biological revolution' because it allows for handling of the enormous data load that comes with sequencing efforts and subsequent analyses of whole genomes, with mRNA profiling techniques and, last but not least, at a later stage of drug discovery the up-to-date application of rational drug design techniques to 3D structures of target proteins. This article covers and explains parts of the steps used in modern pharmaceutical research by means of a small number of examples. Bioinformatics is likely to play a pivotal role in the rational approaches for the search of new medicines.

  11. Optimisation of protein-fortified beef patties targeted to the needs of older adults: a mixture design approach.

    Science.gov (United States)

    Baugreet, Sephora; Kerry, Joseph P; Allen, Paul; Hamill, Ruth M

    2017-12-01

    Mixture design was used to technologically optimise inclusions of protein ingredients [rice protein (RP) 0-10%, and lentil flour (LF) 0-10%] in fortified beef patties [meat (M) 90-100%] to ensure acceptable technological and sensorial properties. 17 formulations were generated. Composition, texture parameters, colour, lipid oxidation, microbiological and sensorial parameters were assessed. Maximal predicted protein content was 28.7% (P<0.01) which positively correlated with RP, but not LF. Models showed that LF inclusion correlated with improved texture and also reduced cook loss. Two optimised formulations (OF1 and OF2), for protein content and technological performance, were experimentally validated. Sensory panellists scored the optimised formulations higher than controls for tenderness and beef aroma (P<0.05). This presents an opportunity to produce protein fortified beef patties with softer texture and acceptable technological characteristics. The consumption of such protein fortified beef patties could assist older adults reach their targeted protein requirements. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. vanA-targeted oligonucleotide DNA probe designed to monitor vancomycin- and teicoplanin-resistant bacteria in surface waters.

    Science.gov (United States)

    Nakipoglu, Mustafa; Yilmaz, Fadime; Icgen, Bulent

    2016-10-01

    The glycopeptide antibiotics teicoplanin and vancomycin are common to treat severe Gram-positive bacterial infections. The gene vanA confers high-level resistance to these antibiotics, and these phenomena have been shown to be transferable. Release of vancomycin- and teicoplanin-resistant bacteria to surface waters is, therefore, of particular concern since they might proliferate and spread in different environments. Monitoring of the fate of vanA gene in these waters provides information on the exposure and potential threats of those bacteria for the environment and public health. Therefore, this study aimed at preparing a 25-mer-oligonucleotide DNA probe based on the 909 bp BamHI-ClaI fragment from Enterococcus faecium plasmids pVEF1 and pVEF2 through the use of Vector NTI Express Software. The newly designed vanA probe displayed highly specific hybridization with vanA-positive Enterococcus faecalis tested at 46 °C, 55 % formamide, and 0.020 M NaCl stringency conditions. In situ fluorescein hybridizations under the same stringency conditions were also used to monitor river water samples by using fluorescein microscopy. The results showed that the vanA-targeted oligonucleotide DNA probe prepared was not only highly specific but also quantitative tool for monitoring vancomycin- and teicoplanin-resistant bacteria in surface waters.

  13. The design of a cryogenic dark matter detector based on the detection of the recoil direction of target nuclei

    Energy Technology Data Exchange (ETDEWEB)

    Gaitskell, R.J. [Oxford Univ. (United Kingdom). Dept. of Physics; Angrave, L.C. [Oxford Univ. (United Kingdom). Dept. of Physics; Booth, N.E. [Oxford Univ. (United Kingdom). Dept. of Physics; Esposito, E. [Oxford Univ. (United Kingdom). Dept. of Physics; Giles, T.J. [Oxford Univ. (United Kingdom). Dept. of Physics; Hoess, C. [Oxford Univ. (United Kingdom). Dept. of Physics; Houwman, E.P. [Oxford Univ. (United Kingdom). Dept. of Physics; Salmon, G.L. [Oxford Univ. (United Kingdom). Dept. of Physics; Van den Putte, M. [Oxford Univ. (United Kingdom). Dept. of Physics; Waenninger, S. [Oxford Univ. (United Kingdom). Dept. of Physics

    1996-02-11

    We discuss the design of a cryogenic detector for a WIMP dark matter search based on single crystal absorbers and using Series Arrays of Superconducting Tunnel Junctions (SASTJs). The distribution of recoil vectors of target nuclei from WIMP interactions are affected by the motion of the laboratory through the dark matter halo. The angular distribution of recoil directions is skewed due to the motion of the solar system around the galaxy and is modulated by the diurnal and annual rotation of the earth. We discuss the kinematics of the recoil events and how a directional signal might be identified in our cryogenic detectors using the fast response of SASTJs to the ballistic phonons arising in the absorber from WIMP interactions. We consider how the anisotropy of a dark matter recoil distribution can be used to place statistical limits on its component relative to the isotropic background signal. We also consider how the dark matter limit is altered if only the axis of the nuclear recoil, rather than the full recoil direction is available. We also briefly consider the effect of phonon focusing within single crystal absorbers. Focusing will modulate strongly the signal detected by the SASTJs, on the crystal surface, as the position of the interaction within the crystal varies. A comparison is made between the behaviour of phonons in strongly focusing crystals, such as Nb, Si and LiF, and their near isotropic propagation in BaF{sub 2}. (orig.).

  14. Modeling and optimization of energy generation and storage systems for thermal conditioning of buildings targeting conceptual building design

    Energy Technology Data Exchange (ETDEWEB)

    Grahovac, Milica

    2012-11-29

    minimal costs, emissions or consumption, while maintaining the quality of the supply and, where specified, achieving the targeted annual solar ratio. Two optimization algorithms, the global bounded Nelder Mead and the Exhaustive search are implemented. Simulation and optimization performance has been evaluated using building and weather data for four cities situated in four different climates. Finally a tool, entitled PROBA, has been proposed by adding a user interface to the mod-els. The major characteristic of the interface is its suitability for non-expert users. This is achieved by, firstly, reducing amount of input data by implementing preset values and, secondly, providing information support. Making this tool available to the architects repre-sents an effective way to consider the primary HVAC during the preliminary design, with-out causing additional cost. Although such a tool can never replace an HVAC engineer, its use can heighten the awareness of architects regarding the significance of building energy consumption and inspire further education in this field.

  15. CRISPR-offinder: a CRISPR guide RNA design and off-target searching tool for user-defined protospacer adjacent motif.

    Science.gov (United States)

    Zhao, Changzhi; Zheng, Xiaoguo; Qu, Wubin; Li, Guanglei; Li, Xinyun; Miao, Yi-Liang; Han, Xiaosong; Liu, Xiangdong; Li, Zhenhua; Ma, Yunlong; Shao, Qianzhi; Li, Haiwei; Sun, Fei; Xie, Shengsong; Zhao, Shuhong

    2017-01-01

    Designing efficient and specific CRISPR single-guide RNAs (sgRNAs) is vital for the successful application of CRISPR technology. Currently, a growing number of new RNA-guided endonucleases with a different protospacer adjacent motif (PAM) have been discovered, suggesting the necessity to develop a versatile tool for designing sgRNA to meet the requirement of different RNA-guided DNA endonucleases. Here, we report the development of a flexible sgRNA design program named "CRISPR-offinder". Support for user-defined PAM and sgRNA length was provided to increase the targeting range and specificity. Additionally, evaluation of on- and off-target scoring algorithms was integrated into the CRISPR-offinder. The CRISPR-offinder has provided the bench biologist a rapid and efficient tool for identification of high quality target sites, and it is freely available at https://sourceforge.net/projects/crispr-offinder-v1-2/ or http://www.biootools.com.

  16. Design, Synthesis, and Characterization of Folate-Targeted Platinum-Loaded Theranostic Nanoemulsions for Therapy and Imaging of Ovarian Cancer.

    Science.gov (United States)

    Patel, Niravkumar R; Piroyan, Aleksandr; Nack, Abbegial H; Galati, Corin A; McHugh, Mackenzi; Orosz, Samantha; Keeler, Amanda W; O'Neal, Sara; Zamboni, William C; Davis, Barbara; Coleman, Timothy P

    2016-06-06

    Platinum (Pt) based chemotherapy is widely used to treat many types of cancer. Pt therapy faces challenges such as dose limiting toxicities, cumulative side effects, and multidrug resistance. Nanoemulsions (NEs) have tremendous potential in overcoming these challenges as they can be designed to improve circulation time, limit non-disease tissue uptake, and enhance tumor uptake by surface modification. We designed novel synthesis of three difattyacid platins, dimyrisplatin, dipalmiplatin, and distearyplatin, suitable for encapsulation in the oil core of an NE. The dimyrisplatin, dipalmiplatin, and distearyplatin were synthesized, characterized, and loaded into the oil core of our NEs, NMI-350, NMI-351, and NMI-352 respectively. Sequestration of the difattyacid platins was accomplished through high energy microfluidization. To target the NE, FA-PEG3400-DSPE was incorporated into the surface during microfluidization. The FA-NEs selectively bind the folate receptor α (FR-α) and utilize receptor mediated endocytosis to deliver Pt past cell surface resistance mechanisms. FR-α is overexpressed in a number of oncological conditions including ovarian cancer. The difattyacid platins, lipidated Gd-DTPA, and lipidated folate were characterized by nuclear magnetic resonance (NMR), mass spectrometry (MS), and elemental analysis. NEs were synthesized using high shear microfluidization process and characterized for size, zeta-potential, and loading efficiency. In vitro cytotoxicity was determined using KB-WT (Pt-sensitive) and KBCR-1000 (Pt-resistant) cancer cells and measured by MTT assay. Pharmacokinetic profiles were studied in CD-1 mice. NEs loaded with difattyacid platins are highly stable and had size distribution in the range of ∼120 to 150 nm with low PDI. Cytotoxicity data indicates the longer the fatty acid chains, the less potent the NEs. The inclusion of C6-ceramide, an apoptosis enhancer, and surface functionalization with folate molecules significantly increased

  17. 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.

  18. Superior control of HIV-1 replication by CD8+ T cells targeting conserved epitopes: implications for HIV vaccine design.

    Directory of Open Access Journals (Sweden)

    Pratima Kunwar

    Full Text Available A successful HIV vaccine will likely induce both humoral and cell-mediated immunity, however, the enormous diversity of HIV has hampered the development of a vaccine that effectively elicits both arms of the adaptive immune response. To tackle the problem of viral diversity, T cell-based vaccine approaches have focused on two main strategies (i increasing the breadth of vaccine-induced responses or (ii increasing vaccine-induced responses targeting only conserved regions of the virus. The relative extent to which set-point viremia is impacted by epitope-conservation of CD8(+ T cell responses elicited during early HIV-infection is unknown but has important implications for vaccine design. To address this question, we comprehensively mapped HIV-1 CD8(+ T cell epitope-specificities in 23 ART-naïve individuals during early infection and computed their conservation score (CS by three different methods (prevalence, entropy and conseq on clade-B and group-M sequence alignments. The majority of CD8(+ T cell responses were directed against variable epitopes (p<0.01. Interestingly, increasing breadth of CD8(+ T cell responses specifically recognizing conserved epitopes was associated with lower set-point viremia (r = - 0.65, p = 0.009. Moreover, subjects possessing CD8(+ T cells recognizing at least one conserved epitope had 1.4 log10 lower set-point viremia compared to those recognizing only variable epitopes (p = 0.021. The association between viral control and the breadth of conserved CD8(+ T cell responses may be influenced by the method of CS definition and sequences used to determine conservation levels. Strikingly, targeting variable versus conserved epitopes was independent of HLA type (p = 0.215. The associations with viral control were independent of functional avidity of CD8(+ T cell responses elicited during early infection. Taken together, these data suggest that the next-generation of T-cell based HIV-1 vaccines should focus

  19. Structural mapping of the ClpB ATPases of Plasmodium falciparum: Targeting protein folding and secretion for antimalarial drug design.

    Science.gov (United States)

    AhYoung, Andrew P; Koehl, Antoine; Cascio, Duilio; Egea, Pascal F

    2015-09-01

    Caseinolytic chaperones and proteases (Clp) belong to the AAA+ protein superfamily and are part of the protein quality control machinery in cells. The eukaryotic parasite Plasmodium falciparum, the causative agent of malaria, has evolved an elaborate network of Clp proteins including two distinct ClpB ATPases. ClpB1 and ClpB2 are involved in different aspects of parasitic proteostasis. ClpB1 is present in the apicoplast, a parasite-specific and plastid-like organelle hosting various metabolic pathways necessary for parasite growth. ClpB2 localizes to the parasitophorous vacuole membrane where it drives protein export as core subunit of a parasite-derived protein secretion complex, the Plasmodium Translocon of Exported proteins (PTEX); this process is central to parasite virulence and survival in the human host. The functional associations of these two chaperones with parasite-specific metabolism and protein secretion make them prime drug targets. ClpB proteins function as unfoldases and disaggregases and share a common architecture consisting of four domains-a variable N-terminal domain that binds different protein substrates, followed by two highly conserved catalytic ATPase domains, and a C-terminal domain. Here, we report and compare the first crystal structures of the N terminal domains of ClpB1 and ClpB2 from Plasmodium and analyze their molecular surfaces. Solution scattering analysis of the N domain of ClpB2 shows that the average solution conformation is similar to the crystalline structure. These structures represent the first step towards the characterization of these two malarial chaperones and the reconstitution of the entire PTEX to aid structure-based design of novel anti-malarial drugs. © 2015 The Protein Society.

  20. New design targets and new automated technology for the production of radionuclides with high specificity radioactivity in nuclear research reactors

    Energy Technology Data Exchange (ETDEWEB)

    Gerasimov, A.S.; Kiselev, G.V. [State Russian Center of the Russian Federation, Moscow (Russian Federation). Institute of Theoretical and Experimental Physics

    1997-10-01

    Current demands of industry require the application of radionuclides with high specific radioactivity under low consumption of neutrons. To provide this aim staff of ITEP Reactor Department investigated the different type AEs of start targets for the production of the main radionuclides; Co-60, Ir-192 and others. In first turn the targets of Co and Ir without the block-effect of neutron flux (with low absorption of neutrons) were investigated. The following principal results were received for example for Ir-192: block effect is equal 0.086 for diameter of Ir target mm and is equal 0.615 for diameter Ir target 0.5mm. It means average neutron flux for Ir target diameter 0.5mm and therefore the production of Ir-192 will be at 10 times more than for diameter 6.0mm. To provide the automated technology of the manufacture of radioactive sources with radionuclides with high specific radioactivity it was proposed that the compound targets for the irradiation of ones and for the management with the irradiated targets. Different types of compound targets were analyzed. (authors)

  1. One size does not fit all: how the tobacco industry has altered cigarette design to target consumer groups with specific psychological and psychosocial needs.

    Science.gov (United States)

    Cook, Benjamin Lê; Wayne, Geoffrey Ferris; Keithly, Lois; Connolly, Gregory

    2003-11-01

    To identify whether the tobacco industry has targeted cigarette product design towards individuals with varying psychological/psychosocial needs. Internal industry documents were identified through searches of an online archival document research tool database using relevancy criteria of consumer segmentation and needs assessment. The industry segmented consumer markets based on psychological needs (stress relief, behavioral arousal, performance enhancement, obesity reduction) and psychosocial needs (social acceptance, personal image). Associations between these segments and smoking behaviors, brand and design preferences were used to create cigarette brands targeting individuals with these needs. Cigarette brands created to address the psychological/psychosocial needs of smokers may increase the likelihood of smoking initiation and addiction. Awareness of targeted product development will improve smoking cessation and prevention efforts.

  2. Design of cholesterol arabinogalactan anchored liposomes for asialoglycoprotein receptor mediated targeting to hepatocellular carcinoma: In silico modeling, in vitro and in vivo evaluation.

    Science.gov (United States)

    Pathak, Pankaj; Dhawan, Vivek; Magarkar, Aniket; Danne, Reinis; Govindarajan, Srinath; Ghosh, Sandipto; Steiniger, Frank; Chaudhari, Pradip; Gopal, Vijaya; Bunker, Alex; Róg, Tomasz; Fahr, Alfred; Nagarsenker, Mangal

    2016-07-25

    We have developed active targeting liposomes to deliver anticancer agents to ASGPR which will contribute to effective treatment of hepatocellular carcinoma. Active targeting is achieved through polymeric ligands on the liposome surface. The liposomes were prepared using reverse phase evaporation method and doxorubicin hydrocholoride, a model drug, was loaded using the ammonium sulphate gradient method. Liposomes loaded with DOX were found to have a particle size of 200nm with more than 90% entrapment efficiency. Systems were observed to release the drug in a sustained manner in acidic pH in vitro. Liposomes containing targeting ligands possessed greater and selective toxicity to ASGPR positive HepG2 cell lines due to specific ligand receptor interaction. Bio-distribution studies revealed that liposomes were concentrated in the liver even after 3h of administration, thus providing conclusive evidence of targeting potential for formulated nanosystems. Tumor regression studies indicated greater tumor suppression with targeted liposomes thereby establishing superiority of the liposomal system. In this work, we used a novel methodology to guide the determination of the optimal composition of the targeting liposomes: molecular dynamics (MD) simulation that aided our understanding of the behaviour of the ligand within the bilayer. This can be seen as a demonstration of the utility of this methodology as a rational design tool for active targeting liposome formulation. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Design of cyclic RGD-conjugated Aib-containing amphipathic helical peptides for targeted delivery of small interfering RNA.

    Science.gov (United States)

    Wada, Shun-Ichi; Iwata, Masashi; Ozaki, Yuka; Ozaki, Takashi; Hayashi, Junsuke; Urata, Hidehito

    2016-09-15

    To achieve the targeted delivery of siRNA, five conjugates of Aib-containing amphipathic helical peptides with mono-, di-, and trivalent cRGDfC [cyclo(-Arg-Gly-Asp-d-Phe-Cys-)], which is known to bind to αVβ3 integrin, at several positions of the amphipathic helical peptide were designed and synthesized. Among the five conjugates, the monovalent cRGDfC conjugating at position 20 of the amino acid sequence of the helical peptide through the formation of a disulfide bond (PI) and the divalent cRGDfC conjugating at positions 2 and 14 of the amino acid sequence of the helical peptide through the formation of disulfide bonds (PIII) significantly enhanced the delivery of fluorescence-labeled siRNA into A549 cells as the peptide/siRNA complex formed by electrostatic interaction. The cellular uptake of the PI/siRNA complex was mediated by both endocytic and non-endocytic pathways, whereas that of the PIII/siRNA complex was enabled by endocytosis. Furthermore, the cellular uptake of the PI/siRNA complex might involve specific interactions of the RGD group with the αVβ3 integrin receptor. Next, the RNAi effect of the peptide/siRNA complex on luciferase expression in A549-Luc cells was examined. Luciferase expression was significantly decreased in the presence of the complex at the concentration of 1.0μM PI/10nM siRNA. In contrast, the PIII/siRNA complex did not show the RNAi effect under the same conditions. However, extending the incubation time led to the suppression of the luciferase expression in the presence of the PIII/siRNA complex. Considering that the cellular uptake of the PIII/siRNA complex is mediated by the endocytic pathway, the release of siRNA from the endosome into the cytosol might require a long time. We present herein a useful and unique tool for the delivery of siRNA. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. ATP-Competitive Inhibitors of the Mammalian Target of Rapamycin: Design and Synthesis of Highly Potent and Selective Pyrazolopyrimidines

    Energy Technology Data Exchange (ETDEWEB)

    Zask, Arie; Verheijen, Jeroen C.; Curran, Kevin; Kaplan, Joshua; Richard, David J.; Nowak, Pawel; Malwitz, David J.; Brooijmans, Natasja; Bard, Joel; Svenson, Kristine; Lucas, Judy; Toral-Barza, Lourdes; Zhang, Wei-Guo; Hollander, Irwin; Gibbons, James J.; Abraham, Robert T.; Ayral-Kaloustian, Semiramis; Mansour, Tarek S.; Yu, Ker; (Wyeth)

    2009-09-18

    The mammalian target of rapamycin (mTOR), a central regulator of growth, survival, and metabolism, is a validated target for cancer therapy. Rapamycin and its analogues, allosteric inhibitors of mTOR, only partially inhibit one mTOR protein complex. ATP-competitive, global inhibitors of mTOR that have the potential for enhanced anticancer efficacy are described. Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models.

  5. Targeted Recombinant Progeny: a design for ultra-high resolution mapping of Quantitative Trait Loci in crosses between inbred or pure lines.

    Science.gov (United States)

    Heifetz, Eliyahu M; Soller, Morris

    2015-07-07

    High-resolution mapping of the loci (QTN) responsible for genetic variation in quantitative traits is essential for positional cloning of candidate genes, and for effective marker assisted selection. The confidence interval (QTL) flanking the point estimate of QTN-location is proportional to the number of individuals in the mapping population carrying chromosomes recombinant in the given interval. Consequently, many designs for high resolution QTN mapping are based on increasing the proportion of recombinants in the mapping population. The "Targeted Recombinant Progeny" (TRP) design is a new design for high resolution mapping of a target QTN in crosses between pure, or inbred lines. It is a three-generation procedure generating a large number of recombinant individuals within a QTL previously shown to contain a QTN. This is achieved by having individuals that carry chromosomes recombinant across the target QTL interval as parents of a large mapping population; most of whom will therefore carry recombinant chromosomes targeted to the given QTL. The TRP design is particularly useful for high resolution mapping of QTN that differentiate inbred or pure lines, and hence are not amenable to high resolution mapping by genome-wide association tests. In the absence of residual polygenic variation, population sizes required for achieving given mapping resolution by the TRP-F2 design relative to a standard F2 design ranged from 0.289 for a QTN with standardized allele substitution effect = 0.2, mapped to an initial QTL of 0.2 Morgan to 0.041 for equivalent QTN mapped to an initial QTL of 0.02 M. In the presence of residual polygenic variation, the relative effectiveness of the TRP design ranges from 1.068 to 0.151 for the same initial QTL intervals and QTN effect. Thus even in the presence of polygenic variation, the TRP can still provide major savings. Simulation showed that mapping by TRP should be based on 30-50 markers spanning the initial interval; and on at least 50 or

  6. Gene design, cloning and protein-expression methods for high-value targets at the Seattle Structural Genomics Center for Infectious Disease.

    Science.gov (United States)

    Raymond, Amy; Haffner, Taryn; Ng, Nathan; Lorimer, Don; Staker, Bart; Stewart, Lance

    2011-09-01

    Any structural genomics endeavor, particularly ambitious ones such as the NIAID-funded Seattle Structural Genomics Center for Infectious Disease (SSGCID) and Center for Structural Genomics of Infectious Disease (CSGID), face technical challenges at all points of the production pipeline. One salvage strategy employed by SSGCID is combined gene engineering and structure-guided construct design to overcome challenges at the levels of protein expression and protein crystallization. Multiple constructs of each target are cloned in parallel using Polymerase Incomplete Primer Extension cloning and small-scale expressions of these are rapidly analyzed by capillary electrophoresis. Using the methods reported here, which have proven particularly useful for high-value targets, otherwise intractable targets can be resolved.

  7. Design and Construction of a Smart Targeting Drug Delivery System Based on Phototriggered Competition of Host-Guest Interaction.

    Science.gov (United States)

    Zhao, Dan; Yi, Xiaoqing; Yuan, Gongdao; Zhuo, Renxi; Li, Feng

    2017-09-01

    A smart targeting drug delivery nanocarrier is successfully constructed based on phototriggered competition of host-guest interaction. The targeting motif, i.e., biotin is first concealed by β-cyclodextrin (β-CD) via host-guest interaction. When the nanoparticles are exposed to UV light, the cleavage of photosensitive groups results in the exposure of adamantane (Ad) groups initially located in the interior of nanoassemblies, and β-CDs capped on biotin ligands can be replaced by Ad because of the higher binding constant between Ad and β-CD than that between biotin and β-CD. The competition of host-guest interaction leads to the recovery of targeting capacity of biotin ligands on the nanocarriers. By virtue of photoregulation, the nanocarriers exhibit controllable ligand-receptor recognition, which is proved by flow cytometry, laser confocal microscopy, and cytotoxicity assay. This strategy has a potential to improve the selectivity and safety of targeting drug delivery systems. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Design of Effective Energy Efficiency Policies : An analysis in the frame of target setting, monitoring and evaluation

    NARCIS (Netherlands)

    Schlomann, B.

    2014-01-01

    Energy efficiency (EE) is widely acknowledged as the most important strategy for achieving global energy and climate targets. Apart from its contribution to the reduction of energy consumption and energy-related greenhouse gas emissions (GHG), improving energy efficiency can deliver a range of

  9. Inforna 2.0: A Platform for the Sequence-Based Design of Small Molecules Targeting Structured RNAs.

    Science.gov (United States)

    Disney, Matthew D; Winkelsas, Audrey M; Velagapudi, Sai Pradeep; Southern, Mark; Fallahi, Mohammad; Childs-Disney, Jessica L

    2016-06-17

    The development of small molecules that target RNA is challenging yet, if successful, could advance the development of chemical probes to study RNA function or precision therapeutics to treat RNA-mediated disease. Previously, we described Inforna, an approach that can mine motifs (secondary structures) within target RNAs, which is deduced from the RNA sequence, and compare them to a database of known RNA motif-small molecule binding partners. Output generated by Inforna includes the motif found in both the database and the desired RNA target, lead small molecules for that target, and other related meta-data. Lead small molecules can then be tested for binding and affecting cellular (dys)function. Herein, we describe Inforna 2.0, which incorporates all known RNA motif-small molecule binding partners reported in the scientific literature, a chemical similarity searching feature, and an improved user interface and is freely available via an online web server. By incorporation of interactions identified by other laboratories, the database has been doubled, containing 1936 RNA motif-small molecule interactions, including 244 unique small molecules and 1331 motifs. Interestingly, chemotype analysis of the compounds that bind RNA in the database reveals features in small molecule chemotypes that are privileged for binding. Further, this updated database expanded the number of cellular RNAs to which lead compounds can be identified.

  10. Dasatinib synergizes with both cytotoxic and signal transduction inhibitors in heterogeneous breast cancer cell lines--lessons for design of combination targeted therapy.

    Science.gov (United States)

    Park, Brian J; Whichard, Zakary L; Corey, Seth J

    2012-07-01

    Molecularly targeted therapies have emerged as the leading theme in cancer therapeutics. Multi-cytotoxic drug regimens have been highly successful, yet many studies in targeted therapeutics have centered on a single agent. We investigated whether the Src/Abl kinase inhibitor dasatinib displays synergy with other agents in molecularly heterogeneous breast cancer cell lines. MCF-7, SKBR-3, and MDA-MB-231 display different signaling and gene signatures profiles due to expression of the estrogen receptor, ErbB2, or neither. Cell proliferation was measured following treatment with dasatinib±cytotoxic (paclitaxel, ixabepilone) or molecularly targeted agents (tamoxifen, rapamycin, sorafenib, pan PI3K inhibitor LY294002, and MEK/ERK inhibitor U0126). Dose-responses for single or combination drugs were calculated and analyzed by the Chou-Talalay method. The drugs with the greatest level of synergy with dasatinib were rapamycin, ixabepilone, and sorafenib, for the MDA-MB-231, MCF-7, and SK-BR-3 cell lines respectively. However, dasatinib synergized with both cytotoxic and molecularly targeted agents in all three molecularly heterogeneous breast cancer cell lines. These results suggest that effectiveness of rationally designed therapies may not entirely rest on precise identification of gene signatures or molecular profiling. Since a systems analysis that reveals emergent properties cannot be easily performed for each cancer case, multi-drug regimens in the near future will still involve empirical design. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  11. Rationale for the design of an oncology trial using a generic targeted therapy multi-drug regimen for NSCLC patients without treatment options (Review)

    Science.gov (United States)

    LANGHAMMER, STEFAN

    2013-01-01

    Despite more than 70 years of research concerning medication for cancer treatment, the disease still remains one of the leading causes of mortality worldwide. Many cancer types lead to death within a period of months to years. The original class of chemotherapeutics is not selective for tumor cells and often has limited efficacy, while treated patients suffer from adverse side-effects. To date, the concept of tumor-specific targeted therapy drugs has not fulfilled its expectation to provide a key for a cure. Today, many oncology trials are designed using a combination of chemotherapeutics with targeted therapy drugs. However, these approaches have limited outcomes in most cancer indications. This perspective review provides a rationale to combine targeted therapy drugs for cancer treatment based on observations of evolutionary principles of tumor development and HIV infections. In both diseases, the mechanisms of immune evasion and drug resistance can be compared to some extent. However, only for HIV is a breakthrough treatment available, which is the highly active antiretroviral therapy (HAART). The principles of HAART and recent findings from cancer research were employed to construct a hypothetical model for cancer treatment with a multi-drug regimen of targeted therapy drugs. As an example of this hypothesis, it is proposed to combine already marketed targeted therapy drugs against VEGFRs, EGFR, CXCR4 and COX2 in an oncology trial for non-small cell lung cancer patients without further treatment options. PMID:23877481

  12. Conceptual design and issues of the laser inertial fusion test (LIFT) reactor—targets and chamber systems

    Science.gov (United States)

    Norimatsu, T.; Kozaki, Y.; Shiraga, H.; Fujita, H.; Okano, K.; Members of LIFT Design Team

    2017-11-01

    We present the conceptual design of an experimental laser fusion plant known as the laser inertial fusion test (LIFT) reactor. The conceptual design aims at technically connecting a single-shot experiment and a commercial power plant. The LIFT reactor is designed on a three-phase scheme, where each phase has specific goals and the dedicated chambers of each phase are driven by the same laser. Technical issues related to the chamber technology including radiation safety to repeat burst mode operation are discussed in this paper.

  13. Leader Peptide-Free In Vitro Reconstitution of Microviridin Biosynthesis Enables Design of Synthetic Protease-Targeted Libraries.

    Science.gov (United States)

    Reyna-González, Emmanuel; Schmid, Bianca; Petras, Daniel; Süssmuth, Roderich D; Dittmann, Elke

    2016-08-01

    Microviridins are a family of ribosomally synthesized and post-translationally modified peptides with a highly unusual architecture featuring non-canonical lactone as well as lactam rings. Individual variants specifically inhibit different types of serine proteases. Here we have established an efficient in vitro reconstitution approach based on two ATP-grasp ligases that were constitutively activated using covalently attached leader peptides and a GNAT-type N-acetyltransferase. The method facilitates the efficient in vitro one-pot transformation of microviridin core peptides to mature microviridins. The engineering potential of the chemo-enzymatic technology was demonstrated for two synthetic peptide libraries that were used to screen and optimize microviridin variants targeting the serine proteases trypsin and subtilisin. Successive analysis of intermediates revealed distinct structure-activity relationships for respective target proteases. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. The calcium-dependent protein kinase 1 from Toxoplasma gondii as target for structure-based drug design.

    Science.gov (United States)

    Cardew, Emily M; Verlinde, Christophe L M J; Pohl, Ehmke

    2018-02-01

    The apicomplexan protozoan parasites include the causative agents of animal and human diseases ranging from malaria (Plasmodium spp.) to toxoplasmosis (Toxoplasma gondii). The complex life cycle of T. gondii is regulated by a unique family of calcium-dependent protein kinases (CDPKs) that have become the target of intensive efforts to develop new therapeutics. In this review, we will summarize structure-based strategies, recent successes and future directions in the pursuit of specific and selective inhibitors of T. gondii CDPK1.

  15. CRISPR is an optimal target for the design of specific PCR assays for salmonella enterica serotypes Typhi and Paratyphi A.

    Directory of Open Access Journals (Sweden)

    Laetitia Fabre

    Full Text Available BACKGROUND: Serotype-specific PCR assays targeting Salmonella enterica serotypes Typhi and Paratyphi A, the causal agents of typhoid and paratyphoid fevers, are required to accelerate formal diagnosis and to overcome the lack of typing sera and, in some situations, the need for culture. However, the sensitivity and specificity of such assays must be demonstrated on large collections of strains representative of the targeted serotypes and all other bacterial populations producing similar clinical symptoms. METHODOLOGY: Using a new family of repeated DNA sequences, CRISPR (clustered regularly interspaced short palindromic repeats, as a serotype-specific target, we developed a conventional multiplex PCR assay for the detection and differentiation of serotypes Typhi and Paratyphi A from cultured isolates. We also developed EvaGreen-based real-time singleplex PCR assays with the same two sets of primers. PRINCIPAL FINDINGS: We achieved 100% sensitivity and specificity for each protocol after validation of the assays on 188 serotype Typhi and 74 serotype Paratyphi A strains from diverse genetic groups, geographic origins and time periods and on 70 strains of bacteria frequently encountered in bloodstream infections, including 29 other Salmonella serotypes and 42 strains from 38 other bacterial species. CONCLUSIONS: The performance and convenience of our serotype-specific PCR assays should facilitate the rapid and accurate identification of these two major serotypes in a large range of clinical and public health laboratories with access to PCR technology. These assays were developed for use with DNA from cultured isolates, but with modifications to the assay, the CRISPR targets could be used in the development of assays for use with clinical and other samples.

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

    National Research Council Canada - National Science Library

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

    2015-01-01

    .... 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...

  17. Theoretical Design and First Test in Laboratory of a Composite Visual Servo-Based Target Spray Robotic System

    Directory of Open Access Journals (Sweden)

    Dongjie Zhao

    2016-01-01

    Full Text Available In order to spray onto the canopy of interval planting crop, an approach of using a target spray robot with a composite vision servo system based on monocular scene vision and monocular eye-in-hand vision was proposed. Scene camera was used to roughly locate target crop, and then the image-processing methods for background segmentation, crop canopy centroid extraction, and 3D positioning were studied. Eye-in-hand camera was used to precisely determine spray position of each crop. Based on the center and area of 2D minimum-enclosing-circle (MEC of crop canopy, a method to calculate spray position and spray time was determined. In addition, locating algorithm for the MEC center in nozzle reference frame and the hand-eye calibration matrix were studied. The processing of a mechanical arm guiding nozzle to spray was divided into three stages: reset, alignment, and hovering spray, and servo method of each stage was investigated. For preliminary verification of the theoretical studies on the approach, a simplified experimental prototype containing one spray mechanical arm was built and some performance tests were carried out under controlled environment in laboratory. The results showed that the prototype could achieve the effect of “spraying while moving and accurately spraying on target.”

  18. Design and evaluation of lipoprotein resembling curcumin-encapsulated protein-free nanostructured lipid carrier for brain targeting.

    Science.gov (United States)

    Meng, Fanfei; Asghar, Sajid; Xu, Yurui; Wang, Jianping; Jin, Xin; Wang, Zhilin; Wang, Jing; Ping, Qineng; Zhou, Jianping; Xiao, Yanyu

    2016-06-15

    Many nanoparticle matrixes have been demonstrated to be efficient in brain targeting, but there are still certain limitations for them. To overcome the shortcomings of the existing nanoparticulate systems for brain-targeted delivery, a lipoprotein resembling protein-free nanostructured lipid carrier (PS80-NLC) loaded with curcumin was constructed and assessed for in vitro and in vivo performance. Firstly, single factor at a time approach was employed to investigate the effects of various formulation factors. Mean particle sizes of ≤100nm, high entrapment efficiency (EE, about 95%) and drug loading (DL, >3%) were obtained for the optimized formulations. In vitro release studies in the presence of plasma indicated stability of the formulation under physiological condition. Compared with NLC, PS80-NLC showed noticeably higher affinity for bEnd.3 cells (1.56 folds greater than NLC) but with lower uptake in macrophages. The brain coronal sections showed strong and widely distributed fluorescence intensity of PS80-NLC than that of NLC in the cortex. Ex vivo imaging studies further confirmed that PS80-NLC could effectively permeate BBB and preferentially accumulate in the brain (2.38 times greater than NLC). The considerable in vitro and in vivo performance of the safe and biocompatible PS80-NLC makes it a suitable option for further investigations in brain targeted drug delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Design

    DEFF Research Database (Denmark)

    Volf, Mette

    This publication is unique in its demystification and operationalization of the complex and elusive nature of the design process. The publication portrays the designer’s daily work and the creative process, which the designer is a part of. Apart from displaying the designer’s work methods...... and design parameters, the publication shows examples from renowned Danish design firms. Through these examples the reader gets an insight into the designer’s reality....

  20. Antiproton Target

    CERN Multimedia

    1980-01-01

    Antiproton target used for the AA (antiproton accumulator). The first type of antiproton production target used from 1980 to 1982 comprised a rod of copper 3mm diameter and 120mm long embedded in a graphite cylinder that was itself pressed into a finned aluminium container. This assembly was air-cooled and it was used in conjunction with the Van der Meer magnetic horn. In 1983 Fermilab provided us with lithium lenses to replace the horn with a view to increasing the antiproton yield by about 30%. These lenses needed a much shorter target made of heavy metal - iridium was chosen for this purpose. The 50 mm iridium rod was housed in an extension to the original finned target container so that it could be brought very close to the entrance to the lithium lens. Picture 1 shows this target assembly and Picture 2 shows it mounted together with the lithium lens. These target containers had a short lifetime due to a combination of beam heating and radiation damage. This led to the design of the water-cooled target in...

  1. Enhanced guide-RNA Design and Targeting Analysis for Precise CRISPR Genome Editing of Single and Consortia of Industrially Relevant and Non-Model Organisms.

    Science.gov (United States)

    Mendoza, Brian J; Trinh, Cong T

    2017-09-08

    Genetic diversity of non-model organisms offers a repertoire of unique phenotypic features for exploration and cultivation for synthetic biology and metabolic engineering applications. To realize this enormous potential, it is critical to have an efficient genome editing tool for rapid strain engineering of these organisms to perform novel programmed functions. To accommodate the use of CRISPR/Cas systems for genome editing across organisms, we have developed a novel method, named CASPER (CRISPR Associated Software for Pathway Engineering and Research), for identifying on- and off-targets with enhanced predictability coupled with an analysis of non-unique (repeated) targets to assist in editing any organism with various endonucleases. Utilizing CASPER, we demonstrated a modest 2.4% and significant 30.2% improvement (F-test, p<0.05) over the conventional methods for predicting on- and off-target activities, respectively. Further we used CASPER to develop novel applications in genome editing: multitargeting analysis (i.e. simultaneous multiple-site modification on a target genome with a sole guide-RNA (gRNA) requirement) and multispecies population analysis (i.e. gRNA design for genome editing across a consortium of organisms). Our analysis on a selection of industrially relevant organisms revealed a number of non-unique target sites associated with genes and transposable elements that can be used as potential sites for multitargeting. The analysis also identified shared and unshared targets that enable genome editing of single or multiple genomes in a consortium of interest. We envision CASPER as a useful platform to enhance the precise CRISPR genome editing for metabolic engineering and synthetic biology applications. https://github.com/TrinhLab/CASPER. Supplementary data are available at Bioinformatics online.

  2. Automated Design of Probes for rRNA-Targeted Fluorescence In Situ Hybridization Reveals the Advantages of Using Dual Probes for Accurate Identification

    Science.gov (United States)

    Yilmaz, L. Safak; Corcoran, Andrew M.; Ökten, Hatice E.; Noguera, Daniel R.

    2014-01-01

    Fluorescence in situ hybridization (FISH) is a common technique for identifying cells in their natural environment and is often used to complement next-generation sequencing approaches as an integral part of the full-cycle rRNA approach. A major challenge in FISH is the design of oligonucleotide probes with high sensitivity and specificity to their target group. The rapidly expanding number of rRNA sequences has increased awareness of the number of potential nontargets for every FISH probe, making the design of new FISH probes challenging using traditional methods. In this study, we conducted a systematic analysis of published probes that revealed that many have insufficient coverage or specificity for their intended target group. Therefore, we developed an improved thermodynamic model of FISH that can be applied at any taxonomic level, used the model to systematically design probes for all recognized genera of bacteria and archaea, and identified potential cross-hybridizations for the selected probes. This analysis resulted in high-specificity probes for 35.6% of the genera when a single probe was used in the absence of competitor probes and for 60.9% when up to two competitor probes were used. Requiring the hybridization of two independent probes for positive identification further increased specificity. In this case, we could design highly specific probe sets for up to 68.5% of the genera without the use of competitor probes and 87.7% when up to two competitor probes were used. The probes designed in this study, as well as tools for designing new probes, are available online (http://DECIPHER.cee.wisc.edu). PMID:24928876

  3. Choline Binding Proteins from Streptococcus pneumoniae: A Dual Role as Enzybiotics and Targets for the Design of New Antimicrobials

    Directory of Open Access Journals (Sweden)

    Beatriz Maestro

    2016-06-01

    Full Text Available Streptococcus pneumoniae (pneumococcus is an important pathogen responsible for acute invasive and non-invasive infections such as meningitis, sepsis and otitis media, being the major cause of community-acquired pneumonia. The fight against pneumococcus is currently hampered both by insufficient vaccine coverage and by rising antimicrobial resistances to traditional antibiotics, making necessary the research on novel targets. Choline binding proteins (CBPs are a family of polypeptides found in pneumococcus and related species, as well as in some of their associated bacteriophages. They are characterized by a structural organization in two modules: a functional module (FM, and a choline-binding module (CBM that anchors the protein to the choline residues present in the cell wall through non-covalent interactions. Pneumococcal CBPs include cell wall hydrolases, adhesins and other virulence factors, all playing relevant physiological roles for bacterial viability and virulence. Moreover, many pneumococcal phages also make use of hydrolytic CBPs to fulfill their infectivity cycle. Consequently, CBPs may play a dual role for the development of novel antipneumococcal drugs, both as targets for inhibitors of their binding to the cell wall and as active cell lytic agents (enzybiotics. In this article, we review the current state of knowledge about host- and phage-encoded pneumococcal CBPs, with a special focus on structural issues, together with their perspectives for effective anti-infectious treatments.

  4. A preliminary controlled comparison of programs designed to reduce risk of eating disorders targeting perfectionism and media literacy.

    Science.gov (United States)

    Wilksch, Simon M; Durbridge, Mitchell R; Wade, Tracey D

    2008-08-01

    The primary objective was to compare the efficacy of two eight-lesson programs, targeting perfectionism and media literacy compared to control classes in reducing eating disorder risk. Students from six classes (N = 127, mean age 15.0 years, SD 0.4) and two schools participated. Linear mixed-model analyses were conducted by group (3: perfectionism, media literacy, control), time (2: postprogram, 3-month follow-up) and eating disorder risk status (2: high, low), with baseline observations included as a covariate. An interaction effect favoring the perfectionism program at 3-month follow-up was found for concern over mistakes (effect size 0.45). A main effect for group, also favoring the perfectionism program, was found for personal standards (effect size 0.44). High-risk participants (i.e., those with high levels of shape and weight concern at baseline) benefited most from the perfectionism program with reliable change indices indicating favorable rates of improvement beyond chance on all of the variables, whereas the media literacy and control participants experienced a comparable rate of change during the course of the study. Targeting perfectionism represents a promising prevention option that requires further investigation in children of mid-adolescence age, and further investigation is required to determine the demographic most likely to benefit from media literacy.

  5. PNA-COMBO-FISH: From combinatorial probe design in silico to vitality compatible, specific labelling of gene targets in cell nuclei

    Energy Technology Data Exchange (ETDEWEB)

    Müller, Patrick; Rößler, Jens; Schwarz-Finsterle, Jutta [University of Heidelberg, Kirchhoff Institute for Physics, Im Neuenheimer Feld 227, D-69120 Heidelberg (Germany); Schmitt, Eberhard, E-mail: eschmitt@kip.uni-heidelberg.de [University of Heidelberg, Kirchhoff Institute for Physics, Im Neuenheimer Feld 227, D-69120 Heidelberg (Germany); University of Göttingen, Institute for Numerical and Applied Mathematics, Lotzestraße 16-18, D-37083 Göttingen (Germany); Hausmann, Michael, E-mail: hausmann@kip.uni-heidelberg.de [University of Heidelberg, Kirchhoff Institute for Physics, Im Neuenheimer Feld 227, D-69120 Heidelberg (Germany)

    2016-07-01

    Recently, advantages concerning targeting specificity of PCR constructed oligonucleotide FISH probes in contrast to established FISH probes, e.g. BAC clones, have been demonstrated. These techniques, however, are still using labelling protocols with DNA denaturing steps applying harsh heat treatment with or without further denaturing chemical agents. COMBO-FISH (COMBinatorial Oligonucleotide FISH) allows the design of specific oligonucleotide probe combinations in silico. Thus, being independent from primer libraries or PCR laboratory conditions, the probe sequences extracted by computer sequence data base search can also be synthesized as single stranded PNA-probes (Peptide Nucleic Acid probes). Gene targets can be specifically labelled with at least about 20 PNA-probes obtaining visibly background free specimens. By using appropriately designed triplex forming oligonucleotides, the denaturing procedures can completely be omitted. These results reveal a significant step towards oligonucleotide-FISH maintaining the 3D-nanostructure and even the viability of the cell target. The method is demonstrated with the detection of Her2/neu and GRB7 genes, which are indicators in breast cancer diagnosis and therapy. - Highlights: • Denaturation free protocols preserve 3D architecture of chromosomes and nuclei. • Labelling sets are determined in silico for duplex and triplex binding. • Probes are produced chemically with freely chosen backbones and base variants. • Peptide nucleic acid backbones reduce hindering charge interactions. • Intercalating side chains stabilize binding of short oligonucleotides.

  6. 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. (American Inst. of Architects, Washington, DC (USA)); McKay, H.N. (Illuminating Engineering Society of North America, New York, NY (USA))

    1990-09-01

    Since 1985, the Pacific Northwest Laboratory (PNL) has managed the Whole-Building Energy Design Targets project for the US Department of Energy (DOE) Office of Building Technologies (formerly the Office of Buildings and Community Systems). The primary focus of the Targets project is to develop a flexible methodology for buildings industry use in setting energy performance guidelines for commercial buildings and for determining compliance with those guidelines. The project is being conducted as a two-phase effort. In Phase 1, Planning, the project team determined the research that was necessary for developing the Targets methodology. In the concept stage of Phase 2, Development, the team sought to define the technical and software development concepts upon which the overall Targets methodology will be based. The concept stage work is documented in four volumes, of which this summary volume is the first. The three other volumes are Volume 2: Technical Concept Development Task Reports, Volume 3: Workshop Summaries, and Volume 4: Software Concept Development Task Reports. 8 refs., 14 figs.

  7. Selection, purification, and characterization of a HER2-targeting soluble designed ankyrin repeat protein by E. coli surface display using HER2-positive melanoma cells.

    Science.gov (United States)

    Chen, Xiaofei; Yu, Xiaoxiao; Song, Xiaoda; Liu, Li; Yi, Yuting; Yao, Wenbing; Gao, Xiangdong

    2018-01-09

    Human epidermal growth factor receptor 2 (HER2) is a powerful target for cancer immune therapy. The development of anti-HER2 monoclonal antibodies targeting different domains of HER2 is quite effective. However, the selection and production of multivalent antibodies are complicated. In this study, a mimivirus-based designed ankyrin repeat protein (DARPin) targeting HER2 was selected from an artificial library by bacteria surface display. The selection was performed on HER2-positive B16BL6/E2 melanoma cells and HER2-nagative cells. DARPin selected from the library could be expressed in soluble form with a yield of 70 mg/L. After purified by two continuous and easy steps, the purity of DARPin was 90% as established by SDS-PAGE and RP-HPLC. Selected DARPin showed significant HER2-targeting ability with an affinity of 1.05 ± 0.47 µM. MTT assay demonstrated that at the concentration of 640 nM, the selected DARPin dimer could inhibit the SK-BR-3 growth at a rate of 36.63 and 46.34% in 48 and 72 hr incubation separately, which was similar to trastuzumab (43.12 and 49.14% separately). These findings suggested that it was an effective method to select antibody mimetic DARPin by bacteria surface display combined with live cells sorting and provided a drug candidate for cancer therapy.

  8. Design of thermostable rhamnogalacturonan lyase mutants from Bacillus licheniformis by combination of targeted single point mutations

    DEFF Research Database (Denmark)

    da Silva, Ines Isabel Cardoso Rodrigues; Jers, Carsten; Otten, Harm

    2014-01-01

    Rhamnogalacturonan I lyases (RGI lyases) (EC 4.2.2.-) catalyze cleavage of α-1,4 bonds between rhamnose and galacturonic acid in the backbone of pectins by β-elimination. In the present study, targeted improvement of the thermostability of a PL family 11 RGI lyase from Bacillus licheniformis (DSM......-FIT). The second-generation mutants involved combinations of two to seven individually favorable single mutations. Thermal stability was examined as half-life at 60 °C and by recording of thermal transitions by circular dichroism. Surprisingly, the biggest increment in thermal stability was achieved by producing...... acids to hydrophobic ones in surface-exposed loops produced favorable thermal stability effects. © 2014 Springer-Verlag Berlin Heidelberg....

  9. Design, synthesis, and evaluation of cisplatin-containing EGFR targeting bioconjugates as potential therapeutic agents for brain tumors

    Directory of Open Access Journals (Sweden)

    Barth RF

    2016-05-01

    Full Text Available Rolf F Barth,1 Gong Wu,1 W Hans Meisen,2 Robin J Nakkula,1 Weilian Yang,1 Tianyao Huo,1 David A Kellough,1 Pravin Kaumaya,3–5 Claudia Turro,6 Lawrence M Agius,7 Balveen Kaur2 1Department of Pathology, 2Department of Neurological Surgery, 3Department of Obstetrics and Gynecology, 4Department of Molecular and Cellular Biochemistry, 5Department of Microbiology, 6Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA; 7Department of Pathology, Mater Dei Hospital, University of Malta Medical School, Msida, Malta Abstract: The aim of this study was to evaluate four different platinated bioconjugates containing a cisplatin (cis-diamminedichloroplatinum [cis-DDP] fragment and epidermal growth factor receptor (EGFR-targeting moieties as potential therapeutic agents for the treatment of brain tumors using a human EGFR-expressing transfectant of the F98 rat glioma (F98EGFR to assess their efficacy. The first two bioconjugates employed the monoclonal antibody cetuximab (C225 or Erbitux® as the targeting moiety, and the second two used genetically engineered EGF peptides. C225-G5-Pt was produced by reacting cis-DDP with a fifth-generation polyamidoamine dendrimer (G5 and then linking it to C225 by means of two heterobifunctional reagents. The second bioconjugate (C225-PG-Pt employed the same methodology except that polyglutamic acid was used as the carrier. The third and fourth bioconjugates used two different EGF peptides, PEP382 and PEP455, with direct coordination to the Pt center of the cis-DDP fragment. In vivo studies with C225-G5-Pt failed to demonstrate therapeutic activity following intracerebral (ic convection-enhanced delivery (CED to F98EGFR glioma-bearing rats. The second bioconjugate, C225-PG-Pt, failed to show in vitro cytotoxicity. Furthermore, because of its high molecular weight, we decided that lower molecular weight peptides might provide better targeting and microdistribution within the tumor. Both PEP

  10. Rational design of vaccine targets and strategies for HIV: a crossroad of statistical physics, biology, and medicine

    Science.gov (United States)

    Chakraborty, Arup K.; Barton, John P.

    2017-03-01

    Vaccination has saved more lives than any other medical procedure. Pathogens have now evolved that have not succumbed to vaccination using the empirical paradigms pioneered by Pasteur and Jenner. Vaccine design strategies that are based on a mechanistic understanding of the pertinent immunology and virology are required to confront and eliminate these scourges. In this perspective, we describe just a few examples of work aimed to achieve this goal by bringing together approaches from statistical physics with biology and clinical research.

  11. Design and Reporting of Targeted Anticancer Preclinical Studies: A Meta-Analysis of Animal Studies Investigating Sorafenib Antitumor Efficacy.

    Science.gov (United States)

    Mattina, James; MacKinnon, Nathalie; Henderson, Valerie C; Fergusson, Dean; Kimmelman, Jonathan

    2016-08-15

    The validity of preclinical studies of candidate therapeutic agents has been questioned given their limited ability to predict their fate in clinical development, including due to design flaws and reporting bias. In this study, we examined this issue in depth by conducting a meta-analysis of animal studies investigating the efficacy of the clinically approved kinase inhibitor, sorafenib. MEDLINE, Embase, and BIOSIS databases were searched for all animal experiments testing tumor volume response to sorafenib monotherapy in any cancer published until April 20, 2012. We estimated effect sizes from experiments assessing changes in tumor volume and conducted subgroup analyses based on prespecified experimental design elements associated with internal, construct, and external validity. The meta-analysis included 97 experiments involving 1,761 animals. We excluded 94 experiments due to inadequate reporting of data. Design elements aimed at reducing internal validity threats were implemented only sporadically, with 66% reporting animal attrition and none reporting blinded outcome assessment or concealed allocation. Anticancer activity against various malignancies was typically tested in only a small number of model systems. Effect sizes were significantly smaller when sorafenib was tested against either a different active agent or combination arm. Trim and fill suggested a 37% overestimation of effect sizes across all malignancies due to publication bias. We detected a moderate dose-response in one clinically approved indication, hepatocellular carcinoma, but not in another approved malignancy, renal cell carcinoma, or when data were pooled across all malignancies tested. In support of other reports, we found that few preclinical cancer studies addressed important internal, construct, and external validity threats, limiting their clinical generalizability. Our findings reinforce the need to improve guidelines for the design and reporting of preclinical cancer studies

  12. The development and testing of the thermal break divertor monoblock target design delivering 20 MW m‑2 heat load capability

    Science.gov (United States)

    Fursdon, M.; Barrett, T.; Domptail, F.; Evans, Ll M.; Luzginova, N.; Greuner, N. H.; You, J.-H.; Li, M.; Richou, M.; Gallay, F.; Visca, E.

    2017-12-01

    The design and development of a novel plasma facing component (for fusion power plants) is described. The component uses the existing ‘monoblock’ construction which consists of a tungsten ‘block’ joined via a copper interlayer to a through CuCrZr cooling pipe. In the new concept the interlayer stiffness and conductivity properties are tuned so that stress in the principal structural element of the component (the cooling pipe) is reduced. Following initial trials with off-the-shelf materials, the concept was realized by machined features in an otherwise solid copper interlayer. The shape and distribution of the features were tuned by finite element analyses subject to ITER structural design criterion in-vessel components (SDC-IC) design rules. Proof of concept mock-ups were manufactured using a two stage brazing process verified by tomography and micrographic inspection. Full assemblies were inspected using ultrasound and thermographic (SATIR) test methods at ENEA and CEA respectively. High heat flux tests using IPP’s GLADIS facility showed that 200 cycles at 20 MW m‑2 and five cycles at 25 MW m‑2 could be sustained without apparent component damage. Further testing and component development is planned.

  13. Design of experiment approach for formulating multi-unit colon-targeted drug delivery system: in vitro and in vivo studies.

    Science.gov (United States)

    Shah, Nitesh; Sharma, Om Prakash; Mehta, Tejal; Amin, Avani

    2016-01-01

    The objective of the present investigation was to develop systematically optimized multiunit formulation for colon targeted delivery of metronidazole (MTZ) by employing design of experiment (DoE) and evaluate it for in vitro as well as in vivo drug release study. Core of mini-tablets of MTZ was prepared using drug along with suitable swelling agents to provide pH sensitive pulsatile drug delivery. Eudragit® S 100 (ES) and ethyl cellulose (EC) were used as coating polymers to prevent initial drug release in gastric region. The coating composition was systematically optimized using 3(2)-full factorial design and optimized formulation was evaluated in vitro and then in vivo, to confirm colon targeting ability of the developed system. Stability study of optimized formulation was performed for 6 months as per ICH guidelines. The optimized coating composition was selected from the results of design batches. The optimized formulation showed 6.99 ± 1.5% drug release up to 5 h and 100% drug release within 7.2 ± 0.2 h indicating pH sensitive pulsatile behavior of formulation. Similar drug release profile was observed while performing in vivo study in rabbits with a lag time of 4 h and Cmax of 190 ± 4.9 ng/ml being achieved after 7 h. Stability study indicated insignificant difference in properties of tablets and their drug release patterns. Optimization of coating composition (EC and ES) and thickness could offer pH sensitive pulsatile release of drugs at colon. Furthermore, in vivo results confirmed the successful development of colon targeted formulation of MTZ.

  14. Structure-guided design affirms inhibitors of hepatitis C virus p7 as a viable class of antivirals targeting virion release.

    Science.gov (United States)

    Foster, Toshana L; Thompson, Gary S; Kalverda, Arnout P; Kankanala, Jayakanth; Bentham, Matthew; Wetherill, Laura F; Thompson, Joseph; Barker, Amy M; Clarke, Dean; Noerenberg, Marko; Pearson, Arwen R; Rowlands, David J; Homans, Steven W; Harris, Mark; Foster, Richard; Griffin, Stephen

    2014-02-01

    Current interferon-based therapy for hepatitis C virus (HCV) infection is inadequate, prompting a shift toward combinations of direct-acting antivirals (DAA) with the first protease-targeted drugs licensed in 2012. Many compounds are in the pipeline yet primarily target only three viral proteins, namely, NS3/4A protease, NS5B polymerase, and NS5A. With concerns growing over resistance, broadening the repertoire for DAA targets is a major priority. Here we describe the complete structure of the HCV p7 protein as a monomeric hairpin, solved using a novel combination of chemical shift and nuclear Overhauser effect (NOE)-based methods. This represents atomic resolution information for a full-length virus-coded ion channel, or "viroporin," whose essential functions represent a clinically proven class of antiviral target exploited previously for influenza A virus therapy. Specific drug-protein interactions validate an allosteric site on the channel periphery and its relevance is demonstrated by the selection of novel, structurally diverse inhibitory small molecules with nanomolar potency in culture. Hit compounds represent a 10,000-fold improvement over prototypes, suppress rimantadine resistance polymorphisms at submicromolar concentrations, and show activity against other HCV genotypes. This proof-of-principle that structure-guided design can lead to drug-like molecules affirms p7 as a much-needed new target in the burgeoning era of HCV DAA. Copyright © 2013 The Authors. HEPATOLOGY published by Wiley on behalf of the American Association for the Study of Liver Diseases.

  15. Design, synthesis, biological evaluation, and 3D-QSAR analysis of podophyllotoxin-dioxazole combination as tubulin targeting anticancer agents.

    Science.gov (United States)

    Wang, Zi-Zhen; Sun, Wen-Xue; Wang, Xue; Zhang, Ya-Han; Qiu, Han-Yue; Qi, Jin-Liang; Pang, Yan-Jun; Lu, Gui-Hua; Wang, Xiao-Ming; Yu, Fu-Gen; Yang, Yong-Hua

    2017-08-01

    The advancement of cancer-fighting drugs has never been a simple linear process. Those drug design professionals begin to find inspiration from the nature after failing to find the ideal products by creative drug design and high-throughput screening. To obtain new molecules for inhibiting tubulin, podophyllotoxin was adopted as the leading compound and 1,3,4-oxadiazole was brought in to the C-4 site of podophyllotoxin in this research. A series of seventeen podophyllotoxin-derived esters have been achieved and then evaluated their antitumor activities against four different cancer cell lines: A549, MCF-7, HepG2, and HeLa. Among all the compounds, compound 7c showed the best antiproliferating properties with IC50  = 2.54 ± 0.82 μm against MCF-7 cancer cell line. It was obvious that the content of ROS grew significantly in MCF-7 in a way depending on the dosage. The time- and dose-dependent cell cycle assays revealed that compound 7c could apparently block cell cycle in the phase of G2/M along with the upregulation of cyclin A2 and CDK2 protein. According to further studies, confocal microscopy experiment has certified that compound 7c could restrain cancer from growing by blocking the polymerization of microtubule. Meanwhile, compound 7c could be ideally integrated with the colchicine site of tubulin. In future, it would be feasible to selectively design tubulin inhibitors with the help of 3D-QSAR. This means that it is hopeful to develop compound 7c as a potential agent against cancer due to its biological characteristics. © 2017 John Wiley & Sons A/S.

  16. Design of a randomized controlled study of a multi-professional and multidimensional intervention targeting frail elderly people

    Directory of Open Access Journals (Sweden)

    Gosman-Hedström Gunilla

    2011-05-01

    Full Text Available Abstract Background Frail elderly people need an integrated and coordinated care. The two-armed study "Continuum of care for frail elderly people" is a multi-professional and multidimensional intervention for frail community-dwelling elderly people. It was designed to evaluate whether the intervention programme for frail elderly people can reduce the number of visits to hospital, increase satisfaction with health and social care and maintain functional abilities. The implementation process is explored and analysed along with the intervention. In this paper we present the study design, the intervention and the outcome measures as well as the baseline characteristics of the study participants. Methods/design The study is a randomised two-armed controlled trial with follow ups at 3, 6 and 12 months. The study group includes elderly people who sought care at the emergency ward and discharged to their own homes in the community. Inclusion criteria were 80 years and older or 65 to 79 years with at least one chronic disease and dependent in at least one activity of daily living. Exclusion criteria were acute severely illness with an immediate need of the assessment and treatment by a physician, severe cognitive impairment and palliative care. The intention was that the study group should comprise a representative sample of frail elderly people at a high risk of future health care consumption. The intervention includes an early geriatric assessment, early family support, a case manager in the community with a multi-professional team and the involvement of the elderly people and their relatives in the planning process. Discussion The design of the study, the randomisation procedure and the protocol meetings were intended to ensure the quality of the study. The implementation of the intervention programme is followed and analysed throughout the whole study, which enables us to generate knowledge on the process of implementing complex interventions. The

  17. Low-Complexity Hierarchical Mode Decision Algorithms Targeting VLSI Architecture Design for the H.264/AVC Video Encoder

    Directory of Open Access Journals (Sweden)

    Guilherme Corrêa

    2012-01-01

    Full Text Available In H.264/AVC, the encoding process can occur according to one of the 13 intraframe coding modes or according to one of the 8 available interframes block sizes, besides the SKIP mode. In the Joint Model reference software, the choice of the best mode is performed through exhaustive executions of the entire encoding process, which significantly increases the encoder's computational complexity and sometimes even forbids its use in real-time applications. Considering this context, this work proposes a set of heuristic algorithms targeting hardware architectures that lead to earlier selection of one encoding mode. The amount of repetitions of the encoding process is reduced by 47 times, at the cost of a relatively small cost in compression performance. When compared to other works, the fast hierarchical mode decision results are expressively more satisfactory in terms of computational complexity reduction, quality, and bit rate. The low-complexity mode decision architecture proposed is thus a very good option for real-time coding of high-resolution videos. The solution is especially interesting for embedded and mobile applications with support to multimedia systems, since it yields good compression rates and image quality with a very high reduction in the encoder complexity.

  18. Surface functionalizing of a lipid nanosystem to promote brain targeting: step-by-step design and physico-chemical characterization.

    Science.gov (United States)

    Cózar-Bernal, M J; García-Esteban, E; Sánchez-Soto, P J; Rabasco, A M; González-Rodríguez, M L

    2016-11-01

    The use of lipid nanosystems as drug delivery to the central nervous system may be advantageous over the current strategies. The aim of this study was to develop and characterize functionalized liposomes for treatment of brain diseases. The covalent method of coupling IgG to liposomes via the derivatized lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[4-(p-maleimidophenyl)butyramide](MPB-PE) was investigated. Optimized coupling conditions are shown to result in the efficient conjugation of IgG to liposomes containing low concentrations of MPB-PE (3/1 SH:IgG). The qualitative analysis has shown that after the extrusion process, more homogeneous populations of vesicles have been obtained with a nanometric size suitable to be effective to further anchor the protein. Negative values of zeta potential demonstrate that they are stable systems. Lyophilization was used to maintain the stability of the formulation. These very interesting results encourage further investigations to formulate peptide- and protein-loaded immunoliposomes, making targeting of liposomes as an attractive approach for brain drug delivery.

  19. Design and conduct of early clinical studies of two or more targeted anticancer therapies: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies.

    Science.gov (United States)

    Seymour, Lesley K; Calvert, A Hilary; Lobbezoo, Marinus W; Eisenhauer, Elizabeth A; Giaccone, Giuseppe

    2013-05-01

    The Methodology for the Development of Innovative Cancer Therapies (MDICT) task force considered aspects of the design and conduct of early (phase I and II) studies of combinations of molecular targeted agents during their 2012 meeting. The task force defined necessary non-clinical data, such as evidence of additive or synergistic effects in multiple molecularly credentialed and validated models, and appropriate pharmacodynamic marker development. A robust hypothesis was considered critical while non-clinical pharmacokinetic studies were also considered valuable. Clinical trials should include clear objectives that will prove or disprove the hypothesis. Predictive biomarkers/classifiers should be explored in phase I studies, rather than used to select patients. Trial design should be efficient and flexible rather than based on a strict progression from phase I to II to III; researchers could consider phase I studies with an expansion cohort, Phase I/II designs or phase II studies with a safety run in. Pharmacokinetics are recommended when interactions or overlapping toxicity is expected. Pharmacodynamic evaluations should be considered especially in a subset of patients closest to the recommended dose; an attempt should be made to validate surrogate tissues to enable inclusion for all patients. Schedule and or dose should be formally explored for e.g. with a randomised or an adaptive design. Data and knowledge sharing was strongly recommended, including the creation of formal or informal consortia of laboratories with individual expertise in pathway or target based models, collaboration between companies to ensure that agents which are 'best in class' are combined, and the development of databases which will be able to inform the development of future recommendations/guidelines. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Preparation, Characterization, and Optimization of Folic Acid-Chitosan-Methotrexate Core-Shell Nanoparticles by Box-Behnken Design for Tumor-Targeted Drug Delivery.

    Science.gov (United States)

    Naghibi Beidokhti, Hamid Reza; Ghaffarzadegan, Reza; Mirzakhanlouei, Sasan; Ghazizadeh, Leila; Dorkoosh, Farid Abedin

    2017-01-01

    The objective of this study was to investigate the combined influence of independent variables in the preparation of folic acid-chitosan-methotrexate nanoparticles (FA-Chi-MTX NPs). These NPs were designed and prepared for targeted drug delivery in tumor. The NPs of each batch were prepared by coaxial electrospray atomization method and evaluated for particle size (PS) and particle size distribution (PSD). The independent variables were selected to be concentration of FA-chitosan, ratio of shell solution flow rate to core solution flow rate, and applied voltage. The process design of experiments (DOE) was obtained with three factors in three levels by Design expert software. Box-Behnken design was used to select 15 batches of experiments randomly. The chemical structure of FA-chitosan was examined by FTIR. The NPs of each batch were collected separately, and morphologies of NPs were investigated by field emission scanning electron microscope (FE-SEM). The captured pictures of all batches were analyzed by ImageJ software. Mean PS and PSD were calculated for each batch. Polynomial equation was produced for each response. The FE-SEM results showed the mean diameter of the core-shell NPs was around 304 nm, and nearly 30% of the produced NPs are in the desirable range. Optimum formulations were selected. The validation of DOE optimization results showed errors around 2.5 and 2.3% for PS and PSD, respectively. Moreover, the feasibility of using prepared NPs to target tumor extracellular pH was shown, as drug release was greater in the pH of endosome (acidic medium). Finally, our results proved that FA-Chi-MTX NPs were active against the human epithelial cervical cancer (HeLa) cells.

  1. What Do Deep Statistical Analysis on Gaming Motivation and Game Characteristics Clusters Reveal about Targeting Demographics when Designing Gamified Contents?

    Directory of Open Access Journals (Sweden)

    Alireza Tavakkoli

    2015-06-01

    Full Text Available This paper presents the comprehensive results of the study of a cohort of college graduate and undergraduate students who participated in playing a Massively Multiplayer Online Role Playing Game (MMORPG as a gameplay rich with social interaction as well as intellectual and aesthetic features. We present the full results of the study in the form of inferential statistics and a review of our descriptive statistics previously reported in [46]. Separate one-way independent-measures multivariate analysis of variance (MANOVA's were used to analyze the data from several instruments to determine if there were statistically significant differences first by gender, then by age group, and then by degree. Moreover, a one-way repeated-measures analysis of variance (ANOVA was used to determine if there was a statistically significant difference between the clusters in the 5 gaming clusters on the Game Characteristic Survey. Follow-up paired samples t-tests were used to see if there was a statistically significant difference between each of the 10 possible combinations of paired clusters. Our results support the hypotheses and outline the features that may need to be taken into account in support of tailoring gamified educational content targeting a certain demographic. Sections 1, 2, and 3 below from our pervious study [46] are included because this is the second part of the two-part study. [46] Tavakkoli, A., Loffredo, D., Ward, M., Sr. (2014. "Insights from Massively Multiplayer Online Role Playing Games to Enhance Gamification in Education", Journal of Systemics, Cybernetics, and Informatics, 12(4, 66-78.

  2. Detection of multiple strains of rabies virus RNA using primers designed to target Mexican vampire bat variants.

    Science.gov (United States)

    Loza-Rubio, E; Rojas-Anaya, E; Banda-Ruíz, V M; Nadin-Davis, S A; Cortez-García, B

    2005-10-01

    A reverse transcription-polymerase chain reaction (RT-PCR), that uses primers specifically designed to amplify a portion of the N gene of vampire bat strains of rabies that circulate in Mexico, but also recognizing most of the rabies variants circulating in endemic areas, was established. This standardized PCR assay was able to detect viral RNA in tenfold serial dilutions up to a 10(7) dilution using stock virus at an original titre of 10(7.5) LD50. The assay was highly specific for rabies virus. Forty different rabies isolates recovered from different species and geographical regions in the country were diagnosed as positive and negative by the fluorescent antibody test (FAT). These same samples were re-examined by both PCR and the mouse inoculation test (MIT). Compared with MIT the PCR exhibited an epidemiological sensitivity of 86% and a specificity of 91% while its positive predictive value was 96%.

  3. Towards spatial isolation design in a multi-core real-time kernel targeting safety-critical applications

    DEFF Research Database (Denmark)

    Li, Gang; Top, Søren

    2013-01-01

    In mixed-criticality systems, applications naturally have different safety criticality levels. Partitioning technology is usually used to enable the integration of such mixed criticality applications upon one platform, aiming at reducing hardware, power consumption and especially certification co...... and software can easily achieve this isolation. At last, the spatial isolation is evaluated using a statistical sampling method and its performance is tested in terms of task switch, system call and footprint........ According to formulated isolation requirements, a simple partitioning multi-core hardware architecture is proposed using SoC and memory protection units, and the kernel is extended to support spatial isolation between the kernel and applications as well as between applications. Combined design of hardware...

  4. Bacterial eukaryotic type serine-threonine protein kinases: from structural biology to targeted anti-infective drug design.

    Science.gov (United States)

    Danilenko, Valery N; Osolodkin, Dmitry I; Lakatosh, Sergey A; Preobrazhenskaya, Maria N; Shtil, Alexander A

    2011-01-01

    Signaling through protein kinases is an evolutionary conserved, widespread language of biological regulation. The eukaryotic type serine-threonine protein kinases (STPKs) found in normal human microbiote and in pathogenic bacteria play a key role in regulation of microbial survival, virulence and pathogenicity. Therefore, down-regulation of bacterial STPKs emerges as an attractive approach to cure infections. In this review we focused on actinobacterial STPKs to demonstrate that these enzymes can be used for crystal structure studies, modeling of 3D structure, construction of test systems and design of novel chemical libraries of low molecule as weight inhibitors. In particular, the prototypic pharmacological antagonists of Mycobacterium tuberculosis STPKs are perspective for development of a novel generation of drugs to combat the socially important disease. These inhibitors may modulate both actinobacterial and host STPKs and trigger programmed death of pathogenic bacteria.

  5. Targeting and design methodology for reduction of fuel, power and CO{sub 2} on total sites

    Energy Technology Data Exchange (ETDEWEB)

    Klemes, J.; Dhole, V.R.; Raissi, K.; Perry, S.J. [University of Manchester Institute of Science and Technology, Manchester (United Kingdom); Puigjaner, L. [Universitat de Catalunya, Barcelona (Spain)

    1997-08-01

    Simultaneous optimisation of production processes and total site utility systems provides a novel methodology that can reduce energy demands and emission on a total factory site whilst simultaneously avoiding loss of cogeneration efficiency. This paper reports on the results of total sites where the application of the methodology has achieved savings in fuel of up to 20%, along with improvements in global CO{sub 2} levels and other emissions levels of at least 50% when compared to those achieved by application to individual processes. The novel methodology took into account the specific features of semi-continuous and batch operations and also the opportunities offered by the multi-objective optimisation of the design strategy for the total site. The environmental costs and potential for regulatory action were also incorporated. Software tools were developed to support total site approach which was subsequently tested and its capabilities validated by successfully solving various case studies from different industrial sectors. (author)

  6. A Smarter Pathway for Delivering Cue Exposure Therapy? The Design and Development of a Smartphone App Targeting Alcohol Use Disorder.

    Science.gov (United States)

    Mellentin, Angelina Isabella; Stenager, Elsebeth; Nielsen, Bent; Nielsen, Anette Søgaard; Yu, Fei

    2017-01-30

    Although the number of alcohol-related treatments in app stores is proliferating, none of them are based on a psychological framework and supported by empirical evidence. Cue exposure treatment (CET) with urge-specific coping skills (USCS) is often used in Danish treatment settings. It is an evidence-based psychological approach that focuses on promoting "confrontation with alcohol cues" as a means of reducing urges and the likelihood of relapse. The objective of this study was to describe the design and development of a CET-based smartphone app; an innovative delivery pathway for treating alcohol use disorder (AUD). The treatment is based on Monty and coworkers' manual for CET with USCS (2002). It was created by a multidisciplinary team of psychiatrists, psychologists, programmers, and graphic designers as well as patients with AUD. A database was developed for the purpose of registering and monitoring training activities. A final version of the CET app and database was developed after several user tests. The final version of the CET app includes an introduction, 4 sessions featuring USCS, 8 alcohol exposure videos promoting the use of one of the USCS, and a results component providing an overview of training activities and potential progress. Real-time urges are measured before, during, and after exposure to alcohol cues and are registered in the app together with other training activity variables. Data packages are continuously sent in encrypted form to an external database and will be merged with other data (in an internal database) in the future. The CET smartphone app is currently being tested at a large-scale, randomized controlled trial with the aim of clarifying whether it can be classified as an evidence-based treatment solution. The app has the potential to augment the reach of psychological treatment for AUD.

  7. Characterization and side effect analysis of a newly designed nanoemulsion targeting human serum albumin for drug delivery.

    Science.gov (United States)

    Divsalar, Adeleh; Saboury, Ali Akbar; Nabiuni, Mohammad; Zare, Zohre; Kefayati, Mohammad Esmaeil; Seyedarabi, Arefeh

    2012-10-01

    Human serum albumin (HSA), the most abundant protein in plasma, plays an important role in the transportation of metabolic and exogenous compounds, particularly drugs. However, it takes a carrier to bring the metabolite or compound to the plasma for subsequent transportation in blood using HSA. A nanoemulsion which constitutes a mixture of two immiscible liquid phases can act as an effective drug carrier due to its unique properties. In this study, we report the characterization results of a newly designed nanoemulsion via dynamic light scattering (DLS) and scanning electron microscopy (SEM), followed by results on the alterations in the structure of HSA upon interaction with the nanoemulsion using circular dichroism (CD) as well as intrinsic and extrinsic fluorescence spectroscopy methods at ambient and physiological temperatures. Results of SEM and DLS show that particles making up the nanoemulsion have a nearly monodisperse size distribution and spherical morphology. Results of intrinsic fluorescence spectroscopy show decreasing emission intensity with increasing nanoemulsion concentration. Results from this study using 1-anilino-8-naphthalene sulfonic acid (ANS) confirm the intrinsic fluorescence data and reveal that adding the nanoemulsion to HSA leads to an increase in fluorescence intensity. These results imply that the interaction between the nanoemulsion and HSA cause a structural transformation in which native HSA turns "inside out" to expose its hydrophobic core to the surrounding environment. Far-UV-CD results indicate that the nanoemulsion induces a loss in α-helical structure of the HSA protein. In summary, the exposure of the blood carrier protein HSA to a newly designed nanoemulsion resulted in significant alterations of protein structure and conformation depicted by a red shift in maximum fluorescence intensity, decreased α-helical structure, and increased exposure of nonpolar or accessible hydrophobic surface of HSA to the solvent. Crown

  8. Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design.

    Directory of Open Access Journals (Sweden)

    Jean Mazella

    2010-04-01

    Full Text Available Current antidepressant treatments are inadequate for many individuals, and when they are effective, they require several weeks of administration before a therapeutic effect can be observed. Improving the treatment of depression is challenging. Recently, the two-pore domain potassium channel TREK-1 has been identified as a new target in depression, and its antagonists might become effective antidepressants. In mice, deletion of the TREK-1 gene results in a depression-resistant phenotype that mimics antidepressant treatments. Here, we validate in mice the antidepressant effects of spadin, a secreted peptide derived from the propeptide generated by the maturation of the neurotensin receptor 3 (NTSR3/Sortilin and acting through TREK-1 inhibition. NTSR3/Sortilin interacted with the TREK-1 channel, as shown by immunoprecipitation of TREK-1 and NTSR3/Sortilin from COS-7 cells and cortical neurons co-expressing both proteins. TREK-1 and NTSR3/Sortilin were colocalized in mouse cortical neurons. Spadin bound specifically to TREK-1 with an affinity of 10 nM. Electrophysiological studies showed that spadin efficiently blocked the TREK-1 activity in COS-7 cells, cultured hippocampal pyramidal neurons, and CA3 hippocampal neurons in brain slices. Spadin also induced in vivo an increase of the 5-HT neuron firing rate in the Dorsal Raphe Nucleus. In five behavioral tests predicting an antidepressant response, spadin-treated mice showed a resistance to depression as found in TREK-1 deficient mice. More importantly, an intravenous 4-d treatment with spadin not only induced a strong antidepressant effect but also enhanced hippocampal phosphorylation of CREB protein and neurogenesis, considered to be key markers of antidepressant action after chronic treatment with selective serotonin reuptake inhibitors. This work also shows the development of a reliable method for dosing the propeptide in serum of mice by using AlphaScreen technology. These findings point out

  9. Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design.

    Science.gov (United States)

    Mazella, Jean; Pétrault, Olivier; Lucas, Guillaume; Deval, Emmanuel; Béraud-Dufour, Sophie; Gandin, Carine; El-Yacoubi, Malika; Widmann, Catherine; Guyon, Alice; Chevet, Eric; Taouji, Said; Conductier, Grégory; Corinus, Alain; Coppola, Thierry; Gobbi, Gabriella; Nahon, Jean-Louis; Heurteaux, Catherine; Borsotto, Marc

    2010-04-13

    Current antidepressant treatments are inadequate for many individuals, and when they are effective, they require several weeks of administration before a therapeutic effect can be observed. Improving the treatment of depression is challenging. Recently, the two-pore domain potassium channel TREK-1 has been identified as a new target in depression, and its antagonists might become effective antidepressants. In mice, deletion of the TREK-1 gene results in a depression-resistant phenotype that mimics antidepressant treatments. Here, we validate in mice the antidepressant effects of spadin, a secreted peptide derived from the propeptide generated by the maturation of the neurotensin receptor 3 (NTSR3/Sortilin) and acting through TREK-1 inhibition. NTSR3/Sortilin interacted with the TREK-1 channel, as shown by immunoprecipitation of TREK-1 and NTSR3/Sortilin from COS-7 cells and cortical neurons co-expressing both proteins. TREK-1 and NTSR3/Sortilin were colocalized in mouse cortical neurons. Spadin bound specifically to TREK-1 with an affinity of 10 nM. Electrophysiological studies showed that spadin efficiently blocked the TREK-1 activity in COS-7 cells, cultured hippocampal pyramidal neurons, and CA3 hippocampal neurons in brain slices. Spadin also induced in vivo an increase of the 5-HT neuron firing rate in the Dorsal Raphe Nucleus. In five behavioral tests predicting an antidepressant response, spadin-treated mice showed a resistance to depression as found in TREK-1 deficient mice. More importantly, an intravenous 4-d treatment with spadin not only induced a strong antidepressant effect but also enhanced hippocampal phosphorylation of CREB protein and neurogenesis, considered to be key markers of antidepressant action after chronic treatment with selective serotonin reuptake inhibitors. This work also shows the development of a reliable method for dosing the propeptide in serum of mice by using AlphaScreen technology. These findings point out spadin as a putative

  10. Design

    DEFF Research Database (Denmark)

    Jensen, Ole B.; Pettiway, Keon

    2017-01-01

    by designers, planners, etc. (staging from above) and mobile subjects (staging from below). A research agenda for studying situated practices of mobility and mobilities design is outlined in three directions: foci of studies, methods and approaches, and epistemologies and frames of thinking. Jensen begins......In this chapter, Ole B. Jensen takes a situational approach to mobilities to examine how ordinary life activities are structured by technology and design. Using “staging mobilities” as a theoretical approach, Jensen considers mobilities as overlapping, actions, interactions and decisions...... with a brief description of how movement is studied within social sciences after the “mobilities turn” versus the idea of physical movement in transport geography and engineering. He then explains how “mobilities design” was derived from connections between traffic and architecture. Jensen concludes...

  11. Designing Strategy and Competence-targeted Analysis of Assessment and Diagnostic Materials for the Master’s Studies Tests

    Directory of Open Access Journals (Sweden)

    A. A. Dorofeev

    2015-01-01

    Full Text Available The paper describes technique, design process, and examples of assessment and diagnostic materials for the written tests for applicants to be admitted to Master’s studies. Their development is based on the objectives of the learning outcomes (LO gained in the course of bachelor, specialist, and master study programmes. The objective is characterised both by category of acquired knowledge, from the fact-gathering one to the meta-knowledge, and by necessary level of activities, which realise gained reproductive-to-creative knowledge, abilities, and skills, and show desirable human personalities appropriate for these activities, i.e. human’s competence.The paper offers and analyses a task option aimed at revealing competence of heterogeneous test for entrance trials. The test includes problems of three levels, which are different in structural complexity and activity in their solution: from reproduction and interpretation of data to the analysis and synthesis of the new information contents with creative elements. It demands that a future graduate has to possess certain personal qualities, be qualified and psychologically ready for the learning activity with a research component.Thus the paper gives examples of tasks with text and graphic interfaces and their benchmark (model solutions. The tasks are formulated on a case technique as a problem situation in the substantive area of the future professional activity. The maximum score assessment is based both on the number of attributive didactic points and on the necessary level of activity. To assess the fulfilled tasks the paper offers a technique that takes into consideration how the result is approximated to the benchmark solution.In developing a substantive ground of the test tasks the paper proposes to use the programmes of propaedeutic disciplines and a local issue of the coursework design. As to drawing up tasks and control of their fulfilment the offer is to involve the faculty staff in

  12. Design, Synthesis and Application of Fluorine-Labeled Taxoids as19F NMR Probes for the Metabolic Stability Assessment of Tumor-Targeted Drug Delivery Systems.

    Science.gov (United States)

    Seitz, Joshua D; Vineberg, Jacob G; Wei, Longfei; Khan, Jonathan F; Lichtenthal, Brendan; Lin, Chi-Feng; Ojima, Iwao

    2015-03-01

    Novel tumor-targeting drug conjugates, BLT-F 2 ( 1 ) and BLT-S-F 6 ( 2 ), bearing a fluorotaxoid as the warhead, a mechanism-based self-immolative disulfide linker, and biotin as the tumor-targeting module, were designed and synthesized as 19 F NMR probes. Fluorine atoms and CF 3 groups were strategically incorporated into the conjugates to investigate the mechanism of linker cleavage and factors that influence their plasma and metabolic stability by real-time monitoring with 19 F NMR. Time-resolved 19 F NMR study on probe 1 disclosed a stepwise mechanism for release of a fluorotaxoid, which might not have been detected by other analytical methods. Probe 2 was designed to bear two CF 3 groups in the taxoid moiety as "3-FAB" reporters for enhanced sensitivity and a polyethylene glycol oligomer insert to improve solubility. The clean analysis of the linker stability and reactivity of drug conjugates in blood plasma or cell culture media by HPLC and 1 H NMR is troublesome, due to the overlap of key signals/peaks with background arising from highly complex ingredients in biological systems. Accordingly, the use of 19 F NMR would provide a practical solution to this problem. In fact, our "3-FAB" probe 2 was proven to be highly useful to investigate the stability and reactivity of the self-immolative disulfide linker system in human blood plasma by 19 F NMR. It has also been revealed that the use of polysorbate 80 as excipient for the formulation of probe 2 dramatically increases the stability of the disulfide linker system. This finding further indicates that the tumor-targeting drug conjugates with polysorbate 80/EtOH/saline formulation for in vivo studies would have high stability in blood plasma, while the drug release in cancer cells proceeds smoothly.

  13. A theory-based educational intervention targeting nurses' attitudes and knowledge concerning cancer-related pain management: A study protocol of a quasi-experimental design

    Directory of Open Access Journals (Sweden)

    Gustafsson Markus

    2011-09-01

    Full Text Available Abstract Background Pain is one of the most frequent problems among patients diagnosed with cancer. Despite the availability of effective pharmacological treatments, this group of patients often receives less than optimal treatment. Research into nurses' pain management highlights certain factors, such as lack of knowledge and attitudes and inadequate procedures for systematic pain assessment, as common barriers to effective pain management. However, educational interventions targeting nurses' pain management have shown promise. As cancer-related pain is also known to have a negative effect on vital aspects of the patient's life, as well as being commonly associated with problems such as sleep, fatigue, depression and anxiety, further development of knowledge within this area is warranted. Methods/design A quasi-experimental study design will be used to investigate whether the implementation of guidelines for systematic daily pain assessments following a theory-based educational intervention will result in an improvement in knowledge and attitude among nurses. A further aim is to investigate whether the intervention that targets nurses' behaviour will improve hospital patients' perception of pain. Data regarding nurses' knowledge and attitudes to pain (primary outcome, patient perception regarding pain (secondary outcome, together with socio-demographic variables, will be collected at baseline and at four weeks and 12 weeks following the intervention. Discussion Nursing care is nowadays acknowledged as an increasingly complicated activity and "nursing complexity is such that it can be seen as the quintessential complex intervention." To be able to change and improve clinical practice thus requires multiple points of attack appropriate to meet complex challenges. Consequently, we expect the theory-based intervention used in our quasi-experimental study to improve care as well as quality of life for this group of patients and we also envisage that

  14. Design

    DEFF Research Database (Denmark)

    Volf, Mette

    Design - proces & metode iBog®  er enestående i sit fokus på afmystificering og operationalisering af designprocessens flygtige og komplekse karakter. Udgivelsen går bag om designerens daglige arbejde og giver et indblik i den kreative skabelsesproces, som designeren er en del af. Udover et bredt...... indblik i designerens arbejdsmetoder og designparametre giver Design - proces & metode en række eksempler fra anerkendte designvirksomheder, der gør det muligt at komme helt tæt på designerens virkelighed....

  15. Vaccinomics Approach for Designing Potential Peptide Vaccine by Targeting Shigella spp. Serine Protease Autotransporter Subfamily Protein SigA

    Directory of Open Access Journals (Sweden)

    Arafat Rahman Oany

    2017-01-01

    Full Text Available Shigellosis, a bacillary dysentery, is closely associated with diarrhoea in human and causes infection of 165 million people worldwide per year. Casein-degrading serine protease autotransporter of enterobacteriaceae (SPATE subfamily protein SigA, an outer membrane protein, exerts both cytopathic and enterotoxic effects especially cytopathic to human epithelial cell type-2 (HEp-2 and is shown to be highly immunogenic. In the present study, we have tried to impose the vaccinomics approach for designing a common peptide vaccine candidate against the immunogenic SigA of Shigella spp. At first, 44 SigA proteins from different variants of S. flexneri, S. dysenteriae, S. boydii, and S. sonnei were assessed to find the most antigenic protein. We retrieved 12 peptides based on the highest score for human leukocyte antigen (HLA supertypes analysed by NetCTL. Initially, these peptides were assessed for the affinity with MHC class I and class II alleles, and four potential core epitopes VTARAGLGY, FHTVTVNTL, HTTWTLTGY, and IELAGTLTL were selected. From these, FHTVTVNTL and IELAGTLTL peptides were shown to have 100% conservancy. Finally, IELAGTLTL was shown to have the highest population coverage (83.86% among the whole world population. In vivo study of the proposed epitope might contribute to the development of functional and unique widespread vaccine, which might be an operative alleyway to thwart dysentery from the world.

  16. Novel inhibitors targeting Venezuelan equine encephalitis virus capsid protein identified using In Silico Structure-Based-Drug-Design.

    Science.gov (United States)

    Shechter, Sharon; Thomas, David R; Lundberg, Lindsay; Pinkham, Chelsea; Lin, Shih-Chao; Wagstaff, Kylie M; Debono, Aaron; Kehn-Hall, Kylene; Jans, David A

    2017-12-18

    Therapeutics are currently unavailable for Venezuelan equine encephalitis virus (VEEV), which elicits flu-like symptoms and encephalitis in humans, with an estimated 14% of cases resulting in neurological disease. Here we identify anti-VEEV agents using in silico structure-based-drug-design (SBDD) for the first time, characterising inhibitors that block recognition of VEEV capsid protein (C) by the host importin (IMP) α/β1 nuclear transport proteins. From an initial screen of 1.5 million compounds, followed by in silico refinement and screening for biological activity in vitro, we identified 21 hit compounds which inhibited IMPα/β1:C binding with IC50s as low as 5 µM. Four compounds were found to inhibit nuclear import of C in transfected cells, with one able to reduce VEEV replication at µM concentration, concomitant with reduced C nuclear accumulation in infected cells. Further, this compound was inactive against a mutant VEEV that lacks high affinity IMPα/β1:C interaction, supporting the mode of its antiviral action to be through inhibiting C nuclear localization. This successful application of SBDD paves the way for lead optimization for VEEV antivirals, and is an exciting prospect to identify inhibitors for the many other viral pathogens of significance that require IMPα/β1 in their infectious cycle.

  17. Design

    Science.gov (United States)

    Buchanan, Richard; Cross, Nigel; Durling, David; Nelson, Harold; Owen, Charles; Valtonen, Anna; Boling, Elizabeth; Gibbons, Andrew; Visscher-Voerman, Irene

    2013-01-01

    Scholars representing the field of design were asked to identify what they considered to be the most exciting and imaginative work currently being done in their field, as well as how that work might change our understanding. The scholars included Richard Buchanan, Nigel Cross, David Durling, Harold Nelson, Charles Owen, and Anna Valtonen. Scholars…

  18. Design novel dual agonists for treating type-2 diabetes by targeting peroxisome proliferator-activated receptors with core hopping approach.

    Directory of Open Access Journals (Sweden)

    Ying Ma

    Full Text Available Owing to their unique functions in regulating glucose, lipid and cholesterol metabolism, PPARs (peroxisome proliferator-activated receptors have drawn special attention for developing drugs to treat type-2 diabetes. By combining the lipid benefit of PPAR-alpha agonists (such as fibrates with the glycemic advantages of the PPAR-gamma agonists (such as thiazolidinediones, the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of the powerful "core hopping" and "glide docking" techniques, a novel class of PPAR dual agonists was discovered based on the compound GW409544, a well-known dual agonist for both PPAR-alpha and PPAR-gamma modified from the farglitazar structure. It was observed by molecular dynamics simulations that these novel agonists not only possessed the same function as GW409544 did in activating PPAR-alpha and PPAR-gamma, but also had more favorable conformation for binding to the two receptors. It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion predictions that the new agonists hold high potential to become drug candidates. Or at the very least, the findings reported here may stimulate new strategy or provide useful insights for discovering more effective dual agonists for treating type-2 diabetes. Since the "core hopping" technique allows for rapidly screening novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties, it has not escaped our notice that the current strategy along with the corresponding computational procedures can also be utilized to find novel and more effective drugs for treating other illnesses.

  19. Deep brain stimulation targeting the fornix for mild Alzheimer dementia: design of the ADvance randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Holroyd KB

    2015-07-01

    stimulation (DBS of memory circuits may improve symptoms and possibly slow disease progression. The ADvance trial was designed to examine DBS of the fornix as a treatment for mild AD. Methods: ADvance is a randomized, double-blind, placebo-controlled, delayed-start, multicenter clinical trial conducted at six sites in the US and one site in Canada. Eighty-five subjects initially consented to be screened for the trial. Of these, 42 subjects who met inclusion and exclusion criteria were implanted with DBS leads anterior to the columns of the fornix bilaterally. They were randomized 1:1 to DBS “off” or DBS “on” groups for the initial 12 months of follow-up. After 1 year, all subjects will have their devices turned “on” for the remainder of the study. Postimplantation, subjects will return for 13 follow-up visits over 48 months for cognitive and psychiatric assessments, brain imaging (up to 12 months, and safety monitoring. The primary outcome measures include Alzheimer's Disease Assessment Scale – cognitive component (ADAS-cog-13, Clinical Dementia Rating sum of boxes (CDR-SB, and cerebral glucose metabolism measured with positron emission tomography. This report details the study methods, baseline subject characteristics of screened and implanted participants, and screen-to-baseline test–retest reliability of the cognitive outcomes. Results: Implanted subjects had a mean age of 68.2 years, were mostly male (55%, and had baseline mean ADAS-cog-13 and CDR-SB scores of 28.9 (SD, 5.2 and 3.9 (SD, 1.6, respectively. There were no significant differences between screened and implanted or nonimplanted subjects on most demographic or clinical assessments. Implanted subjects had significantly lower (better ADAS-cog-11 (17.5 vs 21.1 scores, but did not differ on CDR-SB. Scores on the major outcome measures for the trial were consistent at screening and baseline. Conclusion: ADvance was successful in enrolling a substantial group of patients for this novel application of

  20. Chemoinformatics in multi-target drug discovery for anti-cancer therapy: in silico design of potent and versatile anti-brain tumor agents.

    Science.gov (United States)

    Speck-Planche, Alejandro; Kleandrova, Valeria V; Luan, Feng; Cordeiro, M Natália D S

    2012-07-01

    A brain tumor (BT) constitutes a neoplasm located in the brain or the central spinal canal. The number of new diagnosed cases with BT increases with the pass of the time. Understanding the biology of BT is essential for the development of novel therapeutic strategies, in order to prevent or deal with this disease. An active area for the search of new anti-BT therapies is the use of Chemoinformatics and/or Bioinformatics toward the design of new and potent anti-BT agents. The principal limitation of all these approaches is that they consider small series of structurally related compounds and/or the studies are realized for only one target like protein. The present work is an effort to overcome this problem. We introduce here the first Chemoinformatics multi-target approach for the in silico design and prediction of anti-BT agents against several cell lines. Here, a fragment-based QSAR model was developed. The model correctly classified 89.63% and 90.93% of active and inactive compounds respectively, in training series. The validation of the model was carried out by using prediction series which showed 88.00% of correct classification for active and 88.59% for inactive compounds. Some fragments were extracted from the molecules and their contributions to anti-BT activity were calculated. Several fragments were identified as potential substructural features responsible of anti-BT activity and new molecular entities designed from fragments with positive contributions were suggested as possible anti-BT agents.

  1. Strongly structured DNA sequences as targets for genosensing: sensing phase design and coupling to PCR amplification for a highly specific 33-mer gliadin DNA fragment.

    Science.gov (United States)

    Martín-Fernández, Begoña; Miranda-Ordieres, Arturo J; Lobo-Castañón, María Jesús; Frutos-Cabanillas, Gloria; de-los-Santos-Álvarez, Noemí; López-Ruiz, Beatriz

    2014-10-15

    Electrochemical genosensors are becoming cost-effective miniaturizable alternatives to real-time PCR (RT-PCR) methods for the detection of sequence-specific DNA fragments. We report on the rapid detection of PCR amplicons without the need of purification or strand separation. A challenging target sequence for both PCR amplification and electrochemical detection allowed us to address some difficulties associated to hybridization on electrode surfaces. The target was a highly specific oligonucleotide sequence of wheat encoding the most immunogenic peptide of gliadin that triggers the immune response of celiac disease (CD), the 33-mer. With a sandwich assay format and a rational design of the capture and tagged-signaling probes the problems posed by the strong secondary structure of the target and complementary probes were alleviated. Using a binary self-assembled monolayer and enzymatic amplification, a limit of detection of 0.3 nM was obtained. The genosensor did not respond to other gluten-containing cereals such as rye and barley. Coupling to PCR to analyze wheat flour samples required tailoring both the capture and signaling probes. This is the first time that deleterious steric hindrance from long single-stranded regions adjacent to the electrode surface is reported for relatively short amplicons (less than 200 bp). The importance of the location of the recognition site within the DNA sequence is discussed. Since the selected gene fragment contains several repetitions of short sequences, a careful optimization of the PCR conditions had to be performed to circumvent the amplification of non-specific fragments from wheat flour. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Validation and Application of a Custom-Designed Targeted Next-Generation Sequencing Panel for the Diagnostic Mutational Profiling of Solid Tumors.

    Directory of Open Access Journals (Sweden)

    Guy Froyen

    Full Text Available The inevitable switch from standard molecular methods to next-generation sequencing for the molecular profiling of tumors is challenging for most diagnostic laboratories. However, fixed validation criteria for diagnostic accreditation are not in place because of the great variability in methods and aims. Here, we describe the validation of a custom panel of hotspots in 24 genes for the detection of somatic mutations in non-small cell lung carcinoma, colorectal carcinoma and malignant melanoma starting from FFPE sections, using 14, 36 and 5 cases, respectively. The targeted hotspots were selected for their present or future clinical relevance in solid tumor types. The target regions were enriched with the TruSeq approach starting from limited amounts of DNA. Cost effective sequencing of 12 pooled libraries was done using a micro flow cell on the MiSeq and subsequent data analysis with MiSeqReporter and VariantStudio. The entire workflow was diagnostically validated showing a robust performance with maximal sensitivity and specificity using as thresholds a variant allele frequency >5% and a minimal amplicon coverage of 300. We implemented this method through the analysis of 150 routine diagnostic samples and identified clinically relevant mutations in 16 genes including KRAS (32%, TP53 (32%, BRAF (12%, APC (11%, EGFR (8% and NRAS (5%. Importantly, the highest success rate was obtained when using also the low quality DNA samples. In conclusion, we provide a workflow for the validation of targeted NGS by a custom-designed pan-solid tumor panel in a molecular diagnostic lab and demonstrate its robustness in a clinical setting.

  3. A theory-based educational intervention targeting nurses' attitudes and knowledge concerning cancer-related pain management: a study protocol of a quasi-experimental design.

    Science.gov (United States)

    Borglin, Gunilla; Gustafsson, Markus; Krona, Hans

    2011-09-23

    Pain is one of the most frequent problems among patients diagnosed with cancer. Despite the availability of effective pharmacological treatments, this group of patients often receives less than optimal treatment. Research into nurses' pain management highlights certain factors, such as lack of knowledge and attitudes and inadequate procedures for systematic pain assessment, as common barriers to effective pain management. However, educational interventions targeting nurses' pain management have shown promise. As cancer-related pain is also known to have a negative effect on vital aspects of the patient's life, as well as being commonly associated with problems such as sleep, fatigue, depression and anxiety, further development of knowledge within this area is warranted. A quasi-experimental study design will be used to investigate whether the implementation of guidelines for systematic daily pain assessments following a theory-based educational intervention will result in an improvement in knowledge and attitude among nurses. A further aim is to investigate whether the intervention that targets nurses' behaviour will improve hospital patients' perception of pain. Data regarding nurses' knowledge and attitudes to pain (primary outcome), patient perception regarding pain (secondary outcome), together with socio-demographic variables, will be collected at baseline and at four weeks and 12 weeks following the intervention. Nursing care is nowadays acknowledged as an increasingly complicated activity and "nursing complexity is such that it can be seen as the quintessential complex intervention." To be able to change and improve clinical practice thus requires multiple points of attack appropriate to meet complex challenges. Consequently, we expect the theory-based intervention used in our quasi-experimental study to improve care as well as quality of life for this group of patients and we also envisage that evidence-based guidelines targeting this patient group's pain

  4. Spiro[pyrrolidine-3, 3´-oxindole] as potent anti-breast cancer compounds: Their design, synthesis, biological evaluation and cellular target identification

    Science.gov (United States)

    Hati, Santanu; Tripathy, Sayantan; Dutta, Pratip Kumar; Agarwal, Rahul; Srinivasan, Ramprasad; Singh, Ashutosh; Singh, Shailja; Sen, Subhabrata

    2016-08-01

    The spiro[pyrrolidine-3, 3´-oxindole] moiety is present as a core in number of alkaloids with substantial biological activities. Here in we report design and synthesis of a library of compounds bearing spiro[pyrrolidine-3, 3´-oxindole] motifs that demonstrated exceptional inhibitory activity against the proliferation of MCF-7 breast cancer cells. The synthesis involved a one pot Pictet Spengler-Oxidative ring contraction of tryptamine to the desired scaffolds and occurred in 1:1 THF and water with catalytic trifluoroacetic acid and stoichiometric N-bromosuccinimide as an oxidant. Phenotypic profiling indicated that these molecules induce apoptotic cell death in MCF-7 cells. Target deconvolution with most potent compound 5l from the library, using chemical proteomics indicated histone deacetylase 2 (HDAC2) and prohibitin 2 as the potential cellular binding partners. Molecular docking of 5l with HDAC2 provided insights pertinent to putative binding interactions.

  5. Mitochondrial, acidic, and cytosolic pHs determination by ³¹P NMR spectroscopy: design of new sensitive targeted pH probes.

    Science.gov (United States)

    Culcasi, Marcel; Thétiot-Laurent, Sophie; Atteia, Ariane; Pietri, Sylvia

    2015-01-01

    (31)P nuclear magnetic resonance (NMR) is a unique technique to monitor noninvasively the energetics of living systems at real time through the detection of a variety of phosphorylated metabolites. Using adequately designed α-aminophosphonates as external probes, we have shown earlier that (31)P NMR can also give access simultaneously to the accurate pH of cytosolic and acidic compartments in normal and stressed cultured cells or isolated perfused organs, a feature that was not possible using endogenous inorganic phosphate as the probe. More recently, we obtained a series of derivatives of these new pH probes that incorporate a triphenylphosphonium cation as a specific vector to the mitochondrion. Here, we describe the synthesis, (31)P NMR pH titrating properties in buffers, and application in cultures of the green alga Chlamydomonas reinhardtii of two of these mitochondria-targeted pH probes in comparison with one nonvectorized, yet still informative α-aminophosphonate.

  6. Design and synthesis of a biotinylated chemical probe for detecting the molecular targets of an inhibitor of the production of the Pseudomonas aeruginosa virulence factor pyocyanin.

    Science.gov (United States)

    Baker, Ysobel R; Galloway, Warren R J D; Hodgkinson, James T; Spring, David R

    2013-09-25

    Pseudomonas aeruginosa is a human pathogen associated with a variety of life-threatening nosocomial infections. This organism produces a range of virulence factors which actively cause damage to host tissues. One such virulence factor is pyocyanin, known to play a crucial role in the pathogenesis of P. aeruginosa infections. Previous studies had identified a novel compound capable of strongly inhibiting the production of pyocyanin. It was postulated that this inhibition results from modulation of an intercellular communication system termed quorum sensing, via direct binding of the compound with the LasR protein receptor. This raised the possibility that the compound could be an antagonist of quorum sensing in P. aeruginosa, which could have important implications as this intercellular signaling mechanism is known to regulate many additional facets of P. aeruginosa pathogenicity. However, there was no direct evidence for the binding of the active compound to LasR (or any other targets). Herein we describe the design and synthesis of a biotin-tagged version of the active compound. This could potentially be used as an affinity-based chemical probe to ascertain, in a direct fashion, the active compound's macromolecular biological targets, and thus better delineate the mechanism by which it reduces the level of pyocyanin production.

  7. Design and Synthesis of a Biotinylated Chemical Probe for Detecting the Molecular Targets of an Inhibitor of the Production of the Pseudomonas aeruginosa Virulence Factor Pyocyanin

    Directory of Open Access Journals (Sweden)

    Ysobel R. Baker

    2013-09-01

    Full Text Available Pseudomonas aeruginosa is a human pathogen associated with a variety of life-threatening nosocomial infections. This organism produces a range of virulence factors which actively cause damage to host tissues. One such virulence factor is pyocyanin, known to play a crucial role in the pathogenesis of P. aeruginosa infections. Previous studies had identified a novel compound capable of strongly inhibiting the production of pyocyanin. It was postulated that this inhibition results from modulation of an intercellular communication system termed quorum sensing, via direct binding of the compound with the LasR protein receptor. This raised the possibility that the compound could be an antagonist of quorum sensing in P. aeruginosa, which could have important implications as this intercellular signaling mechanism is known to regulate many additional facets of P. aeruginosa pathogenicity. However, there was no direct evidence for the binding of the active compound to LasR (or any other targets. Herein we describe the design and synthesis of a biotin-tagged version of the active compound. This could potentially be used as an affinity-based chemical probe to ascertain, in a direct fashion, the active compound’s macromolecular biological targets, and thus better delineate the mechanism by which it reduces the level of pyocyanin production.

  8. Targeting children of substance-using parents with the community-based group intervention TRAMPOLINE: A randomised controlled trial - design, evaluation, recruitment issues

    Directory of Open Access Journals (Sweden)

    Bröning Sonja

    2012-03-01

    Full Text Available Abstract Background Children of substance-abusing parents are at risk for developing psychosocial development problems. In Germany it is estimated that approx. 2.65 million children are affected by parental substance abuse or dependence. Only ten percent of them receive treatment when parents are treated. To date, no evaluated programme for children from substance-affected families exists in Germany. The study described in this protocol is designed to test the effectiveness of the group programme TRAMPOLINE for children aged 8-12 years with at least one substance-abusing or -dependent caregiver. The intervention is specifically geared to issues and needs of children from substance-affected families. Methods/Design The effectiveness of the manualised nine-session group programme TRAMPOLINE is tested among N = 218 children from substance-affected families in a multicentre randomised controlled trial. Outpatient counselling facilities across the nation from different settings (rural/urban, Northern/Southern/Eastern/Western regions of the country will deliver the interventions, as they hold the primary access to the target group in Germany. The control condition is a group programme with the same duration that is not addiction-specific. We expect that participants in the intervention condition will show a significant improvement in the use of adaptive coping strategies (in general and within the family compared to the control condition as a direct result of the intervention. Data is collected shortly before and after as well as six months after the intervention. Discussion In Germany, the study presented here is the first to develop and evaluate a programme for children of substance-abusing parents. Limitations and strengths are discussed with a special focus on recruitment challenges as they appear to be the most potent threat to feasibility in the difficult-to-access target group at hand (Trial registration: ISRCTN81470784.

  9. Targeting children of substance-using parents with the community-based group intervention TRAMPOLINE: A randomised controlled trial - design, evaluation, recruitment issues

    Science.gov (United States)

    2012-01-01

    Background Children of substance-abusing parents are at risk for developing psychosocial development problems. In Germany it is estimated that approx. 2.65 million children are affected by parental substance abuse or dependence. Only ten percent of them receive treatment when parents are treated. To date, no evaluated programme for children from substance-affected families exists in Germany. The study described in this protocol is designed to test the effectiveness of the group programme TRAMPOLINE for children aged 8-12 years with at least one substance-abusing or -dependent caregiver. The intervention is specifically geared to issues and needs of children from substance-affected families. Methods/Design The effectiveness of the manualised nine-session group programme TRAMPOLINE is tested among N = 218 children from substance-affected families in a multicentre randomised controlled trial. Outpatient counselling facilities across the nation from different settings (rural/urban, Northern/Southern/Eastern/Western regions of the country) will deliver the interventions, as they hold the primary access to the target group in Germany. The control condition is a group programme with the same duration that is not addiction-specific. We expect that participants in the intervention condition will show a significant improvement in the use of adaptive coping strategies (in general and within the family) compared to the control condition as a direct result of the intervention. Data is collected shortly before and after as well as six months after the intervention. Discussion In Germany, the study presented here is the first to develop and evaluate a programme for children of substance-abusing parents. Limitations and strengths are discussed with a special focus on recruitment challenges as they appear to be the most potent threat to feasibility in the difficult-to-access target group at hand (Trial registration: ISRCTN81470784). PMID:22439919

  10. A practical strategy to design and develop an isoform-specific fluorescent probe for a target enzyme: CYP1A1 as a case study.

    Science.gov (United States)

    Dai, Zi-Ru; Feng, Lei; Jin, Qiang; Cheng, Hailing; Li, Yan; Ning, Jing; Yu, Yang; Ge, Guang-Bo; Cui, Jing-Nan; Yang, Ling

    2017-04-01

    The development of isoform-specific probe(s) for a target enzyme with multiple homologs is always challenging. Herein, a practical strategy was used to design and develop an isoform-specific probe for CYP1A1, a key cytochrome P450 isoenzyme involved in xenobiotic metabolism and bioactivation. On the basis of the subtle differences in 3D structure and substrate preference between CYP1A1 and its homolog CYP1A2, we proposed that it was possible to design a CYP1A1-specific probe via local modification of the reaction site on known CYP1A substrates. To validate this hypothesis, 4-hydroxy-1,8-naphthalimide (HN) was selected as the basic fluorophore due to its excellent optical properties, while a series of O-alkylated HN derivatives were prepared to evaluate their specificity towards CYP1A1. Our results revealed that the introduction of a chloroethyl to HN could get the best isoform selectivity towards CYP1A1 over other CYPs including CYP1A2. The newly developed probe NBCeN exhibited excellent specificity, high sensitivity, and a ratiometric fluorescence response following CYP1A1-catalyzed O-dechloroethylation. NBCeN was successfully used to real-time monitor the activity of CYP1A1 in complex biological samples and to rapidly screen CYP1A1 modulators in living systems. NBCeN could also be used for two-photon imaging of intracellular CYP1A1 in living cells and tissues with high ratiometric imaging resolution and deep tissue penetration. All these findings demonstrated that local modification of non-specific substrates was a practical strategy to develop an isoform-specific probe for a target isoenzyme, while NBCeN could serve as a specific imaging tool to explore the biological functions of CYP1A1 in complex biological systems.

  11. Design and Fabrication of Multifunctional Sericin Nanoparticles for Tumor Targeting and pH-Responsive Subcellular Delivery of Cancer Chemotherapy Drugs.

    Science.gov (United States)

    Huang, Lei; Tao, Kaixiong; Liu, Jia; Qi, Chao; Xu, Luming; Chang, Panpan; Gao, Jinbo; Shuai, Xiaoming; Wang, Guobin; Wang, Zheng; Wang, Lin

    2016-03-01

    The severe cytotoxicity of cancer chemotherapy drugs limits their clinical applications. Various protein-based nanoparticles with good biocompatibility have been developed for chemotherapy drug delivery in hope of reducing drugs' side effects. Sericin, a natural protein from silk, has no immunogenicity and possesses diverse bioactivities that have prompted sericin's application studies. However, the potential of sericin as a multifunctional nanoscale vehicle for cancer therapy have not been fully explored. Here we report the successful fabrication and characterization of folate-conjugated sericin nanoparticles with cancer-targeting capability for pH-responsive release of doxorubicin (these nanoparticles are termed "FA-SND"). DOX is covalently linked to sericin through pH-sensitive hydrazone bonds that render a pH-triggered release property. The hydrophobicity of DOX and the hydrophilicity of sericin promote the self-assembly of sericin-DOX (SND) nanoconjugates. Folate (FA) is then covalently grafted to SND nanoconjugates as a binding unit for actively targeting cancer cells that overexpress folate receptors. Our characterization study shows that FA-SND nanoparticles exhibit negative surface charges that would reduce nonspecific clearance by circulation. These nanoparticles possess good cytotoxicity and hemocompatibiliy. Acidic environment (pH 5.0) triggers effective DOX release from FA-SND, 5-fold higher than does a neutral condition (pH 7.4). Further, FA-SND nanoparticles specifically target folate-receptor-rich KB cells, and endocytosed into lysosomes, an acidic organelle. The acidic microenvironment of lysosomes promotes a rapid release of DOX to nuclei, producing cancer specific chemo-cytotoxicity. Thus, FA-mediated cancer targeting and lysosomal-acidity promoting DOX release, two sequentially-occurring cellular events triggered by the designed components of FA-SND, form the basis for FA-SND to achieve its localized and intracellular chemo

  12. Statistical linkage analysis of substitutions in patient-derived sequences of genotype 1a hepatitis C virus nonstructural protein 3 exposes targets for immunogen design.

    Science.gov (United States)

    Quadeer, Ahmed A; Louie, Raymond H Y; Shekhar, Karthik; Chakraborty, Arup K; Hsing, I-Ming; McKay, Matthew R

    2014-07-01

    Chronic hepatitis C virus (HCV) infection is one of the leading causes of liver failure and liver cancer, affecting around 3% of the world's population. The extreme sequence variability of the virus resulting from error-prone replication has thwarted the discovery of a universal prophylactic vaccine. It is known that vigorous and multispecific cellular immune responses, involving both helper CD4(+) and cytotoxic CD8(+) T cells, are associated with the spontaneous clearance of acute HCV infection. Escape mutations in viral epitopes can, however, abrogate protective T-cell responses, leading to viral persistence and associated pathologies. Despite the propensity of the virus to mutate, there might still exist substitutions that incur a fitness cost. In this paper, we identify groups of coevolving residues within HCV nonstructural protein 3 (NS3) by analyzing diverse sequences of this protein using ideas from random matrix theory and associated methods. Our analyses indicate that one of these groups comprises a large percentage of residues for which HCV appears to resist multiple simultaneous substitutions. Targeting multiple residues in this group through vaccine-induced immune responses should either lead to viral recognition or elicit escape substitutions that compromise viral fitness. Our predictions are supported by published clinical data, which suggested that immune genotypes associated with spontaneous clearance of HCV preferentially recognized and targeted this vulnerable group of residues. Moreover, mapping the sites of this group onto the available protein structure provided insight into its functional significance. An epitope-based immunogen is proposed as an alternative to the NS3 epitopes in the peptide-based vaccine IC41. Despite much experimental work on HCV, a thorough statistical study of the HCV sequences for the purpose of immunogen design was missing in the literature. Such a study is vital to identify epistatic couplings among residues that can

  13. Design and statistical modeling of mannose-decorated dapsone-containing nanoparticles as a strategy of targeting intestinal M-cells.

    Science.gov (United States)

    Vieira, Alexandre Cc; Chaves, Luíse L; Pinheiro, Marina; Ferreira, Domingos; Sarmento, Bruno; Reis, Salette

    2016-01-01

    The aim of the present work was to develop and optimize surface-functionalized solid lipid nanoparticles (SLNs) for improvement of the therapeutic index of dapsone (DAP), with the application of a design of experiments. The formulation was designed to target intestinal microfold (M-cells) as a strategy to increase internalization of the drug by the infected macrophages. DAP-loaded SLNs and mannosylated SLNs (M-SLNs) were successfully developed by hot ultrasonication method employing a three-level, three-factor Box-Behnken design, after the preformulation study was carried out with different lipids. All the formulations were systematically characterized regarding their diameter, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency, and loading capacity. They were also subjected to morphological studies using transmission electron microscopy, in vitro release study, infrared analysis (Fourier transform infrared spectroscopy), calorimetry studies (differential scanning calorimetry), and stability studies. The diameter of SLNs, SLN-DAP, M-SLNs, and M-SLN-DAP was approximately 300 nm and the obtained PDI was <0.2, confirming uniform populations. Entrapment efficiency and loading capacity were approximately 50% and 12%, respectively. Transmission electron microscopy showed spherical shape and nonaggregated nanoparticles. Fourier transform infrared spectroscopy was used to confirm the success of mannose coating process though Schiff's base formation. The variation of the ZP between uncoated (approximately -30 mV) and mannosylated formulations (approximately +60 mV) also confirmed the successful coating process. A decrease in the enthalpy and broadening of the lipid melting peaks of the differential scanning calorimetry thermograms are consistent with the nanostructure of the SLNs. Moreover, the drug release was pH-sensitive, with a faster drug release at acidic pH than at neutral pH. Storage stability for the formulations for at least 8 weeks is expected

  14. Novel drug design for Chagas disease via targeting Trypanosoma cruzi tubulin: Homology modeling and binding pocket prediction on Trypanosoma cruzi tubulin polymerization inhibition by naphthoquinone derivatives.

    Science.gov (United States)

    Ogindo, Charles O; Khraiwesh, Mozna H; George, Matthew; Brandy, Yakini; Brandy, Nailah; Gugssa, Ayele; Ashraf, Mohammad; Abbas, Muneer; Southerland, William M; Lee, Clarence M; Bakare, Oladapo; Fang, Yayin

    2016-08-15

    Chagas disease, also called American trypanosomiasis, is a parasitic disease caused by Trypanosoma cruzi (T. cruzi). Recent findings have underscored the abundance of the causative organism, (T. cruzi), especially in the southern tier states of the US and the risk burden for the rural farming communities there. Due to a lack of safe and effective drugs, there is an urgent need for novel therapeutic options for treating Chagas disease. We report here our first scientific effort to pursue a novel drug design for treating Chagas disease via the targeting of T. cruzi tubulin. First, the anti T. cruzi tubulin activities of five naphthoquinone derivatives were determined and correlated to their anti-trypanosomal activities. The correlation between the ligand activities against the T. cruzi organism and their tubulin inhibitory activities was very strong with a Pearson's r value of 0.88 (P value cruzi tubulin polymerization inhibition. Subsequent molecular modeling studies were carried out to understand the mechanisms of the anti-tubulin activities, wherein, the homology model of T. cruzi tubulin dimer was generated and the putative binding site of naphthoquinone derivatives was predicted. The correlation coefficient for ligand anti-tubulin activities and their binding energies at the putative pocket was found to be r=0.79, a high correlation efficiency that was not replicated in contiguous candidate pockets. The homology model of T. cruzi tubulin and the identification of its putative binding site lay a solid ground for further structure based drug design, including molecular docking and pharmacophore analysis. This study presents a new opportunity for designing potent and selective drugs for Chagas disease. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. Target Window Reliability

    Energy Technology Data Exchange (ETDEWEB)

    Woloshun, Keith Albert [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-02-11

    The target window design implemented and tested in experiments at ANL have performed without failure for the available beam of 6 mm FWHM on a 12 mm diameter target. However, scaling that design to a 25 mm diameter target size for a 12 mm FWHM beam has proven problematic. Combined thermal and mechanical (pressure induced) stresses and strains are too high to maintain the small coolant gaps and provide adequate fatigue lifetime.

  16. Design Considerations for mHealth Programs Targeting Smokers Not Yet Ready to Quit: Results of a Sequential Mixed-Methods Study.

    Science.gov (United States)

    McClure, Jennifer B; Heffner, Jaimee; Hohl, Sarah; Klasnja, Predrag; Catz, Sheryl L

    2017-03-10

    Mobile health (mHealth) smoking cessation programs are typically designed for smokers who are ready to quit smoking. In contrast, most smokers want to quit someday but are not yet ready to quit. If mHealth apps were designed for these smokers, they could potentially encourage and assist more people to quit smoking. No prior studies have specifically examined the design considerations of mHealth apps targeting smokers who are not yet ready to quit. To inform the user-centered design of mHealth apps for smokers who were not yet ready to quit by assessing (1) whether these smokers were interested in using mHealth tools to change their smoking behavior; (2) their preferred features, functionality, and content of mHealth programs addressing smoking; and (3) considerations for marketing or distributing these programs to promote their uptake. We conducted a sequential exploratory, mixed-methods study. Qualitative interviews (phase 1, n=15) were completed with a demographically diverse group of smokers who were smartphone owners and wanted to quit smoking someday, but not yet. Findings informed a Web-based survey of smokers from across the United States (phase 2, n=116). Data were collected from April to September, 2016. Findings confirmed that although smokers not yet ready to quit are not actively seeking treatment or using cessation apps, most would be interested in using these programs to help them reduce or change their smoking behavior. Among phase 2 survey respondents, the app features, functions, and content rated most highly were (1) security of personal information; (2) the ability to track smoking, spending, and savings; (3) content that adaptively changes with one's needs; (4) the ability to request support as needed; (5) the ability to earn and redeem awards for program use; (6) guidance on how to quit smoking; and (7) content specifically addressing management of nicotine withdrawal, stress, depression, and anxiety. Results generally did not vary by stage of

  17. Tacrine, Trolox and Tryptoline as Lead Compounds for the Design and Synthesis of Multi-target Agents for Alzheimer's Disease Therapy.

    Science.gov (United States)

    Teponnou, Gerard A K; Joubert, Jacques; Malan, Sarel F

    2017-01-01

    The versatile biological activities of tacrine, trolox and β-carboline derivatives make them promising lead structures for the development of multifunctional Alzheimer's disease (AD) agents. Based on the topology of the active site of cholinesterases and other target proteins involved in the pathogenesis of AD, we have designed and synthesized tacrine-trolox and tacrine-tryptoline hybrids with various linker chain lengths. The hybrids containing the trolox moiety (8a-8d) showed moderate to high TcAChE inhibition (IC50: 17.37 - 2200 nM), eqBuChE inhibition (IC50: 3.16 - 128.82 nM) and free radical scavenging activities (IC50: 11.48 - 49.23 µM). The hybrids with longer linker chain lengths in general showed better ChE inhibitory activity. As expected, free radical scavenging activities were not significantly affected by varying linker chain lengths. The hybrid compound containing the tryptoline moiety linked with a 7 carbon spacer to tacrine (14) displayed the best AChE and BuChE inhibitory activity (IC50 = 17.37 and 3.16 nM). Docking experiments exhibited that compounds 8d and 14 were able to bind to both the CAS and PAS of TcAChE and eqBuChE, suggesting that they will be able to inhibit ChE induced Aβ aggregation. Novel multi-target agents that exhibit good ChE inhibition (8d and 14) and anti-oxidant (8d) activity were identified as suitable candidates for further investigation.

  18. Improved design of hammerhead ribozyme for selective digestion of target RNA through recognition of site-specific adenosine-to-inosine RNA editing

    Science.gov (United States)

    Fukuda, Masatora; Kurihara, Kei; Yamaguchi, Shota; Oyama, Yui; Deshimaru, Masanobu

    2014-01-01

    Adenosine-to-inosine (A-to-I) RNA editing is an endogenous regulatory mechanism involved in various biological processes. Site-specific, editing-state–dependent degradation of target RNA may be a powerful tool both for analyzing the mechanism of RNA editing and for regulating biological processes. Previously, we designed an artificial hammerhead ribozyme (HHR) for selective, site-specific RNA cleavage dependent on the A-to-I RNA editing state. In the present work, we developed an improved strategy for constructing a trans-acting HHR that specifically cleaves target editing sites in the adenosine but not the inosine state. Specificity for unedited sites was achieved by utilizing a sequence encoding the intrinsic cleavage specificity of a natural HHR. We used in vitro selection methods in an HHR library to select for an extended HHR containing a tertiary stabilization motif that facilitates HHR folding into an active conformation. By using this method, we successfully constructed highly active HHRs with unedited-specific cleavage. Moreover, using HHR cleavage followed by direct sequencing, we demonstrated that this ribozyme could cleave serotonin 2C receptor (HTR2C) mRNA extracted from mouse brain, depending on the site-specific editing state. This unedited-specific cleavage also enabled us to analyze the effect of editing state at the E and C sites on editing at other sites by using direct sequencing for the simultaneous quantification of the editing ratio at multiple sites. Our approach has the potential to elucidate the mechanism underlying the interdependencies of different editing states in substrate RNA with multiple editing sites. PMID:24448449

  19. Targeting children of substance-using parents with the community-based group intervention TRAMPOLINE: a randomised controlled trial--design, evaluation, recruitment issues.

    Science.gov (United States)

    Bröning, Sonja; Wiedow, Annika; Wartberg, Lutz; Ruths, Sylvia; Haevelmann, Andrea; Kindermann, Sally-Sophie; Moesgen, Diana; Schaunig-Busch, Ines; Klein, Michael; Thomasius, Rainer

    2012-03-22

    Children of substance-abusing parents are at risk for developing psychosocial development problems. In Germany it is estimated that approx. 2.65 million children are affected by parental substance abuse or dependence. Only ten percent of them receive treatment when parents are treated. To date, no evaluated programme for children from substance-affected families exists in Germany. The study described in this protocol is designed to test the effectiveness of the group programme TRAMPOLINE for children aged 8-12 years with at least one substance-abusing or -dependent caregiver. The intervention is specifically geared to issues and needs of children from substance-affected families. The effectiveness of the manualised nine-session group programme TRAMPOLINE is tested among N = 218 children from substance-affected families in a multicentre randomised controlled trial. Outpatient counselling facilities across the nation from different settings (rural/urban, Northern/Southern/Eastern/Western regions of the country) will deliver the interventions, as they hold the primary access to the target group in Germany. The control condition is a group programme with the same duration that is not addiction-specific. We expect that participants in the intervention condition will show a significant improvement in the use of adaptive coping strategies (in general and within the family) compared to the control condition as a direct result of the intervention. Data is collected shortly before and after as well as six months after the intervention. In Germany, the study presented here is the first to develop and evaluate a programme for children of substance-abusing parents. Limitations and strengths are discussed with a special focus on recruitment challenges as they appear to be the most potent threat to feasibility in the difficult-to-access target group at hand (Trial registration: ISRCTN81470784).

  20. Improved design of hammerhead ribozyme for selective digestion of target RNA through recognition of site-specific adenosine-to-inosine RNA editing.

    Science.gov (United States)

    Fukuda, Masatora; Kurihara, Kei; Yamaguchi, Shota; Oyama, Yui; Deshimaru, Masanobu

    2014-03-01

    Adenosine-to-inosine (A-to-I) RNA editing is an endogenous regulatory mechanism involved in various biological processes. Site-specific, editing-state-dependent degradation of target RNA may be a powerful tool both for analyzing the mechanism of RNA editing and for regulating biological processes. Previously, we designed an artificial hammerhead ribozyme (HHR) for selective, site-specific RNA cleavage dependent on the A-to-I RNA editing state. In the present work, we developed an improved strategy for constructing a trans-acting HHR that specifically cleaves target editing sites in the adenosine but not the inosine state. Specificity for unedited sites was achieved by utilizing a sequence encoding the intrinsic cleavage specificity of a natural HHR. We used in vitro selection methods in an HHR library to select for an extended HHR containing a tertiary stabilization motif that facilitates HHR folding into an active conformation. By using this method, we successfully constructed highly active HHRs with unedited-specific cleavage. Moreover, using HHR cleavage followed by direct sequencing, we demonstrated that this ribozyme could cleave serotonin 2C receptor (HTR2C) mRNA extracted from mouse brain, depending on the site-specific editing state. This unedited-specific cleavage also enabled us to analyze the effect of editing state at the E and C sites on editing at other sites by using direct sequencing for the simultaneous quantification of the editing ratio at multiple sites. Our approach has the potential to elucidate the mechanism underlying the interdependencies of different editing states in substrate RNA with multiple editing sites.

  1. Feasibility and effectiveness of a targeted diabetes prevention program for 18 to 60-year-old South Asian migrants: design and methods of the DH!AAN study

    Directory of Open Access Journals (Sweden)

    Vlaar Everlina MA

    2012-05-01

    Full Text Available Abstract Background South Asian migrants are at particularly high risk of type 2 diabetes. Previous studies have shown that intensive lifestyle interventions may prevent the onset of diabetes. Such interventions have not been culturally adapted and evaluated among South Asians in industrialized countries. Therefore, we have set up a randomized controlled trial to study the effectiveness of a targeted lifestyle intervention for the risk of type 2 diabetes and cardiovascular risk factors among 18 to 60-year-old Hindustani Surinamese (South Asians in The Hague, the Netherlands. Here we present the study design and describe the characteristics of those recruited. Methods Between May 18, 2009 and October 11, 2010, we screened 2307 Hindustani Surinamese (18–60 years old living in The Hague. We sent invitations to participate to those who had an impaired fasting glucose of 5.6-6.9 mmol/l, an impaired glucose tolerance of 7.8-11.0 mmol/L, a glycated hemoglobin level of 6.0% or more and/or a value of 2.39 or more for the homeostasis model assessment of estimated insulin resistance. In total, 536 people (56.1% of those eligible participated. People with a higher level of education and a family history of type 2 diabetes were more likely to participate. The control and intervention groups were similar with regard to important background characteristics. The intervention group will receive a culturally targeted intervention consisting of dietary counseling using motivational interviewing and a supervised physical activity program. The control group will receive generic lifestyle advice. To determine the effectiveness, a physical examination (anthropometrics, cardiorespiratory test, lipid profile, and measures of oral glucose tolerance, glycated hemoglobin, and insulin and interview (physical activity, diet, quality of life, and intermediate outcomes were carried out at baseline and will be repeated at 1 year and 2 years. The process and the

  2. Rational drug design for anti-cancer chemotherapy: multi-target QSAR models for the in silico discovery of anti-colorectal cancer agents.

    Science.gov (United States)

    Speck-Planche, Alejandro; Kleandrova, Valeria V; Luan, Feng; Cordeiro, M Natália D S

    2012-08-01

    The discovery of new and more potent anti-cancer agents constitutes one of the most active fields of research in chemotherapy. Colorectal cancer (CRC) is one of the most studied cancers because of its high prevalence and number of deaths. In the current pharmaceutical design of more efficient anti-CRC drugs, the use of methodologies based on Chemoinformatics has played a decisive role, including Quantitative-Structure-Activity Relationship (QSAR) techniques. However, until now, there is no methodology able to predict anti-CRC activity of compounds against more than one CRC cell line, which should constitute the principal goal. In an attempt to overcome this problem we develop here the first multi-target (mt) approach for the virtual screening and rational in silico discovery of anti-CRC agents against ten cell lines. Here, two mt-QSAR classification models were constructed using a large and heterogeneous database of compounds. The first model was based on linear discriminant analysis (mt-QSAR-LDA) employing fragment-based descriptors while the second model was obtained using artificial neural networks (mt-QSAR-ANN) with global 2D descriptors. Both models correctly classified more than 90% of active and inactive compounds in training and prediction sets. Some fragments were extracted from the molecules and their contributions to anti-CRC activity were calculated using mt-QSAR-LDA model. Several fragments were identified as potential substructural features responsible for the anti-CRC activity and new molecules designed from those fragments with positive contributions were suggested and correctly predicted by the two models as possible potent and versatile anti-CRC agents. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. Design and development of novel azo prodrugs using various permutations and combinations of 5- and 4-aminosalicylic acids for inflammatory bowel disease: a colon-targeted approach.

    Science.gov (United States)

    Suneela, Dhaneshwar; Gaurav, Vadnerkar; Himanshu, Rai

    2013-10-01

    Novel carrier-linked azo prodrugs of 4 and 5-aminosalicylic acids (4-ASA and 5-ASA respectively) using the same drugs as carriers in different permutations and combinations were designed for targeting colon affected with inflammatory bowel disease (IBD). Improved hydrophilic nature of the prodrugs assisted in minimizing their absorption in upper GIT and efficient delivery of the active drugs to colon as evidenced from their stability in aqueous buffers (pH 1.2 and 7.4) and upper GIT homogenates with 68-91% release on incubation with rat cecal matter. Amongst the series, 4A4AAZ (prodrug of 4-ASA with 4-ASA) at a dose of 53 mg/Kg was found to be the most promising candidate as it substantially alleviated the quantifying markers of colonic inflammation in TNBS-induced experimental colitis in Wistar rats. Moreover it displayed significantly lower GI toxicity (at ten times higher dose). 5-ASA- induced pancreatitis and sulfapyridine-induced adverse effects on liver that are characteristic of sulfasalazine were not observed with 4A4AAZ. It could be explored further as a potential candidate for IBD patients intolerant to pancreatitis induced by oral administration of 5-ASA.

  4. Application of persuasion and health behavior theories for behavior change counseling: design of the ADAPT (Avoiding Diabetes Thru Action Plan Targeting) program.

    Science.gov (United States)

    Lin, Jenny J; Mann, Devin M

    2012-09-01

    Diabetes incidence is increasing worldwide and providers often do not feel they can effectively counsel about preventive lifestyle changes. The goal of this paper is to describe the development and initial feasibility testing of the Avoiding Diabetes Thru Action Plan Targeting (ADAPT) program to enhance counseling about behavior change for patients with pre-diabetes. Primary care providers and patients were interviewed about their perspectives on lifestyle changes to prevent diabetes. A multidisciplinary design team incorporated this data to translate elements from behavior change theories to create the ADAPT program. The ADAPT program was pilot tested to evaluate feasibility. Leveraging elements from health behavior theories and persuasion literature, the ADAPT program comprises a shared goal-setting module, implementation intentions exercise, and tailored reminders to encourage behavior change. Feasibility data demonstrate that patients were able to use the program to achieve their behavior change goals. Initial findings show that the ADAPT program is feasible for helping improve primary care providers' counseling for behavior change in patients with pre-diabetes. If successful, the ADAPT program may represent an adaptable and scalable behavior change tool for providers to encourage lifestyle changes to prevent diabetes. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  5. Design, characterization, and aerosol dispersion performance modeling of advanced spray-dried microparticulate/nanoparticulate mannitol powders for targeted pulmonary delivery as dry powder inhalers.

    Science.gov (United States)

    Li, Xiaojian; Vogt, Frederick G; Hayes, Don; Mansour, Heidi M

    2014-04-01

    The purpose was to design and characterize inhalable microparticulate/nanoparticulate dry powders of mannitol with essential particle properties for targeted dry powder delivery for cystic fibrosis mucolytic treatment by dilute organic solution spray drying, and, in addition, to tailor and correlate aerosol dispersion performance delivered as dry powder inhalers based on spray-drying conditions and solid-state physicochemical properties. Organic solution advanced spray drying from dilute solution followed by comprehensive solid-state physicochemical characterization and in vitro dry powder aerosolization were used. The particle size distribution of the spray-dried (SD) powders was narrow, unimodal, and in the range of ∼500 nm to 2.0 μm. The particles possessed spherical particle morphology, relatively smooth surface morphology, low water content and vapor sorption (crystallization occurred at exposure above 65% relative humidity), and retention of crystallinity by polymorphic interconversion. The emitted dose, fine particle fraction (FPF), and respirable fraction (RF) were all relatively high. The mass median aerodynamic diameters were below 4 μm for all SD mannitol aerosols. The in vitro aerosol deposition stage patterns could be tailored based on spray-drying pump rate. Positive linear correlation was observed between both FPF and RF values with spray-drying pump rates. The interplay between various spray-drying conditions, particle physicochemical properties, and aerosol dispersion performance was observed and examined, which enabled tailoring and modeling of high aerosol deposition patterns.

  6. Design, Characterization, and Aerosol Dispersion Performance Modeling of Advanced Spray-Dried Microparticulate/Nanoparticulate Mannitol Powders for Targeted Pulmonary Delivery as Dry Powder Inhalers

    Science.gov (United States)

    Li, Xiaojian; Vogt, Frederick G.; Hayes, Don

    2014-01-01

    Abstract Background: The purpose was to design and characterize inhalable microparticulate/nanoparticulate dry powders of mannitol with essential particle properties for targeted dry powder delivery for cystic fibrosis mucolytic treatment by dilute organic solution spray drying, and, in addition, to tailor and correlate aerosol dispersion performance delivered as dry powder inhalers based on spray-drying conditions and solid-state physicochemical properties. Methods: Organic solution advanced spray drying from dilute solution followed by comprehensive solid-state physicochemical characterization and in vitro dry powder aerosolization were used. Results: The particle size distribution of the spray-dried (SD) powders was narrow, unimodal, and in the range of ∼500 nm to 2.0 μm. The particles possessed spherical particle morphology, relatively smooth surface morphology, low water content and vapor sorption (crystallization occurred at exposure above 65% relative humidity), and retention of crystallinity by polymorphic interconversion. The emitted dose, fine particle fraction (FPF), and respirable fraction (RF) were all relatively high. The mass median aerodynamic diameters were below 4 μm for all SD mannitol aerosols. Conclusion: The in vitro aerosol deposition stage patterns could be tailored based on spray-drying pump rate. Positive linear correlation was observed between both FPF and RF values with spray-drying pump rates. The interplay between various spray-drying conditions, particle physicochemical properties, and aerosol dispersion performance was observed and examined, which enabled tailoring and modeling of high aerosol deposition patterns. PMID:24502451

  7. The auto-inhibitory state of Rho guanine nucleotide exchange factor ARHGEF5/TIM can be relieved by targeting its SH3 domain with rationally designed peptide aptamers.

    Science.gov (United States)

    He, Ping; Tan, De-Li; Liu, Hong-Xiang; Lv, Feng-Lin; Wu, Wei

    2015-04-01

    The short isoform of Rho guanine nucleotide exchange factor ARHGEF5 is known as TIM, which plays diverse roles in, for example, tumorigenesis, neuronal development and Src-induced podosome formation through the activation of its substrates, the Rho family of GTPases. The activation is auto-inhibited by a putative helix N-terminal to the DH domain of TIM, which is stabilized by the intramolecular interaction of C-terminal SH3 domain with a poly-proline sequence between the putative helix and the DH domain. In this study, we systematically investigated the structural basis, energetic landscape and biological implication underlying TIM auto-inhibition by using atomistic molecular dynamics simulations and binding free energy analysis. The computational study revealed that the binding of SH3 domain to poly-proline sequence is the prerequisite for the stabilization of TIM auto-inhibition. Thus, it is suggested that targeting SH3 domain with competitors of the poly-proline sequence would be a promising strategy to relieve the auto-inhibitory state of TIM. In this consideration, we rationally designed a number of peptide aptamers for competitively inhibiting the SH3 domain based on modeled TIM structure and computationally generated data. Peptide binding test and guanine nucleotide exchange analysis solidified that these designed peptides can both bind to the SH3 domain potently and activate TIM-catalyzed RhoA exchange reaction effectively. Interestingly, a positive correlation between the peptide affinity and induced exchange activity was observed. In addition, separate mutation of three conserved residues Pro49, Pro52 and Lys54 - they are required for peptide recognition by SH3 domain -- in a designed peptide to Ala would completely abolish the capability of this peptide activating TIM. All these come together to suggest an intrinsic relationship between peptide binding to SH3 domain and the activation of TIM. Copyright © 2015 Elsevier B.V. and Société Française de

  8. Target Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — [Part of the ATLAS user facility.] The Physics Division operates a target development laboratory that produces targets and foils of various thickness and substrates,...

  9. A family-based intervention targeting parents of preschool children with overweight and obesity: conceptual framework and study design of LOOPS- Lund overweight and obesity preschool study

    Directory of Open Access Journals (Sweden)

    Önnerfält Jenny

    2012-10-01

    Full Text Available Abstract Background As the rate of overweight among children is rising there is a need for evidence-based research that will clarify what the best interventional strategies to normalize weight development are. The overall aim of the Lund Overweight and Obesity Preschool Study (LOOPS is to evaluate if a family-based intervention, targeting parents of preschool children with overweight and obesity, has a long-term positive effect on weight development of the children. The hypothesis is that preschool children with overweight and obesity, whose parents participate in a one-year intervention, both at completion of the one-year intervention and at long term follow up (2-, 3- and 5-years will have reduced their BMI-for-age z-score. Methods/Design The study is a randomized controlled trial, including overweight (n=160 and obese (n=80 children 4-6-years-old. The intervention is targeting the parents, who get general information about nutrition and exercise recommendations through a website and are invited to participate in a group intervention with the purpose of supporting them to accomplish preferred lifestyle changes, both in the short and long term. To evaluate the effect of various supports, the parents are randomized to different interventions with the main focus of: 1 supporting the parents in limit setting by emphasizing the importance of positive interactions between parents and children and 2 influencing the patterns of daily activities to induce alterations of everyday life that will lead to healthier lifestyle. The primary outcome variable, child BMI-for-age z-score will be measured at referral, inclusion, after 6 months, at the end of intervention and at 2-, 3- and 5-years post intervention. Secondary outcome variables, measured at inclusion and at the end of intervention, are child activity pattern, eating habits and biochemical markers as well as parent BMI, exercise habits, perception of health, experience of parenthood and level of

  10. Patterns of failure after postoperative radiotherapy for incompletely resected (R1) non-small cell lung cancer: implications for radiation target volume design.

    Science.gov (United States)

    Olszyna-Serementa, Marta; Socha, Joanna; Wierzchowski, Marek; Kępka, Lucyna

    2013-05-01

    Overall survival (OS) and pattern of failure in R1-resected non-small cell lung cancer (NSCLC) patients treated with 3D-planned postoperative radiotherapy (PORT) was retrospectively evaluated. The outcomes and patterns of failure in patients with (+) and without (-) extracapsular nodal extension (ECE) were compared and analyzed with respect to the radiation target volume design. Eighty R1-resected (37 ECE+ and 43 ECE-) patients received PORT (60Gy, 2Gy daily) between 2002 and 2011. Patients with N2 disease received limited elective nodal irradiation (ENI); for pN0-1 disease the use of ENI was optional. Among ECE- (extranodal-R1) patients there were 35 pN0-1 and eight pN2 cases; in pN0-1 patients, patterns of failure and outcomes were analyzed with respect to the use of ENI. Loco-regional failure (LRF) was defined as in-field relapse; isolated nodal failure (INF) was defined as out-of-field regional nodal recurrence occurring without LRF, irrespective of distant metastases. The actuarial 3-year OS rate was 36.3% (median: 30 months). Three-year OS rates in the ECE- and ECE+ group were 40.4% and 31.4%, with median OS of 31 and 24 months, respectively (p=0.43). In multivariate analysis, the presence of ECE was correlated with OS (HR=3.02; 95% CI: 1.00-9.16; p=0.05). Three-year cumulative incidence of LRF (CILRF) was 14.5% and 15.5% in the ECE- and ECE+ groups, respectively (p=0.98). Three-year cumulative incidence of INF (CIINF) was 14.1% in the ECE- group and 11.1% in the ECE+ group (p=0.76). For pN0-1 patients treated with and without ENI (13 and 22 patients) 3-year CILRF rates were 7.7% and 20.8%, respectively (p=0.20); 3-year CIINF rates were 9.1% and 16.3%, respectively (p=0.65). PORT resulted in a relatively good survival of R1-resected NSCLC patients. Relatively high incidence of INF was found in both ECE+ and ECE- patients. For ECE+ patients, treated with limited ENI, distant failure remains a major concern, so the design of ENI fields seems of lesser

  11. Design, synthesis and evaluation in an LPS rodent model of neuroinflammation of a novel (18)F-labelled PET tracer targeting P2X7.

    Science.gov (United States)

    Fantoni, Enrico Raffaele; Dal Ben, Diego; Falzoni, Simonetta; Di Virgilio, Francesco; Lovestone, Simon; Gee, Antony

    2017-12-01

    The P2X7 receptor has been shown to play a fundamental role in the initiation and sustenance of the inflammatory cascade. The development of a novel fluorine-18 PET tracer superior and with a longer half-life to those currently available is a promising step towards harnessing the therapeutic and diagnostic potential offered by this target. Inspired by the known antagonist A-804598, the present study outlines the design via molecular docking, synthesis and biological evaluation of the novel P2X7 tracer [(18)F]EFB. The tracer was radiolabelled via a three-step procedure, in vitro binding assessed in P2X7-transfected HEK293 and in B16 cells by calcium influx assays and an initial preclinical evaluation was performed in a lipopolysaccharide (LPS)-injected rat model of neuroinflammation. The novel tracer [(18)F]EFB was synthesised in 210 min in 3-5% decay-corrected radiochemical yield (DC RCY), >99% radiochemical purity (RCP) and >300 GBq/μmol and fully characterised. Functional assays showed that the compound binds with nM K i to human, rat and mouse P2X7 receptors. In vivo, [(18)F]EFB displayed a desirable distribution profile, and while it showed low blood-brain barrier penetration, brain uptake was quantifiable and displayed significantly higher mean longitudinal uptake in inflamed versus control rat CNS regions. [(18)F]EFB demonstrates strong in vitro affinity to human and rodent P2X7 and limited yet quantifiable BBB penetration. Considering the initial promising in vivo data in an LPS rat model with elevated P2X7 expression, this work constitutes an important step in the development of a radiotracer useful for the diagnosis and monitoring of clinical disorders with associated neuroinflammatory processes.

  12. Harnessing mechanistic knowledge on beneficial versus deleterious IFN-I effects to design innovative immunotherapies targeting cytokine activity to specific cell types

    Directory of Open Access Journals (Sweden)

    Marc eDALOD

    2014-10-01

    Full Text Available Type I interferons (IFN-I were identified over 50 years ago as cytokines critical for host defense against viral infections. IFN-I promote antiviral defense through two main mechanisms. First, IFN-I directly reinforce or induce de novo in potentially all cells the expression of effector molecules of intrinsic antiviral immunity. Second, IFN-I orchestrate innate and adaptive antiviral immunity. However, IFN-I responses can be deleterious for the host in a number of circumstances, including secondary bacterial or fungal infections, several autoimmune diseases, and, paradoxically, certain chronic viral infections. We will review the proposed nature of protective versus deleterious IFN-I responses in selected diseases. Emphasis will be put on the potentially deleterious functions of IFN-I in human immunodeficiency virus type 1 (HIV-1 infection, and on the respective roles of IFN-I and IFN-III in promoting resolution of hepatitis C virus (HCV infection. We will then discuss how the balance between beneficial versus deleterious IFN-I responses is modulated by several key parameters including i the subtypes and dose of IFN-I produced, ii the cell types affected by IFN-I and iii the source and timing of IFN-I production. Finally we will speculate how integration of this knowledge combined with advanced biochemical manipulation of the activity of the cytokines should allow designing innovative immunotherapeutic treatments in patients. Specifically, we will discuss how induction or blockade of specific IFN-I responses in targeted cell types could promote the beneficial functions of IFN-I and/or dampen their deleterious effects, in a manner adapted to each disease.

  13. Investigation of the mycobacterial enzyme HsaD as a potential novel target for anti-tubercular agents using a fragment-based drug design approach.

    Science.gov (United States)

    Ryan, Ali; Polycarpou, Elena; Lack, Nathan A; Evangelopoulos, Dimitrios; Sieg, Christian; Halman, Alice; Bhakta, Sanjib; Eleftheriadou, Olga; McHugh, Timothy D; Keany, Sebastian; Lowe, Edward D; Ballet, Romain; Abuhammad, Areej; Jacobs, William R; Ciulli, Alessio; Sim, Edith

    2017-07-01

    With the emergence of extensively drug-resistant tuberculosis, there is a need for new anti-tubercular drugs that work through novel mechanisms of action. The meta cleavage product hydrolase, HsaD, has been demonstrated to be critical for the survival of Mycobacterium tuberculosis in macrophages and is encoded in an operon involved in cholesterol catabolis