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Sample records for efficiency release targets

  1. 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...

  2. Relationship among reaction rate, release rate and efficiency of nanomachine-based targeted drug delivery.

    Science.gov (United States)

    Zhao, Qingying; Li, Min; Luo, Jun

    2017-12-04

    In nanomachine applications towards targeted drug delivery, drug molecules released by nanomachines propagate and chemically react with tumor cells in aqueous environment. If the nanomachines release drug molecules faster than the tumor cells react, it will result in loss and waste of drug molecules. It is a potential issue associated with the relationship among reaction rate, release rate and efficiency. This paper aims to investigate the relationship among reaction rate, release rate and efficiency based on two drug reception models. We expect to pave a way for designing a control method of drug release. We adopted two analytical methods that one is drug reception process based on collision with tumors and another is based on Michaelis Menten enzymatic kinetics. To evaluate the analytical formulations, we used the well-known simulation framework N3Sim to establish simulations. The analytical results of the relationship among reaction rate, release rate and efficiency is obtained, which match well with the numerical simulation results in a 3-D environment. Based upon two drug reception models, the results of this paper would be beneficial for designing a control method of nanomahine-based drug release.

  3. 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).

  4. Influence of target thickness on the release of radioactive atoms

    Energy Technology Data Exchange (ETDEWEB)

    Guillot, Julien, E-mail: guillotjulien@ipno.in2p3.fr [Institut de Physique Nucléaire CNRS/IN2P3 UMR 8608 – Université Paris Sud – Université Paris Saclay, F-91406 Orsay Cedex (France); Roussière, Brigitte [Institut de Physique Nucléaire CNRS/IN2P3 UMR 8608 – Université Paris Sud – Université Paris Saclay, F-91406 Orsay Cedex (France); Tusseau-Nenez, Sandrine [Physique de la Matière Condensée Ecole Polytechnique/CNRS UMR 7643 – Université Paris Saclay, F-91128 Palaiseau Cedex (France); Barré-Boscher, Nicole; Borg, Elie; Martin, Julien [Institut de Physique Nucléaire CNRS/IN2P3 UMR 8608 – Université Paris Sud – Université Paris Saclay, F-91406 Orsay Cedex (France)

    2017-03-01

    Nowadays, intense exotic beams are needed in order to study nuclei with very short half-life. To increase the release efficiency of the fission products, all the target characteristics involved must be improved (e.g. chemical composition, dimensions, physicochemical properties such as grain size, porosity, density…). In this article, we study the impact of the target thickness. Released fractions measured from graphite and uranium carbide pellets are presented as well as Monte-Carlo simulations of the Brownian motion.

  5. China's energy efficiency target 2010

    International Nuclear Information System (INIS)

    Yang Ming

    2008-01-01

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

  6. Optimization of ISOL targets based on Monte-Carlo simulations of ion release curves

    International Nuclear Information System (INIS)

    Mustapha, B.; Nolen, J.A.

    2003-01-01

    A detailed model for simulating release curves from ISOL targets has been developed. The full 3D geometry is implemented using Geant-4. Produced particles are followed individually from production to release. The delay time is computed event by event. All processes involved: diffusion, effusion and decay are included to obtain the overall release curve. By fitting to the experimental data, important parameters of the release process (diffusion coefficient, sticking time, ...) are extracted. They can be used to improve the efficiency of existing targets and design new ones more suitable to produce beams of rare isotopes

  7. Optimization of ISOL targets based on Monte-Carlo simulations of ion release curves

    CERN Document Server

    Mustapha, B

    2003-01-01

    A detailed model for simulating release curves from ISOL targets has been developed. The full 3D geometry is implemented using Geant-4. Produced particles are followed individually from production to release. The delay time is computed event by event. All processes involved: diffusion, effusion and decay are included to obtain the overall release curve. By fitting to the experimental data, important parameters of the release process (diffusion coefficient, sticking time, ...) are extracted. They can be used to improve the efficiency of existing targets and design new ones more suitable to produce beams of rare isotopes.

  8. Release properties of UC sub x and molten U targets

    CERN Document Server

    Roussière, B; Sauvage, J; Bajeat, O; Barre, N; Clapier, F; Cottereau, E; Donzaud, C; Ducourtieux, M; Essabaa, S; Guillemaud-Müller, D; Lau, C; Lefort, H; Liang, C F; Le Blanc, F; Müller, A C; Obert, J; Pauwels, N; Potier, J C; Pougheon, F; Proust, J; Sorlin, O; Verney, D; Wojtasiewicz, A

    2002-01-01

    The release properties of UC sub x and molten U thick targets associated with a Nier-Bernas ion source have been studied. Two experimental methods are used to extract the release time. Results are presented and discussed for Kr, Cd, I and Xe.

  9. Efficient reconstruction of contaminant release history

    Energy Technology Data Exchange (ETDEWEB)

    Alezander, Francis [Los Alamos National Laboratory; Anghel, Marian [Los Alamos National Laboratory; Gulbahce, Natali [NON LANL; Tartakovsky, Daniel [NON LANL

    2009-01-01

    We present a generalized hybrid Monte Carlo (GHMC) method for fast, statistically optimal reconstruction of release histories of reactive contaminants. The approach is applicable to large-scale, strongly nonlinear systems with parametric uncertainties and data corrupted by measurement errors. The use of discrete adjoint equations facilitates numerical implementation of GHMC, without putting any restrictions on the degree of nonlinearity of advection-dispersion-reaction equations that are used to described contaminant transport in the subsurface. To demonstrate the salient features of the proposed algorithm, we identify the spatial extent of a distributed source of contamination from concentration measurements of a reactive solute.

  10. Environmental release targets for fusion power plants

    International Nuclear Information System (INIS)

    Gulden, W.; Raskob, W.

    2005-01-01

    Within the European fission community, so called European Utility Requirements were developed to define common targets, criteria and evaluation methods for, amongst others, safety, environmental protection and public health with respect to future nuclear fission power plant development. In the case of severe accidents, the objective is to restrict the radiological consequences to the vicinity of the plant, i.e., to avoid early and late countermeasures such as evacuation or relocation of the population, and to restrict food banning to small areas and the first year after the accident. Within the European Fusion Technology Programme, a methodology is being developed in compliance with these European Utility Requirements, to define design requirements for future fusion reactors. First results are presented. Concerning food banning, calculations revealed extremely conservative values for tritium in EU regulations and recommendations. This does not affect assessments for fission reactors, but is an overestimation of the tritium dose impact from ingestion. Therefore, in compliance with scientific justification, considerably higher maximum permissible activity levels for tritium should be considered

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

    International Nuclear Information System (INIS)

    Alton, G.D.

    1993-01-01

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

  12. Building an Efficient Model for Afterburn Energy Release

    Energy Technology Data Exchange (ETDEWEB)

    Alves, S; Kuhl, A; Najjar, F; Tringe, J; McMichael, L; Glascoe, L

    2012-02-03

    Many explosives will release additional energy after detonation as the detonation products mix with the ambient environment. This additional energy release, referred to as afterburn, is due to combustion of undetonated fuel with ambient oxygen. While the detonation energy release occurs on a time scale of microseconds, the afterburn energy release occurs on a time scale of milliseconds with a potentially varying energy release rate depending upon the local temperature and pressure. This afterburn energy release is not accounted for in typical equations of state, such as the Jones-Wilkins-Lee (JWL) model, used for modeling the detonation of explosives. Here we construct a straightforward and efficient approach, based on experiments and theory, to account for this additional energy release in a way that is tractable for large finite element fluid-structure problems. Barometric calorimeter experiments have been executed in both nitrogen and air environments to investigate the characteristics of afterburn for C-4 and other materials. These tests, which provide pressure time histories, along with theoretical and analytical solutions provide an engineering basis for modeling afterburn with numerical hydrocodes. It is toward this end that we have constructed a modified JWL equation of state to account for afterburn effects on the response of structures to blast. The modified equation of state includes a two phase afterburn energy release to represent variations in the energy release rate and an afterburn energy cutoff to account for partial reaction of the undetonated fuel.

  13. Encapsulation of methotrexate loaded magnetic microcapsules for magnetic drug targeting and controlled drug release

    Energy Technology Data Exchange (ETDEWEB)

    Chakkarapani, Prabu [Department of Pharmaceutical Technology & Centre for Excellence in Nanobio Translational Research, Anna University, Bharathidasan Institute of Technology Campus, Tiruchirappalli 620024, Tamil Nadu (India); Subbiah, Latha, E-mail: lathasuba2010@gmail.com [Department of Pharmaceutical Technology & Centre for Excellence in Nanobio Translational Research, Anna University, Bharathidasan Institute of Technology Campus, Tiruchirappalli 620024, Tamil Nadu (India); Palanisamy, Selvamani; Bibiana, Arputha [Department of Pharmaceutical Technology & Centre for Excellence in Nanobio Translational Research, Anna University, Bharathidasan Institute of Technology Campus, Tiruchirappalli 620024, Tamil Nadu (India); Ahrentorp, Fredrik; Jonasson, Christian; Johansson, Christer [Acreo Swedish ICT AB, Arvid Hedvalls backe 4, SE-411 33 Göteborg (Sweden)

    2015-04-15

    We report on the development and evaluation of methotrexate magnetic microcapsules (MMC) for targeted rheumatoid arthritis therapy. Methotrexate was loaded into CaCO{sub 3}-PSS (poly (sodium 4-styrenesulfonate)) doped microparticles that were coated successively with poly (allylamine hydrochloride) and poly (sodium 4-styrenesulfonate) by layer-by-layer technique. Ferrofluid was incorporated between the polyelectrolyte layers. CaCO{sub 3}-PSS core was etched by incubation with EDTA yielding spherical MMC. The MMC were evaluated for various physicochemical, pharmaceutical parameters and magnetic properties. Surface morphology, crystallinity, particle size, zeta potential, encapsulation efficiency, loading capacity, drug release pattern, release kinetics and AC susceptibility studies revealed spherical particles of ~3 µm size were obtained with a net zeta potential of +24.5 mV, 56% encapsulation and 18.6% drug loading capacity, 96% of cumulative drug release obeyed Hixson-Crowell model release kinetics. Drug excipient interaction, surface area, thermal and storage stability studies for the prepared MMC was also evaluated. The developed MMC offer a promising mode of targeted and sustained release drug delivery for rheumatoid arthritis therapy. - Highlights: • Development of methotrexate magnetic microcapsules (MMC) by layer-by-layer method. • Characterization of physicochemical, pharmaceutical and magnetic properties of MMC. • Multiple layers of alternative polyelectrolytes prolongs methotrexate release time. • MMC is capable for targeted and sustained release rheumatoid arthritis therapy.

  14. High efficiency diffusion molecular retention tumor targeting.

    Directory of Open Access Journals (Sweden)

    Yanyan Guo

    Full Text Available Here we introduce diffusion molecular retention (DMR tumor targeting, a technique that employs PEG-fluorochrome shielded probes that, after a peritumoral (PT injection, undergo slow vascular uptake and extensive interstitial diffusion, with tumor retention only through integrin molecular recognition. To demonstrate DMR, RGD (integrin binding and RAD (control probes were synthesized bearing DOTA (for (111 In(3+, a NIR fluorochrome, and 5 kDa PEG that endows probes with a protein-like volume of 25 kDa and decreases non-specific interactions. With a GFP-BT-20 breast carcinoma model, tumor targeting by the DMR or i.v. methods was assessed by surface fluorescence, biodistribution of [(111In] RGD and [(111In] RAD probes, and whole animal SPECT. After a PT injection, both probes rapidly diffused through the normal and tumor interstitium, with retention of the RGD probe due to integrin interactions. With PT injection and the [(111In] RGD probe, SPECT indicated a highly tumor specific uptake at 24 h post injection, with 352%ID/g tumor obtained by DMR (vs 4.14%ID/g by i.v.. The high efficiency molecular targeting of DMR employed low probe doses (e.g. 25 ng as RGD peptide, which minimizes toxicity risks and facilitates clinical translation. DMR applications include the delivery of fluorochromes for intraoperative tumor margin delineation, the delivery of radioisotopes (e.g. toxic, short range alpha emitters for radiotherapy, or the delivery of photosensitizers to tumors accessible to light.

  15. Highly Efficient Thermoresponsive Nanocomposite for Controlled Release Applications

    KAUST Repository

    Yassine, Omar

    2016-06-23

    Highly efficient magnetic release from nanocomposite microparticles is shown, which are made of Poly (N-isopropylacrylamide) hydrogel with embedded iron nanowires. A simple microfluidic technique was adopted to fabricate the microparticles with a high control of the nanowire concentration and in a relatively short time compared to chemical synthesis methods. The thermoresponsive microparticles were used for the remotely triggered release of Rhodamine (B). With a magnetic field of only 1 mT and 20 kHz a drug release of 6.5% and 70% was achieved in the continuous and pulsatile modes, respectively. Those release values are similar to the ones commonly obtained using superparamagnetic beads but accomplished with a magnetic field of five orders of magnitude lower power. The high efficiency is a result of the high remanent magnetization of the nanowires, which produce a large torque when exposed to a magnetic field. This causes the nanowires to vibrate, resulting in friction losses and heating. For comparison, microparticles with superparamagnetic beads were also fabricated and tested; while those worked at 73 mT and 600 kHz, no release was observed at the low field conditions. Cytotoxicity assays showed similar and high cell viability for microparticles with nanowires and beads.

  16. Highly Efficient Thermoresponsive Nanocomposite for Controlled Release Applications

    KAUST Repository

    Yassine, Omar; Zaher, Amir; Li, Erqiang; Alfadhel, Ahmed; Perez, Jose E.; Kavaldzhiev, Mincho; Contreras, Maria F.; Thoroddsen, Sigurdur T; Khashab, Niveen M.; Kosel, Jü rgen

    2016-01-01

    Highly efficient magnetic release from nanocomposite microparticles is shown, which are made of Poly (N-isopropylacrylamide) hydrogel with embedded iron nanowires. A simple microfluidic technique was adopted to fabricate the microparticles with a high control of the nanowire concentration and in a relatively short time compared to chemical synthesis methods. The thermoresponsive microparticles were used for the remotely triggered release of Rhodamine (B). With a magnetic field of only 1 mT and 20 kHz a drug release of 6.5% and 70% was achieved in the continuous and pulsatile modes, respectively. Those release values are similar to the ones commonly obtained using superparamagnetic beads but accomplished with a magnetic field of five orders of magnitude lower power. The high efficiency is a result of the high remanent magnetization of the nanowires, which produce a large torque when exposed to a magnetic field. This causes the nanowires to vibrate, resulting in friction losses and heating. For comparison, microparticles with superparamagnetic beads were also fabricated and tested; while those worked at 73 mT and 600 kHz, no release was observed at the low field conditions. Cytotoxicity assays showed similar and high cell viability for microparticles with nanowires and beads.

  17. Spatial Release from Masking with a Moving Target

    Directory of Open Access Journals (Sweden)

    M. Torben Pastore

    2017-12-01

    Full Text Available In the visual domain, a stationary object that is difficult to detect usually becomes far more salient if it moves while the objects around it do not. This “pop out” effect is important for parsing the visual world into figure/ground relationships that allow creatures to detect food, threats, etc. We tested for an auditory correlate to this visual effect by asking listeners to identify a single word, spoken by a female, embedded with two or four masking words spoken by males. Percentage correct scores were analyzed and compared between conditions where target and maskers were presented from the same position vs. when the target was presented from one position while maskers were presented from different positions. In some trials, the target word was moved across the speaker array using amplitude panning, while in other trials that target was played from a single, static position. Results showed a spatial release from masking for all conditions where the target and maskers were not located at the same position, but there was no statistically significant difference between identification performance when the target was moving vs. when it was stationary. These results suggest that, at least for short stimulus durations (0.75 s for the stimuli in this experiment, there is unlikely to be a “pop out” effect for moving target stimuli in the auditory domain as there is in the visual domain.

  18. Advances in Targeted Pesticides with Environmentally Responsive Controlled Release by Nanotechnology

    Directory of Open Access Journals (Sweden)

    Bingna Huang

    2018-02-01

    Full Text Available Pesticides are the basis for defending against major biological disasters and important for ensuring national food security. Biocompatible, biodegradable, intelligent, and responsive materials are currently an emerging area of interest in the field of efficient, safe, and green pesticide formulation. Using nanotechnology to design and prepare targeted pesticides with environmentally responsive controlled release via compound and chemical modifications has also shown great potential in creating novel formulations. In this review, special attention has been paid to intelligent pesticides with precise controlled release modes that can respond to micro-ecological environment changes such as light-sensitivity, thermo-sensitivity, humidity sensitivity, soil pH, and enzyme activity. Moreover, establishing intelligent and controlled pesticide release technologies using nanomaterials are reported. These technologies could increase pesticide-loading, improve the dispersibility and stability of active ingredients, and promote target ability.

  19. Efficient cellular release of Rift Valley fever virus requires genomic RNA.

    Directory of Open Access Journals (Sweden)

    Mary E Piper

    2011-03-01

    Full Text Available The Rift Valley fever virus is responsible for periodic, explosive epizootics throughout sub-Saharan Africa. The development of therapeutics targeting this virus is difficult due to a limited understanding of the viral replicative cycle. Utilizing a virus-like particle system, we have established roles for each of the viral structural components in assembly, release, and virus infectivity. The envelope glycoprotein, Gn, was discovered to be necessary and sufficient for packaging of the genome, nucleocapsid protein and the RNA-dependent RNA polymerase into virus particles. Additionally, packaging of the genome was found to be necessary for the efficient release of particles, revealing a novel mechanism for the efficient generation of infectious virus. Our results identify possible conserved targets for development of anti-phlebovirus therapies.

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

    African Journals Online (AJOL)

    Erah

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

  1. Target Improves Efficiency in New Construction

    Energy Technology Data Exchange (ETDEWEB)

    None

    2013-03-01

    Target Corporation partnered with the U.S. Department of Energy (DOE) to develop and implement solutions to reduce annual energy consumption in new stores by at least 50% versus requirements set by ASHRAE/ANSI/IESNA Standard 90.1-20041 as part of DOE’s Commercial Building Partnership (CBP) program.

  2. An efficient targeted drug delivery through apotransferrin loaded nanoparticles.

    Directory of Open Access Journals (Sweden)

    Athuluri Divakar Sai Krishna

    Full Text Available BACKGROUND: Cancerous state is a highly stimulated environment of metabolically active cells. The cells under these conditions over express selective receptors for assimilation of factors essential for growth and transformation. Such receptors would serve as potential targets for the specific ligand mediated transport of pharmaceutically active molecules. The present study demonstrates the specificity and efficacy of protein nanoparticle of apotransferrin for targeted delivery of doxorubicin. METHODOLOGY/PRINCIPAL FINDINGS: Apotransferrin nanoparticles were developed by sol-oil chemistry. A comparative analysis of efficiency of drug delivery in conjugated and non-conjugated forms of doxorubicin to apotransferrin nanoparticle is presented. The spherical shaped apotransferrin nanoparticles (nano have diameters of 25-50 etam, which increase to 60-80 etam upon direct loading of drug (direct-nano, and showed further increase in dimension (75-95 etam in conjugated nanoparticles (conj-nano. The competitive experiments with the transferrin receptor specific antibody showed the entry of both conj-nano and direct-nano into the cells through transferrin receptor mediated endocytosis. Results of various studies conducted clearly establish the superiority of the direct-nano over conj-nano viz. (a localization studies showed complete release of drug very early, even as early as 30 min after treatment, with the drug localizing in the target organelle (nucleus (b pharmacokinetic studies showed enhanced drug concentrations, in circulation with sustainable half-life (c the studies also demonstrated efficient drug delivery, and an enhanced inhibition of proliferation in cancer cells. Tissue distribution analysis showed intravenous administration of direct nano lead to higher drug localization in liver, and blood as compared to relatively lesser localization in heart, kidney and spleen. Experiments using rat cancer model confirmed the efficacy of the formulation in

  3. In situ targeted activation of an anticancer agent using ultrasound-triggered release of composite droplets.

    Science.gov (United States)

    Bezagu, Marine; Clarhaut, Jonathan; Renoux, Brigitte; Monti, Fabrice; Tanter, Mickael; Tabeling, Patrick; Cossy, Janine; Couture, Olivier; Papot, Sebastien; Arseniyadis, Stellios

    2017-12-15

    The efficiency of a drug is usually highly dependent on the way it is administered or delivered. As such, targeted-therapy, which requires conceiving drug-delivery vehicles that will change their state from a relatively stable structure with a very slow leak-rate to an unstable structure with a fast release, clearly improves the pharmacokinetics, the absorption, the distribution, the metabolism and the therapeutic index of a given drug. In this context, we have developed a particularly effective double stimuli-responsive drug-delivery method allowing an ultrasound-induced release of a monomethylauristatin E-glucuronide prodrug and its subsequent activation by a β-glucuronidase. This led to an increase of cytotoxicity of about 80% on cancer cells. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

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

    Energy Technology Data Exchange (ETDEWEB)

    Sugai, I; Takaku, S; Hasegawa, T [Tokyo Univ., Tanashi (Japan). Inst. for Nuclear Study

    1978-06-01

    Several kinds of materials were examined for the usefulness as releasing agents in the preparation of various thin self-supporting target films for use in nuclear reaction experiments. NaCl, BaCl/sub 2/, KCl, CsI, Teepol, glucose, KIO/sub 3/, mica, nitrocellulose of Formvar was deposited onto glass plates as the release agent by vacuum evaporation or dipping method. The obtained target film was tested on impurities from the release agent by using nuclear reactions. The relative effectiveness of each release agent was also considered from ease in the stripping of target films.

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

    International Nuclear Information System (INIS)

    Sugai, Isao; Takaku, Seisaku; Hasegawa, Takeo

    1978-01-01

    Several kinds of materials were examined for the usefulness as releasing agents in the preparation of various thin self-supporting target films for use in nuclear reaction experiments. NaCl, BaCl 2 , KCl, CsI, Teepol, glucose, KIO 3 , mica, nitrocellulose of Formvar was deposited onto glass plates as the release agent by vacuum evaporation or dipping method. The obtained target film was tested on impurities from the release agent by using nuclear reactions. The relative effectiveness of each release agent was also considered from ease in the stripping of target films. (auth.)

  6. Efficient payload delivery by a bispecific antibody-drug conjugate targeting HER2 and CD63

    DEFF Research Database (Denmark)

    de Goeij, Bart E.C.G.; Vink, Tom; Ten Napel, Hendrik

    2016-01-01

    Antibody-drug conjugates (ADC) are designed to be stable in circulation and to release potent cytotoxic drugs intracellularly following antigen-specific binding, uptake, and degradation in tumor cells. Efficient internalization and routing to lysosomes where proteolysis can take place is therefore......, for the first time, that intracellular trafficking of ADCs can be improved using a bsAb approach that targets the lysosomal membrane protein CD63 and provide a rationale for the development of novel bsADCs that combine tumor-specific targeting with targeting of rapidly internalizing antigens. © 2016 American...

  7. Biodegradable Drug-Loaded Hydroxyapatite Nanotherapeutic Agent for Targeted Drug Release in Tumors.

    Science.gov (United States)

    Sun, Wen; Fan, Jiangli; Wang, Suzhen; Kang, Yao; Du, Jianjun; Peng, Xiaojun

    2018-03-07

    Tumor-targeted drug delivery systems have been increasingly used to improve the therapeutic efficiency of anticancer drugs and reduce their toxic side effects in vivo. Focused on this point, doxorubicin (DOX)-loaded hydroxyapatite (HAP) nanorods consisting of folic acid (FA) modification (DOX@HAP-FA) were developed for efficient antitumor treatment. The DOX-loaded nanorods were synthesized through in situ coprecipitation and hydrothermal method with a DOX template, demonstrating a new procedure for drug loading in HAP materials. DOX could be efficiently released from DOX@HAP-FA within 24 h in weakly acidic buffer solution (pH = 6.0) because of the degradation of HAP nanorods. With endocytosis under the mediation of folate receptors, the nanorods exhibited enhanced cellular uptake and further degraded, and consequently, the proliferation of targeted cells was inhibited. More importantly, in a tumor-bearing mouse model, DOX@HAP-FA treatment demonstrated excellent tumor growth inhibition. In addition, no apparent side effects were observed during the treatment. These results suggested that DOX@HAP-FA may be a promising nanotherapeutic agent for effective cancer treatment in vivo.

  8. Rhamnogalacturonan-I based microcapsules for targeted drug release

    DEFF Research Database (Denmark)

    Svagan, Anna J.; Kusic, Anja; De Gobba, Cristian

    2016-01-01

    Drug targeting to the colon via the oral administration route for local treatment of e.g. inflammatory bowel disease and colonic cancer has several advantages such as needle-free administration and low infection risk. A new source for delivery is plant-polysaccharide based delivery platforms...... such as Rhamnogalacturonan-I (RG-I). In the gastro-intestinal tract the RG-I is only degraded by the action of the colonic microflora. For assessment of potential drug delivery properties, RG-I based microcapsules (~1 μm in diameter) were prepared by an interfacial poly-addition reaction. The cross-linked capsules were...

  9. Mechanical efficiency of the energy release during a steam explosion

    International Nuclear Information System (INIS)

    Krieg, R.

    1997-01-01

    The mechanical processes during the expansion phase of a steam explosion with intimately fragmented liquid particles is investigated based on elementary principles and analytical solutions. During a short load pulse, the different densities of the water and the melted particles lead to different velocities. After the load pulse, viscosity effects lead to a slow down of the higher velocities and to a corresponding reconversion of the kinetic energy of the mixture into thermal energy. It is shown that both effects are proportional to each other. The ratio between the residual and the applied mechanical energy is defined as the mechanical efficiency of the steam explosion. Using data typical for a steam explosion in a pressurized water reactor, mechanical efficiencies of <50% are estimated. Considering that the thermodynamic efficiencies are quite limited, the very low conversion rates from thermal energy into mechanical energy observed during steam explosion experiments can be more easily understood

  10. Analytical model for release calculations in solid thin-foils ISOL targets

    Energy Technology Data Exchange (ETDEWEB)

    Egoriti, L. [Belgian Nuclear Research Centre (SCK-CEN), Boeretang 200, B-2400 Mol (Belgium); Politecnico di Milano, Department of Energy, CeSNEF-Nuclear Engineering Division, Via Ponzio, 34/3, 20133 Milano (Italy); Boeckx, S. [Belgian Nuclear Research Centre (SCK-CEN), Boeretang 200, B-2400 Mol (Belgium); ICTEAM Inst., Univ. Catholique de Louvain, Louvain-la-Neuve (Belgium); Ghys, L. [Belgian Nuclear Research Centre (SCK-CEN), Boeretang 200, B-2400 Mol (Belgium); Houngbo, D., E-mail: donald.houngbo@sckcen.be [Belgian Nuclear Research Centre (SCK-CEN), Boeretang 200, B-2400 Mol (Belgium); Department of Flow, Heat and Combustion Mechanics, Gent University (UGent), St.-Pietersnieuwstraat 41, B-9000 Gent (Belgium); Popescu, L. [Belgian Nuclear Research Centre (SCK-CEN), Boeretang 200, B-2400 Mol (Belgium)

    2016-10-01

    A detailed analytical model has been developed to simulate isotope-release curves from thin-foils ISOL targets. It involves the separate modeling of diffusion and effusion inside the target. The former has been modeled using both first and second Fick's law. The latter, effusion from the surface of the target material to the end of the ionizer, was simulated with the Monte Carlo code MolFlow+. The calculated delay-time distribution for this process was then fitted using a double-exponential function. The release curve obtained from the convolution of diffusion and effusion shows good agreement with experimental data from two different target geometries used at ISOLDE. Moreover, the experimental yields are well reproduced when combining the release fraction with calculated in-target production.

  11. Multifunctional halloysite nanotubes for targeted delivery and controlled release of doxorubicin in-vitro and in-vivo studies

    Science.gov (United States)

    Hu, Yuwei; Chen, Jian; Li, Xiufang; Sun, Yanhua; Huang, Shen; Li, Yuqing; Liu, Hui; Xu, Jiangfeng; Zhong, Shian

    2017-09-01

    The current state of cancer therapy encourages researchers to develop novel efficient nanocarriers. Halloysite nanotubes (HNTs) are good nanocarrier candidates due to their unique nanoscale (40-80 nm in diamter and 200-500 nm in length) and hollow lumen, as well as good biocompatibility and low cost. In our study, we prepared a type of folate-mediated targeting and redox-triggered anticancer drug delivery system, so that Doxorubicin (DOX) can be specifically transported to tumor sites due to the over-expressed folate-receptors on the surface of cancer cells. Furthermore, it can then be released by the reductive agent glutathione (GSH) in cancer cells where the content of GSH is nearly 103-fold higher than in the extracellular matrix. A series of methods have demonstrated that per-thiol-β-cyclodextrin (β-CD-(SH)7) was successfully combined with HNTs via a redox-responsive disulfide bond, and folic acid-polyethylene glycol-adamantane (FA-PEG-Ad) was immobilized on the HNTs through the strong complexation between β-CD/Ad. In vitro studies indicated that the release rate of DOX raised sharply in dithiothreitol (DTT) reducing environment and the amount of released DOX reached 70% in 10 mM DTT within the first 10 h, while only 40% of DOX was released in phosphate buffer solution (PBS) even after 79 h. Furthermore, the targeted HNTs could be specifically endocytosed by over-expressed folate-receptor cancer cells and significantly accelerate the apoptosis of cancer cells compared to non-targeted HNTs. In vivo studies further verified that the targeted HNTs had the best therapeutic efficacy and no obvious side effects for tumor-bearing nude mice, while free DOX showed damaging effects on normal tissues. In summary, this novel nanocarrier system shows excellent potential for targeted delivery and controlled release of anticancer drugs and provides a potential platform for tumor therapy.

  12. Layer-by-layer assembled magnetic prednisolone microcapsules (MPC) for controlled and targeted drug release at rheumatoid arthritic joints

    Energy Technology Data Exchange (ETDEWEB)

    Prabu, Chakkarapani [Department of Pharmaceutical Technology & Centre for Excellence in Nanobio Translational Research, Anna University, Bharathidasan Institute of Technology Campus, Tiruchirappalli, Tamil Nadu (India); Latha, Subbiah, E-mail: lathasuba2010@gmail.com [Department of Pharmaceutical Technology & Centre for Excellence in Nanobio Translational Research, Anna University, Bharathidasan Institute of Technology Campus, Tiruchirappalli, Tamil Nadu (India); Selvamani, Palanisamy [Department of Pharmaceutical Technology & Centre for Excellence in Nanobio Translational Research, Anna University, Bharathidasan Institute of Technology Campus, Tiruchirappalli, Tamil Nadu (India); Ahrentorp, Fredrik; Johansson, Christer [Acreo Swedish ICT AB, Arvid Hedvalls Backe 4, Göteborg (Sweden); Takeda, Ryoji; Takemura, Yasushi [Electrical & Computer Engineering & Faculty of Engineering Division of Intelligent Systems Engineering, Yokohama National University (Japan); Ota, Satoshi [Department of Electrical and Electronic Engineering, Shizuoka University (Japan)

    2017-04-01

    We report here in about the formulation and evaluation of Magnetic Prednisolone Microcapsules (MPC) developed in order to improve the therapeutic efficacy relatively at a low dose than the conventional dosage formulations by means of magnetic drug targeting and thus enhancing bioavailability at the arthritic joints. Prednisolone was loaded to poly (sodium 4-styrenesulfonate) (PSS) doped calcium carbonate microspheres confirmed by the decrease in surface area from 97.48 m{sup 2}/g to 12.05 of m{sup 2}/g by BET analysis. Adsorption with oppositely charged polyelectrolytes incorporated with iron oxide nanoparticles was confirmed through zeta analysis. Removal of calcium carbonate core yielded MPC with particle size of ~3.48 µm, zeta potential of +29.7 mV was evaluated for its magnetic properties. Functional integrity of MPC was confirmed through FT-IR spectrum. Stability studies were performed at 25 °C±65% relative humidity for 60 days showed no considerable changes. Further the encapsulation efficiency of 63%, loading capacity of 18.2% and drug release of 88.3% for 36 h and its kinetics were also reported. The observed results justify the suitability of MPC for possible applications in the magnetic drug targeting for efficient therapy of rheumatoid arthritis. - Highlights: • Development of magnetic prednisolone microcapsules (MPC). • Physicochemical, pharmaceutical and magnetic properties of MPC were characterized. • Multiple layers of alternative polyelectrolytes prolonged prednisolone release time. • MPC is capable for targeted and sustained release rheumatoid arthritis therapy.

  13. Contemporary Targets for Control of Efficient Energy Use

    Directory of Open Access Journals (Sweden)

    Yu. S. Petrusha

    2012-01-01

    Full Text Available The paper describes main principles of the methodology for control of efficient energy use in power engineering and economy sectors as a whole. Targets for control of energy use at different levels have been considered in the paper. A special attention has been paid to technical, organizational and legal aspects of energy efficiency improvement. The paper contains an analysis of the history of the given issue, the present level of its development and near-term prospects under conditions of the Republic of Belarus.

  14. Energy Efficient and Reliable Target Monitoring in the Tactical Battlefield

    Science.gov (United States)

    Li, Yan-Xiao; Guan, Hua; Zhang, Yue-Ling

    In the tactical battlefield target monitoring it is crucial to take into account the energy efficiency and data reliability issues for the purpose of military decision making, especially in large scale sensor networks. However, due to the inherent nature of power constraint and wireless communication medium it is a challenging problem in the process of actual application. An efficient and reliable data aggregation scheme is proposed to enhance the performance of wireless sensor network used in the target monitoring. Firstly, the energy consumption model is presented and analyzed in the multihop WSNs. Then idea of mobile sinks, adaptive energy saving mechanism is introduced and the concept of multiple sinks cooperation is used to assure the reliability of the data aggregation. The simulation and the associated analysis show the improved results of the presented schema. At last the future discussion about the large scale tactical battlefield application is made to broaden the coming research scope.

  15. Target-ion source unit ionization efficiency measurement by method of stable ion beam implantation

    CERN Document Server

    Panteleev, V.N; Fedorov, D.V; Moroz, F.V; Orlov, S.Yu; Volkov, Yu.M

    The ionization efficiency is one of the most important parameters of an on-line used target-ion source system exploited for production of exotic radioactive beams. The ionization efficiency value determination as a characteristic of a target-ion source unit in the stage of its normalizing before on-line use is a very important step in the course of the preparation for an on-line experiment. At the IRIS facility (Petersburg Nuclear Physics Institute, Gatchina) a reliable and rather precise method of the target-ion source unit ionization efficiency measurement by the method of stable beam implantation has been developed. The method worked out exploits an off-line mass-separator for the implantation of the ion beams of selected stable isotopes of different elements into a tantalum foil placed inside the Faraday cup in the focal plane of the mass-separator. The amount of implanted ions has been measured with a high accuracy by the current integrator connected to the Faraday cup. After the implantation of needed a...

  16. DASPfind: new efficient method to predict drug–target interactions

    KAUST Repository

    Ba Alawi, Wail

    2016-03-16

    Background Identification of novel drug–target interactions (DTIs) is important for drug discovery. Experimental determination of such DTIs is costly and time consuming, hence it necessitates the development of efficient computational methods for the accurate prediction of potential DTIs. To-date, many computational methods have been proposed for this purpose, but they suffer the drawback of a high rate of false positive predictions. Results Here, we developed a novel computational DTI prediction method, DASPfind. DASPfind uses simple paths of particular lengths inferred from a graph that describes DTIs, similarities between drugs, and similarities between the protein targets of drugs. We show that on average, over the four gold standard DTI datasets, DASPfind significantly outperforms other existing methods when the single top-ranked predictions are considered, resulting in 46.17 % of these predictions being correct, and it achieves 49.22 % correct single top ranked predictions when the set of all DTIs for a single drug is tested. Furthermore, we demonstrate that our method is best suited for predicting DTIs in cases of drugs with no known targets or with few known targets. We also show the practical use of DASPfind by generating novel predictions for the Ion Channel dataset and validating them manually. Conclusions DASPfind is a computational method for finding reliable new interactions between drugs and proteins. We show over six different DTI datasets that DASPfind outperforms other state-of-the-art methods when the single top-ranked predictions are considered, or when a drug with no known targets or with few known targets is considered. We illustrate the usefulness and practicality of DASPfind by predicting novel DTIs for the Ion Channel dataset. The validated predictions suggest that DASPfind can be used as an efficient method to identify correct DTIs, thus reducing the cost of necessary experimental verifications in the process of drug discovery. DASPfind

  17. Targeting an efficient target-to-target interval for P300 speller brain–computer interfaces

    Science.gov (United States)

    Sellers, Eric W.; Wang, Xingyu

    2013-01-01

    Longer target-to-target intervals (TTI) produce greater P300 event-related potential amplitude, which can increase brain–computer interface (BCI) classification accuracy and decrease the number of flashes needed for accurate character classification. However, longer TTIs requires more time for each trial, which will decrease the information transfer rate of BCI. In this paper, a P300 BCI using a 7 × 12 matrix explored new flash patterns (16-, 18- and 21-flash pattern) with different TTIs to assess the effects of TTI on P300 BCI performance. The new flash patterns were designed to minimize TTI, decrease repetition blindness, and examine the temporal relationship between each flash of a given stimulus by placing a minimum of one (16-flash pattern), two (18-flash pattern), or three (21-flash pattern) non-target flashes between each target flashes. Online results showed that the 16-flash pattern yielded the lowest classification accuracy among the three patterns. The results also showed that the 18-flash pattern provides a significantly higher information transfer rate (ITR) than the 21-flash pattern; both patterns provide high ITR and high accuracy for all subjects. PMID:22350331

  18. Limited mobility of target pests crucially lowers controllability when sterile insect releases are spatiotemporally biased.

    Science.gov (United States)

    Ikegawa, Yusuke; Himuro, Chihiro

    2017-05-21

    The sterile insect technique (SIT) is a genetic pest control method wherein mass-reared sterile insects are periodically released into the wild, thereby impeding the successful reproduction of fertile pests. In Okinawa Prefecture, Japan, the SIT has been implemented to eradicate the West Indian sweet potato weevil Euscepes postfasciatus (Fairmaire), which is a flightless agricultural pest of sweet potatoes. It is known that E. postfasciatus is much less mobile than other insects to which the SIT has been applied. However, previous theoretical studies have rarely examined effects of low mobility of target pests and variation in the spatiotemporal evenness of sterile insect releases. To theoretically examine the effects of spatiotemporal evenness on the regional eradication of less mobile pests, we constructed a simple two-patch population model comprised of a pest and sterile insect moving between two habitats, and numerically simulated different release strategies (varying the number of released sterile insects and release intervals). We found that spatially biased releases allowed the pest to spatially escape from the sterile insect, and thus intensively lowered its controllability. However, we showed that the temporally counterbalancing spatially biased releases by swapping the number of released insects in the two habitats at every release (called temporal balancing) could greatly mitigate this negative effect and promote the controllability. We also showed that the negative effect of spatiotemporally biased releases was a result of the limited mobility of the target insect. Although directed dispersal of the insects in response to habitats of differing quality could lower the controllability in the more productive habitat, the temporal balancing could promote and eventually maximize the controllability as released insects increased. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Encapsulation of Volatile Citronella Essential Oil by Coacervation: Efficiency and Release Study

    Science.gov (United States)

    Manaf, M. A.; Subuki, I.; Jai, J.; Raslan, R.; Mustapa, A. N.

    2018-05-01

    The volatile citronella essential oil was encapsulated by simple coacervation and complex coacervation using Arabic gum and gelatin as wall material. Glutaraldehyde was used in the methodology as crosslinking agent. The citronella standard calibration graph obtained with R2 of 0.9523 was used for the accurate determination of encapsulation efficiency and release study. The release kinetic was analysed based on Fick"s law of diffusion for polymeric system and linear graph of Log fraction release over Log time was constructed to determine the release rate constant, k and diffusion coefficient, n. Both coacervation methods in the present study produce encapsulation efficiency around 94%. The produced capsules for both coacervation processes were discussed based on the capsules morphology and release kinetic mechanisms.

  20. Photometric Calibration of the Barium Cloud Image in a Space Active Experiment: Determining the Release Efficiency

    International Nuclear Information System (INIS)

    Xie Liang-Hai; Li Lei; Wang Jing-Dong; Tao Ran; Cheng Bing-Jun; Zhang Yi-Teng

    2014-01-01

    The barium release experiment is an effective method to explore the near-earth environment and to study all kinds of space physics processes. The first space barium release experiment in China was successfully carried out by a sounding rocket on April 5, 2013. This work is devoted to calculating the release efficiency of the barium release by analyzing the optical image observed during the experiment. First, we present a method to calibrate the images grey value of barium cloud with the reference stars to obtain the radiant fluxes at different moments. Then the release efficiency is obtained by a curve fitting with the theoretical evolution model of barium cloud. The calculated result is basically consistent with the test value on ground

  1. Munc13 controls the location and efficiency of dense-core vesicle release in neurons.

    Science.gov (United States)

    van de Bospoort, Rhea; Farina, Margherita; Schmitz, Sabine K; de Jong, Arthur; de Wit, Heidi; Verhage, Matthijs; Toonen, Ruud F

    2012-12-10

    Neuronal dense-core vesicles (DCVs) contain diverse cargo crucial for brain development and function, but the mechanisms that control their release are largely unknown. We quantified activity-dependent DCV release in hippocampal neurons at single vesicle resolution. DCVs fused preferentially at synaptic terminals. DCVs also fused at extrasynaptic sites but only after prolonged stimulation. In munc13-1/2-null mutant neurons, synaptic DCV release was reduced but not abolished, and synaptic preference was lost. The remaining fusion required prolonged stimulation, similar to extrasynaptic fusion in wild-type neurons. Conversely, Munc13-1 overexpression (M13OE) promoted extrasynaptic DCV release, also without prolonged stimulation. Thus, Munc13-1/2 facilitate DCV fusion but, unlike for synaptic vesicles, are not essential for DCV release, and M13OE is sufficient to produce efficient DCV release extrasynaptically.

  2. Efficient energy-saving targets for APEC economies

    International Nuclear Information System (INIS)

    Hu, J.-L.; Kao, C.-H.

    2007-01-01

    Energy-saving target ratios (ESTR) for 17 APEC economies during 1991-2000 are computed in a total-factor framework. All nominal variables are transformed into real variables by the purchasing power parity (PPP) at the 1995 price level. The data envelopment analysis (DEA) approach is used to find the energy-saving target (EST) for APEC economies without reducing their maximum potential gross domestic productions (GDPs) in each year. Energy, labor, and capital are the three inputs, while GDP is the single output. Our major findings are as follows: (1) China has the largest EST up to almost half of its current usage. (2) Hong Kong, the Philippines, and the United States have the highest energy efficiency. (3) The energy efficiency generally increases for APEC economies except for Canada and New Zealand. (4) Chile, Mexico, and Taiwan have significantly improved their energy efficiency in the last 5 years. (5) An inverted U-shape relation exists between per capita EST and per capita GDP. (6) ESTR has a positive relation with the value-added percentage of GDP of the industry sector and a negative relation with that of the service sector

  3. Targeted delivery and controlled release of Paclitaxel for the treatment of lung cancer using single-walled carbon nanotubes

    International Nuclear Information System (INIS)

    Yu, Baodan; Tan, Li; Zheng, Runhui; Tan, Huo; Zheng, Lixia

    2016-01-01

    A new type of drug delivery system (DDS) based on single-walled carbon nanotubes (SWNTs) for controlled-release of the anti-cancer drug Paclitaxel (PTX) was constructed in this study. Chitosan (CHI) was non-covalently attached to the SWNTs to improve biocompatibility. Biocompatible hyaluronan was also combined to the outer CHI layer to realise the specific targeting property. The results showed that the release of PTX was pH-triggered and was better at lower pH (pH 5.5). The modified SWNTs showed a significant improvement in intracellular reactive oxygen species (ROS), which may have enhanced mitogen-activated protein kinase activation and further promoted cell apoptosis. The results of western blotting indicated that the apoptosis-related proteins were abundantly expressed in A549 cells. Lactate dehydrogenase (LDH) release assay and cell viability assay demonstrated that PTX-loaded SWNTs could destroy cell membrane integrity, thus inducing lower cell viability of the A549 cells. Thus, this targeting DDS could effectively inhibit cell proliferation and kill A549 cells, is a promising system for cancer therapy. - Highlights: • Chitosan and hyaluronan modified single-walled carbon nanotubes (SWNTs) were prepared for delivery of Paclitaxel (PTX). • Morphology, drug loading efficiency and drug release amount of the nanotubes were studied. • Cell viability, LDH, intracellular ROS levels and western blotting were evaluated. • The drug delivery system could effectively inhibit A549 cells proliferation.

  4. Targeted delivery and controlled release of Paclitaxel for the treatment of lung cancer using single-walled carbon nanotubes

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Baodan; Tan, Li; Zheng, Runhui; Tan, Huo, E-mail: tanhuo.2008@163.com; Zheng, Lixia, E-mail: 66593953@qq.com

    2016-11-01

    A new type of drug delivery system (DDS) based on single-walled carbon nanotubes (SWNTs) for controlled-release of the anti-cancer drug Paclitaxel (PTX) was constructed in this study. Chitosan (CHI) was non-covalently attached to the SWNTs to improve biocompatibility. Biocompatible hyaluronan was also combined to the outer CHI layer to realise the specific targeting property. The results showed that the release of PTX was pH-triggered and was better at lower pH (pH 5.5). The modified SWNTs showed a significant improvement in intracellular reactive oxygen species (ROS), which may have enhanced mitogen-activated protein kinase activation and further promoted cell apoptosis. The results of western blotting indicated that the apoptosis-related proteins were abundantly expressed in A549 cells. Lactate dehydrogenase (LDH) release assay and cell viability assay demonstrated that PTX-loaded SWNTs could destroy cell membrane integrity, thus inducing lower cell viability of the A549 cells. Thus, this targeting DDS could effectively inhibit cell proliferation and kill A549 cells, is a promising system for cancer therapy. - Highlights: • Chitosan and hyaluronan modified single-walled carbon nanotubes (SWNTs) were prepared for delivery of Paclitaxel (PTX). • Morphology, drug loading efficiency and drug release amount of the nanotubes were studied. • Cell viability, LDH, intracellular ROS levels and western blotting were evaluated. • The drug delivery system could effectively inhibit A549 cells proliferation.

  5. Advances in research of targeting delivery and controlled release of drug-loaded nanoparticles

    International Nuclear Information System (INIS)

    Tan Zhonghua

    2003-01-01

    Biochemistry drug, at present, is still the main tool that human struggle to defeat the diseases. So, developing safe and efficacious technique of drug targeting delivery and controlled release is key to enhance curative effect, decrease drug dosage, and lessen its side effect. Drug-loaded nanoparticles, which is formed by conjugate between nanotechnology and modern pharmaceutics, is a new fashioned pharmic delivery carrier. Because of advantages in pharmic targeting transport and controlled or slow release and improving bioavailability, it has been one of developing trend of modern pharmaceutical dosage forms

  6. DASPfind: new efficient method to predict drug–target interactions

    KAUST Repository

    Ba Alawi, Wail; Soufan, Othman; Essack, Magbubah; Kalnis, Panos; Bajic, Vladimir B.

    2016-01-01

    DASPfind is a computational method for finding reliable new interactions between drugs and proteins. We show over six different DTI datasets that DASPfind outperforms other state-of-the-art methods when the single top-ranked predictions are considered, or when a drug with no known targets or with few known targets is considered. We illustrate the usefulness and practicality of DASPfind by predicting novel DTIs for the Ion Channel dataset. The validated predictions suggest that DASPfind can be used as an efficient method to identify correct DTIs, thus reducing the cost of necessary experimental verifications in the process of drug discovery. DASPfind can be accessed online at: http://​www.​cbrc.​kaust.​edu.​sa/​daspfind.

  7. Efficient visualization of high-throughput targeted proteomics experiments: TAPIR.

    Science.gov (United States)

    Röst, Hannes L; Rosenberger, George; Aebersold, Ruedi; Malmström, Lars

    2015-07-15

    Targeted mass spectrometry comprises a set of powerful methods to obtain accurate and consistent protein quantification in complex samples. To fully exploit these techniques, a cross-platform and open-source software stack based on standardized data exchange formats is required. We present TAPIR, a fast and efficient Python visualization software for chromatograms and peaks identified in targeted proteomics experiments. The input formats are open, community-driven standardized data formats (mzML for raw data storage and TraML encoding the hierarchical relationships between transitions, peptides and proteins). TAPIR is scalable to proteome-wide targeted proteomics studies (as enabled by SWATH-MS), allowing researchers to visualize high-throughput datasets. The framework integrates well with existing automated analysis pipelines and can be extended beyond targeted proteomics to other types of analyses. TAPIR is available for all computing platforms under the 3-clause BSD license at https://github.com/msproteomicstools/msproteomicstools. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  8. Intestinal Targeting of Ganciclovir Release Employing a Novel HEC-PAA Blended Lyomatrix.

    Science.gov (United States)

    Mabrouk, Mostafa; Mulla, Jameel A S; Kumar, Pradeep; Chejara, Dharmesh R; Badhe, Ravindra V; Choonara, Yahya E; du Toit, Lisa C; Pillay, Viness

    2016-10-01

    A hydroxyethylcellulose-poly(acrylic acid) (HEC-PAA) lyomatrix was developed for ganciclovir (GCV) intestine targeting to overcome its undesirable degradation in the stomach. GCV was encapsulated within the HEC-PAA lyomatrix prepared by lyophilization. Conventional tablets were also prepared with identical GCV concentrations in order to compare the GCV release behavior from the lyomatrix and tablets. GCV incorporation (75.12%) was confirmed using FTIR, DSC, and TGA. The effect of GCV loading on the microstructure properties of the lyomatrix was evaluated by SEM, AFM, and BET surface area measurements. The in vitro drug release study showed steady and rapid release profiles from the GCV-loaded lyomatrix compared with the tablet formulation at identical pH values. Minimum GCV release was observed at acidic pH (≤40%) and maximum release occurred at intestinal pH values (≥90%) proving the intestinal targeting ability of the lyomatrix. Kinetic modeling revealed that the GCV-loaded lyomatrix exhibited zero-order release kinetics (n = 1), while the tablets were best described via the Peppas model. Textural analysis highlighted enhanced matrix resilience and rigidity gradient (12.5%, 20 Pa) for the GCV-loaded lyomatrix compared to the pure (7%, 9.5 Pa) HEC-PAA lyomatrix. Bench-top MRI imaging was used to confirm the mechanism of GCV release behavior by monitoring the swelling and erosion rates. The swelling and erosion rate of the tablets was not sufficient to achieve rapid zero-order GCV release as with the lyomatrix. These combined results suggest that the HEC-PAA lyomatrix may be suitable for GCV intestinal targeting after oral administration.

  9. Energy efficiency improvement target for SIC 34 - fabricated metal products. Revised target support document

    Energy Technology Data Exchange (ETDEWEB)

    Byrer, T. G.; Billhardt, C. F.; Farkas, M. S.

    1977-02-15

    In accordance with section 374 of the Energy Policy and Conservation Act (EPCA), Pub. L. 94-163, the Federal Energy Administration (FEA) proposed industrial energy efficiency improvement targets for the ten most energy-consumptive manufacturing industries in the U.S. Following public hearings and a review of the comments made, the final targets for Fabricated Metal Products (SIC 34) were established and are described. Using 1972 data on the energy consumed to produce specific metal products, it was concluded that a 24% reduction in energy consumption for SIC 34 is a viable goal for achievement by 1980. (ERA citation 04:045006)

  10. Energy efficient hotspot-targeted embedded liquid cooling of electronics

    International Nuclear Information System (INIS)

    Sharma, Chander Shekhar; Tiwari, Manish K.; Zimmermann, Severin; Brunschwiler, Thomas; Schlottig, Gerd; Michel, Bruno; Poulikakos, Dimos

    2015-01-01

    Highlights: • We present a novel concept for hotspot-targeted, energy efficient ELC for electronic chips. • Microchannel throttling zones distribute flow optimally without any external control. • Design is optimized for highly non-uniform multicore chip heat flux maps. • Optimized design minimizes chip temperature non-uniformity. • This is achieved with pumping power consumption less than 1% of total chip power. - Abstract: Large data centers today already account for nearly 1.31% of total electricity consumption with cooling responsible for roughly 33% of that energy consumption. This energy intensive cooling problem is exacerbated by the presence of hotspots in multicore microprocessors due to excess coolant flow requirement for thermal management. Here we present a novel liquid-cooling concept, for targeted, energy efficient cooling of hotspots through passively optimized microchannel structures etched into the backside of a chip (embedded liquid cooling or ELC architecture). We adopt an experimentally validated and computationally efficient modeling approach to predict the performance of our hotspot-targeted ELC design. The design is optimized for exemplar non-uniform chip power maps using Response Surface Methodology (RSM). For industrially acceptable limits of approximately 0.4 bar (40 kPa) on pressure drop and one percent of total chip power on pumping power, the optimized designs are computationally evaluated against a base, standard ELC design with uniform channel widths and uniform flow distribution. For an average steady-state heat flux of 150 W/cm 2 in core areas (hotspots) and 20 W/cm 2 over remaining chip area (background), the optimized design reduces the maximum chip temperature non-uniformity by 61% to 3.7 °C. For a higher average, steady-state hotspot heat flux of 300 W/cm 2 , the maximum temperature non-uniformity is reduced by 54% to 8.7 °C. It is shown that the base design requires a prohibitively high level of pumping power (about

  11. A multifunctional magnetic nanocarrier bearing fluorescent dye for targeted drug delivery by enhanced two-photon triggered release

    International Nuclear Information System (INIS)

    Banerjee, Shashwat S; Chen, D-H

    2009-01-01

    We report a novel nanoformulation for targeted drug delivery which utilizes nanophotonics through the fusion of nanotechnology with biomedical application. The approach involves an energy-transferring magnetic nanoscopic co-assembly fabricated of rhodamine B (RDB) fluorescent dye grafted gum arabic modified Fe 3 O 4 magnetic nanoparticle and photosensitive linker by which dexamethasone drug is conjugated to the magnetic nano-assembly. The advantage offered by this nanoformulation is the indirect photo-triggered-on-demand drug release by efficient up-converting energy of the near-IR (NIR) light to higher energy and intraparticle energy transfer from the dye grafted magnetic nanoparticle to the linker for drug release by cleavage. The synthesized nanoparticles were found to be of ultra-small size (13.33 nm) and are monodispersed in an aqueous suspension. Dexamethasone (Dexa) drug conjugated to RDB-GAMNP by photosensitive linker showed appreciable release of Dexa by photo-triggered response on exposure to radiation having a wavelength in the NIR region whereas no detectable release was observed in the dark. Photo-triggered response for the nanoformulation not bearing the rhodamine B dye was drastically less as less Dexa was released on exposure to NIR radiation which suggest that the photo-cleavage of linker and release of Dexa mainly originated from the indirect excitation through the uphill energy conversions based on donor-acceptor model FRET. The promising pathway of nanophotonics for the on-demand release of the drug makes this nanocarrier very promising for applications in nanomedicine.

  12. Mechanism of energy release from nucleus-target in hadron-nucleus collision

    International Nuclear Information System (INIS)

    Strugalski, Z.; Strugalska-Gola, E.

    2000-01-01

    The collisions of hadrons (protons, mesons) with 131 Xe nucleus and arising light nuclear fragments as nuclear refraction products have been observed in bubble chamber. Mechanism of energy release during these collisions has been discussed. The quantitative calculations has proved that this phenomena can be treated as potential energy source with use of many different target materials

  13. Liver cancer cells: targeting and prolonged-release drug carriers consisting of mesoporous silica nanoparticles and alginate microspheres.

    Science.gov (United States)

    Liao, Yu-Te; Liu, Chia-Hung; Yu, Jiashing; Wu, Kevin C-W

    2014-01-01

    A new microsphere consisting of inorganic mesoporous silica nanoparticles (MSNs) and organic alginate (denoted as MSN@Alg) was successfully synthesized by air-dynamic atomization and applied to the intracellular drug delivery systems (DDS) of liver cancer cells with sustained release and specific targeting properties. MSN@Alg microspheres have the advantages of MSN and alginate, where MSN provides a large surface area for high drug loading and alginate provides excellent biocompatibility and COOH functionality for specific targeting. Rhodamine 6G was used as a model drug, and the sustained release behavior of the rhodamine 6G-loaded MSN@Alg microspheres can be prolonged up to 20 days. For targeting therapy, the anticancer drug doxorubicin was loaded into MSN@Alg microspheres, and the (lysine)4-tyrosine-arginine-glycine-aspartic acid (K4YRGD) peptide was functionalized onto the surface of MSN@Alg for targeting liver cancer cells, hepatocellular carcinoma (HepG2). The results of the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay and confocal laser scanning microscopy indicate that the MSN@Alg microspheres were successfully uptaken by HepG2 without apparent cytotoxicity. In addition, the intracellular drug delivery efficiency was greatly enhanced (ie, 3.5-fold) for the arginine-glycine-aspartic acid (RGD)-labeled, doxorubicin-loaded MSN@Alg drug delivery system compared with the non-RGD case. The synthesized MSN@Alg microspheres show great potential as drug vehicles with high biocompatibility, sustained release, and targeting features for future intracellular DDS.

  14. Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release.

    Science.gov (United States)

    Hosoya, Hitomi; Dobroff, Andrey S; Driessen, Wouter H P; Cristini, Vittorio; Brinker, Lina M; Staquicini, Fernanda I; Cardó-Vila, Marina; D'Angelo, Sara; Ferrara, Fortunato; Proneth, Bettina; Lin, Yu-Shen; Dunphy, Darren R; Dogra, Prashant; Melancon, Marites P; Stafford, R Jason; Miyazono, Kohei; Gelovani, Juri G; Kataoka, Kazunori; Brinker, C Jeffrey; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

    2016-02-16

    A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.

  15. Multifunctional Polymer Nanoparticles for Dual Drug Release and Cancer Cell Targeting

    Directory of Open Access Journals (Sweden)

    Yu-Han Wen

    2017-06-01

    Full Text Available Multifunctional polymer nanoparticles have been developed for cancer treatment because they could be easily designed to target cancer cells and to enhance therapeutic efficacy according to cancer hallmarks. In this study, we synthesized a pH-sensitive polymer, poly(methacrylic acid-co-histidine/doxorubicin/biotin (HBD in which doxorubicin (DOX was conjugated by a hydrazone bond to encapsulate an immunotherapy drug, imiquimod (IMQ, to form dual cancer-targeting and dual drug-loaded nanoparticles. At low pH, polymeric nanoparticles could disrupt and simultaneously release DOX and IMQ. Our experimental results show that the nanoparticles exhibited pH-dependent drug release behavior and had an ability to target cancer cells via biotin and protonated histidine.

  16. The dependence of neuronal encoding efficiency on Hebbian plasticity and homeostatic regulation of neurotransmitter release

    Science.gov (United States)

    Faghihi, Faramarz; Moustafa, Ahmed A.

    2015-01-01

    Synapses act as information filters by different molecular mechanisms including retrograde messenger that affect neuronal spiking activity. One of the well-known effects of retrograde messenger in presynaptic neurons is a change of the probability of neurotransmitter release. Hebbian learning describe a strengthening of a synapse between a presynaptic input onto a postsynaptic neuron when both pre- and postsynaptic neurons are coactive. In this work, a theory of homeostatic regulation of neurotransmitter release by retrograde messenger and Hebbian plasticity in neuronal encoding is presented. Encoding efficiency was measured for different synaptic conditions. In order to gain high encoding efficiency, the spiking pattern of a neuron should be dependent on the intensity of the input and show low levels of noise. In this work, we represent spiking trains as zeros and ones (corresponding to non-spike or spike in a time bin, respectively) as words with length equal to three. Then the frequency of each word (here eight words) is measured using spiking trains. These frequencies are used to measure neuronal efficiency in different conditions and for different parameter values. Results show that neurons that have synapses acting as band-pass filters show the highest efficiency to encode their input when both Hebbian mechanism and homeostatic regulation of neurotransmitter release exist in synapses. Specifically, the integration of homeostatic regulation of feedback inhibition with Hebbian mechanism and homeostatic regulation of neurotransmitter release in the synapses leads to even higher efficiency when high stimulus intensity is presented to the neurons. However, neurons with synapses acting as high-pass filters show no remarkable increase in encoding efficiency for all simulated synaptic plasticity mechanisms. This study demonstrates the importance of cooperation of Hebbian mechanism with regulation of neurotransmitter release induced by rapid diffused retrograde

  17. A smart multifunctional nanocomposite for intracellular targeted drug delivery and self-release

    International Nuclear Information System (INIS)

    Wang Chan; Tao Shengyang; Hu Tao; Yang Jingbang; Meng Changgong; Lv Piping; Wei Wei

    2011-01-01

    A multifunctional 'all-in-one' nanocomposite is fabricated using a colloid, template and surface-modification method. This material encompasses magnetic induced target delivery, cell uptake promotion and controlled drug release in one system. The nanocomposite is characterized by scanning electron microscopy, transmission electron microscopy, x-ray diffraction, N 2 adsorption and vibrating sample magnetometry. The prepared material has a diameter of 350-400 nm, a high surface area of 420.29 m 2 g -1 , a pore size of 1.91 nm and a saturation magnetization of 32 emu g -1 . Doxorubicin (DOX) is loaded in mesopores and acid-sensitive blockers are introduced onto the orifices of the mesopores by a Schiff base linker to implement pH-dependent self-release. Folate was also introduced to improve DOX targeted delivery and endocytosis. The linkers remained intact to block pores with ferrocene valves and inhibit the diffusion of DOX at neutral pH. However, in lysosomes of cancer cells, which have a weak acidic pH, hydrolysis of the Schiff base group removes the nanovalves and allows the trapped DOX to be released. These processes are demonstrated by UV-visible absorption spectra, confocal fluorescence microscopy images and methyl thiazolyl tetrazolium assays in vitro, which suggest that the smart nanocomposite successfully integrates targeted drug delivery with internal stimulus induced self-release and is a potentially useful material for nanobiomedicine.

  18. A smart multifunctional nanocomposite for intracellular targeted drug delivery and self-release

    Science.gov (United States)

    Wang, Chan; Lv, Piping; Wei, Wei; Tao, Shengyang; Hu, Tao; Yang, Jingbang; Meng, Changgong

    2011-10-01

    A multifunctional 'all-in-one' nanocomposite is fabricated using a colloid, template and surface-modification method. This material encompasses magnetic induced target delivery, cell uptake promotion and controlled drug release in one system. The nanocomposite is characterized by scanning electron microscopy, transmission electron microscopy, x-ray diffraction, N2 adsorption and vibrating sample magnetometry. The prepared material has a diameter of 350-400 nm, a high surface area of 420.29 m2 g - 1, a pore size of 1.91 nm and a saturation magnetization of 32 emu g - 1. Doxorubicin (DOX) is loaded in mesopores and acid-sensitive blockers are introduced onto the orifices of the mesopores by a Schiff base linker to implement pH-dependent self-release. Folate was also introduced to improve DOX targeted delivery and endocytosis. The linkers remained intact to block pores with ferrocene valves and inhibit the diffusion of DOX at neutral pH. However, in lysosomes of cancer cells, which have a weak acidic pH, hydrolysis of the Schiff base group removes the nanovalves and allows the trapped DOX to be released. These processes are demonstrated by UV-visible absorption spectra, confocal fluorescence microscopy images and methyl thiazolyl tetrazolium assays in vitro, which suggest that the smart nanocomposite successfully integrates targeted drug delivery with internal stimulus induced self-release and is a potentially useful material for nanobiomedicine.

  19. A smart multifunctional nanocomposite for intracellular targeted drug delivery and self-release

    Energy Technology Data Exchange (ETDEWEB)

    Wang Chan; Tao Shengyang; Hu Tao; Yang Jingbang; Meng Changgong [School of Chemical Engineering, Dalian University of Technology, Dalian, Liaoning (China); Lv Piping; Wei Wei, E-mail: taosy@dlut.edu.cn [National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing (China)

    2011-10-14

    A multifunctional 'all-in-one' nanocomposite is fabricated using a colloid, template and surface-modification method. This material encompasses magnetic induced target delivery, cell uptake promotion and controlled drug release in one system. The nanocomposite is characterized by scanning electron microscopy, transmission electron microscopy, x-ray diffraction, N{sub 2} adsorption and vibrating sample magnetometry. The prepared material has a diameter of 350-400 nm, a high surface area of 420.29 m{sup 2} g{sup -1}, a pore size of 1.91 nm and a saturation magnetization of 32 emu g{sup -1}. Doxorubicin (DOX) is loaded in mesopores and acid-sensitive blockers are introduced onto the orifices of the mesopores by a Schiff base linker to implement pH-dependent self-release. Folate was also introduced to improve DOX targeted delivery and endocytosis. The linkers remained intact to block pores with ferrocene valves and inhibit the diffusion of DOX at neutral pH. However, in lysosomes of cancer cells, which have a weak acidic pH, hydrolysis of the Schiff base group removes the nanovalves and allows the trapped DOX to be released. These processes are demonstrated by UV-visible absorption spectra, confocal fluorescence microscopy images and methyl thiazolyl tetrazolium assays in vitro, which suggest that the smart nanocomposite successfully integrates targeted drug delivery with internal stimulus induced self-release and is a potentially useful material for nanobiomedicine.

  20. Safety aspects of targets for ADTT: Activity, volatile products, residual heat release

    International Nuclear Information System (INIS)

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

    1999-01-01

    Safety aspects of heavy metal liquid targets for the accelerator driven systems connected with the activity accumulation and residual energy release due to the irradiation with high energy proton beam are discussed. The results obtained for the lead-bismuth target that are under construction in IPPE now in the frame of ISTC Project No. 559 are briefly presented. The calculations and the analysis of the accumulation of the spallation reaction products, activity and energy release at various moments after the accelerator shutdown are presented. The concentrations of the reaction products, the total and partial activities, the activities of volatile products are determined. The contributions of the short-lived nuclides important for the prediction of the facility behaviour in regimes with the accelerator beam trips. The calculations and analysis of the residual energy release due to different decay type have been performed. The conclusions are as follows. The obtained results showed that long lived radioactivity accumulates mainly due to primary nuclear reactions. Secondary reactions are responsible for the production of small number of long-lived isotopes Bi-207, Po-210 and some others, being generated by radiative capture of low energy neutrons. It is possible to make a conclusion that neutrons in the energy range 20 - 800 MeV and protons with energy above 100 MeV give main contribution to the total activity generation although these parts of spectra inside the target give comparatively small contribution to the total flux. The correct consideration of short-lived nuclides contribution is the main problem in the analysis of the target behaviour in the case of short accelerator shutdowns. They make the determining contribution to the both activity and the heat release at the first moments after the accelerator shutdown, creating the intermediate links and additional channels for the long-lived nuclides accumulation chains. The strong dependence of calculated

  1. Galactosylated DNA lipid nanocapsules for efficient hepatocyte targeting.

    Science.gov (United States)

    Morille, M; Passirani, C; Letrou-Bonneval, E; Benoit, J-P; Pitard, B

    2009-09-11

    The main objective of gene therapy via a systemic pathway is the development of a stable and non-toxic gene vector that can encapsulate and deliver foreign genetic materials into specific cell types with the transfection efficiency of viral vectors. With this objective, DNA complexed with cationic lipids of DOTAP/DOPE was encapsulated into lipid nanocapsules (LNCs) forming nanocarriers (DNA LNCs) with a size suitable for systemic injection (109+/-6 nm). With the goal of increasing systemic delivery, LNCs were stabilised with long chains of poly(ethylene glycol) (PEG), either from a PEG lipid derivative (DSPE-mPEG(2000)) or from an amphiphilic block copolymer (F108). In order to overcome internalisation difficulties encountered with PEG shield, a specific ligand (galactose) was covalently added at the distal end of the PEG chains, in order to provide active targeting of the asialoglycoprotein-receptor present on hepatocytes. This study showed that DNA LNCs were as efficient as positively charged DOTAP/DOPE lipoplexes for transfection. In primary hepatocytes, when non-galactosylated, the two polymers significantly decreased the transfection, probably by creating a barrier around the DNA LNCs. Interestingly, galactosylated F108 coated DNA LNCs led to a 18-fold increase in luciferase expression compared to non-galactosylated ones.

  2. Liver cancer cells: targeting and prolonged-release drug carriers consisting of mesoporous silica nanoparticles and alginate microspheres

    Directory of Open Access Journals (Sweden)

    Liao YT

    2014-06-01

    Full Text Available Yu-Te Liao,1 Chia-Hung Liu,2 Jiashing Yu,1 Kevin C-W Wu1,3 1Department of Chemical Engineering, National Taiwan University, Taipei, Taiwan; 2Department of Urology, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; 3Division of Medical Engineering Research, National Health Research Institutes, Zhunan Township, Miaoli County, Taiwan Abstract: A new microsphere consisting of inorganic mesoporous silica nanoparticles (MSNs and organic alginate (denoted as MSN@Alg was successfully synthesized by air-dynamic atomization and applied to the intracellular drug delivery systems (DDS of liver cancer cells with sustained release and specific targeting properties. MSN@Alg microspheres have the advantages of MSN and alginate, where MSN provides a large surface area for high drug loading and alginate provides excellent biocompatibility and COOH functionality for specific targeting. Rhodamine 6G was used as a model drug, and the sustained release behavior of the rhodamine 6G-loaded MSN@Alg microspheres can be prolonged up to 20 days. For targeting therapy, the anticancer drug doxorubicin was loaded into MSN@Alg microspheres, and the (lysine4-tyrosine-arginine-glycine-aspartic acid (K4YRGD peptide was functionalized onto the surface of MSN@Alg for targeting liver cancer cells, hepatocellular carcinoma (HepG2. The results of the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT assay and confocal laser scanning microscopy indicate that the MSN@Alg microspheres were successfully uptaken by HepG2 without apparent cytotoxicity. In addition, the intracellular drug delivery efficiency was greatly enhanced (ie, 3.5-fold for the arginine-glycine-aspartic acid (RGD-labeled, doxorubicin-loaded MSN@Alg drug delivery system compared with the non-RGD case. The synthesized MSN@Alg microspheres show great potential as drug vehicles with high biocompatibility, sustained release, and targeting features for future intracellular DDS. Keywords

  3. Biocompatible magnetic and molecular dual-targeting polyelectrolyte hybrid hollow microspheres for controlled drug release.

    Science.gov (United States)

    Du, Pengcheng; Zeng, Jin; Mu, Bin; Liu, Peng

    2013-05-06

    Well-defined biocompatible magnetic and molecular dual-targeting polyelectrolyte hybrid hollow microspheres have been accomplished via the layer-by-layer (LbL) self-assembly technique. The hybrid shell was fabricated by the electrostatic interaction between the polyelectrolyte cation, chitosan (CS), and the hybrid anion, citrate modified ferroferric oxide nanoparticles (Fe3O4-CA), onto the uniform polystyrene sulfonate microsphere templates. Then the magnetic hybrid core/shell composite particles were modified with a linear, functional poly(ethylene glycol) (PEG) monoterminated with a biotargeting molecule (folic acid (FA)). Afterward the dual targeting hybrid hollow microspheres were obtained after etching the templates by dialysis. The dual targeting hybrid hollow microspheres exhibit exciting pH response and stability in high salt-concentration media. Their pH-dependent controlled release of the drug molecule (anticancer drug, doxorubicin (DOX)) was also investigated in different human body fluids. As expected, the cell viability of the HepG2 cells which decreased more rapidly was treated by the FA modified hybrid hollow microspheres rather than the unmodified one in the in vitro study. The dual-targeting hybrid hollow microspheres demonstrate selective killing of the tumor cells. The precise magnetic and molecular targeting properties and pH-dependent controlled release offers promise for cancer treatment.

  4. Community Targets for JWST's Early Release Science Program: Evaluation of Transiting Exoplanet WASP-63b.

    Science.gov (United States)

    Kilpatrick, Brian; Cubillos, Patricio; Bruno, Giovanni; Lewis, Nikole K.; Stevenson, Kevin B.; Wakeford, Hannah; Blecic, Jasmina; Burrows, Adam Seth; Deming, Drake; Heng, Kevin; Line, Michael R.; Madhusudhan, Nikku; Morley, Caroline; Waldmann, Ingo P.; Transiting Exoplanet Early Release Science Community

    2017-06-01

    We present observations of the Hubble Space Telescope (HST) ``A Preparatory Program to Identify the Single Best Transiting Exoplanet for JWST Early Release Science" for WASP-63b, one of the community targets proposed for the James Webb Space Telescope (JWST) Early Release Science (ERS) program. A large collaboration of transiting exoplanet scientists identified a set of ``community targets" which meet a certain set of criteria for ecliptic latitude, period, host star brightness, well constrained orbital parameters, and strength of spectroscopic features. WASP-63b was one of the targets identified as a potential candidate for the ERS program. It is presented as an inflated planet with a large signal. It will be accessible to JWST approximately six months after the planned start of Cycle 1/ERS in April 2019 making it an ideal candidate should there be any delays in the JWST timetable. Here, we observe WASP-63b to evaluate its suitability as the best target to test the capabilities of JWST. Ideally, a clear atmosphere will be best suited for bench marking the instruments ability to detect spectroscopic features. We can use the strength of the water absorption feature at 1.4 μm as a way to determine the presence of obscuring clouds/hazes. The results of atmospheric retrieval are presented along with a discussion on the suitability of WASP-63b as the best target to be observed during the ERS Program.

  5. The dependence of neuronal encoding efficiency on Hebbian plasticity and homeostatic regulation of neurotransmitter release

    Directory of Open Access Journals (Sweden)

    Faramarz eFaghihi

    2015-04-01

    Full Text Available Synapses act as information filters by different molecular mechanisms including retrograde messenger that affect neuronal spiking activity. One of the well-known effects of retrograde messenger in presynaptic neurons is a change of the probability of neurotransmitter release. Hebbian learning describe a strengthening of a synapse between a presynaptic input onto a postsynaptic neuron when both pre- and postsynaptic neurons are coactive. In this work, a theory of homeostatic regulation of neurotransmitter release by retrograde messenger and Hebbian plasticity in neuronal encoding is presented. Encoding efficiency was measured for different synaptic conditions. In order to gain high encoding efficiency, the spiking pattern of a neuron should be dependent on the intensity of the input and show low levels of noise. In this work, we represent spiking trains as zeros and ones (corresponding to non-spike or spike in a time bin, respectively as words with length equal to three. Then the frequency of each word (here eight words is measured using spiking trains. These frequencies are used to measure neuronal efficiency in different conditions and for different parameter values. Results show that neurons that have synapses acting as band-pass filters show the highest efficiency to encode their input when both Hebbian mechanism and homeostatic regulation of neurotransmitter release exist in synapses. Specifically, the integration of homeostatic regulation of feedback inhibition with Hebbian mechanism and homeostatic regulation of neurotransmitter release in the synapses leads to even higher efficiency when high stimulus intensity is presented to the neurons. However, neurons with synapses acting as high-pass filters show no remarkable increase in encoding efficiency for all simulated synaptic plasticity mechanisms.

  6. Enhancing bioactive peptide release and identification using targeted enzymatic hydrolysis of milk proteins.

    Science.gov (United States)

    Nongonierma, Alice B; FitzGerald, Richard J

    2018-06-01

    Milk proteins have been extensively studied for their ability to yield a range of bioactive peptides following enzymatic hydrolysis/digestion. However, many hurdles still exist regarding the widespread utilization of milk protein-derived bioactive peptides as health enhancing agents for humans. These mostly arise from the fact that most milk protein-derived bioactive peptides are not highly potent. In addition, they may be degraded during gastrointestinal digestion and/or have a low intestinal permeability. The targeted release of bioactive peptides during the enzymatic hydrolysis of milk proteins may allow the generation of particularly potent bioactive hydrolysates and peptides. Therefore, the development of milk protein hydrolysates capable of improving human health requires, in the first instance, optimized targeted release of specific bioactive peptides. The targeted hydrolysis of milk proteins has been aided by a range of in silico tools. These include peptide cutters and predictive modeling linking bioactivity to peptide structure [i.e., molecular docking, quantitative structure activity relationship (QSAR)], or hydrolysis parameters [design of experiments (DOE)]. Different targeted enzymatic release strategies employed during the generation of milk protein hydrolysates are reviewed herein and their limitations are outlined. In addition, specific examples are provided to demonstrate how in silico tools may help in the identification and discovery of potent milk protein-derived peptides. It is anticipated that the development of novel strategies employing a range of in silico tools may help in the generation of milk protein hydrolysates containing potent and bioavailable peptides, which in turn may be used to validate their health promoting effects in humans. Graphical abstract The targeted enzymatic hydrolysis of milk proteins may allow the generation of highly potent and bioavailable bioactive peptides.

  7. Competitive release and outbreaks of non-target pests associated with transgenic Bt cotton.

    Science.gov (United States)

    Zeilinger, Adam R; Olson, Dawn M; Andow, David A

    2016-06-01

    The adoption of transgenic Bt cotton has, in some cases, led to environmental and economic benefits through reduced insecticide use. However, the distribution of these benefits and associated risks among cotton growers and cotton-growing regions has been uneven due in part to outbreaks of non-target or secondary pests, thereby requiring the continued use of synthetic insecticides. In the southeastern USA, Bt cotton adoption has resulted in increased abundance of and damage from stink bug pests, Euschistus servus and Nezara viridula (Heteroptera: Pentatomidae). While the impact of increased stink bug abundance has been well-documented, the causes have remained unclear. We hypothesize that release from competition with Bt-susceptible target pests may drive stink bug outbreaks in Bt cotton. We first examined the evidence for competitive release of stink bugs through meta-analysis of previous studies. We then experimentally tested if herbivory by Bt-susceptible Helicoverpa zea increases stink bug leaving rates and deters oviposition on non-Bt cotton. Consistent with previous studies, we found differences in leaving rates only for E servus, but we found that both species strongly avoided ovipositing on H. zea-damaged plants. Considering all available evidence, competitive release of stink bug populations in Bt cotton likely contributes to outbreaks, though the relative importance of competitive release remains an open question. Ecological risk assessments of Bt crops and other transgenic insecticidal crops would benefit from greater understanding of the ecological mechanisms underlying non-target pest outbreaks and greater attention to indirect ecological effects more broadly.

  8. Orthogonal Clickable Iron Oxide Nanoparticle Platform for Targeting, Imaging, and On-Demand Release.

    Science.gov (United States)

    Guldris, Noelia; Gallo, Juan; García-Hevia, Lorena; Rivas, José; Bañobre-López, Manuel; Salonen, Laura M

    2018-04-12

    A versatile iron oxide nanoparticle platform is reported that can be orthogonally functionalized to obtain highly derivatized nanomaterials required for a wide variety of applications, such as drug delivery, targeted therapy, or imaging. Facile functionalization of the nanoparticles with two ligands containing isocyanate moieties allows for high coverage of the surface with maleimide and alkyne groups. As a proof-of-principle, the nanoparticles were subsequently functionalized with a fluorophore as a drug model and with biotin as a targeting ligand towards tumor cells through Diels-Alder and azide-alkyne cycloaddition reactions, respectively. The thermoreversibility of the Diels-Alder product was exploited to induce the on-demand release of the loaded molecules by magnetic hyperthermia. Additionally, the nanoparticles were shown to target cancer cells through in vitro experiments, as analyzed by magnetic resonance imaging. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Target-responsive aptamer release from manganese dioxide nanosheets for electrochemical sensing of cocaine with target recycling amplification.

    Science.gov (United States)

    Chen, Zongbao; Lu, Minghua

    2016-11-01

    A novel electrochemical sensing platform based on manganese dioxide (MnO2) nanosheets was developed for sensitive screening of target cocaine with the signal amplification. Ferrocene-labeled cocaine aptamers were initially immobilized onto MnO2 nanosheets-modified screen-printed carbon electrode because of π-stacking interaction between nucleobases and nanosheets. The immobilized ferrocene-aptamer activated the electrical contact with the electrode, thereby resulting in the sensor circuit to switch on. Upon target cocaine introduction, the analyte reacted with the aptamer and caused the dissociation of ferrocene-aptamer from the electrode, thus giving rise to the detection circuit to switch off. The released aptamer was cleaved by DNase I with target recycling. Under optimal conditions, the decreasing percentage of the electronic signal relative to background current increased with the increasing cocaine concentration in the dynamic range of 0.1-20nM, and the detection limit was 32pM. The reproducibility, selectivity and method accuracy were acceptable. Importantly, this concept offers promise for rapid, simple, and cost-effective analysis of cocaine biological samples without the needs of sample separation and multiple washing steps. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Effect of different polyphenol sources on the efficiency of ellagic acid release by Aspergillus niger.

    Science.gov (United States)

    Sepúlveda, Leonardo; de la Cruz, Reynaldo; Buenrostro, José Juan; Ascacio-Valdés, Juan Alberto; Aguilera-Carbó, Antonio Francisco; Prado, Arely; Rodríguez-Herrera, Raúl; Aguilar, Cristóbal Noé

    2016-01-01

    Fungal hydrolysis of ellagitannins produces hexahydroxydiphenic acid, which is considered an intermediate molecule in ellagic acid release. Ellagic acid has important and desirable beneficial health properties. The aim of this work was to identify the effect of different sources of ellagitannins on the efficiency of ellagic acid release by Aspergillus niger. Three strains of A. niger (GH1, PSH and HT4) were assessed for ellagic acid release from different polyphenol sources: cranberry, creosote bush, and pomegranate used as substrate. Polyurethane foam was used as support for solid-state culture in column reactors. Ellagitannase activity was measured for each of the treatments. Ellagic acid was quantified by high performance liquid chromatography. When pomegranate polyphenols were used, a maximum value of ellagic acid (350.21 mg/g) was reached with A. niger HT4 in solid-state culture. The highest amount of ellagitannase (5176.81 U/l) was obtained at 8h of culture when cranberry polyphenols and strain A. niger PSH were used. Results demonstrated the effect of different polyphenol sources and A. niger strains on ellagic acid release. It was observed that the best source for releasing ellagic acid was pomegranate polyphenols and A. niger HT4 strain, which has the ability to degrade these compounds for obtaining a potent bioactive molecule such as ellagic acid. Copyright © 2015 Asociación Argentina de Microbiología. Publicado por Elsevier España, S.L.U. All rights reserved.

  11. O&M Best Practices - A Guide to Achieving Operational Efficiency (Release 2.0)

    Energy Technology Data Exchange (ETDEWEB)

    Sullivan, Gregory P.; Pugh, Ray; Melendez, Aldo P.; Hunt, W. D.

    2004-07-31

    This guide, sponsored by DOE's Federal Energy Management Program, highlights operations and maintenance (O&M) programs targeting energy efficiency that are estimated to save 5% to 20% on energy bills without a significant capital investment. The purpose of this guide is to provide the federal O&M energy manager and practitioner with useful information about O&M management, technologies, energy efficiency and cost-reduction approaches.

  12. MHI-148 Cyanine Dye Conjugated Chitosan Nanomicelle with NIR Light-Trigger Release Property as Cancer Targeting Theranostic Agent.

    Science.gov (United States)

    Thomas, Reju George; Moon, Myeong Ju; Surendran, Suchithra Poilil; Park, Hyeong Ju; Park, In-Kyu; Lee, Byeong-Il; Jeong, Yong Yeon

    2018-02-15

    Paclitaxel (PTX) loaded hydrophobically modified glycol chitosan (HGC) micelle is biocompatible in nature, but it requires cancer targeting ability and stimuli release property for better efficiency. To improve tumor retention and drug release characteristic of HGC-PTX nanomicelles, we conjugated cancer targeting heptamethine dye, MHI-148, which acts as an optical imaging agent, targeting moiety and also trigger on-demand drug release on application of NIR 808 nm laser. The amine group of glycol chitosan modified with hydrophobic 5β-cholanic acid and the carboxyl group of MHI-148 were bonded by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide chemistry. Paclitaxel was loaded to MHI-HGC nanomicelle by an oil-in-water emulsion method, thereby forming MHI-HGC-PTX. Comparison of near infrared (NIR) dyes, MHI-148, and Flamma-774 conjugated to HGC showed higher accumulation for MHI-HGC in 4T1 tumor and 4T1 tumor spheroid. In vitro studies showed high accumulation of MHI-HGC-PTX in 4T1 and SCC7 cancer cell lines compared to NIH3T3 cell line. In vivo fluorescence imaging of the 4T1 and SCC7 tumor showed peak accumulation of MHI-HGC-PTX at day 1 and elimination from the body at day 6. MHI-HGC-PTX showed good photothermal heating ability (50.3 °C), even at a low concentration of 33 μg/ml in 1 W/cm 2 808 nm laser at 1 min time point. Tumor reduction studies in BALB/c nude mice with SCC7 tumor showed marked reduction in MHI-HGC-PTX in the PTT group combined with photothermal therapy compared to MHI-HGC-PTX in the group without PTT. MHI-HGC-PTX is a cancer theranostic agent with cancer targeting and optical imaging capability. Our studies also showed that it has cancer targeting property independent of tumor type and tumor reduction property by combined photothermal and chemotherapeutic effects.

  13. Novel Dual Mitochondrial and CD44 Receptor Targeting Nanoparticles for Redox Stimuli-Triggered Release

    Science.gov (United States)

    Wang, Kaili; Qi, Mengjiao; Guo, Chunjing; Yu, Yueming; Wang, Bingjie; Fang, Lei; Liu, Mengna; Wang, Zhen; Fan, Xinxin; Chen, Daquan

    2018-02-01

    In this work, novel mitochondrial and CD44 receptor dual-targeting redox-sensitive multifunctional nanoparticles (micelles) based on oligomeric hyaluronic acid (oHA) were proposed. The amphiphilic nanocarrier was prepared by (5-carboxypentyl)triphenylphosphonium bromide (TPP), oligomeric hyaluronic acid (oHA), disulfide bond, and curcumin (Cur), named as TPP-oHA-S-S-Cur. The TPP targeted the mitochondria, the antitumor drug Cur served as a hydrophobic core, the CD44 receptor targeting oHA worked as a hydrophilic shell, and the disulfide bond acted as a connecting arm. The chemical structure of TPP-oHA-S-S-Cur was characterized by 1HNMR technology. Cur was loaded into the TPP-oHA-S-S-Cur micelles by self-assembly. Some properties, including the preparation of micelles, morphology, redox sensitivity, and mitochondrial targeting, were studied. The results showed that TPP-oHA-S-S-Cur micelles had a mean diameter of 122.4 ± 23.4 nm, zeta potential - 26.55 ± 4.99 mV. In vitro release study and cellular uptake test showed that TPP-oHA-S-S-Cur micelles had redox sensibility, dual targeting to mitochondrial and CD44 receptor. This work provided a promising smart multifunctional nanocarrier platform to enhance the solubility, decrease the side effects, and improve the therapeutic efficacy of anticancer drugs.

  14. Kepler Planet Detection Metrics: Per-Target Detection Contours for Data Release 25

    Science.gov (United States)

    Burke, Christopher J.; Catanzarite, Joseph

    2017-01-01

    A necessary input to planet occurrence calculations is an accurate model for the pipeline completeness (Burke et al., 2015). This document describes the use of the Kepler planet occurrence rate products in order to calculate a per-target detection contour for the measured Data Release 25 (DR25) pipeline performance. A per-target detection contour measures for a given combination of orbital period, Porb, and planet radius, Rp, what fraction of transit signals are recoverable by the Kepler pipeline (Twicken et al., 2016; Jenkins et al., 2017). The steps for calculating a detection contour follow the procedure outlined in Burke et al. (2015), but have been updated to provide improved accuracy enabled by the substantially larger database of transit injection and recovery tests that were performed on the final version (i.e., SOC 9.3) of the Kepler pipeline (Christiansen, 2017; Burke Catanzarite, 2017a). In the following sections, we describe the main inputs to the per-target detection contour and provide a worked example of the python software released with this document (Kepler Planet Occurrence Rate Tools KeplerPORTs)1 that illustrates the generation of a detection contour in practice. As background material for this document and its nomenclature, we recommend the reader be familiar with the previous method of calculating a detection contour (Section 2 of Burke et al.,2015), input parameters relevant for describing the data quantity and quality of Kepler targets (Burke Catanzarite, 2017b), and the extensive new transit injection and recovery tests of the Kepler pipeline (Christiansen et al., 2016; Burke Catanzarite, 2017a; Christiansen, 2017).

  15. Kepler Planet Detection Metrics: Per-Target Flux-Level Transit Injection Tests of TPS for Data Release 25

    Science.gov (United States)

    Burke, Christopher J.; Catanzarite, Joseph

    2017-01-01

    Quantifying the ability of a transiting planet survey to recover transit signals has commonly been accomplished through Monte-Carlo injection of transit signals into the observed data and subsequent running of the signal search algorithm (Gilliland et al., 2000; Weldrake et al., 2005; Burke et al., 2006). In order to characterize the performance of the Kepler pipeline (Twicken et al., 2016; Jenkins et al., 2017) on a sample of over 200,000 stars, two complementary injection and recovery tests are utilized:1. Injection of a single transit signal per target into the image or pixel-level data, hereafter referred to as pixel-level transit injection (PLTI), with subsequent processing through the Photometric Analysis (PA), Presearch Data Conditioning (PDC), Transiting Planet Search (TPS), and Data Validation (DV) modules of the Kepler pipeline. The PLTI quantification of the Kepler pipeline's completeness has been described previously by Christiansen et al. (2015, 2016); the completeness of the final SOC 9.3 Kepler pipeline acting on the Data Release 25 (DR25) light curves is described by Christiansen (2017).2. Injection of multiple transit signals per target into the normalized flux time series data with a subsequent transit search using a stream-lined version of the Transiting Planet Search (TPS) module. This test, hereafter referred to as flux-level transit injection (FLTI), is the subject of this document. By running a heavily modified version of TPS, FLTI is able to perform many injections on selected targets and determine in some detail which injected signals are recoverable. Significant numerical efficiency gains are enabled by precomputing the data conditioning steps at the onset of TPS and limiting the search parameter space (i.e., orbital period, transit duration, and ephemeris zero-point) to a small region around each injected transit signal.The PLTI test has the advantage that it follows transit signals through all processing steps of the Kepler pipeline, and

  16. Orexin–Corticotropin-Releasing Factor Receptor Heteromers in the Ventral Tegmental Area as Targets for Cocaine

    Science.gov (United States)

    Navarro, Gemma; Quiroz, César; Moreno-Delgado, David; Sierakowiak, Adam; McDowell, Kimberly; Moreno, Estefanía; Rea, William; Cai, Ning-Sheng; Aguinaga, David; Howell, Lesley A.; Hausch, Felix; Cortés, Antonio; Mallol, Josefa; Casadó, Vicent; Lluís, Carme; Canela, Enric I.

    2015-01-01

    Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R–OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target σ1 receptor (σ1R) also associates with the CRF1R–OX1R heteromer. Cocaine binding to the σ1R–CRF1R–OX1R complex promotes a long-term disruption of the orexin-A–CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking. PMID:25926444

  17. Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine.

    Science.gov (United States)

    Navarro, Gemma; Quiroz, César; Moreno-Delgado, David; Sierakowiak, Adam; McDowell, Kimberly; Moreno, Estefanía; Rea, William; Cai, Ning-Sheng; Aguinaga, David; Howell, Lesley A; Hausch, Felix; Cortés, Antonio; Mallol, Josefa; Casadó, Vicent; Lluís, Carme; Canela, Enric I; Ferré, Sergi; McCormick, Peter J

    2015-04-29

    Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R-OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target σ1 receptor (σ1R) also associates with the CRF1R-OX1R heteromer. Cocaine binding to the σ1R-CRF1R-OX1R complex promotes a long-term disruption of the orexin-A-CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking. Copyright © 2015 the authors 0270-6474/15/356639-15$15.00/0.

  18. Highly Complementary Target RNAs Promote Release of Guide RNAs from Human Argonaute2

    Science.gov (United States)

    De, Nabanita; Young, Lisa; Lau, Pick-Wei; Meisner, Nicole-Claudia; Morrissey, David V.; MacRae, Ian J.

    2013-01-01

    SUMMARY Argonaute proteins use small RNAs to guide the silencing of complementary target RNAs in many eukaryotes. Although small RNA biogenesis pathways are well studied, mechanisms for removal of guide RNAs from Argonaute are poorly understood. Here we show that the Argonaute2 (Ago2) guide RNA complex is extremely stable, with a half-life on the order of days. However, highly complementary target RNAs destabilize the complex and significantly accelerate release of the guide RNA from Ago2. This “unloading” activity can be enhanced by mismatches between the target and the guide 5′ end and attenuated by mismatches to the guide 3′ end. The introduction of 3′ mismatches leads to more potent silencing of abundant mRNAs in mammalian cells. These findings help to explain why the 3′ ends of mammalian microRNAs (miRNAs) rarely match their targets, suggest a mechanism for sequence-specific small RNA turnover, and offer insights for controlling small RNAs in mammalian cells. PMID:23664376

  19. Targeting thyroid cancer with acid-triggered release of doxorubicin from silicon dioxide nanoparticles

    Directory of Open Access Journals (Sweden)

    Li SJ

    2017-08-01

    Full Text Available Shijie Li,1 Daqi Zhang,1 Shihou Sheng,2 Hui Sun1 1Department of Thyroid Surgery, 2Department of Gastrointestinal Colorectal and Anal Surgery, China–Japan Union Hospital of Jilin University, Chang Chun, People’s Republic of China Abstract: Currently, therapy for thyroid cancer mainly involves surgery and radioiodine therapy. However, chemotherapy can be used in advanced and aggressive thyroid cancer that cannot be treated by other options. Nevertheless, a major obstacle to the successful treatment of thyroid cancer is the delivery of drugs to the thyroid gland. Here, we present an example of the construction of silicon dioxide nanoparticles with thyroid–stimulating-hormone receptor-targeting ligand that can specifically target the thyroid cancer. Doxorubicin nanoparticles can be triggered by acid to release the drug payload for cancer therapy. These nanoparticles shrink the tumor size in vivo with less toxic side effects. This research paves the way toward effective chemotherapy for thyroid cancer. Keywords: thyroid cancer, silicon dioxide nanoparticle, doxorubicin, acid-triggered release

  20. Analysis and prospectives of the mechanism of release of energy efficiency titles

    International Nuclear Information System (INIS)

    Pastore, P.

    2009-01-01

    Starting from the Third annual report on the mechanism of release of energetic efficiency titles and considering the Decree Ministerial 21/12/2007, there is an analysis of the better aspects of the mechanism of release of energetic efficiency titles introduced from the norms regarding the previous annual relations. Particularly important is the role carried out from the Authority of the Electric Power and the Gas in the action of control and monitoring of the market. In this direction they have been formulated various deliberations. Analyzing the results obtained from the market of energetic efficiency titles in the course of 2007, it has been caught up 98% of the established objectives. In the course of the same year they have been cancelled many titles, as a result of verification activity. The obtained results refer to the geographic distribution, to the exchanged volumes and to the costs of the titles. At last some criticalities are placed in evidence that remain in the mechanism and that they can be resolved in order to improve the market. [it

  1. Factors affecting the efficiency of the sterile insect release method for tsetse

    International Nuclear Information System (INIS)

    Curtis, C.F.

    1980-01-01

    Data are reviewed on the levels of sterility, survival and competitiveness of Glossina males after irradiation with various gamma-ray doses delivered in air or nitrogen. A simple population model helps in the choice of the optimum dose. Field studies of mating competitiveness require a measure of the ratio of sterile to fertile males and of sterile to fertile matings, and both ratio estimates will be subject to sampling error. Data on multiple mating of female Glossina are reviewed. There is some degree of precedence for sperm from the first mating but sterile sperm are fully competitive for fertilization and, following the early death of an embryo, the timing of the next ovulation is only advanced to a slight extent. Thus in an isolated population the occurrence or non-occurrence of female polygamy would be of almost no consequence. Where mated females were immigrating into the release area female polygamy would be advantageous. The low recovery potential of tsetse populations is the main reason for thinking them suitable for control by the introduction of sterility. In trying to measure this recovery potential it is important to distinguish it from natural seasonal increase. If natural population fluctuations are studied to detect density dependent effects it is important not to confuse cause with effect. Non-isolation of the 'target' population is almost certainly the most serious obstacle to practical application of the sterile insect release method, and a steady 'rolling forward' of the release area may be a possible solution. (author)

  2. On the efficiency of conical targets for laser thermonuclear fusion

    International Nuclear Information System (INIS)

    Borovskij, A.V.; Korobkin, V.V.

    1981-01-01

    Advantages and drawbacks of conical targets (CT) for laser fusion (LF) are discussed. Possibility of the laser power reduction, laser pulse lengthening and neutron yield increase are analyzed for an ideal conical target with absolutely rigid and heat-proof walls as compared to a spherical target of the same mass. A simple theory is suggested which makes it possible to take into account an effect of walls on the fusion process in the conical target with gaseous fuel and heavy shell. Energy losses due to wall deformations and heat conduction are estimated. An influence of these effects on the neutron yield is estimated. CT used in the LF experiments are found to have serious drawbacks in comparison with spherical ones. These drawbacks are connected with the effect of walls on the processes taking place in CT. Analysis of CT, for which the effect of walls is not significant, points up some definite advantages of CT as compared with spherical one. These advantages are the possibility of laser pulse lengthening and laser power reduction in comparison with the irradiation of a sphere of an equal mass. These two positive qualities are connected with the fact that CT has large linear dimensions [ru

  3. Energy efficiency improvement target for SIC 34 - fabricated metal products

    Energy Technology Data Exchange (ETDEWEB)

    Byrer, T. G.; Billhardt, C. F.; Farkas, M. S.

    1977-03-15

    A March 15, 1977 revision of a February 15, 1977 document on the energy improvement target for the Fabricated Metal Products industry (SIC 34) is presented. A net energy savings in 1980 of 24% as compared with 1972 energy consumption in SIC 34 is considered a realistic goal. (ERA citation 04:045008)

  4. System with embedded drug release and nanoparticle degradation sensor showing efficient rifampicin delivery into macrophages.

    Science.gov (United States)

    Trousil, Jiří; Filippov, Sergey K; Hrubý, Martin; Mazel, Tomáš; Syrová, Zdeňka; Cmarko, Dušan; Svidenská, Silvie; Matějková, Jana; Kováčik, Lubomír; Porsch, Bedřich; Konefał, Rafał; Lund, Reidar; Nyström, Bo; Raška, Ivan; Štěpánek, Petr

    2017-01-01

    We have developed a biodegradable, biocompatible system for the delivery of the antituberculotic antibiotic rifampicin with a built-in drug release and nanoparticle degradation fluorescence sensor. Polymer nanoparticles based on poly(ethylene oxide) monomethyl ether-block-poly(ε-caprolactone) were noncovalently loaded with rifampicin, a combination that, to best of our knowledge, was not previously described in the literature, which showed significant benefits. The nanoparticles contain a Förster resonance energy transfer (FRET) system that allows real-time assessment of drug release not only in vitro, but also in living macrophages where the mycobacteria typically reside as hard-to-kill intracellular parasites. The fluorophore also enables in situ monitoring of the enzymatic nanoparticle degradation in the macrophages. We show that the nanoparticles are efficiently taken up by macrophages, where they are very quickly associated with the lysosomal compartment. After drug release, the nanoparticles in the cmacrophages are enzymatically degraded, with half-life 88±11 min. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Feline Tetherin Efficiently Restricts Release of Feline Immunodeficiency Virus but Not Spreading of Infection▿

    Science.gov (United States)

    Dietrich, Isabelle; McMonagle, Elizabeth L.; Petit, Sarah J.; Vijayakrishnan, Swetha; Logan, Nicola; Chan, Chi N.; Towers, Greg J.; Hosie, Margaret J.; Willett, Brian J.

    2011-01-01

    Domestic cats endure infections by all three subfamilies of the retroviridae: lentiviruses (feline immunodeficiency virus [FIV]), gammaretroviruses (feline leukemia virus [FeLV]), and spumaretroviruses (feline foamy virus [FFV]). Thus, cats present an insight into the evolution of the host-retrovirus relationship and the development of intrinsic/innate immune mechanisms. Tetherin (BST-2) is an interferon-inducible transmembrane protein that inhibits the release of enveloped viruses from infected cells. Here, we characterize the feline homologue of tetherin and assess its effects on the replication of FIV. Tetherin was expressed in many feline cell lines, and expression was induced by interferons, including alpha interferon (IFN-α), IFN-ω, and IFN-γ. Like human tetherin, feline tetherin displayed potent inhibition of FIV and HIV-1 particle release; however, this activity resisted antagonism by either HIV-1 Vpu or the FIV Env and “OrfA” proteins. Further, as overexpression of complete FIV genomes in trans could not overcome feline tetherin, these data suggest that FIV lacks a functional tetherin antagonist. However, when expressed stably in feline cell lines, tetherin did not abrogate the replication of FIV; indeed, syncytium formation was significantly enhanced in tetherin-expressing cells infected with cell culture-adapted (CD134-independent) strains of FIV (FIV Fca-F14 and FIV Pco-CoLV). Thus, while tetherin may prevent the release of nascent viral particles, cell-to-cell spread remains efficient in the presence of abundant viral receptors and tetherin upregulation may enhance syncytium formation. Accordingly, tetherin expression in vivo may promote the selective expansion of viral variants capable of more efficient cell-to-cell spread. PMID:21490095

  6. Feline tetherin efficiently restricts release of feline immunodeficiency virus but not spreading of infection.

    Science.gov (United States)

    Dietrich, Isabelle; McMonagle, Elizabeth L; Petit, Sarah J; Vijayakrishnan, Swetha; Logan, Nicola; Chan, Chi N; Towers, Greg J; Hosie, Margaret J; Willett, Brian J

    2011-06-01

    Domestic cats endure infections by all three subfamilies of the retroviridae: lentiviruses (feline immunodeficiency virus [FIV]), gammaretroviruses (feline leukemia virus [FeLV]), and spumaretroviruses (feline foamy virus [FFV]). Thus, cats present an insight into the evolution of the host-retrovirus relationship and the development of intrinsic/innate immune mechanisms. Tetherin (BST-2) is an interferon-inducible transmembrane protein that inhibits the release of enveloped viruses from infected cells. Here, we characterize the feline homologue of tetherin and assess its effects on the replication of FIV. Tetherin was expressed in many feline cell lines, and expression was induced by interferons, including alpha interferon (IFN-α), IFN-ω, and IFN-γ. Like human tetherin, feline tetherin displayed potent inhibition of FIV and HIV-1 particle release; however, this activity resisted antagonism by either HIV-1 Vpu or the FIV Env and "OrfA" proteins. Further, as overexpression of complete FIV genomes in trans could not overcome feline tetherin, these data suggest that FIV lacks a functional tetherin antagonist. However, when expressed stably in feline cell lines, tetherin did not abrogate the replication of FIV; indeed, syncytium formation was significantly enhanced in tetherin-expressing cells infected with cell culture-adapted (CD134-independent) strains of FIV (FIV Fca-F14 and FIV Pco-CoLV). Thus, while tetherin may prevent the release of nascent viral particles, cell-to-cell spread remains efficient in the presence of abundant viral receptors and tetherin upregulation may enhance syncytium formation. Accordingly, tetherin expression in vivo may promote the selective expansion of viral variants capable of more efficient cell-to-cell spread.

  7. Double targeting and aptamer-assisted controlled release delivery of epirubicin to cancer cells by aptamers-based dendrimer in vitro and in vivo.

    Science.gov (United States)

    Taghdisi, Seyed Mohammad; Danesh, Noor Mohammad; Ramezani, Mohammad; Lavaee, Parirokh; Jalalian, Seyed Hamid; Robati, Rezvan Yazdian; Abnous, Khalil

    2016-05-01

    Clinical use of epirubicin (Epi) in the treatment of cancer has been limited, due to its cardiotoxicity. Targeted delivery of chemotherapeutic agents could increase their efficacy and reduce their off-target effects. High drug loading and excellent stability of DNA dendrimers make these DNA nanostructures unique candidates for biological applications. In this study a modified and promoted dendrimer using three kinds of aptamers (MUC1, AS1411 and ATP aptamers) was designed for targeted delivery of Epi and its efficacy was evaluated in target cells including MCF-7 cells (breast cancer cell) and C26 cells (murine colon carcinoma cell). Aptamers (Apts)-Dendrimer-Epi complex formation was analyzed by fluorometric analysis and gel retardation assay. Release profiles of Epi from the designed complex were assessed at pHs 5.4 and 7.4. For MTT assay (cytotoxic study) MCF-7 and C26 cells (target cells) and CHO cells (Chinese hamster ovary cell, nontarget) were treated with Epi, Apts-Dendrimer-Epi complex and Apts-Dendrimer conjugate. Internalization was evaluated using flow cytometry analysis. Finally, the developed complex was used for inhibition of tumor growth in vivo. 25μM Epi was efficiently intercalated to 1μM dendrimer. Epi was released from the Apts-Dendrimer-Epi complex in a pH-sensitive manner (more release at pH 5.5). The results of flow cytometry analysis indicated that the designed complex was efficiently internalized into target cells, but not into control cells. The internalization data were confirmed by the results of MTT assay. Apts-Dendrimer-Epi complex had less cytotoxicity in CHO cells compared to Epi alone. The complex had more cytotoxicity in C26 and MCF-7 cells compared to Epi alone. Moreover, the Apts-Dendrimer-Epi complex could efficiently prohibit tumor growth in vivo. In conclusion, the designed targeted drug delivery system inherited characteristics of pH-dependent drug release, high drug loading and tumor targeting in vitro and in vivo

  8. Impact of controlled release urea on maize yield and nitrogen use efficiency under different water conditions.

    Directory of Open Access Journals (Sweden)

    Guanghao Li

    Full Text Available Controlled release urea (CRU has been widely adopted to increase nitrogen (N use efficiency and maize production, but the impacts can range widely depending on water availability in the soil. In an experiment using Zhengdan 958 (a popular summer maize hybrid, three levels of water treatments (adequate water condition [W3], which maintained soil moisture at about 75% ± 5% of the soil's field capacity; mild water stress [W2], which maintained moisture content at 55% ± 5% of field capacity; and severe water stress [W1], which had a moisture content of 35% ± 5% of field capacity and four levels of controlled release urea fertilizer (N0, N1, N2 and N3 were 0, 105, 210 and 315 kg N ha-1, respectively were compared in a rainout shelter system with soil. The results revealed that CRU had significant effects on maize yields and N use efficiencies under different water conditions. The mean yields increased with increasing water levels and showed significant differences. Under W1, the accumulation of dry matter and N were limited, and N internal efficiency (NIE and the apparent recovery efficiency of applied N (REN decreased with N increases; yields of N1, N2, and N3 were similar. Under W2, the dry matter and N accumulation, as well as the yield, showed an increasing trend with an increase in N application, and the NIE and REN of N3 showed no difference from N2. Under W3, yields of N2 and N3 were similar and they were significantly higher than that of N1, but the agronomic N use efficiency (ANUE, REN, and the physiological NUE (PNUE of N2 were 54.2, 34.9, and 14.4% higher, respectively, than those of N3. N application beyond the optimal N rate did not consistently increase maize yield, and caused a decrease in N use efficiencies. Highest overall dry matter, N accumulation, and yields were observed with N3 under W2, and those showed no differences with N2 and N3 under W3. Under this experimental condition, the CRU of 210 kg ha-1 was optimized when soil

  9. Physically Targeted Intravenous Polyurethane Nanoparticles for Controlled Release of Atorvastatin Calcium

    Science.gov (United States)

    Eftekhari, Behnaz Sadat; Karkhaneh, Akbar; Alizadeh, Ali

    2017-01-01

    Background: Intravenous drug delivery is an advantageous choice for rapid administration, immediate drug effect, and avoidance of first-pass metabolism in oral drug delivery. In this study, the synthesis, formulation, and characterization of atorvastatin-loaded polyurethane (PU) nanoparticles were investigated for intravenous route of administration. Method: First, PU was synthesized and characterized. Second, nanoparticles were prepared in four different ratios of drug to polymer through two different techniques, including emulsion-diffusion and single-emulsion. Finally, particle size and polydispersity index, shape and surface morphology, drug entrapment efficiency (EE), drug loading, and in vitro release were evaluated by dynamics light scattering, scanning electron microscopy, and UV visible spectroscopy, respectively. Results: Within two methods, the prepared nanoparticles had a spherical shape and a smooth surface with a diversity of size ranged from 174.04 nm to 277.24 nm in emulsion-diffusion and from 306.5 nm to 393.12 in the single-emulsion method. The highest EE was 84.76%, for (1:4) sample in the emulsion-diffusion method. It has also been shown that in vitro release of nanoparticles, using the emulsion-diffusion method, was sustained up to eight days by two mechanisms: drug diffusion and polymer relaxation. Conclusion: PU nanoparticles, that were prepared by the emulsion-diffusion method, could be used as effective carriers for the controlled drug delivery of poorly water soluble drugs such as atorvastatin calcium. PMID:28532144

  10. Kinetic analysis of the effects of target structure on siRNA efficiency

    Science.gov (United States)

    Chen, Jiawen; Zhang, Wenbing

    2012-12-01

    RNAi efficiency for target cleavage and protein expression is related to the target structure. Considering the RNA-induced silencing complex (RISC) as a multiple turnover enzyme, we investigated the effect of target mRNA structure on siRNA efficiency with kinetic analysis. The 4-step model was used to study the target cleavage kinetic process: hybridization nucleation at an accessible target site, RISC-mRNA hybrid elongation along with mRNA target structure melting, target cleavage, and enzyme reactivation. At this model, the terms accounting for the target accessibility, stability, and the seed and the nucleation site effects are all included. The results are in good agreement with that of experiments which show different arguments about the structure effects on siRNA efficiency. It shows that the siRNA efficiency is influenced by the integrated factors of target's accessibility, stability, and the seed effects. To study the off-target effects, a simple model of one siRNA binding to two mRNA targets was designed. By using this model, the possibility for diminishing the off-target effects by the concentration of siRNA was discussed.

  11. Chitosan-based DNA delivery vector targeted to gonadotropin-releasing hormone (GnRH) receptor.

    Science.gov (United States)

    Boonthum, Chatwalee; Namdee, Katawut; Boonrungsiman, Suwimon; Chatdarong, Kaywalee; Saengkrit, Nattika; Sajomsang, Warayuth; Ponglowhapan, Suppawiwat; Yata, Teerapong

    2017-02-10

    The main purpose of this study was to investigate the application of modified chitosan as a potential vector for gene delivery to gonadotropin-releasing hormone receptor (GnRHR)-expressing cells. Such design of gene carrier could be useful in particular for gene therapy for cancers related to the reproductive system, gene disorders of sexual development, and contraception and fertility control. In this study, a decapeptide GnRH was successfully conjugated to chitosan (CS) as confirmed by proton nuclear magnetic resonance spectroscopy ( 1 H NMR) and Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). The synthesized GnRH-conjugated chitosan (GnRH-CS) was able to condense DNA to form positively charged nanoparticles and specifically deliver plasmid DNA to targeted cells in both two-dimensional (2D) and three-dimensional (3D) cell cultures systems. Importantly, GnRH-CS exhibited higher transfection activity compared to unmodified CS. In conclusion, GnRH-conjugated chitosan can be a promising carrier for targeted DNA delivery to GnRHR-expressing cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Evaluating Efficiencies of Dual AAV Approaches for Retinal Targeting

    Directory of Open Access Journals (Sweden)

    Livia S. Carvalho

    2017-09-01

    Full Text Available Retinal gene therapy has come a long way in the last few decades and the development and improvement of new gene delivery technologies has been exponential. The recent promising results from the first clinical trials for inherited retinal degeneration due to mutations in RPE65 have provided a major breakthrough in the field and have helped cement the use of recombinant adeno-associated viruses (AAV as the major tool for retinal gene supplementation. One of the key problems of AAV however, is its limited capacity for packaging genomic information to a maximum of around 4.8 kb. Previous studies have demonstrated that homologous recombination and/or inverted terminal repeat (ITR mediated concatemerization of two overlapping AAV vectors can partially overcome the size limitation and help deliver larger transgenes. The aim of this study was to investigate and compare the use of different AAV dual-vector approaches in the mouse retina using a systematic approach comparing efficiencies in vitro and in vivo using a unique oversized reporter construct. We show that the hybrid approach relying on vector genome concatemerization by highly recombinogenic sequences and ITRs sequence overlap offers the best levels of reconstitution both in vitro and in vivo compared to trans-splicing and overlap strategies. Our data also demonstrate that dose and vector serotype do not affect reconstitution efficiency but a discrepancy between mRNA and protein expression data suggests a bottleneck affecting translation.

  13. THE SDSS-III BARYON OSCILLATION SPECTROSCOPIC SURVEY: QUASAR TARGET SELECTION FOR DATA RELEASE NINE

    Energy Technology Data Exchange (ETDEWEB)

    Ross, Nicholas P.; Kirkpatrick, Jessica A.; Carithers, William C.; Ho, Shirley [Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720 (United States); Myers, Adam D. [Department of Astronomy, MC-221, University of Illinois, 1002 West Green Street, Urbana, IL 61801 (United States); Sheldon, Erin S. [Brookhaven National Laboratory, Blgd 510, Upton, NY 11375 (United States); Yeche, Christophe; Aubourg, Eric [CEA, Centre de Saclay, IRFU, 91191 Gif-sur-Yvette (France); Strauss, Michael A.; Lee, Khee-Gan [Department of Astrophysical Sciences, Princeton University, Princeton, NJ 08544 (United States); Bovy, Jo; Blanton, Michael R.; Hogg, David W. [Center for Cosmology and Particle Physics, New York University, 4 Washington Place, New York, NY 10003 (United States); Richards, Gordon T. [Department of Physics, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104 (United States); Brandt, W. N. [Department of Astronomy and Astrophysics, The Pennsylvania State University, 525 Davey Laboratory, University Park, PA 16802 (United States); Croft, Rupert A. C. [Bruce and Astrid McWilliams Center for Cosmology, Carnegie Mellon University, Pittsburgh, PA 15213 (United States); Da Silva, Robert [Department of Astronomy and Astrophysics, University of California, Santa Cruz, Santa Cruz, CA 95064 (United States); Dawson, Kyle [Department of Physics and Astronomy, University of Utah, UT (United States); Eisenstein, Daniel J. [Steward Observatory, 933 North Cherry Avenue, Tucson, AZ 85721 (United States); Hennawi, Joseph F., E-mail: npross@lbl.gov [Max-Planck-Institut fuer Astronomie, Konigstuhl 17, 69117 Heidelberg (Germany); and others

    2012-03-01

    The SDSS-III Baryon Oscillation Spectroscopic Survey (BOSS), a five-year spectroscopic survey of 10,000 deg{sup 2}, achieved first light in late 2009. One of the key goals of BOSS is to measure the signature of baryon acoustic oscillations (BAOs) in the distribution of Ly{alpha} absorption from the spectra of a sample of {approx}150,000 z > 2.2 quasars. Along with measuring the angular diameter distance at z Almost-Equal-To 2.5, BOSS will provide the first direct measurement of the expansion rate of the universe at z > 2. One of the biggest challenges in achieving this goal is an efficient target selection algorithm for quasars in the redshift range 2.2 < z < 3.5, where their colors tend to overlap those of the far more numerous stars. During the first year of the BOSS survey, quasar target selection (QTS) methods were developed and tested to meet the requirement of delivering at least 15 quasars deg{sup -2} in this redshift range, with a goal of 20 out of 40 targets deg{sup -2} allocated to the quasar survey. To achieve these surface densities, the magnitude limit of the quasar targets was set at g {<=} 22.0 or r {<=} 21.85. While detection of the BAO signature in the distribution of Ly{alpha} absorption in quasar spectra does not require a uniform target selection algorithm, many other astrophysical studies do. We have therefore defined a uniformly selected subsample of 20 targets deg{sup -2}, for which the selection efficiency is just over 50% ({approx}10 z > 2.20 quasars deg{sup -2}). This 'CORE' subsample will be fixed for Years Two through Five of the survey. For the remaining 20 targets deg{sup -2}, we will continue to develop improved selection techniques, including the use of additional data sets beyond the Sloan Digital Sky Survey (SDSS) imaging data. In this paper, we describe the evolution and implementation of the BOSS QTS algorithms during the first two years of BOSS operations (through 2011 July), in support of the science investigations

  14. High efficiency targets for high gain inertial confinement fusion

    International Nuclear Information System (INIS)

    Gardner, J.H.; Bodner, S.E.

    1986-01-01

    Rocket efficiencies as high as 15% are possible using short wavelength lasers and moderately high aspect ratio pellet designs. These designs are made possible by two recent breakthroughs in physics constraints. First is the development of the Induced Spatial Incoherence (ISI) technique which allows uniform illumination of the pellet and relaxes the constraint of thermal smoothing, permitting the use of short wavelength laser light. Second is the discovery that the Rayleigh-Taylor growth rate is considerably reduced at the short laser wavelengths. By taking advantage of the reduced constraints imposed by nonuniform laser illumination and Rayleigh-Taylor instability, pellets using 1/4 micron laser light and initial aspect ratios of about 10 (with in flight aspect ratios of about 150 to 200) may produce energy gains as high as 200 to 250

  15. Comparison of the calcium release channel of cardiac and skeletal muscle sarcoplasmic reticulum by target inactivation analysis

    International Nuclear Information System (INIS)

    McGrew, S.G.; Inui, Makoto; Chadwick, C.C.; Boucek, R.J. Jr.; Jung, C.Y.; Fleischer, S.

    1989-01-01

    The calcium release channel of sarcoplasmic reticulum which triggers muscle contraction in excitation-contraction coupling has recently been isolated. The channel has been found to be morphologically identical with the feet structures of the junctional face membrane of terminal cisternae and consists of an oligomer of a unique high molecular weight polypeptide. In this study, the authors compare the target size of the calcium release channel from heart and skeletal muscle using target inactivation analysis. The target molecular weights of the calcium release channel estimated by measuring ryanodine binding after irradiation are similar for heart (139,000) and skeletal muscle (143,000) and are smaller than the monomeric unit (estimated to be about 360,000). The target size, estimated by measuring polypeptide remaining after irradiation, was essentially the same for heart and skeletal muscle, 1,061,000 and 1,070,000, respectively, indicating an oligomeric association of protomers. Thus, the calcium release channel of both cardiac and skeletal muscle reacts uniquely with regard to target inactivation analysis in that (1) the size by ryanodine binding is smaller than the monomeric unit and (2) a single hit leads to destruction of more than one polypeptide, by measuring polypeptide remaining. The target inactivation analysis studies indicate that heart and skeletal muscle receptors are structurally very similar

  16. Artificial Chemical Reporter Targeting Strategy Using Bioorthogonal Click Reaction for Improving Active-Targeting Efficiency of Tumor.

    Science.gov (United States)

    Yoon, Hong Yeol; Shin, Min Lee; Shim, Man Kyu; Lee, Sangmin; Na, Jin Hee; Koo, Heebeom; Lee, Hyukjin; Kim, Jong-Ho; Lee, Kuen Yong; Kim, Kwangmeyung; Kwon, Ick Chan

    2017-05-01

    Biological ligands such as aptamer, antibody, glucose, and peptide have been widely used to bind specific surface molecules or receptors in tumor cells or subcellular structures to improve tumor-targeting efficiency of nanoparticles. However, this active-targeting strategy has limitations for tumor targeting due to inter- and intraheterogeneity of tumors. In this study, we demonstrated an alternative active-targeting strategy using metabolic engineering and bioorthogonal click reaction to improve tumor-targeting efficiency of nanoparticles. We observed that azide-containing chemical reporters were successfully generated onto surface glycans of various tumor cells such as lung cancer (A549), brain cancer (U87), and breast cancer (BT-474, MDA-MB231, MCF-7) via metabolic engineering in vitro. In addition, we compared tumor targeting of artificial azide reporter with bicyclononyne (BCN)-conjugated glycol chitosan nanoparticles (BCN-CNPs) and integrin α v β 3 with cyclic RGD-conjugated CNPs (cRGD-CNPs) in vitro and in vivo. Fluorescence intensity of azide-reporter-targeted BCN-CNPs in tumor tissues was 1.6-fold higher and with a more uniform distribution compared to that of cRGD-CNPs. Moreover, even in the isolated heterogeneous U87 cells, BCN-CNPs could bind artificial azide reporters on tumor cells more uniformly (∼92.9%) compared to cRGD-CNPs. Therefore, the artificial azide-reporter-targeting strategy can be utilized for targeting heterogeneous tumor cells via bioorthogonal click reaction and may provide an alternative method of tumor targeting for further investigation in cancer therapy.

  17. Nordic views on the next generation of EU energy efficiency targets

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2012-11-15

    EU has a target for energy efficiency for 2020, namely a 20 % reduction in the primary energy consumption relative to the PRIMES 2007 forecast for 2020. According to the new energy efficiency directive, that was agreed upon in June 2012, the target is that primary energy consumption must be no more than 1,474 Mtoe or that final energy consumption must be no more than 1,078 Mtoe by 2020. This is an absolute target for EU as a whole. There are no binding targets for member states. Due to the time lapse from goal setting, to policy formulation and practical implementation it is found that 2020 is just around the corner, and that it is high time to start discussion about the next goals. This could be concrete targets for 2030 and indicative targets for 2050. In this report target design and policy instruments are discussed from a Nordic perspective: Is it relevant to have an energy efficiency target? Should targets for energy efficiency be set in terms of primary energy or final energy? In absolute numbers or in relative numbers? Whether and how to divide the burden sharing? What are the Nordic positions of strength with regard to policy instruments? (LN)

  18. Supplementary Material for: DASPfind: new efficient method to predict drug–target interactions

    KAUST Repository

    Ba Alawi, Wail; Soufan, Othman; Essack, Magbubah; Kalnis, Panos; Bajic, Vladimir B.

    2016-01-01

    Abstract Background Identification of novel drug–target interactions (DTIs) is important for drug discovery. Experimental determination of such DTIs is costly and time consuming, hence it necessitates the development of efficient computational

  19. Release studies of a thin foil tantalum target for the production of short-lived radioactive nuclei

    CERN Document Server

    Bennett, J R J; Drumm, P V; Lettry, Jacques; Nilsson, T; Catherall, R; Jonsson, O C; Ravn, H L; Simon, H

    2002-01-01

    Measurements have been made at ISOLDE, of the release curves and yields of radioactive beams of lithium, sodium and beryllium from a target constructed from 2 $\\mu$m thick foils. The release curves have been analysed by fitting to a mathematical model to determine the coefficients of diffusion of the particles in the foils and effusion through the target and ionizer at several temperatures. Through a better understanding of the rate of transport of the particles, it is possible to design targets and ionizers with improved yields. This is most important for the rare, short-lived isotopes in which there is considerable interest for physics experiments. This target has demonstrated large increases in the yields of $^{11}$Li and $^{12}$Be, in agreement with the predictions of the model. (11 refs).

  20. High-Efficiency Retrofit Lessons for Retail from a SuperTarget: Preprint

    Energy Technology Data Exchange (ETDEWEB)

    Langner, R.; Deru, M.; Hirsch, A.; Williams, S.

    2013-02-01

    The National Renewable Energy Laboratory partnered with Target under the Commercial Building Program to design and implement a retrofit of a SuperTarget in Thornton, CO. The result was a retrofit design that predicted 37% energy savings over ASHRAE Standard 90.1-2004, and 29% compared to existing (pre-retrofit) store consumption. The largest savings came from energy efficient lighting, energy efficient cooling systems, improved refrigeration, and better control of plug loads.

  1. Effects of Controlled-Release Urea on Grain Yield of Spring Maize, Nitrogen Use Efficiency and Nitrogen Balance

    Directory of Open Access Journals (Sweden)

    JI Jing-hong

    2017-03-01

    Full Text Available The effects of mixing controlled-released urea (CRU (release period of resin coated urea is 90 days and urea (U on maize yield, nitrogen use efficiency and nitrogen balance were studied by 4 plot experiments (site:Shuangcheng, Binxian, Harbin and Zhaoyuan in two years (from year 2011 to 2012 to clarify the effect of controlled release urea on spring maize and soil nitrogen balance. Results were as follow:Spring maize yield and nitrogen absorption were increased with the increasing nitrogen fertilizer. Compared with applying urea treatment, applying CRU could increase yield, nitrogen absorption, nitrogen use efficiency, agriculture efficiency of nitrogen and nitrogen contribution rate. Under the same amount of nitrogen (100%, 75%, 50%, compared with 100% U as basic fertilizer treatment, maize yield of 100% CRU treatment increased 391, 427, 291 kg·hm-2, nitrogen use efficiency increased by 5.9%,4.9% and 5.1%, agriculture efficiency of nitrogen increased 2.0, 2.6, 2.6 kg·kg-1, and nitrogen contribution rate increased 2.7%, 3.1% and 2.4%, respectively. The value of maize yield, nitrogen absorption, nitrogen use efficiency and agriculture efficiency of nitrogen between the treatment four (40% urea as basic fertilizer+60% urea as topdressing and treatment five (40% urea plus 60% controlled release urea as basic fertilizer were similar. Apparent profit and loss of nitrogen decreased with the increase of nitrogen nitrogen fertilizer. Nitrogen apparent loss by applying 100% controlled release urea was reduced of 15.0 kg·hm-2 than applying 100% U treatment;Nitrogen apparent loss amount was decreased of 23.9 kg·hm-2 under treatment five. The method of mixing 40% urea and 60% controlled release urea should be applied in maize production in Heilongjiang Province.

  2. Analytical definition of fission chain reaction parameters for cylindrical uranium bar and energy release evaluations for HIF hybrid targets

    International Nuclear Information System (INIS)

    Imshennik, V.S.

    2006-01-01

    Within the conditions of Heavy-Ion Fusion (HIF) arises a possibility to obtain the fission chain reaction for a cylindrical HIF target. The paper contains the solution interpolated with the diffusion approximation in order to receive the general approximation expressions for the bar critical radius as well as for over-critical state. The obtained critical parameters generalized for uranium envelope are used for rough evaluation of the energy release in HIF hybrid targets [ru

  3. Toward high-efficiency and detailed Monte Carlo simulation study of the granular flow spallation target

    Science.gov (United States)

    Cai, Han-Jie; Zhang, Zhi-Lei; Fu, Fen; Li, Jian-Yang; Zhang, Xun-Chao; Zhang, Ya-Ling; Yan, Xue-Song; Lin, Ping; Xv, Jian-Ya; Yang, Lei

    2018-02-01

    The dense granular flow spallation target is a new target concept chosen for the Accelerator-Driven Subcritical (ADS) project in China. For the R&D of this kind of target concept, a dedicated Monte Carlo (MC) program named GMT was developed to perform the simulation study of the beam-target interaction. Owing to the complexities of the target geometry, the computational cost of the MC simulation of particle tracks is highly expensive. Thus, improvement of computational efficiency will be essential for the detailed MC simulation studies of the dense granular target. Here we present the special design of the GMT program and its high efficiency performance. In addition, the speedup potential of the GPU-accelerated spallation models is discussed.

  4. A targeted liposome delivery system for combretastatin A4: formulation optimization through drug loading and in vitro release studies.

    Science.gov (United States)

    Nallamothu, Ramakrishna; Wood, George C; Kiani, Mohammad F; Moore, Bob M; Horton, Frank P; Thoma, Laura A

    2006-01-01

    Efficient liposomal therapeutics require high drug loading and low leakage. The objective of this study is to develop a targeted liposome delivery system for combretastatin A4 (CA4), a novel antivascular agent, with high loading and stable drug encapsulation. Liposomes composed of hydrogenated soybean phosphatidylcholine (HSPC), cholesterol, and distearoyl phosphoethanolamine-PEG-2000 conjugate (DSPE-PEG) were prepared by the lipid film hydration and extrusion process. Cyclic arginine-glycine-aspartic acid (RGD) peptides with affinity for alphav beta3-integrins overexpressed on tumor vascular endothelial cells were coupled to the distal end of polyethylene glycol (PEG) on the liposomes sterically stabilized with PEG (non-targeted liposomes; LCLs). Effect of lipid concentration, drug-to-lipid ratio, cholesterol, and DSPE-PEG content in the formulation on CA4 loading and its release from the liposomes was studied. Total liposomal CA4 levels obtained increased with increasing lipid concentration in the formulation. As the drug-to-lipid ratio increased from 10:100 to 20:100, total drug in the liposome formulation increased from 1.05+/-0.11 mg/mL to 1.55+/-0.13 mg/mL, respectively. When the drug-to-lipid ratio was further raised to 40:100, the total drug in liposome formulation did not increase, but the amount of free drug increased significantly, thereby decreasing the percent of entrapped drug. Increasing cholesterol content in the formulation decreased drug loading. In vitro drug leakage from the liposomes increased with increase in drug-to-lipid ratio or DSPE-PEG content in the formulation; whereas increasing cholesterol content of the formulation up to 30 mol-percent, decreased CA4 leakage from the liposomes. Ligand coupling to the liposome surface increased drug leakage as a function of ligand density. Optimized liposome formulation with 100 mM lipid concentration, 20:100 drug-to-lipid ratio, 30 mol-percent cholesterol, 4 mol-percent DSPE-PEG, and 1 mol

  5. Method for detecting binding efficiencies of synthetic oligonucleotides: Targeting bacteria and insects

    Science.gov (United States)

    Expanding applications of gene-based targeting biotechnology in functional genomics and the treatment of plants, animals, and microbes has synergized the need for new methods to measure binding efficiencies of these products to their genetic targets. The adaptation and innovative use of Cell–Penetra...

  6. Learning networks as an enabler for informed decisions to target energy-efficiency potentials in companies

    NARCIS (Netherlands)

    Wohlfarth, Katharina; Eichhammer, W.A.; Schlomann, Barbara; Mielicke, Ursula

    2017-01-01

    his paper deals with possibilities of targeting energy efficiency potentials in German companies by delivering information and support within a cooperative management system “Learning Energy Efficiency Networks” (LEEN). Information deficits are pointed out as a relevant barrier to implementing

  7. Progress in target materials for high-efficiency X-ray backlight

    International Nuclear Information System (INIS)

    Du Ai; Zhou Bin; Li Longxiang; Zhu Xiurong; Li Yu'nong; Shen Jun; Gao Guohua; Zhang Zhihua; Wu Guangming

    2012-01-01

    The composition, microstructure and density of the target materials are the key parameters to determinate the photon energy and intensity of the laser-induced X-ray backlight. Thus the classification of backlight targets, the preparation of target materials and the interaction between targets and high power laser were introduced in this paper. Underdense targets were more competitive than traditional dense targets among the backlight targets. Nano-structured foam targets, which could be classified into nanofiber targets and aerogel targets, were regarded as novel high-efficiency underdense targets. Nanofiber, which was commonly prepared via electro spinning and thermal treatment, exhibited good formability and high concentration of emission atoms; while aerogel, which was prepared via sol-gel processes and supercritical fluid drying, possesses the advantages of homogeneous microstructure and theoretically high conversion efficiency, but accompanied with the disadvantages of complex synthetic processes and low concentration of emission atoms. To prepare monolithic aerogels with low density and high concentration of emission atoms via combined sol-gel theories may be the better design for the development of the laser-induced X-ray backlight. (authors)

  8. Effect of co-administration of probiotics with polysaccharide based colon targeted delivery systems to optimize site specific drug release.

    Science.gov (United States)

    Prudhviraj, G; Vaidya, Yogyata; Singh, Sachin Kumar; Yadav, Ankit Kumar; Kaur, Puneet; Gulati, Monica; Gowthamarajan, K

    2015-11-01

    Significant clinical success of colon targeted dosage forms has been limited by their inappropriate release profile at the target site. Their failure to release the drug completely in the colon may be attributed to changes in the colonic milieu because of pathological state, drug effect and psychological stress accompanying the diseased state or, a combination of these. Alteration in normal colonic pH and bacterial picture leads to incomplete release of drug from the designed delivery system. We report the effectiveness of a targeted delivery system wherein the constant replenishment of the colonic microbiota is achieved by concomitant administration of probiotics along with the polysaccharide based drug delivery system. Guar gum coated spheroids of sulfasalazine were prepared. In the dissolution studies, these spheroids showed markedly higher release in the simulated colonic fluid. In vivo experiments conducted in rats clearly demonstrated the therapeutic advantage of co-administration of probiotics with guar gum coated spheroids. Our results suggest that concomitant use of probiotics along with the polysaccharide based delivery systems can be a simple strategy to achieve satisfactory colon targeting of drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Improved laser-to-proton conversion efficiency in isolated reduced mass targets

    Energy Technology Data Exchange (ETDEWEB)

    Morace, A. [Center for Energy Research, University of California, 9500 Gilman Drive, La Jolla, California 92093 (United States); Dipartimento di Fisica, Università degli Studi di Milano, via Celoria 16, 20133 Milano (Italy); Bellei, C.; Patel, P. K. [Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, California 94550 (United States); Bartal, T.; Kim, J.; Beg, F. N. [Center for Energy Research, University of California, 9500 Gilman Drive, La Jolla, California 92093 (United States); Willingale, L.; Maksimchuk, A.; Krushelnick, K. [University of Michigan, 2200 Bonisteel Blvd. Ann Arbor, Michigan 48109 (United States); Wei, M. S. [Center for Energy Research, University of California, 9500 Gilman Drive, La Jolla, California 92093 (United States); General Atomics, 3550 General Atomics Court, San Diego, California 92121 (United States); Batani, D. [Univ. Bordeaux, CNRS, CEA, CELIA (Centre Lasers Intenses et Applications), UMR 5107, F-33405 Talence (France); Piovella, N. [Dipartimento di Fisica, Università degli Studi di Milano, via Celoria 16, 20133 Milano (Italy); Stephens, R. B. [General Atomics, 3550 General Atomics Court, San Diego, California 92121 (United States)

    2013-07-29

    We present experimental results of laser-to-proton conversion efficiency as a function of lateral confinement of the refluxing electrons. Experiments were carried out using the T-Cubed laser at the Center for Ultrafast Optical Science, University of Michigan. We demonstrate that the laser-to-proton conversion efficiency increases by 50% with increased confinement of the target from surroundings with respect to a flat target of the same thickness. Three-dimensional hybrid particle-in-cell simulations using LSP code agree with the experimental data. The adopted target design is suitable for high repetition rate operation as well as for Inertial Confinement Fusion applications.

  10. Rescue of HIV-1 release by targeting widely divergent NEDD4-type ubiquitin ligases and isolated catalytic HECT domains to Gag.

    Directory of Open Access Journals (Sweden)

    Eric R Weiss

    2010-09-01

    Full Text Available Retroviruses engage the ESCRT pathway through late assembly (L domains in Gag to promote virus release. HIV-1 uses a PTAP motif as its primary L domain, which interacts with the ESCRT-I component Tsg101. In contrast, certain other retroviruses primarily use PPxY-type L domains, which constitute ligands for NEDD4-type ubiquitin ligases. Surprisingly, although HIV-1 Gag lacks PPxY motifs, the release of HIV-1 L domain mutants is potently enhanced by ectopic NEDD4-2s, a native isoform with a naturally truncated C2 domain that appears to account for the residual titer of L domain-defective HIV-1. The reason for the unique potency of the NEDD4-2s isoform has remained unclear. We now show that the naturally truncated C2 domain of NEDD4-2s functions as an autonomous Gag-targeting module that can be functionally replaced by the unrelated Gag-binding protein cyclophilin A (CypA. The residual C2 domain of NEDD4-2s was sufficient to transfer the ability to stimulate HIV-1 budding to other NEDD4 family members, including the yeast homologue Rsp5, and even to isolated catalytic HECT domains. The isolated catalytic domain of NEDD4-2s also efficiently promoted HIV-1 budding when targeted to Gag via CypA. We conclude that the regions typically required for substrate recognition by HECT ubiquitin ligases are all dispensable to stimulate HIV-1 release, implying that the relevant target for ubiquitination is Gag itself or can be recognized by divergent isolated HECT domains. However, the mere ability to ubiquitinate Gag was not sufficient to stimulate HIV-1 budding. Rather, our results indicate that the synthesis of K63-linked ubiquitin chains is critical for ubiquitin ligase-mediated virus release.

  11. Measuring the Acoustic Release of a Chemotherapeutic Agent from Folate-Targeted Polymeric Micelles.

    Science.gov (United States)

    Abusara, Ayah; Abdel-Hafez, Mamoun; Husseini, Ghaleb

    2018-08-01

    In this paper, we compare the use of Bayesian filters for the estimation of release and re-encapsulation rates of a chemotherapeutic agent (namely Doxorubicin) from nanocarriers in an acoustically activated drug release system. The study is implemented using an advanced kinetic model that takes into account cavitation events causing the antineoplastic agent's release from polymeric micelles upon exposure to ultrasound. This model is an improvement over the previous representations of acoustic release that used simple zero-, first- and second-order release and re-encapsulation kinetics to study acoustically triggered drug release from polymeric micelles. The new model incorporates drug release and micellar reassembly events caused by cavitation allowing for the controlled release of chemotherapeutics specially and temporally. Different Bayesian estimators are tested for this purpose including Kalman filters (KF), Extended Kalman filters (EKF), Particle filters (PF), and multi-model KF and EKF. Simulated and experimental results are used to verify the performance of the above-mentioned estimators. The proposed methods demonstrate the utility and high-accuracy of using estimation methods in modeling this drug delivery technique. The results show that, in both cases (linear and non-linear dynamics), the modeling errors are expensive but can be minimized using a multi-model approach. In addition, particle filters are more flexible filters that perform reasonably well compared to the other two filters. The study improved the accuracy of the kinetic models used to capture acoustically activated drug release from polymeric micelles, which may in turn help in designing hardware and software capable of precisely controlling the delivered amount of chemotherapeutics to cancerous tissue.

  12. Multiple cues on the physiochemical, mesenchymal, and intracellular trafficking interactions with nanocarriers to maximize tumor target efficiency

    Directory of Open Access Journals (Sweden)

    Kim SW

    2015-06-01

    Full Text Available Sang-Woo Kim, Dongwoo Khang Nanomedicine Laboratory, Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, South Korea Abstract: Over the past 60 years, numerous medical strategies have been employed to overcome neoplasms. In fact, with the exception of lung, bronchial, and pancreatic cancers, the 5-year survival rate of most cancers currently exceeds 70%. However, the quality of life of patients during chemotherapy remains unsatisfactory despite the increase in survival rate. The side effects of current chemotherapies stem from poor target efficiency at tumor sites due to the uncontrolled biodistribution of anticancer agents (ie, conventional or current approved nanodrugs. This review discusses the effective physiochemical factors for determining biodistribution of nanocarriers and, ultimately, increasing tumor-targeting probability by avoiding the reticuloendothelial system. Second, stem cell-conjugated nanotherapeutics was addressed to maximize the tumor searching ability and to inhibit tumor growth. Lastly, physicochemical material properties of anticancer nanodrugs were discussed for targeting cellular organelles with modulation of drug-release time. A better understanding of suggested topics will increase the tumor-targeting ability of anticancer drugs and, ultimately, promote the quality of life of cancer patients during chemotherapy. Keywords: cancer, anticancer nanodrugs, mesenchymal stem cell, intracellular trafficking

  13. Formulation and Characterization of Pyrazinamide Polymeric Nanoparticles for Pulmonary Tuberculosis: Efficiency for Alveolar Macrophage Targeting

    OpenAIRE

    Varma, J. N. Ravi; Kumar, T. Santosh; Prasanthi, B.; Ratna, J. Vijaya

    2015-01-01

    Pyrazinamide, a highly specific agent against Mycobacterium tuberculosis is used as first-line drug to treat tuberculosis. The current work aims to formulate polymeric nanoparticles based drug delivery system to sustain the release profile and reduce the dosing frequency of pyrazinamide. Further aim was to target the macrophages within body fluid. These polymeric nanoparticles were prepared by simultaneous double-emulsion (W/O/W) solvent evaporation/diffusion technique. The prepared dispersio...

  14. Operations & Maintenance Best Practices - A Guide to Achieving Operational Efficiency (Release 3)

    Energy Technology Data Exchange (ETDEWEB)

    Sullivan, Greg; Pugh, Ray; Melendez, Aldo P.; Hunt, W. D.

    2010-08-04

    This guide highlights operations and maintenance programs targeting energy and water efficiency that are estimated to save 5% to 20% on energy bills without a significant capital investment. The purpose of this guide is to provide you, the Operations and Maintenance (O&M)/Energy manager and practitioner, with useful information about O&M management, technologies, energy and water efficiency, and cost-reduction approaches. To make this guide useful and to reflect your needs and concerns, the authors met with O&M and Energy managers via Federal Energy Management Program (FEMP) workshops. In addition, the authors conducted extensive literature searches and contacted numerous vendors and industry experts. The information and case studies that appear in this guide resulted from these activities. It needs to be stated at the outset that this guide is designed to provide information on effective O&M as it applies to systems and equipment typically found at Federal facilities. This guide is not designed to provide the reader with step-by-step procedures for performing O&M on any specific piece of equipment. Rather, this guide first directs the user to the manufacturer's specifications and recommendations. In no way should the recommendations in this guide be used in place of manufacturer's recommendations. The recommendations in this guide are designed to supplement those of the manufacturer, or, as is all too often the case, provide guidance for systems and equipment for which all technical documentation has been lost. As a rule, this guide will first defer to the manufacturer's recommendations on equipment operation and maintenance.

  15. Mannosylated Chitosan Nanoparticles Based Macrophage-Targeting Gene Delivery System Enhanced Cellular Uptake and Improved Transfection Efficiency.

    Science.gov (United States)

    Peng, Yixing; Yao, Wenjun; Wang, Bo; Zong, Li

    2015-04-01

    Gene transfer mediated by mannosylated chitosan (MCS) is a safe and promising approach for gene and vaccine delivery. MCS nanoparticles based gene delivery system showed high in vivo delivery efficiency and elicited strong immune responses in mice. However, little knowledge about the cell binding, transfection efficiency and intracellular trafficking of MCS nanoparticles had been acquired. In this study, using gastrin-releasing peptide as a model plasmid (pGRP), the binding of MCS/pGRP nanoparticles to macrophages and the intracellular trafficking of MCS/pGRP nanoparticles in macrophages were investigated. MCS-mediated transfection efficiency in macrophages was also evaluated using pGL-3 as a reporter gene. The results showed that the binding and transfection efficiency of MCS nanoparticles in macrophages was higher than that of CS, which was attributed to the interaction between mannose ligands in MCS and mannose receptors on the surface of macrophages. Observation with a confocal laser scanning microscope indicated the cellular uptake of MCS/pGRP nanoparticles were more than that of CS/pGRP nanoparticles in macrophages. MCS/pGRP nanoparticles were taken up by macrophages and most of them were entrapped in endosomal/lysosomal compartments. After the nanoparticles escaping from endosomal/lysosomal compartments, naked pGRP entered the nucleus, and a few MCS might enter the nucleus in terms of nanoparticles. Overall, MCS has the potential to be an excellent macrophage-targeting gene delivery carrier.

  16. A model system for targeted drug release triggered by biomolecular signals logically processed through enzyme logic networks.

    Science.gov (United States)

    Mailloux, Shay; Halámek, Jan; Katz, Evgeny

    2014-03-07

    A new Sense-and-Act system was realized by the integration of a biocomputing system, performing analytical processes, with a signal-responsive electrode. A drug-mimicking release process was triggered by biomolecular signals processed by different logic networks, including three concatenated AND logic gates or a 3-input OR logic gate. Biocatalytically produced NADH, controlled by various combinations of input signals, was used to activate the electrochemical system. A biocatalytic electrode associated with signal-processing "biocomputing" systems was electrically connected to another electrode coated with a polymer film, which was dissolved upon the formation of negative potential releasing entrapped drug-mimicking species, an enzyme-antibody conjugate, operating as a model for targeted immune-delivery and consequent "prodrug" activation. The system offers great versatility for future applications in controlled drug release and personalized medicine.

  17. Efficiency of an LBE spallation target in an accelerator-driven molten salt subcritical reactor

    Energy Technology Data Exchange (ETDEWEB)

    Bak, Sang-In [Sungkyunkwan University, Suwon (Korea, Republic of); Hong, Seung-Woo [Sungkyunkwan University, Suwon (Korea, Republic of); Kadi, Yacine [CERN, Geneva (Switzerland)

    2016-10-15

    An Accelerator-Driven System (ADS) combined with a subcritical Molten Salt Reactor (MSR) is a type of hybrid reactor originally designed to breed uranium from thorium or to incinerate long-lived minor actinides in nuclear wastes. In an MSR, the salt material is used not only as a nuclear fuel but also as a primary coolant. In addition, this material is used as a target for inducing spallation neutrons in most AD-MSR concepts. A high energy proton beam impinges on a heavy metal target to induce spallation reactions and produces neutrons. Accordingly, a reliable proton accelerator is needed to feed the source neutrons. As ADSs have been criticized for requiring high power accelerators, minimization of beam power is an important aspect of ADS design. A primary concern associated with ADS development is stable high-power accelerators. We therefore studied the neutron source efficiencies of an AD-MSR involving chloride fuels by including a Pb-Bi eutectic (LBE) spallation target. The proton source efficiency and the accelerator beam power required have been studied for an AD-MSR. Adoption of an LBE spallation target induces an increase in proton source efficiencies in comparison to the case without a spallation target. Thus the presence of an efficient spallation target is useful in the reduction of the beam power of an accelerator. Almost 33 % of the beam power can be reduced in comparison to the case without the target for NaCl-Th/{sup 233}U fuel, and about 16 % for NaCl-U/TRU fuel. The beam power amplifications increase by 1.5 times for NaCl-Th/{sup 233}U and 1.2 times for NaCl-U/TRU in comparison with the no target AD-MSR.

  18. An efficient method of fuel ice formation in moving free-standing ICF/IFE targets

    Science.gov (United States)

    Aleksandrova, I. V.; Bazdenkov, S. V.; Chtcherbakov, V. I.; Gromov, A. I.; Koresheva, E. R.; Koshelev, E. A.; Osipov, I. E.; Yaguzinskiy, L. S.

    2004-04-01

    Currently, research fields related to the elaboration of efficient layering methods for ICF/IFE applications are rapidly expanding. Significant progress has been made in the technology development based on rapid fuel layering inside moving free-standing targets (FST) which is referred to as the FST layering method. This paper presents our new results obtained in this area and describes technologically elegant solutions towards demonstrating a credible pathway for mass production of IFE cryogenic targets.

  19. An efficient method of fuel ice formation in moving free-standing ICF/IFE targets

    International Nuclear Information System (INIS)

    Aleksandrova, I V; Bazdenkov, S V; Chtcherbakov, V I; Gromov, A I; Koresheva, E R; Koshelev, E A; Osipov, I E; Yaguzinskiy, L S

    2004-01-01

    Currently, research fields related to the elaboration of efficient layering methods for ICF/IFE applications are rapidly expanding. Significant progress has been made in the technology development based on rapid fuel layering inside moving free-standing targets (FST) which is referred to as the FST layering method. This paper presents our new results obtained in this area and describes technologically elegant solutions towards demonstrating a credible pathway for mass production of IFE cryogenic targets

  20. Search efficiency of biased migration towards stationary or moving targets in heterogeneously structured environments

    Science.gov (United States)

    Azimzade, Youness; Mashaghi, Alireza

    2017-12-01

    Efficient search acts as a strong selective force in biological systems ranging from cellular populations to predator-prey systems. The search processes commonly involve finding a stationary or mobile target within a heterogeneously structured environment where obstacles limit migration. An open generic question is whether random or directionally biased motions or a combination of both provide an optimal search efficiency and how that depends on the motility and density of targets and obstacles. To address this question, we develop a simple model that involves a random walker searching for its targets in a heterogeneous medium of bond percolation square lattice and used mean first passage time (〈T 〉 ) as an indication of average search time. Our analysis reveals a dual effect of directional bias on the minimum value of 〈T 〉 . For a homogeneous medium, directionality always decreases 〈T 〉 and a pure directional migration (a ballistic motion) serves as the optimized strategy, while for a heterogeneous environment, we find that the optimized strategy involves a combination of directed and random migrations. The relative contribution of these modes is determined by the density of obstacles and motility of targets. Existence of randomness and motility of targets add to the efficiency of search. Our study reveals generic and simple rules that govern search efficiency. Our findings might find application in a number of areas including immunology, cell biology, ecology, and robotics.

  1. Hydrodynamic efficiency and thermal transport in planar target experiments at LLE

    International Nuclear Information System (INIS)

    Boehly, T.; Goldman, L.M.; Seka, W.; Craxton, R.S.

    1984-01-01

    The authors report the results of single beam irradiation of thin CH foils at laser intensities of 10 13 to 10 15 W/cm 2 in 0.8 ns pulses containing 20 to 50 J of 350 nm and 1054 nm light. They also discuss the hydrodynamic efficiency, thermal transport and preheat in these targets. Included is the measurement of the ion blowoff energy distribution and velocity. The efficient acceleration by short wavelength radiation causes target displacements comparable to the spot size resulting in two-dimension effects. The results are adequately modeled with the 2-D hydrocode SAGE using a flux limiter of f=0.04

  2. Enhancing cognate target elution efficiency in gel-free chemical proteomics

    Directory of Open Access Journals (Sweden)

    Branka Radic-Sarikas

    2015-12-01

    Full Text Available Gel-free liquid chromatography mass spectrometry coupled to chemical proteomics is a powerful approach for characterizing cellular target profiles of small molecules. We have previously described a fast and efficient elution protocol; however, altered target profiles were observed. We hypothesised that elution conditions critically impact the effectiveness of disrupting drug-protein interactions. Thus, a number of elution conditions were systematically assessed with the aim of improving the recovery of all classes of proteins whilst maintaining compatibility with immunoblotting procedures. A double elution with formic acid combined with urea emerged as the most efficient and generically applicable elution method for chemical proteomics

  3. High-efficiency extracellular release of free fatty acids from Aspergillus oryzae using non-ionic surfactants.

    Science.gov (United States)

    Tamano, Koichi; Miura, Ai; Koike, Hideaki; Kamisaka, Yasushi; Umemura, Myco; Machida, Masayuki

    2017-04-20

    Free fatty acids (FFAs) are useful for generating biofuel compounds and functional lipids. Microbes are increasingly exploited to produce FFAs via metabolic engineering. However, in many microorganisms, FFAs accumulate in the cytosol, and disrupting cells to extract them is energy intensive. Thus, a simple cost-effective extraction technique must be developed to remove this drawback. We found that FFAs were released from cells of the filamentous fungus Aspergillus oryzae with high efficiency when they were cultured or incubated with non-ionic surfactants such as Triton X-100. The surfactants did not reduce hyphal growth, even at 5% (w/v). When the faaA disruptant was cultured with 1% Triton X-100, more than 80% of the FFAs synthesized de novo were released. When the disruptant cells grown without surfactants were incubated for 1h in 1% Triton X-100 solution, more than 50% of the FFAs synthesized de novo were also released. Other non-ionic surfactants in the same ether series, such as Brij 58, IGEPAL CA-630, and Tergitol NP-40, elicited a similar FFA release. The dry cell weight of total hyphae decreased when grown with 1% Triton X-100. The decrement was 4.9-fold greater than the weight of the released FFAs, implying release of other intracellular compounds. Analysis of the culture supernatant showed that intracellular lactate dehydrogenase was also released, suggesting that FFAs are not released by a specific transporter. Therefore, ether-type non-ionic surfactants probably cause non-specific release of FFAs and other intracellular compounds by increasing cell membrane permeability. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Thermo-sensitively and magnetically ordered mesoporous carbon nanospheres for targeted controlled drug release and hyperthermia application.

    Science.gov (United States)

    Chen, Lin; Zhang, Huan; Zheng, Jing; Yu, Shiping; Du, Jinglei; Yang, Yongzhen; Liu, Xuguang

    2018-03-01

    A multifunctional nanoplatform based on thermo-sensitively and magnetically ordered mesoporous carbon nanospheres (TMOMCNs) is developed for effective targeted controlled release of doxorubicin hydrochloride (DOX) and hyperthermia in this work. The morphology, specific surface area, porosity, thermo-stability, thermo-sensitivity, as well as magnetism properties of TMOMCNs were verified by high resolution transmission electron microscopy, field emission scanning electron microscopy, thermo-gravimetric analysis, X-ray diffraction, Brunauer-Emmeltt-Teller surface area analysis, dynamic light scattering and vibrating sample magnetometry measurement. The results indicate that TMOMCNs have an average diameter of ~146nm with a lower critical solution temperature at around 39.5°C. They are superparamagnetic with a magnetization of 10.15emu/g at 20kOe. They generate heat when inductive magnetic field is applied to them and have a normalized specific absorption rate of 30.23W/g at 230kHz and 290Oe, showing good potential for hyperthermia. The DOX loading and release results illustrate that the loading capacity is 135.10mg/g and release performance could be regulated by changing pH and temperature. The good targeting, DOX loading and release and hyperthermia properties of TMOMCNs offer new probabilities for high effectiveness and low toxicity of cancer chemotherapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Improved Algorithms for Blending Dam Releases to Meet Downstream Water-Temperature Targets in the CE-QUAL-W2 Water-Quality Model

    Science.gov (United States)

    Rounds, S. A.; Buccola, N. L.

    2014-12-01

    The two-dimensional (longitudinal, vertical) water-quality model CE-QUAL-W2, version 3.7, was enhanced with new features to help dam operators and managers efficiently explore and optimize potential solutions for temperature management downstream of thermally stratified reservoirs. Such temperature management often is accomplished by blending releases from multiple dam outlets that access water of different temperatures at different depths in the reservoir. The original blending algorithm in this version of the model was limited to mixing releases from two outlets at a time, and few constraints could be imposed. The new enhanced blending algorithm allows the user to (1) specify a time-series of target release temperatures, (2) designate from 2 to 10 floating or fixed-elevation outlets for blending, (3) impose maximum head constraints as well as minimum and maximum flow constraints for any blended outlet, and (4) set a priority designation for each outlet that allows the model to choose which outlets to use and how to balance releases among them. The modified model was tested against a previously calibrated model of Detroit Lake on the North Santiam River in northwestern Oregon, and the results compared well. The enhanced model code is being used to evaluate operational and structural scenarios at multiple dam/reservoir systems in the Willamette River basin in Oregon, where downstream temperature management for endangered fish is a high priority for resource managers and dam operators. These updates to the CE-QUAL-W2 blending algorithm allow scenarios involving complicated dam operations and/or hypothetical outlet structures to be evaluated more efficiently with the model, with decreased need for multiple/iterative model runs or preprocessing of model inputs to fully characterize the operational constraints.

  6. Targeting utility customers to improve energy savings from conservation and efficiency programs

    International Nuclear Information System (INIS)

    Taylor, Nicholas W.; Jones, Pierce H.; Kipp, M. Jennison

    2014-01-01

    Highlights: • Improving DSM program impacts by targeting high energy users. • DSM energy savings potential hinges on pre-participation performance. • Targeting can benefit different utilities and energy efficiency programs. • Overall performance can be improved by up to 250% via targeting strategies. - Abstract: Electric utilities, government agencies, and private interests in the US have committed and continue to invest substantial resources – including billions of dollars of financial capital – in the pursuit of energy efficiency and conservation through demand-side management (DSM) programs. While most of these programs are deemed to be cost effective, and therefore in the public interest, opportunities exist to improve cost effectiveness by targeting programs to those customers with the greatest potential for energy savings. This article details an analysis of three DSM programs offered by three Florida municipal electric utilities to explore such opportunities. First, we estimate programs’ energy savings impacts; second, we measure and compare energy savings across subgroups of program participants as determined by their pre-intervention energy performance, and third, we explore potential changes in program impacts that might be realized by targeting specific customers for participation in the DSM programs. All three programs resulted in statistically significant average (per-participant) energy savings, yet average savings varied widely, with the customers who performed best (i.e., most efficient) before the intervention saving the least energy and those who performed worst (i.e., least efficient) before the intervention saving the most. Assessment of alternative program participation scenarios with varying levels of customer targeting suggests that program impacts could be increased by as much as 80% for a professional energy audit program, just over 100% for a high-efficiency heat pump upgrade program, and nearly 250% for an attic insulation

  7. Increased Energy Efficiency in Slovenian Industry - A Contribution to the Kyoto Target

    International Nuclear Information System (INIS)

    Selan, B.; Urbancic, A.

    1998-01-01

    In Slovenia the actual fast growth of greenhouse emissions will require substantial efforts to fulfil the target set in Kyoto. The end-use emissions in the in the industrial sectors represented one third of the total CO 2 emissions in the country in 1996. The cost-effective potential in the sector for CO 2 emission reduction is significant. In the paper, the most important ongoing energy efficiency activities in the industrial sector are presented: information and awareness building, energy advising to larger industrial consumers, energy audition programme, demonstration programme of energy efficiency technologies, financial incentives for energy efficiency investment and the energy efficiency investment fund. A CO 2 tax has been in force since 1997. The results of an evaluation of energy efficiency strategies in industry in the frame of the project 'Integrated resource planning for the energy efficiency in Slovenia' are discussed from the viewpoint of greenhouse gases reduction targets set by Slovenia, and a brief information on the ongoing and expected post Kyoto activities and studies is given. The most important points of the future GHG reduction strategy related to industrial sector in Slovenia will be focused on intensified energy efficiency programme, increased combined heat and power production (CHP), and the effects of incentives through the CO 2 tax. (author)

  8. Metering Best Practices, A Guide to Achieving Utility Resource Efficiency, Release 2.0

    Energy Technology Data Exchange (ETDEWEB)

    Sullivan, Greg; Hunt, W. D.; Pugh, Ray; Sandusky, William F.; Koehler, Theresa M.; Boyd, Brian K.

    2011-08-31

    This release is an update and expansion of the information provided in Release 1.0 of the Metering Best Practice Guide that was issued in October 2007. This release, as was the previous release, was developed under the direction of the U.S. Department of Energy's Federal Energy Management Program (FEMP). The mission of FEMP is to facilitate the Federal Government's implementation of sound cost-effective energy management and investment practices to enhance the nation's energy security and environmental stewardship. Each of these activities is directly related to achieving requirements set forth in the Energy Policy Acts of 1992 and 2005, the Energy Independence and Security Act (EISA) of 2007, and the goals that have been established in Executive Orders 13423 and 13514 - and also those practices that are inherent in sound management of Federal financial and personnel resources.

  9. An integrated CRISPR Bombyx mori genome editing system with improved efficiency and expanded target sites.

    Science.gov (United States)

    Ma, Sanyuan; Liu, Yue; Liu, Yuanyuan; Chang, Jiasong; Zhang, Tong; Wang, Xiaogang; Shi, Run; Lu, Wei; Xia, Xiaojuan; Zhao, Ping; Xia, Qingyou

    2017-04-01

    Genome editing enabled unprecedented new opportunities for targeted genomic engineering of a wide variety of organisms ranging from microbes, plants, animals and even human embryos. The serial establishing and rapid applications of genome editing tools significantly accelerated Bombyx mori (B. mori) research during the past years. However, the only CRISPR system in B. mori was the commonly used SpCas9, which only recognize target sites containing NGG PAM sequence. In the present study, we first improve the efficiency of our previous established SpCas9 system by 3.5 folds. The improved high efficiency was also observed at several loci in both BmNs cells and B. mori embryos. Then to expand the target sites, we showed that two newly discovered CRISPR system, SaCas9 and AsCpf1, could also induce highly efficient site-specific genome editing in BmNs cells, and constructed an integrated CRISPR system. Genome-wide analysis of targetable sites was further conducted and showed that the integrated system cover 69,144,399 sites in B. mori genome, and one site could be found in every 6.5 bp. The efficiency and resolution of this CRISPR platform will probably accelerate both fundamental researches and applicable studies in B. mori, and perhaps other insects. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Setting up GHG-based energy efficiency targets in buildings: The Ecolabel

    International Nuclear Information System (INIS)

    José Vinagre Díaz, Juan; Richard Wilby, Mark; Belén Rodríguez González, Ana

    2013-01-01

    The European Union has recently updated the regulations for energy performance of buildings and on the certification of energy-related products. The world is in the process of constructing policy frameworks to underwrite carbon emission reduction targets, best exemplified by the Kyoto Protocol. This requires complex technical and economical concepts to be presented in an understandable, transparent, and justifiable format. A building's energy efficiency was traditionally determined based on its annual consumption relative to some average performance level. Emissions are calculated as a derivative of consumptions and their aggregated values allow verification of the level of fulfillment of the objectives. Here we take a different approach: considering that the greenhouse gas emissions (GHG) objectives must be achieved; hence, we fix the efficiency standard based on emissions objectives, and then derive the corresponding reference values of consumption. Accordingly, we propose a certification scheme for energy efficiency in buildings based on targets of GHG emissions levels. This proposed framework includes both a label, namely the Ecolabel, and a fiche showing a set of indices and complementary information. The Ecolabel is designed to provide a flexible, evolvable, simple to use at the point of application, and transparent framework. - Highlights: • In this paper we consider the interaction between greenhouse gas emission reduction targets and building energy efficiency. • Specifically we propose an ‘‘Ecolabel” for buildings that is a GHG emissions liability index, which forms a labeling process. • The label follows the Kyoto Protocol philosophy and translates national GHG targets to targets for each and every building. • The approach provides both a new form of efficiency rating on which emissions reduction policy can be based

  11. Target-nontarget similarity decreases search efficiency and increases stimulus-driven control in visual search.

    Science.gov (United States)

    Barras, Caroline; Kerzel, Dirk

    2017-10-01

    Some points of criticism against the idea that attentional selection is controlled by bottom-up processing were dispelled by the attentional window account. The attentional window account claims that saliency computations during visual search are only performed for stimuli inside the attentional window. Therefore, a small attentional window may avoid attentional capture by salient distractors because it is likely that the salient distractor is located outside the window. In contrast, a large attentional window increases the chances of attentional capture by a salient distractor. Large and small attentional windows have been associated with efficient (parallel) and inefficient (serial) search, respectively. We compared the effect of a salient color singleton on visual search for a shape singleton during efficient and inefficient search. To vary search efficiency, the nontarget shapes were either similar or dissimilar with respect to the shape singleton. We found that interference from the color singleton was larger with inefficient than efficient search, which contradicts the attentional window account. While inconsistent with the attentional window account, our results are predicted by computational models of visual search. Because of target-nontarget similarity, the target was less salient with inefficient than efficient search. Consequently, the relative saliency of the color distractor was higher with inefficient than with efficient search. Accordingly, stronger attentional capture resulted. Overall, the present results show that bottom-up control by stimulus saliency is stronger when search is difficult, which is inconsistent with the attentional window account.

  12. Pharmaceutical micelles featured with singlet oxygen-responsive cargo release and mitochondrial targeting for enhanced photodynamic therapy

    Science.gov (United States)

    Zhang, Xin; Yan, Qi; Naer Mulatihan, Di; Zhu, Jundong; Fan, Aiping; Wang, Zheng; Zhao, Yanjun

    2018-06-01

    The efficacy of nanoparticulate photodynamic therapy is often compromised by the short life time and limited diffusion radius of singlet oxygen as well as uncontrolled intracellular distribution of photosensitizer. It was hypothesized that rapid photosensitizer release upon nanoparticle internalization and its preferred accumulation in mitochondria would address the above problems. Hence, the aim of this study was to engineer a multifunctional micellar nanosystem featured with singlet oxygen-responsive cargo release and mitochondria-targeting. An imidazole-bearing amphiphilic copolymer was employed as the micelle building block to encapsulate triphenylphosphonium-pyropheophorbide a (TPP-PPa) conjugate or PPa. Upon laser irradiation, the singlet oxygen produced by TPP-PPa/PPa oxidized the imidazole moiety to produce hydrophilic urea, leading to micelle disassembly and rapid cargo release. The co-localization analysis showed that the TPP moiety significantly enhanced the photosensitizer uptake by mitochondria, improved mitochondria depolarization upon irradiation, and hence boosted the cytotoxicity in 4T1 cells. The targeting strategy also dramatically reduced the intracellular ATP concentration as a consequence of mitochondria injury. The mitochondria damage was accompanied with the activation of the apoptosis signals (caspase 3 and caspase 9), whose level was directly correlated to the apoptosis extent. The current work provides a facile and robust means to enhance the efficacy of photodynamic therapy.

  13. Iontophoresis on minoxidil sulphate-loaded chitosan nanoparticles accelerates drug release, decreasing their targeting effect to hair follicles

    Directory of Open Access Journals (Sweden)

    Breno N. Matos

    Full Text Available The experiments described in this paper tested the hypothesis whether iontophoresis applied on a chitosan nanoparticle formulation could combine the enhanced drug accumulation into the follicular casts obtained using iontophoresis and the sustained drug release, reducing dermal exposure, provided by nanoparticles. Results showed that even though iontophoresis presented comparable minoxidil targeting potential to hair follicles than passive delivery of chitosan-nanoparticles (4.1 ± 0.9 and 5.3 ± 1.0 µg cm-2, respectively, it was less effective on preventing dermal exposure, since chitosan-nanoparticles presented a drug permeation in the receptor solution of 15.3 ± 4.3 µg cm-2 after 6 h of iontophoresis, while drug amounts from passive nanoparticle delivery were not detected. Drug release experiments showed particles were not able to sustain the drug release under the influence of a potential gradient. In conclusion, the application of MXS-loaded chitosan nanoparticles remains the best way to target MXS to the hair follicles while preventing dermal exposure.

  14. Production and Release of ISOL Beams from Molten Fluoride Salt Targets

    CERN Document Server

    Mendonca, T M; Ghetta, V; Alibert, M; Heuer, D; Noah, E; Cimmino, S; Delonca, M; Gottberg, A; Kronberger, M; Ramos, J; Seiffert, C; Stora, T; CERN. Geneva. ATS Department

    2014-01-01

    In the framework of the Beta Beams study, a molten fluoride target has been proposed for the production of the required 1013 18Ne/s. The production and extraction of such rates are obtained on a circulating molten salt with proton beam energy beams at close to 1 MW power. As a most important step to validate the concept, a prototype has been designed and investigated at CERN-ISOLDE using a static target unit. The target material consisted of a binary fluoride system, NaF:LiF (39:61 % mol.), with melting point at 649ºC. The production of Ne beams has been monitored as a function of the target temperature and proton beam intensity. The prototype development and the results of the first online tests with 1.4 GeV proton beam are presented in this paper.

  15. Efficient and robust identification of cortical targets in concurrent TMS-fMRI experiments

    Science.gov (United States)

    Yau, Jeffrey M.; Hua, Jun; Liao, Diana A.; Desmond, John E.

    2014-01-01

    Transcranial magnetic stimulation (TMS) can be delivered during fMRI scans to evoke BOLD responses in distributed brain networks. While concurrent TMS-fMRI offers a potentially powerful tool for non-invasively investigating functional human neuroanatomy, the technique is currently limited by the lack of methods to rapidly and precisely localize targeted brain regions – a reliable procedure is necessary for validly relating stimulation targets to BOLD activation patterns, especially for cortical targets outside of motor and visual regions. Here we describe a convenient and practical method for visualizing coil position (in the scanner) and identifying the cortical location of TMS targets without requiring any calibration or any particular coil-mounting device. We quantified the precision and reliability of the target position estimates by testing the marker processing procedure on data from 9 scan sessions: Rigorous testing of the localization procedure revealed minimal variability in coil and target position estimates. We validated the marker processing procedure in concurrent TMS-fMRI experiments characterizing motor network connectivity. Together, these results indicate that our efficient method accurately and reliably identifies TMS targets in the MR scanner, which can be useful during scan sessions for optimizing coil placement and also for post-scan outlier identification. Notably, this method can be used generally to identify the position and orientation of MR-compatible hardware placed near the head in the MR scanner. PMID:23507384

  16. Self-targeting of TNF-releasing cancer cells in preclinical models of primary and metastatic tumors.

    Science.gov (United States)

    Dondossola, Eleonora; Dobroff, Andrey S; Marchiò, Serena; Cardó-Vila, Marina; Hosoya, Hitomi; Libutti, Steven K; Corti, Angelo; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

    2016-02-23

    Circulating cancer cells can putatively colonize distant organs to form metastases or to reinfiltrate primary tumors themselves through a process termed "tumor self-seeding." Here we exploit this biological attribute to deliver tumor necrosis factor alpha (TNF), a potent antitumor cytokine, directly to primary and metastatic tumors in a mechanism that we have defined as "tumor self-targeting." For this purpose, we genetically engineered mouse mammary adenocarcinoma (TSA), melanoma (B16-F10), and Lewis lung carcinoma cells to produce and release murine TNF. In a series of intervention trials, systemic administration of TNF-expressing tumor cells was associated with reduced growth of both primary tumors and metastatic colonies in immunocompetent mice. We show that these malignant cells home to tumors, locally release TNF, damage neovascular endothelium, and induce massive cancer cell apoptosis. We also demonstrate that such tumor-cell-mediated delivery avoids or minimizes common side effects often associated with TNF-based therapy, such as acute inflammation and weight loss. Our study provides proof of concept that genetically modified circulating tumor cells may serve as targeted vectors to deliver anticancer agents. In a clinical context, this unique paradigm represents a personalized approach to be translated into applications potentially using patient-derived circulating tumor cells as self-targeted vectors for drug delivery.

  17. Efficient four fragment cloning for the construction of vectors for targeted gene replacement in filamentous fungi

    DEFF Research Database (Denmark)

    Frandsen, Rasmus John Normand; Andersson, Jens A.; Kristensen, Matilde Bylov

    2008-01-01

    Background: The rapid increase in whole genome fungal sequence information allows large scale functional analyses of target genes. Efficient transformation methods to obtain site-directed gene replacement, targeted over-expression by promoter replacement, in-frame epitope tagging or fusion...... of coding sequences with fluorescent markers such as GFP are essential for this process. Construction of vectors for these experiments depends on the directional cloning of two homologous recombination sequences on each side of a selection marker gene. Results: Here, we present a USER Friendly cloning based...

  18. High neutronic efficiency, low current targets for accelerator-based BNCT applications

    International Nuclear Information System (INIS)

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

    1998-01-01

    The neutronic efficiency of target/filters for accelerator-based BNCT applications is measured by the proton current required to achieve a desirable neutron current at the treatment port (10 9 n/cm 2 /s). In this paper the authors describe two possible targeyt/filter concepts wihch minimize the required current. Both concepts are based on the Li-7 (p,n)Be-7 reaction. Targets that operate near the threshold energy generate neutrons that are close tothe desired energy for BNCT treatment. Thus, the filter can be extremely thin (∼ 5 cm iron). However, this approach has an extremely low neutron yield (n/p ∼ 1.0(-6)), thus requiring a high proton current. The proposed solutino is to design a target consisting of multiple extremely thin targets (proton energy loss per target ∼ 10 keV), and re-accelerate the protons between each target. Targets operating at ihgher proton energies (∼ 2.5 MeV) have a much higher yield (n/p ∼ 1.0(-4)). However, at these energies the maximum neutron energy is approximately 800 keV, and thus a neutron filter is required to degrade the average neutron energy to the range of interest for BNCT (10--20 keV). A neutron filter consisting of fluorine compounds and iron has been investigated for this case. Typically a proton current of approximately 5 mA is required to generate the desired neutron current at the treatment port. The efficiency of these filter designs can be further increased by incorporating neutron reflectors that are co-axial with the neutron source. These reflectors are made of materials which have high scattering cross sections in the range 0.1--1.0 MeV

  19. High loading efficiency and sustained release of siRNA encapsulated in PLGA nanoparticles: quality by design optimization and characterization.

    Science.gov (United States)

    Cun, Dongmei; Jensen, Ditte Krohn; Maltesen, Morten Jonas; Bunker, Matthew; Whiteside, Paul; Scurr, David; Foged, Camilla; Nielsen, Hanne Mørck

    2011-01-01

    Poly(DL-lactide-co-glycolide acid) (PLGA) is an attractive polymer for delivery of biopharmaceuticals owing to its biocompatibility, biodegradability and outstanding controlled release characteristics. The purpose of this study was to understand and define optimal parameters for preparation of small interfering RNA (siRNA)-loaded PLGA nanoparticles by the double emulsion solvent evaporation method and characterize their properties. The experiments were performed according to a 2(5-1) fractional factorial design based on five independent variables: The volume ratio between the inner water phase and the oil phase, the PLGA concentration, the sonication time, the siRNA load and the amount of acetylated bovine serum albumin (Ac-BSA) in the inner water phase added to stabilize the primary emulsion. The effects on the siRNA encapsulation efficiency and the particle size were investigated. The most important factors for obtaining an encapsulation efficiency as high as 70% were the PLGA concentration and the volume ratio whereas the size was mainly affected by the PLGA concentration. The viscosity of the oil phase was increased at high PLGA concentration, which explains the improved encapsulation by stabilization of the primary emulsion and reduction of siRNA leakage to the outer water phase. Addition of Ac-BSA increased the encapsulation efficiency at low PLGA concentrations. The PLGA matrix protected siRNA against nuclease degradation, provided a burst release of surface-localized siRNA followed by a triphasic sustained release for two months. These results enable careful understanding and definition of optimal process parameters for preparation of PLGA nanoparticles encapsulating high amounts of siRNA with immediate and long-term sustained release properties. Copyright © 2010 Elsevier B.V. All rights reserved.

  20. Dominant dwarfism in transgenic rats by targeting human growth hormone (GH) expression to hypothalamic GH-releasing factor neurons.

    OpenAIRE

    Flavell, D M; Wells, T; Wells, S E; Carmignac, D F; Thomas, G B; Robinson, I C

    1996-01-01

    Expression of human growth hormone (hGH) was targeted to growth hormone-releasing (GRF) neurons in the hypothalamus of transgenic rats. This induced dominant dwarfism by local feedback inhibition of GRF. One line, bearing a single copy of a GRF-hGH transgene, has been characterized in detail, and has been termed Tgr (for Transgenic growth-retarded). hGH was detected by immunocytochemistry in the brain, restricted to the median eminence of the hypothalamus. Low levels were also detected in the...

  1. Sticking efficiency of nanoparticles in high-velocity collisions with various target materials

    International Nuclear Information System (INIS)

    Reissaus, Philipp; Waldemarsson, Tomas; Blum, Juergen; Clement, Dominik; Llamas, Isabel; Mutschke, Harald; Giovane, Frank

    2006-01-01

    In order to find reliable collector surfaces for the Mesospheric Aerosol - Genesis, Interaction and Composition (MAGIC) sounding rocket experiment, intended to collect atmospheric nanoparticles, the sticking efficiency of nanoparticles was measured on several targets of different materials. The nanoparticles were generated by a molecular beam apparatus in Jena, Germany, by laser ablation (Al 2 O 3 particles, diameter 5-50 nm) and by laser pyrolysis (carbon particles, diameter 10-20 nm). In a vacuum environment (>10 -5 mbar) the particles condensed from the gas phase, formed a particle beam, and were accelerated to ∼∼1 km/s. The sticking efficiency on the target materials carbon, gold and grease was measured by a microbalance. Results demonstrate moderate to high sticking probabilities. Thus, the capture and retrieval of atmospheric nanoparticles was found to be quantitatively feasible

  2. psRNATarget: a plant small RNA target analysis server (2017 release).

    Science.gov (United States)

    Dai, Xinbin; Zhuang, Zhaohong; Zhao, Patrick Xuechun

    2018-04-30

    Plant regulatory small RNAs (sRNAs), which include most microRNAs (miRNAs) and a subset of small interfering RNAs (siRNAs), such as the phased siRNAs (phasiRNAs), play important roles in regulating gene expression. Although generated from genetically distinct biogenesis pathways, these regulatory sRNAs share the same mechanisms for post-translational gene silencing and translational inhibition. psRNATarget was developed to identify plant sRNA targets by (i) analyzing complementary matching between the sRNA sequence and target mRNA sequence using a predefined scoring schema and (ii) by evaluating target site accessibility. This update enhances its analytical performance by developing a new scoring schema that is capable of discovering miRNA-mRNA interactions at higher 'recall rates' without significantly increasing total prediction output. The scoring procedure is customizable for the users to search both canonical and non-canonical targets. This update also enables transmitting and analyzing 'big' data empowered by (a) the implementation of multi-threading chunked file uploading, which can be paused and resumed, using HTML5 APIs and (b) the allocation of significantly more computing nodes to its back-end Linux cluster. The updated psRNATarget server has clear, compelling and user-friendly interfaces that enhance user experiences and present data clearly and concisely. The psRNATarget is freely available at http://plantgrn.noble.org/psRNATarget/.

  3. Children of mothers being released from incarceration : Characteristics and potential targets for intervention

    NARCIS (Netherlands)

    Menting, Ankie T A; Orobio de Castro, Bram; Matthys, Walter

    2016-01-01

    Incarcerated mothers and their children may face a multitude of problems. To identify possible targets for intervention, more clarity is needed about characteristics of these children and their mothers. This study examined children’s life events, behaviour problems and social cognitions and mothers’

  4. Beam transmission efficiency between injector and target in the GANIL complex

    International Nuclear Information System (INIS)

    Beck, R.; Bru, B.; Ricaud, C.

    1984-06-01

    In order to achieve a maximum transmission efficiency, efforts have been made in three directions: beam measurements, understanding of the physical phenomenon, tuning method. The characteristics of the beam extracted from the three cyclotrons have been measured. The ensuing optical effects are analysed. The tuning of the transport-lines, depending on the characteristics of the extracted beams and the required beam properties on the target, is described

  5. Chemical Characterization and Release Efficiency of Defatted Mustard Meals: 2000-2002

    Energy Technology Data Exchange (ETDEWEB)

    Morra, M. J.

    2005-07-01

    Glucosinolates, compounds that occur in agronomically important crops, may represent a viable source of allelochemic control for various soil-borne plant pests. Toxicity is not attributed to intact glucosinolates, but instead to biologically active products such as isothiocyanates (ITCs), organic cyanides, oxazolidinethiones, and ionic thiocyanate (SCN-) released upon enzymatic degradation by myrosinase (thioglucoside glucohydrolase, EC 3.2.3.1) in the presence of water.

  6. The efficiency of ceramic-faced metal targets at high-velocity impact

    Science.gov (United States)

    Tolkachev, V. F.; Konyaev, A. A.; Pakhnutova, N. V.

    2017-11-01

    The paper represents experimental results and engineering evaluation concerning the efficiency of composite materials to be used as an additional protection during the high- velocity interaction of a tungsten rod with a target in the velocity range of 1...5 km/s. The main parameter that characterizes the high-velocity interaction of a projectile with a layered target is the penetration depth. Experimental data, numerical simulation and engineering evaluation by modified models are used to determine the penetration depth. Boron carbide, aluminum oxide, and aluminum nickelide are applied as a front surface of targets. Based on experimental data and numerical simulation, the main characteristics of ceramics are determined, which allows composite materials to be effectively used as additional elements of protection.

  7. Ultramild protein-mediated click chemistry creates efficient oligonucleotide probes for targeting and detecting nucleic acids

    DEFF Research Database (Denmark)

    Nåbo, Lina J.; Madsen, Charlotte S.; Jensen, Knud J.

    2015-01-01

    Functionalized synthetic oligonucleotides are finding growing applications in research, clinical studies, and therapy. However, it is not easy to prepare them in a biocompatible and highly efficient manner. We report a new strategy to synthesize oligonucleotides with promising nucleic acid...... targeting and detection properties. We focus in particular on the pH sensitivity of these new probes and their high target specificity. For the first time, human copper(I)-binding chaperon Cox17 was applied to effectively catalyze click labeling of oligonucleotides. This was performed under ultramild...... conditions with fluorophore, peptide, and carbohydrate azide derivatives. In thermal denaturation studies, the modified probes showed specific binding to complementary DNA and RNA targets. Finally, we demonstrated the pH sensitivity of the new rhodamine-based fluorescent probes in vitro and rationalize our...

  8. Targeted Delivery of Toxoplasma gondii Antigens to Dendritic Cells Promote Immunogenicity and Protective Efficiency against Toxoplasmosis

    Directory of Open Access Journals (Sweden)

    Zineb Lakhrif

    2018-02-01

    Full Text Available Toxoplasmosis is a major public health problem and the development of a human vaccine is of high priority. Efficient vaccination against Toxoplasma gondii requires both a mucosal and systemic Th1 immune response. Moreover, dendritic cells play a critical role in orchestrating the innate immune functions and driving specific adaptive immunity to T. gondii. In this study, we explore an original vaccination strategy that combines administration via mucosal and systemic routes of fusion proteins able to target the major T. gondii surface antigen SAG1 to DCs using an antibody fragment single-chain fragment variable (scFv directed against DEC205 endocytic receptor. Our results show that SAG1 targeting to DCs by scFv via intranasal and subcutaneous administration improved protection against chronic T. gondii infection. A marked reduction in brain parasite burden is observed when compared with the intranasal or the subcutaneous route alone. DC targeting improved both local and systemic humoral and cellular immune responses and potentiated more specifically the Th1 response profile by more efficient production of IFN-γ, interleukin-2, IgG2a, and nasal IgA. This study provides evidence of the potential of DC targeting for the development of new vaccines against a range of Apicomplexa parasites.

  9. Productivity, utilization efficiency and sward targets for mixed pastures of marandugrass, forage peanut and tropical kudzu

    Directory of Open Access Journals (Sweden)

    Carlos Mauricio Soares de Andrade

    2012-03-01

    Full Text Available This study was carried out to evaluate the productivity and utilization efficiency of a mixed marandugrass (Brachiaria brizantha cv. Marandu, forage peanut (Arachis pintoi cv. Mandobi and tropical kudzu (Pueraria phaseoloides pasture, rotationally stocked at four daily forage allowance levels (6.6, 10.3, 14.3 and 17.9% of live weight, in order to define sward management targets for these mixtures. In each stocking cycle, dry matter (DM accumulation rates, defoliation intensity (%, grazing depth (% and grazed horizon (cm were evaluated. Sward targets were defined according to the sward condition that best conciliated the grass-legume balance and the equilibrium between forage production and utilization. Pastures submitted to higher forage allowance levels showed higher productivity, but were less efficiently utilized. It was not possible to establish sward management targets for marandugrass-tropical kudzu pastures. For marandugrass-forage peanut pastures the best sward state was set with forage allowance of 10.3% of live weight. Under rotational stocking, the following sward targets were suggested for these pastures in the Western Amazon: pre-grazing height of 30-35 cm (June to September or 45-50 cm (October to May and post-grazing sward height of 20-25 cm (June to September or 25-30 cm (October to May.

  10. Efficient immunoglobulin gene disruption and targeted replacement in rabbit using zinc finger nucleases.

    Directory of Open Access Journals (Sweden)

    Tatiana Flisikowska

    Full Text Available Rabbits are widely used in biomedical research, yet techniques for their precise genetic modification are lacking. We demonstrate that zinc finger nucleases (ZFNs introduced into fertilized oocytes can inactivate a chosen gene by mutagenesis and also mediate precise homologous recombination with a DNA gene-targeting vector to achieve the first gene knockout and targeted sequence replacement in rabbits. Two ZFN pairs were designed that target the rabbit immunoglobulin M (IgM locus within exons 1 and 2. ZFN mRNAs were microinjected into pronuclear stage fertilized oocytes. Founder animals carrying distinct mutated IgM alleles were identified and bred to produce offspring. Functional knockout of the immunoglobulin heavy chain locus was confirmed by serum IgM and IgG deficiency and lack of IgM(+ and IgG(+ B lymphocytes. We then tested whether ZFN expression would enable efficient targeted sequence replacement in rabbit oocytes. ZFN mRNA was co-injected with a linear DNA vector designed to replace exon 1 of the IgM locus with ∼1.9 kb of novel sequence. Double strand break induced targeted replacement occurred in up to 17% of embryos and in 18% of fetuses analyzed. Two major goals have been achieved. First, inactivation of the endogenous IgM locus, which is an essential step for the production of therapeutic human polyclonal antibodies in the rabbit. Second, establishing efficient targeted gene manipulation and homologous recombination in a refractory animal species. ZFN mediated genetic engineering in the rabbit and other mammals opens new avenues of experimentation in immunology and many other research fields.

  11. Production and release of gas and volatile elements from sodium-based targets

    CERN Multimedia

    Plewinski, F; Wildner, E; Catherall, R

    Several large scale facilities being studied for Europe use sodium or a sodium-based alloy either as a target or as a coolant for heavier solid targets subjected to MW proton beams, such as the European Spallation Source (ESS) and $\\beta$-beam projects. ESS will be the neutron source in use from the year 2020 in Europe, providing high intensity neutron fluxes over large energy spectra ( from 10$^{-3}$ eV to 10$^{3}$ eV) to scientists, to explore materials from 10$^{-2}$m to 10$^{-16}$m scale. A sodium-cooled array of tungsten blocks is one of the potential solutions for the target that will convert protons from the 5 MW 2.5 GeV linac into neutrons. Sodium is a tried and tested coolant in fast nuclear reactors with associated technologies and design standards. Its application to a spallation environment however remains to be validated. The ISOLDE facility is well placed to perform detailed measurements of radioisotopes produced in sodium with a proton beam whose energy of 1.4 GeV is very close to the ESS base...

  12. Release of Corrosive Species above the Grate in a Waste Boiler and the Implication for Improved Electrical Efficiency

    DEFF Research Database (Denmark)

    Bøjer, Martin; Jensen, Peter Arendt; Dam-Johansen, Kim

    2010-01-01

    A relatively low electrical efficiency of 20−25% is obtained in typical west European waste boilers. Ash species released from the grate combustion zone form boiler deposits with high concentrations of Cl, Na, K, Zn, Pb, and S that cause corrosion of superheater tubes at high temperature....... The superheater steam temperature has to be limited to around 425 °C, and thereby, the electrical efficiency remains low compared to wood or coal-fired boilers. If a separate part of the flue gas from the grate has a low content of corrosive species, it may be used to superheat steam to a higher temperature......, and thereby, the electrical efficiency of the plant can be increased. In this study, the local temperature, the gas concentrations of CO, CO2, and O2, and the release of the volatile elements Cl, S, Na, K, Pb, Zn, Cu, and Sn were measured above the grate in a waste boiler to investigate if a selected fraction...

  13. Comparison of CRISPR/Cas9 expression constructs for efficient targeted mutagenesis in rice.

    Science.gov (United States)

    Mikami, Masafumi; Toki, Seiichi; Endo, Masaki

    2015-08-01

    The CRISPR/Cas9 system is an efficient tool used for genome editing in a variety of organisms. Despite several recent reports of successful targeted mutagenesis using the CRISPR/Cas9 system in plants, in each case the target gene of interest, the Cas9 expression system and guide-RNA (gRNA) used, and the tissues used for transformation and subsequent mutagenesis differed, hence the reported frequencies of targeted mutagenesis cannot be compared directly. Here, we evaluated mutation frequency in rice using different Cas9 and/or gRNA expression cassettes under standardized experimental conditions. We introduced Cas9 and gRNA expression cassettes separately or sequentially into rice calli, and assessed the frequency of mutagenesis at the same endogenous targeted sequences. Mutation frequencies differed significantly depending on the Cas9 expression cassette used. In addition, a gRNA driven by the OsU6 promoter was superior to one driven by the OsU3 promoter. Using an all-in-one expression vector harboring the best combined Cas9/gRNA expression cassette resulted in a much improved frequency of targeted mutagenesis in rice calli, and bi-allelic mutant plants were produced in the T0 generation. The approach presented here could be adapted to optimize the construction of Cas9/gRNA cassettes for genome editing in a variety of plants.

  14. Suppress orthotopic colon cancer and its metastasis through exact targeting and highly selective drug release by a smart nanomicelle.

    Science.gov (United States)

    Zhu, Chunqi; Zhang, Hanbo; Li, Wei; Luo, Lihua; Guo, Xiaomeng; Wang, Zuhua; Kong, Fenfen; Li, Qingpo; Yang, Jie; Du, Yongzhong; You, Jian

    2018-04-01

    The treatment of metastatic cancer is a huge challenge at the moment. Highly precise targeting delivery and drug release in tumor have always been our pursuit in cancer therapy, especially to advance cancer with metastasis, for increasing the efficacy and biosafety. We established a smart nanosized micelle, formed by tocopherol succinate (TOS) conjugated hyaluronic acid (HA) using a disulfide bond linker. The micelle (HA-SS-TOS, HSST) can highly specifically bind with CD44 receptor over-expressed tumor, and response selectively to high GSH level in the cells, inducing disulfide bond breakage and the release of the payload (paclitaxel, PTX). To predict the antitumor efficacy of the micelles more clinically, we established an orthotopic colon cancer model with high metastasis rate, which could be visualized by the luciferase bioluminescence. Our data confirmed CD44 high expression in the colon cancer cells. Highly matching between the micellar fluorescence and bioluminescence of cancer cells in intestines demonstrated an exact recognition of our micelles to orthotopic colon tumor and its metastatic cells, attributing to the mediation of CD44 receptors. Furthermore, the fluorescence of the released Nile Red from the micelles was found only in the tumor and its metastatic cells, and almost completely overlapped with the bioluminescence of the cancer cells, indicating a highly selective drug release. Our micelles presented an excellent therapeutic effect against metastatic colon cancer, and induced significantly prolonged survival time for the mice, which might become a promising nanomedicine platform for the future clinical application against advanced cancers with high CD44 receptor expression. Copyright © 2018 Elsevier Ltd. All rights reserved.

  15. Efficient gene targeting by homology-directed repair in rat zygotes using TALE nucleases.

    Science.gov (United States)

    Remy, Séverine; Tesson, Laurent; Menoret, Séverine; Usal, Claire; De Cian, Anne; Thepenier, Virginie; Thinard, Reynald; Baron, Daniel; Charpentier, Marine; Renaud, Jean-Baptiste; Buelow, Roland; Cost, Gregory J; Giovannangeli, Carine; Fraichard, Alexandre; Concordet, Jean-Paul; Anegon, Ignacio

    2014-08-01

    The generation of genetically modified animals is important for both research and commercial purposes. The rat is an important model organism that until recently lacked efficient genetic engineering tools. Sequence-specific nucleases, such as ZFNs, TALE nucleases, and CRISPR/Cas9 have allowed the creation of rat knockout models. Genetic engineering by homology-directed repair (HDR) is utilized to create animals expressing transgenes in a controlled way and to introduce precise genetic modifications. We applied TALE nucleases and donor DNA microinjection into zygotes to generate HDR-modified rats with large new sequences introduced into three different loci with high efficiency (0.62%-5.13% of microinjected zygotes). Two of these loci (Rosa26 and Hprt1) are known to allow robust and reproducible transgene expression and were targeted for integration of a GFP expression cassette driven by the CAG promoter. GFP-expressing embryos and four Rosa26 GFP rat lines analyzed showed strong and widespread GFP expression in most cells of all analyzed tissues. The third targeted locus was Ighm, where we performed successful exon exchange of rat exon 2 for the human one. At all three loci we observed HDR only when using linear and not circular donor DNA. Mild hypothermic (30°C) culture of zygotes after microinjection increased HDR efficiency for some loci. Our study demonstrates that TALE nuclease and donor DNA microinjection into rat zygotes results in efficient and reproducible targeted donor integration by HDR. This allowed creation of genetically modified rats in a work-, cost-, and time-effective manner. © 2014 Remy et al.; Published by Cold Spring Harbor Laboratory Press.

  16. The impact of preparation parameters on typical attributes of chitosan-heparin nanohydrogels: particle size, loading efficiency, and drug release.

    Science.gov (United States)

    Shahbazi, Mohammad-Ali; Hamidi, Mehrdad

    2013-11-01

    Today, developing an optimized nanoparticle (NP) preparation procedure is of paramount importance in all nanoparticulate drug delivery researches, leading to expanding more operative and clinically validated nanomedicines. In this study, a one-at-a-time experimental approach was used for evaluating the effect of various preparation factors on size, loading, and drug release of hydrogel NPs prepared with ionotropic gelation between heparin and chitosan. The size, loading efficiency (LE) and drug release profile of the NPs were evaluated when the chitosan molecular weight, chitosan concentration, heparin addition time to chitosan solution, heparin concentration, pH value of chitosan solution, temperature, and mixing rate were changed separately while other factors were in optimum condition. The results displayed that size and LE are highly influenced by chitosan concentration, getting an optimum of 63 ± 0.57 and 75.19 ± 2.65, respectively, when chitosan concentration was 0.75 mg/ml. Besides, heparin addition time of 3 min leaded to 74.1 ± 0.79 % LE with no sensible effect on size and release profile. In addition, pH 5.5 showed a minimum size of 63 ± 1.87, maximum LE of 73.81 ± 3.13 and the slowest drug release with 63.71 ± 3.84 % during one week. Although LE was not affected by temperature, size and release reduced to 63 ± 0 and 74.21 ± 1.99% when temperature increased from 25°C to 55°C. Also, continuous increase of mixer rate from 500 to 3500 rpm resulted in constant enhancement of LE from 58.3 ± 3.6 to 74.4 ± 2.59 as well as remarkable decrease in size from 148 ± 4.88 to 63 ± 2.64.

  17. CRISPR-DT: designing gRNAs for the CRISPR-Cpf1 system with improved target efficiency and specificity

    OpenAIRE

    Liang, Chun; Zhu, Houxiang

    2018-01-01

    The CRISPR-Cpf1 system has been successfully applied in genome editing. However, target efficiency of the CRISPR-Cpf1 system varies among different gRNA sequences. We reanalyzed the published CRISPR-Cpf1 gRNAs data and found many sequence and structural features related to their target efficiency. Using machine learning technology, a SVM model was created to predict target efficiency for any given gRNAs. We have developed the first web service application, CRISPR-DT (CRISPR DNA Targeting), to...

  18. Efficient interruption of infection chains by targeted removal of central holdings in an animal trade network.

    Science.gov (United States)

    Büttner, Kathrin; Krieter, Joachim; Traulsen, Arne; Traulsen, Imke

    2013-01-01

    Centrality parameters in animal trade networks typically have right-skewed distributions, implying that these networks are highly resistant against the random removal of holdings, but vulnerable to the targeted removal of the most central holdings. In the present study, we analysed the structural changes of an animal trade network topology based on the targeted removal of holdings using specific centrality parameters in comparison to the random removal of holdings. Three different time periods were analysed: the three-year network, the yearly and the monthly networks. The aim of this study was to identify appropriate measures for the targeted removal, which lead to a rapid fragmentation of the network. Furthermore, the optimal combination of the removal of three holdings regardless of their centrality was identified. The results showed that centrality parameters based on ingoing trade contacts, e.g. in-degree, ingoing infection chain and ingoing closeness, were not suitable for a rapid fragmentation in all three time periods. More efficient was the removal based on parameters considering the outgoing trade contacts. In all networks, a maximum percentage of 7.0% (on average 5.2%) of the holdings had to be removed to reduce the size of the largest component by more than 75%. The smallest difference from the optimal combination for all three time periods was obtained by the removal based on out-degree with on average 1.4% removed holdings, followed by outgoing infection chain and outgoing closeness. The targeted removal using the betweenness centrality differed the most from the optimal combination in comparison to the other parameters which consider the outgoing trade contacts. Due to the pyramidal structure and the directed nature of the pork supply chain the most efficient interruption of the infection chain for all three time periods was obtained by using the targeted removal based on out-degree.

  19. An aptamer cocktail-functionalized photocatalyst with enhanced antibacterial efficiency towards target bacteria

    Energy Technology Data Exchange (ETDEWEB)

    Song, Min Young [Center for Environment, Health and Welfare Research, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792 (Korea, Republic of); Jurng, Jongsoo [Center for Environment, Health and Welfare Research, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792 (Korea, Republic of); Department of Energy and Environmental Engineering, University of Science and Technology (UST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792 (Korea, Republic of); Park, Young-Kwon [School of Environmental Engineering, University of Seoul, Seoulsiripdae-ro 163, Dongdaemun-gu, Seoul 02504 (Korea, Republic of); Kim, Byoung Chan, E-mail: bchankim@kist.re.kr [Center for Environment, Health and Welfare Research, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792 (Korea, Republic of); Department of Energy and Environmental Engineering, University of Science and Technology (UST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792 (Korea, Republic of)

    2016-11-15

    Highlights: • Aptamer-conjugated TiO{sub 2} was developed for target-specific bacterial inactivation. • TiO{sub 2}-aptamer cocktail can enhance inactivation of target bacteria faster than TiO{sub 2}. • TiO{sub 2}-aptamer cocktail can enhance inactivation of target bacteria in mixed culture. • Efficient ROS transfer to the bacteria is caused by close contact of TiO{sub 2}-aptamer. - Abstract: We developed TiO{sub 2} particles conjugated with an Escherichia coli surface-specific ssDNA aptamer cocktail (composed of three different aptamers isolated from E. coli) for targeted and enhanced disinfection of E. coli. We examined the target-specific and enhanced inactivation of this composite (TiO{sub 2}-Apc), which were compared to those of TiO{sub 2} conjugated with a single aptamer (one of the three different aptamers, TiO{sub 2}-Aps) and non-modified TiO{sub 2}. We found that TiO{sub 2}-Apc enhanced the inactivation of targeted E. coli under UV irradiation compared to both the non-modified TiO{sub 2} and TiO{sub 2}-Aps. A higher number of TiO{sub 2}-Apc than TiO{sub 2}-Aps particles was observed on the surface of E. coli. The amount of TiO{sub 2}-Apc required to inactivate ∼99.9% of E. coli (10{sup 6} CFU/ml) was 10 times lower than that of non-modified TiO{sub 2}. The close proximity of functionalized particles with E. coli resulting from the interaction between the target surface and the aptamer induced the efficient and fast transfer of reactive oxygen species to the cells. In a mixed culture of different bacteria (E. coli and Staphylococcus epidermidis), TiO{sub 2}-Apc enhanced the inactivation of only E. coli. Taken together, these results support the use of aptamer cocktail-conjugated TiO{sub 2} for improvement of the target-specific inactivation of bacteria.

  20. An efficient and accurate method for computation of energy release rates in beam structures with longitudinal cracks

    DEFF Research Database (Denmark)

    Blasques, José Pedro Albergaria Amaral; Bitsche, Robert

    2015-01-01

    This paper proposes a novel, efficient, and accurate framework for fracture analysis of beam structures with longitudinal cracks. The three-dimensional local stress field is determined using a high-fidelity beam model incorporating a finite element based cross section analysis tool. The Virtual...... Crack Closure Technique is used for computation of strain energy release rates. The devised framework was employed for analysis of cracks in beams with different cross section geometries. The results show that the accuracy of the proposed method is comparable to that of conventional three......-dimensional solid finite element models while using only a fraction of the computation time....

  1. Performance and efficiency evaluation and heat release study of a direct-injection stratified-charge rotary engine

    Science.gov (United States)

    Nguyen, H. L.; Addy, H. E.; Bond, T. H.; Lee, C. M.; Chun, K. S.

    1987-01-01

    A computer simulation which models engine performance of the Direct Injection Stratified Charge (DISC) rotary engines was used to study the effect of variations in engine design and operating parameters on engine performance and efficiency of an Outboard Marine Corporation (OMC) experimental rotary combustion engine. Engine pressure data were used in a heat release analysis to study the effects of heat transfer, leakage, and crevice flows. Predicted engine data were compared with experimental test data over a range of engine speeds and loads. An examination of methods to improve the performance of the rotary engine using advanced heat engine concepts such as faster combustion, reduced leakage, and turbocharging is also presented.

  2. An Energy-Efficient Target Tracking Framework in Wireless Sensor Networks

    Directory of Open Access Journals (Sweden)

    Zhijun Yu

    2009-01-01

    Full Text Available This study devises and evaluates an energy-efficient distributed collaborative signal and information processing framework for acoustic target tracking in wireless sensor networks. The distributed processing algorithm is based on mobile agent computing paradigm and sequential Bayesian estimation. At each time step, the short detection reports of cluster members will be collected by cluster head, and a sensor node with the highest signal-to-noise ratio (SNR is chosen there as reference node for time difference of arrive (TDOA calculation. During the mobile agent migration, the target state belief is transmitted among nodes and updated using the TDOA measurement of these fusion nodes one by one. The computing and processing burden is evenly distributed in the sensor network. To decrease the wireless communications, we propose to represent the belief by parameterized methods such as Gaussian approximation or Gaussian mixture model approximation. Furthermore, we present an attraction force function to handle the mobile agent migration planning problem, which is a combination of the node residual energy, useful information, and communication cost. Simulation examples demonstrate the estimation effectiveness and energy efficiency of the proposed distributed collaborative target tracking framework.

  3. A highly efficient targeted recombination system for engineering linear chromosomes of industrial bacteria Streptomyces.

    Science.gov (United States)

    Pan, Hung-Yin; Chen, Carton W; Huang, Chih-Hung

    2018-04-17

    Soil bacteria Streptomyces are the most important producers of secondary metabolites, including most known antibiotics. These bacteria and their close relatives are unique in possessing linear chromosomes, which typically harbor 20 to 30 biosynthetic gene clusters of tens to hundreds of kb in length. Many Streptomyces chromosomes are accompanied by linear plasmids with sizes ranging from several to several hundred kb. The large linear plasmids also often contain biosynthetic gene clusters. We have developed a targeted recombination procedure for arm exchanges between a linear plasmid and a linear chromosome. A chromosomal segment inserted in an artificially constructed plasmid allows homologous recombination between the two replicons at the homology. Depending on the design, the recombination may result in two recombinant replicons or a single recombinant chromosome with the loss of the recombinant plasmid that lacks a replication origin. The efficiency of such targeted recombination ranges from 9 to 83% depending on the locations of the homology (and thus the size of the chromosomal arm exchanged), essentially eliminating the necessity of selection. The targeted recombination is useful for the efficient engineering of the Streptomyces genome for large-scale deletion, addition, and shuffling.

  4. CRISPRscan: designing highly efficient sgRNAs for CRISPR/Cas9 targeting in vivo

    Science.gov (United States)

    Moreno-Mateos, Miguel A.; Vejnar, Charles E.; Beaudoin, Jean-Denis; Fernandez, Juan P.; Mis, Emily K.; Khokha, Mustafa K.; Giraldez, Antonio J.

    2015-01-01

    CRISPR/Cas9 technology provides a powerful system for genome engineering. However, variable activity across different single guide RNAs (sgRNAs) remains a significant limitation. We have analyzed the molecular features that influence sgRNA stability, activity and loading into Cas9 in vivo. We observe that guanine enrichment and adenine depletion increase sgRNA stability and activity, while loading, nucleosome positioning and Cas9 off-target binding are not major determinants. We additionally identified truncated and 5′ mismatch-containing sgRNAs as efficient alternatives to canonical sgRNAs. Based on these results, we created a predictive sgRNA-scoring algorithm (CRISPRscan.org) that effectively captures the sequence features affecting Cas9/sgRNA activity in vivo. Finally, we show that targeting Cas9 to the germ line using a Cas9-nanos-3′-UTR fusion can generate maternal-zygotic mutants, increase viability and reduce somatic mutations. Together, these results provide novel insights into the determinants that influence Cas9 activity and a framework to identify highly efficient sgRNAs for genome targeting in vivo. PMID:26322839

  5. An Energy-Efficient Sleep Strategy for Target Tracking Sensor Networks

    Directory of Open Access Journals (Sweden)

    Juan FENG

    2014-02-01

    Full Text Available Energy efficiency is very important for sensor networks since sensor nodes have limited energy supply from battery. So far, many researches have been focused on this issue, while less emphasis was placed on the optimal sleep time of each node. This paper proposed an adaptive energy conservation strategy for target tracking based on a grid network structure, where each node autonomously determines when and if to sleep. It allows sensor nodes far away from targets to sleep to save energy and guarantee the tracking accuracy. The proposed approach extend network lifetime by adopting an adaptive sleep scheduling scheme that combines the local power management (PM and the adaptive coordinate PM strategies to schedule the activities of sensor nodes. And each node can choose an optimal sleep time so as to make system adaptive and energy-efficient. We show the performance of our approach in terms of energy drop, comparing it to a naive approach, dynamic PM with fixed sleep time and the coordinate PM strategies. From the experimental results, it is readily seen that the efficiency of the proposed approach.

  6. Safety and Clinical Efficiency of Using Combined Preparation of Metformin Extended-Release and Glimepiride

    Directory of Open Access Journals (Sweden)

    V.I. Pankiv

    2013-04-01

    Conclusions. Administration of a combined anti-diabetic therapy with Duglimax for 24 weeks results in a significant reduction in HbA1c and the achievement of the targets of carbohydrate metabolism in patients with DM type 2. On the background of normalization of carbohydrate metabolism using combination therapy helps moderate decrease in body weight and WC value, to reduce serum LDL. Good tolerability and high degree of safety of Duglimax throughout the observation period were noted.

  7. [Nutrient use efficiency and yield-increasing effect of single basal application of rice specific controlled release fertilizer].

    Science.gov (United States)

    Chen, Jiansheng; Xu, Peizhi; Tang, Shuanhu; Zhang, Fabao; Xie, Chunsheng

    2005-10-01

    A series of pot and field experiments and field demonstrations showed that in comparing with the commonly used specific-fertilizers containing same amounts of nutrients, single basal application of rice-specific controlled release fertilizer could increase the use efficiency of N and P by 12.2% - 22.7% and 7.0% - 35.0%, respectively in pot experiment, and the use efficiency of N by 17.1% in field experiment. In 167 field demonstrations successively conducted for 3 years in various rice production areas of Guangdong Province, single basal application of the fertilizer saved the application rate of N and P by 22.1% and 21.8%, respectively, and increased the yield by 8.2%, compared with normal split fertilization.

  8. Supplementary Material for: DASPfind: new efficient method to predict drug–target interactions

    KAUST Repository

    Ba Alawi, Wail

    2016-01-01

    Abstract Background Identification of novel drug–target interactions (DTIs) is important for drug discovery. Experimental determination of such DTIs is costly and time consuming, hence it necessitates the development of efficient computational methods for the accurate prediction of potential DTIs. To-date, many computational methods have been proposed for this purpose, but they suffer the drawback of a high rate of false positive predictions. Results Here, we developed a novel computational DTI prediction method, DASPfind. DASPfind uses simple paths of particular lengths inferred from a graph that describes DTIs, similarities between drugs, and similarities between the protein targets of drugs. We show that on average, over the four gold standard DTI datasets, DASPfind significantly outperforms other existing methods when the single top-ranked predictions are considered, resulting in 46.17 % of these predictions being correct, and it achieves 49.22 % correct single top ranked predictions when the set of all DTIs for a single drug is tested. Furthermore, we demonstrate that our method is best suited for predicting DTIs in cases of drugs with no known targets or with few known targets. We also show the practical use of DASPfind by generating novel predictions for the Ion Channel dataset and validating them manually. Conclusions DASPfind is a computational method for finding reliable new interactions between drugs and proteins. We show over six different DTI datasets that DASPfind outperforms other state-of-the-art methods when the single top-ranked predictions are considered, or when a drug with no known targets or with few known targets is considered. We illustrate the usefulness and practicality of DASPfind by predicting novel DTIs for the Ion Channel dataset. The validated predictions suggest that DASPfind can be used as an efficient method to identify correct DTIs, thus reducing the cost of necessary experimental verifications in the process of drug discovery

  9. Hierarchical mesosilicalite nanoformulation integrated with cisplatin exhibits target-specific efficient anticancer activity

    Science.gov (United States)

    Jermy, B. Rabindran; Acharya, Sadananda; Ravinayagam, Vijaya; Alghamdi, Hajer Saleh; Akhtar, Sultan; Basuwaidan, Rehab S.

    2018-04-01

    Hierarchically structured zeolitic ZSM-5 and meso MCM-41 interlinked domain had an impeccable use as catalysis in many applications. The aim of the study was to develop a new drug delivery nanoformulation, specifically, cisplatin/mesosilicalite using top-down approach for cancer therapy. Hierarchical mesosilicalite with variable porosity was synthesized using alkaline molar solution (0.2 and 0.7 M NaOH) and was loaded with cisplatin through equilibrium adsorption technique. Physico-chemical properties of the nanoformulation (IAUM-56—Imam Abdulrahman Bin Faisal University Mesosilicalite-56) were characterized using X-ray diffraction, surface area analysis (BET), Fourier transformed infrared spectroscopy (FT-IR), diffuse reflectance UV-Vis spectroscopy, and transmission electron microscopy. Drug release study and anticancer activity were assayed on HeLa and MCF7 cancer cells using MTT assay. X-ray diffraction pattern showed interrelated meso- and microphases, while BET analysis revealed considerable mesoporosity formation with a remodulation of isotherm hysteresis indicating the presence of hierarchical pores. FT-IR showed the presence of nanozeolitic subunits into mesostructure with a band at about 550 cm-1. IAUM-56 demonstrated high cytotoxic activity against HeLa cancer cells with an LC50 of 0.02 mg/ml, MCF7 cancer cells with an LC50 of 0.05 mg/ml, and less toxic to normal fibroblast cells with an LC50 of approximately ten times higher at 0.5 mg/ml. Overall, IAUM-56 showed a high rate of sustained release of cisplatin imparting target specific cytotoxic effect against tumor cells with at least tenfold lower toxicity on normal fibroblast cells. Our nanoformulation has the potential use in cancer therapy as a targeted drug delivery system.

  10. Increased efficiency of targeted mutagenesis by CRISPR/Cas9 in plants using heat stress.

    Science.gov (United States)

    LeBlanc, Chantal; Zhang, Fei; Mendez, Josefina; Lozano, Yamile; Chatpar, Krishna; Irish, Vivian F; Jacob, Yannick

    2018-01-01

    The CRISPR/Cas9 system has greatly improved our ability to engineer targeted mutations in eukaryotic genomes. While CRISPR/Cas9 appears to work universally, the efficiency of targeted mutagenesis and the adverse generation of off-target mutations vary greatly between different organisms. In this study, we report that Arabidopsis plants subjected to heat stress at 37°C show much higher frequencies of CRISPR-induced mutations compared to plants grown continuously at the standard temperature (22°C). Using quantitative assays relying on green fluorescent protein (GFP) reporter genes, we found that targeted mutagenesis by CRISPR/Cas9 in Arabidopsis is increased by approximately 5-fold in somatic tissues and up to 100-fold in the germline upon heat treatment. This effect of temperature on the mutation rate is not limited to Arabidopsis, as we observed a similar increase in targeted mutations by CRISPR/Cas9 in Citrus plants exposed to heat stress at 37°C. In vitro assays demonstrate that Cas9 from Streptococcus pyogenes (SpCas9) is more active in creating double-stranded DNA breaks at 37°C than at 22°C, thus indicating a potential contributing mechanism for the in vivo effect of temperature on CRISPR/Cas9. This study reveals the importance of temperature in modulating SpCas9 activity in eukaryotes, and provides a simple method to increase on-target mutagenesis in plants using CRISPR/Cas9. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

  11. Highly Efficient Release of Glycopeptides from Hydrazide Beads by Hydroxylamine Assisted PNGase F Deglycosylation for N-Glycoproteome Analysis.

    Science.gov (United States)

    Huang, Junfeng; Wan, Hao; Yao, Yating; Li, Jinan; Cheng, Kai; Mao, Jiawei; Chen, Jin; Wang, Yan; Qin, Hongqiang; Zhang, Weibing; Ye, Mingliang; Zou, Hanfa

    2015-10-20

    Selective enrichment of glycopeptides from complex sample followed by cleavage of N-glycans by PNGase F to expose an easily detectable mark on the former glycosylation sites has become the popular protocol for comprehensive glycoproteome analysis. On account of the high enrichment specificity, hydrazide chemistry based solid-phase extraction of N-linked glycopeptides technique has sparked numerous interests. However, the enzymatic release of glycopeptides captured by hydrazide beads through direct incubation of the beads with PNGase F is not efficient due to the inherent steric hindrance effect. In this study, we developed a hydroxylamine assisted PNGase F deglycosylation (HAPD) method using the hydroxylamine to release glycopeptides captured on the hydrazide beads through the cleavage of hydrazone bonds by transamination followed with the PNGase F deglycosylation of the released glycopeptides in the free solution. Because of the homogeneous condition for the deglycosylation, the recovery of deglycosylated peptides (deglycopeptides) was improved significantly. It was found that 27% more N-glycosylation sites were identified by the HAPD strategy compared with the conventional method. Moreover, the ratio of identified N-terminal glycosylated peptides was improved over 5-fold.

  12. An Energy-Efficient Target-Tracking Strategy for Mobile Sensor Networks.

    Science.gov (United States)

    Mahboubi, Hamid; Masoudimansour, Walid; Aghdam, Amir G; Sayrafian-Pour, Kamran

    2017-02-01

    In this paper, an energy-efficient strategy is proposed for tracking a moving target in an environment with obstacles, using a network of mobile sensors. Typically, the most dominant sources of energy consumption in a mobile sensor network are sensing, communication, and movement. The proposed algorithm first divides the field into a grid of sufficiently small cells. The grid is then represented by a graph whose edges are properly weighted to reflect the energy consumption of sensors. The proposed technique searches for near-optimal locations for the sensors in different time instants to route information from the target to destination, using a shortest path algorithm. Simulations confirm the efficacy of the proposed algorithm.

  13. Specific and Efficient Regression of Cancers Harboring KRAS Mutation by Targeted RNA Replacement.

    Science.gov (United States)

    Kim, Sung Jin; Kim, Ju Hyun; Yang, Bitna; Jeong, Jin-Sook; Lee, Seong-Wook

    2017-02-01

    Mutations in the KRAS gene, which persistently activate RAS function, are most frequently found in many types of human cancers. Here, we proposed and verified a new approach against cancers harboring the KRAS mutation with high cancer selectivity and efficient anti-cancer effects based on targeted RNA replacement. To this end, trans-splicing ribozymes from Tetrahymena group I intron were developed, which can specifically target and reprogram the mutant KRAS G12V transcript to induce therapeutic gene activity in cells. Adenoviral vectors containing the specific ribozymes with downstream suicide gene were constructed and then infection with the adenoviruses specifically downregulated KRAS G12V expression and killed KRAS G12V-harboring cancer cells additively upon pro-drug treatment, but it did not affect the growth of wild-type KRAS-expressing cells. Minimal liver toxicity was noted when the adenoviruses were administered systemically in vivo. Importantly, intratumoral injection of the adenoviruses with pro-drug treatment specifically and significantly impeded the growth of xenografted tumors harboring KRAS G12V through a trans-splicing reaction with the target RNA. In contrast, xenografted tumors harboring wild-type KRAS were not affected by the adenoviruses. Therefore, RNA replacement with a mutant KRAS-targeting trans-splicing ribozyme is a potentially useful therapeutic strategy to combat tumors harboring KRAS mutation. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  14. Premature drug release of polymeric micelles and its effects on tumor targeting.

    Science.gov (United States)

    Miller, Tobias; Breyer, Sandra; van Colen, Gwenaelle; Mier, Walter; Haberkorn, Uwe; Geissler, Simon; Voss, Senta; Weigandt, Markus; Goepferich, Achim

    2013-03-10

    Based on the enhanced permeability and retention (EPR) effect, nanoparticles are believed to accumulate in tumors. In this conjunction, the stability of drug encapsulation is assumed to be sufficient. For clarification purposes, PEGylated poly-(D,L-lactic acid) (PEG-PDLLA) micelles which incorporated the hydrophobic model drug dechloro-4-iodo-fenofibrate (IFF) were investigated. H2N-PEG-PDLLA was synthesized, coupled to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labeled with 111-indium. From this polymeric species, mixed micelles with H3CO-PEG-PDLLA were prepared which encapsulated the 125-iodine or 131-iodine labeled drug IFF. Bioimaging and biodistribution experiments in healthy and AR42J-tumor bearing mice were carried out to quantify the uptake of the drug and its carrier in single organs. As a result, upon injection of this system, a rapid dissociation of the polymeric carrier and the incorporated drug (system allowed for successful solubilization of the hydrophobic drug by physical incorporation into micelles whereas the tumor targeting properties of the drug delivery system could not be sufficiently shown. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. The roles of energy and material efficiency in meeting steel industry CO2 targets.

    Science.gov (United States)

    Milford, Rachel L; Pauliuk, Stefan; Allwood, Julian M; Müller, Daniel B

    2013-04-02

    Identifying strategies for reducing greenhouse gas emissions from steel production requires a comprehensive model of the sector but previous work has either failed to consider the whole supply chain or considered only a subset of possible abatement options. In this work, a global mass flow analysis is combined with process emissions intensities to allow forecasts of future steel sector emissions under all abatement options. Scenario analysis shows that global capacity for primary steel production is already near to a peak and that if sectoral emissions are to be reduced by 50% by 2050, the last required blast furnace will be built by 2020. Emissions reduction targets cannot be met by energy and emissions efficiency alone, but deploying material efficiency provides sufficient extra abatement potential.

  16. Control of laser absorbing efficiency and proton quality by a specific double target

    Czech Academy of Sciences Publication Activity Database

    Yu, Q.; Gu, Yanjun; Li, X.F.; Qu, J.F.; Kong, Q.; Kawata, S.

    2016-01-01

    Roč. 18, č. 8 (2016), 1-9, č. článku 083024. ISSN 1367-2630 R&D Projects: GA MŠk LQ1606; GA MŠk EF15_008/0000162 Grant - others:ELI Beamlines(XE) CZ.02.1.01/0.0/0.0/15_008/0000162 Institutional support: RVO:68378271 Keywords : improved proton beam quality * increased laser absorption efficiency * specific double-layer target Subject RIV: BL - Plasma and Gas Discharge Physics Impact factor: 3.786, year: 2016

  17. Efficient inhibition of heavy metal release from mine tailings against acid rain exposure by triethylenetetramine intercalated montmorillonite (TETA-Mt).

    Science.gov (United States)

    Gong, Beini; Wu, Pingxiao; Huang, Zhujian; Li, Yuanyuan; Yang, Shanshan; Dang, Zhi; Ruan, Bo; Kang, Chunxi

    2016-11-15

    The potential application of triethylenetetramine intercalated montmorillonite (TETA-Mt) in mine tailings treatment and AMD (acid mine drainage) remediation was investigated with batch experiments. The structural and morphological characteristics of TETA-Mt were analyzed with XRD, FTIR, DTG-TG and SEM. The inhibition efficiencies of TETA-Mt against heavy metal release from mine tailings when exposed to acid rain leaching was examined and compared with that of triethylenetetramine (TETA) and Mt. Results showed that the overall inhibition by TETA-Mt surpassed that by TETA or Mt for various heavy metal ions over an acid rain pH range of 3-5.6 and a temperature range of 25-40°C. When mine tailings were exposed to acid rain of pH 4.8 (the average rain pH of the mining site where the mine tailings were from), TETA-Mt achieved an inhibition efficiency of over 90% for Cu(2+), Zn(2+), Cd(2+) and Mn(2+) release, and 70% for Pb(2+) at 25°C. It was shown that TETA-Mt has a strong buffering capacity. Moreover, TETA-Mt was able to adsorb heavy metal ions and the adsorption process was fast, suggesting that coordination was mainly responsible. These results showed the potential of TETA-Mt in AMD mitigation, especially in acid rain affected mining area. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Reactive oxygen species responsive drug releasing nanoparticle based on chondroitin sulfate-anthocyanin nanocomplex for efficient tumor therapy.

    Science.gov (United States)

    Jeong, Dooyong; Bae, Byoung-Chan; Park, Sin-Jung; Na, Kun

    2016-01-28

    To develop a reactive oxygen species (ROS) sensitive drug carrier, a chondroitin sulfate (CS)-anthocyanin (ATC) based nanocomplex was developed. Doxorubicin hydrochloride (DOX) was loaded in the CS-ATC nanocomplex (CS-ATC-DOX) via intermolecular stacking interaction. The nanocomplex was fabricated by a simple mixing method in the aqueous phase. The morphology and size of CS-ATC-DOX were determined by ATC content. In the group with 1.5mg/ml of ATC loaded CS-ATC-DOX (CS-ATC2-DOX), the drug content and loading efficiency were 8.5% and 99.1%, respectively. The ROS sensitive drug release of CS-ATC2-DOX was confirmed under in vitro physiological conditions. The results demonstrated that 1.67 times higher DOX release occurred in CS-ATC2-DOX for 48h compared to CS-DOX (ATC absent sample). Drug release and nanocomplex destruction were induced by ROS mediated ATC degradation. We determined that 66.7% of ROS was scavenged by CS-ATC2-DOX. Additionally, an HCT-116 tumor bearing animal model was used to confirm ROS sensitive therapeutic effects of CS-ATC2-DOX. The results indicate that DOX was released from the intravenously injected CS-ATC2-DOX in the tumor tissue. Thus, nuclei shrinkage and dead cells were observed in H&E staining and TUNEL assay, respectively. These data suggest that the tumor growth was effectively inhibited. This study means that CS-ATC2-DOX has potential in improving tumor therapy. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Adiponectin release and insulin receptor targeting share trans-Golgi-dependent endosomal trafficking routes

    Directory of Open Access Journals (Sweden)

    Maria Rödiger

    2018-02-01

    Full Text Available Objective: Intracellular vesicle trafficking maintains cellular structures and functions. The assembly of cargo-laden vesicles at the trans-Golgi network is initiated by the ARF family of small GTPases. Here, we demonstrate the role of the trans-Golgi localized monomeric GTPase ARFRP1 in endosomal-mediated vesicle trafficking of mature adipocytes. Methods: Control (Arfrp1flox/flox and inducible fat-specific Arfrp1 knockout (Arfrp1iAT−/− mice were metabolically characterized. In vitro experiments on mature 3T3-L1 cells and primary mouse adipocytes were conducted to validate the impact of ARFRP1 on localization of adiponectin and the insulin receptor. Finally, secretion and transferrin-based uptake and recycling assays were performed with HeLa and HeLa M-C1 cells. Results: We identified the ARFRP1-based sorting machinery to be involved in vesicle trafficking relying on the endosomal compartment for cell surface delivery. Secretion of adiponectin from fat depots was selectively reduced in Arfrp1iAT−/− mice, and Arfrp1-depleted 3T3-L1 adipocytes revealed an accumulation of adiponectin in Rab11-positive endosomes. Plasma adiponectin deficiency of Arfrp1iAT−/− mice resulted in deteriorated hepatic insulin sensitivity, increased gluconeogenesis and elevated fasting blood glucose levels. Additionally, the insulin receptor, undergoing endocytic recycling after ligand binding, was less abundant at the plasma membrane of adipocytes lacking Arfrp1. This had detrimental effects on adipose insulin signaling, followed by insufficient suppression of basal lipolytic activity and impaired adipose tissue expansion. Conclusions: Our findings suggest that adiponectin secretion and insulin receptor surface targeting utilize the same post-Golgi trafficking pathways that are essential for an appropriate systemic insulin sensitivity and glucose homeostasis. Keywords: Adiponectin, ARFRP1, Exocytosis, Insulin receptor, trans-Golgi

  20. Controlled and targeted release of antigens by intelligent shell for improving applicability of oral vaccines.

    Science.gov (United States)

    Zhang, Lei; Zeng, Zhanzhuang; Hu, Chaohua; Bellis, Susan L; Yang, Wendi; Su, Yintao; Zhang, Xinyan; Wu, Yunkun

    2016-01-01

    Conventional oral vaccines with simple architecture face barriers with regard to stimulating effective immunity. Here we describe oral vaccines with an intelligent phase-transitional shielding layer, poly[(methyl methacrylate)-co-(methyl acrylate)-co-(methacrylic acid)]-poly(D,L-lactide-co-glycolide) (PMMMA-PLGA), which can protect antigens in the gastro-intestinal tract and achieve targeted vaccination in the large intestine. With the surface immunogenic protein (SIP) from group B Streptococcus (GBS) entrapped as the antigen, oral administration with PMMMA-PLGA (PTRBL)/Trx-SIP nanoparticles stimulated robust immunity in tilapia, an animal with a relatively simple immune system. The vaccine succeeded in protecting against Streptococcus agalactiae, a pathogen of worldwide importance that threatens human health and is transmitted in water with infected fish. After oral vaccination with PTRBL/Trx-SIP, tilapia produced enhanced levels of SIP specific antibodies and displayed durability of immune protection. 100% of the vaccinated tilapia were protected from GBS infection, whereas the control groups without vaccines or vaccinated with Trx-SIP only exhibited respective infection rates of 100% or >60% within the initial 5 months after primary vaccination. Experiments in vivo demonstrated that the recombinant antigen Trx-SIP labeled with FITC was localized in colon, spleen and kidney, which are critical sites for mounting an immune response. Our results revealed that, rather than the size of the nanoparticles, it is more likely that the negative charge repulsion produced by ionization of the carboxyl groups in PMMMA shielded the nanoparticles from uptake by small intestinal epithelial cells. This system resolves challenges arising from gastrointestinal damage to antigens, and more importantly, offers a new approach applicable for oral vaccination. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Cratering efficiency on coarse-grain targets: Implications for the dynamical evolution of asteroid 25143 Itokawa

    Science.gov (United States)

    Tatsumi, Eri; Sugita, Seiji

    2018-01-01

    Remote sensing observations made by the spacecraft Hayabusa provided the first direct evidence of a rubble-pile asteroid: 25143 Itokawa. Itokawa was found to have a surface structure very different from other explored asteroids; covered with coarse pebbles and boulders ranging at least from cm to meter size. The cumulative size distribution of small circular depressions on Itokawa, most of which may be of impact origin, has a significantly shallower slope than that on the Moon; small craters are highly depleted on Itokawa compared to the Moon. This deficiency of small circular depressions and other features, such as clustered fragments and pits on boulders, suggest that the boulders on Itokawa might behave like armor, preventing crater formation: the ;armoring effect;. This might contribute to the low number density of small crater candidates. In this study, the cratering efficiency reduction due to coarse-grained targets was investigated based on impact experiments at velocities ranging from ∼ 70 m/s to ∼ 6 km/s using two vertical gas gun ranges. We propose a scaling law extended for cratering on coarse-grained targets (i.e., target grain size ≳ projectile size). We have found that the crater efficiency reduction is caused by energy dissipation at the collision site where momentum is transferred from the impactor to the first-contact target grain, and that the armoring effect can be classified into three regimes: (1) gravity scaled regime, (2) reduced size crater regime, or (3) no apparent crater regime, depending on the ratio of the impactor size to the target grain size and the ratio of the impactor kinetic energy to the disruption energy of a target grain. We found that the shallow slope of the circular depressions on Itokawa cannot be accounted for by this new scaling law, suggesting that obliteration processes, such as regolith convection and migration, play a greater role in the depletion of circular depressions on Itokawa. Based on the new extended

  2. Enhanced Anti-Tumoral Activity of Methotrexate-Human Serum Albumin Conjugated Nanoparticles by Targeting with Luteinizing Hormone-Releasing Hormone (LHRH) Peptide

    Science.gov (United States)

    Taheri, Azade; Dinarvand, Rassoul; Atyabi, Fatemeh; Ahadi, Fatemeh; Nouri, Farank Salman; Ghahremani, Mohammad Hossein; Ostad, Seyed Nasser; Borougeni, Atefeh Taheri; Mansoori, Pooria

    2011-01-01

    Active targeting could increase the efficacy of anticancer drugs. Methotrexate-human serum albumin (MTX-HSA) conjugates, functionalized by luteinizing hormone-releasing hormone (LHRH) as targeting moieties, with the aim of specifically targeting the cancer cells, were prepared. Owing to the high expression of LHRH receptors in many cancer cells as compared to normal cells, LHRH was used as the targeting ligand in this study. LHRH was conjugated to MTX-HSA nanoparticles via a cross-linker. Three types of LHRH targeted nanoparticles with a mean particle size between 120–138 nm were prepared. The cytotoxicity of LHRH targeted and non-targeted nanoparticles were determined on the LHRH positive and negative cell lines. The internalization of the targeted and non-targeted nanoparticles in LHRH receptor positive and negative cells was investigated using flow cytometry analysis and fluorescence microscopy. The cytotoxicity of the LHRH targeted nanoparticles on the LHRH receptor positive cells were significantly more than non-targeted nanoparticles. LHRH targeted nanoparticles were also internalized by LHRH receptor positive cells significantly more than non-targeted nanoparticles. There were no significant differences between the uptake of targeted and non-targeted nanoparticles to the LHRH receptor negative cells. The active targeting procedure using LHRH targeted MTX-HSA nanoparticles could increase the anti-tumoral activity of MTX. PMID:21845098

  3. Design of effective energy efficiency policies. An analysis in the frame of target setting, monitoring and evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Schlomann, Barbara

    2014-07-01

    Energy efficiency 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 co-benefits to the economy and society. There are, however, indications that energy efficiency policy is still insufficiently anchored both in the EU and many Member States as well as at an international level. This thesis focuses on the question how to create more favourable preconditions for an effective anchoring of energy efficiency policy in energy and climate policy. The design of energy efficiency policies is analyzed in the frame of the setting of energy efficiency targets and the monitoring and evaluation of their success. This provides new insights in the functioning of policies and hence their improvement in view of target achievement.

  4. Human endogenous retrovirus K Gag coassembles with HIV-1 Gag and reduces the release efficiency and infectivity of HIV-1.

    Science.gov (United States)

    Monde, Kazuaki; Contreras-Galindo, Rafael; Kaplan, Mark H; Markovitz, David M; Ono, Akira

    2012-10-01

    Human endogenous retroviruses (HERVs), which are remnants of ancestral retroviruses integrated into the human genome, are defective in viral replication. Because activation of HERV-K and coexpression of this virus with HIV-1 have been observed during HIV-1 infection, it is conceivable that HERV-K could affect HIV-1 replication, either by competition or by cooperation, in cells expressing both viruses. In this study, we found that the release efficiency of HIV-1 Gag was 3-fold reduced upon overexpression of HERV-K(CON) Gag. In addition, we observed that in cells expressing Gag proteins of both viruses, HERV-K(CON) Gag colocalized with HIV-1 Gag at the plasma membrane. Furthermore, HERV-K(CON) Gag was found to coassemble with HIV-1 Gag, as demonstrated by (i) processing of HERV-K(CON) Gag by HIV-1 protease in virions, (ii) coimmunoprecipitation of virion-associated HERV-K(CON) Gag with HIV-1 Gag, and (iii) rescue of a late-domain-defective HERV-K(CON) Gag by wild-type (WT) HIV-1 Gag. Myristylation-deficient HERV-K(CON) Gag localized to nuclei, suggesting cryptic nuclear trafficking of HERV-K Gag. Notably, unlike WT HERV-K(CON) Gag, HIV-1 Gag failed to rescue myristylation-deficient HERV-K(CON) Gag to the plasma membrane. Efficient colocalization and coassembly of HIV-1 Gag and HERV-K Gag also required nucleocapsid (NC). These results provide evidence that HIV-1 Gag heteromultimerizes with HERV-K Gag at the plasma membrane, presumably through NC-RNA interaction. Intriguingly, HERV-K Gag overexpression reduced not only HIV-1 release efficiency but also HIV-1 infectivity in a myristylation- and NC-dependent manner. Altogether, these results indicate that Gag proteins of endogenous retroviruses can coassemble with HIV-1 Gag and modulate the late phase of HIV-1 replication.

  5. Simple and Efficient Targeting of Multiple Genes Through CRISPR-Cas9 in Physcomitrella patens

    Directory of Open Access Journals (Sweden)

    Mauricio Lopez-Obando

    2016-11-01

    Full Text Available Powerful genome editing technologies are needed for efficient gene function analysis. The CRISPR-Cas9 system has been adapted as an efficient gene-knock-out technology in a variety of species. However, in a number of situations, knocking out or modifying a single gene is not sufficient; this is particularly true for genes belonging to a common family, or for genes showing redundant functions. Like many plants, the model organism Physcomitrella patens has experienced multiple events of polyploidization during evolution that has resulted in a number of families of duplicated genes. Here, we report a robust CRISPR-Cas9 system, based on the codelivery of a CAS9 expressing cassette, multiple sgRNA vectors, and a cassette for transient transformation selection, for gene knock-out in multiple gene families. We demonstrate that CRISPR-Cas9-mediated targeting of five different genes allows the selection of a quintuple mutant, and all possible subcombinations of mutants, in one experiment, with no mutations detected in potential off-target sequences. Furthermore, we confirmed the observation that the presence of repeats in the vicinity of the cutting region favors deletion due to the alternative end joining pathway, for which induced frameshift mutations can be potentially predicted. Because the number of multiple gene families in Physcomitrella is substantial, this tool opens new perspectives to study the role of expanded gene families in the colonization of land by plants.

  6. Distributed Bees Algorithm Parameters Optimization for a Cost Efficient Target Allocation in Swarms of Robots

    Directory of Open Access Journals (Sweden)

    Álvaro Gutiérrez

    2011-11-01

    Full Text Available Swarms of robots can use their sensing abilities to explore unknown environments and deploy on sites of interest. In this task, a large number of robots is more effective than a single unit because of their ability to quickly cover the area. However, the coordination of large teams of robots is not an easy problem, especially when the resources for the deployment are limited. In this paper, the Distributed Bees Algorithm (DBA, previously proposed by the authors, is optimized and applied to distributed target allocation in swarms of robots. Improved target allocation in terms of deployment cost efficiency is achieved through optimization of the DBA’s control parameters by means of a Genetic Algorithm. Experimental results show that with the optimized set of parameters, the deployment cost measured as the average distance traveled by the robots is reduced. The cost-efficient deployment is in some cases achieved at the expense of increased robots’ distribution error. Nevertheless, the proposed approach allows the swarm to adapt to the operating conditions when available resources are scarce.

  7. Efficient and Heritable Gene Targeting in Tilapia by CRISPR/Cas9

    Science.gov (United States)

    Li, Minghui; Yang, Huihui; Zhao, Jiue; Fang, Lingling; Shi, Hongjuan; Li, Mengru; Sun, Yunlv; Zhang, Xianbo; Jiang, Dongneng; Zhou, Linyan; Wang, Deshou

    2014-01-01

    Studies of gene function in non-model animals have been limited by the approaches available for eliminating gene function. The CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR associated) system has recently become a powerful tool for targeted genome editing. Here, we report the use of the CRISPR/Cas9 system to disrupt selected genes, including nanos2, nanos3, dmrt1, and foxl2, with efficiencies as high as 95%. In addition, mutations in dmrt1 and foxl2 induced by CRISPR/Cas9 were efficiently transmitted through the germline to F1. Obvious phenotypes were observed in the G0 generation after mutation of germ cell or somatic cell-specific genes. For example, loss of Nanos2 and Nanos3 in XY and XX fish resulted in germ cell-deficient gonads as demonstrated by GFP labeling and Vasa staining, respectively, while masculinization of somatic cells in both XY and XX gonads was demonstrated by Dmrt1 and Cyp11b2 immunohistochemistry and by up-regulation of serum androgen levels. Our data demonstrate that targeted, heritable gene editing can be achieved in tilapia, providing a convenient and effective approach for generating loss-of-function mutants. Furthermore, our study shows the utility of the CRISPR/Cas9 system for genetic engineering in non-model species like tilapia and potentially in many other teleost species. PMID:24709635

  8. Orally Targeted Delivery of Tripeptide KPV via Hyaluronic Acid-Functionalized Nanoparticles Efficiently Alleviates Ulcerative Colitis.

    Science.gov (United States)

    Xiao, Bo; Xu, Zhigang; Viennois, Emilie; Zhang, Yuchen; Zhang, Zhan; Zhang, Mingzhen; Han, Moon Kwon; Kang, Yuejun; Merlin, Didier

    2017-07-05

    Overcoming adverse effects and selectively delivering drug to target cells are two major challenges in the treatment of ulcerative colitis (UC). Lysine-proline-valine (KPV), a naturally occurring tripeptide, has been shown to attenuate the inflammatory responses of colonic cells. Here, we loaded KPV into hyaluronic acid (HA)-functionalized polymeric nanoparticles (NPs). The resultant HA-KPV-NPs had a desirable particle size (∼272.3 nm) and a slightly negative zeta potential (∼-5.3 mV). These NPs successfully mediated the targeted delivery of KPV to key UC therapy-related cells (colonic epithelial cells and macrophages). In addition, these KPV-loaded NPs appear to be nontoxic and biocompatible with intestinal cells. Intriguingly, we found that HA-KPV-NPs exert combined effects against UC by both accelerating mucosal healing and alleviating inflammation. Oral administration of HA-KPV-NPs encapsulated in a hydrogel (chitosan/alginate) exhibited a much stronger capacity to prevent mucosa damage and downregulate TNF-α, thus they showed a much better therapeutic efficacy against UC in a mouse model, compared with a KPV-NP/hydrogel system. These results collectively demonstrate that our HA-KPV-NP/hydrogel system has the capacity to release HA-KPV-NPs in the colonic lumen and that these NPs subsequently penetrate into colitis tissues and enable KPV to be internalized into target cells, thereby alleviating UC. Copyright © 2016 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  9. Impact of the recession on the realization of the Kyoto target and the 2011 target of the working programme 'Clean and Efficient'. Memo

    International Nuclear Information System (INIS)

    2009-01-01

    By request of the Dutch Ministry of Housing, Spatial Planning and the Environment the Environmental Assessment Agency (PBL) drew up this memo on the impact of the recession on the realization of the Kyoto target and the intermediate target for 2011 from the working programme Clean and Efficient. The main conclusion of this memo is that both with and without the recession the Kyoto target will probably be realized. The main difference lies in the volume of emission allowances deployed by the government to realize the target [mk] [nl

  10. Efficient and Adaptive Node Selection for Target Tracking in Wireless Sensor Network

    Directory of Open Access Journals (Sweden)

    Juan Feng

    2016-01-01

    Full Text Available In target tracking wireless sensor network, choosing the proper working nodes can not only minimize the number of active nodes, but also satisfy the tracking reliability requirement. However, most existing works focus on selecting sensor nodes which are the nearest to the target for tracking missions and they did not consider the correlation of the location of the sensor nodes so that these approaches can not meet all the goals of the network. This work proposes an efficient and adaptive node selection approach for tracking a target in a distributed wireless sensor network. The proposed approach combines the distance-based node selection strategy and particle filter prediction considering the spatial correlation of the different sensing nodes. Moreover, a joint distance weighted measurement is proposed to estimate the information utility of sensing nodes. Experimental results show that EANS outperformed the state-of-the-art approaches by reducing the energy cost and computational complexity as well as guaranteeing the tracking accuracy.

  11. Can we improve the identification of cold homes for targeted home energy-efficiency improvements?

    International Nuclear Information System (INIS)

    Hutchinson, Emma J.; Wilkinson, Paul; Hong, Sung H.; Oreszczyn, Tadj

    2006-01-01

    Objective: To investigate the extent to which homes with low indoor-temperatures can be identified from dwelling and household characteristics. Design: Analysis of data from a national survey of dwellings, occupied by low-income households, scheduled for home energy-efficiency improvements. Setting: Five urban areas of England: Birmingham, Liverpool, Manchester, Newcastle and Southampton. Methods: Half-hourly living-room temperatures were recorded for two to four weeks in dwellings over the winter periods November to April 2001-2002 and 2002-2003. Regression of indoor on outdoor temperatures was used to identify cold-homes in which standardized daytime living-room and/or nighttime bedroom-temperatures were o C (when the outdoor temperature was 5 o C). Tabulation and logistic regression were used to examine the extent to which these cold-homes can be identified from dwelling and household characteristics. Results: Overall, 21.0% of dwellings had standardized daytime living-room temperatures o C, and 46.4% had standardized nighttime bedroom-temperatures below the same temperature. Standardized indoor-temperatures were influenced by a wide range of household and dwelling characteristics, but most strongly by the energy efficiency (SAP) rating and by standardized heating costs. However, even using these variables, along with other dwelling and household characteristics in a multi-variable prediction model, it would be necessary to target more than half of all dwellings in our sample to ensure at least 80% sensitivity for identifying dwellings with cold living-room temperatures. An even higher proportion would have to be targeted to ensure 80% sensitivity for identifying dwellings with cold-bedroom temperatures. Conclusion: Property and household characteristics provide only limited potential for identifying dwellings where winter indoor temperatures are likely to be low, presumably because of the multiple influences on home heating, including personal choice and

  12. Development of Houttuynia cordata Extract-Loaded Solid Lipid Nanoparticles for Oral Delivery: High Drug Loading Efficiency and Controlled Release

    Directory of Open Access Journals (Sweden)

    Ju-Heon Kim

    2017-12-01

    Full Text Available Houttuynia cordata (H. cordata has been used for diuresis and detoxification in folk medicine as well as a herbal medicine with antiviral and antibacterial activities. H. cordata extract-loaded solid lipid nanoparticles (H-SLNs were prepared with various concentration of poloxamer 188 or poloxamer 407 by a hot homogenization and ultrasonication method. H-SLNs dispersion was freeze-dried with or without trehalose as a cryoprotectant. The physicochemical characteristics of H-SLNs were evaluated by dynamic laser scattering (DLS, differential scanning calorimetry (DSC, Fourier transform infrared spectroscopy (FT-IR, and scanning electron microscopy (SEM. Additionally, the in vitro release and in vitro cytotoxicity of H-SLNs were measured. Encapsulation efficiencies of H-SLNs (as quercitrin were 92.9–95.9%. The SEM images of H-SLNs showed that H-SLNs have a spherical morphology. DSC and FT-IR showed that there were no interactions between ingredients. The increased extent of particle size of freeze-dried H-SLNs with trehalose was significantly lower than that of H-SLNs without trehalose. H-SLNs provided sustained release of quercitrin from H. cordata extracts. Cell viability of Caco-2 cells was over 70% according to the concentration of various formulation. Therefore, it was suggested that SLNs could be good carrier for administering H. cordata extracts.

  13. High efficiency dry coating of non-subcoated pellets for sustained drug release formulations using amino methacrylate copolymers.

    Science.gov (United States)

    Klar, Fabian; Urbanetz, Nora Anne

    2017-12-12

    Dry coating utilizing a fluidized bed was evaluated in order to produce films with sustained drug release using amino methacrylate copolymers as film former. In contrast to other dry coating procedures using amino methacrylate copolymers, the described method enables an appropriate polymer adhesion by the selection of a plasticizer additive mixture in combination with the use of a three-way nozzle for simultaneous application. Well spreading fatty acid esters were found to increase the coating efficiency from 73% to approximately 86%, when they were used in conjunction with the plasticizer. Pellets were used as drug cores without previous treatment. After a curing step at 55 °C, the pellets exhibited a prolongation of the drug release over a period of about 6 h. Mainly the three parameters, coating level, composition of the polymers in the coating mixture, and the type of plasticizer, were found to exert distinct influence on the dissolution profile. Despite the differences in the coating procedure, the dissolution profiles of the coated pellets as well as the influencing parameters were similar to those known from conventional coating techniques.

  14. International Experience with Key Program Elements of IndustrialEnergy Efficiency or Greenhouse Gas Emissions Reduction Target-SettingPrograms

    Energy Technology Data Exchange (ETDEWEB)

    Price, Lynn; Galitsky, Christina; Kramer, Klaas Jan

    2008-02-02

    Target-setting agreements, also known as voluntary ornegotiated agreements, have been used by a number of governments as amechanism for promoting energy efficiency within the industrial sector. Arecent survey of such target-setting agreement programs identified 23energy efficiency or GHG emissions reduction voluntary agreement programsin 18 countries. International best practice related to target-settingagreement programs calls for establishment of a coordinated set ofpolicies that provide strong economic incentives as well as technical andfinancial support to participating industries. The key program elementsof a target-setting program are the target-setting process,identification of energy-saving technologies and measures usingenergy-energy efficiency guidebooks and benchmarking as well as byconducting energy-efficiency audits, development of an energy-savingsaction plan, development and implementation of energy managementprotocols, development of incentives and supporting policies, monitoringprogress toward targets, and program evaluation. This report firstprovides a description of three key target-setting agreement programs andthen describes international experience with the key program elementsthat comprise such programs using information from the three keytarget-setting programs as well as from other international programsrelated to industrial energy efficiency or GHG emissionsreductions.

  15. Efficient energy absorption of intense ps-laser pulse into nanowire target

    Energy Technology Data Exchange (ETDEWEB)

    Habara, H.; Honda, S.; Katayama, M.; Tanaka, K. A. [Graduate School of Engineering, Osaka University, 2-1 Suita, Osaka 565-0871 (Japan); Sakagami, H. [National Institute for Fusion Science, Toki, Gifu 509-5292 (Japan); Nagai, K. [Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Nagatsuda 4259, Midori-ku, Yokohama 226-8503, Kanagawa (Japan)

    2016-06-15

    The interaction between ultra-intense laser light and vertically aligned carbon nanotubes is investigated to demonstrate efficient laser-energy absorption in the ps laser-pulse regime. Results indicate a clear enhancement of the energy conversion from laser to energetic electrons and a simultaneously small plasma expansion on the surface of the target. A two-dimensional plasma particle calculation exhibits a high absorption through laser propagation deep into the nanotube array, even for a dense array whose structure is much smaller than the laser wavelength. The propagation leads to the radial expansion of plasma perpendicular to the nanotubes rather than to the front side. These features may contribute to fast ignition in inertial confinement fusion and laser particle acceleration, both of which require high current and small surface plasma simultaneously.

  16. 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

  17. Nonmyopic Sensor Scheduling and its Efficient Implementation for Target Tracking Applications

    Directory of Open Access Journals (Sweden)

    Morrell Darryl

    2006-01-01

    Full Text Available We propose two nonmyopic sensor scheduling algorithms for target tracking applications. We consider a scenario where a bearing-only sensor is constrained to move in a finite number of directions to track a target in a two-dimensional plane. Both algorithms provide the best sensor sequence by minimizing a predicted expected scheduler cost over a finite time-horizon. The first algorithm approximately computes the scheduler costs based on the predicted covariance matrix of the tracker error. The second algorithm uses the unscented transform in conjunction with a particle filter to approximate covariance-based costs or information-theoretic costs. We also propose the use of two branch-and-bound-based optimal pruning algorithms for efficient implementation of the scheduling algorithms. We design the first pruning algorithm by combining branch-and-bound with a breadth-first search and a greedy-search; the second pruning algorithm combines branch-and-bound with a uniform-cost search. Simulation results demonstrate the advantage of nonmyopic scheduling over myopic scheduling and the significant savings in computational and memory resources when using the pruning algorithms.

  18. Adaptive Energy-Efficient Target Detection Based on Mobile Wireless Sensor Networks

    Directory of Open Access Journals (Sweden)

    Tengyue Zou

    2017-05-01

    Full Text Available Target detection is a widely used application for area surveillance, elder care, and fire alarms; its purpose is to find a particular object or event in a region of interest. Usually, fixed observing stations or static sensor nodes are arranged uniformly in the field. However, each part of the field has a different probability of being intruded upon; if an object suddenly enters an area with few guardian devices, a loss of detection will occur, and the stations in the safe areas will waste their energy for a long time without any discovery. Thus, mobile wireless sensor networks may benefit from adaptation and pertinence in detection. Sensor nodes equipped with wheels are able to move towards the risk area via an adaptive learning procedure based on Bayesian networks. Furthermore, a clustering algorithm based on k-means++ and an energy control mechanism is used to reduce the energy consumption of nodes. The extended Kalman filter and a voting data fusion method are employed to raise the localization accuracy of the target. The simulation and experimental results indicate that this new system with adaptive energy-efficient methods is able to achieve better performance than the traditional ones.

  19. Highly efficient targeted mutagenesis in axolotl using Cas9 RNA-guided nuclease

    Science.gov (United States)

    Flowers, G. Parker; Timberlake, Andrew T.; Mclean, Kaitlin C.; Monaghan, James R.; Crews, Craig M.

    2014-01-01

    Among tetrapods, only urodele salamanders, such as the axolotl Ambystoma mexicanum, can completely regenerate limbs as adults. The mystery of why salamanders, but not other animals, possess this ability has for generations captivated scientists seeking to induce this phenomenon in other vertebrates. Although many recent advances in molecular biology have allowed limb regeneration and tissue repair in the axolotl to be investigated in increasing detail, the molecular toolkit for the study of this process has been limited. Here, we report that the CRISPR-Cas9 RNA-guided nuclease system can efficiently create mutations at targeted sites within the axolotl genome. We identify individual animals treated with RNA-guided nucleases that have mutation frequencies close to 100% at targeted sites. We employ this technique to completely functionally ablate EGFP expression in transgenic animals and recapitulate developmental phenotypes produced by loss of the conserved gene brachyury. Thus, this advance allows a reverse genetic approach in the axolotl and will undoubtedly provide invaluable insight into the mechanisms of salamanders' unique regenerative ability. PMID:24764077

  20. Adaptive Energy-Efficient Target Detection Based on Mobile Wireless Sensor Networks.

    Science.gov (United States)

    Zou, Tengyue; Li, Zhenjia; Li, Shuyuan; Lin, Shouying

    2017-05-04

    Target detection is a widely used application for area surveillance, elder care, and fire alarms; its purpose is to find a particular object or event in a region of interest. Usually, fixed observing stations or static sensor nodes are arranged uniformly in the field. However, each part of the field has a different probability of being intruded upon; if an object suddenly enters an area with few guardian devices, a loss of detection will occur, and the stations in the safe areas will waste their energy for a long time without any discovery. Thus, mobile wireless sensor networks may benefit from adaptation and pertinence in detection. Sensor nodes equipped with wheels are able to move towards the risk area via an adaptive learning procedure based on Bayesian networks. Furthermore, a clustering algorithm based on k -means++ and an energy control mechanism is used to reduce the energy consumption of nodes. The extended Kalman filter and a voting data fusion method are employed to raise the localization accuracy of the target. The simulation and experimental results indicate that this new system with adaptive energy-efficient methods is able to achieve better performance than the traditional ones.

  1. An efficient hybrid technique in RCS predictions of complex targets at high frequencies

    Science.gov (United States)

    Algar, María-Jesús; Lozano, Lorena; Moreno, Javier; González, Iván; Cátedra, Felipe

    2017-09-01

    Most computer codes in Radar Cross Section (RCS) prediction use Physical Optics (PO) and Physical theory of Diffraction (PTD) combined with Geometrical Optics (GO) and Geometrical Theory of Diffraction (GTD). The latter approaches are computationally cheaper and much more accurate for curved surfaces, but not applicable for the computation of the RCS of all surfaces of a complex object due to the presence of caustic problems in the analysis of concave surfaces or flat surfaces in the far field. The main contribution of this paper is the development of a hybrid method based on a new combination of two asymptotic techniques: GTD and PO, considering the advantages and avoiding the disadvantages of each of them. A very efficient and accurate method to analyze the RCS of complex structures at high frequencies is obtained with the new combination. The proposed new method has been validated comparing RCS results obtained for some simple cases using the proposed approach and RCS using the rigorous technique of Method of Moments (MoM). Some complex cases have been examined at high frequencies contrasting the results with PO. This study shows the accuracy and the efficiency of the hybrid method and its suitability for the computation of the RCS at really large and complex targets at high frequencies.

  2. Kepler Planet Detection Metrics: Pixel-Level Transit Injection Tests of Pipeline Detection Efficiency for Data Release 25

    Science.gov (United States)

    Christiansen, Jessie L.

    2017-01-01

    This document describes the results of the fourth pixel-level transit injection experiment, which was designed to measure the detection efficiency of both the Kepler pipeline (Jenkins 2002, 2010; Jenkins et al. 2017) and the Robovetter (Coughlin 2017). Previous transit injection experiments are described in Christiansen et al. (2013, 2015a,b, 2016).In order to calculate planet occurrence rates using a given Kepler planet catalogue, produced with a given version of the Kepler pipeline, we need to know the detection efficiency of that pipeline. This can be empirically determined by injecting a suite of simulated transit signals into the Kepler data, processing the data through the pipeline, and examining the distribution of successfully recovered transits. This document describes the results for the pixel-level transit injection experiment performed to accompany the final Q1-Q17 Data Release 25 (DR25) catalogue (Thompson et al. 2017)of the Kepler Objects of Interest. The catalogue was generated using the SOC pipeline version 9.3 and the DR25 Robovetter acting on the uniformly processed Q1-Q17 DR25 light curves (Thompson et al. 2016a) and assuming the Q1-Q17 DR25 Kepler stellar properties (Mathur et al. 2017).

  3. Overall effect of carbon production and nutrient release in sludge holding tank on mainstream biological nutrient removal efficiency.

    Science.gov (United States)

    Jabari, Pouria; Yuan, Qiuyan; Oleszkiewicz, Jan A

    2017-09-11

    The potential of hydrolysis/fermentation of activated sludge in sludge holding tank (SHT) to produce additional carbon for the biological nutrient removal (BNR) process was investigated. The study was conducted in anaerobic batch tests using the BNR sludge (from a full-scale Westside process) and the mixture of BNR sludge with conventional non-BNR activated sludge (to have higher biodegradable particulate chemical oxygen demand (bpCOD) in sludge). The BioWin 4.1 was used to simulate the anaerobic batch test of the BNR sludge. Also, the overall effect of FCOD production and nutrient release on BNR efficiency of the Westside process was estimated. The experimental results showed that the phosphorous uptake of sludge increased during hydrolysis/ fermentation condition up to the point when poly-P was completely utilized; afterwards, it decreased significantly. The BioWin simulation could not predict the loss of aerobic phosphorous uptake after poly-P was depleted. The results showed that in the case of activated sludge with relatively higher bpCOD (originating from plants with short sludge retention time or without primary sedimentation), beneficial effect of SHT on BNR performance is feasible. In order to increase the potential of SHT to enhance BNR efficiency, a relatively low retention time and high sludge load is recommended.

  4. Targeting for energy efficiency and improved energy collaboration between different companies using total site analysis (TSA)

    International Nuclear Information System (INIS)

    Hackl, Roman; Andersson, Eva; Harvey, Simon

    2011-01-01

    Rising fuel prices, increasing costs associated with emissions of green house gases and the threat of global warming make efficient use of energy more and more important. Industrial clusters have the potential to significantly increase energy efficiency by energy collaboration. In this paper Sweden's largest chemical cluster is analysed using the total site analysis (TSA) method. TSA delivers targets for the amount of utility consumed and generated through excess energy recovery by the different processes. The method enables investigation of opportunities to deliver waste heat from one process to another using a common utility system. The cluster consists of 5 chemical companies producing a variety of products, including polyethylene (PE), polyvinyl chloride (PVC), amines, ethylene, oxygen/nitrogen and plasticisers. The companies already work together by exchanging material streams. In this study the potential for energy collaboration is analysed in order to reach an industrial symbiosis. The overall heating and cooling demands of the site are around 442 MW and 953 MW, respectively. 122 MW of heat is produced in boilers and delivered to the processes. TSA is used to stepwise design a site-wide utility system which improves energy efficiency. It is shown that heat recovery in the cluster can be increased by 129 MW, i.e. the current utility demand could be completely eliminated and further 7 MW excess steam can be made available. The proposed retrofitted utility system involves the introduction of a site-wide hot water circuit, increased recovery of low pressure steam and shifting of heating steam pressure to lower levels in a number heat exchangers when possible. Qualitative evaluation of the suggested measures shows that 60 MW of the savings potential could to be achieved with moderate changes to the process utility system corresponding to 50% of the heat produced from purchased fuel in the boilers of the cluster. Further analysis showed that after implementation

  5. Controlled release of optimized electroporation enhances the transdermal efficiency of sinomenine hydrochloride for treating arthritis in vitro and in clinic

    Science.gov (United States)

    Feng, Shun; Zhu, Lijun; Huang, Zhisheng; Wang, Haojia; Li, Hong; Zhou, Hua; Lu, Linlin; Wang, Ying; Liu, Zhongqiu; Liu, Liang

    2017-01-01

    Sinomenine hydrochloride (SH) is an ideal drug for the treatment of rheumatoid arthritis and osteoarthritis. However, high plasma concentration of systemically administered SH can release histamine, which can cause rash and gastrointestinal side effects. Topical delivery can increase SH concentration in the synovial fluid without high plasma level, thus minimizing systemic side effects. However, passive diffusion of SH was found to be inefficient because of the presence of the stratum corneum layer. Therefore, an effective method is required to compensate for the low efficiency of SH passive diffusion. In this study, transdermal experiments in vitro and clinical tests were utilized to explore the optimized parameters for electroporation of topical delivery for SH. Fluorescence experiment and hematoxylin and eosin staining analysis were performed to reveal the mechanism by which electroporation promoted permeation. In vitro, optimized electroporation parameters were 3 KHz, exponential waveform, and intensity 10. Using these parameters, transdermal permeation of SH was increased by 1.9–10.1 fold in mice skin and by 1.6–47.1 fold in miniature pig skin compared with passive diffusion. After the electroporation stimulation, the intercellular intervals and epidermal cracks in the skin increased. In clinical tests, SH concentration in synovial fluid was 20.84 ng/mL after treatment with electroporation. Therefore, electroporation with optimized parameters could significantly enhance transdermal permeation of SH. The mechanism by which electroporation promoted permeation was that the electronic pulses made the skin structure looser. To summarize, electroporation may be an effective complementary method for transdermal permeation of SH. The controlled release of electroporation may be a promising clinical method for transdermal drug administration. PMID:28670109

  6. Efficient in planta gene targeting in tomato using geminiviral replicons and the CRISPR/Cas9 system.

    Science.gov (United States)

    Dahan-Meir, Tal; Filler-Hayut, Shdema; Melamed-Bessudo, Cathy; Bocobza, Samuel; Czosnek, Henryk; Aharoni, Asaph; Levy, Avraham A

    2018-04-18

    Current breeding relies mostly on random mutagenesis and recombination to generate novel genetic variation. However, targeted genome editing is becoming an increasingly important tool for precise plant breeding. Using the CRISPR-Cas system combined with the bean yellow dwarf virus rolling circle replicon we optimized a method for targeted mutagenesis and gene replacement in tomato. The carotenoid isomerase (CRTISO) and phytoene synthase 1 (PSY1) genes from the carotenoid biosynthesis pathway were chosen as targets due to their easily detectable change of phenotype. We took advantage of the geminiviral replicon amplification as a mean to provide a large amount of donor template for the repair of a CRISPR-Cas-induced DNA double strand break (DSB) in the target gene, via homologous recombination. Mutagenesis experiments, performed in the Micro-Tom variety achieved precise modification of the CRTISO and PSY1 loci at an efficiency of up to 90%. In the gene targeting experiments, our target was a fast-neutron-induced crtiso allele that contained a 281bp deletion. This deletion was repaired with the wildtype sequence through homologous recombination between the CRISPR-Cas-induced DSB in the crtiso target and the amplified donor in 25% of the plants transformed. This shows that efficient gene targeting can be achieved in the absence of selection markers or reporters using a single and modular construct that is adaptable to other tomato targets and other crops. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  7. High-efficiency targeted editing of large viral genomes by RNA-guided nucleases.

    Science.gov (United States)

    Bi, Yanwei; Sun, Le; Gao, Dandan; Ding, Chen; Li, Zhihua; Li, Yadong; Cun, Wei; Li, Qihan

    2014-05-01

    A facile and efficient method for the precise editing of large viral genomes is required for the selection of attenuated vaccine strains and the construction of gene therapy vectors. The type II prokaryotic CRISPR-Cas (clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas)) RNA-guided nuclease system can be introduced into host cells during viral replication. The CRISPR-Cas9 system robustly stimulates targeted double-stranded breaks in the genomes of DNA viruses, where the non-homologous end joining (NHEJ) and homology-directed repair (HDR) pathways can be exploited to introduce site-specific indels or insert heterologous genes with high frequency. Furthermore, CRISPR-Cas9 can specifically inhibit the replication of the original virus, thereby significantly increasing the abundance of the recombinant virus among progeny virus. As a result, purified recombinant virus can be obtained with only a single round of selection. In this study, we used recombinant adenovirus and type I herpes simplex virus as examples to demonstrate that the CRISPR-Cas9 system is a valuable tool for editing the genomes of large DNA viruses.

  8. High-efficiency targeted editing of large viral genomes by RNA-guided nucleases.

    Directory of Open Access Journals (Sweden)

    Yanwei Bi

    2014-05-01

    Full Text Available A facile and efficient method for the precise editing of large viral genomes is required for the selection of attenuated vaccine strains and the construction of gene therapy vectors. The type II prokaryotic CRISPR-Cas (clustered regularly interspaced short palindromic repeats (CRISPR-associated (Cas RNA-guided nuclease system can be introduced into host cells during viral replication. The CRISPR-Cas9 system robustly stimulates targeted double-stranded breaks in the genomes of DNA viruses, where the non-homologous end joining (NHEJ and homology-directed repair (HDR pathways can be exploited to introduce site-specific indels or insert heterologous genes with high frequency. Furthermore, CRISPR-Cas9 can specifically inhibit the replication of the original virus, thereby significantly increasing the abundance of the recombinant virus among progeny virus. As a result, purified recombinant virus can be obtained with only a single round of selection. In this study, we used recombinant adenovirus and type I herpes simplex virus as examples to demonstrate that the CRISPR-Cas9 system is a valuable tool for editing the genomes of large DNA viruses.

  9. A Viral Receptor Complementation Strategy to Overcome CAV-2 Tropism for Efficient Retrograde Targeting of Neurons.

    Science.gov (United States)

    Li, Shu-Jing; Vaughan, Alexander; Sturgill, James Fitzhugh; Kepecs, Adam

    2018-06-06

    Retrogradely transported neurotropic viruses enable genetic access to neurons based on their long-range projections and have become indispensable tools for linking neural connectivity with function. A major limitation of viral techniques is that they rely on cell-type-specific molecules for uptake and transport. Consequently, viruses fail to infect variable subsets of neurons depending on the complement of surface receptors expressed (viral tropism). We report a receptor complementation strategy to overcome this by potentiating neurons for the infection of the virus of interest-in this case, canine adenovirus type-2 (CAV-2). We designed AAV vectors for expressing the coxsackievirus and adenovirus receptor (CAR) throughout candidate projection neurons. CAR expression greatly increased retrograde-labeling rates, which we demonstrate for several long-range projections, including some resistant to other retrograde-labeling techniques. Our results demonstrate a receptor complementation strategy to abrogate endogenous viral tropism and thereby facilitate efficient retrograde targeting for functional analysis of neural circuits. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Dual tumor-targeted poly(lactic-co-glycolic acid–polyethylene glycol–folic acid nanoparticles: a novel biodegradable nanocarrier for secure and efficient antitumor drug delivery

    Directory of Open Access Journals (Sweden)

    Chen J

    2017-08-01

    Full Text Available Jia Chen,1,2,* Qi Wu,1,* Li Luo,1 Yi Wang,1 Yuan Zhong,1 Han-Bin Dai,1 Da Sun,1,3 Mao-Ling Luo,4 Wei Wu,1 Gui-Xue Wang1 1Key Laboratory for Biorheological Science and Technology, Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College, Chongqing University, Chongqing, 2Institute of Laboratory Animals, Sichuan Academy of Medical Science, Sichuan Provincial People’s Hospital, Chengdu, 3Institute of Life Sciences, Wenzhou University, Wenzhou, 4School of Medicine, Wuhan University, Wuhan, China *These authors contributed equally to this work Abstract: Further specific target-ability development of biodegradable nanocarriers is extremely important to promote their security and efficiency in antitumor drug-delivery applications. In this study, a facilely prepared poly(lactic-co-glycolic acid (PLGA–polyethylene glycol (PEG–folic acid (FA copolymer was able to self-assemble into nanoparticles with favorable hydrodynamic diameters of around 100 nm and negative surface charge in aqueous solution, which was expected to enhance intracellular antitumor drug delivery by advanced dual tumor-target effects, ie, enhanced permeability and retention induced the passive target, and FA mediated the positive target. Fluorescence-activated cell-sorting and confocal laser-scanning microscopy results confirmed that doxorubicin (model drug loaded into PLGA-PEG-FA nanoparticles was able to be delivered efficiently into tumor cells and accumulated at nuclei. In addition, all hemolysis, 3-(4,5-dimethylthiazol-2-yl-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl-2H-tetrazolium, and zebrafish-development experiments demonstrated that PLGA-PEG-FA nanoparticles were biocompatible and secure for biomedical applications, even at high polymer concentration (0.1 mg/mL, both in vitro and in vivo. Therefore, PLGA-PEG-FA nanoparticles provide a feasible controlled-release platform for secure and efficient antitumor drug

  11. High efficiency of targeted mutagenesis in arabidopsis via meiotic promoter-driven expression of Cas9 endonuclease

    KAUST Repository

    Eid, Ayman

    2016-05-28

    Key message: The use of a meiosis I-specific promoter increased the efficiency of targeted mutagenesis and will facilitate the manipulation of homologous recombination. Abstract: The CRISPR/Cas9 system has been harnessed for targeted engineering of eukaryotic genomes, including plants; however, CRISPR/Cas9 efficiency varies considerably in different plant tissues and species. In Arabidopsis, the generation of homozygous or bi-allelic mutants in the first (T1) generation is inefficient. Here, we used specific promoters to drive the expression of Cas9 during meiosis to maximize the efficiency of recovering heritable mutants in T1 plants. Our data reveal that the use of a promoter active in meiosis I resulted in high-efficiency (28 %) recovery of targeted mutants in the T1 generation. Moreover, this method enabled efficient simultaneous targeting of three genes for mutagenesis. Taken together, our results show that the use of meiosis-specific promoters will improve methods for functional genomic analysis and studying the molecular underpinnings of homologous recombination. © 2016, Springer-Verlag Berlin Heidelberg.

  12. Ratio between autoflocculating and target microalgae affects the energy-efficient harvesting by bio-flocculation

    NARCIS (Netherlands)

    Salim, S.; Vermuë, M.H.; Wijffels, R.H.

    2012-01-01

    The effect of ratio between autoflocculating and target microalgae in bio-flocculation was studied with emphasis on the recovery, sedimentation rate and energy demand for harvesting the target microalgae. When the autoflocculating microalgae Ettlia texensis, Ankistrodesmus falcatus and Scenedesmus

  13. Whole genome analysis of CRISPR Cas9 sgRNA off-target homologies via an efficient computational algorithm.

    Science.gov (United States)

    Zhou, Hong; Zhou, Michael; Li, Daisy; Manthey, Joseph; Lioutikova, Ekaterina; Wang, Hong; Zeng, Xiao

    2017-11-17

    The beauty and power of the genome editing mechanism, CRISPR Cas9 endonuclease system, lies in the fact that it is RNA-programmable such that Cas9 can be guided to any genomic loci complementary to a 20-nt RNA, single guide RNA (sgRNA), to cleave double stranded DNA, allowing the introduction of wanted mutations. Unfortunately, it has been reported repeatedly that the sgRNA can also guide Cas9 to off-target sites where the DNA sequence is homologous to sgRNA. Using human genome and Streptococcus pyogenes Cas9 (SpCas9) as an example, this article mathematically analyzed the probabilities of off-target homologies of sgRNAs and discovered that for large genome size such as human genome, potential off-target homologies are inevitable for sgRNA selection. A highly efficient computationl algorithm was developed for whole genome sgRNA design and off-target homology searches. By means of a dynamically constructed sequence-indexed database and a simplified sequence alignment method, this algorithm achieves very high efficiency while guaranteeing the identification of all existing potential off-target homologies. Via this algorithm, 1,876,775 sgRNAs were designed for the 19,153 human mRNA genes and only two sgRNAs were found to be free of off-target homology. By means of the novel and efficient sgRNA homology search algorithm introduced in this article, genome wide sgRNA design and off-target analysis were conducted and the results confirmed the mathematical analysis that for a sgRNA sequence, it is almost impossible to escape potential off-target homologies. Future innovations on the CRISPR Cas9 gene editing technology need to focus on how to eliminate the Cas9 off-target activity.

  14. Carnauba wax as a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of highly soluble drugs.

    Science.gov (United States)

    Nart, Viviane; Beringhs, André O'Reilly; França, Maria Terezinha; de Espíndola, Brenda; Pezzini, Bianca Ramos; Stulzer, Hellen Karine

    2017-01-01

    Mini-tablets are a new tendency in solid dosage form design for overcoming therapeutic obstacles such as impaired swallowing and polypharmacy therapy. Among their advantages, these systems offer therapeutic benefits such as dose flexibility and combined drug release patterns. The use of lipids in the formulation has also drawn considerable interest as means to modify the drug release from the dosage form. Therefore, this paper aimed at developing sustained release mini-tablets containing the highly soluble drugs captopril and metformin hydrochloride. Carnauba wax was used as a lipid component in melt granulation, targeting the improvement of the drugs poor flowability and tabletability, as well as to sustain the drug release profiles in association with other excipients. To assist sustaining the drug release, Ethocel™ (EC) and Kollicoat® SR 30D associated with Opadry® II were employed as matrix-forming and reservoir-forming materials, respectively. The neat drugs, granules and the bulk formulations were evaluated for their angle of repose, compressibility index, Hausner ratio and tabletability. Mini-tablets were evaluated for their weight variation, hardness, friability, drug content and in-vitro drug release. The results indicated that melt granulation with carnauba wax improved the flow and the tabletability of the drugs, allowing the preparation of mini-tablets with adequate tensile strength under reduced compaction pressures. All mini-tablet formulations showed acceptable hardness (within the range of 1.16 to 3.93Kp) and friability (carnauba wax proved to be a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of soluble drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Efficient characterization of labeling uncertainty in closely-spaced targets tracking

    NARCIS (Netherlands)

    Moreno Leon, Carlos; Moreno Leon, Carlos; Driessen, Hans; Mandal, Pranab K.

    2016-01-01

    In this paper we propose a novel solution to the labeled multi-target tracking problem. The method presented is specially effective in scenarios where the targets have once moved in close proximity. When this is the case, disregarding the labeling uncertainty present in a solution (after the targets

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

    Science.gov (United States)

    Higashiguchi, Takeshi; Hamada, Masaya; Kubodera, Shoichi

    2007-03-01

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

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

    Science.gov (United States)

    Higashiguchi, Takeshi; Hamada, Masaya; Kubodera, Shoichi

    2007-03-01

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

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

    International Nuclear Information System (INIS)

    Higashiguchi, Takeshi; Hamada, Masaya; Kubodera, Shoichi

    2007-01-01

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

  19. Efficient Isothermal Titration Calorimetry Technique Identifies Direct Interaction of Small Molecule Inhibitors with the Target Protein.

    Science.gov (United States)

    Gal, Maayan; Bloch, Itai; Shechter, Nelia; Romanenko, Olga; Shir, Ofer M

    2016-01-01

    Protein-protein interactions (PPI) play a critical role in regulating many cellular processes. Finding novel PPI inhibitors that interfere with specific binding of two proteins is considered a great challenge, mainly due to the complexity involved in characterizing multi-molecular systems and limited understanding of the physical principles governing PPIs. Here we show that the combination of virtual screening techniques, which are capable of filtering a large library of potential small molecule inhibitors, and a unique secondary screening by isothermal titration calorimetry, a label-free method capable of observing direct interactions, is an efficient tool for finding such an inhibitor. In this study we applied this strategy in a search for a small molecule capable of interfering with the interaction of the tumor-suppressor p53 and the E3-ligase MDM2. We virtually screened a library of 15 million small molecules that were filtered to a final set of 80 virtual hits. Our in vitro experimental assay, designed to validate the activity of mixtures of compounds by isothermal titration calorimetry, was used to identify an active molecule against MDM2. At the end of the process the small molecule (4S,7R)-4-(4-chlorophenyl)-5-hydroxy-2,7-dimethyl-N-(6-methylpyridin-2-yl)-4,6,7,8 tetrahydrIoquinoline-3-carboxamide was found to bind MDM2 with a dissociation constant of ~2 µM. Following the identification of this single bioactive compound, spectroscopic measurements were used to further characterize the interaction of the small molecule with the target protein. 2D NMR spectroscopy was used to map the binding region of the small molecule, and fluorescence polarization measurement confirmed that it indeed competes with p53.

  20. Energy Efficient Sensor Scheduling with a Mobile Sink Node for the Target Tracking Application

    Directory of Open Access Journals (Sweden)

    Malin Premaratne

    2009-01-01

    Full Text Available Measurement losses adversely affect the performance of target tracking. The sensor network’s life span depends on how efficiently the sensor nodes consume energy. In this paper, we focus on minimizing the total energy consumed by the sensor nodes whilst avoiding measurement losses. Since transmitting data over a long distance consumes a significant amount of energy, a mobile sink node collects the measurements and transmits them to the base station. We assume that the default transmission range of the activated sensor node is limited and it can be increased to maximum range only if the mobile sink node is out-side the default transmission range. Moreover, the active sensor node can be changed after a certain time period. The problem is to select an optimal sensor sequence which minimizes the total energy consumed by the sensor nodes. In this paper, we consider two different problems depend on the mobile sink node’s path. First, we assume that the mobile sink node’s position is known for the entire time horizon and use the dynamic programming technique to solve the problem. Second, the position of the sink node is varied over time according to a known Markov chain, and the problem is solved by stochastic dynamic programming. We also present sub-optimal methods to solve our problem. A numerical example is presented in order to discuss the proposed methods’ performance.

  1. Cutting costs by achieving energy efficiency using monitoring, targeting and teamwork

    Energy Technology Data Exchange (ETDEWEB)

    Dittburner, D. [Unilever Canada, Toronto, ON (Canada)

    2004-07-01

    Unilever is a world leader of consumer goods with annual sales of $70 billion. This paper focuses on energy management projects developed at Unilever's Rexdale Plant, where 180 million pounds of edible oils and margarine are produced annually. The project is a response to corporate and market pressures to reduce costs. An overview of Unilever's relationship with Natural Resources Canada was provided. Results of the overall project were highlighted and included: $3 million in annual savings from increased efficiency in operations and equipment retrofits. An outline of the energy team at Unilever was presented, with their mission statement, rules and achievements, as well the company's overall goal of total productive manufacturing. A list of awards and financial incentives was presented, as well as details of financial savings incurred at the Rexdale Plant. Total energy reductions were presented, with a natural gas year to year comparison and utility to production ratios from 1999 to the present. A statement concerning the issue of corporate support by the vice president was provided. Seven steps to savings were presented, as well as details of the company's implementation of the steps. Details of the extended team involved in the project were provided, as well as extensive details about the employee awareness program instigated by the company, including a database of ideas achieved since 2001, as well as details of specific projects accomplished, with estimated savings for each project. An outline of the company's business model and methodology was presented, along with details of reduced costs, risk and improved management and communications. An outline of scoping studies was presented as well as a flow chart of projects and target-setting goals. Success factors were reviewed. Montage applications included energy management; performance contracting; energy forecasting; emissions and waste minimization; and cost allocation. tabs., figs.

  2. Supporting Data for Multifunctional all-in-one drug delivery systems for tumor targeting and sequential release of three different anti-tumor drugs

    Directory of Open Access Journals (Sweden)

    Guowei Wu

    2016-06-01

    Full Text Available Although nanoparticulate drug delivery systems (NDDSs can preferentially accumulate in tumors, active targeting by targeting ligands (e.g. monoclonal antibody is necessary for increasing its targeting efficacy in vivo. We conjugated mAb198.3 on the SiO2@AuNP system surface to make it obtain active targeting efficacy. The FAT1 targeting capability of SiO2@AuNP system is the first issue to be solved. Thus, flow cytometry analysis was attempted to demonstrate that the SiO2@AuNP system could bind to native FAT1 molecules on the surface of Colo205 cells. Also, together with the drug release behavior study of self-decomposable SiO2 NPs, the continuous morphological evolution needed to be clarified. Therefore, to characterize the morphological evolution in vitro, we analyzed the morphology of inner self-decomposable NPs in different time intervals using transmission electron microscopy (TEM. A more comprehensive analysis of this data may be obtained from the article “Multifunctional all-in-one drug delivery systems for tumor targeting and sequential release of three different anti-tumor drugs” in Biomaterials.

  3. Transient overexpression of DNA adenine methylase enables efficient and mobile genome engineering with reduced off-target effects

    DEFF Research Database (Denmark)

    Lennen, Rebecca; Nilsson Wallin, Annika; Pedersen, Margit

    2016-01-01

    Homologous recombination of single-stranded oligonucleotides is a highly efficient process for introducing precise mutations into the genome of E. coli and other organisms when mismatch repair (MMR) is disabled. This can result in the rapid accumulation of off-target mutations that can mask desir...

  4. Receptor-targeted liposome-peptide-siRNA nanoparticles represent an efficient delivery system for MRTF silencing in conjunctival fibrosis.

    Science.gov (United States)

    Yu-Wai-Man, Cynthia; Tagalakis, Aristides D; Manunta, Maria D; Hart, Stephen L; Khaw, Peng T

    2016-02-24

    There is increasing evidence that the Myocardin-related transcription factor/Serum response factor (MRTF/SRF) pathway plays a key role in fibroblast activation and that knocking down MRTF can lead to reduced scarring and fibrosis. Here, we have developed a receptor-targeted liposome-peptide-siRNA nanoparticle as a non-viral delivery system for MRTF-B siRNA in conjunctival fibrosis. Using 50 nM siRNA, the MRTF-B gene was efficiently silenced by 76% and 72% with LYR and LER nanoparticles, respectively. The silencing efficiency was low when non-targeting peptides or siRNA alone or liposome-siRNA alone were used. LYR and LER nanoparticles also showed higher silencing efficiency than PEGylated LYR-P and LER-P nanoparticles. The nanoparticles were not cytotoxic using different liposomes, targeting peptides, and 50 nM siRNA. Three-dimensional fibroblast-populated collagen matrices were also used as a functional assay to measure contraction in vitro, and showed that MRTF-B LYR nanoparticles completely blocked matrix contraction after a single transfection treatment. In conclusion, this is the first study to develop and show that receptor-targeted liposome-peptide-siRNA nanoparticles represent an efficient and safe non-viral siRNA delivery system that could be used to prevent fibrosis after glaucoma filtration surgery and other contractile scarring conditions in the eye.

  5. Nitrogen release, tree uptake, and ecosystem retention in a mid-rotation loblolly pine plantation following fertilization with 15N-enriched enhanced efficiency fertilizers.

    OpenAIRE

    Werner, Amy

    2013-01-01

    Nitrogen is the most frequently limiting nutrient in southern pine plantations.  Previous studies found that only 10 to 25% of applied urea fertilizer N is taken up by trees.  Enhanced efficiency fertilizers could increase tree uptake efficiency by controlling the release of N and/or stabilize N.  Three enhanced efficiency fertilizers were selected as a representation of fertilizers that could be used in forestry: 1) NBPT treated urea (NBPT urea), 2) polymer coated urea (PC urea), and 3) mono...

  6. The Gastrin-Releasing Peptide Receptor as Target for Molecular Imaging of Prostate Cancer : GRPR expression in prostate cancer and targeting with Bombesin-like radiopharmaceuticals

    NARCIS (Netherlands)

    Ananias, Hildo

    2014-01-01

    Prostaatkanker is wereldwijd een veel voorkomende oorzaak van kanker, morbiditeit en sterfte. Nauwkeurige stagering is moeilijk en nog steeds suboptimaal. De Gastrin-Releasing Peptide Receptor (GRPR) is een tumor-geassocieerd antigeen dat tot overexpressie wordt gebracht in prostaatkanker. Gerichte

  7. The critical role of the industrial sector in reaching long-term emission reduction, energy efficiency and renewable targets

    International Nuclear Information System (INIS)

    Fais, Birgit; Sabio, Nagore; Strachan, Neil

    2016-01-01

    Highlights: • A new industrial modelling approach in a whole energy systems model is developed. • The contribution of UK industry to long-term energy policy targets is analysed. • Emission reductions of up to 77% can be achieved in the UK industry until 2050. • The UK industry sector is essential for achieving the overall efficiency commitments. • UK industry can make a moderate contribution to the expansion of renewable energies. - Abstract: This paper evaluates the critical contribution of the industry sector to long-term decarbonisation, efficiency and renewable energy policy targets. Its methodological novelty is the incorporation of a process-oriented modelling approach based on a comprehensive technology database for the industry sector in a national energy system model for the UK (UKTM), allowing quantification of the role of both decarbonisation of upstream energy vectors and of mitigation options in the industrial sub-categories. This enhanced model is then applied in a comparative policy scenario analysis that explores various target dimensions on emission mitigation, renewable energy and energy efficiency at both a national and European level. The results show that ambitious emission cuts in the industry sector of up to 77% until 2050 compared to 2010 can be achieved. Moreover, with a reduction in industrial energy demand of up to 31% between 2010 and 2050, the sector is essential for achieving the overall efficiency commitments. The industry sector also makes a moderate contribution to the expansion of renewable energies mostly through the use of biomass for low-temperature heating services. However, additional sub-targets on renewable sources and energy efficiency need to be assessed critically, as they can significantly distort the cost-efficiency of the long-term mitigation pathway.

  8. Evaluation of Efficiency Activities in the Industrial Sector Undertaken in Response to Greenhouse Gas Emission Reduction Targets

    Energy Technology Data Exchange (ETDEWEB)

    Price, Lynn; de la Rue du Can, Stephane; Lu, Hongyou; Horvath, Arpad

    2010-05-21

    The 2006 California Global Warming Solutions Act calls for reducing greenhouse gas (GHG) emissions to 1990 levels by 2020. Meeting this target will require action from all sectors of the California economy, including industry. The industrial sector consumes 25% of the energy used and emits 28% of the carbon dioxide (CO{sub 2}) produced in the state. Many countries around the world have national-level GHG reduction or energy-efficiency targets, and comprehensive programs focused on implementation of energy efficiency and GHG emissions mitigation measures in the industrial sector are essential for achieving their goals. A combination of targets and industry-focused supporting programs has led to significant investments in energy efficiency as well as reductions in GHG emissions within the industrial sectors in these countries. This project has identified program and policies that have effectively targeted the industrial sector in other countries to achieve real energy and CO{sub 2} savings. Programs in Ireland, France, The Netherlands, Denmark, and the UK were chosen for detailed review. Based on the international experience documented in this report, it is recommended that companies in California's industrial sector be engaged in a program to provide them with support to meet the requirements of AB32, The Global Warming Solution Act. As shown in this review, structured programs that engage industry, require members to evaluate their potential efficiency measures, plan how to meet efficiency or emissions reduction goals, and provide support in achieving the goals, can be quite effective at assisting companies to achieve energy efficiency levels beyond those that can be expected to be achieved autonomously.

  9. Real-time observation of DNA target interrogation and product release by the RNA-guided endonuclease CRISPR Cpf1 (Cas12a).

    Science.gov (United States)

    Singh, Digvijay; Mallon, John; Poddar, Anustup; Wang, Yanbo; Tippana, Ramreddy; Yang, Olivia; Bailey, Scott; Ha, Taekjip

    2018-05-22

    CRISPR-Cas9, which imparts adaptive immunity against foreign genomic invaders in certain prokaryotes, has been repurposed for genome-engineering applications. More recently, another RNA-guided CRISPR endonuclease called Cpf1 (also known as Cas12a) was identified and is also being repurposed. Little is known about the kinetics and mechanism of Cpf1 DNA interaction and how sequence mismatches between the DNA target and guide-RNA influence this interaction. We used single-molecule fluorescence analysis and biochemical assays to characterize DNA interrogation, cleavage, and product release by three Cpf1 orthologs. Our Cpf1 data are consistent with the DNA interrogation mechanism proposed for Cas9. They both bind any DNA in search of protospacer-adjacent motif (PAM) sequences, verify the target sequence directionally from the PAM-proximal end, and rapidly reject any targets that lack a PAM or that are poorly matched with the guide-RNA. Unlike Cas9, which requires 9 bp for stable binding and ∼16 bp for cleavage, Cpf1 requires an ∼17-bp sequence match for both stable binding and cleavage. Unlike Cas9, which does not release the DNA cleavage products, Cpf1 rapidly releases the PAM-distal cleavage product, but not the PAM-proximal product. Solution pH, reducing conditions, and 5' guanine in guide-RNA differentially affected different Cpf1 orthologs. Our findings have important implications on Cpf1-based genome engineering and manipulation applications.

  10. Setting SMART targets for industrial energy use and industrial energy efficiency

    NARCIS (Netherlands)

    Rietbergen, M.G.|info:eu-repo/dai/nl/14111634X; Blok, K.|info:eu-repo/dai/nl/07170275X

    2010-01-01

    Industrial energy policies often require the setting of quantitative targets to reduce energy use and/or greenhouse gas emissions. In this paper a taxonomy has been developed for categorizing SMART industrial energy use or greenhouse gas emission reduction targets. The taxonomy includes volume

  11. Targeting energy justice: Exploring spatial, racial/ethnic and socioeconomic disparities in urban residential heating energy efficiency

    International Nuclear Information System (INIS)

    Reames, Tony Gerard

    2016-01-01

    Fuel poverty, the inability of households to afford adequate energy services, such as heating, is a major energy justice concern. Increasing residential energy efficiency is a strategic fuel poverty intervention. However, the absence of easily accessible household energy data impedes effective targeting of energy efficiency programs. This paper uses publicly available data, bottom-up modeling and small-area estimation techniques to predict the mean census block group residential heating energy use intensity (EUI), an energy efficiency proxy, in Kansas City, Missouri. Results mapped using geographic information systems (GIS) and statistical analysis, show disparities in the relationship between heating EUI and spatial, racial/ethnic, and socioeconomic block group characteristics. Block groups with lower median incomes, a greater percentage of households below poverty, a greater percentage of racial/ethnic minority headed-households, and a larger percentage of adults with less than a high school education were, on average, less energy efficient (higher EUIs). Results also imply that racial segregation, which continues to influence urban housing choices, exposes Black and Hispanic households to increased fuel poverty vulnerability. Lastly, the spatial concentration and demographics of vulnerable block groups suggest proactive, area- and community-based targeting of energy efficiency assistance programs may be more effective than existing self-referral approaches. - Highlights: • Develops statistical model to predict block group (BG) residential heating energy use intensity (EUI), an energy efficiency proxy. • Bivariate and multivariate analyses explore racial/ethnic and socioeconomic relationships with heating EUI. • BGs with more racial/ethnic minority households had higher heating EUI. • BGs with lower socioeconomics had higher heating EUI. • Mapping heating EUI can facilitate effective energy efficiency intervention targeting.

  12. Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction.

    Science.gov (United States)

    Amenta, F; Tayebati, S K

    2008-01-01

    Acetylcholine (ACh) is a neurotransmitter widely diffused in central, peripheral, autonomic and enteric nervous system. This paper has reviewed the main mechanisms of ACh synthesis, storage, and release. Presynaptic choline transport supports ACh production and release, and cholinergic terminals express a unique transporter critical for neurotransmitter release. Neurons cannot synthesize choline, which is ultimately derived from the diet and is delivered through the blood stream. ACh released from cholinergic synapses is hydrolyzed by acetylcholinesterase into choline and acetyl coenzyme A and almost 50% of choline derived from ACh hydrolysis is recovered by a high-affinity choline transporter. Parallel with the development of cholinergic hypothesis of geriatric memory dysfunction, cholinergic precursor loading strategy was tried for treating cognitive impairment occurring in Alzheimer's disease. Controlled clinical studies denied clinical usefulness of choline and lecithin (phosphatidylcholine), whereas for other phospholipids involved in choline biosynthetic pathways such as cytidine 5'-diphosphocholine (CDP-choline) or alpha-glyceryl-phosphorylcholine (choline alphoscerate) a modest improvement of cognitive dysfunction in adult-onset dementia disorders is documented. These inconsistencies have probably a metabolic explanation. Free choline administration increases brain choline availability but it does not increase ACh synthesis/or release. Cholinergic precursors to serve for ACh biosynthesis should be incorporate and stored into phospholipids in brain. It is probable that appropriate ACh precursors and other correlated molecules (natural or synthesized) could represent a tool for developing therapeutic strategies by revisiting and updating treatments/supplementations coming out from this therapeutic stalemate.

  13. Tailoring cross-sectional energy-efficiency measures to target groups in industry

    NARCIS (Netherlands)

    Wohlfarth, Katharina; Eichhammer, Wolfgang; Schlomann, Barbara; Worrell, Ernst

    2018-01-01

    The improvement of energy efficiency in industrial companies plays a crucial role for the energy transition. Although significant economic potentials have been identified, the concerned actors are still struggling to realize them fully. To support the implementation of energy efficiency measures by

  14. On the efficiency calibration of Si(Li) detector in the low-energy region using thick-target bremsstrahlung

    Energy Technology Data Exchange (ETDEWEB)

    An, Z. E-mail: anzhu@scu.edu.cn; Liu, M.T

    2002-10-01

    In this paper, the efficiency calibration of a Si(Li) detector in the low-energy region down to 0.58 keV has been performed using thick-carbon-target bremsstrahlung by 19 keV electron impact. The shape of the efficiency calibration curve was determined from the thick-carbon-target bremsstrahlung spectrum, and the absolute value for the efficiency calibration was obtained from the use of {sup 241}Am radioactive standard source. The modified Wentzel's formula for thick-target bremsstrahlung was employed and it was also compared with the most recently developed theoretical model based upon the doubly differential cross-sections for bremsstrahlung of Kissel, Quarles and Pratt. In the present calculation of theoretical bremsstrahlung, the self-absorption correction and the convolution of detector's response function with the bremsstrahlung spectrum have simultaneously been taken into account. The accuracy for the efficiency calibration in the low-energy region with the method described here was estimated to be about 6%. Moreover, the self-absorption correction calculation based upon the prescription of Wolters et al. has also been presented as an analytical factor with the accuracy of {approx}1%.

  15. Better Targeting, Better Efficiency for Wide-Scale Neuronal Transduction with the Synapsin Promoter and AAV-PHP.B.

    Science.gov (United States)

    Jackson, Kasey L; Dayton, Robert D; Deverman, Benjamin E; Klein, Ronald L

    2016-01-01

    Widespread genetic modification of cells in the central nervous system (CNS) with a viral vector has become possible and increasingly more efficient. We previously applied an AAV9 vector with the cytomegalovirus/chicken beta-actin (CBA) hybrid promoter and achieved wide-scale CNS transduction in neonatal and adult rats. However, this method transduces a variety of tissues in addition to the CNS. Thus we studied intravenous AAV9 gene transfer with a synapsin promoter to better target the neurons. We noted in systematic comparisons that the synapsin promoter drives lower level expression than does the CBA promoter. The engineered adeno-associated virus (AAV)-PHP.B serotype was compared with AAV9, and AAV-PHP.B did enhance the efficiency of expression. Combining the synapsin promoter with AAV-PHP.B could therefore be advantageous in terms of combining two refinements of targeting and efficiency. Wide-scale expression was used to model a disease with widespread pathology. Vectors encoding the amyotrophic lateral sclerosis (ALS)-related protein transactive response DNA-binding protein, 43 kDa (TDP-43) with the synapsin promoter and AAV-PHP.B were used for efficient CNS-targeted TDP-43 expression. Intracerebroventricular injections were also explored to limit TDP-43 expression to the CNS. The neuron-selective promoter and the AAV-PHP.B enhanced gene transfer and ALS disease modeling in adult rats.

  16. Better Targeting, Better Efficiency for Wide-scale Neuronal Transduction with the Synapsin Promoter and AAV-PHP.B

    Directory of Open Access Journals (Sweden)

    Kasey L Jackson

    2016-11-01

    Full Text Available Widespread genetic modification of cells in the central nervous system (CNS with a viral vector has become possible and increasingly more efficient. We previously applied an AAV9 vector with the cytomegalovirus/chicken beta-actin hybrid (CBA promoter and achieved wide-scale CNS transduction in neonatal and adult rats. However, this method transduces a variety of tissues in addition to the CNS. Thus we studied intravenous AAV9 gene transfer with a synapsin promoter to better target the neurons. We noted in systematic comparisons that the synapsin promoter drives lower level expression than does the CBA promoter. The engineered AAV-PHP.B serotype was compared with AAV9, and AAV-PHP.B did enhance the efficiency of expression. Combining the synapsin promoter with AAV-PHP.B could therefore be advantageous in terms of combining two refinements of targeting and efficiency. Wide-scale expression was used to model a disease with widespread pathology. Vectors encoding the amyotrophic lateral sclerosis (ALS-related protein TDP-43 with the synapsin promoter and AAV-PHP.B were used for efficient CNS-targeted TDP-43 expression. Intracerebroventricular injections were also explored to limit TDP-43 expression to the CNS. The neuron-selective promoter and the AAV-PHP.B enhanced gene transfer and ALS disease modeling in adult rats.

  17. Computationally Efficient Automatic Coast Mode Target Tracking Based on Occlusion Awareness in Infrared Images.

    Science.gov (United States)

    Kim, Sohyun; Jang, Gwang-Il; Kim, Sungho; Kim, Junmo

    2018-03-27

    This paper proposes the automatic coast mode tracking of centroid trackers for infrared images to overcome the target occlusion status. The centroid tracking method, using only the brightness information of an image, is still widely used in infrared imaging tracking systems because it is difficult to extract meaningful features from infrared images. However, centroid trackers are likely to lose the track because they are highly vulnerable to screened status by the clutter or background. Coast mode, one of the tracking modes, maintains the servo slew rate with the tracking rate right before the loss of track. The proposed automatic coast mode tracking method makes decisions regarding entering coast mode by the prediction of target occlusion and tries to re-lock the target and resume the tracking after blind time. This algorithm comprises three steps. The first step is the prediction process of the occlusion by checking both matters which have target-likelihood brightness and which may screen the target despite different brightness. The second step is the process making inertial tracking commands to the servo. The last step is the process of re-locking a target based on the target modeling of histogram ratio. The effectiveness of the proposed algorithm is addressed by presenting experimental results based on computer simulation with various test imagery sequences compared to published tracking algorithms. The proposed algorithm is tested under a real environment with a naval electro-optical tracking system (EOTS) and airborne EO/IR system.

  18. Computationally Efficient Automatic Coast Mode Target Tracking Based on Occlusion Awareness in Infrared Images

    Directory of Open Access Journals (Sweden)

    Sohyun Kim

    2018-03-01

    Full Text Available This paper proposes the automatic coast mode tracking of centroid trackers for infrared images to overcome the target occlusion status. The centroid tracking method, using only the brightness information of an image, is still widely used in infrared imaging tracking systems because it is difficult to extract meaningful features from infrared images. However, centroid trackers are likely to lose the track because they are highly vulnerable to screened status by the clutter or background. Coast mode, one of the tracking modes, maintains the servo slew rate with the tracking rate right before the loss of track. The proposed automatic coast mode tracking method makes decisions regarding entering coast mode by the prediction of target occlusion and tries to re-lock the target and resume the tracking after blind time. This algorithm comprises three steps. The first step is the prediction process of the occlusion by checking both matters which have target-likelihood brightness and which may screen the target despite different brightness. The second step is the process making inertial tracking commands to the servo. The last step is the process of re-locking a target based on the target modeling of histogram ratio. The effectiveness of the proposed algorithm is addressed by presenting experimental results based on computer simulation with various test imagery sequences compared to published tracking algorithms. The proposed algorithm is tested under a real environment with a naval electro-optical tracking system (EOTS and airborne EO/IR system.

  19. Human lactoferrin efficiently targeted into caprine beta-lactoglobulin locus with transcription activator-like effector nucleases

    Directory of Open Access Journals (Sweden)

    Yu-Guo Yuan

    2017-08-01

    Full Text Available Objective To create genetically modified goat as a biopharming source of recombinant human lacotoferrin (hLF with transcription activator-like effector nucleases. Methods TALENs and targeting vector were transferred into cultured fibroblasts to insert hLF cDNA in the goat beta-lactoglobulin (BLG locus with homology-directed repair. The gene targeted efficiency was checked using sequencing and TE7I assay. The bi-allelic gene targeted colonies were isolated and confirmed with polymerase chain reaction, and used as donor cells for somatic cell nuclear transfer (SCNT. Results The targeted efficiency for BLG gene was approximately 10%. Among 12 Bi-allelic gene targeted colonies, five were used in first round SCNT and 4 recipients (23% were confirmed pregnant at 30 d. In second round SCNT, 7 (53%, 4 (31%, and 3 (23% recipients were confirmed to be pregnant by ultrasound on 30 d, 60 d, and 90 d. Conclusion This finding signifies the combined use of TALENs and SCNT can generate bi-allelic knock-in fibroblasts that can be cloned in a fetus. Therefore, it might lay the foundation for transgenic hLF goat generation and possible use of their mammary gland as a bioreactor for large-scale production of recombinant hLF.

  20. A pre-protective strategy for precise tumor targeting and efficient photodynamic therapy with a switchable DNA/upconversion nanocomposite.

    Science.gov (United States)

    Yu, Zhengze; Ge, Yegang; Sun, Qiaoqiao; Pan, Wei; Wan, Xiuyan; Li, Na; Tang, Bo

    2018-04-14

    Tumor-specific targeting based on folic acid (FA) is one of the most common and significant approaches in cancer therapy. However, the expression of folate receptors (FRs) in normal tissues will lead to unexpected targeting and unsatisfactory therapeutic effect. To address this issue, we develop a pre-protective strategy for precise tumor targeting and efficient photodynamic therapy (PDT) using a switchable DNA/upconversion nanocomposite, which can be triggered in the acidic tumor microenvironment. The DNA/upconversion nanocomposite is composed of polyacrylic acid (PAA) coated upconversion nanoparticles (UCNPs), the surface of which is modified using FA and chlorin e6 (Ce6) functionalized DNA sequences with different lengths. Initially, FA on the shorter DNA was protected by a longer DNA to prevent the bonding to FRs on normal cells. Once reaching the acidic tumor microenvironment, C base-rich longer DNA forms a C-quadruplex, resulting in the exposure of the FA groups and the bonding of FA and FRs on cancer cell membranes to achieve precise targeting. Simultaneously, the photosensitizer chlorin e6 (Ce6) gets close to the surface of UCNPs, enabling the excitation of Ce6 to generate singlet oxygen ( 1 O 2 ) under near infrared light via Förster resonance energy transfer (FRET). In vivo experiments indicated that higher tumor targeting efficiency was achieved and the tumor growth was greatly inhibited through the pre-protective strategy.

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

    Science.gov (United States)

    Maity, Amit Ranjan; Stepensky, David

    2016-01-27

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

  2. Efficient Committed Budget for Implementing Target Audit Probability for Many Inspectees

    OpenAIRE

    Yim, Andrew

    2009-01-01

    Strategic models of auditor-inspectee interaction have neglected implementation details in multiple-inspectee settings. With multiple inspectees, the target audit probability derived from the standard analysis can be implemented with sampling plans differing in the budgets committed to support them. Overly committed audit budgets tie up unneeded resources that could have been allocated for better uses. This paper studies the minimum committed budget required to implement a target audit probab...

  3. Gene-carried hepatoma targeting complex induced high gene transfection efficiency with low toxicity and significant antitumor activity

    Directory of Open Access Journals (Sweden)

    Zhao QQ

    2012-06-01

    Full Text Available Qing-Qing Zhao,1,2 Yu-Lan Hu,1 Yang Zhou,3 Ni Li,1 Min Han,1 Gu-Ping Tang,4 Feng Qiu,2 Yasuhiko Tabata,5 Jian-Qing Gao,11Institute of Pharmaceutics, Zhejiang University, Hangzhou, China; 2Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; 3Institute of Biochemistry, Iowa State University, Ames, IA, USA; 4Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou, China; 5Institute for Frontier Medical Sciences, Kyoto University, Kyoto, JapanBackground: The success of gene transfection is largely dependent on the development of a vehicle or vector that can efficiently deliver a gene to cells with minimal toxicity.Methods: A liver cancer-targeted specific peptide (FQHPSF sequence was successfully synthesized and linked with chitosan-linked polyethylenimine (CP to form a new targeted gene delivery vector called CPT (CP/peptide. The structure of CPT was confirmed by 1H nuclear magnetic resonance spectroscopy and ultraviolet spectrophotometry. The particle size of CPT/DNA complexes was measured using laser diffraction spectrometry and the cytotoxicity of the copolymer was evaluated by methylthiazol tetrazolium method. The transfection efficiency evaluation of the CP copolymer was performed using luciferase activity assay. Cellular internalization of the CP/DNA complex was observed under confocal laser scanning microscopy. The targeting specificity of the polymer coupled to peptide was measured by competitive inhibition transfection study. The liver targeting specificity of the CPT copolymer in vivo was demonstrated by combining the copolymer with a therapeutic gene, interleukin-12, and assessed by its abilities in suppressing the growth of ascites tumor in mouse model.Results: The results showed that the liver cancer-targeted specific peptide was successfully synthesized and linked with CP to form a new targeted gene delivery vector called CPT. The composition of CPT

  4. TALE nickase mediates high efficient targeted transgene integration at the human multi-copy ribosomal DNA locus.

    Science.gov (United States)

    Wu, Yong; Gao, Tieli; Wang, Xiaolin; Hu, Youjin; Hu, Xuyun; Hu, Zhiqing; Pang, Jialun; Li, Zhuo; Xue, Jinfeng; Feng, Mai; Wu, Lingqian; Liang, Desheng

    2014-03-28

    Although targeted gene addition could be stimulated strikingly by a DNA double strand break (DSB) created by either zinc finger nucleases (ZFNs) or TALE nucleases (TALENs), the DSBs are really mutagenic and toxic to human cells. As a compromised solution, DNA single-strand break (SSB) or nick has been reported to mediate high efficient gene addition but with marked reduction of random mutagenesis. We previously demonstrated effective targeted gene addition at the human multicopy ribosomal DNA (rDNA) locus, a genomic safe harbor for the transgene with therapeutic potential. To improve the transgene integration efficiency by using TALENs while lowering the cytotoxicity of DSBs, we created both TALENs and TALE nickases (TALENickases) targeting this multicopy locus. A targeting vector which could integrate a GFP cassette at the rDNA locus was constructed and co-transfected with TALENs or TALENickases. Although the fraction of GFP positive cells using TALENs was greater than that using TALENickases during the first few days after transfection, it reduced to a level less than that using TALENickases after continuous culture. Our findings showed that the TALENickases were more effective than their TALEN counterparts at the multi-copy rDNA locus, though earlier studies using ZFNs and ZFNickases targeting the single-copy loci showed the reverse. Besides, TALENickases mediated the targeted integration of a 5.4 kb fragment at a frequency of up to 0.62% in HT1080 cells after drug selection, suggesting their potential application in targeted gene modification not being limited at the rDNA locus. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Versatile and Efficient Targeting Using a Single Nanoparticulate Platform: Application to Cancer and Alzheimer's Disease

    NARCIS (Netherlands)

    Le Droumaguet, Benjamin; Nicolas, Julien; Brambilla, Davide; Mura, Simona; Maksimenko, Andrei; de Kimpe, Line; Salvati, Elisa; Zona, Cristiano; Airoldi, Cristina; Canovi, Mara; Gobbi, Marco; Magali, Noiray; La Ferla, Barbara; Nicotra, Francesco; Scheper, Wiep; Flores, Orfeu; Masserini, Massimo; Andrieux, Karine; Couvreur, Patrick

    2012-01-01

    A versatile and efficient functionalization strategy for polymeric nanoparticles (NPs) has been reported and successfully applied to PEGylated, biodegradable poly(alkyl cyanoacrylate) (PACA) nanocarriers. The relevance of this platform was demonstrated in both the fields of cancer and Alzheimer's

  6. Fast and efficient three-step target-specific curing of a virulence plasmid in Salmonella enterica.

    Science.gov (United States)

    de Moraes, Marcos H; Teplitski, Max

    2015-12-01

    Virulence plasmids borne by serovars of Salmonella enterica carry genes involved in its pathogenicity, as well as other functions. Characterization of phenotypes associated with virulence plasmids requires a system for efficiently curing strains of their virulence plasmids. Here, we developed a 3-step protocol for targeted curing of virulence plasmids. The protocol involves insertion of an I-SecI restriction site linked to an antibiotic resistance gene into the target plasmid using λ-Red mutagenesis, followed by the transformation with a temperature-sensitive auxiliary plasmid which carries I-SecI nuclease expressed from a tetracycline-inducible promoter. Finally, the auxiliary plasmid is removed by incubation at 42 °C and the plasmid-less strains are verified on antibiotic-containing media. This method is fast and very efficient: over 90 % of recovered colonies lacked their virulence plasmid.

  7. Heated uranium tetrafluoride target system to release non-rare gas fission products for the TRISTAN isotope separator

    International Nuclear Information System (INIS)

    Gill, R.L.

    1977-10-01

    Off-line experiments indicated that fluorides of As, Se, Br, Kr, Zr, Nb, Mo, Tc, Ru, Sb, Te, I and Xe could be volatilized, but except for Br, Kr, I and Xe, none of these elements were observed after mass separation in the on-line experiments. The results of the on-line experiments indicated a very low level of hydride contamination at ambient temperature and consequently, uranium tetrafluoride replaced uranyl stearate as the primary gaseous fission product target. Possible reasons for the failure of the heated target system to yield non-rare gas activities are discussed and suggestions for designing a new heated target system are presented

  8. Antibody-drug conjugates: Promising and efficient tools for targeted cancer therapy.

    Science.gov (United States)

    Nasiri, Hadi; Valedkarimi, Zahra; Aghebati-Maleki, Leili; Majidi, Jafar

    2018-09-01

    Over the recent decades, the use of antibody-drug conjugates (ADCs) has led to a paradigm shift in cancer chemotherapy. Antibody-based treatment of various human tumors has presented dramatic efficacy and is now one of the most promising strategies used for targeted therapy of patients with a variety of malignancies, including hematological cancers and solid tumors. Monoclonal antibodies (mAbs) are able to selectively deliver cytotoxic drugs to tumor cells, which express specific antigens on their surface, and has been suggested as a novel category of agents for use in the development of anticancer targeted therapies. In contrast to conventional treatments that cause damage to healthy tissues, ADCs use mAbs to specifically attach to antigens on the surface of target cells and deliver their cytotoxic payloads. The therapeutic success of future ADCs depends on closely choosing the target antigen, increasing the potency of the cytotoxic cargo, improving the properties of the linker, and reducing drug resistance. If appropriate solutions are presented to address these issues, ADCs will play a more important role in the development of targeted therapeutics against cancer in the next years. We review the design of ADCs, and focus on how ADCs can be exploited to overcome multiple drug resistance (MDR). © 2018 Wiley Periodicals, Inc.

  9. Moab, Utah: Using Energy Data to Target Carbon Reductions from Building Energy Efficiency (City Energy: From Data to Decisions)

    Energy Technology Data Exchange (ETDEWEB)

    Strategic Priorities and Impact Analysis Team, Office of Strategic Programs

    2017-11-01

    This fact sheet "Moab, Utah: Using Energy Data to Target Carbon Reductions from Building Energy Efficiency" explains how the City of Moab used data from the U.S. Department of Energy's Cities Leading through Energy Analysis and Planning (Cities-LEAP) and the State and Local Energy Data (SLED) programs to inform its city energy planning. It is one of ten fact sheets in the "City Energy: From Data to Decisions" series.

  10. Specific and efficient targeting of cyanobacterial bicarbonate transporters to the inner envelope membrane of chloroplasts in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Susumu eUehara

    2016-02-01

    Full Text Available Installation of cyanobacterial bicarbonate transporters to the inner envelope membrane (IEM of chloroplasts in C3 plants has been thought to improve photosynthetic performance. However, the method to deliver cyanobacterial bicarbonate transporters to the chloroplast IEM remains to be established. In this study, we provide evidence that the cyanobacterial bicarbonate transporters, BicA and SbtA, can be specifically installed into the chloroplast IEM using the chloroplast IEM targeting signal in conjunction with the transit peptide. We fused the transit peptide and the mature portion of Cor413im1, whose targeting mechanism to the IEM has been characterized in detail, to either BicA or SbtA isolated from Synechocystis sp. PCC6803. Among the seven chimeric constructs tested, we confirmed that four chimeric bicarbonate transporters, designated as BicAI, BicAII, SbtAII, and SbtAIII, were expressed in Arabidopsis. Furthermore, these chimeric transporters were specifically targeted to the chloroplast IEM. They were also resistant to alkaline extraction but can be solubilized by Triton X-100, indicating that they are integral membrane proteins in the chloroplast IEM. One of the transporters, BicA, could reside in the chloroplast IEM even after removal of the IEM targeting signal. Taken together, our results indicate that the addition of IEM targeting signal, as well as the transit peptide, to bicarbonate transporters allows us to efficiently target nuclear-encoded chimeric bicarbonate transporters to the chloroplast IEM.

  11. Efficient CRISPR-Cas9-mediated generation of knockin human pluripotent stem cells lacking undesired mutations at the targeted locus.

    Science.gov (United States)

    Merkle, Florian T; Neuhausser, Werner M; Santos, David; Valen, Eivind; Gagnon, James A; Maas, Kristi; Sandoe, Jackson; Schier, Alexander F; Eggan, Kevin

    2015-05-12

    The CRISPR-Cas9 system has the potential to revolutionize genome editing in human pluripotent stem cells (hPSCs), but its advantages and pitfalls are still poorly understood. We systematically tested the ability of CRISPR-Cas9 to mediate reporter gene knockin at 16 distinct genomic sites in hPSCs. We observed efficient gene targeting but found that targeted clones carried an unexpectedly high frequency of insertion and deletion (indel) mutations at both alleles of the targeted gene. These indels were induced by Cas9 nuclease, as well as Cas9-D10A single or dual nickases, and often disrupted gene function. To overcome this problem, we designed strategies to physically destroy or separate CRISPR target sites at the targeted allele and developed a bioinformatic pipeline to identify and eliminate clones harboring deleterious indels at the other allele. This two-pronged approach enables the reliable generation of knockin hPSC reporter cell lines free of unwanted mutations at the targeted locus. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Efficient Nonlocal M-Control and N-Target Controlled Unitary Gate Using Non-symmetric GHZ States

    Science.gov (United States)

    Chen, Li-Bing; Lu, Hong

    2018-03-01

    Efficient local implementation of a nonlocal M-control and N-target controlled unitary gate is considered. We first show that with the assistance of two non-symmetric qubit(1)-qutrit(N) Greenberger-Horne-Zeilinger (GHZ) states, a nonlocal 2-control and N-target controlled unitary gate can be constructed from 2 local two-qubit CNOT gates, 2 N local two-qutrit conditional SWAP gates, N local qutrit-qubit controlled unitary gates, and 2 N single-qutrit gates. At each target node, the two third levels of the two GHZ target qutrits are used to expose one and only one initial computational state to the local qutrit-qubit controlled unitary gate, instead of being used to hide certain states from the conditional dynamics. This scheme can be generalized straightforwardly to implement a higher-order nonlocal M-control and N-target controlled unitary gate by using M non-symmetric qubit(1)-qutrit(N) GHZ states as quantum channels. Neither the number of the additional levels of each GHZ target particle nor that of single-qutrit gates needs to increase with M. For certain realistic physical systems, the total gate time may be reduced compared with that required in previous schemes.

  13. Targeted delivery and pH-responsive release of stereoisomeric anti-cancer drugs using β-cyclodextrin assemblied Fe{sub 3}O{sub 4} nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Congli; Huang, Lizhen; Song, Shengmei; Saif, Bassam; Zhou, Yehong; Dong, Chuan; Shuang, Shaomin, E-mail: smshuang@sxu.edu.cn

    2015-12-01

    Graphical abstract: - Highlights: • β-Cyclodextrin assemblied magnetic Fe{sub 3}O{sub 4} nanoparticles (β-CD-MNPs) with good stability were successfully fabricated. • Stereoisomeric doxorubicin (DOX) and epirubicin (EPI) were used to explore the loading and release performance. • The loading properties of β-CD-MNPs were investigated using the Langmuir and Freundlich adsorption equilibrium models. • {sup 1}H NMR and the computer simulation were used to demonstrate the inclusion position between drug molecules and β-CD. - Abstract: The β-cyclodextrin assemblied magnetic Fe{sub 3}O{sub 4} nanoparticles (β-CD-MNPs) were successfully fabricated via a layer-by-layer method. Possessing an average size 14 nm, good stability and super-paramagnetic response (Ms 64 emu/g), the resultant nanocomposites could be served as a versatile biocompatible platform for selective loading, targeted delivery and pH-responsive release of stereoisomeric doxorubicin (DOX) and epirubicin (EPI). {sup 1}H-nuclear magnetic resonance ({sup 1}H NMR) and the computer simulation further give the evidence that partial anthracene ring of drug molecule is included by β-CD. In addition, non-toxic β-CD-MNPs have excellent biocompatibility on MCF-7 cells, and cellular uptake indicate that different amounts of DOX or EPI can be transported to targeting site and released from the internalized carriers. The results demonstrate that as-prepared β-CD-MNPs could be a very promising vehicle for DOX and EPI.

  14. An Efficient Method for Identifying Gene Fusions by Targeted RNA Sequencing from Fresh Frozen and FFPE Samples.

    Directory of Open Access Journals (Sweden)

    Jonathan A Scolnick

    Full Text Available Fusion genes are known to be key drivers of tumor growth in several types of cancer. Traditionally, detecting fusion genes has been a difficult task based on fluorescent in situ hybridization to detect chromosomal abnormalities. More recently, RNA sequencing has enabled an increased pace of fusion gene identification. However, RNA-Seq is inefficient for the identification of fusion genes due to the high number of sequencing reads needed to detect the small number of fusion transcripts present in cells of interest. Here we describe a method, Single Primer Enrichment Technology (SPET, for targeted RNA sequencing that is customizable to any target genes, is simple to use, and efficiently detects gene fusions. Using SPET to target 5701 exons of 401 known cancer fusion genes for sequencing, we were able to identify known and previously unreported gene fusions from both fresh-frozen and formalin-fixed paraffin-embedded (FFPE tissue RNA in both normal tissue and cancer cells.

  15. Efficient VEGF targeting delivery of DOX using Bevacizumab conjugated SiO2@LDH for anti-neuroblastoma therapy.

    Science.gov (United States)

    Zhu, Rongrong; Wang, Zhaoqi; Liang, Peng; He, Xiaolie; Zhuang, Xizhen; Huang, Ruiqi; Wang, Mei; Wang, Qigang; Qian, Yechang; Wang, Shilong

    2017-11-01

    Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and is highly expressed in carcinoma, which make it an important target for tumor targeting therapy. Neuroblastoma is the main cause for cancer-related death in children. Like most solid tumors, it is also accompanied with the overexpression of VEGF. Doxorubicin Hydrochloride (DOX), a typical chemotherapeutic agent, exhibits efficient anticancer activities for various cancers. However, DOX, without targeting ability, usually causes severe damage to normal tissues. To overcome the shortages, we designed a novel nano-composite, which is Bevacizumab (Bev) modified SiO 2 @LDH nanoparticles (SiO 2 @LDH-Bev), loading with DOX to achieve targeting ability and curative efficiency. SiO 2 @LDH-DOX and SiO 2 @LDH-Bev-DOX nanoparticles were synthesized and the physicochemical properties were characterized by TEM detection, Zeta potential analysis, FTIR, Raman and XPS analysis. Then in vitro and in vivo anti-neuroblastoma efficiency, targeting ability and mechanisms of anti-carcinoma and anti-angiogenesis of SiO 2 @LDH-Bev-DOX were explored. Our results indicated that we obtained the core-shell structure SiO 2 @LDH-Bev with an average diameter of 253±10nm and the amount of conjugated Bev was 4.59±0.38μg/mg SiO 2 @LDH-Bev. SiO 2 @LDH-Bev-DOX could improve the cellular uptake and the targeting effect of DOX to brain and tumor, enhance the anti-neuroblastoma and anti-angiogenesis efficiency both in vitro and in vivo, and alleviate side effects of DOX sharply, especially hepatic injury. In addition, we also demonstrated that angiogenesis inhibitory effect was mediated by DOX and VEGF triggered signal pathways, including PI3K/Akt, Raf/MEK/ERK, and adhesion related pathways. In summary, SiO 2 @LDH-Bev could be a potential VEGF targeting nanocarrier applied in VEGF positive cancer therapy. This paper explored that a novel core-shell structure nanomaterial SiO 2 @LDH and modified SiO 2 @LDH with

  16. Efficient intracellular delivery of 5-fluorodeoxyuridine into colon cancer cells by targeted immunoliposomes

    NARCIS (Netherlands)

    Koning, GA; Kamps, JAAM; Scherphof, GL

    2002-01-01

    Immunoliposomes, liposomes with monoclonal antibodies attached, are being developed for targeting the anti-cancer drug 5-fluoro-2'-deoxyuridine (FUdR) to colon cancer cells. A monoclonal antibody against the rat colon carcinoma CC531 was covalently coupled to liposomes containing a dipalmitoylated

  17. Efficient committed budget for implementing target audit probability for many inspectees

    NARCIS (Netherlands)

    Yim, A.T.L.

    2009-01-01

    Strategic models of auditor-inspectee interaction have neglected implementation details in multiple-inspectee settings. With multiple inspectees, the target audit probability derived from the standard analysis can be implemented with sampling plans differing in the budgets committed to support them.

  18. Target Pilots Energy Efficiency Measures for Broad Rollout in Existing Stores

    Energy Technology Data Exchange (ETDEWEB)

    None

    2013-03-01

    Target Corporation partnered with the U.S. Department of Energy (DOE) to develop and implement solutions to retrofit existing buildings to reduce annual energy consumption by at least 30% versus requirements set by ASHRAE/ANSI/IESNA Standard 90.1-20041 as part of DOE’s Commercial Building Partnership (CBP) program.

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

    International Nuclear Information System (INIS)

    Cao Quanliang; Han Xiaotao; Li Liang

    2011-01-01

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

  20. An efficient numerical target strength prediction model: Validation against analysis solutions

    NARCIS (Netherlands)

    Fillinger, L.; Nijhof, M.J.J.; Jong, C.A.F. de

    2014-01-01

    A decade ago, TNO developed RASP (Rapid Acoustic Signature Prediction), a numerical model for the prediction of the target strength of immersed underwater objects. The model is based on Kirchhoff diffraction theory. It is currently being improved to model refraction, angle dependent reflection and

  1. Efficient methods for targeted mutagenesis in zebrafish using zinc-finger nucleases: data from targeting of nine genes using CompoZr or CoDA ZFNs.

    Directory of Open Access Journals (Sweden)

    Raman Sood

    Full Text Available Recently, it has been shown that targeted mutagenesis using zinc-finger nucleases (ZFNs and transcription activator-like effector nucleases (TALENs can be used to generate knockout zebrafish lines for analysis of their function and/or developing disease models. A number of different methods have been developed for the design and assembly of gene-specific ZFNs and TALENs, making them easily available to most zebrafish researchers. Regardless of the choice of targeting nuclease, the process of generating mutant fish is similar. It is a time-consuming and multi-step process that can benefit significantly from development of efficient high throughput methods. In this study, we used ZFNs assembled through either the CompoZr (Sigma-Aldrich or the CoDA (context-dependent assembly platforms to generate mutant zebrafish for nine genes. We report our improved high throughput methods for 1 evaluation of ZFNs activity by somatic lesion analysis using colony PCR, eliminating the need for plasmid DNA extractions from a large number of clones, and 2 a sensitive founder screening strategy using fluorescent PCR with PIG-tailed primers that eliminates the stutter bands and accurately identifies even single nucleotide insertions and deletions. Using these protocols, we have generated multiple mutant alleles for seven genes, five of which were targeted with CompoZr ZFNs and two with CoDA ZFNs. Our data also revealed that at least five-fold higher mRNA dose was required to achieve mutagenesis with CoDA ZFNs than with CompoZr ZFNs, and their somatic lesion frequency was lower (<5% when compared to CopmoZr ZFNs (9-98%. This work provides high throughput protocols for efficient generation of zebrafish mutants using ZFNs and TALENs.

  2. How to Design a Targeted Agricultural Subsidy System: Efficiency or Equity?

    DEFF Research Database (Denmark)

    Cong, Ronggang; Brady, Mark

    2012-01-01

    for environmental protection, social cohesion, etc. Based on a simplified economic model, we prove that there is “reverse redistribution” in the current tax-subsidy system, which cannot be avoided. To find a possible way to distribute subsidies more efficiently and equitably, several alternative subsidy systems...... (the pure loan, the harvest tax and the income contingent loan) are presented and examined....

  3. Pathways for the release of polonium from a lead-bismuth spallation target (thermochemical calculation); Verfluechtigungspfade des Poloniums aus einem Pb-Bi-Spallationstarget (Thermochemische Kalkulation)

    Energy Technology Data Exchange (ETDEWEB)

    Eichler, B.; Neuhausen, J

    2004-06-01

    An analysis of literature data for the thermochemical constants of polonium reveals considerable discrepancies in the relations of these data among each other as well as in their expected trends within the chalcogen group. This fact hinders a reliable assessment of possible reaction paths for the release of polonium from a liquid lead-bismuth spallation target. In this work an attempt is made to construct a coherent data set for the thermochemical properties of polonium and some of its compounds that are of particular importance with respect to the behaviour of polonium in a liquid Pb-Bi target. This data set is based on extrapolations using general trends throughout the periodic table and, in particular, within the chalcogen group. Consequently, no high accuracy should be attributed to the derived data set. However, the data set derived in this work is consistent with definitely known experimental data. Furthermore, it complies with the general trends of physicochemical properties within the chalcogen group. Finally, well known relations between thermochemical quantities are fulfilled by the data derived in this work. Thus, given the lack of accurate experimental data it can be regarded as best available data. Thermochemical constants of polonium hydride, lead polonide and polonium dioxide are derived based on extrapolative procedures. Furthermore, the possibility of formation of the gaseous intermetallic molecule BiPo, which has been omitted from discussion up to now, is investigated. From the derived thermochemical data the equilibrium constants of formation, release and dissociation reactions are calculated for different polonium containing species. Furthermore equilibrium constants are determined for the reaction of lead polonide and polonium dioxide with hydrogen, water vapour and the target components lead and bismuth. The most probable release pathways are discussed. From thermochemical evaluations polonium is expected to be released from liquid lead

  4. Graphene oxide as a nanocarrier for controlled release and targeted delivery of an anticancer active agent, chlorogenic acid

    Energy Technology Data Exchange (ETDEWEB)

    Barahuie, Farahnaz [Materials Synthesis and Characterization Laboratory, Institute of Advanced Technology (ITMA), Universiti Putra Malaysia UPM, 43400 Serdang, Selangor (Malaysia); Zabol University of Medical Sciences, Zabol (Iran, Islamic Republic of); Saifullah, Bullo [Materials Synthesis and Characterization Laboratory, Institute of Advanced Technology (ITMA), Universiti Putra Malaysia UPM, 43400 Serdang, Selangor (Malaysia); Dorniani, Dena [Materials Synthesis and Characterization Laboratory, Institute of Advanced Technology (ITMA), Universiti Putra Malaysia UPM, 43400 Serdang, Selangor (Malaysia); Chemistry Department, University of Sheffield, Dainton Building, Brook Hill, Sheffield S3 7HF (United Kingdom); Fakurazi, Sharida [Laboratory of Vaccines and Immunotherapeutics, Institute of Bioscience, Universiti Putra Malaysia UPM, 43400 Serdang, Selangor (Malaysia); Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia UPM, 43400 Serdang, Selangor (Malaysia); Karthivashan, Govindarajan [Laboratory of Vaccines and Immunotherapeutics, Institute of Bioscience, Universiti Putra Malaysia UPM, 43400 Serdang, Selangor (Malaysia); Hussein, Mohd Zobir, E-mail: mzobir@upm.edu.my [Materials Synthesis and Characterization Laboratory, Institute of Advanced Technology (ITMA), Universiti Putra Malaysia UPM, 43400 Serdang, Selangor (Malaysia); Elfghi, Fawzi M. [Department of Chemical and Petrochemical Engineering, The College of Engineering & Architecture, Initial Campus, Birkat Al Mouz Nizwa (Oman)

    2017-05-01

    We have synthesized graphene oxide using improved Hummer's method in order to explore the potential use of the resulting graphene oxide as a nanocarrier for an active anticancer agent, chlorogenic acid (CA). The synthesized graphene oxide and chlorogenic acid-graphene oxide nanocomposite (CAGO) were characterized using Fourier transform infrared (FTIR) spectroscopy, thermogravimetry and differential thermogravimetry analysis, Raman spectroscopy, powder X-ray diffraction (PXRD), UV–vis spectroscopy and high resolution transmission electron microscopy (HRTEM) techniques. The successful conjugation of chlorogenic acid onto graphene oxide through hydrogen bonding and π–π interaction was confirmed by Raman spectroscopy, FTIR analysis and X-ray diffraction patterns. The loading of CA in the nanohybrid was estimated to be around 13.1% by UV–vis spectroscopy. The release profiles showed favourable, sustained and pH-dependent release of CA from CAGO nanocomposite and conformed well to the pseudo-second order kinetic model. Furthermore, the designed anticancer nanohybrid was thermally more stable than its counterpart. The in vitro cytotoxicity results revealed insignificant toxicity effect towards normal cell line, with a viability of > 80% even at higher concentration of 50 μg/mL. Contrarily, CAGO nanocomposite revealed enhanced toxic effect towards evaluated cancer cell lines (HepG2 human liver hepatocellular carcinoma cell line, A549 human lung adenocarcinoma epithelial cell line, and HeLa human cervical cancer cell line) compared to its free form. - Highlights: • Graphene oxide is synthesized using improved Hummer's method • The suppression of cancer cell growth was higher for chlorogenic acid/graphene oxide nanocomposite than for pure chlorogenic acid • Chlorogenic acid/graphene oxide nanocomposite has the potential to be used as a sustained release formulation.

  5. Directional R-Loop Formation by the CRISPR-Cas Surveillance Complex Cascade Provides Efficient Off-Target Site Rejection

    Directory of Open Access Journals (Sweden)

    Marius Rutkauskas

    2015-03-01

    Full Text Available CRISPR-Cas systems provide bacteria and archaea with adaptive immunity against foreign nucleic acids. In type I CRISPR-Cas systems, invading DNA is detected by a large ribonucleoprotein surveillance complex called Cascade. The crRNA component of Cascade is used to recognize target sites in foreign DNA (protospacers by formation of an R-loop driven by base-pairing complementarity. Using single-molecule supercoiling experiments with near base-pair resolution, we probe here the mechanism of R-loop formation and detect short-lived R-loop intermediates on off-target sites bearing single mismatches. We show that R-loops propagate directionally starting from the protospacer-adjacent motif (PAM. Upon reaching a mismatch, R-loop propagation stalls and collapses in a length-dependent manner. This unambiguously demonstrates that directional zipping of the R-loop accomplishes efficient target recognition by rapidly rejecting binding to off-target sites with PAM-proximal mutations. R-loops that reach the protospacer end become locked to license DNA degradation by the auxiliary Cas3 nuclease/helicase without further target verification.

  6. Effect of linkers on the αvβ3 integrin targeting efficiency of cyclic RGD-conjugates

    Science.gov (United States)

    Karmakar, Partha; Grabowska, Dorota; Sudlow, Gail; Ziabrev, Kostiantyn; Sanyal, Nibedita; Achilefu, Samuel

    2018-02-01

    Cyclic arginine-glycine-aspartic acid (cRGD) peptides are well known to target ανβ3 integrin expressed on cancer cells and neovasculature. Conjugation of these peptides with dyes, drugs, antibodies and other biomolecules through covalent linkers provides a facile way to deliver these products to tumor cells for targeted cancer therapy and diagnosis. Click chemistry and acid-amine couplings are widely used conjugation strategies. However, the effects of different linkers and the distance between the cRGD and the conjugates on the binding of cRGD ligand with ανβ3 has been underexplored. In this present study, we prepared cRGD-conjugates using different linkers and determined how they altered the tumor targeting efficiency in vitro and in vivo. The results demonstrate that different linkers significantly altered the pharmacokinetics of the cRGD conjugates and the tumor uptake kinetics. Unlike large antibodies, this preliminary finding shows that linkers used to attach drugs and fluorescent molecular probes to small peptides play a major role in the accuracy of tumor targeting and treatment outcomes. As a result, considerable attention should be paid to the nature of linkers used in the design of molecular probes and targeted therapeutics.

  7. Clickable and imageable multiblock polymer micelles with magnetically guided and PEG-switched targeting and release property for precise tumor theranosis.

    Science.gov (United States)

    Wei, Jing; Shuai, Xiaoyu; Wang, Rui; He, Xueling; Li, Yiwen; Ding, Mingming; Li, Jiehua; Tan, Hong; Fu, Qiang

    2017-11-01

    Targeted delivery of therapeutics and diagnostics using nanotechnology holds great promise to minimize the side effects of conventional chemotherapy and enable specific and real-time detection of diseases. To realize this goal, we report a clickable and imageable nanovehicle assembled from multiblock polyurethanes (MPUs). The soft segments of the polymers are based on detachable poly(ethylene glycol) (PEG) and degradable poly(ε-caprolactone) (PCL), and the hard segments are constructed from lysine- and cystine-derivatives bearing reduction-responsive disulfide linkages and click-active alkynyl moieties, allowing for post-conjugation of targeting ligands via a click chemistry. It was found that the cleavage of PEG corona bearing a pH-sensitive benzoic-imine linkage (BPEG) could act as an on-off switch, which is capable of activating the clicked targeting ligands under extracellular acidic condition, followed by triggering the core degradation and payload release within tumor cells. In combination with superparamagnetic iron oxide nanoparticles (SPION) clustered within the micellar core, the MPUs exhibit excellent magnetic resonance imaging (MRI) contrast effects and T 2 relaxation in vitro, as well as magnetically guided MR imaging and multimodal targeting of therapeutics to tumor precisely, leading to significant inhibition of cancer with minimal side effect. This work provides a safe and versatile platform for the further development of smart theranostic systems for potential magnetically-targeted and imaging-guided personalized medicine. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. External tandem target system for efficient production of short-lived positron emitting radionuclides

    International Nuclear Information System (INIS)

    Koh, K.; Dwyer, J.; Finn, R.; Sheh, Y.; Sinnreich, J.; Wooten, T.

    1983-01-01

    Recent developments in radiopharmaceutical chemistry allow the incorporation of short-lived, positron-emitting radionuclides into a variety of compounds which when used with a positron emission tomograph provide a means of monitoring physiological disorders by a standard technique. To effectively meet the increased ''in-house'' clinical demands while maintaining a production schedule, a tandem target was designed and has been installed for the simultaneous ''on-line'' preparation of oxygen-15 labelled compounds such as CO 2 15 , H 2 O 15 ; and nitrogen-13 labelled compounds such as 13 NH 3 , 13 N 2 O, and 13 N 2 . The processing time required for the synthesis of the nitrogen-13 products as compared to the essentially instantaneous formation of oxygen-15 labelled compounds has provided the necessary time delay for clinical utilization. The characterisitcs of this external tandem target system as well as the automation for the dual processing are presented

  9. Nerve growth factor alters microtubule targeting agent-induced neurotransmitter release but not MTA-induced neurite retraction in sensory neurons.

    Science.gov (United States)

    Pittman, Sherry K; Gracias, Neilia G; Fehrenbacher, Jill C

    2016-05-01

    Peripheral neuropathy is a dose-limiting side effect of anticancer treatment with the microtubule-targeted agents (MTAs), paclitaxel and epothilone B (EpoB); however, the mechanisms by which the MTAs alter neuronal function and morphology are unknown. We previously demonstrated that paclitaxel alters neuronal sensitivity, in vitro, in the presence of nerve growth factor (NGF). Evidence in the literature suggests that NGF may modulate the neurotoxic effects of paclitaxel. Here, we examine whether NGF modulates changes in neuronal sensitivity and morphology induced by paclitaxel and EpoB. Neuronal sensitivity was assessed using the stimulated release of calcitonin gene-related peptide (CGRP), whereas morphology of established neurites was evaluated using a high content screening system. Dorsal root ganglion cultures, maintained in the absence or presence of NGF, were treated from day 7 to day 12 in culture with paclitaxel (300nM) or EpoB (30nM). Following treatment, the release of CGRP was stimulated using capsaicin or high extracellular potassium. In the presence of NGF, EpoB mimicked the effects of paclitaxel: capsaicin-stimulated release was attenuated, potassium-stimulated release was slightly enhanced and the total peptide content was unchanged. In the absence of NGF, both paclitaxel and EpoB decreased capsaicin- and potassium-stimulated release and the total peptide content, suggesting that NGF may reverse MTA-induced hyposensitivity. Paclitaxel and EpoB both decreased neurite length and branching, and this attenuation was unaffected by NGF in the growth media. These differential effects of NGF on neuronal sensitivity and morphology suggest that neurite retraction is not a causative factor to alter neuronal sensitivity. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Biodegradable microspheres for the sustained release of PDGF-receptor directed pPB-HSA targeted to the fibrotic kidney

    NARCIS (Netherlands)

    Teekamp, Naomi; van Dijk, Fransien; Beljaars, Eleonora; Hinrichs, Wouter; Steendam, Rob; Zuidema, Johan; Poelstra, Klaas; Frijlink, H.W.; Olinga, Peter

    2016-01-01

    Platelet Derived Growth Factor (PDGF) plays a key role in the development of fibrotic processes in several tissues. Accordingly, the PDGF receptor is abundantly present in these fibrotic tissues. Specific targeting to this receptor is established for a series of compounds in different animal models,

  11. Biodegradable microspheres for the sustained release of ppB-HSA to target PDGFβ-receptors in fibrotic tissues

    NARCIS (Netherlands)

    Teekamp, Naomi; van Dijk, Fransien; Beljaars, Eleonora; Post, Eduard; Hinrichs, Wouter; Poelstra, Klaas; Olinga, Peter

    2016-01-01

    Introduction pPB-HSA is a protein construct, which consists of human serum albumin (HSA), coupled to a cyclic peptide (pPB). This cyclic peptide binds specifically to the PDGF receptor without eliciting an intracellular response. Hence, this construct can be used as a carrier vehicle to target drugs

  12. Biodegradable microspheres for the sustained release of PDGF-receptor directed PPB-HSA targeted to the fibrotic kidney

    NARCIS (Netherlands)

    Teekamp, Naomi; van Dijk, Fransien; Beljaars, Eleonora; Hinrichs, Wouter; Poelstra, Klaas; Frijlink, H.W.; Olinga, Peter

    2016-01-01

    Platelet Derived Growth Factor (PDGF) plays a key role in the development of fibrotic processes in several tissues. Accordingly, the PDGFβ receptor is abundantly present in these fibrotic tissues. Specific targeting to this receptor is established for a series of compounds in different animal

  13. Graphene oxide as a nanocarrier for controlled release and targeted delivery of an anticancer active agent, chlorogenic acid.

    Science.gov (United States)

    Barahuie, Farahnaz; Saifullah, Bullo; Dorniani, Dena; Fakurazi, Sharida; Karthivashan, Govindarajan; Hussein, Mohd Zobir; Elfghi, Fawzi M

    2017-05-01

    We have synthesized graphene oxide using improved Hummer's method in order to explore the potential use of the resulting graphene oxide as a nanocarrier for an active anticancer agent, chlorogenic acid (CA). The synthesized graphene oxide and chlorogenic acid-graphene oxide nanocomposite (CAGO) were characterized using Fourier transform infrared (FTIR) spectroscopy, thermogravimetry and differential thermogravimetry analysis, Raman spectroscopy, powder X-ray diffraction (PXRD), UV-vis spectroscopy and high resolution transmission electron microscopy (HRTEM) techniques. The successful conjugation of chlorogenic acid onto graphene oxide through hydrogen bonding and π-π interaction was confirmed by Raman spectroscopy, FTIR analysis and X-ray diffraction patterns. The loading of CA in the nanohybrid was estimated to be around 13.1% by UV-vis spectroscopy. The release profiles showed favourable, sustained and pH-dependent release of CA from CAGO nanocomposite and conformed well to the pseudo-second order kinetic model. Furthermore, the designed anticancer nanohybrid was thermally more stable than its counterpart. The in vitro cytotoxicity results revealed insignificant toxicity effect towards normal cell line, with a viability of >80% even at higher concentration of 50μg/mL. Contrarily, CAGO nanocomposite revealed enhanced toxic effect towards evaluated cancer cell lines (HepG2 human liver hepatocellular carcinoma cell line, A549 human lung adenocarcinoma epithelial cell line, and HeLa human cervical cancer cell line) compared to its free form. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Controlled Release Urea as a Nitrogen Source for Spring Wheat in Western Canada: Yield, Grain N Content, and N Use Efficiency

    Directory of Open Access Journals (Sweden)

    Lenz Haderlein

    2001-01-01

    Full Text Available Controlled release nitrogen (N fertilizers have been commonly used in horticultural applications such as turf grasses and container-grown woody perennials. Agrium, a major N manufacturer in North and South America, is developing a low-cost controlled release urea (CRU product for use in field crops such as grain corn, canola, wheat, and other small grain cereals. From 1998 to 2000, 11 field trials were conducted across western Canada to determine if seed-placed CRU could maintain crop yields and increase grain N and N use efficiency when compared to the practice of side-banding of urea N fertilizer. CRU was designed to release timely and adequate, but not excessive, amounts of N to the crop. Crop uptake of N from seed-placed CRU was sufficient to provide yields similar to those of side-banded urea N. Grain N concentrations of the CRU treatments were higher, on average, than those from side-banded urea, resulting in 4.2% higher N use efficiency across the entire N application range from 25 to 100 kg ha-1. Higher levels of removal of N in grain from CRU compared to side-banded urea can result in less residual N remaining in the soil, and limit the possibility of N losses due to denitrification and leaching.

  15. Nifedipine-loaded polymeric nanocapsules: validation of a stability-indicating HPLC method to evaluate the drug entrapment efficiency and in vitro release profiles.

    Science.gov (United States)

    Granada, Andréa; Tagliari, Monika Piazzon; Soldi, Valdir; Silva, Marcos António Segatto; Zanetti-Ramos, Betina Ghiel; Fernandes, Daniel; Stulzer, Hellen Karine

    2013-01-01

    A simple stability-indicating analytical method was developed and validated to quantify nifedipine in polymeric nanocapsule suspensions; an in vitro drug release study was then carried out. The analysis was performed using an RP C18 column, UV-Vis detection at 262 nm, and methanol-water (70 + 30, v/v) mobile phase at a flow rate of 1.2 mL/min. The method was validated in terms of specificity, linearity and range, LOQ, accuracy, precision, and robustness. The results obtained were within the acceptable ranges. The nanocapsules, made of poly(epsilon-caprolactone), were prepared by the solvent displacement technique and showed high entrapment efficiency. The entrapment efficiency was 97.6 and 98.2% for the nifedipine-loaded polymeric nanocapsules prepared from polyvinyl alcohol (PVA) and Pluronic F68 (PF68), respectively. The particle size and zeta potential of nanocapsules were found to be influenced by the nature of the stabilizer used. The mean diameter and zeta potential for nanocapsules with PVA and PF68 were 290.9 and 179.9 nm, and -17.7 mV and -32.7 mV, respectively. The two formulations prepared showed a drug release of up to 70% over 4 days. This behavior indicates the viability of this drug delivery system for use as a controlled-release system.

  16. Badoca Safari Park : a proposition on how to efficiently target the young segment

    OpenAIRE

    Almeida, Francisca Simões de

    2016-01-01

    Badoca Safari Park is an Animal Theme Park, which provides the opportunity to spend a day in contact with nature and different animal species. The Safari Park, pioneer in Portugal, achieved successful performances during the first years of activity. However, annual attendance has been declining over the last years across all age groups. The current study focuses on the 15-24 years old target, who are of strategic relevance, given the Park’s poor performance in retaining the young sement as th...

  17. Target Plate Material Influence on Fullerene-C60 Laser Desorption/Ionization Efficiency

    Science.gov (United States)

    Zeegers, Guido P.; Günthardt, Barbara F.; Zenobi, Renato

    2016-04-01

    Systematic laser desorption/ionization (LDI) experiments of fullerene-C60 on a wide range of target plate materials were conducted to gain insight into the initial ion formation in matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. The positive and negative ion signal intensities of precursor, fragment, and cluster ions were monitored, varying both the laser fluence (0-3.53 Jcm-2) and the ion extraction delay time (0-950 ns). The resulting species-specific ion signal intensities are an indication for the ionization mechanisms that contribute to LDI and the time frames in which they operate, providing insight in the (MA)LDI primary ionization. An increasing electrical resistivity of the target plate material increases the fullerene-C60 precursor and fragment anion signal intensity. Inconel 625 and Ti90/Al6/V4, both highly electrically resistive, provide the highest anion signal intensities, exceeding the cation signal intensity by a factor ~1.4 for the latter. We present a mechanism based on transient electrical field strength reduction to explain this trend. Fullerene-C60 cluster anion formation is negligible, which could be due to the high extraction potential. Cluster cations, however, are readily formed, although for high laser fluences, the preferred channel is formation of precursor and fragment cations. Ion signal intensity depends greatly on the choice of substrate material, and careful substrate selection could, therefore, allow for more sensitive (MA)LDI measurements.

  18. Clathrin to Lipid Raft-Endocytosis via Controlled Surface Chemistry and Efficient Perinuclear Targeting of Nanoparticle.

    Science.gov (United States)

    Chakraborty, Atanu; Jana, Nikhil R

    2015-09-17

    Nanoparticle interacts with live cells depending on their surface chemistry, enters into cell via endocytosis, and is commonly trafficked to an endosome/lysozome that restricts subcellular targeting options. Here we show that nanoparticle surface chemistry can be tuned to alter their cell uptake mechanism and subcellular trafficking. Quantum dot based nanoprobes of 20-30 nm hydrodynamic diameters have been synthesized with tunable surface charge (between +15 mV to -25 mV) and lipophilicity to influence their cellular uptake processes and subcellular trafficking. It is observed that cationic nanoprobe electrostatically interacts with cell membrane and enters into cell via clathrin-mediated endocytosis. At lower surface charge (between +10 mV to -10 mV), the electrostatic interaction with cell membrane becomes weaker, and additional lipid raft endocytosis is initiated. If a lipophilic functional group is introduced on a weakly anionic nanoparticle surface, the uptake mechanism shifts to predominant lipid raft-mediated endocytosis. In particular, the zwitterionic-lipophilic nanoprobe has the unique advantage as it weakly interacts with anionic cell membrane, migrates toward lipid rafts for interaction through lipophilic functional group, and induces lipid raft-mediated endocytosis. While predominate or partial clathrin-mediated entry traffics most of the nanoprobes to lysozome, predominate lipid raft-mediated entry traffics them to perinuclear region, particularly to the Golgi apparatus. This finding would guide in designing appropriate nanoprobe for subcellular targeting and delivery.

  19. Open Access Target Validation Is a More Efficient Way to Accelerate Drug Discovery

    Science.gov (United States)

    Lee, Wen Hwa

    2015-01-01

    There is a scarcity of novel treatments to address many unmet medical needs. Industry and academia are finally coming to terms with the fact that the prevalent models and incentives for innovation in early stage drug discovery are failing to promote progress quickly enough. Here we will examine how an open model of precompetitive public–private research partnership is enabling efficient derisking and acceleration in the early stages of drug discovery, whilst also widening the range of communities participating in the process, such as patient and disease foundations. PMID:26042736

  20. How to design a targeted agricultural subsidy system: efficiency or equity?

    Science.gov (United States)

    Cong, Rong-Gang; Brady, Mark

    2012-01-01

    In this paper we appraise current agricultural subsidy policy in the EU. Several sources of its inefficiency are identified: it is inefficient for supporting farmers' incomes or guaranteeing food security, and irrational transfer payments decoupled from actual performance that may be negative for environmental protection, social cohesion, etc. Based on a simplified economic model, we prove that there is "reverse redistribution" in the current tax-subsidy system, which cannot be avoided. To find a possible way to distribute subsidies more efficiently and equitably, several alternative subsidy systems (the pure loan, the harvest tax and the income contingent loan) are presented and examined.

  1. How to design a targeted agricultural subsidy system: efficiency or equity?

    Directory of Open Access Journals (Sweden)

    Rong-Gang Cong

    Full Text Available In this paper we appraise current agricultural subsidy policy in the EU. Several sources of its inefficiency are identified: it is inefficient for supporting farmers' incomes or guaranteeing food security, and irrational transfer payments decoupled from actual performance that may be negative for environmental protection, social cohesion, etc. Based on a simplified economic model, we prove that there is "reverse redistribution" in the current tax-subsidy system, which cannot be avoided. To find a possible way to distribute subsidies more efficiently and equitably, several alternative subsidy systems (the pure loan, the harvest tax and the income contingent loan are presented and examined.

  2. Theranostic pH-sensitive nanoparticles for highly efficient targeted delivery of doxorubicin for breast tumor treatment.

    Science.gov (United States)

    Pan, Changqie; Liu, Yuqing; Zhou, Minyu; Wang, Wensheng; Shi, Min; Xing, Malcolm; Liao, Wangjun

    2018-01-01

    A multifunctional theranostic nanoplatform integrated with environmental responses has been developed rapidly over the past few years as a novel treatment strategy for several solid tumors. We synthesized pH-sensitive poly(β-thiopropionate) nanoparticles with a supermagnetic core and folic acid (FA) conjugation (FA-doxorubicin-iron oxide nanoparticles [FA-DOX@ IONPs]) to deliver an antineoplastic drug, DOX, for the treatment of folate receptor (FR)-overexpressed breast cancer. In addition to an imaging function, the nanoparticles can release their payloads in response to an environment of pH 5, such as the acidic environment found in tumors. After chemical ( 1 H nuclear magnetic resonance) and physical (morphology and super-magnetic) characterization, FA-DOX@IONPs were shown to demonstrate pH-dependent drug release profiles. Western blotting analysis revealed the expression of FRs in three breast cancer cell lines, MCF-7, BT549, and MD-MBA-231. The cell counting kit-8 assay and transmission electron microscopy showed that FA-DOX@IONPs had the strongest cytotoxicity against breast cancer cells, compared with free DOX and non-FR targeted nanoparticles (DOX@IONPs), and caused cellular apoptosis. The FA-DOX@IONP-mediated cellular uptake and intracellular internalization were clarified by fluorescence microscopy. FA-DOX@IONPs plus magnetic field treatment suppressed in vivo tumor growth in mice to a greater extent than either treatment alone; furthermore, the nanoparticles exerted no toxicity against healthy organs. Magnetic resonance imaging was successfully applied to monitor the nanoparticle accumulation. Our results suggest that theranostic pH-sensitive nanoparticles with dual targeting could enhance the available therapies for cancer.

  3. Galaxy And Mass Assembly (GAMA): the G02 field, Herschel-ATLAS target selection and Data Release 3 arXiv

    CERN Document Server

    Baldry, I.K.; Brown, M.J.I.; Robotham, A.S.G.; Driver, S.P.; Dunne, L.; Alpaslan, M.; Brough, S.; Cluver, M.E.; Eardley, E.; Farrow, D.J.; Heymans, C.; Hildebrandt, H.; Hopkins, A.M.; Kelvin, L.S.; Loveday, J.; Moffett, A.J.; Norberg, P.; Owers, M.S.; Taylor, E.N.; Wright, A.H.; Bamford, S.P.; Bland-Hawthorn, J.; Bourne, N.; Bremer, M.N.; Colless, M.; Conselice, C.J.; Croom, S.M.; Davies, L.J.M.; Foster, C.; Grootes, M.W.; Holwerda, B.W.; Jones, D.H.; Kafle, P.R.; Kuijken, K.; Lara-Lopez, M.A.; Lopez-Sanchez, A.R.; Meyer, M.J.; Phillipps, S.; Sutherland, W.J.; van Kampen, E.; Wilkins, S.M.

    We describe data release 3 (DR3) of the Galaxy And Mass Assembly (GAMA) survey. The GAMA survey is a spectroscopic redshift and multi-wavelength photometric survey in three equatorial regions each of 60.0 deg^2 (G09, G12, G15), and two southern regions of 55.7 deg^2 (G02) and 50.6 deg^2 (G23). DR3 consists of: the first release of data covering the G02 region and of data on H-ATLAS sources in the equatorial regions; and updates to data on sources released in DR2. DR3 includes 154809 sources with secure redshifts across four regions. A subset of the G02 region is 95.5% redshift complete to r<19.8 over an area of 19.5 deg^2, with 20086 galaxy redshifts, that overlaps substantially with the XXL survey (X-ray) and VIPERS (redshift survey). In the equatorial regions, the main survey has even higher completeness (98.5%), and spectra for about 75% of H-ATLAS filler targets were also obtained. This filler sample extends spectroscopic redshifts, for probable optical counterparts to H-ATLAS sub-mm sources, to 0.8 ma...

  4. Detection of glutathione based on MnO2 nanosheet-gated mesoporous silica nanoparticles and target induced release of glucose measured with a portable glucose meter.

    Science.gov (United States)

    Tan, Qingqing; Zhang, Ruirui; Kong, Rongmei; Kong, Weisu; Zhao, Wenzhi; Qu, Fengli

    2017-12-08

    The authors describe a novel method for the determination of glutathione (GSH). Detection is based on target induced release of glucose from MnO 2 nanosheet-gated aminated mesoporous silica nanoparticles (MSNs). In detail, glucose is loaded into the pores of MSNs. Negatively charged MnO 2 nanosheets are assembled on the MSNs through electrostatic interactions. The nanosheets are reduced by GSH, and this results in the release of glucose which is quantified by using a commercial electrochemical glucose meter. GSH can be quantified by this method in the 100 nM to 10 μM concentration range, with a 34 nM limit of detection. Graphical abstract Glucose is loaded into the pores of mesoporous silica nanoparticles (MSNs). MnO 2 nanosheets are assembled on MSNs through electrostatic interactions. Glutathione (GSH) can reduce the nanosheets, and this results in the release of glucose which is quantified by using a commercial glucose meter.

  5. Anti-EGFR-iRGD recombinant protein conjugated silk fibroin nanoparticles for enhanced tumor targeting and antitumor efficiency

    Directory of Open Access Journals (Sweden)

    Bian X

    2016-05-01

    Full Text Available Xinyu Bian,* Puyuan Wu,* Huizi Sha, Hanqing Qian, Qing Wang, Lei Cheng, Yang Yang, Mi Yang, Baorui LiuComprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People’s Republic of China*These authors contributed equally to this workAbstract: In this study, we report a novel kind of targeting with paclitaxel (PTX-loaded silk fibroin nanoparticles conjugated with iRGD–EGFR nanobody recombinant protein (anti-EGFR-iRGD. The new nanoparticles (called A-PTX-SF-NPs were prepared using the carbodiimide-mediated coupling procedure and their characteristics were evaluated. The cellular cytotoxicity and cellular uptake of A-PTX-SF-NPs were also investigated. The results in vivo suggested that NPs conjugated with the recombinant protein exhibited more targeting and anti-neoplastic property in cells with high EGFR expression. In the in vivo antitumor efficacy assay, the A-PTX-SF-NPs group showed slower tumor growth and smaller tumor volumes than PTX-SF-NPs in a HeLa xenograft mouse model. A real-time near-infrared fluorescence imaging study showed that A-PTX-SF-NPs could target the tumor more effectively. These results suggest that the anticancer activity and tumor targeting of A-PTX-SF-NPs were superior to those of PTX-SF-NPs and may have the potential to be used for targeted delivery for tumor therapies. Keywords: EGFR, nanobody, iRGD, recombinant protein, targeting drug carriers, antitumor efficiency

  6. Impact of target mRNA structure on siRNA silencing efficiency: A large-scale study.

    Science.gov (United States)

    Gredell, Joseph A; Berger, Angela K; Walton, S Patrick

    2008-07-01

    The selection of active siRNAs is generally based on identifying siRNAs with certain sequence and structural properties. However, the efficiency of RNA interference has also been shown to depend on the structure of the target mRNA, primarily through studies using exogenous transcripts with well-defined secondary structures in the vicinity of the target sequence. While these studies provide a means for examining the impact of target sequence and structure independently, the predicted secondary structures for these transcripts are often not reflective of structures that form in full-length, native mRNAs where interactions can occur between relatively remote segments of the mRNAs. Here, using a combination of experimental results and analysis of a large dataset, we demonstrate that the accessibility of certain local target structures on the mRNA is an important determinant in the gene silencing ability of siRNAs. siRNAs targeting the enhanced green fluorescent protein were chosen using a minimal siRNA selection algorithm followed by classification based on the predicted minimum free energy structures of the target transcripts. Transfection into HeLa and HepG2 cells revealed that siRNAs targeting regions of the mRNA predicted to have unpaired 5'- and 3'-ends resulted in greater gene silencing than regions predicted to have other types of secondary structure. These results were confirmed by analysis of gene silencing data from previously published siRNAs, which showed that mRNA target regions unpaired at either the 5'-end or 3'-end were silenced, on average, approximately 10% more strongly than target regions unpaired in the center or primarily paired throughout. We found this effect to be independent of the structure of the siRNA guide strand. Taken together, these results suggest minimal requirements for nucleation of hybridization between the siRNA guide strand and mRNA and that both mRNA and guide strand structure should be considered when choosing candidate si

  7. Efficient photoreceptor-targeted gene expression in vivo by recombinant adeno-associated virus.

    Science.gov (United States)

    Flannery, J G; Zolotukhin, S; Vaquero, M I; LaVail, M M; Muzyczka, N; Hauswirth, W W

    1997-06-24

    We describe a general approach for achieving efficient and cell type-specific expression of exogenous genes in photoreceptor cells of the mammalian retina. Recombinant adeno-associated virus (rAAV) vectors were used to transfer the bacterial lacZ gene or a synthetic green fluorescent protein gene (gfp) to mouse or rat retinas after injection into the subretinal space. Using a proximal murine rod opsin promoter (+86 to -385) to drive expression, reporter gene product was found exclusively in photoreceptors, not in any other retinal cell type or in the adjacent retinal pigment epithelium. GFP-expressing photoreceptors typically encompassed 10-20% of the total retinal area after a single 2-microl injection. Photoreceptors were transduced with nearly 100% efficiency in the region directly surrounding the injection site. We estimate approximately 2.5 million photoreceptors were transduced as a result of the single subretinal inoculation. This level of gene transfer and expression suggests the feasibility of genetic therapy for retinal disease. The gfp-containing rAAV stock was substantially free of both adenovirus and wild-type AAV, as judged by plaque assay and infectious center assay, respectively. Thus, highly purified, helper virus-free rAAV vectors can achieve high-frequency tissue-specific transduction of terminally differentiated, postmitotic photoreceptor cells.

  8. Implementing targeted region capture sequencing for the clinical detection of Alagille syndrome: An efficient and cost‑effective method.

    Science.gov (United States)

    Huang, Tianhong; Yang, Guilin; Dang, Xiao; Ao, Feijian; Li, Jiankang; He, Yizhou; Tang, Qiyuan; He, Qing

    2017-11-01

    Alagille syndrome (AGS) is a highly variable, autosomal dominant disease that affects multiple structures including the liver, heart, eyes, bones and face. Targeted region capture sequencing focuses on a panel of known pathogenic genes and provides a rapid, cost‑effective and accurate method for molecular diagnosis. In a Chinese family, this method was used on the proband and Sanger sequencing was applied to validate the candidate mutation. A de novo heterozygous mutation (c.3254_3255insT p.Leu1085PhefsX24) of the jagged 1 gene was identified as the potential disease‑causing gene mutation. In conclusion, the present study suggested that target region capture sequencing is an efficient, reliable and accurate approach for the clinical diagnosis of AGS. Furthermore, these results expand on the understanding of the pathogenesis of AGS.

  9. Nanoparticle-neural stem cells for targeted ovarian cancer treatment: optimization of silica nanoparticles for efficient drug loading

    Science.gov (United States)

    Patel, Z.; Berlin, J.; Abidi, W.

    2018-02-01

    One of the drugs used to treat ovarian cancer is cisplatin. However, cisplatin kills normal surrounding tissue in addition to cancer cells. To improve tumor targeting efficiency, our lab uses neural stem cells (NSCs), which migrate directly to ovarian tumors. If free cisplatin is loaded into NSCs for targeted drug delivery, it will kill the NSCs. To prevent the drug cisplatin from killing both the NSCs and normal surrounding tissue, our lab synthesizes silica nanoparticles (SiNPs) that act as a protective carrier. The big picture here is to maximize efficiency of tumor targeting using NSCs and minimize toxicity to these NSCs using SiNPs. The goal of this project is to optimize the stability of SiNPs, which is important for efficient drug loading. To do this, the concentration of tetraethyl orthosilicate (TEOS), one of the main components of SiNPs, was varied. We hypothesized that more TEOS equates to more stable SiNPs because TEOS contributes carbon to SiNPs, and thus a tightly-packed chemical structure results in a stable particle. Then, the stability of the SiNPs were checked in cell media and phosphate buffered saline (PBS). Lastly, the SiNPs were analyzed for their porosity using the transmission electron microscope (TEM). TEM imaging showed white spots in the 200-800 μL TEOS batches and no white spots in the 1000-1800 μL TEOS batches. The white spots were pores, which indicate instability. We concluded that the ultimate factor that determines the stability of SiNPs (100 nm) is the concentration of organic substance.

  10. Simultaneous fitting of real-time PCR data with efficiency of amplification modeled as Gaussian function of target fluorescence

    Directory of Open Access Journals (Sweden)

    Lazar Andreas

    2008-02-01

    Full Text Available Abstract Background In real-time PCR, it is necessary to consider the efficiency of amplification (EA of amplicons in order to determine initial target levels properly. EAs can be deduced from standard curves, but these involve extra effort and cost and may yield invalid EAs. Alternatively, EA can be extracted from individual fluorescence curves. Unfortunately, this is not reliable enough. Results Here we introduce simultaneous non-linear fitting to determine – without standard curves – an optimal common EA for all samples of a group. In order to adjust EA as a function of target fluorescence, and still to describe fluorescence as a function of cycle number, we use an iterative algorithm that increases fluorescence cycle by cycle and thus simulates the PCR process. A Gauss peak function is used to model the decrease of EA with increasing amplicon accumulation. Our approach was validated experimentally with hydrolysis probe or SYBR green detection with dilution series of 5 different targets. It performed distinctly better in terms of accuracy than standard curve, DART-PCR, and LinRegPCR approaches. Based on reliable EAs, it was possible to detect that for some amplicons, extraordinary fluorescence (EA > 2.00 was generated with locked nucleic acid hydrolysis probes, but not with SYBR green. Conclusion In comparison to previously reported approaches that are based on the separate analysis of each curve and on modelling EA as a function of cycle number, our approach yields more accurate and precise estimates of relative initial target levels.

  11. DDR: Efficient computational method to predict drug–target interactions using graph mining and machine learning approaches

    KAUST Repository

    Olayan, Rawan S.

    2017-11-23

    Motivation Finding computationally drug-target interactions (DTIs) is a convenient strategy to identify new DTIs at low cost with reasonable accuracy. However, the current DTI prediction methods suffer the high false positive prediction rate. Results We developed DDR, a novel method that improves the DTI prediction accuracy. DDR is based on the use of a heterogeneous graph that contains known DTIs with multiple similarities between drugs and multiple similarities between target proteins. DDR applies non-linear similarity fusion method to combine different similarities. Before fusion, DDR performs a pre-processing step where a subset of similarities is selected in a heuristic process to obtain an optimized combination of similarities. Then, DDR applies a random forest model using different graph-based features extracted from the DTI heterogeneous graph. Using five repeats of 10-fold cross-validation, three testing setups, and the weighted average of area under the precision-recall curve (AUPR) scores, we show that DDR significantly reduces the AUPR score error relative to the next best start-of-the-art method for predicting DTIs by 34% when the drugs are new, by 23% when targets are new, and by 34% when the drugs and the targets are known but not all DTIs between them are not known. Using independent sources of evidence, we verify as correct 22 out of the top 25 DDR novel predictions. This suggests that DDR can be used as an efficient method to identify correct DTIs.

  12. Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis

    Science.gov (United States)

    Huang, Jia-Lin; Jiang, Gan; Song, Qing-Xiang; Gu, Xiao; Hu, Meng; Wang, Xiao-Lin; Song, Hua-Hua; Chen, Le-Pei; Lin, Ying-Ying; Jiang, Di; Chen, Jun; Feng, Jun-Feng; Qiu, Yong-Ming; Jiang, Ji-Yao; Jiang, Xin-Guo; Chen, Hong-Zhuan; Gao, Xiao-Ling

    2017-05-01

    Hyperactivated Ras regulates many oncogenic pathways in several malignant human cancers including glioblastoma and it is an attractive target for cancer therapies. Ras activation in cancer cells drives protein internalization via macropinocytosis as a key nutrient-gaining process. By utilizing this unique endocytosis pathway, here we create a biologically inspired nanostructure that can induce cancer cells to `drink drugs' for targeting activating transcription factor-5 (ATF5), an overexpressed anti-apoptotic transcription factor in glioblastoma. Apolipoprotein E3-reconstituted high-density lipoprotein is used to encapsulate the siRNA-loaded calcium phosphate core and facilitate it to penetrate the blood-brain barrier, thus targeting the glioblastoma cells in a macropinocytosis-dependent manner. The nanostructure carrying ATF5 siRNA exerts remarkable RNA-interfering efficiency, increases glioblastoma cell apoptosis and inhibits tumour cell growth both in vitro and in xenograft tumour models. This strategy of targeting the macropinocytosis caused by Ras activation provides a nanoparticle-based approach for precision therapy in glioblastoma and other Ras-activated cancers.

  13. Host-Guest Recognition-Assisted Electrochemical Release: Its Reusable Sensing Application Based on DNA Cross Configuration-Fueled Target Cycling and Strand Displacement Reaction Amplification.

    Science.gov (United States)

    Chang, Yuanyuan; Zhuo, Ying; Chai, Yaqin; Yuan, Ruo

    2017-08-15

    In this work, an elegantly designed host-guest recognition-assisted electrochemical release was established and applied in a reusable electrochemical biosensor for the detection of microRNA-182-5p (miRNA-182-5p), a prostate cancer biomarker in prostate cancer, based on the DNA cross configuration-fueled target cycling and strand displacement reaction (SDR) amplification. With such a design, the single target miRNA input could be converted to large numbers of single-stranded DNA (S1-Trp and S2-Trp) output, which could be trapped by cucurbit[8]uril methyl viologen (CB-8-MV 2+ ) based on the host-guest recognition, significantly enhancing the sensitivity for miRNA detection. Moreover, the nucleic acids products obtained from the process of cycling amplification could be utilized sufficiently, avoiding the waste and saving the experiment cost. Impressively, by resetting a settled voltage, the proposed biosensor could release S1-Trp and S2-Trp from the electrode surface, attributing that the guest ion methyl viologen (MV 2+ ) was reduced to MV +· under this settled voltage and formed a more-stable CB-8-MV +· -MV +· complex. Once O 2 was introduced in this system, MV +· could be oxidized to MV 2+ , generating the complex of CB-8-MV 2+ for capturing S1-Trp and S2-Trp again in only 5 min. As a result, the simple and fast regeneration of biosensor for target detection was realized on the base of electrochemical redox-driven assembly and release, overcoming the challenges of time-consuming, burdensome operations and expensive experimental cost in traditional reusable biosensors and updating the construction method for a reusable bisensor. Furthermore, the biosensor could be reused for more than 10 times with a regeneration rate of 93.20%-102.24%. After all, the conception of this work provides a novel thought for the construction of effective reusable biosensor to detect miRNA and other biomarkers and has great potential application in the area requiring the release of

  14. Cancer Patient T Cells Genetically Targeted to Prostate-Specific Membrane Antigen Specifically Lyse Prostate Cancer Cells and Release Cytokines in Response to Prostate-Specific Membrane Antigen

    Directory of Open Access Journals (Sweden)

    Michael C. Gong

    1999-06-01

    Full Text Available The expression of immunoglobulin-based artificial receptors in normal T lymphocytes provides a means to target lymphocytes to cell surface antigens independently of major histocompatibility complex restriction. Such artificial receptors have been previously shown to confer antigen-specific tumoricidal properties in murine T cells. We constructed a novel ζ chain fusion receptor specific for prostate-specific membrane antigen (PSMA termed Pz-1. PSMA is a cell-surface glycoprotein expressed on prostate cancer cells and the neovascular endothelium of multiple carcinomas. We show that primary T cells harvested from five of five patients with different stages of prostate cancer and transduced with the Pz-1 receptor readily lyse prostate cancer cells. Having established a culture system using fibroblasts that express PSMA, we next show that T cells expressing the Pz-1 receptor release cytokines in response to cell-bound PSMA. Furthermore, we show that the cytokine release is greatly augmented by B7.1-mediated costimulation. Thus, our findings support the feasibility of adoptive cell therapy by using genetically engineered T cells in prostate cancer patients and suggest that both CD4+ and CD8+ T lymphocyte functions can be synergistically targeted against tumor cells.

  15. WAYS TO IMPROVE THE EFFICIENCY OF THE PROGAM-TARGETED OF INFRASTRUCTURE OBJECTS IN RUSSIA

    Directory of Open Access Journals (Sweden)

    A. V. Frolova

    2014-01-01

    Full Text Available The relevance of this article due to the fact that the current situation inRussiais complemented by the negative eff ects of market reforms in the economy, initiated economic sanctions that have been taken against our country. In view of this, for the eff ective fi nancing costs of the federal budget for the development of transport infrastructure is a very topical issues related to the targeted program planning. The study aims to study ways to improve the effi ciency of program fi nancing expenditures of the federal budget for the development of transport infrastructure. The results will contribute to solving urgent problems in the development of transport infrastructure, high technology and housing sectors.

  16. Synthesis of taurine–fluorescein conjugate and evaluation of its retina-targeted efficiency in vitro

    Directory of Open Access Journals (Sweden)

    Meihong Huang

    2014-12-01

    Full Text Available In this work, retinal penetration of fluorescein was achieved in vitro by covalent attachment of taurine to fluorescein, yielding the F–Tau conjugate. Nuclear magnetic resonance (NMR and high resolution mass spectrometry (HRMS were used to confirm the successful synthesis of F–Tau. The cellular uptake of F–Tau in adult retinal pigment epithelial cells (ARPE-19 and human retinal microvascular endothelial cells (hRMECs was visualized via confocal scanning microscopy. The results indicated an improvement of solubility and a reduction of logP of F–Tau compared with fluorescein. As compared with fluorescein, F–Tau showed little toxicity, and was retained longer by cells in uptake experiments. F–Tau also displayed higher transepithelial permeabilities than fluorescein in ARPE-19 and hRMECs monolayer cells (P<0.05. These results showed that taurine may be a useful ligand for targeting small-molecule hydrophobic pharmaceuticals into the retina.

  17. Highly efficient magnetic targeting of mesenchymal stem cells in spinal cord injury

    Czech Academy of Sciences Publication Activity Database

    Vaněček, Václav; Zablotskyy, Vitaliy A.; Forostyak, Serhiy; Růžička, Jiří; Herynek, V.; Babič, Michal; Jendelová, Pavla; Kubinová, Šárka; Dejneka, Alexandr; Syková, Eva

    2012-01-01

    Roč. 7, 16 Jul (2012), s. 3719-3730 E-ISSN 1178-2013 R&D Projects: GA ČR(CZ) GAP304/12/1370; GA ČR GAP304/11/0731; GA ČR(CZ) GAP304/11/0189; GA ČR GAP304/11/0653; GA AV ČR IAA500390902 Institutional research plan: CEZ:AV0Z50390703; CEZ:AV0Z10100522; CEZ:AV0Z40500505 Keywords : nanoparticles * mesenchymal stem cells * magnetic targeting Subject RIV: FH - Neurology; BM - Solid Matter Physics ; Magnetism (FZU-D); FH - Neurology (UMCH-V) Impact factor: 3.463, year: 2012

  18. Polynomial algorithms for the Maximal Pairing Problem: efficient phylogenetic targeting on arbitrary trees

    Directory of Open Access Journals (Sweden)

    Stadler Peter F

    2010-06-01

    Full Text Available Abstract Background The Maximal Pairing Problem (MPP is the prototype of a class of combinatorial optimization problems that are of considerable interest in bioinformatics: Given an arbitrary phylogenetic tree T and weights ωxy for the paths between any two pairs of leaves (x, y, what is the collection of edge-disjoint paths between pairs of leaves that maximizes the total weight? Special cases of the MPP for binary trees and equal weights have been described previously; algorithms to solve the general MPP are still missing, however. Results We describe a relatively simple dynamic programming algorithm for the special case of binary trees. We then show that the general case of multifurcating trees can be treated by interleaving solutions to certain auxiliary Maximum Weighted Matching problems with an extension of this dynamic programming approach, resulting in an overall polynomial-time solution of complexity (n4 log n w.r.t. the number n of leaves. The source code of a C implementation can be obtained under the GNU Public License from http://www.bioinf.uni-leipzig.de/Software/Targeting. For binary trees, we furthermore discuss several constrained variants of the MPP as well as a partition function approach to the probabilistic version of the MPP. Conclusions The algorithms introduced here make it possible to solve the MPP also for large trees with high-degree vertices. This has practical relevance in the field of comparative phylogenetics and, for example, in the context of phylogenetic targeting, i.e., data collection with resource limitations.

  19. Octadecylamine-Mediated Versatile Coating of CoFe2O4 NPs for the Sustained Release of Anti-Inflammatory Drug Naproxen and in Vivo Target Selectivity.

    Science.gov (United States)

    Georgiadou, Violetta; Makris, George; Papagiannopoulou, Dionysia; Vourlias, Georgios; Dendrinou-Samara, Catherine

    2016-04-13

    Magnetic nanoparticles (MNPs) can play a distinct role in magnetic drug delivery via their distribution to the targeted area. The preparation of such MNPs is a challenging multiplex task that requires the optimization of size, magnetic, and surface properties for the achievement of desirable target selectivity, along with the sustained drug release as a prerequisite. In that context, CoFe2O4 MNPs with a small size of ∼7 nm and moderate saturation magnetization of ∼60 emu g(-1) were solvothermally synthesized in the presence of octadecylamine (ODA) with a view to investigate the functionalization route effect on the drug release. Synthetic regulations allowed us to prepare MNPs with aminated (AmMNPs) and amine-free (FAmMNPs) surface. The addition of the nonsteroidal anti-inflammatory drug with a carboxylate donor, Naproxen (NAP), was achieved by direct coupling with the NH2 groups, rendered by ODA, through the formation of an amide bond in the case of AmMNPs. In the case of FAmMNPs, indirect coupling of NAP was performed through an intermediate linker (polyethylenimine) and on PEG-ylated MNPs. FT-IR, (1)H NMR, (13)C NMR, and UV-vis data confirmed the addition of NAP, whereas diverse drug-release behavior was observed for the different functionalization approaches. The biological behavior of the MNPs@NAP was evaluated in vitro in rat serum and in vivo in mice, after radiolabeling with a γ-emitting radionuclide, (99m)Tc. The in vivo fate of MNPs@NAP carriers was in straightforward relation with the direct or indirect coupling of NAP. Furthermore, an inflammation was induced intramuscularly, where the directly coupled (99m)Tc-MNPs@NAP carriers showed increased accumulation at the inflammation site.

  20. High-efficiency targets for high-gain inertial confinement fusion

    International Nuclear Information System (INIS)

    Gardner, J.H.; Bodner, S.E.

    1986-01-01

    Rocket efficiencies as high as 15% are possible using short wavelength lasers and moderately high aspect ratio pellet designs. These designs are made possible by two recent breakthroughs in physics constraints. First is the development of the induced spatial incoherence (ISI) technique, which allows uniform illumination of the pellet and relaxes the constraint of thermal smoothing, permitting the use of short wavelength laser light. Second is the discovery that the Rayleigh--Taylor growth rate is considerably reduced at short laser wavelengths. By taking advantage of the reduced constraints imposed by nonuniform laser illumination and Rayleigh--Taylor instability, pellets using (1)/(4) μm laser light and initial aspect ratios of about 10 (with in flight aspect ratios of about 150--200) may produce energy gains as high as 200--250

  1. Targeted NGS meets expert clinical characterization: Efficient diagnosis of spastic paraplegia type 11

    Directory of Open Access Journals (Sweden)

    Cristina Castro-Fernández

    2015-06-01

    Full Text Available Next generation sequencing (NGS is transforming the diagnostic approach for neurological disorders, since it allows simultaneous analysis of hundreds of genes, even based on just a broad, syndromic patient categorization. However, such an approach bears a high risk of incidental and uncertain genetic findings. We report a patient with spastic paraplegia whose comprehensive neurological and imaging examination raised a high clinical suspicion of SPG11. Thus, although our NGS pipeline for this group of disorders includes gene panel and exome sequencing, in this sample only the spatacsin gene region was captured and subsequently searched for mutations. Two probably pathogenic variants were quickly and clearly identified, confirming the diagnosis of SPG11. This case illustrates how combination of expert clinical characterization with highly oriented NGS protocols leads to a fast, cost-efficient diagnosis, minimizing the risk of findings with unclear significance.

  2. Organic-Inorganic Hybrid Hollow Mesoporous Organosilica Nanoparticles for Efficient Ultrasound-Based Imaging and Controlled Drug Release

    Directory of Open Access Journals (Sweden)

    Xiaoqin Qian

    2014-01-01

    Full Text Available A novel anticancer drug delivery system with contrast-enhanced ultrasound-imaging performance was synthesized by a typical hard-templating method using monodispersed silica nanoparticles as the templates, which was based on unique molecularly organic/inorganic hybrid hollow periodic mesoporous organosilicas (HPMOs. The highly dispersed HPMOs show the uniform spherical morphology, large hollow interior, and well-defined mesoporous structures, which are very beneficial for ultrasound-based theranostics. The obtained HPMOs exhibit excellent performances in contrast-enhanced ultrasonography both in vitro and in vivo and can be used for the real-time determination of the progress of lesion tissues during the chemotherapeutic process. Importantly, hydrophobic paclitaxel- (PTX- loaded HPMOs combined with ultrasound irradiation show fast ultrasound responsiveness for controlled drug release and higher in vitro and in vivo tumor inhibition rates compared with free PTX and PTX-loaded HPMOs, which is due to the enhanced ultrasound-triggered drug release and ultrasound-induced cavitation effect. Therefore, the achieved novel HPMOs-based nanoparticle systems will find broad application potentials in clinically ultrasound-based imaging and auxiliary tumor chemotherapy.

  3. Gastrin-releasing peptide receptors in the central nervous system: role in brain function and as a drug target

    Directory of Open Access Journals (Sweden)

    Rafael eRoesler

    2012-12-01

    Full Text Available Neuropeptides acting on specific cell membrane receptors of the G protein-coupled receptor (GPCR superfamily regulate a range of important aspects of nervous and neuroendocrine function. Gastrin-releasing peptide (GRP is a mammalian neuropeptide that binds to the GRP receptor (GRPR, BB2. Increasing evidence indicates that GRPR-mediated signaling in the central nervous system (CNS plays an important role in regulating brain function, including aspects related to emotional responses, social interaction, memory, and feeding behavior. In addition, some alterations in GRP or GRPR expression or function have been described in patients with neurodegenerative, neurodevelopmental, and psychiatric disorders, as well as in brain tumors. Findings from preclinical models are consistent with the view that the GRPR might play a role in brain disorders, and raise the possibility that GRPR agonists might ameliorate cognitive and social deficits associated with neurological diseases, while antagonists may reduce anxiety and inhibit the growth of some types of brain cancer. Further preclinical and translational studies evaluating the potential therapeutic effects of GRPR ligands are warranted.

  4. Correction of acid beta-galactosidase deficiency in GM1 gangliosidosis human fibroblasts by retrovirus vector-mediated gene transfer: higher efficiency of release and cross-correction by the murine enzyme.

    Science.gov (United States)

    Sena-Esteves, M; Camp, S M; Alroy, J; Breakefield, X O; Kaye, E M

    2000-03-20

    Mutations in the lysosomal acid beta-galactosidase (EC 3.2.1.23) underlie two different disorders: GM1 gangliosidosis, which involves the nervous system and visceral organs to varying extents, and Morquio's syndrome type B (Morquio B disease), which is a skeletal-connective tissue disease without any CNS symptoms. This article shows that transduction of human GM1 gangliosidosis fibroblasts with retrovirus vectors encoding the human acid beta-galactosidase cDNA leads to complete correction of the enzymatic deficiency. The newly synthesized enzyme is correctly processed and targeted to the lysosomes in transduced cells. Cross-correction experiments using retrovirus-modified cells as enzyme donors showed, however, that the human enzyme is transferred at low efficiencies. Experiments using a different retrovirus vector carrying the human cDNA confirmed this observation. Transduction of human GM1 fibroblasts and mouse NIH 3T3 cells with a retrovirus vector encoding the mouse beta-galactosidase cDNA resulted in high levels of enzymatic activity. Furthermore, the mouse enzyme was found to be transferred to human cells at high efficiency. Enzyme activity measurements in medium conditioned by genetically modified cells suggest that the human beta-galactosidase enzyme is less efficiently released to the extracellular space than its mouse counterpart. This study suggests that lysosomal enzymes, contrary to the generalized perception in the field of gene therapy, may differ significantly in their properties and provides insights for design of future gene therapy interventions in acid beta-galactosidase deficiency.

  5. A lentivirus-free inducible CRISPR-Cas9 system for efficient targeting of human genes.

    Science.gov (United States)

    Bisht, Kamlesh; Grill, Sherilyn; Graniel, Jacqueline; Nandakumar, Jayakrishnan

    2017-08-01

    CRISPR-Cas9 is a cutting-edge tool for modifying genomes. The efficacy with which Cas9 recognizes its target has revolutionized the engineering of knockouts. However this efficacy complicates the knocking out of important genes in cultured cells. Unedited cells holding a survival advantage within an edited population can confound the knockout phenotype. Here we develop a HeLa-based system that overcomes this limitation, incorporating several attractive features. First, we use Flp-recombinase to generate clones stably integrated for Cas9 and guide RNAs, eliminating the possibility of unedited cells. Second, Cas9 can be induced uniformly in the clonal cultures using doxycycline to measure the knockout phenotype. Third, two genes can be simultaneously knocked out using this approach. Finally, by not involving lentiviruses, our method is appealing to a broad research audience. Using this methodology we generated an inducible AGO2-knockout cell line showing normal RNA interference in the absence of doxycycline. Upon induction of Cas9, the AGO2 locus was cleaved, the AGO2 protein was depleted, and RNA interference was compromised. In addition to generating inducible knockouts, our technology can be adapted to improve other applications of Cas9, including transcriptional/epigenetic modulation and visualization of cellular DNA loci. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  6. 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.

  7. Improved bioavailability of targeted Curcumin delivery efficiently regressed cardiac hypertrophy by modulating apoptotic load within cardiac microenvironment

    International Nuclear Information System (INIS)

    Ray, Aramita; Rana, Santanu; Banerjee, Durba; Mitra, Arkadeep; Datta, Ritwik; Naskar, Shaon; Sarkar, Sagartirtha

    2016-01-01

    Cardiomyocyte apoptosis acts as a prime modulator of cardiac hypertrophy leading to heart failure, a major cause of human mortality worldwide. Recent therapeutic interventions have focussed on translational applications of diverse pharmaceutical regimes among which, Curcumin (from Curcuma longa) is known to have an anti-hypertrophic potential but with limited pharmacological efficacies due to low aqueous solubility and poor bioavailability. In this study, Curcumin encapsulated by carboxymethyl chitosan (CMC) nanoparticle conjugated to a myocyte specific homing peptide was successfully delivered in bioactive form to pathological myocardium for effective regression of cardiac hypertrophy in a rat (Rattus norvegicus) model. Targeted nanotization showed higher cardiac bioavailability of Curcumin at a low dose of 5 mg/kg body weight compared to free Curcumin at 35 mg/kg body weight. Moreover, Curcumin/CMC-peptide treatment during hypertrophy significantly improved cardiac function by downregulating expression of hypertrophy marker genes (ANF, β-MHC), apoptotic mediators (Bax, Cytochrome-c) and activity of apoptotic markers (Caspase 3 and PARP); whereas free Curcumin in much higher dose showed minimal improvement during compromised cardiac function. Targeted Curcumin treatment significantly lowered p53 expression and activation in diseased myocardium via inhibited interaction of p53 with p300-HAT. Thus attenuated acetylation of p53 facilitated p53 ubiquitination and reduced the apoptotic load in hypertrophied cardiomyocytes; thereby limiting cardiomyocytes' need to enter the regeneration cycle during hypertrophy. This study elucidates for the first time an efficient targeted delivery regimen for Curcumin and also attributes towards probable mechanistic insight into its therapeutic potential as a cardio-protective agent for regression of cardiac hypertrophy. - Highlights: • Cardiomyocyte targeted Curcumin/CMC-peptide increases bioavailability of the drug.

  8. Reduced nighttime transpiration is a relevant breeding target for high water-use efficiency in grapevine.

    Science.gov (United States)

    Coupel-Ledru, Aude; Lebon, Eric; Christophe, Angélique; Gallo, Agustina; Gago, Pilar; Pantin, Florent; Doligez, Agnès; Simonneau, Thierry

    2016-08-09

    Increasing water scarcity challenges crop sustainability in many regions. As a consequence, the enhancement of transpiration efficiency (TE)-that is, the biomass produced per unit of water transpired-has become crucial in breeding programs. This could be achieved by reducing plant transpiration through a better closure of the stomatal pores at the leaf surface. However, this strategy generally also lowers growth, as stomatal opening is necessary for the capture of atmospheric CO2 that feeds daytime photosynthesis. Here, we considered the reduction in transpiration rate at night (En) as a possible strategy to limit water use without altering growth. For this purpose, we carried out a genetic analysis for En and TE in grapevine, a major crop in drought-prone areas. Using recently developed phenotyping facilities, potted plants of a cross between Syrah and Grenache cultivars were screened for 2 y under well-watered and moderate soil water deficit scenarios. High genetic variability was found for En under both scenarios and was primarily associated with residual diffusion through the stomata. Five quantitative trait loci (QTLs) were detected that underlay genetic variability in En Interestingly, four of them colocalized with QTLs for TE. Moreover, genotypes with favorable alleles on these common QTLs exhibited reduced En without altered growth. These results demonstrate the interest of breeding grapevine for lower water loss at night and pave the way to breeding other crops with this underexploited trait for higher TE.

  9. Energy efficient bead milling of microalgae: Effect of bead size on disintegration and release of proteins and carbohydrates.

    Science.gov (United States)

    Postma, P R; Suarez-Garcia, E; Safi, C; Yonathan, K; Olivieri, G; Barbosa, M J; Wijffels, R H; Eppink, M H M

    2017-01-01

    The disintegration of three industry relevant algae (Chlorella vulgaris, Neochloris oleoabundans and Tetraselmis suecica) was studied in a lab scale bead mill at different bead sizes (0.3-1mm). Cell disintegration, proteins and carbohydrates released into the water phase followed a first order kinetics. The process is selective towards proteins over carbohydrates during early stages of milling. In general, smaller beads led to higher kinetic rates, with a minimum specific energy consumption of ⩽0.47kWhkg DW -1 for 0.3mm beads. After analysis of the stress parameters (stress number and stress intensity), it appears that optimal disintegration and energy usage for all strains occurs in the 0.3-0.4mm range. During the course of bead milling, the native structure of the marker protein Rubisco was retained, confirming the mildness of the disruption process. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  10. LuIII parvovirus selectively and efficiently targets, replicates in, and kills human glioma cells.

    Science.gov (United States)

    Paglino, Justin C; Ozduman, Koray; van den Pol, Anthony N

    2012-07-01

    Because productive infection by parvoviruses requires cell division and is enhanced by oncogenic transformation, some parvoviruses may have potential utility in killing cancer cells. To identify the parvovirus(es) with the optimal oncolytic effect against human glioblastomas, we screened 12 parvoviruses at a high multiplicity of infection (MOI). MVMi, MVMc, MVM-G17, tumor virus X (TVX), canine parvovirus (CPV), porcine parvovirus (PPV), rat parvovirus 1A (RPV1A), and H-3 were relatively ineffective. The four viruses with the greatest oncolytic activity, LuIII, H-1, MVMp, and MVM-G52, were tested for the ability, at a low MOI, to progressively infect the culture over time, causing cell death at a rate higher than that of cell proliferation. LuIII alone was effective in all five human glioblastomas tested. H-1 progressively infected only two of five; MVMp and MVM-G52 were ineffective in all five. To investigate the underlying mechanism of LuIII's phenotype, we used recombinant parvoviruses with the LuIII capsid replacing the MVMp capsid or with molecular alteration of the P4 promoter. The LuIII capsid enhanced efficient replication and oncolysis in MO59J gliomas cells; other gliomas tested required the entire LuIII genome to exhibit enhanced infection. LuIII selectively infected glioma cells over normal glial cells in vitro. In mouse models, human glioblastoma xenografts were selectively infected by LuIII when administered intratumorally; LuIII reduced tumor growth by 75%. LuIII also had the capacity to selectively infect subcutaneous or intracranial gliomas after intravenous inoculation. Intravenous or intracranial LuIII caused no adverse effects. Intracranial LuIII caused no infection of mature mouse neurons or glia in vivo but showed a modest infection of developing neurons.

  11. Two-step membrane binding by the bacterial SRP receptor enable efficient and accurate Co-translational protein targeting.

    Science.gov (United States)

    Hwang Fu, Yu-Hsien; Huang, William Y C; Shen, Kuang; Groves, Jay T; Miller, Thomas; Shan, Shu-Ou

    2017-07-28

    The signal recognition particle (SRP) delivers ~30% of the proteome to the eukaryotic endoplasmic reticulum, or the bacterial plasma membrane. The precise mechanism by which the bacterial SRP receptor, FtsY, interacts with and is regulated at the target membrane remain unclear. Here, quantitative analysis of FtsY-lipid interactions at single-molecule resolution revealed a two-step mechanism in which FtsY initially contacts membrane via a Dynamic mode, followed by an SRP-induced conformational transition to a Stable mode that activates FtsY for downstream steps. Importantly, mutational analyses revealed extensive auto-inhibitory mechanisms that prevent free FtsY from engaging membrane in the Stable mode; an engineered FtsY pre-organized into the Stable mode led to indiscriminate targeting in vitro and disrupted FtsY function in vivo. Our results show that the two-step lipid-binding mechanism uncouples the membrane association of FtsY from its conformational activation, thus optimizing the balance between the efficiency and fidelity of co-translational protein targeting.

  12. Mitochondrially targeted vitamin E succinate efficiently kills breast tumour-initiating cells in a complex II-dependent manner

    International Nuclear Information System (INIS)

    Yan, Bing; Stantic, Marina; Zobalova, Renata; Bezawork-Geleta, Ayenachew; Stapelberg, Michael; Stursa, Jan; Prokopova, Katerina; Dong, Lanfeng; Neuzil, Jiri

    2015-01-01

    Accumulating evidence suggests that breast cancer involves tumour-initiating cells (TICs), which play a role in initiation, metastasis, therapeutic resistance and relapse of the disease. Emerging drugs that target TICs are becoming a focus of contemporary research. Mitocans, a group of compounds that induce apoptosis of cancer cells by destabilising their mitochondria, are showing their potential in killing TICs. In this project, we investigated mitochondrially targeted vitamin E succinate (MitoVES), a recently developed mitocan, for its in vitro and in vivo efficacy against TICs. The mammosphere model of breast TICs was established by culturing murine NeuTL and human MCF7 cells as spheres. This model was verified by stem cell marker expression, tumour initiation capacity and chemotherapeutic resistance. Cell susceptibility to MitoVES was assessed and the cell death pathway investigated. In vivo efficacy was studied by grafting NeuTL TICs to form syngeneic tumours. Mammospheres derived from NeuTL and MCF7 breast cancer cells were enriched in the level of stemness, and the sphere cells featured altered mitochondrial function. Sphere cultures were resistant to several established anti-cancer agents while they were susceptible to MitoVES. Killing of mammospheres was suppressed when the mitochondrial complex II, the molecular target of MitoVES, was knocked down. Importantly, MitoVES inhibited progression of syngeneic HER2 high tumours derived from breast TICs by inducing apoptosis in tumour cells. These results demonstrate that using mammospheres, a plausible model for studying TICs, drugs that target mitochondria efficiently kill breast tumour-initiating cells. The online version of this article (doi:10.1186/s12885-015-1394-7) contains supplementary material, which is available to authorized users

  13. Fabrication and application of a magnetic-targeting and controlled-release system using ST68-based microbubbles

    International Nuclear Information System (INIS)

    Xing Zhanwen; Ke Hengte; Wang Jinrui; Zhao Bo; Qu Enze; Yue Xiuli; Dai Zhifei

    2013-01-01

    Objective: To manufacture magnetic microbubbles with dual-response to ultrasound and magnetic fields. Methods: Microbubbles of ultrasound contrast agent (ST68) based on a surfactant were prepared by the acoustic cavitation method. Fe 3 O 4 magnetic nanoparticles with negative charge were synthesized using the polyol procedure. Magnetic microbubbles were generated by depositing polyethylenimine and Fe 3 O 4 magnetic nanoparticles alternately onto the microbubbles using the layer-by-layer self-assembly. In vitro ultrasonography was performed on a silicone tube with/without magnetic microbubbles (3 × 10 8 /ml) by a self-made device to observe the movement of magnetic microbubbles under the effects of magnetic field. In vivo imaging was performed on the kidney of New Zealand rabbits before and after the injection of magnetic microbubbles. Results: The Fe 3 O 4 nanoparticles carried a stable negative charge of (-24.6 ± 6.7) mV and more than 98% of the particles were less than 8 μm in diameter, meeting the size requirement of an ultrasound contrast agent for intravenous administration. There was no echoic signal in the silicone tube before injection of magnetic microbubbles, but there were strong echoic signals after injection. After applying a magnetic field, the magnetic microbubbles moved along the direction of the magnetic flux. In vivo ultrasound imaging could not visualize the kidney before injection of magnetic microbubbles, but could remarkably visualize the kidney after injection. Conclusions: The magnetic microbubbles exhibit favorable magnetic targeting and ultrasound contrast enhancement characteristics. Such properties may serve as the foundation to study their potential for simultaneous diagnosis and treatment in the future. (authors)

  14. Supply and demand: application of Lean Six Sigma methods to improve drug round efficiency and release nursing time.

    Science.gov (United States)

    Kieran, Maríosa; Cleary, Mary; De Brún, Aoife; Igoe, Aileen

    2017-10-01

    To improve efficiency, reduce interruptions and reduce the time taken to complete oral drug rounds. Lean Six Sigma methods were applied to improve drug round efficiency using a pre- and post-intervention design. A 20-bed orthopaedic ward in a large teaching hospital in Ireland. Pharmacy, nursing and quality improvement staff. A multifaceted intervention was designed which included changes in processes related to drug trolley organization and drug supply planning. A communications campaign aimed at reducing interruptions during nurse-led during rounds was also developed and implemented. Average number of interruptions, average drug round time and variation in time taken to complete drug round. At baseline, the oral drug round took an average of 125 min. Following application of Lean Six Sigma methods, the average drug round time decreased by 51 min. The average number of interruptions per drug round reduced from an average of 12 at baseline to 11 following intervention, with a 75% reduction in drug supply interruptions. Lean Six Sigma methodology was successfully employed to reduce interruptions and to reduce time taken to complete the oral drug round. © The Author 2017. Published by Oxford University Press in association with the International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  15. HSA-based multi-target combination therapy: regulating drugs' release from HSA and overcoming single drug resistance in a breast cancer model.

    Science.gov (United States)

    Gou, Yi; Zhang, Zhenlei; Li, Dongyang; Zhao, Lei; Cai, Meiling; Sun, Zhewen; Li, Yongping; Zhang, Yao; Khan, Hamid; Sun, Hongbing; Wang, Tao; Liang, Hong; Yang, Feng

    2018-11-01

    Multi-drug delivery systems, which may be promising solution to overcome obstacles, have limited the clinical success of multi-drug combination therapies to treat cancer. To this end, we used three different anticancer agents, Cu(BpT)Br, NAMI-A, and doxorubicin (DOX), to build human serum albumin (HSA)-based multi-drug delivery systems in a breast cancer model to investigate the therapeutic efficacy of overcoming single drug (DOX) resistance to cancer cells in vivo, and to regulate the drugs' release from HSA. The HSA complex structure revealed that NAMI-A and Cu(BpT)Br bind to the IB and IIA sub-domain of HSA by N-donor residue replacing a leaving group and coordinating to their metal centers, respectively. The MALDI-TOF mass spectra demonstrated that one DOX molecule is conjugated with lysine of HSA by a pH-sensitive linker. Furthermore, the release behavior of three agents form HSA can be regulated at different pH levels. Importantly, in vivo results revealed that the HSA-NAMI-A-Cu(BpT)Br-DOX complex not only increases the targeting ability compared with a combination of the three agents (the NAMI-A/Cu(BpT)Br/DOX mixture), but it also overcomes DOX resistance to drug-resistant breast cancer cell lines.

  16. Coaxial Electrospinning with Mixed Solvents: From Flat to Round Eudragit L100 Nanofibers for Better Colon-Targeted Sustained Drug Release Profiles

    Directory of Open Access Journals (Sweden)

    Deng-Guang Yu

    2014-01-01

    Full Text Available A modified coaxial electrospinning process was developed for creating drug-loaded composite nanofibers. Using a mixed solvent of ethanol and N,N-dimethylacetamide as a sheath fluid, the electrospinning of a codissolving solution of diclofenac sodium (DS and Eudragit L100 (EL100 could run smoothly and continuously without any clogging. A series of analyses were undertaken to characterize the resultant nanofibers from both the modified coaxial process and a one-fluid electrospinning in terms of their morphology, physical form of the components, and their functional performance. Compared with those from the one-fluid electrospinning, the DS-loaded EL100 fibers from the modified coaxial process were rounder and smoother and possessed higher quality in terms of diameter and distribution with the DS existing in the EL100 matrix in an amorphous state; they also provided a better colon-targeted sustained drug release profile with a longer release time period. The modified coaxial process not only can smooth the electrospinning process to prevent clogging of spinneret, but also is a useful tool to tailor the shape of electrospun nanofibers and thus endow them improved functions.

  17. Efficient extreme ultraviolet plasma source generated by a CO2 laser and a liquid xenon microjet target

    Science.gov (United States)

    Ueno, Yoshifumi; Ariga, Tatsuya; Soumagne, George; Higashiguchi, Takeshi; Kubodera, Shoichi; Pogorelsky, Igor; Pavlishin, Igor; Stolyarov, Daniil; Babzien, Marcus; Kusche, Karl; Yakimenko, Vitaly

    2007-05-01

    We demonstrated efficacy of a CO2-laser-produced xenon plasma in the extreme ultraviolet (EUV) spectral region at 13.5nm at variable laser pulse widths between 200ps and 25ns. The plasma target was a 30μm liquid xenon microjet. To ensure the optimum coupling of CO2 laser energy with the plasma, they applied a prepulse yttrium aluminum garnet laser. The authors measured the conversion efficiency (CE) of the 13.5nm EUV emission for different pulse widths of the CO2 laser. A maximum CE of 0.6% was obtained for a CO2 laser pulse width of 25ns at an intensity of 5×1010W/cm2.

  18. Efficient extreme ultraviolet plasma source generated by a CO2 laser and a liquid xenon microjet target

    International Nuclear Information System (INIS)

    Ueno, Yoshifumi; Ariga, Tatsuya; Soumagne, George; Higashiguchi, Takeshi; Kubodera, Shoichi; Pogorelsky, Igor; Pavlishin, Igor; Stolyarov, Daniil; Babzien, Marcus; Kusche, Karl; Yakimenko, Vitaly

    2007-01-01

    We demonstrated efficacy of a CO 2 -laser-produced xenon plasma in the extreme ultraviolet (EUV) spectral region at 13.5 nm at variable laser pulse widths between 200 ps and 25 ns. The plasma target was a 30 μm liquid xenon microjet. To ensure the optimum coupling of CO 2 laser energy with the plasma, they applied a prepulse yttrium aluminum garnet laser. The authors measured the conversion efficiency (CE) of the 13.5 nm EUV emission for different pulse widths of the CO 2 laser. A maximum CE of 0.6% was obtained for a CO 2 laser pulse width of 25 ns at an intensity of 5x10 10 W/cm 2

  19. Efficient approach for determining four-dimensional computed tomography-based internal target volume in stereotactic radiotherapy of lung cancer

    International Nuclear Information System (INIS)

    Yeo, Seung Gu; Kim, Eun Seog

    2013-01-01

    This study aimed to investigate efficient approaches for determining internal target volume (ITV) from four-dimensional computed tomography (4D CT) images used in stereotactic body radiotherapy (SBRT) for patients with early-stage non-small cell lung cancer (NSCLC). 4D CT images were analyzed for 15 patients who received SBRT for stage I NSCLC. Three different ITVs were determined as follows: combining clinical target volume (CTV) from all 10 respiratory phases (ITV 10Phases ); combining CTV from four respiratory phases, including two extreme phases (0% and 50%) plus two intermediate phases (20% and 70%) (ITV 4Phases ); and combining CTV from two extreme phases (ITV 2Phases ). The matching index (MI) of ITV 4Phases and ITV 2Phases was defined as the ratio of ITV 4Phases and ITV 2Phases , respectively, to the ITV 10Phases . The tumor motion index (TMI) was defined as the ratio of ITV 10Phases to CTV mean , which was the mean of 10 CTVs delineated on 10 respiratory phases. The ITVs were significantly different in the order of ITV 10Phases , ITV 4Phases , and ITV 2Phases (all p 4Phases was significantly higher than that of ITV 2Phases (p 4Phases was inversely related to TMI (r = -0.569, p = 0.034). In a subgroup with low TMI (n = 7), ITV 4Phases was not statistically different from ITV 10Phases (p = 0.192) and its MI was significantly higher than that of ITV 2Phases (p = 0.016). The ITV 4Phases may be an efficient approach alternative to optimal ITV 10Phases in SBRT for early-stage NSCLC with less tumor motion.

  20. Low-debris, efficient laser-produced plasma extreme ultraviolet source by use of a regenerative liquid microjet target containing tin dioxide (SnO2) nanoparticles

    Science.gov (United States)

    Higashiguchi, Takeshi; Dojyo, Naoto; Hamada, Masaya; Sasaki, Wataru; Kubodera, Shoichi

    2006-05-01

    We demonstrated a low-debris, efficient laser-produced plasma extreme ultraviolet (EUV) source by use of a regenerative liquid microjet target containing tin-dioxide (SnO2) nanoparticles. By using a low SnO2 concentration (6%) solution and dual laser pulses for the plasma control, we observed the EUV conversion efficiency of 1.2% with undetectable debris.

  1. Low-debris, efficient laser-produced plasma extreme ultraviolet source by use of a regenerative liquid microjet target containing tin dioxide (SnO2) nanoparticles

    International Nuclear Information System (INIS)

    Higashiguchi, Takeshi; Dojyo, Naoto; Hamada, Masaya; Sasaki, Wataru; Kubodera, Shoichi

    2006-01-01

    We demonstrated a low-debris, efficient laser-produced plasma extreme ultraviolet (EUV) source by use of a regenerative liquid microjet target containing tin-dioxide (SnO 2 ) nanoparticles. By using a low SnO 2 concentration (6%) solution and dual laser pulses for the plasma control, we observed the EUV conversion efficiency of 1.2% with undetectable debris

  2. Korea's emission trading scheme and policy design issues to achieve market-efficiency and abatement targets

    International Nuclear Information System (INIS)

    Park, Hojeong; Hong, Won Kyung

    2014-01-01

    In 2008, the government of Republic of Korea (Korea) announced the national abatement target aiming at 30% reductions from the Business-as-Usual projections by 2020. Accordingly, the Emission Trading Scheme (ETS) will be implemented from 2015 onwards. As ETS performance substantially depends on the structural design, it is critically important to examine the details of Korean ETS for the achievement of cost effectiveness and concurrent development of an active emission trading market. This paper addresses several policy design issues for this purpose. After providing an overview on the current framework of Korean ETS, we propose ways to achieve flexibility, consistency and market efficiency of the program in consideration of the preexisting policies. Issues in policy design are discussed by focusing on allowance allocation, market stabilization measures and price mechanism in the emission and energy markets in Korea. This paper will serve as a practical guideline for establishing sustainable and market-efficient Korean ETS that can be compatible with the international standards as in the EU ETS. - Highlights: • Emission Trading Scheme (ETS) will be implemented from 2015 in Korea to reduce CO 2 . • ETS performance substantially depends on structural design. • We provide policy overview on the current framework of Korean ETS. • Several policy design issues are discussed for developing policy consistency. • We focus on allowance allocation, allowance reserve and market stabilization measures

  3. cRGD-installed docetaxel-loaded mertansine prodrug micelles: redox-triggered ratiometric dual drug release and targeted synergistic treatment of B16F10 melanoma

    Science.gov (United States)

    Zhong, Ping; Qiu, Min; Zhang, Jian; Sun, Huanli; Cheng, Ru; Deng, Chao; Meng, Fenghua; Zhong, Zhiyuan

    2017-07-01

    Combinatorial chemotherapy, which has emerged as a promising treatment modality for intractable cancers, is challenged by a lack of tumor-targeting, robust and ratiometric dual drug release systems. Here, docetaxel-loaded cRGD peptide-decorated redox-activable micellar mertansine prodrug (DTX-cRGD-MMP) was developed for targeted and synergistic treatment of B16F10 melanoma-bearing C57BL/6 mice. DTX-cRGD-MMP exhibited a small size of ca. 49 nm, high DTX and DM1 loading, low drug leakage under physiological conditions, with rapid release of both DTX and DM1 under a cytoplasmic reductive environment. Notably, MTT and flow cytometry assays showed that DTX-cRGD-MMP brought about a synergistic antitumor effect to B16F10 cancer cells, with a combination index of 0.37 and an IC50 over 3- and 13-fold lower than cRGD-MMP (w/o DTX) and DTX-cRGD-Ms (w/o DM1) controls, respectively. In vivo studies revealed that DTX-cRGD-MMP had a long circulation time and a markedly improved accumulation in the B16F10 tumor compared with the non-targeting DTX-MMP control (9.15 versus 3.13% ID/g at 12 h post-injection). Interestingly, mice treated with DTX-cRGD-MMP showed almost complete growth inhibition of B16F10 melanoma, with tumor inhibition efficacy following an order of DTX-cRGD-MMP > DTX-MMP (w/o cRGD) > cRGD-MMP (w/o DTX) > DTX-cRGD-Ms (w/o DM1) > free DTX. Consequently, DTX-cRGD-MMP significantly improved the survival rates of B16F10 melanoma-bearing mice. Importantly, DTX-cRGD-MMP caused little adverse effects as revealed by mice body weights and histological analyses. The combination of two mitotic inhibitors, DTX and DM1, appears to be an interesting approach for effective cancer therapy.

  4. Gastrin-releasing peptide receptor-targeted gadolinium oxide-based multifunctional nanoparticles for dual magnetic resonance/fluorescent molecular imaging of prostate cancer

    Directory of Open Access Journals (Sweden)

    Cui DT

    2017-09-01

    Full Text Available Danting Cui,1 Xiaodan Lu,1 Chenggong Yan,1 Xiang Liu,1 Meirong Hou,1 Qi Xia,2 Yikai Xu,1 Ruiyuan Liu2,3 1Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People’s Republic of China; 3School of Biomedical Engineering, Southern Medical University, Guangzhou, People’s Republic of China Abstract: Bombesin (BBN, an analog of gastrin-releasing peptide (GRP, specifically binds to GRP receptors, which are overexpressed in human prostate cancer (PC. Here, we synthesized a BBN-modified gadolinium oxide (Gd2O3 nanoprobe containing fluorescein (Gd2O3-5(6-carboxyfluorescein [FI]-polyethylene glycol [PEG]-BBN for targeted magnetic resonance (MR/optical dual-modality imaging of PC. The Gd2O3-FI-PEG-BBN nanoparticles exhibited a relatively uniform particle size with an average diameter of 52.3 nm and spherical morphology as depicted by transmission electron microscopy. The longitudinal relaxivity (r1 of Gd2O3-FI-PEG-BBN (r1 =4.23 mM–1s–1 is comparable to that of clinically used Magnevist (Gd-DTPA. Fluorescence microscopy and in vitro cellular MRI demonstrated GRP receptor-specific and enhanced cellular uptake of the Gd2O3-FI-PEG-BBN in PC-3 tumor cells. Moreover, Gd2O3-FI-PEG-BBN showed more remarkable contrast enhancement than the corresponding nontargeted Gd2O3-FI-PEG according to in vivo MRI and fluorescent imaging. Tumor immunohistochemical analysis further demonstrated improved accumulation of the targeted nanoprobe in tumors. BBN-conjugated Gd2O3 may be a promising nanoplatform for simultaneous GRP receptor-targeted molecular cancer diagnosis and antitumor drug delivery in future clinical applications. Keywords: magnetic resonance imaging, gadolinium oxide, bombesin, gastrin-releasing peptide receptor, molecular imaging

  5. Evaluation of an Efficient Approach for Target Tracking from Acoustic Imagery for the Perception System of an Autonomous Underwater Vehicle

    Directory of Open Access Journals (Sweden)

    Sebastián A. Villar

    2014-02-01

    Full Text Available This article describes the core algorithms of the perception system to be included within an autonomous underwater vehicle (AUV. This perception system is based on the acoustic data acquired from side scan sonar (SSS. These data should be processed in an efficient time, so that the perception system is able to detect and recognize a predefined target. This detection and recognition outcome is therefore an important piece of knowledge for the AUVs dynamic mission planner (DMP. Effectively, the DMP should propose different trajectories, navigation depths and other parameters that will change the robot's behaviour according to the perception system output. Hence, the time in which to make a decision is critical in order to assure safe robot operation and to acquire good quality data; consequently, the efficiency of the on-line image processing from acoustic data is a key issue. Current techniques for acoustic data processing are time and computationally intensive. Hence, it was decided to process data coming from a SSS using a technique that is used for radars, due to its efficiency and its amenability to on-line processing. The engineering problem to solve in this case was underwater pipeline tracking for routine inspections in the off-shore industry. Then, an automatic oil pipeline detection system was developed borrowing techniques from the processing of radar measurements. The radar technique is known as Cell Average – Constant False Alarm Rate (CA – CFAR. With a slight variation of the algorithms underlying this radar technique, which consisted of the previous accumulation of partial sums, a great improvement in computing time and effort was achieved. Finally, a comparison with previous approaches over images acquired with a SSS from a vessel in the Salvador de Bahia bay in Brazil showed the feasibility of using this on-board technique for AUV perception.

  6. Gas release-based prescreening combined with reversed-phase HPLC quantitation for efficient selection of high-γ-aminobutyric acid (GABA)-producing lactic acid bacteria.

    Science.gov (United States)

    Wu, Qinglong; Shah, Nagendra P

    2015-02-01

    High γ-aminobutyric acid (GABA)-producing lactobacilli are promising for the manufacture of GABA-rich foods and to synthesize GRAS (generally recognized as safe)-grade GABA. However, common chromatography-based screening is time-consuming and inefficient. In the present study, Korean kimchi was used as a model of lactic acid-based fermented foods, and a gas release-based prescreening of potential GABA producers was developed. The ability to produce GABA by potential GABA producers in de Man, Rogosa, and Sharpe medium supplemented with or without monosodium glutamate was further determined by HPLC. Based on the results, 9 isolates were regarded as high GABA producers, and were further genetically identified as Lactobacillus brevis based on the sequences of 16S rRNA gene. Gas release-based prescreening combined with reversed-phase HPLC confirmation was an efficient and cost-effective method to identify high-GABA-producing LAB, which could be good candidates for probiotics. The GABA that is naturally produced by these high-GABA-producing LAB could be used as a food additive. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  7. Investigations on ideal mode of cell disruption in extremely halophilic Actinopolyspora halophila (MTCC 263 for efficient release of glycine betaine and trehalose

    Directory of Open Access Journals (Sweden)

    Jayaranjan R. Kar

    2015-03-01

    Full Text Available Actinopolyspora halophila produces glycine betaine and trehalose intracellularly in considerable quantities. These biomolecules are commercially important as they have applications in food, pharmaceuticals, and agricultural sector. Development of an efficient cell disruption technique is an important step for the release of these biomolecules. In this study, various cell disruption methods such as chemical, enzymatic, physico-mechanical and physical methods were evaluated. Cell disruption by osmotic shock was found to be the best suited method for A. halophila which also has a potential to be industrially scaled up. Cell bursting pressure that is generated during osmotic shock in A. halophila was computed using Morse equation and was found to be π = 238.37 ± 29.54 atm or 2.35 ± 0.29 kPa. In addition, it was found that osmotic shock followed a first order release rate kinetics in A. halophila. The findings can be used for commercially important biomolecules from other halophilic and/or halotolerant microbes.

  8. Gastrin-releasing peptide receptor-based targeting using bombesin analogues is superior to metabolism-based targeting using choline for in vivo imaging of human prostate cancer xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Schroeder, Rogier P.J. [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands); Erasmus MC, Department of Urology, Rotterdam (Netherlands); Weerden, W.M. van; Bangma, C.H.; Reneman, S. [Erasmus MC, Department of Urology, Rotterdam (Netherlands); Krenning, E.P.; Berndsen, S.; Grievink-de Ligt, C.H.; Groen, H.C.; Blois, E. de; Breeman, W.A.P.; Jong, M. de [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands)

    2011-07-15

    Prostate cancer (PC) is a major health problem. Overexpression of the gastrin-releasing peptide receptor (GRPR) in PC, but not in the hyperplastic prostate, provides a promising target for staging and monitoring of PC. Based on the assumption that cancer cells have increased metabolic activity, metabolism-based tracers are also being used for PC imaging. We compared GRPR-based targeting using the {sup 68}Ga-labelled bombesin analogue AMBA with metabolism-based targeting using {sup 18}F-methylcholine ({sup 18}F-FCH) in nude mice bearing human prostate VCaP xenografts. PET and biodistribution studies were performed with both {sup 68}Ga-AMBA and {sup 18}F-FCH in all VCaP tumour-bearing mice, with PC-3 tumour-bearing mice as reference. Scanning started immediately after injection. Dynamic PET scans were reconstructed and analysed quantitatively. Biodistribution of tracers and tissue uptake was expressed as percent of injected dose per gram tissue (%ID/g). All tumours were clearly visualized using {sup 68}Ga-AMBA. {sup 18}F-FCH showed significantly less contrast due to poor tumour-to-background ratios. Quantitative PET analyses showed fast tumour uptake and high retention for both tracers. VCaP tumour uptake values determined from PET at steady-state were 6.7 {+-} 1.4%ID/g (20-30 min after injection, N = 8) for {sup 68}Ga-AMBA and 1.6 {+-} 0.5%ID/g (10-20 min after injection, N = 8) for {sup 18}F-FCH, which were significantly different (p <0.001). The results in PC-3 tumour-bearing mice were comparable. Biodistribution data were in accordance with the PET results showing VCaP tumour uptake values of 9.5 {+-} 4.8%ID/g (N = 8) for {sup 68}Ga-AMBA and 2.1 {+-} 0.4%ID/g (N = 8) for {sup 18}F-FCH. Apart from the GRPR-expressing organs, uptake in all organs was lower for {sup 68}Ga-AMBA than for {sup 18}F-FCH. Tumour uptake of {sup 68}Ga-AMBA was higher while overall background activity was lower than observed for {sup 18}F-FCH in the same PC-bearing mice. These results

  9. Studies of the efficiency of nitrogen placement methods and slow release nitrogen fertilizers for rice and wheat, using N-15 labelled fertilizers

    International Nuclear Information System (INIS)

    Shaukat, A.

    1979-12-01

    A series of experiments with rice and wheat were carried out to study the efficiency of nitrogen placement methods and slow-release nitrogen fertilizers for these two crops using N-15-labelled fertilizer. The results show that (1) reduced N levels, of the order of 75 percent of the full recommended dose, are equally efficient as the full dose for wheat. The yield of rice grain increased with the increased dose of nitrogen; (2) Point placement of fertilizers for rice was superior to broadcast application in terms of uptake and yield. For optimum yield of wheat grain, urea should perferably be applied as a single dose banded between the rows at 5 cm depth or by broadcasting and incorporation in the soil at the time of sowing; (3) Sulphur-coated urea (SCU) at a comparable dose and mode of application gave better yields of rice grain than the application of urea and IBDU (Isobutylidine Diurea); (4) More nitrogen was taken up by wheat when SCU was applied. The best uptake was when it was applied half at sowing and half at tillering. The nitrogen uptake from the SCU by point placement was better for rice plants than broadcast application and was higher in magnitude than the IBDU

  10. Increasing on-target cleavage efficiency for CRISPR/Cas9-induced large fragment deletion in Myxococcus xanthus.

    Science.gov (United States)

    Yang, Ying-Jie; Wang, Ye; Li, Zhi-Feng; Gong, Ya; Zhang, Peng; Hu, Wen-Chao; Sheng, Duo-Hong; Li, Yue-Zhong

    2017-08-16

    The CRISPR/Cas9 system is a powerful tool for genome editing, in which the sgRNA binds and guides the Cas9 protein for the sequence-specific cleavage. The protocol is employable in different organisms, but is often limited by cell damage due to the endonuclease activity of the introduced Cas9 and the potential off-target DNA cleavage from incorrect guide by the 20 nt spacer. In this study, after resolving some critical limits, we have established an efficient CRISPR/Cas9 system for the deletion of large genome fragments related to the biosynthesis of secondary metabolites in Myxococcus xanthus cells. We revealed that the high expression of a codon-optimized cas9 gene in M. xanthus was cytotoxic, and developed a temporally high expression strategy to reduce the cell damage from high expressions of Cas9. We optimized the deletion protocol by using the tRNA-sgRNA-tRNA chimeric structure to ensure correct sgRNA sequence. We found that, in addition to the position-dependent nucleotide preference, the free energy of a 20 nt spacer was a key factor for the deletion efficiency. By using the developed protocol, we achieved the CRISPR/Cas9-induced deletion of large biosynthetic gene clusters for secondary metabolites in M. xanthus DK1622 and its epothilone-producing mutant. The findings and the proposals described in this paper were suggested to be workable in other organisms, for example, other Gram negative bacteria with high GC content.

  11. Respiration and nitrogen assimilation: targeting mitochondria-associated metabolism as a means to enhance nitrogen use efficiency.

    Science.gov (United States)

    Foyer, Christine H; Noctor, Graham; Hodges, Michael

    2011-02-01

    Considerable advances in our understanding of the control of mitochondrial metabolism and its interactions with nitrogen metabolism and associated carbon/nitrogen interactions have occurred in recent years, particularly highlighting important roles in cellular redox homeostasis. The tricarboxylic acid (TCA) cycle is a central metabolic hub for the interacting pathways of respiration, nitrogen assimilation, and photorespiration, with components that show considerable flexibility in relation to adaptations to the different functions of mitochondria in photosynthetic and non-photosynthetic cells. By comparison, the operation of the oxidative pentose phosphate pathway appears to represent a significant limitation to nitrogen assimilation in non-photosynthetic tissues. Valuable new insights have been gained concerning the roles of the different enzymes involved in the production of 2-oxoglutarate (2-OG) for ammonia assimilation, yielding an improved understanding of the crucial role of cellular energy balance as a broker of co-ordinate regulation. Taken together with new information on the mechanisms that co-ordinate the expression of genes involved in organellar functions, including energy metabolism, and the potential for exploiting the existing flexibility for NAD(P)H utilization in the respiratory electron transport chain to drive nitrogen assimilation, the evidence that mitochondrial metabolism and machinery are potential novel targets for the enhancement of nitrogen use efficiency (NUE) is explored.

  12. Ultrasmall cationic superparamagnetic iron oxide nanoparticles as nontoxic and efficient MRI contrast agent and magnetic-targeting tool

    Science.gov (United States)

    Uchiyama, Mayara Klimuk; Toma, Sergio Hiroshi; Rodrigues, Stephen Fernandes; Shimada, Ana Lucia Borges; Loiola, Rodrigo Azevedo; Cervantes Rodríguez, Hernán Joel; Oliveira, Pedro Vitoriano; Luz, Maciel Santos; Rabbani, Said Rahnamaye; Toma, Henrique Eisi; Poliselli Farsky, Sandra Helena; Araki, Koiti

    2015-01-01

    Fully dispersible, cationic ultrasmall (7 nm diameter) superparamagnetic iron oxide nanoparticles, exhibiting high relaxivity (178 mM−1s−1 in 0.47 T) and no acute or subchronic toxicity in Wistar rats, were studied and their suitability as contrast agents for magnetic resonance imaging and material for development of new diagnostic and treatment tools demonstrated. After intravenous injection (10 mg/kg body weight), they circulated throughout the vascular system causing no microhemorrhage or thrombus, neither inflammatory processes at the mesentery vascular bed and hepatic sinusoids (leukocyte rolling, adhesion, or migration as evaluated by intravital microscopy), but having been spontaneously concentrated in the liver, spleen, and kidneys, they caused strong negative contrast. The nanoparticles are cleared from kidneys and bladder in few days, whereas the complete elimination from liver and spleen occurred only after 4 weeks. Ex vivo studies demonstrated that cationic ultrasmall superparamagnetic iron oxide nanoparticles caused no effects on hepatic and renal enzymes dosage as well as on leukocyte count. In addition, they were readily concentrated in rat thigh by a magnet showing its potential as magnetically targeted carriers of therapeutic and diagnostic agents. Summarizing, cationic ultrasmall superparamagnetic iron oxide nanoparticles are nontoxic and efficient magnetic resonance imaging contrast agents useful as platform for the development of new materials for application in theranostics. PMID:26251595

  13. Methane release

    International Nuclear Information System (INIS)

    Seifert, M.

    1999-01-01

    The Swiss Gas Industry has carried out a systematic, technical estimate of methane release from the complete supply chain from production to consumption for the years 1992/1993. The result of this survey provided a conservative value, amounting to 0.9% of the Swiss domestic output. A continuation of the study taking into account new findings with regard to emission factors and the effect of the climate is now available, which provides a value of 0.8% for the target year of 1996. These results show that the renovation of the network has brought about lower losses in the local gas supplies, particularly for the grey cast iron pipelines. (author)

  14. WE-G-BRE-09: Targeted Radiotherapy Enhancement During Accelerated Partial Breast Irradiation (ABPI) Using Controlled Release of Gold Nanoparticles (GNPs)

    International Nuclear Information System (INIS)

    Cifter, G; Ngwa, W; Chin, J; Cifter, F; Sajo, E; Sinha, N; Bellon, J

    2014-01-01

    Purpose: Several studies have demonstrated low rates of local recurrence with brachytherapy-based accelerated partial breast irradiation (APBI). However, long-term outcomes on toxicity (e.g. telangiectasia), and cosmesis remain a major concern. The purpose of this study is to investigate the dosimetric feasibility of using targeted non-toxic radiosensitizing gold nanoparticles (GNPs) for localized dose enhancement to the planning target volume (PTV) during APBI while reducing dose to normal tissue. Methods: Two approaches for administering the GNPs were considered. In one approach, GNPs are assumed to be incorporated in a micrometer-thick polymer film on the surface of routinely used mammosite balloon applicators, for sustained controlled in-situ release, and subsequent treatment using 50-kVp Xoft devices. In case two, GNPs are administered directly into the lumpectomy cavity e.g. via injection or using fiducials coated with the GNP-loaded polymer film. Recent studies have validated the use of fiducials for reducing the PTV margin during APBI with 6 MV beams. An experimentally determined diffusion coefficient was used to determine space-time customizable distribution of GNPs for feasible in-vivo concentrations of 43 mg/g. An analytic calculational approach from previously published work was employed to estimate the dose enhancement due to GNPs (2 and 10 nm) as a function of distance up to 1 cm from lumpectomy cavity. Results: Dose enhancement due to GNP was found to be about 130% for 50-kVp x-rays, and 110% for 6-MV external beam radiotherapy, 1 cm away from the lumpectomy cavity wall. Higher customizable dose enhancement could be achieved at other distances as a function of nanoparticle size. Conclusion: Our preliminary results suggest that significant dose enhancement can be achieved to residual tumor cells targeted with GNPs during APBI with electronic brachytherapy or external beam therapy. The findings provide a useful basis for developing nanoparticle

  15. Enhancement of conversion efficiency of extreme ultraviolet radiation from a liquid aqueous solution microjet target by use of dual laser pulses

    Science.gov (United States)

    Higashiguchi, Takeshi; Dojyo, Naoto; Hamada, Masaya; Kawasaki, Keita; Sasaki, Wataru; Kubodera, Shoichi

    2006-03-01

    We demonstrated a debris-free, efficient laser-produced plasma extreme ultraviolet (EUV) source by use of a regenerative liquid microjet target containing tin-dioxide (SnO II) nano-particles. By using a low SnO II concentration (6%) solution and dual laser pulses for the plasma control, we observed the EUV conversion efficiency of 1.2% with undetectable debris.

  16. Ultrasmall cationic superparamagnetic iron oxide nanoparticles as nontoxic and efficient MRI contrast agent and magnetic-targeting tool

    Directory of Open Access Journals (Sweden)

    Uchiyama MK

    2015-07-01

    thigh by a magnet showing its potential as magnetically targeted carriers of therapeutic and diagnostic agents. Summarizing, cationic ultrasmall superparamagnetic iron oxide nanoparticles are nontoxic and efficient magnetic resonance imaging contrast agents useful as platform for the development of new materials for application in theranostics.Keywords: cationic USPIOs, MRI, contrast agent, magnetic targeting, in vivo toxicity, intravital microscopy

  17. In Vitro Transduction and Target-Mutagenesis Efficiency of HIV-1 pol Gene Targeting ZFN and CRISPR/Cas9 Delivered by Various Plasmids and/or Vectors: Toward an HIV Cure.

    Science.gov (United States)

    Okee, Moses; Bayiyana, Alice; Musubika, Carol; Joloba, Moses L; Ashaba-Katabazi, Fred; Bagaya, Bernard; Wayengera, Misaki

    2018-01-01

    Efficiency of artificial restriction enzymes toward curing HIV has only been separately examined, using differing delivery vehicles. We compared the in vitro transduction and target-mutagenesis efficiency of consortium plasmid and adenoviral vector delivered HIV-1 pol gene targeting zinc finger nuclease (ZFN) with CRISPR/Cas, Custom-ZFN, CRISPR-Cas-9, and plasmids and vectors (murCTSD_pZFN, pGS-U-gRNA, pCMV-Cas-D01A, Ad5-RGD); cell lines (TZM-bl and ACH-2/J-Lat cells); and the latency reversing agents prostratin, suberoylanilide hydroxamic acid, and phorbol myristate acetate. Cell lines were grown in either Dulbecco's modified Eagle's medium or Roswell Park Memorial Institute with the antibiotics kanamycin, zeocin, and efavirenz. Efficiency was assayed by GFP/luciferase activity and/or validated by yeast MEL1 reporter assay, CEL1 restriction fragment assay, and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Ad5-RGD vectors had better transduction efficiency than murCTSD and pGS-U-gRNA/pCMV-Cas-D01A plasmids. CRISPR/Cas9 exhibited better target-mutagenesis efficiency relative to ZFN (delivered by either plasmid or Ad5 vector) based on gel electrophoresis of pol gene amplicons within ACH-2 and J-Lat cells. Ad-5-RGD vectors enhanced target mutagenesis of ZFN, relative to murCTSD_pZFN plasmids, to levels of CRISPR/Cas9 plasmids. Similar reduction of luciferase activity among TZM-bl treated with Ad5-ZFN vectors relative to CRISPR/Cas-9 and murCTSD_pZFN plasmids was observed on challenge with HIV-1. qRT-PCR of HIV-1 pol gene transcripts affirmed that Ad5 (RGD) vectors enhanced target mutagenesis of ZFN. Whereas CRISPR/Cas-9 may possess inherent superior target-mutagenesis efficiency; the efficiency of ZFN (off-target toxicity withstanding) can be enhanced by altering delivery vehicle from plasmid to Ad5 (RGD) vectors.

  18. Pre-clinical evaluation of eight DOTA coupled gastrin-releasing peptide receptor (GRP-R) ligands for in vivo targeting of receptor-expressing tumors.

    Science.gov (United States)

    Accardo, Antonella; Galli, Filippo; Mansi, Rosalba; Del Pozzo, Luigi; Aurilio, Michela; Morisco, Anna; Ringhieri, Paola; Signore, Alberto; Morelli, Giancarlo; Aloj, Luigi

    2016-12-01

    Overexpression of the gastrin-releasing peptide receptor (GRP-R) has been documented in several human neoplasms such as breast, prostate, and ovarian cancer. There is growing interest in developing radiolabeled peptide-based ligands toward these receptors for the purpose of in vivo imaging and radionuclide therapy of GRP-R-overexpressing tumors. A number of different peptide sequences, isotopes, and labeling methods have been proposed for this purpose. The aim of this work is to perform a direct side-by-side comparison of different GRP-R binding peptides utilizing a single labeling strategy to identify the most suitable peptide sequence. Solid-phase synthesis of eight derivatives (BN1-8) designed based on literature analysis was carried out. Peptides were coupled to the DOTA chelator through a PEG4 spacer at the N-terminus. Derivatives were characterized for serum stability, binding affinity on PC-3 human prostate cancer cells, biodistribution in tumor-bearing mice, and gamma camera imaging at 1, 6, and 24 h after injection. Serum stability was quite variable among the different compounds with half-lives ranging from 16 to 400 min at 37 °C. All compounds tested showed K d values in the nanomolar range with the exception of BN3 that showed no binding. Biodistribution and imaging studies carried out for compounds BN1, BN4, BN7, and BN8 showed targeting of the GRP-R-positive tumors and the pancreas. The BN8 compound (DOTA-PEG-DPhe-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH2) showed high affinity, the longest serum stability, and the highest target-to-background ratios in biodistribution and imaging experiments among the compounds tested. Our results indicate that the NMeGly for Gly substitution and the Sta-Leu substitution at the C-terminus confer high serum stability while maintaining high receptor affinity, resulting in biodistribution properties that outperform those of the other peptides.

  19. The effect of macrocyclic chelators on the targeting properties of the 68Ga-labeled gastrin releasing peptide receptor antagonist PEG2-RM26

    International Nuclear Information System (INIS)

    Varasteh, Zohreh; Mitran, Bogdan; Rosenström, Ulrika; Velikyan, Irina; Rosestedt, Maria; Lindeberg, Gunnar; Sörensen, Jens; Larhed, Mats; Tolmachev, Vladimir; Orlova, Anna

    2015-01-01

    Introduction: Overexpression of gastrin-releasing peptide receptors (GRPR) has been reported in several cancers. Bombesin (BN) analogs are short peptides with a high affinity for GRPR. Different BN analogs were evaluated for radionuclide imaging and therapy of GRPR-expressing tumors. We have previously investigated an antagonistic analog of BN (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 , RM26) conjugated to NOTA via a PEG 2 spacer (NOTA-PEG 2 -RM26) labeled with 68 Ga, 111 In and Al 18 F. 68 Ga-labeled NOTA-PEG 2 -RM26 showed high tumor-to-organ ratios. Methods: The influence of different macrocyclic chelators (NOTA, NODAGA, DOTA and DOTAGA) on the targeting properties of 68 Ga-labeled PEG 2 -RM26 was studied in vitro and in vivo. Results: All conjugates were labeled with generator-produced 68 Ga with high yields and demonstrated high stability and specific binding to GRPR. The IC 50 values of nat Ga-X-PEG 2 -RM26 (X = NOTA, DOTA, NODAGA, DOTAGA) were 2.3 ± 0.2, 3.0 ± 0.3, 2.9 ± 0.3 and 10.0 ± 0.6 nM, respectively. The internalization of the conjugates by PC-3 cells was low. However, the DOTA-conjugated analog demonstrated a higher internalization rate compared to other analogs. GRPR-specific uptake was found in receptor-positive normal tissues and PC-3 xenografts for all conjugates. The biodistribution of the conjugates was influenced by the choice of the chelator moiety. Although all radiotracers cleared rapidly from the blood, [ 68 Ga]Ga-NOTA-PEG 2 -RM26 showed significantly lower uptake in lung, muscle and bone compared to the other analogs. The uptake in tumors (5.40 ± 1.04 %ID/g at 2 h p.i.) and the tumor-to-organ ratios (25 ± 3, 157 ± 23 and 39 ± 4 for blood, muscle and bone, respectively) were significantly higher for the NOTA-conjugate than the other analogs. Conclusions: Chelators had a clear influence on the biodistribution and targeting properties of 68 Ga-labeled antagonistic BN analogs. Positively charged [ 68 Ga]Ga-NOTA-PEG 2 -RM26 provided

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

    Science.gov (United States)

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

    2016-01-01

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

  1. Functional single-walled carbon nanotubes based on an integrin αvβ3 monoclonal antibody for highly efficient cancer cell targeting

    International Nuclear Information System (INIS)

    Ou Zhongmin; Wu Baoyan; Xing Da; Zhou Feifan; Wang Huiying; Tang Yonghong

    2009-01-01

    The application of single-walled carbon nanotubes (SWNTs) in the field of biomedicine is becoming an entirely new and exciting topic. In this study, a novel functional SWNT based on an integrin α v β 3 monoclonal antibody was developed and was used for cancer cell targeting in vitro. SWNTs were first modified by phospholipid-bearing polyethylene glycol (PL-PEG). The PL-PEG functionalized SWNTs were then conjugated with protein A. A SWNT-integrin α v β 3 monoclonal antibody system (SWNT-PEG-mAb) was thus constructed by conjugating protein A with the fluorescein labeled integrin α v β 3 monoclonal antibody. In vitro study revealed that SWNT-PEG-mAb presented a high targeting efficiency on integrin α v β 3 -positive U87MG cells with low cellular toxicity, while for integrin α v β 3 -negative MCF-7 cells, the system had a low targeting efficiency, indicating that the high targeting to U87MG cells was due to the specific integrin targeting of the monoclonal antibody. In conclusion, SWNT-PEG-mAb developed in this research is a potential candidate for cancer imaging and drug delivery in cancer targeting therapy.

  2. Design and characterization of a device to quantify the magnetic drug targeting efficiency of magnetic nanoparticles in a tube flow phantom by magnetic particle spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Radon, Patricia, E-mail: patricia.radon@ptb.de; Löwa, Norbert; Gutkelch, Dirk; Wiekhorst, Frank

    2017-04-01

    The aim of magnetic drug targeting (MDT) is to transfer a therapeutic drug coupled to magnetic nanoparticles (MNP) to desired disease locations (e.g. tumor region) with the help of magnetic field gradients. To transfer the MDT approach into clinical practice a number of important issues remain to be solved. We developed and characterized an in-vitro flow phantom to provide a defined and reproducible MDT environment. The tube system of the flow phantom is directed through the detection coil of a magnetic particle spectroscopy (MPS) device to determine the targeting efficiency. MPS offers an excellent temporal resolution of seconds and an outstanding specific sensitivity of some nanograms of iron. In the flow phantom different MNP types, magnet geometries and tube materials can be employed to vary physical parameters like diameter, flow rate, magnetic targeting gradient, and MNP properties. - Highlights: • Flow phantom for magnetic targeting. • MPS for quantitative MNP detection. • ng detection limit for MNP.

  3. Targeted imaging of gastrin-releasing peptide receptors with 99mTc-EDDA/HYNIC-[Lys3]-bombesin: biokinetics and dosimetry in women.

    Science.gov (United States)

    Santos-Cuevas, Clara L; Ferro-Flores, Guillermina; Arteaga de Murphy, Consuelo; Pichardo-Romero, Pablo A

    2008-08-01

    The gastrin-releasing peptide receptor (GRP-R) is expressed in several normal human tissues and is overexpressed in various human tumors including breast, prostate, small-cell lung cancer and pancreatic cancer. Recently, 99mTc-EDDA/HYNIC-[Lys]-bombesin (99mTc-HYNIC-BN) was reported as a radiopharmaceutical with high stability in human serum, specific cell GRP-R binding and rapid cell internalization. The aim of this study was to determine the biokinetics and dosimetry of 99mTc-HYNIC-BN and the feasibility of using this radiopharmaceutical to image GRP-R in four early breast cancer patients and seven healthy women. Whole-body images were acquired at 20, 90, 180 min, and 24 h after 99mTc-HYNIC-BN administration. The same regions of interest were drawn around source organs on each time frame and regions of interest were converted to activity (conjugate view counting method). The image sequence was used to extrapolate 99mTc-HYNIC-BN time-activity curves in each organ to calculate the total number of disintegrations (N) that occurred in the source regions. N data were the input for the OLINDA/EXM code to calculate internal radiation dose estimates. 99mTc-HYNIC-BN had a rapid blood clearance with mainly renal excretion. No statistically significant differences (P>0.05) in the radiation-absorbed doses among cancer patients and healthy women were observed. The average equivalent doses (n=11) were 24.8+/-8.8 mSv (kidneys), 7.3+/-1.8 mSv (lungs), 6.5+/-4.0 mSv (breast), 2.0+/-0.3 mSv (pancreas), 1.6+/-0.3 mSv (liver), 1.2+/-0.2 mSv (ovaries), and 1.0+/-0.2 mSv (red marrow). The effective dose was 3.3+/-0.6 mSv. The images showed well-differentiated concentration of 99mTc-HYNIC-BN in cancer mammary tissue. All the absorbed doses were comparable with those known for most of the 99mTc studies. 99mTc-HYNIC-BN shows high tumor uptake in breasts with malignant tumors so it is a promising imaging radiopharmaceutical to target site-specific early breast cancer. The results obtained

  4. BODIPY-Labeled DC-SIGN-Targeting Glycodendrons Efficiently Internalize and Route to Lysosomes in Human Dendritic Cells

    NARCIS (Netherlands)

    Ribeiro-Viana, R.; Garcia Vallejo, J.J.; Collado, D.; Perez-Inestrosa, E.; Bloem, K.; van Kooijk, Y.; Rojo, J.

    2012-01-01

    Glycodendrons bearing nine copies of mannoses or fucoses have been prepared by an efficient convergent strategy based on Cu(I) catalyzed azide-alkyne cycloaddition (CuAAC). These glycodendrons present a well-defined structure and have an adequate size and shape to interact efficiently with the

  5. {open_quotes}Transmutation efficiency calculation in the blanket on melted salts with central neptunium target{close_quotes}

    Energy Technology Data Exchange (ETDEWEB)

    Kolesov, V.F.; Shtarev, S.K.; Khoruzhiy, V.K. [Russia Federal Nuclear Center, Arzamas (Russian Federation)] [and others

    1995-10-01

    In the limits of ABC project version of two-sectional reactor system in the form of combination of subcritical blanket on melted salts and multiplying target from threshold fissile material {sup 237}Np is considered. This research is the development of the VNIIEF`s earlier work`s (Russia) investigating of usage possibilities in ABC project the conception of multisectional blankets with single-sided neutron coupling between sections. With the help of Monte-Carlo program the calculations results of system mentioned are given. The possibility of accelerator`s considerable power reduction at the account of thorium target substitution with neptunium-237 multiplying target is shown.

  6. Costs and benefits of industrial reporting and voluntary targets for energy efficiency. A report to the Congress of the United States. Volume II: Appendices

    Energy Technology Data Exchange (ETDEWEB)

    1994-02-01

    This part sets forth the regulations for the Industrial Energy conservation Program established under Part E of Title III of the Act. It includes criteria and procedures for the identification of reporting corporations, reporting requirements, criteria and procedures for exemption from filing reports directly with DOE, voluntary industrial energy efficiency improvement targets and voluntary recovered materials utilization targets. The purpose of the program is to promote increased energy conservation by American industry and, as it relates to the use of recovered materials, to conserve valuable energy and scarce natural resources.

  7. Efficient laser-induced 6-8 keV x-ray production from iron oxide aerogel and foil-lined cavity targets

    Energy Technology Data Exchange (ETDEWEB)

    Pérez, F.; Kay, J. J.; Patterson, J. R.; Kane, J.; Villette, B.; Girard, F.; Reverdin, C.; May, M.; Emig, J.; Sorce, C.; Colvin, J.; Gammon, S.; Jaquez, J.; Satcher, J. H.; Fournier, K. B.

    2012-08-01

    The performance of new iron-based laser-driven x-ray sources has been tested at the OMEGA laser facility for production of x rays in the 6.5–8.5 keV range. Two types of targets were experimentally investigated: low-density iron oxide aerogels (density 6-16 mg/cm36-16 mg/cm3) and stainless steel foil-lined cavity targets (steel thickness 1-5 μm1-5 μm). The targets were irradiated by 40 beams of the OMEGA laser (500 J/beam, 1 ns pulse, wavelength 351 nm). All targets showed good coupling with the laser, with <5%<5% of the incident laser light backscattered by the resulting plasma in all cases (typically <2.5%<2.5%). The aerogel targets produced Te=2Te=2 to 3 keV, ne=0.12-0.2ne=0.12-0.2 critical density plasmas yielding a 40%–60% laser-to-x-ray total conversion efficiency (CE) (1.2%–3% in the Fe K-shell range). The foil cavity targets produced Te~2 keV, Te~2 keV, ne~0.15ne~0.15 critical density plasmas yielding a 60%–75% conversion efficiency (1.6%–2.2% in the Fe K-shell range). Time-resolved images illustrate that the volumetric heating of low-density aerogels allow them to emit a higher K-shell x-ray yield even though they contain fewer Fe atoms. However, their challenging fabrication process leads to a larger shot-to-shot variation than cavity targets.

  8. Differential Impact of Plasma Proteins on the Adhesion Efficiency of Vascular-Targeted Carriers (VTCs) in Blood of Common Laboratory Animals.

    Science.gov (United States)

    Namdee, Katawut; Sobczynski, Daniel J; Onyskiw, Peter J; Eniola-Adefeso, Omolola

    2015-12-16

    Vascular-targeted carrier (VTC) interaction with human plasma is known to reduce targeted adhesion efficiency in vitro. However, the role of plasma proteins on the adhesion efficiency of VTCs in laboratory animals remains unknown. Here, in vitro blood flow assays are used to explore the effects of plasma from mouse, rabbit, and porcine on VTC adhesion. Porcine blood exhibited a strong negative plasma effect on VTC adhesion while no significant plasma effect was found with rabbit and mouse blood. A brush density poly(ethylene glycol) (PEG) on VTCs was effective at improving adhesion of microsized, but not nanosized, VTCs in porcine blood. Overall, the results suggest that porcine models, as opposed to mouse, can serve as better models in preclinical research for predicting the in vivo functionality of VTCs for use in humans. These considerations hold great importance for the design of various pharmaceutical products and development of reliable drug delivery systems.

  9. Incorporation of podoplanin into HIV released from HEK-293T cells, but not PBMC, is required for efficient binding to the attachment factor CLEC-2

    Science.gov (United States)

    2010-01-01

    Background Platelets are associated with HIV in the blood of infected individuals and might modulate viral dissemination, particularly if the virus is directly transmitted into the bloodstream. The C-type lectin DC-SIGN and the novel HIV attachment factor CLEC-2 are expressed by platelets and facilitate HIV transmission from platelets to T-cells. Here, we studied the molecular mechanisms behind CLEC-2-mediated HIV-1 transmission. Results Binding studies with soluble proteins indicated that CLEC-2, in contrast to DC-SIGN, does not recognize the viral envelope protein, but a cellular factor expressed on kidney-derived 293T cells. Subsequent analyses revealed that the cellular mucin-like membranous glycoprotein podoplanin, a CLEC-2 ligand, was expressed on 293T cells and incorporated into virions released from these cells. Knock-down of podoplanin in 293T cells by shRNA showed that virion incorporation of podoplanin was required for efficient CLEC-2-dependent HIV-1 interactions with cell lines and platelets. Flow cytometry revealed no evidence for podoplanin expression on viable T-cells and peripheral blood mononuclear cells (PBMC). Podoplanin was also not detected on HIV-1 infected T-cells. However, apoptotic bystander cells in HIV-1 infected cultures reacted with anti-podoplanin antibodies, and similar results were obtained upon induction of apoptosis in a cell line and in PBMCs suggesting an unexpected link between apoptosis and podoplanin expression. Despite the absence of detectable podoplanin expression, HIV-1 produced in PBMC was transmitted to T-cells in a CLEC-2-dependent manner, indicating that T-cells might express an as yet unidentified CLEC-2 ligand. Conclusions Virion incorporation of podoplanin mediates CLEC-2 interactions of HIV-1 derived from 293T cells, while incorporation of a different cellular factor seems to be responsible for CLEC-2-dependent capture of PBMC-derived viruses. Furthermore, evidence was obtained that podoplanin expression is

  10. Incorporation of podoplanin into HIV released from HEK-293T cells, but not PBMC, is required for efficient binding to the attachment factor CLEC-2

    Directory of Open Access Journals (Sweden)

    Münch Jan

    2010-05-01

    Full Text Available Abstract Background Platelets are associated with HIV in the blood of infected individuals and might modulate viral dissemination, particularly if the virus is directly transmitted into the bloodstream. The C-type lectin DC-SIGN and the novel HIV attachment factor CLEC-2 are expressed by platelets and facilitate HIV transmission from platelets to T-cells. Here, we studied the molecular mechanisms behind CLEC-2-mediated HIV-1 transmission. Results Binding studies with soluble proteins indicated that CLEC-2, in contrast to DC-SIGN, does not recognize the viral envelope protein, but a cellular factor expressed on kidney-derived 293T cells. Subsequent analyses revealed that the cellular mucin-like membranous glycoprotein podoplanin, a CLEC-2 ligand, was expressed on 293T cells and incorporated into virions released from these cells. Knock-down of podoplanin in 293T cells by shRNA showed that virion incorporation of podoplanin was required for efficient CLEC-2-dependent HIV-1 interactions with cell lines and platelets. Flow cytometry revealed no evidence for podoplanin expression on viable T-cells and peripheral blood mononuclear cells (PBMC. Podoplanin was also not detected on HIV-1 infected T-cells. However, apoptotic bystander cells in HIV-1 infected cultures reacted with anti-podoplanin antibodies, and similar results were obtained upon induction of apoptosis in a cell line and in PBMCs suggesting an unexpected link between apoptosis and podoplanin expression. Despite the absence of detectable podoplanin expression, HIV-1 produced in PBMC was transmitted to T-cells in a CLEC-2-dependent manner, indicating that T-cells might express an as yet unidentified CLEC-2 ligand. Conclusions Virion incorporation of podoplanin mediates CLEC-2 interactions of HIV-1 derived from 293T cells, while incorporation of a different cellular factor seems to be responsible for CLEC-2-dependent capture of PBMC-derived viruses. Furthermore, evidence was obtained that

  11. Efficient moving target analysis for inverse synthetic aperture radar images via joint speeded-up robust features and regular moment

    Science.gov (United States)

    Yang, Hongxin; Su, Fulin

    2018-01-01

    We propose a moving target analysis algorithm using speeded-up robust features (SURF) and regular moment in inverse synthetic aperture radar (ISAR) image sequences. In our study, we first extract interest points from ISAR image sequences by SURF. Different from traditional feature point extraction methods, SURF-based feature points are invariant to scattering intensity, target rotation, and image size. Then, we employ a bilateral feature registering model to match these feature points. The feature registering scheme can not only search the isotropic feature points to link the image sequences but also reduce the error matching pairs. After that, the target centroid is detected by regular moment. Consequently, a cost function based on correlation coefficient is adopted to analyze the motion information. Experimental results based on simulated and real data validate the effectiveness and practicability of the proposed method.

  12. A potyvirus vector efficiently targets recombinant proteins to chloroplasts, mitochondria and nuclei in plant cells when expressed at the amino terminus of the polyprotein.

    Science.gov (United States)

    Majer, Eszter; Navarro, José-Antonio; Daròs, José-Antonio

    2015-09-01

    Plant virus-based expression systems allow quick and efficient production of recombinant proteins in plant biofactories. Among them, a system derived from tobacco etch virus (TEV; genus potyvirus) permits coexpression of equimolar amounts of several recombinant proteins. This work analyzed how to target recombinant proteins to different subcellular localizations in the plant cell using this system. We constructed TEV clones in which green fluorescent protein (GFP), with a chloroplast transit peptide (cTP), a nuclear localization signal (NLS) or a mitochondrial targeting peptide (mTP) was expressed either as the most amino-terminal product or embedded in the viral polyprotein. Results showed that cTP and mTP mediated efficient translocation of GFP to the corresponding organelle only when present at the amino terminus of the viral polyprotein. In contrast, the NLS worked efficiently at both positions. Viruses expressing GFP in the amino terminus of the viral polyprotein produced milder symptoms. Untagged GFPs and cTP and NLS tagged amino-terminal GFPs accumulated to higher amounts in infected tissues. Finally, viral progeny from clones with internal GFPs maintained the extra gene better. These observations will help in the design of potyvirus-based vectors able to coexpress several proteins while targeting different subcellular localizations, as required in plant metabolic engineering. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Target-aimed versus wishful-thinking in designing efficient GHG reduction strategies for a metropolitan city: Taipei

    International Nuclear Information System (INIS)

    Liu, C.-M.; Liou, M.-L.; Yeh, S.-C.; Shang, N.-C.

    2009-01-01

    In recent years, many national and local governments claim for a specific GHG (greenhouse gas) reduction goal targeted for many years later. In 2005, the Taipei City government announced that Taipei's total GHG emission in 2015 will reach the same level as that in 2005 and then down to 75% of that level at year 2030. However, based on the estimated energy consumption and GHG emission and the proposed emission reduction plans from the local government, it is clear that these goals are not going to be accomplished. In Taipei, the residential and commercial sector contributes more than 78% of the total GHG emission. Thus, in a business as usual scenario, the total GHG emission in 2030 would be 79% more than that in 2005, far more than the target value proclaimed. As many key factors are uncontrollable by the local government, a target-aimed strategy designing process by looking into changes in Taipei and identifying major targets is proposed in this study. It is demonstrated that such a universally applicable approach will give more confidence to the public on working toward the expected GHG reduction goal

  14. Assisting People with Multiple Disabilities by Improving Their Computer Pointing Efficiency with an Automatic Target Acquisition Program

    Science.gov (United States)

    Shih, Ching-Hsiang; Shih, Ching-Tien; Peng, Chin-Ling

    2011-01-01

    This study evaluated whether two people with multiple disabilities would be able to improve their pointing performance through an Automatic Target Acquisition Program (ATAP) and a newly developed mouse driver (i.e. a new mouse driver replaces standard mouse driver, and is able to monitor mouse movement and intercept click action). Initially, both…

  15. Mitochondrially targeted vitamin E succinate efficiently kills breast tumour-initiating cells in a complex II-dependent manner

    Czech Academy of Sciences Publication Activity Database

    Yan, B.; Stantic, M.; Zobalová, Renata; Bezawork-Geleta, A.; Stapelberg, M.; Stursa, J.; Prokopová, Kateřina; Dong, L.; Neužil, Jiří

    2015-01-01

    Roč. 15, č. 401 (2015) ISSN 1471-2407 R&D Projects: GA MZd NT14078; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:86652036 Keywords : Tumour-initiating cells * Mitochondrially targeted vitamin E succinate * Complex II Subject RIV: FD - Oncology ; Hematology Impact factor: 3.265, year: 2015

  16. Disruption of Pseudomonas putida by high pressure homogenization: a comparison of the predictive capacity of three process models for the efficient release of arginine deiminase.

    Science.gov (United States)

    Patil, Mahesh D; Patel, Gopal; Surywanshi, Balaji; Shaikh, Naeem; Garg, Prabha; Chisti, Yusuf; Banerjee, Uttam Chand

    2016-12-01

    Disruption of Pseudomonas putida KT2440 by high-pressure homogenization in a French press is discussed for the release of arginine deiminase (ADI). The enzyme release response of the disruption process was modelled for the experimental factors of biomass concentration in the broth being disrupted, the homogenization pressure and the number of passes of the cell slurry through the homogenizer. For the same data, the response surface method (RSM), the artificial neural network (ANN) and the support vector machine (SVM) models were compared for their ability to predict the performance parameters of the cell disruption. The ANN model proved to be best for predicting the ADI release. The fractional disruption of the cells was best modelled by the RSM. The fraction of the cells disrupted depended mainly on the operating pressure of the homogenizer. The concentration of the biomass in the slurry was the most influential factor in determining the total protein release. Nearly 27 U/mL of ADI was released within a single pass from slurry with a biomass concentration of 260 g/L at an operating pressure of 510 bar. Using a biomass concentration of 100 g/L, the ADI release by French press was 2.7-fold greater than in a conventional high-speed bead mill. In the French press, the total protein release was 5.8-fold more than in the bead mill. The statistical analysis of the completely unseen data exhibited ANN and SVM modelling as proficient alternatives to RSM for the prediction and generalization of the cell disruption process in French press.

  17. Compatibility of the SE4ALL Energy Efficiency Objective with Renewable Energy, Energy Access, and Climate Mitigation Targets

    DEFF Research Database (Denmark)

    Gregg, Jay Sterling; Balyk, Olexandr; Solér, Ola

    over pre-industrial times. To accomplish this, pathways are constructed for each objective, which then form the basis for a scenario analysis using the Energy Technology System Analysis Program TIMES Integrated Assessment Model (ETSAP-TIAM). We find that, in general, the energy efficiency objective...

  18. Delivery of the Cre recombinase by a self-deleting lentiviral vector: efficient gene targeting in vivo

    NARCIS (Netherlands)

    Pfeifer, A.; Brandon, E. P.; Kootstra, N.; Gage, F. H.; Verma, I. M.

    2001-01-01

    The Cre recombinase (Cre) from bacteriophage P1 is an important tool for genetic engineering in mammalian cells. We constructed lentiviral vectors that efficiently deliver Cre in vitro and in vivo. Surprisingly, we found a significant reduction in proliferation and an accumulation in the G(2)/M

  19. High efficiency of targeted mutagenesis in arabidopsis via meiotic promoter-driven expression of Cas9 endonuclease

    KAUST Repository

    Eid, Ayman; Ali, Zahir; Mahfouz, Magdy M.

    2016-01-01

    of eukaryotic genomes, including plants; however, CRISPR/Cas9 efficiency varies considerably in different plant tissues and species. In Arabidopsis, the generation of homozygous or bi-allelic mutants in the first (T1) generation is inefficient. Here, we used

  20. DDR: Efficient computational method to predict drug–target interactions using graph mining and machine learning approaches

    KAUST Repository

    Olayan, Rawan S.; Ashoor, Haitham; Bajic, Vladimir B.

    2017-01-01

    but not all DTIs between them are not known. Using independent sources of evidence, we verify as correct 22 out of the top 25 DDR novel predictions. This suggests that DDR can be used as an efficient method to identify correct DTIs.

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

    Science.gov (United States)

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

    2018-03-01

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

  2. Highly Efficient Transfer of Chromosomes to a Broad Range of Target Cells Using Chinese Hamster Ovary Cells Expressing Murine Leukemia Virus-Derived Envelope Proteins.

    Directory of Open Access Journals (Sweden)

    Teruhiko Suzuki

    Full Text Available Microcell-mediated chromosome transfer (MMCT is an essential step for introducing chromosomes from donor cells to recipient cells. MMCT allows not only for genetic/epigenetic analysis of specific chromosomes, but also for utilization of human and mouse artificial chromosomes (HACs/MACs as gene delivery vectors. Although the scientific demand for genome scale analyses is increasing, the poor transfer efficiency of the current method has hampered the application of chromosome engineering technology. Here, we developed a highly efficient chromosome transfer method, called retro-MMCT, which is based on Chinese hamster ovary cells expressing envelope proteins derived from ecotropic or amphotropic murine leukemia viruses. Using this method, we transferred MACs to NIH3T3 cells with 26.5 times greater efficiency than that obtained using the conventional MMCT method. Retro-MMCT was applicable to a variety of recipient cells, including embryonic stem cells. Moreover, retro-MMCT enabled efficient transfer of MAC to recipient cells derived from humans, monkeys, mice, rats, and rabbits. These results demonstrate the utility of retro-MMCT for the efficient transfer of chromosomes to various types of target cell.

  3. Identification of corticotropin-releasing factor (CRF) target cells and effects of dexamethasone on binding in anterior pituitary using a fluorescent analog of CRF

    DEFF Research Database (Denmark)

    Schwartz, J; Billestrup, Nils; Perrin, M

    1986-01-01

    A fluorescein-conjugated bioactive analog of corticotropin-releasing factor (CRF) was synthesized and used to label cells that have high affinity CRF-binding sites. Of cultured bovine anterior pituitary cells, 6.1 +/- 0.6% were visible by fluorescence microscopy after incubation with the analog......-binding sites and suggest that binding of CRF to anterior pituitary cells is altered by glucocorticoids....

  4. Dual fluorescent N-(2-hydroxypropyl) methacrylamide-based conjugates for passive tumor targeting with reduction-sensitive drug release: proof of the concept, tumor accumulation, and biodistribution

    Czech Academy of Sciences Publication Activity Database

    Studenovský, Martin; Heinrich, A. K.; Lucas, H.; Mueller, T.; Mäder, K.; Etrych, Tomáš

    2016-01-01

    Roč. 31, č. 4 (2016), s. 348-360 ISSN 0883-9115 R&D Projects: GA ČR(CZ) GCP207/12/J030; GA ČR(CZ) GA14-12742S; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 Keywords : HPMA copolymers * reduction-responsive drug release * tumor accumulation Subject RIV: CD - Macromolecular Chemistry Impact factor: 1.310, year: 2016

  5. Fluorescent-increase kinetics of different fluorescent reporters used for qPCR depend on monitoring chemistry, targeted sequence, type of DNA input and PCR efficiency

    International Nuclear Information System (INIS)

    Ruijter, Jan M.; Hoff, Maurice J. B. van den; Lorenz, Peter; Tuomi, Jari M.; Hecker, Michael

    2014-01-01

    The analysis of quantitative PCR data usually does not take into account the fact that the increase in fluorescence depends on the monitoring chemistry, the input of ds-DNA or ss-cDNA, and the directionality of the targeting of probes or primers. The monitoring chemistries currently available can be categorized into six groups: (A) DNA-binding dyes; (B) hybridization probes; (C) hydrolysis probes; (D) LUX primers; (E) hairpin primers; and (F) the QZyme system. We have determined the kinetics of the increase in fluorescence for each of these groups with respect to the input of both ds-DNA and ss-cDNA. For the latter, we also evaluated mRNA and cDNA targeting probes or primers. This analysis revealed three situations. Hydrolysis probes and LUX primers, compared to DNA-binding dyes, do not require a correction of the observed quantification cycle. Hybridization probes and hairpin primers require a correction of −1 cycle (dubbed C-lag), while the QZyme system requires the C-lag correction and an efficiency-dependent C-shift correction. A PCR efficiency value can be derived from the relative increase in fluorescence in the exponential phase of the amplification curve for all monitoring chemistries. In case of hydrolysis probes, LUX primers and hairpin primers, however, this should be performed after cycle 12, and for the QZyme system after cycle 19, to keep the overestimation of the PCR efficiency below 0.5 %. (author)

  6. Targeted Vessel Ablation for More Efficient Magnetic Resonance-Guided High-Intensity Focused Ultrasound Ablation of Uterine Fibroids

    Energy Technology Data Exchange (ETDEWEB)

    Voogt, Marianne J., E-mail: m.voogt@umcutrecht.nl [University Medical Center Utrecht, Department of Radiology (Netherlands); Stralen, Marijn van [University Medical Center Utrecht, Image Sciences Institute (Netherlands); Ikink, Marlijne E. [University Medical Center Utrecht, Department of Radiology (Netherlands); Deckers, Roel; Vincken, Koen L.; Bartels, Lambertus W. [University Medical Center Utrecht, Image Sciences Institute (Netherlands); Mali, Willem P. Th. M.; Bosch, Maurice A. A. J. van den [University Medical Center Utrecht, Department of Radiology (Netherlands)

    2012-10-15

    Purpose: To report the first clinical experience with targeted vessel ablation during magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) treatment of symptomatic uterine fibroids. Methods: Pretreatment T1-weighted contrast-enhanced magnetic resonance angiography was used to create a detailed map of the uterine arteries and feeding branches to the fibroids. A three-dimensional overlay of the magnetic resonance angiography images was registered on 3D T2-weighted pretreatment imaging data. Treatment was focused primarily on locations where supplying vessels entered the fibroid. Patients were followed 6 months after treatment with a questionnaire to assess symptoms and quality of life (Uterine Fibroid Symptom and Quality of Life) and magnetic resonance imaging to quantify shrinkage of fibroid volumes. Results: In two patients, three fibroids were treated with targeted vessel ablation during MR-HIFU. The treatments resulted in almost total fibroid devascularization with nonperfused volume to total fibroid volume ratios of 84, 68, and 86%, respectively, of treated fibroids. The predicted ablated volumes during MR-HIFU in patients 1 and 2 were 45, 40, and 82 ml, respectively, while the nonperfused volumes determined immediately after treatment were 195, 92, and 190 ml respectively, which is 4.3 (patient 1) and 2.3 (patient 2) times higher than expected based on the thermal dose distribution. Fibroid-related symptoms reduced after treatment, and quality of life improved. Fibroid volume reduction ranged 31-59% at 6 months after treatment. Conclusion: Targeted vessel ablation during MR-HIFU allowed nearly complete fibroid ablation in both patients. This technique may enhance the use of MR-HIFU for fibroid treatment in clinical practice.

  7. Selectivity and Efficiency of Late Transgene Expression by Transcriptionally Targeted Oncolytic Adenoviruses Are Dependent on the Transgene Insertion Strategy

    Science.gov (United States)

    Quirin, Christina; Rohmer, Stanimira; Fernández-Ulibarri, Inés; Behr, Michael; Hesse, Andrea; Engelhardt, Sarah; Erbs, Philippe; Enk, Alexander H.

    2011-01-01

    Abstract Key challenges facing cancer therapy are the development of tumor-specific drugs and potent multimodal regimens. Oncolytic adenoviruses possess the potential to realize both aims by restricting virus replication to tumors and inserting therapeutic genes into the virus genome, respectively. A major effort in this regard is to express transgenes in a tumor-specific manner without affecting virus replication. Using both luciferase as a sensitive reporter and genetic prodrug activation, we show that promoter control of E1A facilitates highly selective expression of transgenes inserted into the late transcription unit. This, however, required multistep optimization of late transgene expression. Transgene insertion via internal ribosome entry site (IRES), splice acceptor (SA), or viral 2A sequences resulted in replication-dependent expression. Unexpectedly, analyses in appropriate substrates and with matching control viruses revealed that IRES and SA, but not 2A, facilitated indirect transgene targeting via tyrosinase promoter control of E1A. Transgene expression via SA was more selective (up to 1,500-fold) but less effective than via IRES. Notably, we also revealed transgene-dependent interference with splicing. Hence, the prodrug convertase FCU1 (a cytosine deaminase–uracil phosphoribosyltransferase fusion protein) was expressed only after optimizing the sequence surrounding the SA site and mutating a cryptic splice site within the transgene. The resulting tyrosinase promoter-regulated and FCU1-encoding adenovirus combined effective oncolysis with targeted prodrug activation therapy of melanoma. Thus, prodrug activation showed potent bystander killing and increased cytotoxicity of the virus up to 10-fold. We conclude that armed oncolytic viruses can be improved substantially by comparing and optimizing strategies for targeted transgene expression, thereby implementing selective and multimodal cancer therapies. PMID:20939692

  8. Folic acid conjugated mPEG-PEI600 as an efficient non-viral vector for targeted nucleic acid delivery.

    Science.gov (United States)

    Xu, Zhenhua; Jin, Jiefu; Siu, Leo K S; Yao, Hong; Sze, Johnny; Sun, Hongzhe; Kung, Hsiang-Fu; Poon, Wai Sang; Ng, Samuel S M; Lin, Marie C

    2012-04-15

    In this study we describe a novel polymer, mPPS-FA, synthesized as a potential gene transfer vector. To complete mPPS-FA, folic acid was conjugated to a backbone (named mPPS) consisting of a copolymer of methyl PEG-2000, PEI-600, and sebacoyl chloride. (1)H NMR, FT-IR, and UV spectroscopy were used to characterize the structure of mPPS-FA. It was revealed that mPPS-FA holds the ability to bind plasmid DNA yielding positively charged particles (polyplexes). Dynamic light scattering (DLS) and TEM techniques were used to study the size and morphology of the formed mPPS-FA/DNA nanocomplexes. The mPPS-FA/DNA nanoparticles exhibited low cytotoxicity as transfection of B16-F0, U87MG, CHO-1, and Ho-8910 cells produced >80% viability indicating low cytotoxicity of the polymer. The ability of mPPS-FA to deliver EGFP plasmid to melanoma B16-F0, U87, CHO-1, Ho-8910, and A549 cells was investigated in vitro as compared to the lipid-based transfection agent Lipofectamine2000 and Linear PEI 22 kDa (L-PEI 22 kDa). We found that mPPS-FA/DNA complexes yielded the highest GFP transfection efficiency in B16-F0, U87, CHO-1, and Ho-8910 cells, which all highly express folate receptors (FR), at an mPPS-FA/DNA ratio (w/w) of 15. Furthermore, the transfection of mPPS-FA/DNA complexes in CHO-1 cells could be competitively blocked by free folic acid molecules. In contrast, in low FR expressing A549 cells, mPPS-FA showed similar low transfection efficiency as mPPS. Taken together, mPPS-FA showed the highest efficiency in vitro and the potential to be developed as a nonviral gene carrier. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. Treatment Efficiency of Free and Nanoparticle-Loaded Mitoxantrone for Magnetic Drug Targeting in Multicellular Tumor Spheroids

    Directory of Open Access Journals (Sweden)

    Annkathrin Hornung

    2015-09-01

    Full Text Available Major problems of cancer treatment using systemic chemotherapy are severe side effects. Magnetic drug targeting (MDT employing superparamagnetic iron oxide nanoparticles (SPION loaded with chemotherapeutic agents may overcome this dilemma by increasing drug accumulation in the tumor and reducing toxic side effects in the healthy tissue. For translation of nanomedicine from bench to bedside, nanoparticle-mediated effects have to be studied carefully. In this study, we compare the effect of SPION, unloaded or loaded with the cytotoxic drug mitoxantrone (MTO with the effect of free MTO, on the viability and proliferation of HT-29 cells within three-dimensional multicellular tumor spheroids. Fluorescence microscopy and flow cytometry showed that both free MTO, as well as SPION-loaded MTO (SPIONMTO are able to penetrate into tumor spheroids and thereby kill tumor cells, whereas unloaded SPION did not affect cellular viability. Since SPIONMTO has herewith proven its effectivity also in complex multicellular tumor structures with its surrounding microenvironment, we conclude that it is a promising candidate for further use in magnetic drug targeting in vivo.

  10. Antisense targeting of 3' end elements involved in DUX4 mRNA processing is an efficient therapeutic strategy for facioscapulohumeral dystrophy: a new gene-silencing approach.

    Science.gov (United States)

    Marsollier, Anne-Charlotte; Ciszewski, Lukasz; Mariot, Virginie; Popplewell, Linda; Voit, Thomas; Dickson, George; Dumonceaux, Julie

    2016-04-15

    Defects in mRNA 3'end formation have been described to alter transcription termination, transport of the mRNA from the nucleus to the cytoplasm, stability of the mRNA and translation efficiency. Therefore, inhibition of polyadenylation may lead to gene silencing. Here, we choose facioscapulohumeral dystrophy (FSHD) as a model to determine whether or not targeting key 3' end elements involved in mRNA processing using antisense oligonucleotide drugs can be used as a strategy for gene silencing within a potentially therapeutic context. FSHD is a gain-of-function disease characterized by the aberrant expression of the Double homeobox 4 (DUX4) transcription factor leading to altered pathogenic deregulation of multiple genes in muscles. Here, we demonstrate that targeting either the mRNA polyadenylation signal and/or cleavage site is an efficient strategy to down-regulate DUX4 expression and to decrease the abnormally high-pathological expression of genes downstream of DUX4. We conclude that targeting key functional 3' end elements involved in pre-mRNA to mRNA maturation with antisense drugs can lead to efficient gene silencing and is thus a potentially effective therapeutic strategy for at least FSHD. Moreover, polyadenylation is a crucial step in the maturation of almost all eukaryotic mRNAs, and thus all mRNAs are virtually eligible for this antisense-mediated knockdown strategy. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. Convection-enhanced delivery of an anti-miR is well-tolerated, preserves anti-miR stability and causes efficient target de-repression

    DEFF Research Database (Denmark)

    Halle, Bo; Marcusson, Eric G; Aaberg-Jessen, Charlotte

    2016-01-01

    Over-expressed microRNAs (miRs) are promising new targets in glioblastoma (GBM) therapy. Inhibition of over-expressed miRs has been shown to diminish GBM proliferation, invasion and angiogenesis, indicating a significant therapeutic potential. However, the methods utilized for miR inhibition have...... had low translational potential. In clinical trials convection-enhanced delivery (CED) has been applied for local delivery of compounds in the brain. The aim of this study was to determine if safe and efficient miR inhibition was possible by CED of an anti-miR. We used a highly invasive GBM orthotopic...

  12. TargetSearch - a Bioconductor package for the efficient preprocessing of GC-MS metabolite profiling data

    Science.gov (United States)

    2009-01-01

    Background Metabolite profiling, the simultaneous quantification of multiple metabolites in an experiment, is becoming increasingly popular, particularly with the rise of systems-level biology. The workhorse in this field is gas-chromatography hyphenated with mass spectrometry (GC-MS). The high-throughput of this technology coupled with a demand for large experiments has led to data pre-processing, i.e. the quantification of metabolites across samples, becoming a major bottleneck. Existing software has several limitations, including restricted maximum sample size, systematic errors and low flexibility. However, the biggest limitation is that the resulting data usually require extensive hand-curation, which is subjective and can typically take several days to weeks. Results We introduce the TargetSearch package, an open source tool which is a flexible and accurate method for pre-processing even very large numbers of GC-MS samples within hours. We developed a novel strategy to iteratively correct and update retention time indices for searching and identifying metabolites. The package is written in the R programming language with computationally intensive functions written in C for speed and performance. The package includes a graphical user interface to allow easy use by those unfamiliar with R. Conclusions TargetSearch allows fast and accurate data pre-processing for GC-MS experiments and overcomes the sample number limitations and manual curation requirements of existing software. We validate our method by carrying out an analysis against both a set of known chemical standard mixtures and of a biological experiment. In addition we demonstrate its capabilities and speed by comparing it with other GC-MS pre-processing tools. We believe this package will greatly ease current bottlenecks and facilitate the analysis of metabolic profiling data. PMID:20015393

  13. TargetSearch - a Bioconductor package for the efficient preprocessing of GC-MS metabolite profiling data

    Directory of Open Access Journals (Sweden)

    Lisec Jan

    2009-12-01

    Full Text Available Abstract Background Metabolite profiling, the simultaneous quantification of multiple metabolites in an experiment, is becoming increasingly popular, particularly with the rise of systems-level biology. The workhorse in this field is gas-chromatography hyphenated with mass spectrometry (GC-MS. The high-throughput of this technology coupled with a demand for large experiments has led to data pre-processing, i.e. the quantification of metabolites across samples, becoming a major bottleneck. Existing software has several limitations, including restricted maximum sample size, systematic errors and low flexibility. However, the biggest limitation is that the resulting data usually require extensive hand-curation, which is subjective and can typically take several days to weeks. Results We introduce the TargetSearch package, an open source tool which is a flexible and accurate method for pre-processing even very large numbers of GC-MS samples within hours. We developed a novel strategy to iteratively correct and update retention time indices for searching and identifying metabolites. The package is written in the R programming language with computationally intensive functions written in C for speed and performance. The package includes a graphical user interface to allow easy use by those unfamiliar with R. Conclusions TargetSearch allows fast and accurate data pre-processing for GC-MS experiments and overcomes the sample number limitations and manual curation requirements of existing software. We validate our method by carrying out an analysis against both a set of known chemical standard mixtures and of a biological experiment. In addition we demonstrate its capabilities and speed by comparing it with other GC-MS pre-processing tools. We believe this package will greatly ease current bottlenecks and facilitate the analysis of metabolic profiling data.

  14. TargetSearch--a Bioconductor package for the efficient preprocessing of GC-MS metabolite profiling data.

    Science.gov (United States)

    Cuadros-Inostroza, Alvaro; Caldana, Camila; Redestig, Henning; Kusano, Miyako; Lisec, Jan; Peña-Cortés, Hugo; Willmitzer, Lothar; Hannah, Matthew A

    2009-12-16

    Metabolite profiling, the simultaneous quantification of multiple metabolites in an experiment, is becoming increasingly popular, particularly with the rise of systems-level biology. The workhorse in this field is gas-chromatography hyphenated with mass spectrometry (GC-MS). The high-throughput of this technology coupled with a demand for large experiments has led to data pre-processing, i.e. the quantification of metabolites across samples, becoming a major bottleneck. Existing software has several limitations, including restricted maximum sample size, systematic errors and low flexibility. However, the biggest limitation is that the resulting data usually require extensive hand-curation, which is subjective and can typically take several days to weeks. We introduce the TargetSearch package, an open source tool which is a flexible and accurate method for pre-processing even very large numbers of GC-MS samples within hours. We developed a novel strategy to iteratively correct and update retention time indices for searching and identifying metabolites. The package is written in the R programming language with computationally intensive functions written in C for speed and performance. The package includes a graphical user interface to allow easy use by those unfamiliar with R. TargetSearch allows fast and accurate data pre-processing for GC-MS experiments and overcomes the sample number limitations and manual curation requirements of existing software. We validate our method by carrying out an analysis against both a set of known chemical standard mixtures and of a biological experiment. In addition we demonstrate its capabilities and speed by comparing it with other GC-MS pre-processing tools. We believe this package will greatly ease current bottlenecks and facilitate the analysis of metabolic profiling data.

  15. α-Imaging Confirmed Efficient Targeting of CD₄₅-Positive Cells After ²¹¹At-Radioimmunotherapy for Hematopoietic Cell Transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Frost, Sophia; Miller, Brian W.; Back, Tom; Santos, E. B.; Hamlin, Donald K.; Knoblaugh, E.; Frayo, Shani; Kenoyer, Aimee L.; Storb, Rainer; Press, O. W.; Wilbur, D. Scott; Pagel, John M.; Sandmaier, B. M.

    2015-09-03

    Alpha-radioimmunotherapy (α-RIT) targeting CD45 may substitute for total body irradiation in hematopoietic cell transplantation (HCT) preparative regimens for lymphoma. Our goal was to optimize the anti-CD45 monoclonal antibody (MAb; CA12.10C12) protein dose for astatine-²¹¹(²¹¹At)-RIT, extending the analysis to include intra-organ ²¹¹At activity distribution and α-imaging-based small-scale dosimetry, along with imunohistochemical staining. Methods: Eight normal dogs were injected with either 0.75 (n=5) or 1.00 mg/kg (n=3) of ²¹¹At-B10-CA12.10C12 (11.5–27.6 MBq/kg). Two were euthanized and necropsied 19–22 hours postinjection (p.i.), and six received autologous HCT three days after ²¹¹At-RIT, following lymph node and bone marrow biopsies at 2–4 and/or 19 hours p.i. Blood was sampled to study toxicity and clearance; CD45 targeting was evaluated by flow cytometry. ²¹¹At localization and small scale dosimetry were assessed using two α-imaging : α-camera and iQID. Results: Uptake of ²¹¹At was highest in spleen (0.31–0.61 %IA/g), lymph nodes (0.02–0.16 %IA/g), liver (0.11–0.12 %IA/g), and marrow (0.06–0.08 %IA/g). Lymphocytes in blood and marrow were efficiently targeted using either MAb dose. Lymph nodes remained unsaturated, but displayed targeted ²¹¹At localization in T lymphocyte-rich areas. Absorbed doses to blood, marrow, and lymph nodes were estimated at 3.9, 3.0, and 4.2 Gy/210 MBq, respectively. All transplanted dogs experienced transient hepatic toxicity. Liver enzyme levels were temporarily elevated in 5 of 6 dogs; 1 treated with 1.00 mg MAb/kg developed ascites and was euthanized 136 days after HCT. Conclusion: ²¹¹At-anti-CD45 RIT with 0.75 mg MAb/kg efficiently targeted blood and marrow without severe toxicity. Dosimetry calculations and observed radiation-induced effects indicated that sufficient ²¹¹At-B10-CA12.10C12 localization was achieved for efficient conditioning for HCT.

  16. Polyplex micelle installing intracellular self-processing functionalities without free catiomers for safe and efficient systemic gene therapy through tumor vasculature targeting.

    Science.gov (United States)

    Chen, Qixian; Osada, Kensuke; Ge, Zhishen; Uchida, Satoshi; Tockary, Theofilus A; Dirisala, Anjaneyulu; Matsui, Akitsugu; Toh, Kazuko; Takeda, Kaori M; Liu, Xueying; Nomoto, Takahiro; Ishii, Tekihiko; Oba, Makoto; Matsumoto, Yu; Kataoka, Kazunori

    2017-01-01

    Both efficiency and safety profiles are crucial for promotion of gene delivery systems towards practical applications. A promising template system was previously developed based on block catiomer of poly(ethylene glycol) (PEG)-b-poly{N'-[N-(2-aminoethyl)-2-aminoehtyl]aspartamide}-cholesteryl [PEG-PAsp(DET)-cholesteryl] with strategies of ligand conjugation at the α-terminus for specific affinity to the targeted cells and cholesteryl conjugation at the ω-terminus for structural stabilization to obtain systemic retention. Aiming for advocating this formulation towards practical applications, in the current study, the binding profile of this polymer to plasmid DNA (pDNA) was carefully studied to address an issue of toxicity origin. Quantification of free polymer composition confirmed that the toxicity mainly results from unbound polymer and polyplex micelle itself has negligible toxicity. This evaluation allowed for identifying an optimal condition to prepare safe polyplex micelles for systemic application that possess maximal polymer-binding but exclude free polymers. The identified polyplex micelles then faced a drawback of limited transfection efficiency due to the absence of free polymer, which is an acknowledged tendency found in various synthetic gene carriers. Thus, series of functional components was strategically compiled to improve the transfection efficiency such as attachment of cyclic (Arg-Gly-Asp) (cRGD) peptide as a ligand onto the polyplex micelles to facilitate cellular uptake, use of endosome membrane disruptive catiomer of PAsp(DET) for facilitating endosome escape along with use of the conjugated cholesteryl group to amplify the effect of PAsp(DET) on membrane disruption, so as to obtain efficient transfection. The mechanistic investigation respecting the appreciated pH dependent protonation behavior of PAsp(DET) permitted to depict an intriguing scenario how the block catiomers manage to escape from the endosome entrapment in response to the p

  17. Synthesis of surface molecular imprinted TiO{sub 2}/graphene photocatalyst and its highly efficient photocatalytic degradation of target pollutant under visible light irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Lai, Cui, E-mail: laicui@hnu.edu.cn [College of Environmental Science and Engineering, Hunan University, Changsha 410082, Hunan (China); Key Laboratory of Environmental Biology and Pollution Control (Hunan University), Ministry of Education, Changsha 410082, Hunan (China); Wang, Man-Man [College of Environmental Science and Engineering, Hunan University, Changsha 410082, Hunan (China); Key Laboratory of Environmental Biology and Pollution Control (Hunan University), Ministry of Education, Changsha 410082, Hunan (China); Zeng, Guang-Ming, E-mail: zgming@hnu.edu.cn [College of Environmental Science and Engineering, Hunan University, Changsha 410082, Hunan (China); Key Laboratory of Environmental Biology and Pollution Control (Hunan University), Ministry of Education, Changsha 410082, Hunan (China); Liu, Yun-Guo; Huang, Dan-Lian; Zhang, Chen; Wang, Rong-Zhong; Xu, Piao; Cheng, Min; Huang, Chao; Wu, Hai-Peng; Qin, Lei [College of Environmental Science and Engineering, Hunan University, Changsha 410082, Hunan (China); Key Laboratory of Environmental Biology and Pollution Control (Hunan University), Ministry of Education, Changsha 410082, Hunan (China)

    2016-12-30

    Highlights: • The surface molecular imprinting technique was successfully combined with photocatalyst. • Molecularly imprinted photocatalyst exhibits recognition ability to the target molecules. • MIP-TiO{sub 2}/GR shows higher adsorption capacity and selectivity than NIP-TiO{sub 2}/GR. • The photocatalytic activity of MIP-TiO{sub 2}/GR is enhanced for target molecules. - Abstract: The molecular imprinted TiO{sub 2}/graphene photocatalyst (MIP-TiO{sub 2}/GR) was successfully prepared with bisphenol A (BPA) as the template molecule (target pollutant) and o-phenylenediamine (OPDA) as functional monomers by the surface molecular imprinting method. The combination between BPA and OPDA led to the formation of the precursor, and the subsequent polymerization of OPDA initiated by ultraviolet radiation can ensure the realization of MIP-TiO{sub 2}/GR. The samples were characterized by SEM, EDS, XRD, BET, UV–vis DRS and Zeta potential. In addition, adsorption capacities, adsorption selectivity and visible light photocatalytic performances of MIP-TiO{sub 2}/GR and non-imprinted TiO{sub 2}/graphene (NIP-TiO{sub 2}/GR) were evaluated. Moreover, the effects of pH and initial BPA concentration on removal efficiency of BPA were also investigated. The results showed that MIP-TiO{sub 2}/GR exhibited better adsorption capacity and adsorption selectivity towards the template molecule compared to NIP-TiO{sub 2}/GR due to the imprinted cavities on the surface of MIP-TiO{sub 2}/GR. Moreover, the photocatalytic activity of MIP-TiO{sub 2}/GR toward the target molecules was stronger than that of NIP-TiO{sub 2}/GR as a result of large adsorption capacity to target molecules and narrow band gap energy on MIP-TiO{sub 2}/GR. Therefore, modifying the photocatalyst by the surface molecular imprinting is a promising method to improve the molecule recognition and photocatalytic efficiency of photocatalyst for target pollutant.

  18. Target selection for the HRIBF Project

    International Nuclear Information System (INIS)

    Dellwo, J.; Alton, G.D.; Batchelder, J.C.

    1994-01-01

    Experiments are in progress at the Oak Ridge National Laboratory (ORNL) which are designed to select the most appropriate target materials for generating particular radioactive ion beams for the Holifield Radioactive Ion Beam Facility (HRIBF). The 25-MV tandem accelerator is used to implant stable complements of interesting radioactive elements into refractory targets mounted in a high-temperature FEBIAD ion source which is on-line at the UNISOR facility. These experiments permit selection of the target material most appropriate for the rapid release of the element of interest, as well as realistic estimates of the efficiency of the FEBIAD source. From diffusion release data information on the release times and diffusion coefficients can be derived. Diffusion coefficients for CI implanted into and diffused from CeS and Zr 5 Si 3 and As, Br, and Se implanted into and diffused from Zr 5 Ge 3 have been derived from the resulting intensity versus time profiles

  19. Lecithin-based microemulsions for targeted delivery of ceramide AP into the stratum corneum: formulation, characterizations, and in vitro release and penetration studies.

    Science.gov (United States)

    Sahle, Fitsum F; Metz, Hendrik; Wohlrab, Johannes; Neubert, Reinhard H H

    2013-02-01

    To improve the solubility and penetration of Ceramide AP (CER [AP]) into the stratum corneum that potentially restores the barrier function of aged and affected skin. CER [AP] microemulsions (MEs) were formulated using lecithin, Miglyol® 812 (miglyol) and water-1,2 pentandiol (PeG) mixture as amphiphilic, oily and hydrophilic components, respectively. The nanostructure of the MEs was revealed using electrical conductivity, differential scanning calorimeter (DSC) and electron paramagnetic resonance (EPR) techniques. Photon correlation spectroscopy (PCS) was used to measure the sizes and shape of ME droplets. The release and penetration of the CER into the stratum corneum was investigated in vitro using a multi-layer membrane model. The MEs exhibited excellent thermodynamic stability (>2 years) and loading capacity (0.5% CER [AP]). The pseudo-ternary phase diagrams of the MEs were obtained and PCS results showed that the droplets are spherical in shape and bigger in size. In vitro investigations showed that the MEs exhibited excellent rate and extent of release and penetration. Stable lecithin-based CER [AP] MEs that significantly enhance the solubility and penetration of CER [AP] into the stratum corneum were developed. The MEs also have better properties than the previously reported polyglycerol fatty acid surfactant-based CER [AP] MEs.

  20. Stress-Induced Synaptic Dysfunction and Neurotransmitter Release in Alzheimer's Disease: Can Neurotransmitters and Neuromodulators be Potential Therapeutic Targets?

    Science.gov (United States)

    Jha, Saurabh Kumar; Jha, Niraj Kumar; Kumar, Dhiraj; Sharma, Renu; Shrivastava, Abhishek; Ambasta, Rashmi K; Kumar, Pravir

    2017-01-01

    The communication between neurons at synaptic junctions is an intriguing process that monitors the transmission of various electro-chemical signals in the central nervous system. Albeit any aberration in the mechanisms associated with transmission of these signals leads to loss of synaptic contacts in both the neocortex and hippocampus thereby causing insidious cognitive decline and memory dysfunction. Compelling evidence suggests that soluble amyloid-β (Aβ) and hyperphosphorylated tau serve as toxins in the dysfunction of synaptic plasticity and aberrant neurotransmitter (NT) release at synapses consequently causing a cognitive decline in Alzheimer's disease (AD). Further, an imbalance between excitatory and inhibitory neurotransmission systems induced by impaired redox signaling and altered mitochondrial integrity is also amenable for such abnormalities. Defective NT release at the synaptic junction causes several detrimental effects associated with altered activity of synaptic proteins, transcription factors, Ca2+ homeostasis, and other molecules critical for neuronal plasticity. These detrimental effects further disrupt the normal homeostasis of neuronal cells and thereby causing synaptic loss. Moreover, the precise mechanistic role played by impaired NTs and neuromodulators (NMs) and altered redox signaling in synaptic dysfunction remains mysterious, and their possible interlink still needs to be investigated. Therefore, this review elucidates the intricate role played by both defective NTs/NMs and altered redox signaling in synaptopathy. Further, the involvement of numerous pharmacological approaches to compensate neurotransmission imbalance has also been discussed, which may be considered as a potential therapeutic approach in synaptopathy associated with AD.

  1. Natural lipid extracts and biomembrane-mimicking lipid compositions are disposed to form nonlamellar phases, and they release DNA from lipoplexes most efficiently

    Energy Technology Data Exchange (ETDEWEB)

    Koynova, Rumiana; MacDonald, Robert C. (NWU)

    2010-01-18

    A viewpoint now emerging is that a critical factor in lipid-mediated transfection (lipofection) is the structural evolution of lipoplexes upon interacting and mixing with cellular lipids. Here we report our finding that lipid mixtures mimicking biomembrane lipid compositions are superior to pure anionic liposomes in their ability to release DNA from lipoplexes (cationic lipid/DNA complexes), even though they have a much lower negative charge density (and thus lower capacity to neutralize the positive charge of the lipoplex lipids). Flow fluorometry revealed that the portion of DNA released after a 30-min incubation of the cationic O-ethylphosphatidylcholine lipoplexes with the anionic phosphatidylserine or phosphatidylglycerol was 19% and 37%, respectively, whereas a mixture mimicking biomembranes (MM: phosphatidylcholine/phosphatidylethanolamine/phosphatidylserine /cholesterol 45:20:20:15 w/w) and polar lipid extract from bovine liver released 62% and 74%, respectively, of the DNA content. A possible reason for this superior power in releasing DNA by the natural lipid mixtures was suggested by structural experiments: while pure anionic lipids typically form lamellae, the natural lipid mixtures exhibited a surprising predilection to form nonlamellar phases. Thus, the MM mixture arranged into lamellar arrays at physiological temperature, but began to convert to the hexagonal phase at a slightly higher temperature, {approx} 40-45 C. A propensity to form nonlamellar phases (hexagonal, cubic, micellar) at close to physiological temperatures was also found with the lipid extracts from natural tissues (from bovine liver, brain, and heart). This result reveals that electrostatic interactions are only one of the factors involved in lipid-mediated DNA delivery. The tendency of lipid bilayers to form nonlamellar phases has been described in terms of bilayer 'frustration' which imposes a nonzero intrinsic curvature of the two opposing monolayers. Because the stored

  2. High Resolution Melting Analysis Targeting hsp70 as a Fast and Efficient Method for the Discrimination of Leishmania Species.

    Science.gov (United States)

    Zampieri, Ricardo Andrade; Laranjeira-Silva, Maria Fernanda; Muxel, Sandra Marcia; Stocco de Lima, Ana Carolina; Shaw, Jeffrey Jon; Floeter-Winter, Lucile Maria

    2016-02-01

    Protozoan parasites of the genus Leishmania cause a large spectrum of clinical manifestations known as Leishmaniases. These diseases are increasingly important public health problems in many countries both within and outside endemic regions. Thus, an accurate differential diagnosis is extremely relevant for understanding epidemiological profiles and for the administration of the best therapeutic protocol. Exploring the High Resolution Melting (HRM) dissociation profiles of two amplicons using real time polymerase chain reaction (real-time PCR) targeting heat-shock protein 70 coding gene (hsp70) revealed differences that allowed the discrimination of genomic DNA samples of eight Leishmania species found in the Americas, including Leishmania (Leishmania) infantum chagasi, L. (L.) amazonensis, L. (L.) mexicana, L. (Viannia) lainsoni, L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) naiffi and L. (V.) shawi, and three species found in Eurasia and Africa, including L. (L.) tropica, L. (L.) donovani and L. (L.) major. In addition, we tested DNA samples obtained from standard promastigote culture, naturally infected phlebotomines, experimentally infected mice and clinical human samples to validate the proposed protocol. HRM analysis of hsp70 amplicons is a fast and robust strategy that allowed for the detection and discrimination of all Leishmania species responsible for the Leishmaniases in Brazil and Eurasia/Africa with high sensitivity and accuracy. This method could detect less than one parasite per reaction, even in the presence of host DNA.

  3. High Resolution Melting Analysis Targeting hsp70 as a Fast and Efficient Method for the Discrimination of Leishmania Species.

    Directory of Open Access Journals (Sweden)

    Ricardo Andrade Zampieri

    2016-02-01

    Full Text Available Protozoan parasites of the genus Leishmania cause a large spectrum of clinical manifestations known as Leishmaniases. These diseases are increasingly important public health problems in many countries both within and outside endemic regions. Thus, an accurate differential diagnosis is extremely relevant for understanding epidemiological profiles and for the administration of the best therapeutic protocol.Exploring the High Resolution Melting (HRM dissociation profiles of two amplicons using real time polymerase chain reaction (real-time PCR targeting heat-shock protein 70 coding gene (hsp70 revealed differences that allowed the discrimination of genomic DNA samples of eight Leishmania species found in the Americas, including Leishmania (Leishmania infantum chagasi, L. (L. amazonensis, L. (L. mexicana, L. (Viannia lainsoni, L. (V. braziliensis, L. (V. guyanensis, L. (V. naiffi and L. (V. shawi, and three species found in Eurasia and Africa, including L. (L. tropica, L. (L. donovani and L. (L. major. In addition, we tested DNA samples obtained from standard promastigote culture, naturally infected phlebotomines, experimentally infected mice and clinical human samples to validate the proposed protocol.HRM analysis of hsp70 amplicons is a fast and robust strategy that allowed for the detection and discrimination of all Leishmania species responsible for the Leishmaniases in Brazil and Eurasia/Africa with high sensitivity and accuracy. This method could detect less than one parasite per reaction, even in the presence of host DNA.

  4. Folic Acid Targeting for Efficient Isolation and Detection of Ovarian Cancer CTCs from Human Whole Blood Based on Two-Step Binding Strategy.

    Science.gov (United States)

    Nie, Liju; Li, Fulai; Huang, Xiaolin; Aguilar, Zoraida P; Wang, Yongqiang Andrew; Xiong, Yonghua; Fu, Fen; Xu, Hengyi

    2018-04-25

    Studies regarding circulating tumor cells (CTCs) have great significance for cancer prognosis, treatment monitoring, and metastasis diagnosis. However, due to their extremely low concentration in peripheral blood, isolation and enrichment of CTCs are the key steps for early detection. To this end, targeting the folic acid receptors (FRs) on the CTC surface for capture with folic acid (FA) using bovine serum albumin (BSA)-tether for multibiotin enhancement in combination with streptavidin-coated magnetic nanoparticles (MNPs-SA) was developed for ovarian cancer CTC isolation. The streptavidin-biotin-system-mediated two-step binding strategy was shown to capture CTCs from whole blood efficiently without the need for a pretreatment process. The optimized parameters for this system exhibited an average capture efficiency of 80%, which was 25% higher than that of FA-decorated magnetic nanoparticles based on the one-step CTC separation method. Moreover, the isolated cells remained highly viable and were cultured directly without detachment from the MNPs-SA-biotin-CTC complex. Furthermore, when the system was applied for the isolation and detection of CTCs in ovarian cancer patients' peripheral blood samples, it exhibited an 80% correlation with clinical diagnostic criteria. The results indicated that FA targeting, in combination with BSA-based multibiotin enhancement magnetic nanoparticle separation, is a promising tool for CTC enrichment and detection of early-stage ovarian cancer.

  5. Indirect radio-chemo-beta therapy: a targeted approach to increase biological efficiency of x-rays based on energy.

    Science.gov (United States)

    Oktaria, Sianne; Corde, Stéphanie; Lerch, Michael L F; Konstantinov, Konstantin; Rosenfeld, Anatoly B; Tehei, Moeava

    2015-10-21

    Despite the use of multimodal treatments incorporating surgery, chemotherapy and radiotherapy, local control of gliomas remains a major challenge. The potential of a new treatment approach called indirect radio-chemo-beta therapy using the synergy created by combining methotrexate (MTX) with bromodeoxyuridine (BrUdR) under optimum energy x-ray irradiation is assessed. 9L rat gliosarcoma cells pre-treated with 0.01 μM MTX and/or 10 μM BrUdR were irradiated in vitro with 50 kVp, 125 kVp, 250 kVp, 6 MV and 10 MV x-rays. The cytotoxicity was assessed using clonogenic survival as the radiobiological endpoint. The photon energy with maximum effect was determined using radiation sensitization enhancement factors at 10% clonogenic survival (SER10%). The cell cycle distribution was investigated using flow cytometric analysis with propidium iodide staining. Incorporation of BrUdR in the DNA was detected by the fluorescence of labelled anti-BrUdR antibodies. The radiation sensitization enhancement exhibits energy dependence with a maximum of 2.3 at 125 kVp for the combined drug treated cells. At this energy, the shape of the clonogenic survival curve of the pharmacological agents treated cells changes substantially. This change is interpreted as an increased lethality of the local radiation environment and is attributed to supplemented inhibition of DNA repair. Radiation induced chemo-beta therapy was demonstrated in vitro by the targeted activation of combined pharmacological agents with optimized energy tuning of x-ray beams on 9 L cells. Our results show that this is a highly effective form of chemo-radiation therapy.

  6. In vitro Evaluation of a Bombesin Antagonistic Analogue Conjugated with DOTA-Ala(SO3H)-Aminooctanoyl for Targeting of the Gastrin-releasing Peptide Receptor

    International Nuclear Information System (INIS)

    Lim, Jae Cheong; Cho, Eun Ha; Kim, Jin Joo; Lee, So Young; Choi, Sang Mu

    2014-01-01

    As Bombesin (BBS) binds with high affinity to GRPR, BBS derivatives have been labeled with various radionuclides such as 99 mTc, 111 In, 90 Y, 64 Cu, 177 Lu, 68 Ga, or 18 F and have proved to be successful candidates for peptide receptor radiotherapy (PRRT). In this study, we employed Ala(SO 3 H)-Aminooctanoyl as a linker of BBS antagonistic peptide sequence, Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH 2 , with DOTA to prepare radiolabeled candidates for GRPR targeting. A DOTA-conjugated BBS antagonistic analogue was synthesized and radiolabeled with 177 Lu, and in vitro characteristics on GRPR-overexpressing human prostate tumor cells were evaluated. In conclusion, a novel BBS antagonistic analogue, 177 Lu-DOTA-sBBNA, is a promising candidate for the targeting of GRPR-over-expressing tumors. Further investigations to evaluate its in vivo characteristics and therapeutic efficacy are needed

  7. Kazakhstan can achieve ambitious HIV targets despite expected donor withdrawal by combining improved ART procurement mechanisms with allocative and implementation efficiencies.

    Directory of Open Access Journals (Sweden)

    Andrew J Shattock

    Full Text Available Despite a non-decreasing HIV epidemic, international donors are soon expected to withdraw funding from Kazakhstan. Here we analyze how allocative, implementation, and technical efficiencies could strengthen the national HIV response under assumptions of future budget levels.We used the Optima model to project future scenarios of the HIV epidemic in Kazakhstan that varied in future antiretroviral treatment unit costs and management expenditure-two areas identified for potential cost-reductions. We determined optimal allocations across HIV programs to satisfy either national targets or ambitious targets. For each scenario, we considered two cases of future HIV financing: the 2014 national budget maintained into the future and the 2014 budget without current international investment.Kazakhstan can achieve its national HIV targets with the current budget by (1 optimally re-allocating resources across programs and (2 either securing a 35% [30%-39%] reduction in antiretroviral treatment drug costs or reducing management costs by 44% [36%-58%] of 2014 levels. Alternatively, a combination of antiretroviral treatment and management cost-reductions could be sufficient. Furthermore, Kazakhstan can achieve ambitious targets of halving new infections and AIDS-related deaths by 2020 compared to 2014 levels by attaining a 67% reduction in antiretroviral treatment costs, a 19% [14%-27%] reduction in management costs, and allocating resources optimally.With Kazakhstan facing impending donor withdrawal, it is important for the HIV response to achieve more with available resources. This analysis can help to guide HIV response planners in directing available funding to achieve the greatest yield from investments. The key changes recommended were considered realistic by Kazakhstan country representatives.

  8. Understanding the magnitude of emergent contaminant releases through target screening and metabolite identification using high resolution mass spectrometry: Illicit drugs in raw sewage influents.

    Science.gov (United States)

    Heuett, Nubia V; Batchu, Sudha Rani; Gardinali, Piero R

    2015-01-23

    A QExactive Orbitrap was used for the identification of phase I and II transformation products (TPs) of illicit drugs in raw sewage influents. Two operating modes (targeted MS(2) and Data-dependent screening) were used for data acquisition. Even though, data-dependent scan is a faster route towards the potential identification of metabolites, it suffered from its limitation to provide enough data points across the chromatographic peak during the MS(2) cycle in contrast to targeted MS(2). Therefore, the later technique was implemented as the method of choice in this study for the positive confirmation and quantitation of TPs (n=54). The vast majority of the identified TPs were products of phase I transformation reactions, with the latter being more prevalent in the nature. Estimated mole fractions showed that for a large number of the analytes, TPs must also be monitored in order to fully understand their environmental fate and calculate potential consumption. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. In vitro Evaluation of a Bombesin Antagonistic Analogue Conjugated with DOTA-Ala(SO{sub 3}H)-Aminooctanoyl for Targeting of the Gastrin-releasing Peptide Receptor

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Jae Cheong; Cho, Eun Ha; Kim, Jin Joo; Lee, So Young; Choi, Sang Mu [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2014-05-15

    As Bombesin (BBS) binds with high affinity to GRPR, BBS derivatives have been labeled with various radionuclides such as {sup 99}mTc, {sup 111}In, {sup 90}Y, {sup 64}Cu, {sup 177}Lu, {sup 68}Ga, or {sup 18}F and have proved to be successful candidates for peptide receptor radiotherapy (PRRT). In this study, we employed Ala(SO{sub 3}H)-Aminooctanoyl as a linker of BBS antagonistic peptide sequence, Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH{sub 2}, with DOTA to prepare radiolabeled candidates for GRPR targeting. A DOTA-conjugated BBS antagonistic analogue was synthesized and radiolabeled with {sup 177}Lu, and in vitro characteristics on GRPR-overexpressing human prostate tumor cells were evaluated. In conclusion, a novel BBS antagonistic analogue, {sup 177}Lu-DOTA-sBBNA, is a promising candidate for the targeting of GRPR-over-expressing tumors. Further investigations to evaluate its in vivo characteristics and therapeutic efficacy are needed.

  10. An efficient PEGylated liposomal nanocarrier containing cell-penetrating peptide and pH-sensitive hydrazone bond for enhancing tumor-targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Ding Y

    2015-10-01

    Full Text Available Yuan Ding,1,* Dan Sun,1,* Gui-Ling Wang,1 Hong-Ge Yang,1 Hai-Feng Xu,1 Jian-Hua Chen,2 Ying Xie,1,3 Zhi-Qiang Wang4 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 2School of Medicine, Jianghan University, Wuhan, 3State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, People’s Republic of China; 4Department of Chemistry and Biochemistry, Kent State University Geauga, Burton, OH, USA *These authors contributed equally to this work Abstract: Cell-penetrating peptides (CPPs as small molecular transporters with abilities of cell penetrating, internalization, and endosomal escape have potential prospect in drug delivery systems. However, a bottleneck hampering their application is the poor specificity for cells. By utilizing the function of hydration shell of polyethylene glycol (PEG and acid sensitivity of hydrazone bond, we constructed a kind of CPP-modified pH-sensitive PEGylated liposomes (CPPL to improve the selectivity of these peptides for tumor targeting. In CPPL, CPP was directly attached to liposome surfaces via coupling with stearate (STR to avoid the hindrance of PEG as a linker on the penetrating efficiency of CPP. A PEG derivative by conjugating PEG with STR via acid-degradable hydrazone bond (PEG2000-Hz-STR, PHS was synthesized. High-performance liquid chromatography and flow cytometry demonstrated that PHS was stable at normal neutral conditions and PEG could be completely cleaved from liposome surface to expose CPP under acidic environments in tumor. An optimal CPP density on liposomes was screened to guaranty a maximum targeting efficiency on tumor cells as well as not being captured by normal cells that consequently lead to a long circulation in blood. In vitro and in vivo studies indicated, in 4 mol% CPP of lipid modified system, that CPP exerted higher efficiency on internalizing the liposomes into

  11. The Combinational Use of CRISPR/Cas9 and Targeted Toxin Technology Enables Efficient Isolation of Bi-Allelic Knockout Non-Human Mammalian Clones

    Directory of Open Access Journals (Sweden)

    Satoshi Watanabe

    2018-04-01

    Full Text Available Recent advances in genome editing systems such as clustered regularly interspaced short palindromic repeats/CRISPR-associated protein-9 nuclease (CRISPR/Cas9 have facilitated genomic modification in mammalian cells. However, most systems employ transient treatment with selective drugs such as puromycin to obtain the desired genome-edited cells, which often allows some untransfected cells to survive and decreases the efficiency of generating genome-edited cells. Here, we developed a novel targeted toxin-based drug-free selection system for the enrichment of genome-edited cells. Cells were transfected with three expression vectors, each of which carries a guide RNA (gRNA, humanized Cas9 (hCas9 gene, or Clostridium perfringens-derived endo-β-galactosidase C (EndoGalC gene. Once EndoGalC is expressed in a cell, it digests the cell-surface α-Gal epitope, which is specifically recognized by BS-I-B4 lectin (IB4. Three days after transfection, these cells were treated with cytotoxin saporin-conjugated IB4 (IB4SAP for 30 min at 37 °C prior to cultivation in a normal medium. Untransfected cells and those weakly expressing EndoGalC will die due to the internalization of saporin. Cells transiently expressing EndoGalC strongly survive, and some of these surviving clones are expected to be genome-edited bi-allelic knockout (KO clones due to their strong co-expression of gRNA and hCas9. When porcine α-1,3-galactosyltransferase gene, which can synthesize the α-Gal epitope, was attempted to be knocked out, 16.7% and 36.7% of the surviving clones were bi-allelic and mono-allelic knockout (KO cells, respectively, which was in contrast to the isolation of clones in the absence of IB4SAP treatment. Namely, 0% and 13.3% of the resulting clones were bi-allelic and mono-allelic KO cells, respectively. A similar tendency was seen when other target genes such as DiGeorge syndrome critical region gene 2 and transforming growth factor-β receptor type 1 gene were

  12. Evaluation of efficient glucose release using sodium hydroxide and phosphoric acid as pretreating agents from the biomass of Sesbania grandiflora (L.) Pers.: A fast growing tree legume.

    Science.gov (United States)

    Mund, Nitesh K; Dash, Debabrata; Barik, Chitta R; Goud, Vaibhav V; Sahoo, Lingaraj; Mishra, Prasannajit; Nayak, Nihar R

    2017-07-01

    Sesbania grandiflora (L.) Pers. is one of the fast growing tree legumes having the efficiency to produce around 50tha -1 above ground dry matters in a year. In this study, biomass of 2years old S. grandiflora was selected for the chemical composition, pretreatments and enzymatic hydrolysis studies. The stem biomass with a wood density of 3.89±0.01gmcm -3 contains about 38% cellulose, 12% hemicellulose and 28% lignin. Enzymatic hydrolysis of pretreated biomass revealed that phosphoric acid (H 3 PO 4 ) pretreated samples even at lower cellulase loadings [1 Filter Paper Units (FPU)], could efficiently convert about 86% glucose, while, even at higher cellulase loadings (60FPU) alkali pretreated biomass could convert only about 58% glucose. The effectiveness of phosphoric acid pretreatment was also supported by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM) and Fourier transform infrared spectroscopy (FTIR) analysis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. CRISPRpred: A flexible and efficient tool for sgRNAs on-target activity prediction in CRISPR/Cas9 systems.

    Directory of Open Access Journals (Sweden)

    Md Khaledur Rahman

    Full Text Available The CRISPR/Cas9-sgRNA system has recently become a popular tool for genome editing and a very hot topic in the field of medical research. In this system, Cas9 protein is directed to a desired location for gene engineering and cleaves target DNA sequence which is complementary to a 20-nucleotide guide sequence found within the sgRNA. A lot of experimental efforts, ranging from in vivo selection to in silico modeling, have been made for efficient designing of sgRNAs in CRISPR/Cas9 system. In this article, we present a novel tool, called CRISPRpred, for efficient in silico prediction of sgRNAs on-target activity which is based on the applications of Support Vector Machine (SVM model. To conduct experiments, we have used a benchmark dataset of 17 genes and 5310 guide sequences where there are only 20% true values. CRISPRpred achieves Area Under Receiver Operating Characteristics Curve (AUROC-Curve, Area Under Precision Recall Curve (AUPR-Curve and maximum Matthews Correlation Coefficient (MCC as 0.85, 0.56 and 0.48, respectively. Our tool shows approximately 5% improvement in AUPR-Curve and after analyzing all evaluation metrics, we find that CRISPRpred is better than the current state-of-the-art. CRISPRpred is enough flexible to extract relevant features and use them in a learning algorithm. The source code of our entire software with relevant dataset can be found in the following link: https://github.com/khaled-buet/CRISPRpred.

  14. A Novel Energy-Efficient Multi-Sensor Fusion Wake-Up Control Strategy Based on a Biomimetic Infectious-Immune Mechanism for Target Tracking.

    Science.gov (United States)

    Zhou, Jie; Liang, Yan; Shen, Qiang; Feng, Xiaoxue; Pan, Quan

    2018-04-18

    A biomimetic distributed infection-immunity model (BDIIM), inspired by the immune mechanism of an infected organism, is proposed in order to achieve a high-efficiency wake-up control strategy based on multi-sensor fusion for target tracking. The resultant BDIIM consists of six sub-processes reflecting the infection-immunity mechanism: occurrence probabilities of direct-infection (DI) and cross-infection (CI), immunity/immune-deficiency of DI and CI, pathogen amount of DI and CI, immune cell production, immune memory, and pathogen accumulation under immunity state. Furthermore, a corresponding relationship between the BDIIM and sensor wake-up control is established to form the collaborative wake-up method. Finally, joint surveillance and target tracking are formulated in the simulation, in which we show that the energy cost and position tracking error are reduced to 50.8% and 78.9%, respectively. Effectiveness of the proposed BDIIM algorithm is shown, and this model is expected to have a significant role in guiding the performance improvement of multi-sensor networks.

  15. RoMo: An efficient strategy for functional mosaic analysis via stochastic Cre recombination and gene targeting in the ROSA26 locus.

    Science.gov (United States)

    Movahedi, Kiavash; Wiegmann, Robert; De Vlaminck, Karen; Van Ginderachter, Jo A; Nikolaev, Viacheslav O

    2018-07-01

    Functional mosaic analysis allows for the direct comparison of mutant cells with differentially marked control cells in the same organism. While this offers a powerful approach for elucidating the role of specific genes or signalling pathways in cell populations of interest, genetic strategies for generating functional mosaicism remain challenging. We describe a novel and streamlined approach for functional mosaic analysis, which combines stochastic Cre/lox recombination with gene targeting in the ROSA26 locus. With the RoMo strategy a cell population of interest is randomly split into a cyan fluorescent and red fluorescent subset, of which the latter overexpresses a chosen transgene. To integrate this approach into high-throughput gene targeting initiatives, we developed a procedure that utilizes Gateway cloning for the generation of new targeting vectors. RoMo can be used for gain-of-function experiments or for altering signaling pathways in a mosaic fashion. To demonstrate this, we developed RoMo-dnGs mice, in which Cre-recombined red fluorescent cells co-express a dominant-negative Gs protein. RoMo-dnGs mice allowed us to inhibit G protein-coupled receptor activation in a fraction of cells, which could then be directly compared to differentially marked control cells in the same animal. We demonstrate how RoMo-dnGs mice can be used to obtain mosaicism in the brain and in peripheral organs for various cell types. RoMo offers an efficient new approach for functional mosaic analysis that extends the current toolbox and may reveal important new insights into in vivo gene function. © 2018 Wiley Periodicals, Inc.

  16. Estimates of internal dose equivalent to 22 target organs for radionuclides occurring in routine releases from nuclear fuel-cycle facilities. Vol. 1

    International Nuclear Information System (INIS)

    Killough, G.G.; Dunning, D.E. Jr.; Bernard, S.R.; Pleasant, J.C.

    1978-01-01

    This report is the first of a two-volume tabulation of internal radiation dose conversion factors for man for radionuclides of interest in environmental assessments of light-water-reactor fuel cycles. This volume treats 68 radionuclides, all of mass number less than 150. Intake by inhalation and ingestion is considered. In the former case, the ICRP Task Group Lung Model has been used to simulate the behavior of particulate matter in the respiratory tract. Results corresponding to activity median aerodynamic diameters (AMAD) of 0.3, 1.0, and 5.0 μm are given. The GI tract has been represented by a four-segment catenary model with exponential transfer of radioactivity from one segment to the next. Retention of radionuclides in other organs was characterized by linear combinations of decaying exponential functions. Dose equivalent per microcurie intake of each parent nuclide is given for 22 target organs with contributions from specified source organs plus surplus activity in the rest of the body. Cross irradiation due to penetrating radiations has also been considered in the calculations

  17. Efficient tumor regression by adoptively transferred CEA-specific CAR-T cells associated with symptoms of mild cytokine release syndrome.

    Science.gov (United States)

    Wang, Linan; Ma, Ning; Okamoto, Sachiko; Amaishi, Yasunori; Sato, Eiichi; Seo, Naohiro; Mineno, Junichi; Takesako, Kazutoh; Kato, Takuma; Shiku, Hiroshi

    2016-01-01

    Carcinoembryonic antigen (CEA) is a cell surface antigen highly expressed in various cancer cell types and in healthy tissues. It has the potential to be a target for chimeric antigen receptor (CAR)-modified T-cell therapy; however, the safety of this approach in terms of on-target/off-tumor effects needs to be determined. To address this issue in a clinically relevant model, we used a mouse model in which the T cells expressing CEA-specific CAR were transferred into tumor-bearing CEA-transgenic (Tg) mice that physiologically expressed CEA as a self-antigen. The adoptive transfer in conjunction with lymphodepleting and myeloablative preconditioning mediated significant tumor regression but caused weight loss in CEA-Tg, but not in wild-type mice. The weight loss was not associated with overt inflammation in the CEA-expressing gastrointestinal tract but was associated with malnutrition, reflected in elevated systemic levels of cytokines linked to anorexia, which could be controlled by the administration of an anti-IL-6 receptor monoclonal antibody without compromising efficacy. The apparent relationship between lymphodepleting and myeloablative preconditioning, efficacy, and off-tumor toxicity of CAR-T cells would necessitate the development of CEA-specific CAR-T cells with improved signaling domains that require less stringent preconditioning for their efficacy. Taken together, these results suggest that CEA-specific CAR-based adoptive T-cell therapy may be effective for patients with CEA + solid tumors. Distinguishing the fine line between therapeutic efficacy and off-tumor toxicity would involve further modifications of CAR-T cells and preconditioning regimens.

  18. A novel fluoride anion modified gelatin nanogel system for ultrasound-triggered drug release.

    Science.gov (United States)

    Wu, Daocheng; Wan, Mingxi

    2008-01-01

    Controlled drug release, especially tumor-targeted drug release, remains a great challenge. Here, we prepare a novel fluoride anion-modified gelatin nanogel system and investigate its characteristics of ultrasound-triggered drug release. Adriamycin gelatin nanogel modified with fluoride anion (ADM-GNMF) was prepared by a modified co-precipitation method with fluoride anion and sodium sulfate. The loading and encapsulation efficiency of the anti-neoplastic agent adriamycin (ADM) were measured by high performance liquid chromatography (HPLC). The size and shape of ADM-GNMF were determined by electron microscopy and photo-correlation spectroscopy. The size distribution and drug release efficiency of ADM-GNMF, before and after sonication, were measured by two designed measuring devices that consisted of either a submicron particle size analyzer and an ultrasound generator as well as an ultrasound generator, automatic sampler, and HPLC. The ADM-GNMF was stable in solution with an average diameter of 46+/-12 nm; the encapsulation and loading efficiency of adriamycin were 87.2% and 6.38%, respectively. The ultrasound-triggered drug release and size change were most efficient at a frequency of 20 kHz, power density of 0.4w/cm2, and a 1~2 min duration. Under this ultrasound-triggered condition, 51.5% of drug in ADM-GNMF was released within 1~2 min, while the size of ADM-GNMF changed from 46 +/- 12 nm to 1212 +/- 35 nm within 1~2 min of sonication and restored to its previous size in 2~3 min after the ultrasound stopped. In contrast, 8.2% of drug in ADM-GNMF was released within 2~3 min without sonication, and only negligible size changes were found. The ADM-GNMF system efficiently released the encompassed drug in response to ultrasound, offering a novel and promising controlled drug release system for targeted therapy for cancer or other diseases.

  19. An efficient and target-oriented sample enrichment method for preparative separation of minor alkaloids by pH-zone-refining counter-current chromatography.

    Science.gov (United States)

    Feng, Rui-Hong; Hou, Jin-Jun; Zhang, Yi-Bei; Pan, Hui-Qin; Yang, Wenzhi; Qi, Peng; Yao, Shuai; Cai, Lu-Ying; Yang, Min; Jiang, Bao-Hong; Liu, Xuan; Wu, Wan-Ying; Guo, De-An

    2015-08-28

    An efficient and target-oriented sample enrichment method was established to increase the content of the minor alkaloids in crude extract by using the corresponding two-phase solvent system applied in pH-zone-refining counter-current chromatography. The enrichment and separation of seven minor indole alkaloids from Uncaria rhynchophylla (Miq.) Miq. ex Havil(UR) were selected as an example to show the advantage of this method. An optimized two-phase solvent system composed of n-hexane-ethyl acetate-methanol-water (3:7:1:9, v/v) was used in this study, where triethylamine (TEA) as the retainer and hydrochloric acid (HCl) as the eluter were added at the equimolar of 10mM. Crude alkaloids of UR dissolved in the corresponding upper phase (containing 10mM TEA) were extracted twice with lower phase (containing 10mM TEA) and lower phase (containing 10mM HCl), respectively, the second lower phase extract was subjected to pH-zone-refining CCC separation after alkalization and desalination. Finally, from 10g of crude alkaloids, 4g of refined alkaloids was obtained and the total content of seven target indole alkaloids was increased from 4.64% to 15.78%. Seven indole alkaloids, including 54mg isocorynoxeine, 21mg corynoxeine, 46mg isorhynchophylline, 35mg rhynchophylline, 65mg hirsutine, 51mg hirsuteine and 27mg geissoschizine methylether were all simultaneously separated from 2.5g of refined alkaloids, with the purity of 86.4%, 97.5%, 90.3%, 92.1%, 98.5%, 92.3%, and 92.8%, respectively. The total content and purities of the seven minor indole alkaloids were tested by HPLC and their chemical structures were elucidated by ESI-HRMS and (1)H NMR. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Disposal of residues according paragraph 97 StrlSchV - Efficient self control and handling of applications for release from regulatory control; Entsorgung von Rueckstaenden nach paragraph 97 StrlSchV - effektive Selbstueberwachung und Bearbeitung von Entlassungsverfahren

    Energy Technology Data Exchange (ETDEWEB)

    Gellermann, R. [HGN Hydrogeologie GmbH, Braunschweig (Germany)

    2005-07-01

    To control residues according to paragraph 97 of the German Radiation Protection Ordinance (StrlSchV), the ordinance earmarks a self - control of involved companies in the case of very low specific activities, an authorisation of release from regulatory control to disposal in the case of higher specific activities and a balancing of disposed activities in the case of large amounts. The realisation of this regulation requires the exchange of information between owners of residues, disposing companies and authorities. In order to make this information available and controllable in an efficient way, a well structured system of documents was developed analogue to an existing system in waste management. Practical experiences with this system are discussed. (orig.)

  1. Efficient internalization of mesoporous silica particles of different sizes by primary human macrophages without impairment of macrophage clearance of apoptotic or antibody-opsonized target cells

    International Nuclear Information System (INIS)

    Witasp, Erika; Kupferschmidt, Natalia; Bengtsson, Linnea; Hultenby, Kjell; Smedman, Christian; Paulie, Staffan; Garcia-Bennett, Alfonso E.; Fadeel, Bengt

    2009-01-01

    Macrophage recognition and ingestion of apoptotic cell corpses, a process referred to as programmed cell clearance, is of considerable importance for the maintenance of tissue homeostasis and in the resolution of inflammation. Moreover, macrophages are the first line of defense against microorganisms and other foreign materials including particles. However, there is sparse information on the mode of uptake of engineered nanomaterials by primary macrophages. In this study, mesoporous silica particles with cubic pore geometries and covalently fluorescein-grafted particles were synthesized through a novel route, and their interactions with primary human monocyte-derived macrophages were assessed. Efficient and active internalization of mesoporous silica particles of different sizes was observed by transmission electron microscopic and flow cytometric analysis and studies using pharmacological inhibitors suggested that uptake occurred through a process of endocytosis. Moreover, uptake of silica particles was independent of serum factors. The silica particles with very high surface areas due to their porous structure did not impair cell viability or function of macrophages, including the ingestion of different classes of apoptotic or opsonized target cells. The current findings are relevant to the development of mesoporous materials for drug delivery and other biomedical applications.

  2. Assessment of cooperation mechanism options: Cost-efficient and sustainable deployment of renewable energy sources towards the 20% target by 2020, and beyond. D3.2

    Energy Technology Data Exchange (ETDEWEB)

    Pade Hansen, L.-L.; Klinge Jacobsen, H.; Skovsgaard Nielsen, L.

    2012-12-15

    The RES Directive 2009/28/EC (European Commission 2009) set legally binding targets for EU Member States on energy consumption from renewable sources - the 2020 RES targets. A part of this can be achieved through the use of cooperation mechanisms: statistical transfer, joint project and joint support schemes. The intention of the cooperation mechanisms is to provide the flexibility needed to achieve Europe's renewable energy targets in a more cost-efficient way. In Task 3 of the RES4Less project we analyse the benefits and challenges of using the two cooperation mechanisms: joint project and joint support schemes. This report is the outcome of the work in Task 3.2 where we analyse how the barriers can be overcome and how different design options can be used under varying conditions and time horizons. Cooperation mechanisms have the potential to reduce the compliance costs of reaching the 2020 RES targets for EU member states. The largest benefits can be achieved under full harmonisation and one joints support scheme. However, the different national objectives along with uneven distribution of benefits and costs make this unrealistic in the near future. Cooperation between pairs or groups of countries with large net benefits that can be relatively easy estimated and shared is attractive and realisable in a shorter time horizon. Joint project cooperation is the most flexible instrument to use as it preserves the national legislation and support schemes (national objectives) and can be easily scaled in size. The drawback is the high transaction costs and some uncertainty regarding which party should carry the project implementation risk and guaranty the support for the projects for the entire lifetime. The joint projects can be realised in a short term horizon and as such pave the way for further cooperation. Large projects has a considerable advantage in the reduced transaction cost relative to project size and governments can be expected to be more willing to

  3. 2',3-dihydroxy-5-methoxybiphenyl suppresses fMLP-induced superoxide anion production and cathepsin G release by targeting the β-subunit of G-protein in human neutrophils.

    Science.gov (United States)

    Liao, Hsiang-Ruei; Chen, Ih-Sheng; Liu, Fu-Chao; Lin, Shinn-Zhi; Tseng, Ching-Ping

    2018-06-15

    This study investigates the effect and the underlying mechanism of 2',3-dihydroxy-5-methoxybiphenyl (RIR-2), a lignan extracted from the roots of Rhaphiolepis indica (L.) Lindl. ex Ker var. tashiroi Hayata ex Matsum. & Hayata (Rosaceae), on N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-induced respiratory burst and cathepsin G in human neutrophils. Signaling pathways regulated by RIR-2 which modulated fMLP-induced respiratory burst were evaluated by an interaction between β subunit of G-protein (Gβ) with downstream signaling induced by fMLP and by immunoblotting analysis of the downstream targets of Gβ-protein. RIR-2 inhibited fMLP-induced superoxide anion production (IC 50 :2.57 ± 0.22 μM), cathepsin G release (IC 50 :18.72 ± 3.76 μM) and migration in a concentration dependent manner. RIR-2 specifically suppresses fMLP-induced Src family kinases phosphorylation by inhibiting the interaction between Gβ-protein with Src kinases without inhibiting Src kinases activities, therefore, RIR-2 attenuated the downstream targets of Src kinase, such as phosphorylation of Raf/ERK, AKT, P38, PLCγ2, PKC and translocation Tec, p47 ph ° x and P40 ph ° x from the cytosol to the inner leaflet of the plasma membrane. Furthermore, RIR-2 attenuated fMLP-induced intracellular calcium mobilization by inhibiting the interaction between Gβ-protein with PLCβ2. RIR-2 was not a competitive or allosteric antagonist of fMLP. On the contrary, phorbol 12-myristate 13-acetate (PMA)-induced phosphorylation of Src, AKT, P38, PKC and membrane localization of p47 ph ° x and P40 ph ° x remained unaffected. RIR-2 specifically modulates fMLP-mediated neutrophil superoxide anion production and cathepsin G release by inhibiting the interaction between Gβ-protein with downstream signaling which subsequently interferes with the activation of intracellular calcium, PLCγ2, AKT, p38, PKC, ERK, p47 ph ° x and p40 phox . Copyright © 2018 Elsevier B.V. All rights reserved.

  4. XIAP over-expression is an independent poor prognostic marker in Middle Eastern breast cancer and can be targeted to induce efficient apoptosis.

    Science.gov (United States)

    Hussain, Azhar R; Siraj, Abdul Khalid; Ahmed, Maqbool; Bu, Rong; Pratheeshkumar, Poyil; Alrashed, Alanood M; Qadri, Zeeshan; Ajarim, Dahish; Al-Dayel, Fouad; Beg, Shaham; Al-Kuraya, Khawla S

    2017-09-11

    Breast cancer is the most common cancer in females and is ranked second in cancer-related deaths all over the world in women. Despite improvement in diagnosis, the survival rate of this disease has still not improved. X-linked Inhibitor of Apoptosis (XIAP) has been shown to be over-expressed in various cancers leading to poor overall survival. However, the role of XIAP in breast cancer from Middle Eastern region has not been fully explored. We examined the expression of XIAP in more than 1000 Middle Eastern breast cancer cases by immunohistochemistry. Apoptosis was measured by flow cytometry. Protein expression was determined by western blotting. Finally, in vivo studies were performed on nude mice following xenografting and treatment with inhibitors. XIAP was found to be over-expressed in 29.5% of cases and directly associated with clinical parameters such as tumor size, extra nodal extension, triple negative breast cancer and poorly differentiated breast cancer subtype. In addition, XIAP over-expression was also significantly associated with PI3-kinase pathway protein; p-AKT, proliferative marker; Ki-67 and anti-apoptotic marker; PARP. XIAP over-expression in our cohort of breast cancer was an independent poor prognostic marker in multivariate analysis. Next, we investigated inhibition of XIAP using a specific inhibitor; embelin and found that embelin treatment led to inhibition of cell viability and induction of apoptosis in breast cancer cells. Finally, breast cancer cells treated with combination of embelin and PI3-kinase inhibitor; LY294002 synergistically induced apoptosis and caused tumor growth regression in vivo. These data suggest that XIAP may be playing an important role in the pathogenesis of breast cancer and can be therapeutically targeted either alone or in combination with PI3-kinase inhibition to induce efficient apoptosis in breast cancer cells.

  5. Direct detection of RNA in vitro and in situ by target-primed RCA: The impact of E. coli RNase III on the detection efficiency of RNA sequences distanced far from the 3'-end.

    Science.gov (United States)

    Merkiene, Egle; Gaidamaviciute, Edita; Riauba, Laurynas; Janulaitis, Arvydas; Lagunavicius, Arunas

    2010-08-01

    We improved the target RNA-primed RCA technique for direct detection and analysis of RNA in vitro and in situ. Previously we showed that the 3' --> 5' single-stranded RNA exonucleolytic activity of Phi29 DNA polymerase converts the target RNA into a primer and uses it for RCA initiation. However, in some cases, the single-stranded RNA exoribonucleolytic activity of the polymerase is hindered by strong double-stranded structures at the 3'-end of target RNAs. We demonstrate that in such hampered cases, the double-stranded RNA-specific Escherichia coli RNase III efficiently assists Phi29 DNA polymerase in converting the target RNA into a primer. These observations extend the target RNA-primed RCA possibilities to test RNA sequences distanced far from the 3'-end and customize this technique for the inner RNA sequence analysis.

  6. An evaluation of energy-environment-economic efficiency for EU, APEC and ASEAN countries: Design of a Target-Oriented DFM model with fixed factors in Data Envelopment Analysis

    International Nuclear Information System (INIS)

    Suzuki, Soushi; Nijkamp, Peter

    2016-01-01

    This paper aims to offer an advanced assessment methodology for sustainable national energy-environment-economic efficiency strategies, based on an extended Data Envelopment Analysis (DEA). The use of novel efficiency-improving approaches based on DEA originates from the so-called Distance Friction Minimisation (DFM) method. To design a feasible improvement strategy for low-efficiency DMUs, we develop here a Target-Oriented (TO) DFM model. However, in many real-world cases input factors may not be flexibly adjusted in the short run. In this study, we integrate the TO-DFM model with a fixed (inflexible) factor (FF) approach to cope with such more realistic circumstances. Super-efficiency DEA is next used in our comparative study on the efficiency assessment of energy-environment-economic targets for the EU, APEC and ASEAN (A&A) countries, employing appropriate data sets from the years 2003 to 2012. We consider two inputs (primary energy consumption and population) and two outputs (CO 2 and GDP), including a fixed input factor (viz. population). On the basis of our DEA analysis results, EU countries appear to exhibit generally a higher efficiency than A&A countries. The above-mentioned TO-DFM-FF projection model is able to address realistic circumstances and requirements in an operational sustainability strategy for efficiency improvement in inefficient countries in the A&A region. - Highlights: • We examine energy-environment-economic efficiency in European and A&A countries. • We present an operational efficiency improvement strategy using DEA. • European countries tend to have higher energy efficiency than A&A countries. • The study provides efficiency-enhancing strategic paths for inefficient countries.

  7. pH-triggered echogenicity and contents release from liposomes.

    Science.gov (United States)

    Nahire, Rahul; Hossain, Rayat; Patel, Rupa; Paul, Shirshendu; Meghnani, Varsha; Ambre, Avinash H; Gange, Kara N; Katti, Kalpana S; Leclerc, Estelle; Srivastava, D K; Sarkar, Kausik; Mallik, Sanku

    2014-11-03

    Liposomes are representative lipid nanoparticles widely used for delivering anticancer drugs, DNA fragments, or siRNA to cancer cells. Upon targeting, various internal and external triggers have been used to increase the rate for contents release from the liposomes. Among the internal triggers, decreased pH within the cellular lysosomes has been successfully used to enhance the rate for releasing contents. However, imparting pH sensitivity to liposomes requires the synthesis of specialized lipids with structures that are substantially modified at a reduced pH. Herein, we report an alternative strategy to render liposomes pH sensitive by encapsulating a precursor which generates gas bubbles in situ in response to acidic pH. The disturbance created by the escaping gas bubbles leads to the rapid release of the encapsulated contents from the liposomes. Atomic force microscopic studies indicate that the liposomal structure is destroyed at a reduced pH. The gas bubbles also render the liposomes echogenic, allowing ultrasound imaging. To demonstrate the applicability of this strategy, we have successfully targeted doxorubicin-encapsulated liposomes to the pancreatic ductal carcinoma cells that overexpress the folate receptor on the surface. In response to the decreased pH in the lysosomes, the encapsulated anticancer drug is efficiently released. Contents released from these liposomes are further enhanced by the application of continuous wave ultrasound (1 MHz), resulting in substantially reduced viability for the pancreatic cancer cells (14%).

  8. Biofortified varieties released under HarvestPlus

    African Journals Online (AJOL)

    Chapter 5: Annex 1 - Biofortified varieties released under HarvestPlus (as of December 2016). Crop. Micronutrient. Country. Variety. Year of Release. Origin. Type. Baseline. (ppm). Target increment. (ppm). Increment. (ppm). % Target. Increment. (ppm). Micronutrient. Content. (ppm). 11940. BRRI dhan64. 2014. BRRI. Boro.

  9. Phosphorus release capacity of soluble P fertilizers and insoluble rock phosphate in response to phosphate solubilizing bacteria and poultry manure and their effect on plant growth promotion and P utilization efficiency of chilli (Capsicum annuum L.)

    Science.gov (United States)

    Abbasi, M. K.; Musa, N.; Manzoor, M.

    2015-01-01

    The ability of soil microorganisms and organic manures to convert insoluble phosphorus (P) to an accessible form offers a biological rescue system for improving P solubilization and utilization in soil-plant systems. Our objective was to examine the P supplying capacity of soluble P fertilizers (SPF) i.e. single super phosphate (SSP) and di-ammonium phosphate (DAP) and insoluble rock phosphate (RP) after adding phosphate solubilizing bacteria (PSB) and poultry manure (PM) and their subsequent effect on the growth, yield and P-utilization efficiency (PUE) of chill (Capsicum annuum L.). An incubation study was carried-out on a sandy loam neutral soil with twelve treatments including T0: control; T1: RP; T2: SSP; T3: DAP; T4: PM; T5: 1/2 RP + 1/2 SSP; T6: 1/2 RP + 1/2 DAP; T7: 1/2 RP + 1/2 PM; T8: RP + PSB; T9: 1/2 RP + 1/2 SSP + PSB; T10: 1/2 RP + 1/2 DAP + PSB; T11: 1/2 RP + 1/2 PM + PSB. Phosphorus release capacity of added amendments was measured by analyzing extractable P from the amended soil incubated under controlled condition at 25 °C for 0, 5, 15, 25, 35, 60 days period. To complement the incubation study, a greenhouse experiment was conducted in pots with chilli (Capsicum annuum L.) used as a test crop. Growth, yield, P-uptake and PUE of the chilli was determined during the study. Results indicated that P release capacity of soil amended with RP varied between 6.0 and 11.5 mg kg-1 while the soluble P fertilizers i.e. SSP and DAP displayed a maximum of 73 and 68 mg P kg-1 at the start of the experiment (day 0). However, the P released tendency from SSP and DAP declined during incubation and at the end 82 and 79% of P initially present had been lost from the mineral pool. Integrated use of PSB and PM with RP in 1/2 RP + 1/2 PM + PSB treatment stimulated P mineralization by releasing a maximum of 25 mg P kg-1 that was maintained at high levels without any loss. Application of PSB tended to decrease pH showing an acidifying effect on soil. In the greenhouse

  10. The Epstein-Barr virus miR-BHRF1-1 targets RNF4 during productive infection to promote the accumulation of SUMO conjugates and the release of infectious virus.

    Directory of Open Access Journals (Sweden)

    Jinlin Li

    2017-04-01

    Full Text Available Post-translational modification by the Small Ubiquitin-like Modifier (SUMO regulates a variety of cellular functions, and is hijacked by viruses to remodel the host cell during latent and productive infection. Here we have monitored the activity of the SUMO conjugation machinery in cells productively infected with Epstein-Barr virus (EBV. We found that SUMO2/3 conjugates accumulate during the late phase of the productive virus cycle, and identified several viral proteins as bone fide SUMOylation substrates. Analysis of the mechanism involved in the accumulation of SUMOylated proteins revealed upregulation of several components of the SUMO-conjugation machinery and post-transcriptional downregulation of the SUMO-targeted ubiquitin ligase RNF4. The latter effect was mediated by selective inhibition of RNF4 protein expression by the viral miR-BHRF1-1. Reconstitution of RNF4 in cells expressing an inducible miR-BHRF1-1 sponge or a miR-BHRF1-1 resistant RNF4 was associated with reduced levels of early and late viral proteins and impaired virus release. These findings illustrate a novel strategy for viral interference with the SUMO pathway, and identify the EBV miR-BHRF1-1 and the cellular RNF4 as regulators of the productive virus cycle.

  11. The Epstein-Barr virus miR-BHRF1-1 targets RNF4 during productive infection to promote the accumulation of SUMO conjugates and the release of infectious virus.

    Science.gov (United States)

    Li, Jinlin; Callegari, Simone; Masucci, Maria G

    2017-04-01

    Post-translational modification by the Small Ubiquitin-like Modifier (SUMO) regulates a variety of cellular functions, and is hijacked by viruses to remodel the host cell during latent and productive infection. Here we have monitored the activity of the SUMO conjugation machinery in cells productively infected with Epstein-Barr virus (EBV). We found that SUMO2/3 conjugates accumulate during the late phase of the productive virus cycle, and identified several viral proteins as bone fide SUMOylation substrates. Analysis of the mechanism involved in the accumulation of SUMOylated proteins revealed upregulation of several components of the SUMO-conjugation machinery and post-transcriptional downregulation of the SUMO-targeted ubiquitin ligase RNF4. The latter effect was mediated by selective inhibition of RNF4 protein expression by the viral miR-BHRF1-1. Reconstitution of RNF4 in cells expressing an inducible miR-BHRF1-1 sponge or a miR-BHRF1-1 resistant RNF4 was associated with reduced levels of early and late viral proteins and impaired virus release. These findings illustrate a novel strategy for viral interference with the SUMO pathway, and identify the EBV miR-BHRF1-1 and the cellular RNF4 as regulators of the productive virus cycle.

  12. Target-mediated pharmacokinetic/pharmacodynamic model based meta-analysis and dosing regimen optimization of a long-acting release formulation of exenatide in patients with type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Hanqing Li

    2015-02-01

    Full Text Available A hybrid pharmacokinetic/pharmacodynamic (PK/PD model with extended-release (ER process and target mediated drug disposition (TMDD was developed for exenatide ER to account for its complex absorption process and glucagon-like peptide 1 receptor (GLP-1R-mediated non-linear PK behaviors along with its influences to fasting plasma glucose (FPG and hemoglobin A1c (HbA1c. Using hybrid PK/PD model, simulations were done to explore the potential dosing regimens which could achieve likelihood of more pharmacodynamic exposure with respect to FPG and HbA1c over a much shorter period compared with the currently used treatment protocol. The mean PK/PD data about exenatide ER for type 2 diabetes mellitus (T2DM were digitized from the publications, and the hybrid PK/PD model was performed using the Monolix 4.3 program. The plasma concentration-time and FPG/HbA1c-time profiles for exenatide ER subcutaneously administrated to patients with T2DM were well described by this hybrid model. Monte Carlo simulation was applied to mimic the PK profiles when higher loading dose 7.5 and 5.0 mg exenatide ER were subcutaneously administrated with different dosing intervals at the first 3 weeks of 30-week treatment. Two potentially optimizing schedules could improve the likelihood of achieving much more FPG and HbA1c exposures than currently used clinical treatment protocol.

  13. Techniques for Reaeration of Hydropower Releases.

    Science.gov (United States)

    1983-02-01

    release improvement. However, selected reservoir aeration studies not conducted primarily for improving hydroturbine releases but which have application...for hydroturbine release reaeration were also reviewed. Because oxygen transfer mechanisms are vitally important to the development of more efficient...the key words turbine aeration, turbine vent, turbine I’ aspiration, hydroturbine aeration, tailrace aeration, draft tube vent, and vacuum breaker. A

  14. Cost-Efficient and Sustainable Deployment of Renewable Energy Sources towards the 20% Target by 2020, and beyond. Summary of case studies for cooperation mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Dalla Longa, F. [ECN Policy Studies, Amsterdam (Netherlands); Klinge Jacobsen, H.; Pade Hnasen, L. [Technical University of Denmark DTU, Lyngby (Denmark); Tantareanu, C. [Center for Promotion of Clean and Efficient Energy ENERO, Bucharest (Romania); Caldes-Gomez, N.; Santamaria-Belda, M. [CIEMAT, Madrid (Spain)

    2012-09-15

    This document is a summary report highlighting the main aspect analyzed in the RES4LESS case studies. The document starts with an introductory chapter where the background that led to the selection of the case studies is outlined. In the following three chapters the case studies are presented, highlighting the most relevant results. A brief chapter concludes the document, giving an outlook on the follow-up activities of the RES4LESS project. This summary is intended not only as an introduction to the RES4LESS cases studies, but also as a guideline to read and interpret the in-depth analysis carried out in the final documents that describe the case studies in detail. These documents will be published in September 2012 on the RES4LESS website, www.res4less.eu. The objective of the RES4LESS project is to develop a Roadmap to cost-efficient deployment of energy from renewable sources (RES) in Europe, via cross-border cooperation mechanisms. The Commission has indicated that the 2020 targets for renewable energy (European Commission 2009) can be achieved through cooperation between Member States. This cooperation could lead to win-win situations, when a country with a large low-cost potential for renewable electricity could sell part of its surplus to a country with a limited and/or expensive potential. In the project, first a scoping exercise has been carried out to identify which countries could be candidates for cooperation. Next, three case studies have been elaborated to give a better view of what these cooperation mechanisms would entail in practice. The analysis has focused on renewable electricity (RES-E), although cooperation mechanisms could also be envisaged for renewable heat. Among the Member States providing the largest and cheapest surpluses Denmark, Romania and Spain have been chosen as Host Countries for the RES4LESS case studies. The technologies considered in the case studies are Offshore Wind for Denmark, Biomass for Romania, and CSP for Spain.

  15. Scale-up of high specific activity {sup 186g}Re production using graphite-encased thick {sup 186}W targets and demonstration of an efficient target recycling process

    Energy Technology Data Exchange (ETDEWEB)

    Balkin, Ethan R.; Gagnon, Katherine; Dorman, Eric [Washington Univ., Seattle, WA (United States). Dept. of Radiation Oncology; and others

    2017-07-01

    Production of high specific activity {sup 186g}Re is of interest for development of theranostic radiopharmaceuticals. Previous studies have shown that high specific activity {sup 186g}Re can be obtained by cyclotron irradiation of enriched {sup 186}W via the {sup 186}W(d,2n){sup 186g}Re reaction, but most irradiations were conducted at low beam currents and for short durations. In this investigation, enriched {sup 186}W metal targets were irradiated at high incident deuteron beam currents to demonstrate production rates and contaminants produced when using thick targets. Full-stopping thick targets, as determined using SRIM, were prepared by uniaxial pressing of powdered natural abundance W metal or 96.86% enriched {sup 186}W metal encased between two layers of graphite flakes for target material stabilization. An assessment of structural integrity was made on each target preparation. To assess the performance of graphite-encased thick {sup 186}W metal targets, along with the impact of encasing on the separation chemistry, targets were first irradiated using a 22 MeV deuteron beam for 10 min at 10, 20, and 27 μA, with an estimated nominal deuteron energy of 18.7 MeV on the {sup 186}W target material (after energy degradation correction from top graphite layer). Gamma-ray spectrometry was performed post EOB on all targets to assess production yields and radionuclidic byproducts. The investigation also evaluated a method to recover and recycle enriched target material from a column isolation procedure. Material composition analyses of target materials, pass-through/wash solutions and recycling process isolates were conducted with SEM, FTIR, XRD, EDS and ICP-MS spectrometry. To demonstrate scaled-up production, a graphite-encased {sup 186}W target made from recycled {sup 186}W was irradiated for ∝2 h with 18.7 MeV deuterons at a beam current of 27 μA to provide 0.90 GBq (24.3 mCi) of {sup 186g}Re, decay-corrected to the end of bombardment. ICP-MS analysis of the

  16. Efficiency of emulsifier-free emulsions and emulsions containing rapeseed lecithin as delivery systems for vectorization and release of coenzyme Q10: physico-chemical properties and in vitro evaluation.

    Science.gov (United States)

    Kaci, M; Arab-Tehrany, E; Dostert, G; Desjardins, I; Velot, E; Desobry, S

    2016-11-01

    To improve the encapsulation and release of coenzyme Q10 (CoQ10), emulsifier-free-emulsions were developed with a new emulsification process using high-frequency ultrasound (HFU) at 1.7MHz. Nano-emulsions containing CoQ10 were prepared with or without rapeseed lecithin as an emulsifier. The emulsions prepared with HFU were compared with an emulsion of CoQ10 containing emulsifier prepared with the same emulsification technique as well as with emulsions prepared with low-frequency ultrasound coupled with high-pressure homogenization (LFU+HPH). The physico-chemical properties of the emulsions were determined by average droplet size measurement with nano-droplet tracking analysis, droplet surface charge with ζ potential measurement, surface tension and rheological behaviour. Emulsions made by LFU+HPH with an emulsifier showed lower droplet sizes due to cavitation generated by the HFU process. Surface tension results showed that there was no significant difference between emulsions containing lecithin emulsifier regardless of the preparation process or the inclusion of CoQ10. In vitro biocompatibility tests were performed on human mesenchymal stem cells in order to show the cytotoxicity of various formulations and the efficiency of CoQ10-loaded emulsions. In vitro tests proved that the vectors were not toxic. Furthermore, CoQ10 facilitated a high rate of cell proliferation and metabolic activity especially when in an emulsifier-free formulation. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Tumor-targeted nanomedicines for cancer theranostics

    Science.gov (United States)

    Lammers, Twan; Shi, Yang

    2017-01-01

    Chemotherapeutic drugs have multiple drawbacks, including severe side effects and suboptimal therapeutic efficacy. Nanomedicines assist in improving the biodistribution and the target accumulation of chemotherapeutic drugs, and are therefore able to enhance the balance between efficacy and toxicity. Multiple different types of nanomedicines have been evaluated over the years, including liposomes, polymer-drug conjugates and polymeric micelles, which rely on strategies such as passive targeting, active targeting and triggered release for improved tumor-directed drug delivery. Based on the notion that tumors and metastases are highly heterogeneous, it is important to integrate imaging properties in nanomedicine formulations in order to enable non-invasive and quantitative assessment of targeting efficiency. By allowing for patient pre-selection, such next generation nanotheranostics are useful for facilitating clinical translation and personalizing nanomedicine treatments. PMID:27865762

  18. Biological evaluation of 177Lu-labeled DOTA-Ala(SO3H)-Aminooctanoyl-Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH2 for gastrin-releasing peptide receptor-positive prostate tumor targeting

    International Nuclear Information System (INIS)

    Lim, Jae Cheong; Cho, Eun Ha; Kim, Jin Joo; Choi, Sang Mu; Lee, So young; Nam, Sung Soo; Park, Ul Jae; Park, Soo Hyun

    2015-01-01

    Bombesin binds with selectivity and high affinity to a Gastrin-releasing peptide receptor (GRPR), which is highly overexpressed in prostate cancer cells. The present study describes the in vitro and in vivo biological characteristics of DOTA-Ala(SO 3 H)-Aminooctanoyl-Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH 2 (DOTA-sBBNA), an antagonist analogue of bombesin peptide for the targeting of GRPR. DOTA-sBBNA was synthesized and labeled with 177 Lu as previously published. A saturation assay on PC-3 human prostate cancer cells revealed that the Kd value of the radiolabeled peptide was 1.88 nM with a maximum binding capacity (Bmax) of 289.3 fmol/10 6 cells. The radio-peptide slowly internalized, and 24.4 ± 0.5% of the total binding was internalized in 4 hr. Biodistribution studies were conducted in healthy and PC-3 xenografted balb/c mice, which showed high uptake and retention of tumor-associated radioactivity in PC-3 xenografted mice. The tumor-to-blood ratio was 126.02 ± 9.36 at 1.5 hr p.i., and was increased to 216.33 ± 61.58 at 24 hr p.i., which means that the radiolabeled peptide was highly accumulated in a tumor and rapidly cleared from the blood pool. The GRPR is also over-expressed in Korean prostate cancer patients. These results suggest that this 177 Lu-labeled peptide has promising characteristics for application in nuclear medicine, namely for the diagnosis and treatment of GRPR over-expressing prostate tumors

  19. Highly efficient gene targeting in Aspergillus oryzae industrial strains under ligD mutation introduced by genome editing: Strain-specific differences in the effects of deleting EcdR, the negative regulator of sclerotia formation.

    Science.gov (United States)

    Nakamura, Hidetoshi; Katayama, Takuya; Okabe, Tomoya; Iwashita, Kazuhiro; Fujii, Wataru; Kitamoto, Katsuhiko; Maruyama, Jun-Ichi

    2017-07-11

    Numerous strains of Aspergillus oryzae are industrially used for Japanese traditional fermentation and for the production of enzymes and heterologous proteins. In A. oryzae, deletion of the ku70 or ligD genes involved in non-homologous end joining (NHEJ) has allowed high gene targeting efficiency. However, this strategy has been mainly applied under the genetic background of the A. oryzae wild strain RIB40, and it would be laborious to delete the NHEJ genes in many A. oryzae industrial strains, probably due to their low gene targeting efficiency. In the present study, we generated ligD mutants from the A. oryzae industrial strains by employing the CRISPR/Cas9 system, which we previously developed as a genome editing method. Uridine/uracil auxotrophic strains were generated by deletion of the pyrG gene, which was subsequently used as a selective marker. We examined the gene targeting efficiency with the ecdR gene, of which deletion was reported to induce sclerotia formation under the genetic background of the strain RIB40. As expected, the deletion efficiencies were high, around 60~80%, in the ligD mutants of industrial strains. Intriguingly, the effects of the ecdR deletion on sclerotia formation varied depending on the strains, and we found sclerotia-like structures under the background of the industrial strains, which have never been reported to form sclerotia. The present study demonstrates that introducing ligD mutation by genome editing is an effective method allowing high gene targeting efficiency in A. oryzae industrial strains.

  20. Hydrophobic Drug-Loaded PEGylated Magnetic Liposomes for Drug-Controlled Release

    Science.gov (United States)

    Hardiansyah, Andri; Yang, Ming-Chien; Liu, Ting-Yu; Kuo, Chih-Yu; Huang, Li-Ying; Chan, Tzu-Yi

    2017-05-01

    Less targeted and limited solubility of hydrophobic-based drug are one of the serious obstacles in drug delivery system. Thus, new strategies to enhance the solubility of hydrophobic drug and controlled release behaviors would be developed. Herein, curcumin, a model of hydrophobic drug, has been loaded into PEGylated magnetic liposomes as a drug carrier platform for drug controlled release system. Inductive magnetic heating (hyperthermia)-stimulated drug release, in vitro cellular cytotoxicity assay of curcumin-loaded PEGylated magnetic liposomes and cellular internalization-induced by magnetic guidance would be investigated. The resultant of drug carriers could disperse homogeneously in aqueous solution, showing a superparamagnetic characteristic and could inductive magnetic heating with external high-frequency magnetic field (HFMF). In vitro curcumin release studies confirmed that the drug carriers exhibited no significant release at 37 °C, whereas exhibited rapid releasing at 45 °C. However, it would display enormous (three times higher) curcumin releasing under the HFMF exposure, compared with that without HFMF exposure at 45 °C. In vitro cytotoxicity test shows that curcumin-loaded PEGylated magnetic liposomes could efficiently kill MCF-7 cells in parallel with increasing curcumin concentration. Fluorescence microscopy observed that these drug carriers could internalize efficiently into the cellular compartment of MCF-7 cells. Thus, it would be anticipated that the novel hydrophobic drug-loaded PEGylated magnetic liposomes in combination with inductive magnetic heating are promising to apply in the combination of chemotherapy and thermotherapy for cancer therapy.

  1. Experimental validation of plant peroxisomal targeting prediction algorithms by systematic comparison of in vivo import efficiency and in vitro PTS1 binding affinity.

    Science.gov (United States)

    Skoulding, Nicola S; Chowdhary, Gopal; Deus, Mara J; Baker, Alison; Reumann, Sigrun; Warriner, Stuart L

    2015-03-13

    Most peroxisomal matrix proteins possess a C-terminal targeting signal type 1 (PTS1). Accurate prediction of functional PTS1 sequences and their relative strength by computational methods is essential for determination of peroxisomal proteomes in silico but has proved challenging due to high levels of sequence variability of non-canonical targeting signals, particularly in higher plants, and low levels of availability of experimentally validated non-canonical examples. In this study, in silico predictions were compared with in vivo targeting analyses and in vitro thermodynamic binding of mutated variants within the context of one model targeting sequence. There was broad agreement between the methods for entire PTS1 domains and position-specific single amino acid residues, including residues upstream of the PTS1 tripeptide. The hierarchy Leu>Met>Ile>Val at the C-terminal position was determined for all methods but both experimental approaches suggest that Tyr is underweighted in the prediction algorithm due to the absence of this residue in the positive training dataset. A combination of methods better defines the score range that discriminates a functional PTS1. In vitro binding to the PEX5 receptor could discriminate among strong targeting signals while in vivo targeting assays were more sensitive, allowing detection of weak functional import signals that were below the limit of detection in the binding assay. Together, the data provide a comprehensive assessment of the factors driving PTS1 efficacy and provide a framework for the more quantitative assessment of the protein import pathway in higher plants. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Reduce in Variation and Improve Efficiency of Target Volume Delineation by a Computer-Assisted System Using a Deformable Image Registration Approach

    International Nuclear Information System (INIS)

    Chao, K.S. Clifford; Bhide, Shreerang FRCR; Chen, Hansen; Asper, Joshua PAC; Bush, Steven; Franklin, Gregg; Kavadi, Vivek; Liengswangwong, Vichaivood; Gordon, William; Raben, Adam; Strasser, Jon; Koprowski, Christopher; Frank, Steven; Chronowski, Gregory; Ahamad, Anesa; Malyapa, Robert; Zhang Lifei; Dong Lei

    2007-01-01

    Purpose: To determine whether a computer-assisted target volume delineation (CAT) system using a deformable image registration approach can reduce the variation of target delineation among physicians with different head and neck (HN) IMRT experiences and reduce the time spent on the contouring process. Materials and Methods: We developed a deformable image registration method for mapping contours from a template case to a patient case with a similar tumor manifestation but different body configuration. Eight radiation oncologists with varying levels of clinical experience in HN IMRT performed target delineation on two HN cases, one with base-of-tongue (BOT) cancer and another with nasopharyngeal cancer (NPC), by first contouring from scratch and then by modifying the contours deformed by the CAT system. The gross target volumes were provided. Regions of interest for comparison included the clinical target volumes (CTVs) and normal organs. The volumetric and geometric variation of these regions of interest and the time spent on contouring were analyzed. Results: We found that the variation in delineating CTVs from scratch among the physicians was significant, and that using the CAT system reduced volumetric variation and improved geometric consistency in both BOT and NPC cases. The average timesaving when using the CAT system was 26% to 29% for more experienced physicians and 38% to 47% for the less experienced ones. Conclusions: A computer-assisted target volume delineation approach, using a deformable image-registration method with template contours, was able to reduce the variation among physicians with different experiences in HN IMRT while saving contouring time

  3. Efficient generation of recombinant RNA viruses using targeted recombination-mediated mutagenesis of bacterial artificial chromosomes containing full-length cDNA

    DEFF Research Database (Denmark)

    Rasmussen, Thomas Bruun; Risager, Peter Christian; Fahnøe, Ulrik

    2013-01-01

    Background Infectious cDNA clones are a prerequisite for directed genetic manipulation of RNA viruses. Here, a strategy to facilitate manipulation and rescue of classical swine fever viruses (CSFVs) from full-length cDNAs present within bacterial artificial chromosomes (BACs) is described....... This strategy allows manipulation of viral cDNA by targeted recombination-mediated mutagenesis within bacteria. Results A new CSFV-BAC (pBeloR26) derived from the Riems vaccine strain has been constructed and subsequently modified in the E2 coding sequence, using the targeted recombination strategy to enable...

  4. Target-oriented obstacle analysis by PESTEL modeling of energy efficiency retrofit for existing residential buildings in China's northern heating region

    Energy Technology Data Exchange (ETDEWEB)

    Shilei, Lv [School of Environment Science and Technology, Tianjin University, Tianjin 300072 (China); Yong, Wu [Department of Science and Technology, Ministry of Housing and Urban-Rural Development of the People' s Republic of China, Beijing 100835 (China)

    2009-06-15

    According to the 'Comprehensive Work Program of Energy Efficiency and Emission Reduction' of the Chinese government, during the period of the '11th Five-Year Plan', 1.5 x 10{sup 8} m{sup 2} of existing residential buildings in China's northern heating region are to be retrofitted for energy efficiency. However, at present, this 'Energy Efficiency Retrofit for Existing Residential Buildings' (EERFERB) faces many obstacles. Under the current working and market system, both the central and local governments and the energy supply companies can not push on this work smoothly. Using both the results of the annual national special inspection of building energy efficiency and some case analyses, this paper examines the necessity for energy efficiency retrofit, along with the relationships among the various Political, Economic, Social, Technological, Environmental and Legal (PESTEL) factors affecting it. Furthermore, organizational, financial and technical support systems are explored to promote the development of retrofit. Finally, some primary principles to be followed toward the implementation of EERFERB are suggested. (author)

  5. Target-oriented obstacle analysis by PESTEL modeling of energy efficiency retrofit for existing residential buildings in China's northern heating region

    International Nuclear Information System (INIS)

    Shilei, Lv; Wu Yong

    2009-01-01

    According to the 'Comprehensive Work Program of Energy Efficiency and Emission Reduction' of the Chinese government, during the period of the '11th Five-Year Plan', 1.5x10 8 m 2 of existing residential buildings in China's northern heating region are to be retrofitted for energy efficiency. However, at present, this 'Energy Efficiency Retrofit for Existing Residential Buildings' (EERFERB) faces many obstacles. Under the current working and market system, both the central and local governments and the energy supply companies can not push on this work smoothly. Using both the results of the annual national special inspection of building energy efficiency and some case analyses, this paper examines the necessity for energy efficiency retrofit, along with the relationships among the various Political, Economic, Social, Technological, Environmental and Legal (PESTEL) factors affecting it. Furthermore, organizational, financial and technical support systems are explored to promote the development of retrofit. Finally, some primary principles to be followed toward the implementation of EERFERB are suggested.

  6. Lorazepam induces multiple disturbances in selective attention: attentional overload, decrement in target processing efficiency, and shifts in perceptual discrimination and response bias.

    Science.gov (United States)

    Michael, George Andrew; Bacon, Elisabeth; Offerlin-Meyer, Isabelle

    2007-09-01

    There is a general consensus that benzodiazepines affect attentional processes, yet only few studies have tried to investigate these impairments in detail. The purpose of the present study was to investigate the effects of a single dose of Lorazepam on performance in a target cancellation task with important time constraints. We measured correct target detections and correct distractor rejections, misses and false positives. The results show that Lorazepam produces multiple kinds of shifts in performance, which suggests that it impairs multipLe processes: (a) the evolution of performance over time was not the same between the placebo and the Lorazepam groups, with the Lorazepam affecting performance quite early after the beginning of the test. This is suggestive of a depletion of attentional resources during sequential attentional processing; (b) Lorazepam affected differently target and distractor processing, with target detection being the most impaired; (c) misses were more frequent under Lorazepam than under placebo, but no such difference was observed as far as false positives were concerned. Signal detection analyses showed that Lorazepam (d) decreased perceptual discrimination, and (e) reliably increased response bias. Our results bring new insights on the multiple effects of Lorazepam on selective attention which, when combined, may have deleterious effects on human performance.

  7. Inhibition of tumor growth by targeted anti-EGFR/IGF-1R Nanobullets depends on efficient blocking of cell survival pathways

    NARCIS (Netherlands)

    van der Meel, Roy; Oliveira, Sabrina; Altintas, Isil; Heukers, R.; Pieters, Ebel H.E.; van Bergen en Henegouwen, Paul M.P.; Storm, Gerrit; Hennink, Wim E.; Kok, Robbert J.; Schiffelers, Raymond M.

    2013-01-01

    The clinical efficacy of epidermal growth factor receptor (EGFR)-targeted inhibitors is limited due to resistance mechanisms of the tumor such as activation of compensatory pathways. Crosstalk between EGFR and insulin-like growth factor 1 (IGF-1R) signaling has been frequently described to be

  8. EPA Releases Neonicotinoid Assessments for Public Comment

    Science.gov (United States)

    Release of preliminary ecological and human health risk assessments for the neonicotinoid insecticides clothianidin, thiamethoxam, and dinotefuran, and a preliminary ecological risk assessment for imidacloprid, assessing risks to birds,mammals, non-target

  9. Natural Resource Management Index (NRMI), 2010 Release

    Data.gov (United States)

    National Aeronautics and Space Administration — The Natural Resource Management Index (NRMI), 2011 Release is a composite index for 174 countries derived from the average of four proximity-to-target indicators for...

  10. Natural Resource Management Index (NRMI), 2009 Release

    Data.gov (United States)

    National Aeronautics and Space Administration — The Natural Resource Management Index (NRMI), 2009 Release is a composite index for 171 countries derived from the average of four proximity-to-target indicators for...

  11. Natural Resource Management Index (NRMI), 2011 Release

    Data.gov (United States)

    National Aeronautics and Space Administration — The Natural Resource Management Index (NRMI), 2011 Release is a composite index for 174 countries derived from the average of four proximity-to-target indicators for...

  12. Natural Resource Management Index (NRMI), 2010 Release

    Data.gov (United States)

    National Aeronautics and Space Administration — The Natural Resource Management Index (NRMI), 2010 Release is a composite index for 157 countries derived from the average of four proximity-to-target indicators for...

  13. Monitoring of released radioactive gaseous and liquid effluent at Rokkasho Reprocessing Plant

    International Nuclear Information System (INIS)

    Oka, M.; Keta, S.; Nagai, S.; Kano, M.; Ishihara, N.; Moriyama, T.; Ogaki, K.; Noda, K.

    2009-01-01

    Rokkasho Reprocessing Plant (RRP) Rokkasho Reprocessing Plant started its active tests with spent fuel at the end of March 2006. When spent fuels are sheared and dissolved, radioactive gaseous effluent and radioactive liquid effluent such as krypton-85, tritium, etc. are released into the environment. In order to limit the public dose as low as reasonably achievable in an efficient way, RRP removes radioactive material by evaporation, rinsing, filtering, etc., and then releases it through the main stack and the sea discharge pipeline that allow to make dispersion and dilution very efficiently. Also, concerning the radioactive gaseous and liquid effluent to be released into the environment, the target values of annual release have been defined in the Safety Rule based on the estimated annual release evaluated at the safety review of RRP. By monitoring the radioactive material in gaseous exhaust and liquid effluent RRP controls it not to exceed the target values. RRP reprocessed 430 tUpr of spent fuel during Active Test (March 2006 to October 2008). In this report, we report about: The outline of gaseous and liquid effluent monitoring. The amount of radioactive gaseous and liquid effluent during the active test. The performance of removal of radioactive materials in gaseous and liquid effluents. The impact on the public from radioactive effluents during the active test. (author)

  14. News/Press Releases

    Data.gov (United States)

    Office of Personnel Management — A press release, news release, media release, press statement is written communication directed at members of the news media for the purpose of announcing programs...

  15. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized

    OpenAIRE

    van Delft, Mark F.; Wei, Andrew H.; Mason, Kylie D.; Vandenberg, Cassandra J.; Chen, Lin; Czabotar, Peter E.; Willis, Simon N.; Scott, Clare L.; Day, Catherine L.; Cory, Suzanne; Adams, Jerry M.; Roberts, Andrew W.; Huang, David C.S.

    2006-01-01

    Since apoptosis is impaired in malignant cells overexpressing pro-survival Bcl-2 proteins, drugs mimicking their natural antagonists, BH3-only proteins, might overcome chemoresistance. Of seven putative BH3 mimetics tested, only ABT-737 triggered Bax/Bak-mediated apoptosis. Despite its high affinity for Bcl-2, Bcl-xL and Bcl-w, many cell types proved refractory to ABT-737. We show that this resistance reflects its inability to target another pro-survival relative, Mcl-1. Down-regulation of Mc...

  16. Mesoporous Fe3O4/hydroxyapatite composite for targeted drug delivery

    International Nuclear Information System (INIS)

    Gu, Lina; He, Xiaomei; Wu, Zhenyu

    2014-01-01

    Highlights: • Mesoporous Fe 3 O 4 /hydroxyapatite composite was synthesized by a simple, efficient and environmental friendly method. • The prepared material had a large surface area, high pore volume, and good magnetic separability. • DOX-loaded Fe 3 O 4 /hydroxyapatite composite exhibited surprising slow drug release behavior and pH-dependent behavior. - Abstract: In this contribution, we introduced a simple, efficient, and green method of preparing a mesoporous Fe 3 O 4 /hydroxyapatite (HA) composite. The as-prepared material had a large surface area, high pore volume, and good magnetic separability, which made it suitable for targeted drug delivery systems. The chemotherapeutic agent doxorubicin (DOX) was used to investigate the drug release behavior of Fe 3 O 4 /HA composite. The drug release profiles displayed a little burst effect and pH-dependent behavior. The release rate of DOX at pH 5.8 was larger than that at pH 7.4, which could be attributed to DOX protonation in acid medium. In addition, the released DOX concentrations remained at 0.83 and 1.39 μg/ml at pH 7.4 and 5.8, respectively, which indicated slow, steady, and safe release rates. Therefore, the as-prepared Fe 3 O 4 /hydroxyapatite composite could be an efficient platform for targeted anticancer drug delivery

  17. Mesoporous Fe{sub 3}O{sub 4}/hydroxyapatite composite for targeted drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Gu, Lina; He, Xiaomei; Wu, Zhenyu, E-mail: zhenyuwuhn@sina.com

    2014-11-15

    Highlights: • Mesoporous Fe{sub 3}O{sub 4}/hydroxyapatite composite was synthesized by a simple, efficient and environmental friendly method. • The prepared material had a large surface area, high pore volume, and good magnetic separability. • DOX-loaded Fe{sub 3}O{sub 4}/hydroxyapatite composite exhibited surprising slow drug release behavior and pH-dependent behavior. - Abstract: In this contribution, we introduced a simple, efficient, and green method of preparing a mesoporous Fe{sub 3}O{sub 4}/hydroxyapatite (HA) composite. The as-prepared material had a large surface area, high pore volume, and good magnetic separability, which made it suitable for targeted drug delivery systems. The chemotherapeutic agent doxorubicin (DOX) was used to investigate the drug release behavior of Fe{sub 3}O{sub 4}/HA composite. The drug release profiles displayed a little burst effect and pH-dependent behavior. The release rate of DOX at pH 5.8 was larger than that at pH 7.4, which could be attributed to DOX protonation in acid medium. In addition, the released DOX concentrations remained at 0.83 and 1.39 μg/ml at pH 7.4 and 5.8, respectively, which indicated slow, steady, and safe release rates. Therefore, the as-prepared Fe{sub 3}O{sub 4}/hydroxyapatite composite could be an efficient platform for targeted anticancer drug delivery.

  18. Simulation study of 3–5 keV x-ray conversion efficiency from Ar K-shell vs. Ag L-shell targets on the National Ignition Facility laser

    Energy Technology Data Exchange (ETDEWEB)

    Kemp, G. E., E-mail: kemp10@llnl.gov; Colvin, J. D.; Fournier, K. B.; May, M. J.; Barrios, M. A.; Patel, M. V.; Scott, H. A.; Marinak, M. M. [Lawrence Livermore National Laboratory, Livermore, California 94550-9698 (United States)

    2015-05-15

    Tailored, high-flux, multi-keV x-ray sources are desirable for studying x-ray interactions with matter for various civilian, space and military applications. For this study, we focus on designing an efficient laser-driven non-local thermodynamic equilibrium 3–5 keV x-ray source from photon-energy-matched Ar K-shell and Ag L-shell targets at sub-critical densities (∼n{sub c}/10) to ensure supersonic, volumetric laser heating with minimal losses to kinetic energy, thermal x rays and laser-plasma instabilities. Using HYDRA, a multi-dimensional, arbitrary Lagrangian-Eulerian, radiation-hydrodynamics code, we performed a parameter study by varying initial target density and laser parameters for each material using conditions readily achievable on the National Ignition Facility (NIF) laser. We employ a model, benchmarked against Kr data collected on the NIF, that uses flux-limited Lee-More thermal conductivity and multi-group implicit Monte-Carlo photonics with non-local thermodynamic equilibrium, detailed super-configuration accounting opacities from CRETIN, an atomic-kinetics code. While the highest power laser configurations produced the largest x-ray yields, we report that the peak simulated laser to 3–5 keV x-ray conversion efficiencies of 17.7% and 36.4% for Ar and Ag, respectively, occurred at lower powers between ∼100–150 TW. For identical initial target densities and laser illumination, the Ag L-shell is observed to have ≳10× higher emissivity per ion per deposited laser energy than the Ar K-shell. Although such low-density Ag targets have not yet been demonstrated, simulations of targets fabricated using atomic layer deposition of Ag on silica aerogels (∼20% by atomic fraction) suggest similar performance to atomically pure metal foams and that either fabrication technique may be worth pursuing for an efficient 3–5 keV x-ray source on NIF.

  19. From leaf to whole-plant water use efficiency (WUE in complex canopies: Limitations of leaf WUE as a selection target

    Directory of Open Access Journals (Sweden)

    Hipólito Medrano

    2015-06-01

    Full Text Available Plant water use efficiency (WUE is becoming a key issue in semiarid areas, where crop production relies on the use of large volumes of water. Improving WUE is necessary for securing environmental sustainability of food production in these areas. Given that climate change predictions include increases in temperature and drought in semiarid regions, improving crop WUE is mandatory for global food production. WUE is commonly measured at the leaf level, because portable equipment for measuring leaf gas exchange rates facilitates the simultaneous measurement of photosynthesis and transpiration. However, when those measurements are compared with daily integrals or whole-plant estimates of WUE, the two sometimes do not agree. Scaling up from single-leaf to whole-plant WUE was tested in grapevines in different experiments by comparison of daily integrals of instantaneous water use efficiency [ratio between CO2 assimilation (AN and transpiration (E; AN/E] with midday AN/E measurements, showing a low correlation, being worse with increasing water stress. We sought to evaluate the importance of spatial and temporal variation in carbon and water balances at the leaf and plant levels. The leaf position (governing average light interception in the canopy showed a marked effect on instantaneous and daily integrals of leaf WUE. Night transpiration and respiration rates were also evaluated, as well as respiration contributions to total carbon balance. Two main components were identified as filling the gap between leaf and whole plant WUE: the large effect of leaf position on daily carbon gain and water loss and the large flux of carbon losses by dark respiration. These results show that WUE evaluation among genotypes or treatments needs to be revised.

  20. Stimuli responsive nanomaterials for controlled release applications

    KAUST Repository

    Li, Song

    2012-01-01

    The controlled release of therapeutics has been one of the major challenges for scientists and engineers during the past three decades. Coupled with excellent biocompatibility profiles, various nanomaterials have showed great promise for biomedical applications. Stimuli-responsive nanomaterials guarantee the controlled release of cargo to a given location, at a specific time, and with an accurate amount. In this review, we have combined the major stimuli that are currently used to achieve the ultimate goal of controlled and targeted release by "smart" nanomaterials. The most heavily explored strategies include (1) pH, (2) enzymes, (3) redox, (4) magnetic, and (5) light-triggered release.

  1. Human CD3+ T-Cells with the Anti-ERBB2 Chimeric Antigen Receptor Exhibit Efficient Targeting and Induce Apoptosis in ERBB2 Overexpressing Breast Cancer Cells

    Science.gov (United States)

    Munisvaradass, Rusheni; Kumar, Suresh; Govindasamy, Chandramohan; Alnumair, Khalid S.; Mok, Pooi Ling

    2017-01-01

    Breast cancer is a common malignancy among women. The innate and adaptive immune responses failed to be activated owing to immune modulation in the tumour microenvironment. Decades of scientific study links the overexpression of human epidermal growth factor receptor 2 (ERBB2) antigen with aggressive tumours. The Chimeric Antigen Receptor (CAR) coding for specific tumour-associated antigens could initiate intrinsic T-cell signalling, inducing T-cell activation, and cytotoxic activity without the need for major histocompatibility complex recognition. This renders CAR as a potentially universal immunotherapeutic option. Herein, we aimed to establish CAR in CD3+ T-cells, isolated from human peripheral blood mononucleated cells that could subsequently target and induce apoptosis in the ERBB2 overexpressing human breast cancer cell line, SKBR3. Constructed CAR was inserted into a lentiviral plasmid containing a green fluorescent protein tag and produced as lentiviral particles that were used to transduce activated T-cells. Transduced CAR-T cells were then primed with SKBR3 cells to evaluate their functionality. Results showed increased apoptosis in SKBR3 cells co-cultured with CAR-T cells compared to the control (non–transduced T-cells). This study demonstrates that CAR introduction helps overcome the innate limitations of native T-cells leading to cancer cell apoptosis. We recommend future studies should focus on in vivo cytotoxicity of CAR-T cells against ERBB2 expressing tumours. PMID:28885562

  2. Condensational Growth of Combination Drug-Excipient Submicrometer Particles for Targeted High Efficiency Pulmonary Delivery: Comparison of CFD Predictions with Experimental Results

    Science.gov (United States)

    Hindle, Michael

    2011-01-01

    Purpose The objective of this study was to investigate the hygroscopic growth of combination drug and excipient submicrometer aerosols for respiratory drug delivery using in vitro experiments and a newly developed computational fluid dynamics (CFD) model. Methods Submicrometer combination drug and excipient particles were generated experimentally using both the capillary aerosol generator and the Respimat inhaler. Aerosol hygroscopic growth was evaluated in vitro and with CFD in a coiled tube geometry designed to provide residence times and thermodynamic conditions consistent with the airways. Results The in vitro results and CFD predictions both indicated that the initially submicrometer particles increased in mean size to a range of 1.6–2.5 µm for the 50:50 combination of a non-hygroscopic drug (budesonide) and different hygroscopic excipients. CFD results matched the in vitro predictions to within 10% and highlighted gradual and steady size increase of the droplets, which will be effective for minimizing extrathoracic deposition and producing deposition deep within the respiratory tract. Conclusions Enhanced excipient growth (EEG) appears to provide an effective technique to increase pharmaceutical aerosol size, and the developed CFD model will provide a powerful design tool for optimizing this technique to produce high efficiency pulmonary delivery. PMID:21948458

  3. Condensational growth of combination drug-excipient submicrometer particles for targeted high efficiency pulmonary delivery: comparison of CFD predictions with experimental results.

    Science.gov (United States)

    Longest, P Worth; Hindle, Michael

    2012-03-01

    The objective of this study was to investigate the hygroscopic growth of combination drug and excipient submicrometer aerosols for respiratory drug delivery using in vitro experiments and a newly developed computational fluid dynamics (CFD) model. Submicrometer combination drug and excipient particles were generated experimentally using both the capillary aerosol generator and the Respimat inhaler. Aerosol hygroscopic growth was evaluated in vitro and with CFD in a coiled tube geometry designed to provide residence times and thermodynamic conditions consistent with the airways. The in vitro results and CFD predictions both indicated that the initially submicrometer particles increased in mean size to a range of 1.6-2.5 μm for the 50:50 combination of a non-hygroscopic drug (budesonide) and different hygroscopic excipients. CFD results matched the in vitro predictions to within 10% and highlighted gradual and steady size increase of the droplets, which will be effective for minimizing extrathoracic deposition and producing deposition deep within the respiratory tract. Enhanced excipient growth (EEG) appears to provide an effective technique to increase pharmaceutical aerosol size, and the developed CFD model will provide a powerful design tool for optimizing this technique to produce high efficiency pulmonary delivery.

  4. Plasma hydrogenated cationic detonation nanodiamonds efficiently deliver to human cells in culture functional siRNA targeting the Ewing sarcoma junction oncogene.

    Science.gov (United States)

    Bertrand, Jean-Rémi; Pioche-Durieu, Catherine; Ayala, Juan; Petit, Tristan; Girard, Hugues A; Malvy, Claude P; Le Cam, Eric; Treussart, François; Arnault, Jean-Charles

    2015-03-01

    The expression of a defective gene can lead to major cell dysfunctions among which cell proliferation and tumor formation. One promising therapeutic strategy consists in silencing the defective gene using small interfering RNA (siRNA). In previous publications we showed that diamond nanocrystals (ND) of primary size 35 nm, rendered cationic by polyethyleneimine-coating, can efficiently deliver siRNA into cell, which further block the expression of EWS/FLI-1 oncogene in a Ewing sarcoma disease model. However, a therapeutic application of such nanodiamonds requires their elimination by the organism, particularly in urine, which is impossible for 35 nm particles. Here, we report that hydrogenated cationic nanodiamonds of primary size 7 nm (ND-H) have also a high affinity for siRNA and are capable of delivering them in cells. With siRNA/ND-H complexes, we measured a high inhibition efficacy of EWS/FLI-1 gene expression in Ewing sarcoma cell line. Electron microscopy investigations showed ND-H in endocytosis compartments, and especially in macropinosomes from which they can escape before siRNA degradation occurred. In addition, the association of EWS/FLI-1 silencing by the siRNA/ND-H complex with a vincristine treatment yielded a potentiation of the toxic effect of this chemotherapeutic drug. Therefore ND-H appears as a promising delivery agent in anti-tumoral gene therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Characterization studies of prototype ISOL targets for the RIA

    International Nuclear Information System (INIS)

    Greene, John P.; Burtseva, Tatiana; Neubauer, Janelle; Nolen, Jerry A.; Villari, Antonio C.C.; Gomes, Itacil C.

    2005-01-01

    Targets employing refractory compounds are being developed for the rare isotope accelerator (RIA) facility to produce ion species far from stability. With the 100 kW beams proposed for the production targets, dissipation of heat becomes a challenging issue. In our two-step target design, neutrons are generated in a refractory primary target, inducing fission in the surrounding uranium carbide. The interplay of density, grain size, thermal conductivity and diffusion properties of the UC 2 needs to be well understood before fabrication. Thin samples of uranium carbide were prepared for thermal conductivity measurements using an electron beam to heat the sample and an optical pyrometer to observe the thermal radiation. Release efficiencies and independent thermal analysis on these samples are being undertaken at Oak Ridge National Laboratory (ORNL). An alternate target concept for RIA, the tilted slab approach promises to be simple with fast ion release and capable of withstanding high beam intensities while providing considerable yields via spallation. A proposed small business innovative research (SBIR) project will design a prototype tilted target, exploring the materials needed for fabrication and testing at an irradiation facility to address issues of heat transfer and stresses within the target

  6. Characterization studies of prototype ISOL targets for the RIA

    Science.gov (United States)

    Greene, John P.; Burtseva, Tatiana; Neubauer, Janelle; Nolen, Jerry A.; Villari, Antonio C. C.; Gomes, Itacil C.

    2005-12-01

    Targets employing refractory compounds are being developed for the rare isotope accelerator (RIA) facility to produce ion species far from stability. With the 100 kW beams proposed for the production targets, dissipation of heat becomes a challenging issue. In our two-step target design, neutrons are generated in a refractory primary target, inducing fission in the surrounding uranium carbide. The interplay of density, grain size, thermal conductivity and diffusion properties of the UC2 needs to be well understood before fabrication. Thin samples of uranium carbide were prepared for thermal conductivity measurements using an electron beam to heat the sample and an optical pyrometer to observe the thermal radiation. Release efficiencies and independent thermal analysis on these samples are being undertaken at Oak Ridge National Laboratory (ORNL). An alternate target concept for RIA, the tilted slab approach promises to be simple with fast ion release and capable of withstanding high beam intensities while providing considerable yields via spallation. A proposed small business innovative research (SBIR) project will design a prototype tilted target, exploring the materials needed for fabrication and testing at an irradiation facility to address issues of heat transfer and stresses within the target.

  7. Mite allergoids coupled to nonoxidized mannan from Saccharomyces cerevisae efficiently target canine dendritic cells for novel allergy immunotherapy in veterinary medicine.

    Science.gov (United States)

    Soria, Irene; Alvarez, Javier; Manzano, Ana I; López-Relaño, Juan; Cases, Bárbara; Mas-Fontao, Ana; Cañada, F Javier; Fernández-Caldas, Enrique; Casanovas, Miguel; Jiménez-Barbero, Jesús; Palomares, Oscar; Viñals-Flórez, Luis M; Subiza, José L

    2017-08-01

    We have recently reported that grass pollen allergoids conjugated with nonoxidized mannan of Saccharomyces cerevisae using glutaraldehyde results in a novel hypoallergenic mannan-allergen complex with improved properties for allergen vaccination. Using this approach, human dendritic cells show a better allergen uptake and cytokine profile production (higher IL-10/IL-4 ratio) for therapeutic purposes. Here we aim to address whether a similar approach can be extended to dogs using canine dendritic cells. Six healthy Spanish Greyhound dogs were used as blood donors to obtain canine dendritic cells (DC) derived from peripheral blood monocytes. Allergens from Dermatophagoides farinae mite were polymerized and conjugated with nonoxidized mannan. Nuclear magnetic resonance (NMR), gel electrophoresis (SDS-PAGE), immunoblotting and IgE-ELISA inhibition studies were conducted to evaluate the main characteristics of the allergoid obtained. Mannan-allergen conjugate and controls were assayed in vitro for canine DC uptake and production of IL-4 and IL-10. The results indicate that the conjugation of D. farinae allergens with nonoxidized mannan was feasible using glutaraldehyde. The resulting product was a polymerized structure showing a high molecular weight as detected by NMR and SDS-PAGE analysis. The mannan-allergen conjugate was hypoallergenic with a reduced reactivity with specific dog IgE. An increase in both allergen uptake and IL-10/IL-4 ratio was obtained when canine DCs were incubated with the mannan-allergen conjugate, as compared with the control allergen preparations (unmodified D. farinae allergens and oxidized mannan-allergen conjugate). We conclude that hypoallergenic D. farinae allergens coupled to nonoxidized mannan is a novel allergen preparation suitable for canine allergy immunotherapy targeting dendritic cells. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  8. Fabrication and Evaluation of Tinidazole Microbeads for Colon Targeting

    Directory of Open Access Journals (Sweden)

    Amit K. Pandey

    2012-05-01

    Full Text Available Objective: The purpose of present investigation was to develop and evaluate multiparticulate system exploiting pH-sensitive property and specific biodegradability of calcium alginate microbeads, for colon- targeted delivery of Tinidazole for the treatment of amoebic colitis. Methods: Calcium alginate beads containing Tinidazole were prepared by ionotropic gelation technique followed by coating with Eudragit S100 using solvent evaporation method to obtain pH sensitive microbeads. Various formulation parameters were optimized which included concentration of sodium alginate (2% w/v, curing time (20 min and concentration of pectin (1% w/ v. All the formulations were evaluated for surface morphology, particle size analysis, entrapment efficiency and in-vitro drug release in conditions simulating colonic fluid in the presence of rat caecal (2% w/v content. Results: The average size of beads of optimized formulation (FT4 was found to be 998.73依5.12 毺 m with entrapment efficiency of 87.28依2.19 %. The invitro release of Eudragit S100 coated beads in presence of rat caecal content was found to be 70.73%依1.91% in 24 hours. Data of in-vitro release was fitted into Higuchi kinetics and Korsmeyer Peppas equation to explain release profile. The optimized formulation (FT4 showed zero order release. Conclusions: It is concluded that calcium alginate microbeads are the potential system for colon delivery of Tinidazole for chemotherapy of amoebic infection.

  9. The gas release programs to increase competition in the European gas market

    International Nuclear Information System (INIS)

    Clastres, Cedric

    2005-01-01

    Regulators have implemented asymmetric regulation measures, such as gas release programs and market share targets, because of European gas supply features and gas market specificities. Empirical experiences show in line with economic theory that these regulation measures favour entry and competition without deterring investments. If we look at impacts on competition, they are mitigated. Some positive effects result from the increase in consumption or in importation and transportation infrastructure developments. But these regulations can also encourage anti-competitive behaviours like collusion, cream-skimming, reverse cherry picking or inefficient entries. Gas release measures establish a link between the incumbent and its competitors. A system of constraints on operators capacities can also appear. Thus, pricing or quantity strategies are more complex. Equilibrium prices are more volatile and very different of competition mark-up. The incumbent, for high gas release quantities and low supplies, can increase its costs to make more profit. This Raising Rivals' Costs strategy often occur if the gas release price is closer to supply costs. This strategy does not impact on consumers surplus but decreases welfare. The regulator can restore incentives to efficiency by setting gas release proportion function of incumbent's supplies. This proportion must be high enough to have a positive impact on the market because of incumbent's incentives to efficiency and greater total quantities sold by the two operators. But, on another way, it must not be too high as it could, thus, increase the probability of Raising Rivals' Costs or favour collusive strategies. (author) [fr

  10. Toxics Release Inventory (TRI)

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Toxics Release Inventory (TRI) is a dataset compiled by the U.S. Environmental Protection Agency (EPA). It contains information on the release and waste...

  11. Controlled Release Formulations of Auxinic Herbicides

    Science.gov (United States)

    Kowalski, Witold J.; Siłowiecki, Andrzej.; Romanowska, Iwona; Glazek, Mariola; Bajor, Justyna; Cieciwa, Katarzyna; Rychter, Piotr

    2013-04-01

    Controlled release formulations are applied extensively for the release of active ingredients such as plant protection agents and fertilizers in response to growing concern for ecological problems associated with increased use of plant protection chemicals required for intensive agricultural practices [1]. We synthesized oligomeric mixtures of (R,S)-3-hydroxy butyric acid chemically bonded with 2,4-D, Dicamba and MCPA herbicides (HBA) respectively, and determined their molecular structure and molecular weight dispersion by the size exclusion chromatography, proton magnetic resonance spectrometry and electro-spray ionization mass spectrometry. Further we carried out bioassays of herbicidal effectiveness of the HBA herbicides vs. series of dicotyledonous weeds and crop injury tests [2, 3, 4]. Field bioassays were accomplished according to the EPPO standards [5]. Groups of representative weeds (the development stages in the BCCH scale: 10 - 30) were selected as targets. Statistical variabilities were assessed by the Fisher LSD test for plants treated with the studied herbicides in form of HBA oligomers, the reference herbicides in form of dimethyl ammonium salts (DMA), and untreated plants. No statistically significant differences in the crop injuries caused by the HBA vs. the DMA reference formulation were observed. The effectiveness of the HBA herbicides was lower through the initial period (ca. 2 weeks) relative to the DMA salts, but a significant increase in the effectiveness of the HBA systems followed during the remaining fraction of each assay. After 6 weeks all observed efficiencies approached 100%. The death of weeds treated with the HBA herbicides was delayed when compared with the DMA reference herbicides. The delayed uptake observed for the HBA oligomers relative to the DMA salts was due to controlled release phenomena. In case of the DMA salts the total amount of active ingredients was available at the target site. By contrast, the amount of an active

  12. Nanostructured Diclofenac Sodium Releasing Material

    Science.gov (United States)

    Nikkola, L.; Vapalahti, K.; Harlin, A.; Seppälä, J.; Ashammakhi, N.

    2008-02-01

    Various techniques have been developed to produce second generation biomaterials for tissue repair. These include extrusion, molding, salt leaching, spinning etc, but success in regenerating tissues has been limited. It is important to develop porous material, yet with a fibrous structure for it to be biomimetic. To mimic biological tissues, the extra-cellular matrix usually contains fibers in nano scale. To produce nanostructures, self-assembly or electrospinning can be used. Adding a drug release function to such a material may advance applications further for use in controlled tissue repair. This turns the resulting device into a multifunctional porous, fibrous structure to support cells and drug releasing properties in order to control tissue reactions. A bioabsorbable poly(ɛ-caprolactone-co-D,L lactide) 95/5 (PCL) was made into diluted solution using a solvent, to which was added 2w-% of diclofenac sodium (DS). Nano-fibers were made by electrospinning onto substrate. Microstructure of the resulting nanomat was studied using SEM and drug release profiles with UV/VIS spectroscopy. Thickness of the electrospun nanomat was about 2 mm. SEM analysis showed that polymeric nano-fibers containing drug particles form a highly interconnected porous nano structure. Average diameter of the nano-fibers was 130 nm. There was a high burst peak in drug release, which decreased to low levels after one day. The used polymer has slow a degradation rate and though the nanomat was highly porous with a large surface area, drug release rate is slow. It is feasible to develop a nano-fibrous porous structure of bioabsorbable polymer, which is loaded with test drug. Drug release is targeted at improving the properties of biomaterial for use in controlled tissue repair and regeneration.

  13. Energy Efficient Cryogenics

    Science.gov (United States)

    Meneghelli, Barry J.; Notardonato, William; Fesmire, James E.

    2016-01-01

    The Cryogenics Test Laboratory, NASA Kennedy Space Center, works to provide practical solutions to low-temperature problems while focusing on long-term technology targets for the energy-efficient use of cryogenics on Earth and in space.

  14. Selection of targets and ion sources for RIB generation at the Holifield Radioactive Ion Beam Facility

    International Nuclear Information System (INIS)

    Alton, G.D.

    1995-01-01

    In this report, the authors describe the performance characteristics for a selected number of target ion sources that will be employed for initial use at the Holifield Radioactive Ion Beam Facility (HRIBF) as well as prototype ion sources that show promise for future use for RIB applications. A brief review of present efforts to select target materials and to design composite target matrix/heat-sink systems that simultaneously incorporate the short diffusion lengths, high permeabilities, and controllable temperatures required to effect fast and efficient diffusion release of the short-lived species is also given

  15. Scheduling with target start times

    NARCIS (Netherlands)

    Hoogeveen, J.A.; Velde, van de S.L.; Klein Haneveld, W.K.; Vrieze, O.J.; Kallenberg, L.C.M.

    1997-01-01

    We address the single-machine problem of scheduling n independent jobs subject to target start times. Target start times are essentially release times that may be violated at a certain cost. The goal is to minimize an objective function that is composed of total completion time and maximum

  16. Progress in transmutation targets from Efttra

    International Nuclear Information System (INIS)

    Haas, D.; Fernandez, A.; Warin, D.; Bonnerot, J.M.; Garzenne, C.; Scaffidi-Argentina, F.; Maschek, W.; Schram, R.; Klaassen, F.

    2007-01-01

    Since 15 years, the EFTTRA partners have organised programmes to demonstrate the feasibility of the transmutation of americium in uranium-free targets. In the related transmutation scenario, the targets are introduced in a thermal neutron zone of a fast reactor, to maximize the efficiency of transmutation. Amongst these programmes, those carried out in the HFR reactor in Petten have led to important conclusions and are still at the core of the research in that field. The analysis of the EFTTRA T4 and T4bis irradiation experiments, carried out with targets of MgAl 2 O 4 +11 wt% 241 Am, showed that the release/trapping of helium is the key issue for target design, and also demonstrated a lack of technical benefits of this material, due to a unsatisfactory in-pile behaviour in terms of irradiation damage and chemical stability. A new irradiation experiment called HELIOS is currently under fabrication and will be carried out in HFR. The in-pile behaviour of U-free fuels and targets such as (Am,Zr)O 2 , (Pu,Am,Zr)O 2 , CERCER (MgO) or CERMET (Mo) will be examined. The irradiation temperature will be high enough in some of the pins to be able to tune the release of a significant fraction of helium produced so that the material swelling can be minimized as much as reasonably possible. The HELIOS irradiation experiment is planned to be carried out in the HFR core and shall last 300 full power days starting in 2007. (authors)

  17. Microwave Activation of Drug Release

    DEFF Research Database (Denmark)

    Jónasson, Sævar Þór

    Due to current limitations in control of pharmaceutical drug release in the body along with increasing medicine use, methods of externally-controlled drug release are of high interest. In this thesis, the use of microwaves is proposed as a technique with the purpose of externally activating...... setup, called the microwave activation system has been developed and tested on a body phantom that emulates the human torso. The system presented in this thesis, operates unobtrusively, i.e. without physically interfering with the target (patient). The torso phantom is a simple dual-layered cylindrical...... the phantom is of interest for disclosing essential information about the limitations of the concept, the phantom and the system. For these purposes, a twofold operation of the microwave activation system was performed, which are reciprocal of each other. In the first operation phase, named mapping...

  18. Sterile insect supply, emergence, and release

    International Nuclear Information System (INIS)

    Dowell, R.V.; Worley, J.; Gomes, P.J.

    2005-01-01

    Insect mass-rearing for a sterile insect technique (SIT) programme is designed to move beyond the large-scale rearing of insects in a laboratory to the industrial production of consistently high-quality insects for sterilization and release. Each facility reflects the unique biology of the insect reared within it, but there are some generalities for all rearing facilities. Rearing insects in self-contained modules offers flexibility, and increased safety from catastrophic occurrences, compared with using a single building which houses all facets of the rearing process. Although mechanizing certain aspects of the rearing steps helps provide a consistently high-quality insect, successful mass-rearing and delivery depends largely upon the human component. Besides production in centralized facilities, insects can be produced from purchased eggs, or nowadays, adult insects are often obtained from specialized satellite emergence/collection facilities. Interest in commercializing insect production and release is increasing. Shipping sterile insects, sometimes over long distances, is now common practice. Procedures for handling and chilling adult insects, and providing food and water prior to release, are continually being improved. Sterile insects are released via static-release receptacles, ground-release systems, or most commonly from the air. The aerial release of chilled sterile insects is the most efficient method of release, especially when aircraft flight paths are guided by a Global Positioning System (GPS) linked to a computer-controlled release mechanism. (author)

  19. Dual integrin and gastrin-releasing peptide receptor targeted tumor imaging using 18F-labeled PEGylated RGD-bombesin heterodimer 18F-FB-PEG3-Glu-RGD-BBN.

    Science.gov (United States)

    Liu, Zhaofei; Yan, Yongjun; Chin, Frederic T; Wang, Fan; Chen, Xiaoyuan

    2009-01-22

    Radiolabeled RGD and bombesin peptides have been extensively investigated for tumor integrin alpha(v)beta(3) and GRPR imaging, respectively. Due to the fact that many tumors are both integrin and GRPR positive, we designed and synthesized a heterodimeric peptide Glu-RGD-BBN, which is expected to be advantageous over the monomeric peptides for dual-receptor targeting. A PEG(3) spacer was attached to the glutamate alpha-amino group of Glu-RGD-BBN to enhance the (18)F labeling yield and to improve the in vivo kinetics. PEG(3)-Glu-RGD-BBN possesses the comparable GRPR and integrin alpha(v)beta(3) receptor-binding affinities as the corresponding monomers, respectively. The dual-receptor targeting properties of (18)F-FB-PEG(3)-Glu-RGD-BBN were observed in PC-3 tumor model. (18)F-FB-PEG(3)-Glu-RGD-BBN with high tumor contrast and favorable pharmacokinetics is a promising PET tracer for dual integrin and GRPR positive tumor imaging. This heterodimer strategy may also be an applicable method to develop other molecules with improved in vitro and in vivo characterizations for tumor diagnosis and therapy.

  20. Microgels produced using microfluidic on-chip polymer blending for controlled released of VEGF encoding lentivectors.

    Science.gov (United States)

    Madrigal, Justin L; Sharma, Shonit N; Campbell, Kevin T; Stilhano, Roberta S; Gijsbers, Rik; Silva, Eduardo A

    2018-03-15

    Alginate hydrogels are widely used as delivery vehicles due to their ability to encapsulate and release a wide range of cargos in a gentle and biocompatible manner. The release of encapsulated therapeutic cargos can be promoted or stunted by adjusting the hydrogel physiochemical properties. However, the release from such systems is often skewed towards burst-release or lengthy retention. To address this, we hypothesized that the overall magnitude of burst release could be adjusted by combining microgels with distinct properties and release behavior. Microgel suspensions were generated using a process we have termed on-chip polymer blending to yield composite suspensions of a range of microgel formulations. In this manner, we studied how alginate percentage and degradation relate to the release of lentivectors. Whereas changes in alginate percentage had a minimal impact on lentivector release, microgel degradation led to a 3-fold increase, and near complete release, over 10 days. Furthermore, by controlling the amount of degradable alginate present within microgels the relative rate of release can be adjusted. A degradable formulation of microgels was used to deliver vascular endothelial growth factor (VEGF)-encoding lentivectors in the chick chorioallantoic membrane (CAM) assay and yielded a proangiogenic response in comparison to the same lentivectors delivered in suspension. The utility of blended microgel suspensions may provide an especially appealing platform for the delivery of lentivectors or similarly sized therapeutics. Genetic therapeutics hold considerable potential for the treatment of diseases and disorders including ischemic cardiovascular diseases. To realize this potential, genetic vectors must be precisely and efficiently delivered to targeted regions of the body. However, conventional methods of delivery do not provide sufficient spatial and temporal control. Here, we demonstrate how alginate microgels provide a basis for developing systems for

  1. CERN: Fixed target targets

    Energy Technology Data Exchange (ETDEWEB)

    Anon.

    1993-03-15

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

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

    Science.gov (United States)

    Gao, Hui-le; Jiang, Xin-guo

    2016-02-01

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

  3. Research and development on materials for the SPES target

    Directory of Open Access Journals (Sweden)

    Corradetti Stefano

    2014-03-01

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

  4. Target swapping in PLD: An efficient approach for CdS/SiO{sub 2} and CdS:Ag(1%)/SiO{sub 2} nanocomposite thin films with enhanced luminescent properties

    Energy Technology Data Exchange (ETDEWEB)

    Saxena, Nupur, E-mail: n1saxena@gmail.com [Department of Physics & Astrophysics, University of Delhi, Delhi 110007 (India); Kumar, Pragati, E-mail: pkumar.phy@gmail.com [Department of Physics & Astrophysics, University of Delhi, Delhi 110007 (India); Department of Nano Sciences and Materials, Central University of Jammu, Rahya-Suchani (Bagla), Samba, 181143 Jammu, J& K (India); Gupta, Vinay [Department of Physics & Astrophysics, University of Delhi, Delhi 110007 (India)

    2017-06-15

    A novel synthesis method for luminescent and by-products (like CdO) free CdS/SiO{sub 2} and CdS:Ag(1%)/SiO{sub 2} (i.e. 1%Ag doped CdS/SiO{sub 2}) nanocomposite thin films at room temperature by pulsed laser deposition is reported. Targets of CdS, CdS:Ag(1%) and SiO{sub 2} are used to deposit CdS/SiO{sub 2} and CdS:Ag(1%)/SiO{sub 2} nanocomposite thin films by swapping them at a frequency ratio of 2:8 laser pulses/sec. X-ray photoelectron spectroscopy analysis ensures the ratio of CdS to SiO{sub 2} in nanocomposite as 21:79 which is nearly same as the ratio of incident pulses/sec (i.e. 2:8) on the two targets. Transmission electron micrographs visualize the formation of CdS/ CdS:Ag(1%) nanocrystals in nanocomposite systems after annealing at 500 °C. Highly intense and broad red emission is achieved from CdS/SiO{sub 2} and CdS:Ag(1%)/SiO{sub 2} nanocomposites. The efficiencies of emission from pristine CdS:SiO{sub 2} and CdS:Ag(1%)/SiO{sub 2} nanocomposites are found to be enhanced by approximately two times as compared to sole nanocrystalline CdS and CdS:Ag(1%) thin films respectively and further enhanced upto 7 times on annealing the nanocomposite systems at 500 °C. - Graphical abstract: A modified synthesis method for luminescent and by-products (like CdO) free undoped &1% Ag doped CdS/SiO{sub 2} (deposit CdS/SiO{sub 2} and CdS:Ag(1%)/SiO{sub 2}) nanocomposite thin films at room temperature by pulsed laser deposition is reported. Targets of CdS or CdS:Ag(1%) and SiO{sub 2} are used to deposit CdS/SiO{sub 2} and CdS:Ag(1%)/SiO{sub 2} nanocomposite thin films by swapping them at a frequency of 2:8 pulses/sec. X-ray photoelectron spectroscopy analysis ensures the ratio of CdS to SiO{sub 2} in nanocomposite as 21:79 which is nearly same as the ratio of incident pulses/sec (2:8) on the two targets. Transmission electron micrographs visualize the formation of CdS nanocrystals in nanocomposite systems after annealing at 500 °C. Intense and broad red emission is

  5. Target swapping in PLD: An efficient approach for CdS/SiO2 and CdS:Ag(1%)/SiO2 nanocomposite thin films with enhanced luminescent properties

    International Nuclear Information System (INIS)

    Saxena, Nupur; Kumar, Pragati; Gupta, Vinay

    2017-01-01

    A novel synthesis method for luminescent and by-products (like CdO) free CdS/SiO 2 and CdS:Ag(1%)/SiO 2 (i.e. 1%Ag doped CdS/SiO 2 ) nanocomposite thin films at room temperature by pulsed laser deposition is reported. Targets of CdS, CdS:Ag(1%) and SiO 2 are used to deposit CdS/SiO 2 and CdS:Ag(1%)/SiO 2 nanocomposite thin films by swapping them at a frequency ratio of 2:8 laser pulses/sec. X-ray photoelectron spectroscopy analysis ensures the ratio of CdS to SiO 2 in nanocomposite as 21:79 which is nearly same as the ratio of incident pulses/sec (i.e. 2:8) on the two targets. Transmission electron micrographs visualize the formation of CdS/ CdS:Ag(1%) nanocrystals in nanocomposite systems after annealing at 500 °C. Highly intense and broad red emission is achieved from CdS/SiO 2 and CdS:Ag(1%)/SiO 2 nanocomposites. The efficiencies of emission from pristine CdS:SiO 2 and CdS:Ag(1%)/SiO 2 nanocomposites are found to be enhanced by approximately two times as compared to sole nanocrystalline CdS and CdS:Ag(1%) thin films respectively and further enhanced upto 7 times on annealing the nanocomposite systems at 500 °C. - Graphical abstract: A modified synthesis method for luminescent and by-products (like CdO) free undoped &1% Ag doped CdS/SiO 2 (deposit CdS/SiO 2 and CdS:Ag(1%)/SiO 2 ) nanocomposite thin films at room temperature by pulsed laser deposition is reported. Targets of CdS or CdS:Ag(1%) and SiO 2 are used to deposit CdS/SiO 2 and CdS:Ag(1%)/SiO 2 nanocomposite thin films by swapping them at a frequency of 2:8 pulses/sec. X-ray photoelectron spectroscopy analysis ensures the ratio of CdS to SiO 2 in nanocomposite as 21:79 which is nearly same as the ratio of incident pulses/sec (2:8) on the two targets. Transmission electron micrographs visualize the formation of CdS nanocrystals in nanocomposite systems after annealing at 500 °C. Intense and broad red emission is achieved from deposit CdS/SiO 2 and CdS:Ag(1%)/SiO 2 nanocomposites. The efficiency of

  6. Development of novel small molecules for imaging and drug release

    Science.gov (United States)

    Cao, Yanting

    Small organic molecules, including small molecule based fluorescent probes, small molecule based drugs or prodrugs, and smart multifunctional fluorescent drug delivery systems play important roles in biological research, drug discovery, and clinical practices. Despite the significant progress made in these fields, the development of novel and diverse small molecules is needed to meet various demands for research and clinical applications. My Ph.D study focuses on the development of novel functional molecules for recognition, imaging and drug release. In the first part, a turn-on fluorescent probe is developed for the detection of intracellular adenosine-5'-triphosphate (ATP) levels based on multiplexing recognitions. Considering the unique and complicated structure of ATP molecules, a fluorescent probe has been implemented with improved sensitivity and selectivity due to two synergistic binding recognitions by incorporating of 2, 2'-dipicolylamine (Dpa)-Zn(II) for targeting of phospho anions and phenylboronic acid group for cis-diol moiety. The novel probe is able to detect intracellular ATP levels in SH-SY5Y cells. Meanwhile, the advantages of multiplexing recognition design concept have been demonstrated using two control molecules. In the second part, a prodrug system is developed to deliver multiple drugs within one small molecule entity. The prodrug is designed by using 1-(2-nitrophenyl)ethyl (NPE) as phototrigger, and biphenol biquaternary ammonium as the prodrug. With controlled photo activation, both DNA cross-linking agents mechlorethamine and o-quinone methide are delivered and released at the preferred site, leading to efficient DNA cross-links formation and cell death. The prodrug shows negligible cytotoxicity towards normal skin cells (Hekn cells) with and without UV activation, but displays potent activity towards cancer cells (HeLa cells) upon UV activation. The multiple drug release system may hold a great potential for practical application. In the

  7. CERN: Fixed target targets

    International Nuclear Information System (INIS)

    Anon.

    1993-01-01

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

  8. Internal targets for LEAR

    International Nuclear Information System (INIS)

    Kilian, K.; Gspann, J.; Mohl, D.; Poth, H.

    1984-01-01

    This chapter considers the use of thin internal targets in conjunction with phase-space cooling at the Low-Energy Antiproton Ring (LEAR). Topics considered include the merits of internal target operation; the most efficient use of antiprotons and of proton synchrotron (PS) protons, highest center-of-mass (c.m.) energy resolution; highest angular resolution and access to extreme angles; the transparent environment for all reaction products; a windowless source and pure targets; highest luminosity and count rates; access to lowest energies with increasing resolution; internal target thickness and vacuum requirements; required cooling performance; and modes of operation. It is demonstrated that an internal target in conjunction with phase-space cooling has the potential of better performance in terms of the economic use of antiprotons and consequently of PS protons; energy resolution; angular resolution; maximum reaction rate capability (statistical precision); efficient parasitic operation; transparency of the target for reaction products; access to low energies; and the ease of polarized target experiments. It is concluded that all p - experiments which need high statistics and high p - flux, such as studies of rare channels or broad, weak resonance structures, would profit from internal targets

  9. Release of RANKERN 16A

    Directory of Open Access Journals (Sweden)

    Bird Adam

    2017-01-01

    Full Text Available RANKERN 16 is the latest version of the point-kernel gamma radiation transport Monte Carlo code from AMEC Foster Wheeler’s ANSWERS Software Service. RANKERN is well established in the UK shielding community for radiation shielding and dosimetry assessments. Many important developments have been made available to users in this latest release of RANKERN. The existing general 3D geometry capability has been extended to include import of CAD files in the IGES format providing efficient full CAD modelling capability without geometric approximation. Import of tetrahedral mesh and polygon surface formats has also been provided. An efficient voxel geometry type has been added suitable for representing CT data. There have been numerous input syntax enhancements and an extended actinide gamma source library. This paper describes some of the new features and compares the performance of the new geometry capabilities.

  10. Release of RANKERN 16A

    Science.gov (United States)

    Bird, Adam; Murphy, Christophe; Dobson, Geoff

    2017-09-01

    RANKERN 16 is the latest version of the point-kernel gamma radiation transport Monte Carlo code from AMEC Foster Wheeler's ANSWERS Software Service. RANKERN is well established in the UK shielding community for radiation shielding and dosimetry assessments. Many important developments have been made available to users in this latest rele