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Sample records for design target fab

  1. PSMA-targeted bispecific Fab conjugates that engage T cells.

    Science.gov (United States)

    Patterson, James T; Isaacson, Jason; Kerwin, Lisa; Atassi, Ghazi; Duggal, Rohit; Bresson, Damien; Zhu, Tong; Zhou, Heyue; Fu, Yanwen; Kaufmann, Gunnar F

    2017-12-15

    Bioconjugate formats provide alternative strategies for antigen targeting with bispecific antibodies. Here, PSMA-targeted Fab conjugates were generated using different bispecific formats. Interchain disulfide bridging of an αCD3 Fab enabled installation of either the PSMA-targeting small molecule DUPA (SynFab) or the attachment of an αPSMA Fab (BisFab) by covalent linkage. Optimization of the reducing conditions was critical for selective interchain disulfide reduction and good bioconjugate yield. Activity of αPSMA/CD3 Fab conjugates was tested by in vitro cytotoxicity assays using prostate cancer cell lines. Both bispecific formats demonstrated excellent potency and antigen selectivity. Copyright © 2017. Published by Elsevier Ltd.

  2. Use of isothiocyanatobenzyl-DTPA derivatized monoclonal antimyosin fab for enhanced in vivo target localization

    International Nuclear Information System (INIS)

    Khaw, B.A.; Gansow, O.; Brechbiel, M.W.; O'Donnell, S.M.; Nossiff, N.

    1990-01-01

    Monoclonal antimyosin Fab (AM-Fab) was radiolabeled with 111In via a new bifunctional chelating agent, isothiocyanatobenzyl-DTPA (SCN-DTPA), and used to visualize acute reperfused experimental myocardial infarction. Antibody localization was compared to 201 Tl (0.6 mCi) distribution in nine animals. Each animal was injected intravenously with 0.5 mCi of 111 In-SCN-DTPA AM-Fab preparations (Prep 1 [n = 5] and 2 [n = 4]). The biodistribution was compared to that of 111 In-labeled conventional bicyclic anhydride DTPA-AM-Fab (n = 5). 111 In-SCN-DTPA AM-Fab Prep 1 (lowest specific activity) showed highest specific target localization (31.6 +/- 3.5, MEAN infarct[0-20% Tl-201] to normal ration +/- SE) and lowest hepatic sequestration (0.0108 +/- 0.002% ID/g). Prep 2 showed similar infarct localization (18.4 +/- 1.2) to control 111 In-DTPA AM-Fab (16.9 +/- 1.1), but had higher hepatic activity (0.0326 +/- 0.014 and 0.0267 +/- 0.006 respectively). This difference in in vivo localization occurred despite the lack of changes in in vitro immunoreactivities of the AM-Fab preparations. The enhanced target localization with minimal hepatic activity may permit a more sensitive diagnostic application of 111 In-labeled AM-Fab in future clinical studies

  3. Ion-driver fast ignition: Reducing heavy-ion fusion driver energy and cost, simplifying chamber design, target fab, tritium fueling and power conversion

    Energy Technology Data Exchange (ETDEWEB)

    Logan, G.; Callahan-Miller, D.; Perkins, J.; Caporaso, G.; Tabak, M.; Moir, R.; Meier, W.; Bangerter, Roger; Lee, Ed

    1998-04-01

    Ion fast ignition, like laser fast ignition, can potentially reduce driver energy for high target gain by an order of magnitude, while reducing fuel capsule implosion velocity, convergence ratio, and required precisions in target fabrication and illumination symmetry, all of which should further improve and simplify IFE power plants. From fast-ignition target requirements, we determine requirements for ion beam acceleration, pulse-compression, and final focus for advanced accelerators that must be developed for much shorter pulses and higher voltage gradients than today's accelerators, to deliver the petawatt peak powers and small focal spots ({approx}100 {micro}m) required. Although such peak powers and small focal spots are available today with lasers, development of such advanced accelerators is motivated by the greater likely efficiency of deep ion penetration and deposition into pre-compressed 1000x liquid density DT cores. Ion ignitor beam parameters for acceleration, pulse compression, and final focus are estimated for two examples based on a Dielectric Wall Accelerator; (1) a small target with {rho}r {approx} 2 g/cm{sup 2} for a small demo/pilot plant producing {approx}40 MJ of fusion yield per target, and (2) a large target with {rho}r {approx} 10 g/cm{sup 2} producing {approx}1 GJ yield for multi-unit electricity/hydrogen plants, allowing internal T-breeding with low T/D ratios, >75 % of the total fusion yield captured for plasma direct conversion, and simple liquid-protected chambers with gravity clearing. Key enabling development needs for ion fast ignition are found to be (1) ''Close-coupled'' target designs for single-ended illumination of both compressor and ignitor beams; (2) Development of high gradient (>25 MV/m) linacs with high charge-state (q {approx} 26) ion sources for short ({approx}5 ns) accelerator output pulses; (3) Small mm-scale laser-driven plasma lens of {approx}10 MG fields to provide steep focusing angles

  4. Ion-driver fast ignition: Reducing heavy-ion fusion driver energy and cost, simplifying chamber design, target fab, tritium fueling and power conversion

    International Nuclear Information System (INIS)

    Logan, G.; Callahan-Miller, D.; Perkins, J.; Caporaso, G.; Tabak, M.; Moir, R.; Meier, W.; Bangerter, Roger; Lee, Ed

    1998-01-01

    Ion fast ignition, like laser fast ignition, can potentially reduce driver energy for high target gain by an order of magnitude, while reducing fuel capsule implosion velocity, convergence ratio, and required precisions in target fabrication and illumination symmetry, all of which should further improve and simplify IFE power plants. From fast-ignition target requirements, we determine requirements for ion beam acceleration, pulse-compression, and final focus for advanced accelerators that must be developed for much shorter pulses and higher voltage gradients than today's accelerators, to deliver the petawatt peak powers and small focal spots (∼100 (micro)m) required. Although such peak powers and small focal spots are available today with lasers, development of such advanced accelerators is motivated by the greater likely efficiency of deep ion penetration and deposition into pre-compressed 1000x liquid density DT cores. Ion ignitor beam parameters for acceleration, pulse compression, and final focus are estimated for two examples based on a Dielectric Wall Accelerator; (1) a small target with ρr ∼ 2 g/cm 2 for a small demo/pilot plant producing ∼40 MJ of fusion yield per target, and (2) a large target with ρr ∼ 10 g/cm 2 producing ∼1 GJ yield for multi-unit electricity/hydrogen plants, allowing internal T-breeding with low T/D ratios, >75 % of the total fusion yield captured for plasma direct conversion, and simple liquid-protected chambers with gravity clearing. Key enabling development needs for ion fast ignition are found to be (1) ''Close-coupled'' target designs for single-ended illumination of both compressor and ignitor beams; (2) Development of high gradient (>25 MV/m) linacs with high charge-state (q ∼ 26) ion sources for short (∼5 ns) accelerator output pulses; (3) Small mm-scale laser-driven plasma lens of ∼10 MG fields to provide steep focusing angles close-in to the target (built-in as part of each target); (4) beam space charge

  5. The Female Athlete Body (FAB) study: Rationale, design, and baseline characteristics.

    Science.gov (United States)

    Stewart, Tiffany M; Pollard, Tarryn; Hildebrandt, Tom; Beyl, Robbie; Wesley, Nicole; Kilpela, Lisa Smith; Becker, Carolyn Black

    2017-09-01

    Eating Disorders (EDs) are serious psychiatric illnesses marked by psychiatric comorbidity, medical complications, and functional impairment. Research indicates that female athletes are often at greater risk for developing ED pathology versus non-athlete females. The Female Athlete Body (FAB) study is a three-site, randomized controlled trial (RCT) designed to assess the efficacy of a behavioral ED prevention program for female collegiate athletes when implemented by community providers. This paper describes the design, intervention, and participant baseline characteristics. Future papers will discuss outcomes. Female collegiate athletes (N=481) aged 17-21 were randomized by site, team, and sport type to either FAB or a waitlist control group. FAB consisted of three sessions (1.3h each) of a behavioral ED prevention program. Assessments were conducted at baseline (pre-intervention), post-intervention (3weeks), and six-, 12-, and 18-month follow-ups. This study achieved 96% (N=481) of target recruitment (N=500). Few group differences emerged at baseline. Total sample analyses revealed moderately low baseline instances of ED symptoms and clinical cases. Health risks associated with EDs necessitate interventions for female athletes. The FAB study is the largest existing RCT for female athletes aimed at both reduction of ED risk factors and ED prevention. The methods presented and population recruited for this study represent an ideal intervention for assessing the effects of FAB on both the aforementioned outcomes. We anticipate that findings of this study (reported in future papers) will make a significant contribution to the ED risk factor reduction and prevention literature. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Impact of surfactants on the target recognition of Fab-conjugated PLGA nanoparticles.

    Science.gov (United States)

    Kennedy, Patrick J; Perreira, Ines; Ferreira, Daniel; Nestor, Marika; Oliveira, Carla; Granja, Pedro L; Sarmento, Bruno

    2018-06-01

    Targeted drug delivery with nanoparticles (NPs) requires proper surface ligand presentation and availability. Surfactants are often used as stabilizers in the production of targeted NPs. Here, we evaluated the impact of surfactants on ligand functionalization and downstream molecular recognition. Our model system consisted of fluorescent poly(lactic-co-glycolic acid) (PLGA) NPs that were nanoprecipitated in one of a small panel of commonly-used surfactants followed by equivalent washes and conjugation of an engineered Fab antibody fragment. Size, polydispersity index and zeta potential were determined by dynamic light scattering and laser Doppler anemometry, and Fab presence on the NPs was assessed by enzyme-linked immunosorbent assay. Most importantly, Fab-decorated NP binding to the cell surface receptor was monitored by fluorescence-activated cell sorting. 2% polyvinyl alcohol, 1% sodium cholate, 0.5% Pluronic F127 (F127) and 2% Tween-80 were initially tested. Of the four surfactants tested, PLGA NPs in 0.5% F127 and 2% Tween-80 had the highest cell binding. These two surfactants were then retested in two different concentrations, 0.5% and 2%. The Fab-decorated PLGA NPs in 2% F127 had the highest cell binding. This study highlights the impact of common surfactants and their concentrations on the downstream targeting of ligand-decorated NPs. Similar principles should be applied in the development of future targeted nanosystems where surfactants are employed. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Fab antibody fragment-functionalized liposomes for specific targeting of antigen-positive cells

    Czech Academy of Sciences Publication Activity Database

    Ohradanova-Repic, A.; Nogueira, E.; Hartl, I.; Gomes, A.C.; Preto, A.; Steinhuber, E.; Muehlgrabner, V.; Repic, M.; Kuttke, M.; Zwirzitz, A.; Prouza, M.; Suchánek, M.; Wozniak-Knopp, G.; Hořejší, Václav; Schabbauer, G.; Cavaco-Paulo, A.; Stockinger, H.

    2018-01-01

    Roč. 14, č. 1 (2018), s. 123-130 ISSN 1549-9634 Institutional support: RVO:68378050 Keywords : Active targeting * Liposome functionalization * Immunoliposome * Antibody engineering * Recombinant Fab antibody fragment Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Cell biology Impact factor: 5.720, year: 2016

  8. Rational optimization of drug-target residence time: Insights from inhibitor binding to the S. aureus FabI enzyme-product complex

    Science.gov (United States)

    Chang, Andrew; Schiebel, Johannes; Yu, Weixuan; Bommineni, Gopal R.; Pan, Pan; Baxter, Michael V.; Khanna, Avinash; Sotriffer, Christoph A.; Kisker, Caroline; Tonge, Peter J.

    2013-01-01

    Drug-target kinetics has recently emerged as an especially important facet of the drug discovery process. In particular, prolonged drug-target residence times may confer enhanced efficacy and selectivity in the open in vivo system. However, the lack of accurate kinetic and structural data for series of congeneric compounds hinders the rational design of inhibitors with decreased off-rates. Therefore, we chose the Staphylococcus aureus enoyl-ACP reductase (saFabI) - an important target for the development of new anti-staphylococcal drugs - as a model system to rationalize and optimize the drug-target residence time on a structural basis. Using our new, efficient and widely applicable mechanistically informed kinetic approach, we obtained a full characterization of saFabI inhibition by a series of 20 diphenyl ethers complemented by a collection of 9 saFabI-inhibitor crystal structures. We identified a strong correlation between the affinities of the investigated saFabI diphenyl ether inhibitors and their corresponding residence times, which can be rationalized on a structural basis. Due to its favorable interactions with the enzyme, the residence time of our most potent compound exceeds 10 hours. In addition, we found that affinity and residence time in this system can be significantly enhanced by modifications predictable by a careful consideration of catalysis. Our study provides a blueprint for investigating and prolonging drug-target kinetics and may aid in the rational design of long-residence-time inhibitors targeting the essential saFabI enzyme. PMID:23697754

  9. Investigation of protein selectivity in multimodal chromatography using in silico designed Fab fragment variants.

    Science.gov (United States)

    Karkov, Hanne Sophie; Krogh, Berit Olsen; Woo, James; Parimal, Siddharth; Ahmadian, Haleh; Cramer, Steven M

    2015-11-01

    In this study, a unique set of antibody Fab fragments was designed in silico and produced to examine the relationship between protein surface properties and selectivity in multimodal chromatographic systems. We hypothesized that multimodal ligands containing both hydrophobic and charged moieties would interact strongly with protein surface regions where charged groups and hydrophobic patches were in close spatial proximity. Protein surface property characterization tools were employed to identify the potential multimodal ligand binding regions on the Fab fragment of a humanized antibody and to evaluate the impact of mutations on surface charge and hydrophobicity. Twenty Fab variants were generated by site-directed mutagenesis, recombinant expression, and affinity purification. Column gradient experiments were carried out with the Fab variants in multimodal, cation-exchange, and hydrophobic interaction chromatographic systems. The results clearly indicated that selectivity in the multimodal system was different from the other chromatographic modes examined. Column retention data for the reduced charge Fab variants identified a binding site comprising light chain CDR1 as the main electrostatic interaction site for the multimodal and cation-exchange ligands. Furthermore, the multimodal ligand binding was enhanced by additional hydrophobic contributions as evident from the results obtained with hydrophobic Fab variants. The use of in silico protein surface property analyses combined with molecular biology techniques, protein expression, and chromatographic evaluations represents a previously undescribed and powerful approach for investigating multimodal selectivity with complex biomolecules. © 2015 Wiley Periodicals, Inc.

  10. Targeting human prostate cancer with In-111-labeled D2B IgG, F(ab ')(2) and Fab fragments in nude mice with PSMA-expressing xenografts

    NARCIS (Netherlands)

    Lutje, Susanne; van Rij, Catharina M.; Franssen, Gerben M.; Fracasso, Giulio; Helfrich, Wijnand; Eek, Annemarie; Oyen, Wim J.; Colombatti, Marco; Boerman, Otto C.

    2014-01-01

    D2B is a new monoclonal antibody directed against an extracellular domain of prostate-specific membrane antigen (PSMA), which is overexpressed in prostate cancer. The potential of D2B IgG, and F(ab)(2) and Fab fragments of this antibody for targeting prostate cancer was determined in mice bearing

  11. Targeting human prostate cancer with (111) In-labeled D2B IgG, F(ab')2 and Fab fragments in nude mice with PSMA-expressing xenografts

    NARCIS (Netherlands)

    Lutje, S.; Rij, C.M. van; Franssen, G.M.; Fracasso, G.; Helfrich, W.; Eek, A.; Oyen, W.J.G.; Colombatti, M.; Boerman, O.C.

    2015-01-01

    D2B is a new monoclonal antibody directed against an extracellular domain of prostate-specific membrane antigen (PSMA), which is overexpressed in prostate cancer. The potential of D2B IgG, and F(ab')2 and Fab fragments of this antibody for targeting prostate cancer was determined in mice bearing

  12. The strength of small: Improved targeting of Insulin-like Growth Factor-1 Receptor (IGF-1R) with F(ab')2-R1507 fragments in Ewing sarcomas

    NARCIS (Netherlands)

    Fleuren, Emmy D. G.; Versleijen-Jonkers, Yvonne M. H.; Heskamp, Sandra; Roeffen, Melissa H. S.; Bouwman, Wilbert H.; Molkenboer-Kuenen, Janneke D. M.; van Laarhoven, Hanneke W. M.; Oyen, Wim J. G.; Boerman, Otto C.; van der Graaf, Winette T. A.

    2013-01-01

    To investigate whether F(ab')2-fragments of the monoclonal Insulin-like Growth Factor-1 Receptor (IGF-1R) antibody R1507 (F(ab')2-R1507) can successfully target IGF-1R in Ewing sarcomas (ES). BALB/c nude mice were subcutaneously implanted with IGF-1R-expressing human ES xenografts (EW-5 and EW-8)

  13. Hepatic targeting and hypocholesterolemic effect of lactosaminated Fab against low density lipoproteins

    International Nuclear Information System (INIS)

    Bernini, F.; Bocan, T.M.A.; Via, D.P.; Gotto, A.M. Jr.; Smith, L.C.

    1986-01-01

    Lactosaminated Fab (lac-Fab) specific for human LDL induces plasma clearance and uptake of circulating [ 125 -I]-iodo-LDL in rat, a process mediated by galactose receptors of the liver. This study demonstrates that lac-Fab is a specific carrier of LDL to the liver parenchymal cells and exhibits hypocholesterolemic activity in vivo. Rats were injected with fluorescent 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-LDL (diI-LDL) or 6 mg of LDL plus tracer amounts of [ 125 I]-iodo-LDL. After 10-20 min, the animals received 3-10 mg of lac-Fab. Histologic examination of the liver sections showed the uptake of diI-LDL in the parenchymal cells, as compared to diI-acetyl-LDL which was localized in sinusoidal cells. More than 85% of human LDL disappeared within 2.5 hr after lac-Fab injection, reducing plasma cholesterol from 133.0 +/- 12.6 mg/dl to 66.4 +/- 8.0 mg/dl, the basal value in the rat. In control rats, only about 20% of radioactivity and cholesterol disappeared at 2.5 hr. HDL levels were unaffected. The authors conclude that lac-Fab is a specific carrier of LDL to hepatocytes and can lower plasma LDL-cholesterol in vivo. Lac-Fab specific for other antigens may act as specific carriers of molecule or macromolecules to hepatocytes

  14. Targeting human prostate cancer with 111In-labeled D2B IgG, F(ab')2 and Fab fragments in nude mice with PSMA-expressing xenografts.

    Science.gov (United States)

    Lütje, Susanne; van Rij, Catharina M; Franssen, Gerben M; Fracasso, Giulio; Helfrich, Wijnand; Eek, Annemarie; Oyen, Wim J; Colombatti, Marco; Boerman, Otto C

    2015-01-01

    D2B is a new monoclonal antibody directed against an extracellular domain of prostate-specific membrane antigen (PSMA), which is overexpressed in prostate cancer. The potential of D2B IgG, and F(ab')2 and Fab fragments of this antibody for targeting prostate cancer was determined in mice bearing subcutaneous prostate cancer xenografts. The optimal time point for imaging was determined in biodistribution and microSPECT imaging studies with (111)In-D2B IgG, (111)In-capromab pendetide, (111)In-D2B F(ab')2 and (111)In-D2B Fab fragments in mice with PSMA-expressing LNCaP and PSMA-negative PC3 tumors at several time points after injection. All (111)In-labeled antibody formats specifically accumulated in the LNCaP tumors, with highest uptake of (111)In-D2B IgG and (111)In-capromab pendetide at 168 h p.i. (94.8 ± 19.2% injected dose per gram (ID/g) and 16.7 ± 2.2% ID/g, respectively), whereas uptake of (111)In-D2B F(ab')2 and (111)In-D2B Fab fragments peaked at 24 h p.i. (12.1 ± 3.0% ID/g and 15.1 ± 2.9% ID/g, respectively). Maximum LNCaP tumor-to-blood ratios were 13.0 ± 2.3 (168 h p.i.), 6.2 ± 0.7 (24 h p.i.), 23.0 ± 4.0 (24 h p.i.) and 4.5 ± 0.6 (168 h p.i.) for (111)In-D2B IgG, (111)In-F(ab')2, (111)In-Fab and (111)In-capromab pendetide, respectively. LNCaP tumors were clearly visualized with microSPECT with all antibody formats. This study demonstrates the feasibility of D2B IgG, F(ab')2 and Fab fragments for targeting PSMA-expressing prostate cancer xenografts. Copyright © 2014 John Wiley & Sons, Ltd.

  15. Targeting Mast Cells and Basophils with Anti-FcεRIα Fab-Conjugated Celastrol-Loaded Micelles Suppresses Allergic Inflammation.

    Science.gov (United States)

    Peng, Xia; Wang, Juan; Li, Xianyang; Lin, Lihui; Xie, Guogang; Cui, Zelin; Li, Jia; Wang, Yuping; Li, Li

    2015-12-01

    Mast cells and basophils are effector cells in the pathophysiology of allergic diseases. Targeted elimination of these cells may be a promising strategy for the treatment of allergic disorders. Our present study aims at targeted delivery of anti-FcεRIα Fab-conjugated celastrol-loaded micelles toward FcεRIα receptors expressed on mast cells and basophils to have enhanced anti-allergic effect. To achieve this aim, we prepared celastrol-loaded (PEO-block-PPO-block-PEO, Pluronic) polymeric nanomicelles using thin-film hydration method. The anti-FcεRIα Fab Fragment was then conjugated to carboxyl groups on drug-loaded micelles via EDC amidation reaction. The anti-FcεRIα Fab-conjugated celastrol-loaded micelles revealed uniform particle size (93.43 ± 12.93 nm) with high loading percentage (21.2 ± 1.5% w/w). The image of micelles showed oval and rod like. The anti-FcεRIα Fab-conjugated micelles demonstrated enhanced cellular uptake and cytotoxity toward target KU812 cells than non-conjugated micelles in vitro. Furthermore, diffusion of the drug into the cells allowed an efficient induction of cell apoptosis. In mouse model of allergic asthma, treatment with anti-FcεRIα Fab-conjugated micelles increased lung accumulation of micelles, and significantly reduced OVA-sIgE, histamine and Th2 cytokines (IL-4, IL-5, TNF-α) levels, eosinophils infiltration and mucus production. In addition, in mouse model of passive cutaneous anaphylaxis, anti-FcεRIα Fab-conjugated celastrol-loaded micelles treatment significantly decreased extravasated evan's in the ear. These results indicate that anti-FcεRIα Fab-conjugated celastrol-loaded micelles can target and selectively kill mast cells and basophils which express FcεRIα, and may be efficient reagents for the treatment of allergic disorders and mast cell related diseases.

  16. Human/murine chimeric 81C6 F(ab')2 fragment: preclinical evaluation of a potential construct for the targeted radiotherapy of malignant glioma

    International Nuclear Information System (INIS)

    Boskovitz, Abraham; Akabani, Gamal H.; Pegram, Charles N.; Bigner, Darrell D.; Zalutsky, Michael R.

    2004-01-01

    We have obtained encouraging responses in recent Phase I studies evaluating 131 I-labeled human/murine chimeric 81C6 anti-tenascin monoclonal antibody (ch81C6) administered into surgically-created tumor resection cavities in brain tumor patients. However, because the blood clearance is slow, hematologic toxicity has been higher than seen with murine 81C6 (mu81C6). In the current study, a series of paired-label experiments were performed in athymic mice bearing subcutaneous D-245 MG human glioma xenografts to compare the biodistribution of the fragment ch81C6 F(ab') 2 labeled using Iodogen to a) intact ch81C6, b) mu81C6, and c) ch81C6 F(ab') 2 labeled using N-succinimidyl 3-[ 131 I]iodobenzoate. Tumor retention of radioiodine activity for the F(ab') 2 fragment was comparable to that for intact ch81C6 for the first 24 h and to that for mu81C6 for the first 48 h; as expected, blood and other normal tissue levels declined faster for ch81C6 F(ab') 2. Radiation dosimetry calculations suggest that 131 I-labeled ch81C6 F(ab') 2 may warrant further evaluation as a targeted radiotherapeutic for the treatment of brain tumors

  17. Pharmacokinetics and tumor targeting of 131I-labeled F(ab')2 fragments of the chimeric monoclonal antibody G250: preclinical and clinical pilot studies.

    NARCIS (Netherlands)

    Brouwers, A.H.; Mulders, P.F.A.; Oosterwijk, E.; Buijs, W.C.A.M.; Corstens, F.H.M.; Boerman, O.C.; Oyen, W.J.G.

    2004-01-01

    INTRODUCTION: Clinical and animal studies of chimeric monoclonal antibody G250 (moAb cG250) for the targeting of clear-cell renal cell carcinoma (RCC), to date, have been with the intact IgG form. To determine whether F(ab')2 fragments are more suited for radioimmunotherapy (RIT) than intact IgG,

  18. Fusion target design

    International Nuclear Information System (INIS)

    Bangerter, R.O.

    1978-01-01

    Most detailed fusion target design is done by numerical simulation using large computers. Although numerical simulation is briefly discussed, this lecture deals primarily with the way in which basic physical arguments, driver technology considerations and economical power production requirements are used to guide and augment the simulations. Physics topics discussed include target energetics, preheat, stability and symmetry. A specific design example is discussed

  19. Evaluation of 177Lu[Lu]-CHX-A″-DTPA-6A10 Fab as a radioimmunotherapy agent targeting carbonic anhydrase XII.

    Science.gov (United States)

    Fiedler, L; Kellner, M; Gosewisch, A; Oos, R; Böning, G; Lindner, S; Albert, N; Bartenstein, P; Reulen, H-J; Zeidler, R; Gildehaus, F J

    2018-05-01

    Due to their infiltrative growth behavior, gliomas have, even after surgical resection, a high recurrence tendency. The approach of intracavitary radioimmunotherapy (RIT) is aimed at inhibiting tumor re-growth by directly administering drugs into the resection cavity (RC). Direct application of the radioconjugate into the RC has the advantage of bypassing the blood-brain barrier, which allows the administration of higher radiation doses than systemic application. Carbonic anhydrase XII (CA XII) is highly expressed on glioma cells while being absent from normal brain and thus an attractive target molecule for RIT. We evaluated a CA XII-specific 6A10 Fab (fragment antigen binding) labelled with 177 Lu as an agent for RIT. 6A10 Fab fragment was modified and radiolabelled with 177 Lu and characterized by MALDI-TOF, flow cytometry and radio-TLC. In vitro stability was determined under physiological conditions. Biodistribution studies, autoradiography tumor examinations and planar scintigraphy imaging were performed on SCID-mice bearing human glioma xenografts. The in vitro CA XII binding capacity of the modified Fab was confirmed. Radiochemical purity was determined to be >90% after 72 h of incubation under physiological conditions. Autoradiography experiments proved the specific binding of the Fab to CA XII on tumor cells. Biodistribution studies revealed a tumor uptake of 3.0%ID/g after 6 h and no detectable brain uptake. The tumor-to-contralateral ratio of 10/1 was confirmed by quantitative planar scintigraphy. The radiochemical stability in combination with a successful in vivo tumor uptake shows the potential suitability for future RIT applications with the 6A10 Fab. Copyright © 2018 Elsevier Inc. All rights reserved.

  20. Fab Chaperone-Assisted RNA Crystallography (Fab CARC).

    Science.gov (United States)

    Sherman, Eileen; Archer, Jennifer; Ye, Jing-Dong

    2016-01-01

    Recent discovery of structured RNAs such as ribozymes and riboswitches shows that there is still much to learn about the structure and function of RNAs. Knowledge learned can be employed in both biochemical research and clinical applications. X-ray crystallography gives unparalleled atomic-level structural detail from which functional inferences can be deduced. However, the difficulty in obtaining high-quality crystals and their phasing information make it a very challenging task. RNA crystallography is particularly arduous due to several factors such as RNA's paucity of surface chemical diversity, lability, repetitive anionic backbone, and flexibility, all of which are counterproductive to crystal packing. Here we describe Fab chaperone assisted RNA crystallography (CARC), a systematic technique to increase RNA crystallography success by facilitating crystal packing as well as expediting phase determination through molecular replacement of conserved Fab domains. Major steps described in this chapter include selection of a synthetic Fab library displayed on M13 phage against a structured RNA crystallization target, ELISA for initial choice of binding Fabs, Fab expression followed by protein A affinity then cation exchange chromatography purification, final choice of Fab by binding specificity and affinity as determined by a dot blot assay, and lastly gel filtration purification of a large quantity of chosen Fabs for crystallization.

  1. Implementing Target Value Design.

    Science.gov (United States)

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

    2017-04-01

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

  2. Structural and dynamical aspects of Streptococcus gordonii FabH through molecular docking and MD simulations.

    Science.gov (United States)

    Shamim, Amen; Abbasi, Sumra Wajid; Azam, Syed Sikander

    2015-07-01

    β-Ketoacyl-ACP-synthase III (FabH or KAS III) has become an attractive target for the development of new antibacterial agents which can overcome the multidrug resistance. Unraveling the fatty acid biosynthesis (FAB) metabolic pathway and understanding structural coordinates of FabH will provide valuable insights to target Streptococcus gordonii for curing oral infection. In this study, we designed inhibitors against therapeutic target FabH, in order to block the FAB pathway. As compared to other targets, FabH has more interactions with other proteins, located on the leading strand with higher codon adaptation index value and associated with lipid metabolism category of COG. Current study aims to gain in silico insights into the structural and dynamical aspect of S. gordonii FabH via molecular docking and molecular dynamics (MD) simulations. The FabH protein is catalytically active in dimerization while it can lock in monomeric state. Current study highlights two residues Pro88 and Leu315 that are close to each other by dimerization. The active site of FabH is composed of the catalytic triad formed by residues Cys112, His249, and Asn279 in which Cys112 is involved in acetyl transfer, while His249 and Asn279 play an active role in decarboxylation. Docking analysis revealed that among the studied compounds, methyl-CoA disulfide has highest GOLD score (82.75), binding affinity (-11 kcal/mol) and exhibited consistently better interactions. During MD simulations, the FabH structure remained stable with the average RMSD value of 1.7 Å and 1.6 Å for undocked protein and docked complex, respectively. Further, crucial hydrogen bonding of the conserved catalytic triad for exhibiting high affinity between the FabH protein and ligand is observed by RDF analysis. The MD simulation results clearly demonstrated that binding of the inhibitor with S. gordonii FabH enhanced the structure and stabilized the dimeric FabH protein. Therefore, the inhibitor has the potential to become

  3. Antibody guided targeting of non-small cell lung cancer using 111In-labeled HMFG1 F(ab')2 fragments

    International Nuclear Information System (INIS)

    Kalofonos, H.P.; Sivolapenko, G.B.; Courtenay-Luck, N.S.

    1988-01-01

    Immunoscintigraphy using F(ab')2 fragments of tumor-associated monoclonal antibody HMFG1 was performed in 14 patients with primary and metastatic non-small cell carcinoma of lung cancer. The antibody was conjugated with diethylenetriamine pentaacetic acid and labeled with 111 In. Quality control studies showed efficient incorporation of 111 In onto antibody (5 mCi/mg), no significant loss of immunoreactivity, and in vitro and in vivo stability. The optimal time for imaging was between 48 and 72 h. Following i.v. administration, serum activity fell rapidly (t1/2a = 2.5 +/- 1.3 (SD) h; t1/2b = 42 +/- 4.5 h). The majority of the radioactivity was associated with the plasma and not with the blood cells. All patients had a significant concentration of 111 In in the liver (approximately 20% of the injected dose, 48 h postadministration). No toxicity was encountered. No human antimurine-IgG antibody was detected in any of the patients within 4 months of follow-up, even in patients receiving two administrations of F(ab')2 fragments. Localization of all primary lesions and the majority (80%) of metastatic lesions was achieved. Seven of 14 patients were also studied using a 111 In-labeled nonspecific antibody (Fab')2 fragment (4C4). In three patients the specificity index was higher than the other four (P less than 0.05). We conclude that although successful targeting of 111 In-labeled (Fab')2 fragments of HMFG1 can be achieved in patients with non-small cell carcinoma of lung, observable tumor localization can also be achieved using a nonspecific antibody

  4. Lithography hotspot discovery at 70nm DRAM 300mm fab: process window qualification using design base binning

    Science.gov (United States)

    Chen, Daniel; Chen, Damian; Yen, Ray; Cheng, Mingjen; Lan, Andy; Ghaskadvi, Rajesh

    2008-11-01

    Identifying hotspots--structures that limit the lithography process window--become increasingly important as the industry relies heavily on RET to print sub-wavelength designs. KLA-Tencor's patented Process Window Qualification (PWQ) methodology has been used for this purpose in various fabs. PWQ methodology has three key advantages (a) PWQ Layout--to obtain the best sensitivity (b) Design Based Binning--for pattern repeater analysis (c) Intelligent sampling--for the best DOI sampling rate. This paper evaluates two different analysis strategies for SEM review sampling successfully deployed at Inotera Memories, Inc. We propose a new approach combining the location repeater and pattern repeaters. Based on a recent case study the new sampling flow reduces the data analysis and sampling time from 6 hours to 1.5 hour maintaining maximum DOI sample rate.

  5. Evaluation of tumor targeting with radiolabeled F(ab2 fragment of a humanized monoclonal antibody

    Directory of Open Access Journals (Sweden)

    "Babaei MH

    2002-08-01

    Full Text Available Humanized monoclonal antibody U36 and its F(ab'2 fragment, radio labeled with 125I, were tested for tumor localization in nude mice bearing a squamous cell carcinoma xenograft line derived from a head and neck carcinoma. Monoclonal antibody IgG or F(ab'2 fragment were injected in parallel and at days 1, 2 and 3, mice were dissected for determination of isotope biodistribution. IgG as well as F(ab'2 showed highly specific localization in tumor tissue. The mean tumor uptake (n=3 is expressed as the percentage of the injected dose per gram of tumor tissue (%ID/g. %ID/g of IgG was 11.7% at day 1 and decreased to 10.9% at day 3 whereas %ID/g of F(ab'2 was 2.9% at day 1 and decreased on following days. Tumor to blood ratios (T/B at day 1 were 0.86 for IgG and 1.32 for F(ab'2 and reached a maximum at day 3 with values of 4.41 and 1.84 respectively. These findings suggest that the superior tumor to non-tumor ratios in the day of 1 render the F(ab'2 fragment more qualified for specific targeting radioisotopes to tumor xenografts in this exprimental setting.

  6. Structural Characterisation of FabG from Yersinia pestis, a Key Component of Bacterial Fatty Acid Synthesis.

    Directory of Open Access Journals (Sweden)

    Jeffrey D Nanson

    Full Text Available Ketoacyl-acyl carrier protein reductases (FabG are ubiquitously expressed enzymes that catalyse the reduction of acyl carrier protein (ACP linked thioesters within the bacterial type II fatty acid synthesis (FASII pathway. The products of these enzymes, saturated and unsaturated fatty acids, are essential components of the bacterial cell envelope. The FASII reductase enoyl-ACP reductase (FabI has been the focus of numerous drug discovery efforts, some of which have led to clinical trials, yet few studies have focused on FabG. Like FabI, FabG appears to be essential for survival in many bacteria, similarly indicating the potential of this enzyme as a drug target. FabG enzymes are members of the short-chain alcohol dehydrogenase/reductase (SDR family, and like other SDRs, exhibit highly conserved secondary and tertiary structures, and contain a number of conserved sequence motifs. Here we describe the crystal structures of FabG from Yersinia pestis (YpFabG, the causative agent of bubonic, pneumonic, and septicaemic plague, and three human pandemics. Y. pestis remains endemic in many parts of North America, South America, Southeast Asia, and Africa, and a threat to human health. YpFabG shares a high degree of structural similarity with bacterial homologues, and the ketoreductase domain of the mammalian fatty acid synthase from both Homo sapiens and Sus scrofa. Structural characterisation of YpFabG, and comparison with other bacterial FabGs and the mammalian fatty acid synthase, provides a strong platform for virtual screening of potential inhibitors, rational drug design, and the development of new antimicrobial agents to combat Y. pestis infections.

  7. Structural Characterisation of FabG from Yersinia pestis, a Key Component of Bacterial Fatty Acid Synthesis.

    Science.gov (United States)

    Nanson, Jeffrey D; Forwood, Jade K

    2015-01-01

    Ketoacyl-acyl carrier protein reductases (FabG) are ubiquitously expressed enzymes that catalyse the reduction of acyl carrier protein (ACP) linked thioesters within the bacterial type II fatty acid synthesis (FASII) pathway. The products of these enzymes, saturated and unsaturated fatty acids, are essential components of the bacterial cell envelope. The FASII reductase enoyl-ACP reductase (FabI) has been the focus of numerous drug discovery efforts, some of which have led to clinical trials, yet few studies have focused on FabG. Like FabI, FabG appears to be essential for survival in many bacteria, similarly indicating the potential of this enzyme as a drug target. FabG enzymes are members of the short-chain alcohol dehydrogenase/reductase (SDR) family, and like other SDRs, exhibit highly conserved secondary and tertiary structures, and contain a number of conserved sequence motifs. Here we describe the crystal structures of FabG from Yersinia pestis (YpFabG), the causative agent of bubonic, pneumonic, and septicaemic plague, and three human pandemics. Y. pestis remains endemic in many parts of North America, South America, Southeast Asia, and Africa, and a threat to human health. YpFabG shares a high degree of structural similarity with bacterial homologues, and the ketoreductase domain of the mammalian fatty acid synthase from both Homo sapiens and Sus scrofa. Structural characterisation of YpFabG, and comparison with other bacterial FabGs and the mammalian fatty acid synthase, provides a strong platform for virtual screening of potential inhibitors, rational drug design, and the development of new antimicrobial agents to combat Y. pestis infections.

  8. Controlled Fab installation onto polymeric micelle nanoparticles for tuned bioactivity

    Science.gov (United States)

    Chen, Shaoyi; Florinas, Stelios; Teitgen, Abigail; Xu, Ze-Qi; Gao, Changshou; Wu, Herren; Kataoka, Kazunori; Cabral, Horacio; Christie, R. James

    2017-12-01

    Antibodies and antigen-binding fragments (Fabs) can be used to modify the surface of nanoparticles for enhanced target binding. In our previous work, site-specific conjugation of Fabs to polymeric micelles using conventional methods was limited to approximately 30% efficiency, possibly due to steric hindrance related to macromolecular reactants. Here, we report a new method that enables conjugation of Fabs onto a micelle surface in a controlled manner with up to quantitative conversion of nanoparticle reactive groups. Variation of (i) PEG spacer length in a heterofunctionalized cross-linker and (ii) Fab/polymer feed ratios resulted in production of nanoparticles with a range of Fab densities on the surface up to the theoretical maximum value. The biological impact of variable Fab density was evaluated in vitro with respect to cell uptake and cytotoxicity of a drug-loaded (SN38) targeted polymeric micelle bearing anti-EphA2 Fabs. Fab conjugation increased cell uptake and potency compared with non-targeted micelles, although a Fab density of 60% resulted in decreased uptake and potency of the targeted micelles. Altogether, our findings demonstrate that conjugation strategies can be optimized to allow control of Fab density on the surface of nanoparticles and also that Fab density may need to be optimized for a given cell-surface target to achieve the highest bioactivity.

  9. Application of a layout/material handling design method to a furnace area in a 300 mm wafer fab

    NARCIS (Netherlands)

    Hesen, P.M.C.; Renders, P.J.J.; Rooda, J.E.

    2001-01-01

    For many years, material handling within the semiconductor industry has become increasingly important. With the introduction of 300 mm wafer production, ergonomics and product safety become more critical. Therefore, the manufacturers of semiconductor wafer fabs are considering the automation of

  10. Beyond Fab Four

    International Nuclear Information System (INIS)

    Babichev, E; Charmousis, C; Langlois, D; Saito, R

    2015-01-01

    We show that the two additional Lagrangians that appear in theories beyond Horndeski can be reexpressed in terms of simple generalizations of the ‘John’ and ‘Paul’ terms of the Fab Four theories. We find that these extended Fab Four satisfy the same properties of self-tuning as the original Fab Four. (fast track communication)

  11. "Fab 13": The Learning Factory.

    Science.gov (United States)

    Crooks, Steven M.; Eucker, Tom R.

    2001-01-01

    Describes how situated learning theory was employed in the design of Fab 13, a four-day simulation-based learning experience for manufacturing professionals at Intel Corporation. Presents a conceptual framework for understanding situated learning and discusses context, content, anchored instruction, facilitation, scaffolding, collaborating,…

  12. Efficient use of design-based binning methodology in a DRAM fab

    Science.gov (United States)

    Karsenti, Laurent; Wehner, Arno; Fischer, Andreas; Seifert, Uwe; Goeckeritz, Jens; Geshel, Mark; Gscheidlen, Dieter; Bartov, Avishai

    2009-03-01

    It is a well established fact that as design rules and printed features shrink, sophisticated techniques are required to ensure the design intent is indeed printed on the wafer. Techniques of this kind are Optical Proximity Correction (OPC), Resolution Enhancement Techniques (RET) and DFM Design for Manufacturing (DFM). As these methods are applied to the overall chip and rely on complex modeling and simulations, they increase the risk of creating local areas or layouts with a limiting process window. Hence, it is necessary to verify the manufacturability (sufficient depth of focus) of the overall die and not only of a pre-defined set of metrology structures. The verification process is commonly based on full chip defect density inspection of a Focus Exposure Matrix (FEM) wafer, combined with appropriate post processing of the inspection data. This is necessary to avoid time consuming search for the Defects of Interest (DOI's) as defect counts are usually too high to be handled by manual SEM review. One way to post process defect density data is the so called design based binning (DBB). The Litho Qualification Monitor (LQM) system allows to classify and also to bin defects based on design information. In this paper we will present an efficient way to combine classification and binning in order to check design rules and to determine the marginal features (layout with low depth of focus). The Design Based Binning has been connected to the Yield Management System (YMS) to allow new process monitoring approaches towards Design Based SPC. This could dramatically cut the time to detect systematic defects inline.

  13. A parallel panning scheme used for selection of a GluA4-specific Fab targeting the ligand-binding domain

    DEFF Research Database (Denmark)

    Clausen, Rasmus P; Mohr, Andreas Ø; Riise, Erik

    2016-01-01

    A method for development of murine Fab fragments towards extracellular domains of a surface receptor is presented. The GluA4 ionotropic glutamate receptor is used as a model system. Recombinant GluA4 ectodomain comprising both the N-terminal domain (NTD) and the ligand-binding domain (LBD) in one...... molecule was used for immunization. A Fab-phage library was constructed and a parallel panning approach enabled selection of murine Fab fragments towards either intact ectodomain or the isolated LBD of the GluA4 receptor. One LBD-Fab (FabL9) showed exclusive selectivity for the GluA4 LBD, over a panel...... of LBDs from GluA2, GluK1, GluK2 and GluD2. Soluble FabL9 was produced in amounts suitable for characterization. Competitive ELISA and rat-brain immunoprecipitation experiments confirmed that the FabL9 epitope is conserved in the LBD and in the intact native receptor. By an alignment of GluA2 and GluA4...

  14. Ecosystem Fabrication (EcoFAB) Protocols for The Construction of Laboratory Ecosystems Designed to Study Plant-microbe Interactions.

    Science.gov (United States)

    Gao, Jian; Sasse, Joelle; Lewald, Kyle M; Zhalnina, Kateryna; Cornmesser, Lloyd T; Duncombe, Todd A; Yoshikuni, Yasuo; Vogel, John P; Firestone, Mary K; Northen, Trent R

    2018-04-10

    Beneficial plant-microbe interactions offer a sustainable biological solution with the potential to boost low-input food and bioenergy production. A better mechanistic understanding of these complex plant-microbe interactions will be crucial to improving plant production as well as performing basic ecological studies investigating plant-soil-microbe interactions. Here, a detailed description for ecosystem fabrication is presented, using widely available 3D printing technologies, to create controlled laboratory habitats (EcoFABs) for mechanistic studies of plant-microbe interactions within specific environmental conditions. Two sizes of EcoFABs are described that are suited for the investigation of microbial interactions with various plant species, including Arabidopsis thaliana, Brachypodium distachyon, and Panicum virgatum. These flow-through devices allow for controlled manipulation and sampling of root microbiomes, root chemistry as well as imaging of root morphology and microbial localization. This protocol includes the details for maintaining sterile conditions inside EcoFABs and mounting independent LED light systems onto EcoFABs. Detailed methods for addition of different forms of media, including soils, sand, and liquid growth media coupled to the characterization of these systems using imaging and metabolomics are described. Together, these systems enable dynamic and detailed investigation of plant and plant-microbial consortia including the manipulation of microbiome composition (including mutants), the monitoring of plant growth, root morphology, exudate composition, and microbial localization under controlled environmental conditions. We anticipate that these detailed protocols will serve as an important starting point for other researchers, ideally helping create standardized experimental systems for investigating plant-microbe interactions.

  15. FabH Mutations Confer Resistance to FabF-Directed Antibiotics in Staphylococcus aureus

    OpenAIRE

    Parsons, Joshua B.; Yao, Jiangwei; Frank, Matthew W.; Rock, Charles O.

    2014-01-01

    Delineating the mechanisms for genetically acquired antibiotic resistance is a robust approach to target validation and anticipates the evolution of clinical drug resistance. This study defines a spectrum of mutations in fabH that render Staphylococcus aureus resistant to multiple natural products known to inhibit the elongation condensing enzyme (FabF) of bacterial type II fatty acid synthesis. Twenty independently isolated clones resistant to platensimycin, platencin, or thiolactomycin were...

  16. Complexes of neutralizing and non-neutralizing affinity matured Fabs with a mimetic of the internal trimeric coiled-coil of HIV-1 gp41.

    Directory of Open Access Journals (Sweden)

    Elena Gustchina

    Full Text Available A series of mini-antibodies (monovalent and bivalent Fabs targeting the conserved internal trimeric coiled-coil of the N-heptad repeat (N-HR of HIV-1 gp41 has been previously constructed and reported. Crystal structures of two closely related monovalent Fabs, one (Fab 8066 broadly neutralizing across a wide panel of HIV-1 subtype B and C viruses, and the other (Fab 8062 non-neutralizing, representing the extremes of this series, were previously solved as complexes with 5-Helix, a gp41 pre-hairpin intermediate mimetic. Binding of these Fabs to covalently stabilized chimeric trimers of N-peptides of HIV-1 gp41 (named (CCIZN363 or 3-H has now been investigated using X-ray crystallography, cryo-electron microscopy, and a variety of biophysical methods. Crystal structures of the complexes between 3-H and Fab 8066 and Fab 8062 were determined at 2.8 and 3.0 Å resolution, respectively. Although the structures of the complexes with the neutralizing Fab 8066 and its non-neutralizing counterpart Fab 8062 were generally similar, small differences between them could be correlated with the biological properties of these antibodies. The conformations of the corresponding CDRs of each antibody in the complexes with 3-H and 5-Helix are very similar. The adaptation to a different target upon complex formation is predominantly achieved by changes in the structure of the trimer of N-HR helices, as well as by adjustment of the orientation of the Fab molecule relative to the N-HR in the complex, via rigid-body movement. The structural data presented here indicate that binding of three Fabs 8062 with high affinity requires more significant changes in the structure of the N-HR trimer compared to binding of Fab 8066. A comparative analysis of the structures of Fabs complexed to different gp41 intermediate mimetics allows further evaluation of biological relevance for generation of neutralizing antibodies, as well as provides novel structural insights into immunogen

  17. Sortase-catalyzed in vitro functionalization of a HER2-specific recombinant Fab for tumor targeting of the plant cytotoxin gelonin

    Science.gov (United States)

    Kornberger, Petra; Skerra, Arne

    2014-01-01

    We report on the preparation of a new type of immunotoxin via in vitro ligation of the αHer2 antigen binding fragment (Fab) of the clinically-validated antibody trastuzumab to the plant toxin gelonin, employing catalysis by the bacterial enzyme sortase A (SrtA). The αHer2 Fab was fused with the extended SrtA recognition motif LPET↓GLEH6 at the C-terminus of its heavy chain, thereby preventing interference with antigen binding, while the toxin was equipped with a Gly2 sequence at its N-terminus, distant to the catalytically active site in the C-terminal region. Site-specific in vitro transpeptidation led to a novel antibody-toxin conjugate wherein gelonin had effectively replaced the Fc region of a conventional (monomerized) immunoglobulin. After optimization of reaction conditions and incubation time, the resulting Fab-Gelonin ligation product was purified to homogeneity in a two-step procedure by means of Strep-Tactin affinity chromatography—utilizing the Strep-tag II appended to gelonin—and size exclusion chromatography. Binding activity of the immunotoxin for the Her2 ectodomain was indistinguishable from the unligated Fab as measured by real-time surface plasmon resonance spectroscopy. Specific cytotoxic potency of Fab-Gelonin was demonstrated against two Her2-positive cell lines, resulting in EC50 values of ~1 nM or lower, indicating a 1000-fold enhanced cell-killing activity compared with gelonin itself. Thus, our strategy provides a convenient route to the modular construction of functional immunotoxins from Fabs of established tumor-specific antibodies with gelonin or related proteotoxins, also avoiding the elevated biosafety levels that would be mandatory for the direct biotechnological preparation of corresponding fusion proteins. PMID:24492291

  18. In vivo characterization of the novel CD44v6-targeting Fab fragment AbD15179 for molecular imaging of squamous cell carcinoma: a dual-isotope study

    Science.gov (United States)

    2014-01-01

    Background Patients with squamous cell carcinoma in the head and neck region (HNSCC) offer a diagnostic challenge due to difficulties to detect small tumours and metastases. Imaging methods available are not sufficient, and radio-immunodiagnostics could increase specificity and sensitivity of diagnostics. The objective of this study was to evaluate, for the first time, the in vivo properties of the radiolabelled CD44v6-targeting fragment AbD15179 and to assess its utility as a targeting agent for radio-immunodiagnostics of CD44v6-expressing tumours. Methods The fully human CD44v6-targeting Fab fragment AbD15179 was labelled with 111In or 125I, as models for radionuclides suitable for imaging with SPECT or PET. Species specificity, antigen specificity and internalization properties were first assessed in vitro. In vivo specificity and biodistribution were then evaluated in tumour-bearing mice using a dual-tumour and dual-isotope setup. Results Both species-specific and antigen-specific binding of the conjugates were demonstrated in vitro, with no detectable internalization. The in vivo studies demonstrated specific tumour binding and favourable tumour targeting properties for both conjugates, albeit with higher tumour uptake, slower tumour dissociation, higher tumour-to-blood ratio and higher CD44v6 sensitivity for the 111In-labelled fragment. In contrast, the 125I-Fab demonstrated more favourable tumour-to-organ ratios for liver, spleen and kidneys. Conclusions We conclude that AbD15179 efficiently targets CD44v6-expressing squamous cell carcinoma xenografts, and particularly, the 111In-Fab displayed high and specific tumour uptake. CD44v6 emerges as a suitable target for radio-immunodiagnostics, and a fully human antibody fragment such as AbD15179 can enable further clinical imaging studies. PMID:24598405

  19. Super liquid density target designs

    International Nuclear Information System (INIS)

    Pan, Y.L.; Bailey, D.S.

    1976-01-01

    The success of laser fusion depends on obtaining near isentropic compression of fuel to very high densities and igniting this fuel. To date, the results of laser fusion experiments have been based mainly on the exploding pusher implosion of fusion capsules consisting of thin glass microballoons (wall thickness of less than 1 micron) filled with low density DT gas (initial density of a few mg/cc). Maximum DT densities of a few tenths of g/cc and temperatures of a few keV have been achieved in these experiments. We will discuss the results of LASNEX target design calculations for targets which: (a) can compress fuel to much higher densities using the capabilities of existing Nd-glass systems at LLL; (b) allow experimental measurement of the peak fuel density achieved

  20. Meditope-Fab interaction: threading the hole.

    Science.gov (United States)

    Bzymek, Krzysztof P; Ma, Yuelong; Avery, Kendra N; Horne, David A; Williams, John C

    2017-12-01

    Meditope, a cyclic 12-residue peptide, binds to a unique binding side between the light and heavy chains of the cetuximab Fab. In an effort to improve the affinity of the interaction, it was sought to extend the side chain of Arg8 in the meditope, a residue that is accessible from the other side of the meditope binding site, in order to increase the number of interactions. These modifications included an n-butyl and n-octyl extension as well as hydroxyl, amine and carboxyl substitutions. The atomic structures of the complexes and the binding kinetics for each modified meditope indicated that each extension threaded through the Fab `hole' and that the carboxyethylarginine substitution makes a favorable interaction with the Fab, increasing the half-life of the complex by threefold compared with the unmodified meditope. Taken together, these studies provide a basis for the design of additional modifications to enhance the overall affinity of this unique interaction.

  1. FabIO

    DEFF Research Database (Denmark)

    Bergbäck Knudsen, Erik; Sørensen, Henning O.; Wright, Jonathan P.

    2013-01-01

    FabIO is a Python module written for easy and transparent reading of raw two-dimensional data from various X-ray detectors. The module provides a function for reading any image and returning a fabioimage object which contains both metadata (header information) and the raw data. All fabioimage...

  2. Design of the FMIT lithium target

    International Nuclear Information System (INIS)

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

    1981-01-01

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

  3. FabQ, a Dual-Function Dehydratase/Isomerase, Circumvents the Last Step of the Classical Fatty Acid Synthesis Cycle

    OpenAIRE

    Bi, Hongkai; Wang, Haihong; Cronan, John E.

    2013-01-01

    In the classical anaerobic pathway of unsaturated fatty acid biosynthesis, that of Escherichia coli, the double bond is introduced into the growing acyl chain by the FabA dehydratase/isomerase. Another dehydratase, FabZ, functions in the chain elongation cycle. In contrast, Aerococcus viridans has only a single FabA/FabZ homolog we designate FabQ. FabQ can not only replace the function of E. coli FabZ in vivo, but it also catalyzes the isomerization required for unsaturated fatty acid biosynt...

  4. Investigation of the effect of physical parameters on the design of tumour targeting agents

    Science.gov (United States)

    Casey, Joanne Lois

    Tumour targeting using radiolabelled antibodies for radioimmunodetection (RAID) and radioimmunotherapy (RIT) has been studied for many years. The main factors that have limited clinical success are low tumour uptake, immunogenicity and poor therapeutic ratios. This thesis has applied current technology to make advances in this area of research. The effect of physical parameters (antibody size, valency, affinity and charge) on the design of tumour targeting agents was studied by constructing divalent (DFM) and trivalent (TFM) forms of the murine anti-CEA antibody A5B7 Fab' by chemical cross-linking. This involves partial reduction of the hinge disulphides to expose thiol (-SH) groups and subsequent reaction with a maleimide cross-linker to form a thioether bond at the hinge region. Previous studies have suggested that the stability of thioether bonds is superior to naturally occurring disulphide bonds present at the hinge region of IgG and F(ab')2. The aim was to compare the functional affinities and in vivo tumour targeting in nude mice bearing human tumour xenografts of DFM and TFM to similar sized parent IgG and F(ab')2. Radiolabelling with 131I and 90Y was also compared with a view to determine which combination would be optimal for RIT. Results clearly demonstrated a significantly faster on-rate of DFM compared to all other antibody forms and estimated dosimetry analysis suggested that DFM would be the most suitable antibody form radiolabelled with 131I for RIT. Both F(ab')2 and DFM showed high kidney uptake levels on labelling with which is unacceptable for RIT. Despite the improved tumour: blood ratios for TFM, the increased estimated dose to normal tissues and lower therapeutic effect in RIT studies suggests that the most promising combination with the radionuclide appears to be IgG. A humanised version of A5B7 hFab' has been constructed previously in order to reduce its immunogenicity in man. The in vivo stability of hDFM proved to be superior to hF(ab')2

  5. IgG Fab Fragments Forming Bivalent Complexes by a Conformational Mechanism That Is Reversible by Osmolytes*

    Science.gov (United States)

    Nelson, Alfreda D.; Hoffmann, Michele M.; Parks, Christopher A.; Dasari, Surendra; Schrum, Adam G.; Gil, Diana

    2012-01-01

    Generated by proteolytic cleavage of immunoglobulin, Fab fragments possess great promise as blocking reagents, able to bind receptors or other targets without inducing cross-linking. However, aggregation of Fab preparations is a common occurrence, which generates intrinsic stimulatory capacity and thwarts signal blockade strategies. Using a panel of biochemical approaches, including size exclusion chromatography, SDS-PAGE, mass spectrometry, and cell stimulation followed by flow cytometry, we have measured the oligomerization and acquisition of stimulatory capacity that occurs in four monoclonal IgG Fabs specific for TCR/CD3. Unexpectedly, we observed that all Fabs spontaneously formed complexes that were precisely bivalent, and these bivalent complexes possessed most of the stimulatory activity of each Fab preparation. Fabs composing bivalent complexes were more susceptible to proteolysis than monovalent Fabs, indicating a difference in conformation between the Fabs involved in these two different states of valency. Because osmolytes represent a class of compounds that stabilize protein folding and conformation, we sought to determine the extent to which the amino acid osmolyte l-proline might impact bivalent Fab complexation. We found that l-proline (i) inhibited the adoption of the conformation associated with bivalent complexation, (ii) preserved Fab monovalency, (iii) reversed the conformation of preformed bivalent Fabs to that of monovalent Fabs, and (iv) separated a significant percentage of preformed bivalent complexes into monovalent species. Thus, Fab fragments can adopt a conformation that is compatible with folding or packing of a bivalent complex in a process that can be inhibited by osmolytes. PMID:23109335

  6. A Case Study of a High School Fab Lab

    Science.gov (United States)

    Lacy, Jennifer E.

    This dissertation examines making and design-based STEM education in a formal makerspace. It focuses on how the design and implementation of a Fab Lab learning environment and curriculum affect how instructors and students see themselves engaging in science, and how the Fab Lab relates to the social sorting practices that already take place at North High School. While there is research examining design-based STEM education in informal and formal learning environments, we know little about how K-12 teachers define STEM in making activities when no university or museum partnership exists. This study sought to help fill this gap in the research literature. This case study of a formal makerspace followed instructors and students in one introductory Fab Lab course for one semester. Additional observations of an introductory woodworking course helped build the case and set it into the school context, and provided supplementary material to better understand the similarities and differences between the Fab Lab course and a more traditional design-based learning course. Using evidence from observational field notes, participant interviews, course materials, and student work, I found that the North Fab Lab relies on artifacts and rhetoric symbolic of science and STEM to set itself apart from other design-based courses at North High School. Secondly, the North Fab Lab instructors and students were unable to explain how what they were doing in the Fab Lab was science, and instead relied on vague and unsupported claims related to interdisciplinary STEM practices and dated descriptions of science. Lastly, the design and implementation of the Fab Lab learning environment and curriculum and its separation from North High School's low tech, design-based courses effectively reinforced social sorting practices and cultural assumptions about student work and intelligence.

  7. Flavored alcoholic beverages: an international marketing campaign that targets youth.

    Science.gov (United States)

    Mosher, James F; Johnsson, Diane

    2005-09-01

    Flavored alcoholic beverages (FABs) were first introduced into the alcohol market in the early I980s in the form of wine coolers. FABs are sweet, relatively low alcohol content beverages that are designed for "entry-level" drinkers. The alcohol industry has introduced new products and production methods to expand the category's popularity. Research suggests that they are popular with underage drinkers, particularly teenage girls, and that the industry uses marketing practices that appear to target youth. FABs are now marketed globally, and their production and marketing vary by country based on national regulatory restraints. In the United States, industry representations that the products are malt beverages for regulatory purposes appears to violate many state laws because the alcohol in the FABs is derived from distilled spirits. Recommendations for regulatory reform, including new legal definitions of FABs, increased taxes, and restrictions on availability, are applicable at both national and state levels.

  8. Multiple Target Laser Designator (MTLD)

    Science.gov (United States)

    2007-03-01

    Optimized Liquid Crystal Scanning Element Optimize the Nonimaging Predictive Algorithm for Target Ranging, Tracking, and Position Estimation...commercial potential. 3.0 PROGRESS THIS QUARTER 3.1 Optimization of Nonimaging Holographic Antenna for Target Tracking and Position Estimation (Task 6) In

  9. Meleagrin, a new FabI inhibitor from Penicillium chryosogenum with at least one additional mode of action.

    Directory of Open Access Journals (Sweden)

    Chang Ji Zheng

    Full Text Available Bacterial enoyl-acyl carrier protein reductase (FabI is a promising novel antibacterial target. We isolated a new class of FabI inhibitor from Penicillium chrysogenum, which produces various antibiotics, the mechanisms of some of them are unknown. The isolated FabI inhibitor was determined to be meleagrin by mass spectroscopy and nuclear magnetic resonance spectral analyses, and its more active and inactive derivatives were chemically prepared. Consistent with their selective inhibition of Staphylococcus aureus FabI, meleagrin and its more active derivatives directly bound to S. aureus FabI in a fluorescence quenching assay, inhibited intracellular fatty acid biosynthesis and growth of S. aureus, and increased the minimum inhibitory concentration for fabI-overexpressing S. aureus. The compounds that were not effective against the FabK isoform, however, inhibited the growth of Streptococcus pneumoniae that contained only the FabK isoform. Additionally no resistant mutant to the compounds was obtained. Importantly, fabK-overexpressing Escherichia coli was not resistant to these compounds, but was resistant to triclosan. These results demonstrate that the compounds inhibited another target in addition to FabI. Thus, meleagrin is a new class of FabI inhibitor with at least one additional mode of action that could have potential for treating multidrug-resistant bacteria.

  10. Cytosolic expression of functional Fab fragments in Escherichia coli using a novel combination of dual SUMO expression cassette and EnBase® cultivation mode.

    Science.gov (United States)

    Rezaie, F; Davami, F; Mansouri, K; Agha Amiri, S; Fazel, R; Mahdian, R; Davoudi, N; Enayati, S; Azizi, M; Khalaj, V

    2017-05-08

    The Escherichia coli expression system is highly effective in producing recombinant proteins. However, there are some limitations in this system, especially in obtaining correctly folded forms of some complex proteins such as Fab fragments. To improve the solubility and folding quality of Fab fragments, we have examined the effect of simultaneous application of a SUMO fusion tag, EnBase ® cultivation mode and a redox mutant strain in the E. coli expression system. A bicistronic gene construct was designed to express an antivascular endothelial growth factor (VEGF) Fab fragment as a model system. The construct contained a dual SUMO fusion gene fragment to encode SUMO-tagged heavy and light chains. While the expression of the construct in batch cultures of BL21 or SHuffle ® transformants produced insoluble and unfolded products, the induction of the transformants in EnBase ® medium resulted in soluble and correctly folded Fab fragment, reaching as high as 19% of the total protein in shuffle strain. The functional assays indicated that the biological activity of the target Fab is similar to the commercial anti-VEGF, Lucentis ® . This study demonstrated that the combination of SUMO fusion technology, EnBase ® cultivation system and recruiting a redox mutant of E. coli can efficiently enhance the solubility and productivity of recombinant Fab fragments. The presented strategy provides not only a novel method to produce soluble and active form of an anti-VEGF Fab but also may use in the efficient production of other antibody fragments. © 2017 The Society for Applied Microbiology.

  11. Target design for shock ignition

    International Nuclear Information System (INIS)

    Schurtz, G; Ribeyre, X; Lafon, M

    2010-01-01

    The conventional approach of laser driven inertial fusion involves the implosion of cryogenic shells of deuterium-tritium ice. At sufficiently high implosion velocities, the fuel ignites by itself from a central hot spot. In order to reduce the risks of hydrodynamic instabilities inherent to large implosion velocities, it was proposed to compress the fuel at low velocity, and ignite the compressed fuel by means of a convergent shock wave driven by an intense spike at the end of the laser pulse. This scheme, known as shock ignition, reduces the risks of shell break-up during the acceleration phase, but it may be impeded by a low coupling efficiency of the laser pulse with plasma at high intensities. This work provides a relationship between the implosion velocity and the laser intensity required to ignite the target by a shock. The operating domain of shock ignition at different energies is described.

  12. A single-domain antibody-linked Fab bispecific antibody Her2-S-Fab has potent cytotoxicity against Her2-expressing tumor cells.

    Science.gov (United States)

    Li, Aifen; Xing, Jieyu; Li, Li; Zhou, Changhua; Dong, Bin; He, Ping; Li, Qing; Wang, Zhong

    2016-12-01

    Her2, which is frequently overexpressed in breast cancer, is one of the most studied tumor-associated antigens for cancer therapy. Anti-HER2 monoclonal antibody, trastuzumab, has achieved significant clinical benefits in metastatic breast cancer. In this study, we describe a novel bispecific antibody Her2-S-Fab targeting Her2 by linking a single domain anti-CD16 VHH to the trastuzumab Fab. The Her2-S-Fab antibody can be efficiently expressed and purified from Escherichia coli, and drive potent cancer cell killing in HER2-overexpressing cancer cells. In xenograft model, the Her2-S-Fab suppresses tumor growth in the presence of human immune cells. Our results suggest that the bispecific Her2-S-Fab may provide a valid alternative to Her2 positive cancer therapy.

  13. A novel engineered interchain disulfide bond in the constant region enhances the thermostability of adalimumab Fab.

    Science.gov (United States)

    Nakamura, Hitomi; Oda-Ueda, Naoko; Ueda, Tadashi; Ohkuri, Takatoshi

    2018-01-01

    We constructed a system for expressing the Fab of the therapeutic human monoclonal antibody adalimumab at a yield of 20 mg/L in the methylotrophic yeast Pichia pastoris. To examine the contribution of interchain disulfide bonds to conformational stability, we prepared adalimumab Fab from which the interchain disulfide bond at the C-terminal region at both the CH 1 and CL domains was deleted by substitution of Cys with Ala (Fab ΔSS ). DSC measurements showed that the Tm values of Fab ΔSS were approximately 5 °C lower than those of wild-type Fab, suggesting that the interchain disulfide bond contributes to conformational thermostability. Using computer simulations, we designed a novel interchain disulfide bond outside the C-terminal region to increase the stability of Fab ΔSS . The resulting Fab (mutSS Fab ΔSS ) had the mutations H:V177C and L:Q160C in Fab ΔSS , confirming the formation of the disulfide bond between CH 1 and CL. The thermostability of mutSS Fab ΔSS was approximately 5 °C higher than that of Fab ΔSS . Therefore, the introduction of the designed interchain disulfide bond enhanced the thermostability of Fab ΔSS and mitigated the destabilization caused by partial reduction of the interchain disulfide bond at the C-terminal region, which occurs in site-specific modification such as PEGylation. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Fab-dsFv: A bispecific antibody format with extended serum half-life through albumin binding.

    Science.gov (United States)

    Davé, Emma; Adams, Ralph; Zaccheo, Oliver; Carrington, Bruce; Compson, Joanne E; Dugdale, Sarah; Airey, Michael; Malcolm, Sarah; Hailu, Hanna; Wild, Gavin; Turner, Alison; Heads, James; Sarkar, Kaushik; Ventom, Andrew; Marshall, Diane; Jairaj, Mark; Kopotsha, Tim; Christodoulou, Louis; Zamacona, Miren; Lawson, Alastair D; Heywood, Sam; Humphreys, David P

    2016-10-01

    An antibody format, termed Fab-dsFv, has been designed for clinical indications that require monovalent target binding in the absence of direct Fc receptor (FcR) binding while retaining substantial serum presence. The variable fragment (Fv) domain of a humanized albumin-binding antibody was fused to the C-termini of Fab constant domains, such that the VL and VH domains were individually connected to the Cκ and CH1 domains by peptide linkers, respectively. The anti-albumin Fv was selected for properties thought to be desirable to ensure a durable serum half-life mediated via FcRn. The Fv domain was further stabilized by an inter-domain disulfide bond. The bispecific format was shown to be thermodynamically and biophysically stable, and retained good affinity and efficacy to both antigens simultaneously. In in vivo studies, the serum half-life of Fab-dsFv, 2.6 d in mice and 7.9 d in cynomolgus monkeys, was equivalent to Fab'-PEG.

  15. Machine learning for fab automated diagnostics

    Science.gov (United States)

    Giollo, Manuel; Lam, Auguste; Gkorou, Dimitra; Liu, Xing Lan; van Haren, Richard

    2017-06-01

    Process optimization depends largely on field engineer's knowledge and expertise. However, this practice turns out to be less sustainable due to the fab complexity which is continuously increasing in order to support the extreme miniaturization of Integrated Circuits. On the one hand, process optimization and root cause analysis of tools is necessary for a smooth fab operation. On the other hand, the growth in number of wafer processing steps is adding a considerable new source of noise which may have a significant impact at the nanometer scale. This paper explores the ability of historical process data and Machine Learning to support field engineers in production analysis and monitoring. We implement an automated workflow in order to analyze a large volume of information, and build a predictive model of overlay variation. The proposed workflow addresses significant problems that are typical in fab production, like missing measurements, small number of samples, confounding effects due to heterogeneity of data, and subpopulation effects. We evaluate the proposed workflow on a real usecase and we show that it is able to predict overlay excursions observed in Integrated Circuits manufacturing. The chosen design focuses on linear and interpretable models of the wafer history, which highlight the process steps that are causing defective products. This is a fundamental feature for diagnostics, as it supports process engineers in the continuous improvement of the production line.

  16. Technical Design Report, Second Target Station

    International Nuclear Information System (INIS)

    Galambos, John D.; Anderson, David E.; Bethea, Katie L.; Carden, W. F.; Chae, Steven M.; Bechtol, D.; Brown, N.; Clark, A.

    2015-01-01

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

  17. From the Paper to the Tablet: On the Design of an AR-Based Tool for the Inspection of Pre-Fab Buildings. Preliminary Results of the SIRAE Project.

    Science.gov (United States)

    Portalés, Cristina; Casas, Sergio; Gimeno, Jesús; Fernández, Marcos; Poza, Montse

    2018-04-19

    Energy-efficient Buildings (EeB) are demanded in today’s constructions, fulfilling the requirements for green cities. Pre-fab buildings, which are modularly fully-built in factories, are a good example of this. Although this kind of building is quite new, the in situ inspection is documented using traditional tools, mainly based on paper annotations. Thus, the inspection process is not taking advantage of new technologies. In this paper, we present the preliminary results of the SIRAE project that aims to provide an Augmented Reality (AR) tool that can seamlessly aid in the regular processes of pre-fab building inspections to detect and eliminate the possible existing quality and energy efficiency deviations. In this regards, we show a description of the current inspection process and how an interactive tool can be designed and adapted to it. Our first results show the design and implementation of our tool, which is highly interactive and involves AR visualizations and 3D data-gathering, allowing the inspectors to quickly manage it without altering the way the inspection process is done. First trials on a real environment show that the tool is promising for massive inspection processes.

  18. From the Paper to the Tablet: On the Design of an AR-Based Tool for the Inspection of Pre-Fab Buildings. Preliminary Results of the SIRAE Project

    Science.gov (United States)

    Fernández, Marcos; Poza, Montse

    2018-01-01

    Energy-efficient Buildings (EeB) are demanded in today’s constructions, fulfilling the requirements for green cities. Pre-fab buildings, which are modularly fully-built in factories, are a good example of this. Although this kind of building is quite new, the in situ inspection is documented using traditional tools, mainly based on paper annotations. Thus, the inspection process is not taking advantage of new technologies. In this paper, we present the preliminary results of the SIRAE project that aims to provide an Augmented Reality (AR) tool that can seamlessly aid in the regular processes of pre-fab building inspections to detect and eliminate the possible existing quality and energy efficiency deviations. In this regards, we show a description of the current inspection process and how an interactive tool can be designed and adapted to it. Our first results show the design and implementation of our tool, which is highly interactive and involves AR visualizations and 3D data-gathering, allowing the inspectors to quickly manage it without altering the way the inspection process is done. First trials on a real environment show that the tool is promising for massive inspection processes. PMID:29671799

  19. Alterations in an indium-111 Fab' under conditions of utilization

    International Nuclear Information System (INIS)

    Halpern, S.E.; Sudora, E.; Tarburton, J.P.; Hagar, P.

    1992-01-01

    This study was conducted to investigate alterations that occur in an indium/111 Fab' of a monoclonal antibody following its in vivo administration. Patients were infused with 111 In-Fab' of the monoclonal antibody ZCE-025. Serum and urine specimens were collected from these pateients. Starting materials, serum, urine and controls samples were studied by electrophoresis. Animal distribution studies were performed in normal Balb/c mice and, in some cases, nude mice bearing a carcinoembryonic antigen (CEA)/producing human colon tumour since the antibody targets CEA. The studies indicated that the molecule circulated almost totally intact for at least 4 h and to a considerable extent for 24 h, with some evidence for in vivo fragmentation by 24 h. Evidence was also obtained suggesting the formation of a high molecular weight species in some patients. Shortly after infusion, some of the 111 In in the urine appeared as the intact Fab', but within hours the majority migrated electro-phoretically as low molecular weight species. We conclude that while the majority of the 111 In-Fab' of this particular antibody remains intact and immunoreactive following its administration, the molecule is structurally changed to some degree shortly after its infusion into humans. Since each monoclonal antibody is unique, the degree and rapidity of degradation of its Fab' in vivo could vary markedly from the above and possibly adversely effect its utility as a radiopharmaceutical. (orig.)

  20. Design of the LBNF Beamline Target Station

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-10-01

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

  1. Design of the MYRRHA Spallation Target Assembly

    International Nuclear Information System (INIS)

    Keijers, S.; Fernandez, R.; Stankovskiy, A.; Kennedy, G.; Van Tichelen, K.

    2015-01-01

    MYRRHA (Multi-purpose hybrid Research Reactor for High-tech Applications) is a multi-purpose research facility currently being developed at SCK.CEN. MYRRHA is based on the ADS (Accelerator Driven System) concept where a proton accelerator, a spallation target and a subcritical reactor are coupled. MYRRHA will demonstrate the ADS full concept by coupling these three components at a reasonable power level. As a flexible irradiation facility, the MYRRHA research reactor will be able to work in both critical and subcritical modes. In this way, MYRRHA will allow fuel developments for innovative reactor systems, material research for GEN IV and fusion reactors, and radioisotope production for medical and industrial applications. MYRRHA will be cooled by Lead Bismuth Eutectic (LBE) and will play an important role in the development of the Pb-alloys technology needed for the LFR (Lead Fast Reactor) GEN IV concept. This paper describes the evolution of the MYRRHA spallation target design. In the early phase of the MYRRHA project (XT-ADS), the target design was based on a dedicated spallation loop inside the primary reactor vessel. Within the core, the 3 central fuel assembly positions were occupied by the spallation target, which enabled a windowless design created by a free surface of LBE facing the proton beam. The windowless option was preferred because of high heat loads in combination with severe irradiation damage in the target region would result in unacceptably short lifetimes of a target window. The LBE in the loop served as spallation target and as target coolant, but was separated from the LBE cooling the reactor core. The loop was equipped with its own pump, heat exchanger and conditioning system. The change from cyclotron to linear accelerator allowed the increase in proton energy from 350 MeV to 600 MeV. This modification led to an important reduction of the specific heat load at the target level and an improvement of the neutronic performance. In addition to

  2. OMEGA polar-drive target designs

    International Nuclear Information System (INIS)

    Radha, P. B.; Marozas, J. A.; Marshall, F. J.; Shvydky, A.; Collins, T. J. B.; Goncharov, V. N.; McKenty, P. W.; Sangster, T. C.; Skupsky, S.; McCrory, R. L.; Meyerhofer, D. D.

    2012-01-01

    Low-adiabat polar-drive (PD) [Skupsky et al., Phys. Plasmas 11, 2763 (2004)] implosion designs for the OMEGA [Boehly et al., Opt. Commun. 133, 495 (1997)] laser are described. These designs for cryogenic deuterium–tritium and warm plastic shells use a temporal laser pulse shape with three pickets followed by a main pulse [Goncharov et al., Phys. Rev. Lett. 104, 165001 (2010)]. The designs are at two different on-target laser intensities, with different in-flight aspect ratios (IFARs). These designs permit studies of implosion energetics and target performance closer to ignition-relevant intensities (∼7 × 10 14 W/cm 2 at the quarter-critical surface, where nonlocal heat conduction and laser–plasma interactions can play an important role) but at lower values of IFAR ∼ 22 or at lower intensity (∼3 × 10 14 W/cm 2 ) but at a higher IFAR (IFAR ∼ 32, where shell instability can play an important role). PD geometry requires repointing of laser beams to improve shell symmetry. The higher-intensity designs optimize target performance by repointing beams to a lesser extent, compensating for the reduced equatorial drive by increasing the energies of the repointed beams. They also use custom beam profiles that improve equatorial illumination at the expense of irradiation at higher latitudes. These latter designs will be studied when new phase plates for the OMEGA Laser System, corresponding to the custom beam profiles, are obtained.

  3. Use of I-131 labeled, murine Fab against a high molecular weight antigen of human melanoma: Preliminary experience

    International Nuclear Information System (INIS)

    Larson, S.M.; Carrasquillo, J.A.; McGuffin, R.W.

    1985-01-01

    High molecular-weight antigen (HMWA) is tumor-associated proteoglycan of human malignant melanoma. I-131 labeled Fab fragments of these specific antibodies were used for preliminary feasibility studies for radioimmunodetection and therapy of human subjects who had inoperable metastatic melanoma. Ten patients received tracer doses of I-131 (anti-HMWA) Fab. All patients (8/8) who had melanoma lesions greater than 1 cm by correlative diagnosis methods had one or more lesions that had localization to tumor of the radiolabelled Fab. In all, 17 of 23 (74%) documented metastases were seen. Two patients who had avid uptake received potentially radiotherapeutic doses. For both of these patients, whole imaging studies showed that the localization of the high dose I-131 Fab was predominantly in tumor. On whole body images, the anti-Fab HMWA appears to be more tumor selective than Fab preparations that target the p97 antigen for melanoma, and there is less uptake in liver

  4. CFD aspects of ADSS target design

    International Nuclear Information System (INIS)

    Shashi Kumar, G.N.; Mahendra, A.K.; Sanyal, A.; Gouthaman, G.

    2004-03-01

    The preliminary studies on CFD aspects of Accelerator Driven Sub-critical System (ADSS) target design has been presented in this report. The studies involve the thermal hydraulic analysis of the Liquid Metal Spallation Target (LMST) using Lead Bismuth Eutectic (LBE) as the target material. Apart from acting as Spallation medium LBE is used to remove the heat deposited by High Energy Proton Beam. Window of the target ( one side vacuum and other side LBE) has been reported in literature to be the most critical zone where high temperatures are reached. Numerical Simulations are carried out with Artificial Neural Network coupled Computational Fluid Dynamics (CFD) code, Various studies were carried out after the verification and validation of the initial results. Window being, the main parameter to be optimised, various designs of window were tried, along with change in the window material. The best possible combination has been proposed. The thermal hydraulic studies were carried out to arrive at the acceptable operating conditions for the target. (author)

  5. Test of a High Power Target Design

    CERN Multimedia

    2002-01-01

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

  6. Expression, purification and characterization of enoyl-ACP reductase II, FabK, from Porphyromonas gingivalis

    Energy Technology Data Exchange (ETDEWEB)

    Hevener, Kirk E.; Mehboob, Shahila; Boci, Teuta; Truong, Kent; Santarsiero, Bernard D.; Johnson, Michael E. (UIC)

    2012-10-25

    The rapid rise in bacterial drug resistance coupled with the low number of novel antimicrobial compounds in the discovery pipeline has led to a critical situation requiring the expedient discovery and characterization of new antimicrobial drug targets. Enzymes in the bacterial fatty acid synthesis pathway, FAS-II, are distinct from their mammalian counterparts, FAS-I, in terms of both structure and mechanism. As such, they represent attractive targets for the design of novel antimicrobial compounds. Enoyl-acyl carrier protein reductase II, FabK, is a key, rate-limiting enzyme in the FAS-II pathway for several bacterial pathogens. The organism, Porphyromonas gingivalis, is a causative agent of chronic periodontitis that affects up to 25% of the US population and incurs a high national burden in terms of cost of treatment. P. gingivalis expresses FabK as the sole enoyl reductase enzyme in its FAS-II cycle, which makes this a particularly appealing target with potential for selective antimicrobial therapy. Herein we report the molecular cloning, expression, purification and characterization of the FabK enzyme from P. gingivalis, only the second organism from which this enzyme has been isolated. Characterization studies have shown that the enzyme is a flavoprotein, the reaction dependent upon FMN and NADPH and proceeding via a Ping-Pong Bi-Bi mechanism to reduce the enoyl substrate. A sensitive assay measuring the fluorescence decrease of NADPH as it is converted to NADP{sup +} during the reaction has been optimized for high-throughput screening. Finally, protein crystallization conditions have been identified which led to protein crystals that diffract x-rays to high resolution.

  7. Conceptual design study of IFMIF target system

    International Nuclear Information System (INIS)

    Kato, Y.; Nakamura, H.; Ida, M.; Maekawa, H.; Katsuta, H.; Hua, T.; Cevolani, S.

    1997-01-01

    IFMIF-CDA (International Fusion Materials Irradiation Facility - Conceptual Design Activity) had been carried out during 1995 and 1996, under the auspices of the IEA. The mission of this facility is to provide an accelerator based deuterium-lithium (D-Li) neutron source to test the candidate materials of radiation - resistant and low - activation materials up to about a full lifetime of anticipated use in fusion energy reactors. The neutrons of about 14 MeV are obtained by the stripping reaction of the deuteron of Max. 40 MeV with target lithium. Total deuteron beam current is about 250 mA and beam footprint is 20 cm x 5 cm on the free surface of lithium jet. In this report general characteristics of the target lithium system and the results of thermal and flow analysis for the target lithium jet are described. (author)

  8. Targeting FR-expressing cells in ovarian cancer with Fab-functionalized nanoparticles: a full study to provide the proof of principle from in vitro to in vivo.

    Science.gov (United States)

    Quarta, Alessandra; Bernareggi, Davide; Benigni, Fabio; Luison, Elena; Nano, Giuseppe; Nitti, Simone; Cesta, Maria Candida; Di Ciccio, Luciano; Canevari, Silvana; Pellegrino, Teresa; Figini, Mariangela

    2015-02-14

    Efficient targeting in tumor therapies is still an open issue: systemic biodistribution and poor specific accumulation of drugs weaken efficacy of treatments. Engineered nanoparticles are expected to bring benefits by allowing specific delivery of drug to the tumor or acting themselves as localized therapeutic agents. In this study we have targeted epithelial ovarian cancer with inorganic nanoparticles conjugated to a human antibody fragment against the folate receptor over-expressed on cancer cells. The conjugation approach is generally applicable. Indeed several types of nanoparticles (either magnetic or fluorescent) were engineered with the fragment, and their biological activity was preserved as demonstrated by biochemical methods in vitro. In vivo studies with mice bearing orthotopic and subcutaneous tumors were performed. Elemental and histological analyses showed that the conjugated magnetic nanoparticles accumulated specifically and were retained at tumor sites longer than the non-conjugated nanoparticles.

  9. Cationization increases brain distribution of an amyloid-beta protofibril selective F(ab')2 fragment

    OpenAIRE

    Syvänen, Stina; Edén, Desireé; Sehlin, Dag

    2017-01-01

    Antibodies and fragments thereof are, because of high selectivity for their targets, considered as potential therapeutics and biomarkers for several neurological disorders. However, due to their large molecular size, antibodies/fragments do not easily penetrate into the brain. The aim of the present study was to improve the brain distribution via adsorptive-mediated transcytosis of an amyloid-beta (A beta) protofibril selective F(ab')2 fragment (F(ab')2-h158). F(ab')2-h158 was cationized to d...

  10. Targeting and design of chilled water network

    International Nuclear Information System (INIS)

    Foo, Dominic C.Y.; Ng, Denny K.S.; Leong, Malwynn K.Y.; Chew, Irene M.L.; Subramaniam, Mahendran; Aziz, Ramlan; Lee, Jui-Yuan

    2014-01-01

    Highlights: • Minimum flowrate targeting for chilled water network. • Mixed series/parallel configuration of chilled water-using units. • Integrated cooling and chilled water networks. - Abstract: Chilled water is a common cooling agent used in various industrial, commercial and institutional facilities. In conventional practice, chilled water is distributed via chilled water networks (CHWNs) in parallel configuration to provide required air conditioning and/or equipment cooling in the heating, ventilating and air conditioning (HVAC) system. In this paper, process integration approach based on pinch analysis technique is used to address energy efficiency issues in the CHWN system for grassroots design problem. Graphical and algebraic targeting techniques are developed to identify the minimum chilled water flowrate needed to remove a given amount of heat load from the CHWN. Doing this leads to higher chilled water return temperature and enhanced energy efficiency of the HVAC system. A recent proposed network design technique is extended to synthesize the CHWN in a mixed series/parallel configuration. A novel concept of integrated cooling and chilled water networks (IWN) is also proposed in this work, with its targeting and design techniques presented. Hypothetical examples and an industrial case study are solved to elucidate the proposed approaches

  11. Fab-based bispecific antibody formats with robust biophysical properties and biological activity.

    Science.gov (United States)

    Wu, Xiufeng; Sereno, Arlene J; Huang, Flora; Lewis, Steven M; Lieu, Ricky L; Weldon, Caroline; Torres, Carina; Fine, Cody; Batt, Micheal A; Fitchett, Jonathan R; Glasebrook, Andrew L; Kuhlman, Brian; Demarest, Stephen J

    2015-01-01

    A myriad of innovative bispecific antibody (BsAb) platforms have been reported. Most require significant protein engineering to be viable from a development and manufacturing perspective. Single-chain variable fragments (scFvs) and diabodies that consist only of antibody variable domains have been used as building blocks for making BsAbs for decades. The drawback with Fv-only moieties is that they lack the native-like interactions with CH1/CL domains that make antibody Fab regions stable and soluble. Here, we utilize a redesigned Fab interface to explore 2 novel Fab-based BsAbs platforms. The redesigned Fab interface designs limit heavy and light chain mixing when 2 Fabs are co-expressed simultaneously, thus allowing the use of 2 different Fabs within a BsAb construct without the requirement of one or more scFvs. We describe the stability and activity of a HER2×HER2 IgG-Fab BsAb, and compare its biophysical and activity properties with those of an IgG-scFv that utilizes the variable domains of the same parental antibodies. We also generated an EGFR × CD3 tandem Fab protein with a similar format to a tandem scFv (otherwise known as a bispecific T cell engager or BiTE). We show that the Fab-based BsAbs have superior biophysical properties compared to the scFv-based BsAbs. Additionally, the Fab-based BsAbs do not simply recapitulate the activity of their scFv counterparts, but are shown to possess unique biological activity.

  12. Clinical usefulness of human-mouse chimeric Fab monoclonal antibody A7 for radioimmunoguided surgery

    International Nuclear Information System (INIS)

    Yamamoto, Kazuhito

    1999-01-01

    This study was designed to determine the clinical usefulness of radioimmunoguided surgery (RIGS) using the human-mouse chimeric Fab monoclonal antibody A7 (chA7Fab) for colorectal cancer patients. Whole murine monoclonal antibody A7 (whole A7) and chA7Fab were labelled with 125 I and 131 I, and their biodistributions were investigated experimentally and clinically. Radioactivities of the antibodies in the tissues were measured by a portable gamma detecting probe (GDP) purchased from Neoprobe Corp.. Of the four labelled antibodies used in a mouse model, 125 I-chA7Fab revealed the highest tumor/surrounding tissue ratio and all values were greater than 2.0. All tumor/surrounding tissue ratios of 131 I-chA7Fab were greater than 1.5, but the values were lower than those of 125 I-chA7Fab. Due to the limited clinical use of 125 I in Japan, 131 I was used as a radio-tracer for chA7Fab in the clinical trial. RIGS using 131 I-chA7Fab was performed on ten colorectal cancer patients. Tumor localization was intraoperatively determined in four of ten patients using the GDP. Liver metastasis and lymph node metastasis were identified in two patients and one patient, respectively. The GDP revealed tumor/surrounding tissue ratios of 1.5 or greater in eight of the ten resected tumors. Although radioimmunoguided surgery using chA7Fab is a promising tool to intraoperatively determine the tumor localization of colorectal cancer, 125 I and not 131 I should be used as a tracer for radioimmunoguided surgery to increase the accuracy of chA7Fab. (author)

  13. The community FabLab platform: applications and implications in biomedical engineering.

    Science.gov (United States)

    Stephenson, Makeda K; Dow, Douglas E

    2014-01-01

    Skill development in science, technology, engineering and math (STEM) education present one of the most formidable challenges of modern society. The Community FabLab platform presents a viable solution. Each FabLab contains a suite of modern computer numerical control (CNC) equipment, electronics and computing hardware and design, programming, computer aided design (CAD) and computer aided machining (CAM) software. FabLabs are community and educational resources and open to the public. Development of STEM based workforce skills such as digital fabrication and advanced manufacturing can be enhanced using this platform. Particularly notable is the potential of the FabLab platform in STEM education. The active learning environment engages and supports a diversity of learners, while the iterative learning that is supported by the FabLab rapid prototyping platform facilitates depth of understanding, creativity, innovation and mastery. The product and project based learning that occurs in FabLabs develops in the student a personal sense of accomplishment, self-awareness, command of the material and technology. This helps build the interest and confidence necessary to excel in STEM and throughout life. Finally the introduction and use of relevant technologies at every stage of the education process ensures technical familiarity and a broad knowledge base needed for work in STEM based fields. Biomedical engineering education strives to cultivate broad technical adeptness, creativity, interdisciplinary thought, and an ability to form deep conceptual understanding of complex systems. The FabLab platform is well designed to enhance biomedical engineering education.

  14. Immobilization of Fab' fragments onto substrate surfaces: A survey of methods and applications.

    Science.gov (United States)

    Crivianu-Gaita, Victor; Thompson, Michael

    2015-08-15

    Antibody immobilization onto surfaces has widespread applications in many different fields. It is desirable to bind antibodies such that their fragment-antigen-binding (Fab) units are oriented away from the surface in order to maximize analyte binding. The immobilization of only Fab' fragments yields benefits over the more traditional whole antibody immobilization technique. Bound Fab' fragments display higher surface densities, yielding a higher binding capacity for the analyte. The nucleophilic sulfide of the Fab' fragments allows for specific orientations to be achieved. For biosensors, this indicates a higher sensitivity and lower detection limit for a target analyte. The last thirty years have shown tremendous progress in the immobilization of Fab' fragments onto gold, Si-based, polysaccharide-based, plastic-based, magnetic, and inorganic surfaces. This review will show the current scope of Fab' immobilization techniques available and illustrate methods employed to minimize non-specific adsorption of undesirables. Furthermore, a variety of examples will be given to show the versatility of immobilized Fab' fragments in different applications and future directions of the field will be addressed, especially regarding biosensors. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Target design for heavy ion beam fusion

    International Nuclear Information System (INIS)

    Meyer-ter-Vehn, J.; Metzler, N.

    1981-07-01

    Target design for Heavy Ion Beam Fusion and related physics are discussed. First, a modified version of the Kidder-Bodner model for pellet gain is presented and is used to define the working point (Esub(beam) = 4.8 MJ, Gain 83) for a reactor size target. Secondly, stopping of heavy ions in hot dense plasma is investigated and numerical results for stopping powers and ranges of 10 GeV Bi-ions in Pb, Li, and PbLi-alloy are given. Finally, results of an explicit implosion calculation, using the 1-D code MINIHY, are discussed in detail. The hydrodynamic efficiency is found to be about 5%. Special attention is given to the shock sequence leading to the ignition configuration. Also the growth of Rayleigh-Taylor instability at the absorber-pusher interface is estimated. (orig.)

  16. Investigation of IFMIF target assembly structure design

    International Nuclear Information System (INIS)

    Ida, Mizuho; Nakamura, Hiroo; Sugimoto, Masayoshi; Yamamura, Toshio

    2006-10-01

    In the International Fusion Materials Irradiation Facility (IFMIF), the back-wall of target assembly is the part suffered the highest neutron-flux. The back-wall and the assembly are designed to have lips for cutting/welding at the back-wall replacement. To reduce thermal stress and deformation of the back-wall under neutron irradiation, contact pressure between the back-wall and the assembly is one of dominant factors. Therefore, an investigation was performed for feasible clamping pressure of a mechanical clamp set in limited space around the back-wall. It was clarified that the clamp can give a pressure difference up to 0.4 MPa between the contact pressure and atmosphere pressure in the test cell room. Also a research was performed for the dissimilar metal welding in the back-wall. Use of 309 steel was found adequate as the intermediate filler metal through the research of previous welding. Maintaining a temperature of the target assembly so as to avoid a freezing of liquid lithium is needed at the lithium charge into the loop before the beam injection. The assembly is covered with thermal insulation. Therefore, a research and an investigation were performed for compact and light thermal-insulation effective even under helium (i.e. high heat-conduction) condition of the test cell room. The result was as follows; in the case that a thermal conductivity 0.008 W/m·K of one of found insulation materials is available in the temperature range up to 300degC of the IFMIF target assembly, needed thickness and weight of the insulation were respectively only 8.2 mm and 32 kg. Also a research was performed for high-heat-density heaters to maintain temperature of the back-wall which can not be cover with insulation due to limited space. A heater made of silicon-nitride was found to be adequate. Total heat of 8.4 kW on the back-wall was found to be achievable through an investigations of heater arrange. Also an investigation was performed for remote-handling device to

  17. Site-specific fab fragment biotinylation at the conserved nucleotide binding site for enhanced Ebola detection.

    Science.gov (United States)

    Mustafaoglu, Nur; Alves, Nathan J; Bilgicer, Basar

    2015-07-01

    The nucleotide binding site (NBS) is a highly conserved region between the variable light and heavy chains at the Fab domains of all antibodies, and a small molecule that we identified, indole-3-butyric acid (IBA), binds specifically to this site. Fab fragment, with its small size and simple production methods compared to intact antibody, is good candidate for use in miniaturized diagnostic devices and targeted therapeutic applications. However, commonly used modification techniques are not well suited for Fab fragments as they are often more delicate than intact antibodies. Fab fragments are of particular interest for sensor surface functionalization but immobilization results in damage to the antigen binding site and greatly reduced activity due to their truncated size that allows only a small area that can bind to surfaces without impeding antigen binding. In this study, we describe an NBS-UV photocrosslinking functionalization method (UV-NBS(Biotin) in which a Fab fragment is site-specifically biotinylated with an IBA-EG11-Biotin linker via UV energy exposure (1 J/cm(2)) without affecting its antigen binding activity. This study demonstrates successful immobilization of biotinylated Ebola detecting Fab fragment (KZ52 Fab fragment) via the UV-NBS(Biotin) method yielding 1031-fold and 2-fold better antigen detection sensitivity compared to commonly used immobilization methods: direct physical adsorption and NHS-Biotin functionalization, respectively. Utilization of the UV-NBS(Biotin) method for site-specific conjugation to Fab fragment represents a proof of concept use of Fab fragment for various diagnostic and therapeutic applications with numerous fluorescent probes, affinity molecules and peptides. © 2015 Wiley Periodicals, Inc.

  18. Targeted proteins for diabetes drug design

    Science.gov (United States)

    Doan Trang Nguyen, Ngoc; Thi Le, Ly

    2012-03-01

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

  19. Targeted proteins for diabetes drug design

    International Nuclear Information System (INIS)

    Trang Nguyen, Ngoc Doan; Le, Ly Thi

    2012-01-01

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

  20. A collagen-binding EGFR antibody fragment targeting tumors with a collagen-rich extracellular matrix.

    Science.gov (United States)

    Liang, Hui; Li, Xiaoran; Wang, Bin; Chen, Bing; Zhao, Yannan; Sun, Jie; Zhuang, Yan; Shi, Jiajia; Shen, He; Zhang, Zhijun; Dai, Jianwu

    2016-02-17

    Many tumors over-express collagen, which constitutes the physical scaffold of tumor microenvironment. Collagen has been considered to be a target for cancer therapy. The collagen-binding domain (CBD) is a short peptide, which could bind to collagen and achieve the sustained release of CBD-fused proteins in collagen scaffold. Here, a collagen-binding EGFR antibody fragment was designed and expressed for targeting the collagen-rich extracellular matrix in tumors. The antibody fragment (Fab) of cetuximab was fused with CBD (CBD-Fab) and expressed in Pichia pastoris. CBD-Fab maintained antigen binding and anti-tumor activity of cetuximab and obtained a collagen-binding ability in vitro. The results also showed CBD-Fab was mainly enriched in tumors and had longer retention time in tumors in A431 s.c. xenografts. Furthermore, CBD-Fab showed a similar therapeutic efficacy as cetuximab in A431 xenografts. Although CBD-Fab hasn't showed better therapeutic effects than cetuximab, its smaller molecular and special target may be applicable as antibody-drug conjugates (ADC) or immunotoxins.

  1. FabLab@School

    DEFF Research Database (Denmark)

    Hjorth, Mikkel; Iversen, Ole Sejer

    2014-01-01

    Digital fabrication is becoming commonplace in the educational systems. As has often been stated, it offers opportunities for strengthening the digital literacy for future generations. In this paper we take the argument further - claiming the need for a design bildung perspective on digital fabri...

  2. Detection of irradiation-induced, membrane heat shock protein 70 (Hsp70) in mouse tumors using Hsp70 Fab fragment

    International Nuclear Information System (INIS)

    Stangl, Stefan; Themelis, George; Friedrich, Lars; Ntziachristos, Vasilis; Sarantopoulos, Athanasios; Molls, Michael; Skerra, Arne; Multhoff, Gabriele

    2011-01-01

    Background and purpose: The major stress-inducible heat shock protein 70 (Hsp70) is frequently overexpressed in highly aggressive tumors, and elevated intracellular Hsp70 levels mediate protection against apoptosis. Following therapeutic intervention, such as ionizing irradiation, translocation of cytosolic Hsp70 to the plasma membrane is selectively increased in tumor cells and therefore, membrane Hsp70 might serve as a therapy-inducible, tumor-specific target structure. Materials and methods: Based on the IgG1 mouse monoclonal antibody (mAb) cmHsp70.1, we produced the Hsp70-specific recombinant Fab fragment (Hsp70 Fab), as an imaging tool for the detection of membrane Hsp70 positive tumor cells in vitro and in vivo. Results: The binding characteristics of Hsp70 Fab towards mouse colon (CT26) and pancreatic (1048) carcinoma cells at 4 deg. C were comparable to that of cmHsp70.1 mAb, as determined by flow cytometry. Following a temperature shift to 37 deg. C, Hsp70 Fab rapidly translocates into subcellular vesicles of mouse tumor cells. Furthermore, in tumor-bearing mice Cy5.5-conjugated Hsp70 Fab, but not unrelated IN-1 control Fab fragment (IN-1 ctrl Fab), gradually accumulates in CT26 tumors between 12 and 55 h after i.v. injection. Conclusions: In summary, the Hsp70 Fab provides an innovative, low immunogenic tool for imaging of membrane Hsp70 positive tumors, in vivo.

  3. Molecular characterization of monoclonal antibodies that inhibit acetylcholinesterase by targeting the peripheral site and backdoor region.

    Directory of Open Access Journals (Sweden)

    Yves Bourne

    Full Text Available The inhibition properties and target sites of monoclonal antibodies (mAbs Elec403, Elec408 and Elec410, generated against Electrophorus electricus acetylcholinesterase (AChE, have been defined previously using biochemical and mutagenesis approaches. Elec403 and Elec410, which bind competitively with each other and with the peptidic toxin inhibitor fasciculin, are directed toward distinctive albeit overlapping epitopes located at the AChE peripheral anionic site, which surrounds the entrance of the active site gorge. Elec408, which is not competitive with the other two mAbs nor fasciculin, targets a second epitope located in the backdoor region, distant from the gorge entrance. To characterize the molecular determinants dictating their binding site specificity, we cloned and sequenced the mAbs; generated antigen-binding fragments (Fab retaining the parental inhibition properties; and explored their structure-function relationships using complementary x-ray crystallography, homology modeling and flexible docking approaches. Hypermutation of one Elec403 complementarity-determining region suggests occurrence of antigen-driven selection towards recognition of the AChE peripheral site. Comparative analysis of the 1.9Å-resolution structure of Fab408 and of theoretical models of its Fab403 and Fab410 congeners evidences distinctive surface topographies and anisotropic repartitions of charges, consistent with their respective target sites and inhibition properties. Finally, a validated, data-driven docking model of the Fab403-AChE complex suggests a mode of binding at the PAS that fully correlates with the functional data. This comprehensive study documents the molecular peculiarities of Fab403 and Fab410, as the largest peptidic inhibitors directed towards the peripheral site, and those of Fab408, as the first inhibitor directed toward the backdoor region of an AChE and a unique template for the design of new, specific modulators of AChE catalysis.

  4. TriFabs—Trivalent IgG-Shaped Bispecific Antibody Derivatives: Design, Generation, Characterization and Application for Targeted Payload Delivery

    Directory of Open Access Journals (Sweden)

    Klaus Mayer

    2015-11-01

    Full Text Available TriFabs are IgG-shaped bispecific antibodies (bsAbs composed of two regular Fab arms fused via flexible linker peptides to one asymmetric third Fab-sized binding module. This third module replaces the IgG Fc region and is composed of the variable region of the heavy chain (VH fused to CH3 with “knob”-mutations, and the variable region of the light chain (VL fused to CH3 with matching “holes”. The hinge region does not contain disulfides to facilitate antigen access to the third binding site. To compensate for the loss of hinge-disulfides between heavy chains, CH3 knob-hole heterodimers are linked by S354C-Y349C disulphides, and VH and VL of the stem region may be linked via VH44C-VL100C disulphides. TriFabs which bind one antigen bivalent in the same manner as IgGs and the second antigen monovalent “in between” these Fabs can be applied to simultaneously engage two antigens, or for targeted delivery of small and large (fluorescent or cytotoxic payloads.

  5. Characterization of Human Colorectal Cancer MDR1/P-gp Fab Antibody

    Directory of Open Access Journals (Sweden)

    Xuemei Zhang

    2013-01-01

    Full Text Available In this study, the peptide sized 21 kDa covering P-gp transmembrane region was first prepared for generating a novel mouse monoclonal antibody Fab fragment with biological activity against multiple drug resistance protein P-gp21 by phage display technology. Phage-displayed antibody library prepared from mice spleen tissues was selected against the recombinant protein P-gp21 with five rounds of panning. A number of clones expressing Fab bound to P-gp21, showing neutralized activity in vitro, were isolated and screened by enzyme-linked immunosorbent assay based on its recognition properties to P-gp21 and human colorectal cancer tissue homogenate, resulting in identification of an optimal recombinant Fab clone (Number 29. Further characterization by recloning number 29 into an expression vector showed significant induction of the Fab antibody in the clone number 29 by Isopropyl β-D-1-thiogalactopyranoside (IPTG. After purified by HiTrap Protein L, the specificity of the Fab antibody to P-gp21 was also confirmed. Not only was the targeted region of this monoclonal Fab antibody identified as a 16-peptide epitope (ALKDKKELEGSGKIAT comprising residues 883–898 within the transmembrane (TM domain of human P-gp, but also the binding ability with it was verified. The clinical implication of our results for development of personalized therapy of colorectal cancer will be further studied.

  6. Imaging Potential Evaluation of Fab Derived from the Anti-EGFRvIII Monoclonal Antibody 4G1.

    Science.gov (United States)

    Jing, Shen; He, Yujia; He, Yanqiong; Wang, Liang; Jia, Jianhua; Shan, Xiaomin; Liu, Shuang; Tang, Min; Peng, Zhiping; Liu, Xujie

    2018-05-31

    As one of the most crucial epidermal growth factor receptor (EGFR) variants, EGFRvIII can be detected in various tumors but rarely in normal tissues, making it an ideal target for prognosis, diagnosis or immune therapy. The recently developed anti-EGFRvIII monoclonal antibody (mAb), 4G1, has been validated as a promising molecular probe to detect EGFRvIII expression in tumors by single-photon emission computed tomography/computed tomography imaging. To overcome shortcomings associated with the whole antibody, including long-term retention, circulation and enhanced permeability and retention effects, the Fab fragment of 4G1 (Fab-4G1) was generated, labeled with 131 I and evaluated in vitro and in vivo to test its potential application in molecular imaging. Whole mAb 4G1 was first digested by immobilized ficin and then purified through a protein A column to generate the Fab fragment, Fab-4G1. Next, SDS-PAGE, Western blot, indirect fluorescence assay, flow cytometry and enzyme-linked immunosorbent assay were performed to verify molecular weight, specificity and affinity of Fab-4G1. Finally, biodistribution planar gamma imaging was performed by injection of 131 I-labeled Fab-4G1 into xenografted EGFRvIII-overexpressed tumors in nude mice. Parallel studies were also performed with intact 4G1. The molecular weight of Fab was determined to be 35-40 kDa by SDS-PAGE. In vitro tests confirmed both intact 4G1 and Fab-4G1 specifically bound EGFRvIII but not wild-type EGFR, and Fab-4G1 showed decreased affinity. Compared to 131 I-4G1, biodistribution studies showed lower tumor uptake of 131 I-Fab-4G1 at all time points, but much faster elimination in all normal organs. As for planar gamma imaging, 131 I-Fab-4G1 and 31 I-4G1 showed similar imaging effect at 2 h after injection of tracer, while 131 I-Fab-4G1 was eliminated more quickly with time, suggesting radiolabeled Fab-4G1 could be potentially used for imaging of EGFRvIII-positive tumors at early time points. Radiolabeled

  7. High contrast tumor imaging with radio-labeled antibody Fab fragments tailored for optimized pharmacokinetics via PASylation.

    Science.gov (United States)

    Mendler, Claudia T; Friedrich, Lars; Laitinen, Iina; Schlapschy, Martin; Schwaiger, Markus; Wester, Hans-Jürgen; Skerra, Arne

    2015-01-01

    Although antigen-binding fragments (Fabs) of antibodies constitute established tracers for in vivo radiodiagnostics, their functionality is hampered by a very short circulation half-life. PASylation, the genetic fusion with a long, conformationally disordered amino acid chain comprising Pro, Ala and Ser, provides a convenient way to expand protein size and, consequently, retard renal filtration. Humanized αHER2 and αCD20 Fabs were systematically fused with 100 to 600 PAS residues and produced in E. coli. Cytofluorimetric titration analysis on tumor cell lines confirmed that antigen-binding activities of the parental antibodies were retained. The radio-iodinated PASylated Fabs were studied by positron emission tomography (PET) imaging and biodistribution analysis in mouse tumor xenograft models. While the unmodified αHER2 and αCD20 Fabs showed weak tumor uptake (0.8% and 0.2% ID/g, respectively; 24 h p.i.) tumor-associated radioactivity was boosted with increasing PAS length (up to 9 and 26-fold, respectively), approaching an optimum for Fab-PAS400. Remarkably, 6- and 5-fold higher tumor-to-blood ratios compared with the unmodified Fabs were measured in the biodistribution analysis (48 h p.i.) for αHER2 Fab-PAS100 and Fab-PAS200, respectively. These findings were confirmed by PET studies, showing high imaging contrast in line with tumor-to-blood ratios of 12.2 and 5.7 (24 h p.i.) for αHER2 Fab-PAS100 and Fab-PAS200. Even stronger tumor signals were obtained with the corresponding αCD20 Fabs, both in PET imaging and biodistribution analysis, with an uptake of 2.8% ID/g for Fab-PAS100 vs. 0.24% ID/g for the unmodified Fab. Hence, by engineering Fabs via PASylation, plasma half-life can be tailored to significantly improve tracer uptake and tumor contrast, thus optimally matching reagent/target interactions.

  8. Baculovirus display of functional antibody Fab fragments.

    Science.gov (United States)

    Takada, Shinya; Ogawa, Takafumi; Matsui, Kazusa; Suzuki, Tasuku; Katsuda, Tomohisa; Yamaji, Hideki

    2015-08-01

    The generation of a recombinant baculovirus that displays antibody Fab fragments on the surface was investigated. A recombinant baculovirus was engineered so that the heavy chain (Hc; Fd fragment) of a mouse Fab fragment was expressed as a fusion to the N-terminus of baculovirus gp64, while the light chain of the Fab fragment was simultaneously expressed as a secretory protein. Following infection of Sf9 insect cells with the recombinant baculovirus, the culture supernatant was analyzed by enzyme-linked immunosorbent assay using antigen-coated microplates and either an anti-mouse IgG or an anti-gp64 antibody. A relatively strong signal was obtained in each case, showing antigen-binding activity in the culture supernatant. In western blot analysis of the culture supernatant using the anti-gp64 antibody, specific protein bands were detected at an electrophoretic mobility that coincided with the molecular weight of the Hc-gp64 fusion protein as well as that of gp64. Flow cytometry using a fluorescein isothiocyanate-conjugated antibody specific to mouse IgG successfully detected the Fab fragments on the surface of the Sf9 cells. These results suggest that immunologically functional antibody Fab fragments can be displayed on the surface of baculovirus particles, and that a fluorescence-activated cell sorter with a fluorescence-labeled antigen can isolate baculoviruses displaying specific Fab fragments. This successful baculovirus display of antibody Fab fragments may offer a novel approach for the efficient selection of specific antibodies.

  9. Comparison of F(ab')2 versus Fab antivenom for pit viper envenomation: a prospective, blinded, multicenter, randomized clinical trial.

    Science.gov (United States)

    Bush, Sean P; Ruha, Anne-Michelle; Seifert, Steven A; Morgan, David L; Lewis, Brandon J; Arnold, Thomas C; Clark, Richard F; Meggs, William J; Toschlog, Eric A; Borron, Stephen W; Figge, Gary R; Sollee, Dawn R; Shirazi, Farshad M; Wolk, Robert; de Chazal, Ives; Quan, Dan; García-Ubbelohde, Walter; Alagón, Alejandro; Gerkin, Richard D; Boyer, Leslie V

    2015-01-01

    Crotalidae Polyvalent Immune Fab (Ovine) has been the only antivenom commercially available in the US since 2007 for treatment of Crotalinae envenomation. Late coagulopathy can occur or recur after clearance of Fab antivenom, often after hospital discharge, lasting in some cases more than 2 weeks. There have been serious, even fatal, bleeding complications associated with recurrence phenomena. Frequent follow-up is required, and additional intervention or hospitalization is often necessary. F(ab')2 immunoglobulin derivatives have longer plasma half life than do Fab. We hypothesized that F(ab')2 antivenom would be superior to Fab in the prevention of late coagulopathy following treatment of patients with Crotalinae envenomation. We conducted a prospective, double-blind, randomized clinical trial, comparing late coagulopathy in snakebitten patients treated with F(ab')2 with maintenance doses [F(ab')2/F(ab')2], or F(ab')2 with placebo maintenance doses [F(ab')2/placebo], versus Fab with maintenance doses [Fab/Fab]. The primary efficacy endpoint was coagulopathy (platelet count Fab/Fab cohort experienced late coagulopathy versus 4/39 (10.3%, p < 0.05) in the F(ab')2/F(ab')2 cohort and 2/38 (5.3%, p < 0.05) in the F(ab')2/placebo cohort. The lowest heterologous protein exposure was with F(ab')2/placebo. No serious adverse events were related to study drug. In each study arm, one patient experienced an acute serum reaction and one experienced serum sickness. In this study, management of coagulopathic Crotalinae envenomation with longer-half-life F(ab')2 antivenom, with or without maintenance dosing, reduced the risk of subacute coagulopathy and bleeding following treatment of envenomation.

  10. Comparison of the efficiency of antibody selection from semi-synthetic scFv and non-immune Fab phage display libraries against protein targets for rapid development of diagnostic immunoassays.

    Science.gov (United States)

    Chan, Conrad E Z; Chan, Annie H Y; Lim, Angeline P C; Hanson, Brendon J

    2011-10-28

    Rapid development of diagnostic immunoassays against novel emerging or genetically modified pathogens in an emergency situation is dependent on the timely isolation of specific antibodies. Non-immune antibody phage display libraries are an efficient in vitro method for selecting monoclonal antibodies and hence ideal in these circumstances. Such libraries can be constructed from a variety of sources e.g. B cell cDNA or synthetically generated, and use a variety of antibody formats, typically scFv or Fab. However, antibody source and format can impact on the quality of antibodies generated and hence the effectiveness of this methodology for the timely production of antibodies. We have carried out a comparative screening of two antibody libraries, a semi-synthetic scFv library and a human-derived Fab library against the protective antigen toxin component of Bacillus anthracis and the epsilon toxin of Clostridium botulinum. We have shown that while the synthetic library produced a diverse collection of specific scFv-phage, these contained a high frequency of unnatural amber stops and glycosylation sites which limited their conversion to IgG, and also a high number which lost specificity when expressed as IgG. In contrast, these limitations were overcome by the use of a natural human library. Antibodies from both libraries could be used to develop sandwich ELISA assays with similar sensitivity. However, the ease and speed with which full-length IgG could be generated from the human-derived Fab library makes screening this type of library the preferable method for rapid antibody generation for diagnostic assay development. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. Production and characterization of anti-human IgG F(ab')2 antibody fragment.

    Science.gov (United States)

    Valedkarimi, Zahra; Nasiri, Hadi; Aghebati-Maleki, Leili; Abdolalizadeh, Jalal; Esparvarinha, Mojghan; Majidi, Jafar

    2018-04-10

    In present study an optimized protocol for the separation of antibodies into antigen-binding fragments F(ab')2 using pepsin digestion was investigated. The production of these fragments is a consequential step in the development of medical research, treatment and diagnosis. For production of polyclonal antibody rabbit received antigen in four steps. The rabbit serum at 1/128000 dilution showed high absorbance in reaction with human IgG at the designed ELISA method. Rabbit IgG was purified by Ion-Exchange Chromatography (IEC) method. Purity was assessed by SDS-PAGE method. In non-reduced condition only one band was seen in about 150 kDa MW position and in reduced form, two bands were seen in 50 and 25 kDa MW positions. Rabbit IgG was digested by pepsin enzyme. The antibody fragments solution was applied to Gel filtration column to isolate the F(ab')2. Non-reduced SDS-PAGE for determining the purity of F(ab')2 fragment resulted in one band in 100 kDa corresponds to F(ab')2 fragment and a band in 150 kDa MW position corresponds to undigested IgG antibodies. The activities of FITC conjugated F(ab')2 fragment and commercial ones were compared using flowcytometry method. The activity results implied that the FITC conjugated- anti human F(ab')2 fragment worked as efficiently as the commercial one.

  12. Structure of the omalizumab Fab

    Science.gov (United States)

    Jensen, Rasmus K.; Plum, Melanie; Tjerrild, Luna; Jakob, Thilo; Spillner, Edzard; Andersen, Gregers Rom

    2015-01-01

    Omalizumab is a humanized anti-IgE antibody that inhibits the binding of IgE to its receptors on mast cells and basophils, thus blocking the IgE-mediated release of inflammatory mediators from these cells. Omalizumab binds to the Fc domains of IgE in proximity to the binding site of the high-affinity IgE receptor Fc∊RI, but the epitope and the mechanisms and conformations governing the recognition remain unknown. In order to elucidate the molecular mechanism of its anti-IgE activity, the aim was to analyse the interaction of omalizumab with human IgE. Therefore, IgE Fc C∊2–4 was recombinantly produced in mammalian HEK-293 cells. Functionality of the IgE Fc was proven by ELISA and mediator-release assays. Omalizumab IgG was cleaved with papain and the resulting Fab was purified by ion-exchange chromatography. The complex of IgE Fc with omalizumab was prepared by size-exclusion chromatography. However, crystals containing the complex were not obtained, suggesting that the process of crystallization favoured the dissociation of the two proteins. Instead, two structures of the omalizumab Fab with maximum resolutions of 1.9 and 3.0 Å were obtained. The structures reveal the arrangement of the CDRs and the position of omalizumab residues known from prior functional studies to be involved in IgE binding. Thus, the structure of omalizumab provides the structural basis for understanding the function of omalizumab, allows optimization of the procedure for complex crystallization and poses questions about the conformational requirements for anti-IgE activity. PMID:25849503

  13. Design of the target area for the National Ignition Facility

    International Nuclear Information System (INIS)

    Foley, R.J.; Karpenko, V.P.; Adams, C.H.

    1997-01-01

    The preliminary design of the target area for the National Ignition Facility has been completed. The target area is required to meet a challenging set of engineering system design requirements and user needs. The target area must provide the appropriate conditions before, during, and after each shot. The repeated introduction of large amounts of laser energy into the chamber and subsequent target emissions represent new design challenges for ICF facility design. Prior to each shot, the target area must provide the required target illumination, target chamber vacuum, diagnostics, and optically stable structures. During the shot, the impact of the target emissions on the target chamber, diagnostics, and optical elements is minimized and the workers and public are protected from excessive prompt radiation doses. After the shot, residual radioactivation is managed to allow the required accessibility. Diagnostic data is retrieved, operations and maintenance activities are conducted, and the facility is ready for the next shot. The target area subsystems include the target chamber, target positioner, structural systems, target diagnostics, environmental systems, and the final optics assembly. The engineering design of the major elements of the target area requires a unique combination of precision engineering, structural analysis, opto-mechanical design, random vibration suppression, thermal stability, materials engineering, robotics, and optical cleanliness. The facility has been designed to conduct both x- ray driven targets and to be converted at a later date for direct drive experiments. The NIF has been configured to provide a wide range of experimental environments for the anticipated user groups of the facility. The design status of the major elements of the target area is described

  14. Review of laser mega joule target area: Design and processes

    International Nuclear Information System (INIS)

    Geitzholz, M.; Lanternier, C.

    2006-01-01

    The Laser Mega Joule (LMJ) target area is currently designed to achieve ignition and significant fusion gain in laboratory. LMJ will be composed of 240 identical large 370 mm * 370 mm square laser beams. These beams will focus 2 mega-joules of energy at the wavelength of 351 nm on the center of an experiment chamber. Design studies for target equipment are well advanced, target chamber and target holder (concrete) works have already begun. A detailed overview of the target area equipment is presented: target chamber, frame, diagnostic inserter manipulator, final optic assembly, dual diagnostic and laser reference, non cryogenic target positioner. Recent technical and architectural choices are detailed including safety transfers and alignment processes (target, laser and diagnostic). All this target equipment allows us to optimize shot chrono-gram, from target metrology to the shot, including calibration process. (authors)

  15. Preparation and radiolabeling of humanized anti-HER1 monoclonal antibody nimotuzumab Fab' fragment with 68Ga and 90Y

    International Nuclear Information System (INIS)

    Alonso Martinez, L. M.; Xiques Castillo, A.; Leyva Montanna, R.; Perez-Malo Cruz, M.; Zamora Barrabi, M.; Manresa Sanchez, Y.

    2013-01-01

    Antibody-based targeted delivery of radioisotopes to malignant tissues is a promising approach in cancer diagnostics and therapy. However, intact antibody molecules are large glycoproteins (∼150 kDa) that have limited application in molecular imaging and therapy due to their relatively slow clearance from the circulation leading to a high background signal rather both cases the sensitivity can be increased with the use of enzymatically produced Fab' fragments. In this work, the ability to get labeled with 62 Ga and 90 Y of a monoclonal antibody (mAb) Fab' fragment against the transmembrane receptor tyrosine kinase HER-1 was studied for future applications in PET imaging and radioimmunotherapy of tumors. In order to obtain the Fab' fragment the mAb was cleaved with pepsin in molar excess. After separating the reaction mixture in two steps using affinity and ion-exchange chromatography, the Fab' fragment was finally obtained by reduction of the F(ab') 2 with a molar excess of 2-mercaptoethanol followed by a size exclusion purification step. The Fab' fragment was derivatized with 1,4,7,10-tetraaza cyclododecane-1,4,7,10-tetraacetic acid mono N-hydroxysuccinimide commercial ester (DOTA-NHS-ester) applying a simple procedure and the number of DOTA groups linked to Fab' were determinate. The labeling of the conjugate with 68 Ga and 90 Y from 'in-house generators yielded radiochemically pure probes that can become a suitable radioimmunoconjugated in a near future. (Author)

  16. Design of the Next Generation Spallation Target

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-06-13

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

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

    International Nuclear Information System (INIS)

    Covrig, S. D.

    2013-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-11-07

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

  19. Crystallization and preliminary X-ray crystallographic analysis of enoyl-ACP reductase III (FabL) from Bacillus subtilis

    International Nuclear Information System (INIS)

    Kim, Kook-Han; Park, Joon Kyu; Ha, Byung Hak; Moon, Jin Ho; Kim, Eunice EunKyeong

    2007-01-01

    Enoyl-ACP reductase III (FabL) from B. subtilis has been overexpressed, purified and crystallized. The crystal belongs to space group P622, with unit-cell parameters a = b = 139.56, c = 62.75 Å, α = β = 90, γ = 120°, and data were collected to 2.5 Å resolution using synchrotron radiation. Enoyl-[acyl-carrier protein] reductase (enoyl-ACP reductase; ENR) is a key enzyme in type II fatty-acid synthase that catalyzes the last step in each elongation cycle. It has been considered as an antibiotic target since it is an essential enzyme in bacteria. However, recent studies indicate that some pathogens have more than one ENR. Bacillus subtilis is reported to have two ENRs, namely BsFabI and BsFabL. While BsFabI is similar to other FabIs, BsFabL shows very little sequence similarity and is NADPH-dependent instead of NADH-dependent as in the case of FabI. In order to understand these differences on a structural basis, BsFabL has been cloned, expressed and and crystallized. The crystal belongs to space group P622, with unit-cell parameters a = b = 139.56, c = 62.75 Å, α = β = 90, γ = 120° and one molecule of FabL in the asymmetric unit. Data were collected using synchrotron radiation (beamline 4A at the Pohang Light Source, Korea). The crystal diffracted to 2.5 Å resolution

  20. Development of positron emission tomography probe of 64Cu-labeled anti-C-kit 12A8 Fab to measure protooncogene C-kit expression

    International Nuclear Information System (INIS)

    Yoshida, Chisato; Tsuji, Atsushi B.; Sudo, Hitomi; Sugyo, Aya; Sogawa, Chizuru; Inubushi, Masayuki; Uehara, Tomoya; Fukumura, Toshimitsu; Koizumi, Mitsuru; Arano, Yasushi; Saga, Tsuneo

    2011-01-01

    Introduction: C-kit is an important diagnostic and therapeutic target molecule for several malignancies, and c-kit-targeted drugs have been used clinically. Because abundant c-kit expression in tumors is a prerequisite for successful c-kit-targeted therapy, imaging of c-kit expression is expected to play a pivotal role in the therapeutic decision for each patient. We evaluated 64 Cu-labeled Fab of anti-c-kit antibody 12A8 as a positron emission tomography (PET) imaging probe. Methods: 111 In- or 125 I-Labeled 12A8 Fab was evaluated in vitro by cell binding, competitive inhibition and cellular internalization assays, and in vivo by biodistribution in mice bearing c-kit-expressing and -non-expressing tumors. Next, Fab fragment was labeled with the positron emitter 64 Cu and evaluated by PET. Results: Radiolabeled 12A8 Fab showed specific binding to c-kit-expressing cells with high affinity and internalized into cells after binding to c-kit on cell surface. Although tumor accumulation of [ 111 In]Fab was lower than that of [ 111 In]IgG, the faster blood clearance of [ 111 In]Fab provided higher tumor-to-blood ratio at 6 h postinjection onwards. Blood clearance of 64 Cu-labeled 12A8 Fab was slower than that of [ 111 In]Fab, but PET using [ 64 Cu]Fab clearly visualized the tumor at 6 h postinjection onwards. Conclusion: The 64 Cu-labeled 12A8 Fab could be used for c-kit-specific PET imaging and might help in selecting appropriate patients for c-kit-targeted treatments.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-11-11

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

  2. Economic targets for small PWR reactor designs

    International Nuclear Information System (INIS)

    Board, J.

    1991-01-01

    Small reactors are likely to be less economic than large reactors, but the lower financial exposure with small reactors may be attractive to utilities contemplating a restart to a nuclear programme. New nuclear plant can be economic, but success will depend more on how the plant are built, rather than what type or size is built. A target for new plant for operation early in the next century should be a generation cost of 3p to 3.5 p/kWh. This corresponds to an overnight capital cost of Pound 1000/kWh to Pound 1100/kWh. (author)

  3. NIF Ignition Target 3D Point Design

    Energy Technology Data Exchange (ETDEWEB)

    Jones, O; Marinak, M; Milovich, J; Callahan, D

    2008-11-05

    We have developed an input file for running 3D NIF hohlraums that is optimized such that it can be run in 1-2 days on parallel computers. We have incorporated increasing levels of automation into the 3D input file: (1) Configuration controlled input files; (2) Common file for 2D and 3D, different types of capsules (symcap, etc.); and (3) Can obtain target dimensions, laser pulse, and diagnostics settings automatically from NIF Campaign Management Tool. Using 3D Hydra calculations to investigate different problems: (1) Intrinsic 3D asymmetry; (2) Tolerance to nonideal 3D effects (e.g. laser power balance, pointing errors); and (3) Synthetic diagnostics.

  4. Optical and mechanical design of beam-target coupling sensor

    International Nuclear Information System (INIS)

    Wang Liquan; Li Tian'en; Feng Bin; Xiang Yong; Li Keyu; Zhong Wei; Liu Guodong

    2012-01-01

    A sensor based on conjugate principle has been designed for matching the light beams and the target in inertial confinement fusion. It can avoid the direct illumination of the simulation collimating light on the target under test in targeting processes. This paper introduces the optical and mechanical design of the sensor, according to its design functions and working principle. The resolution of the optical images obtained in experiments reaches 6 μm and the beam-target matching accuracy is 8.8 μm. The sensor has been successfully applied to the Shenguang-Ⅲ facility. Statistical analyses of the four-hole CH target images derived with pinhole camera shows that the targeting accuracy of the facility is better than 25 μm, satisfying the design requirements. (authors)

  5. Reorienting the Fab domains of trastuzumab results in potent HER2 activators.

    Directory of Open Access Journals (Sweden)

    Justin M Scheer

    Full Text Available The structure of the Fab region of antibodies is critical to their function. By introducing single cysteine substitutions into various positions of the heavy and light chains of the Fab region of trastuzumab, a potent antagonist of HER2, and using thiol chemistry to link the different Fabs together, we produced a variety of monospecific F(ab'(2-like molecules with activities spanning from activation to inhibition of breast tumor cell growth. These isomers (or bis-Fabs of trastuzumab, with varying relative spatial arrangements between the Fv-regions, were able to either promote or inhibit cell-signaling activities through the PI3K/AKT and MAPK pathways. A quantitative phosphorylation mapping of HER2 indicated that the agonistic isomers produced a distinct phosphorylation pattern associated with activation. This study suggests that antibody geometric isomers, found both in nature and during synthetic antibody development, can have profoundly different biological activities independent of their affinities for their target molecules.

  6. Optimizing Production of Antigens and Fabs in the Context of Generating Recombinant Antibodies to Human Proteins.

    Directory of Open Access Journals (Sweden)

    Nan Zhong

    Full Text Available We developed and optimized a high-throughput project workflow to generate renewable recombinant antibodies to human proteins involved in epigenetic signalling. Three different strategies to produce phage display compatible protein antigens in bacterial systems were compared, and we found that in vivo biotinylation through the use of an Avi tag was the most productive method. Phage display selections were performed on 265 in vivo biotinylated antigen domains. High-affinity Fabs (<20nM were obtained for 196. We constructed and optimized a new expression vector to produce in vivo biotinylated Fabs in E. coli. This increased average yields up to 10-fold, with an average yield of 4 mg/L. For 118 antigens, we identified Fabs that could immunoprecipitate their full-length endogenous targets from mammalian cell lysates. One Fab for each antigen was converted to a recombinant IgG and produced in mammalian cells, with an average yield of 15 mg/L. In summary, we have optimized each step of the pipeline to produce recombinant antibodies, significantly increasing both efficiency and yield, and also showed that these Fabs and IgGs can be generally useful for chromatin immunoprecipitation (ChIP protocols.

  7. 188Re DD-3B6/22 Fab' for use in therapy of ovarian cancer: labelling and animal studies

    International Nuclear Information System (INIS)

    Schmidt, Peter F.; Smith, Suzanne V.; Bundesen, Peter G.

    1998-01-01

    A fast and high yielding method of 188 Re radiolabelling DD-3B6/22 Fab' is described. An inert atmosphere [N 2 (g)] and ascorbic acid was essential for preparation and storage of therapeutic levels (≤2 GBq/mg) for up to 24 h. Immunoreactivity was greater than 75%. Pharmacokinetic studies in nu/nu mice demonstrated localisation of 188 Re DD-3B6/22 Fab' was equivalent and correlated well with the behaviour observed for 99m Tc DD-3B6/22 Fab' used to image ovarian cancer. Excellent stability at the target site in vivo supports the potential use of 188 Re DD-3B6/22 Fab' in the therapy of ovarian cancer

  8. Structure of Rotavirus Outer-Layer Protein VP7 Bound with a Neutralizing Fab

    Energy Technology Data Exchange (ETDEWEB)

    Aoki, Scott T.; Settembre, Ethan C.; Trask, Shane D.; Greenberg, Harry B.; Harrison, Stephen C.; Dormitzer, Philip R.; (Stanford-MED); (CH-Boston)

    2009-06-17

    Rotavirus outer-layer protein VP7 is a principal target of protective antibodies. Removal of free calcium ions (Ca{sup 2+}) dissociates VP7 trimers into monomers, releasing VP7 from the virion, and initiates penetration-inducing conformational changes in the other outer-layer protein, VP4. We report the crystal structure at 3.4 angstrom resolution of VP7 bound with the Fab fragment of a neutralizing monoclonal antibody. The Fab binds across the outer surface of the intersubunit contact, which contains two Ca{sup 2+} sites. Mutations that escape neutralization by other antibodies suggest that the same region bears the epitopes of most neutralizing antibodies. The monovalent Fab is sufficient to neutralize infectivity. We propose that neutralizing antibodies against VP7 act by stabilizing the trimer, thereby inhibiting the uncoating trigger for VP4 rearrangement. A disulfide-linked trimer is a potential subunit immunogen.

  9. Extending green technology innovations to enable greener fabs

    Science.gov (United States)

    Takahisa, Kenji; Yoo, Young Sun; Fukuda, Hitomi; Minegishi, Yuji; Enami, Tatsuo

    2015-03-01

    Semiconductor manufacturing industry has growing concerns over future environmental impacts as fabs expand and new generations of equipment become more powerful. Especially rare gases supply and price are one of prime concerns for operation of high volume manufacturing (HVM) fabs. Over the past year it has come to our attention that Helium and Neon gas supplies could be unstable and become a threat to HVM fabs. To address these concerns, Gigaphoton has implemented various green technologies under its EcoPhoton program. One of the initiatives is GigaTwin deep ultraviolet (DUV) lithography laser design which enables highly efficient and stable operation. Under this design laser systems run with 50% less electric energy and gas consumption compared to conventional laser designs. In 2014 we have developed two technologies to further reduce electric energy and gas efficiency. The electric energy reduction technology is called eGRYCOS (enhanced Gigaphoton Recycled Chamber Operation System), and it reduces electric energy by 15% without compromising any of laser performances. eGRYCOS system has a sophisticated gas flow design so that we can reduce cross-flow-fan rotation speed. The gas reduction technology is called eTGM (enhanced Total gas Manager) and it improves gas management system optimizing the gas injection and exhaust amount based on laser performances, resulting in 50% gas savings. The next steps in our roadmap technologies are indicated and we call for potential partners to work with us based on OPEN INNOVATION concept to successfully develop faster and better solutions in all possible areas where green innovation may exist.

  10. Rapportage LTO FAB II 2008 : Functionele Agro Biodiversiteit

    NARCIS (Netherlands)

    Scheele, J.; Gurp, van H.; Alebeek, van F.A.N.; Belder, den E.; Elderson, J.

    2009-01-01

    Doel van het LTO FAB II project is een gebruiksklaar FAB concept te ontwikkelen voor een aantal ziekten en plagen in een aantal gewassen die op eenvoudige wijze door telers benut kan worden en voor de toepasser kostenneutraal zijn. Uitgangspunt in het FAB project is een evenwichtige balans tussen de

  11. FAB (Functionally Alert Behavior Strategies) to Improve Self-Control

    Science.gov (United States)

    Pagano, John

    2015-01-01

    This paper describes the FAB (Functionally Alert Behavior) Strategies approach to improve behavior in children and adolescents with complex behavioral challenges. FAB Strategies include evidence-based environmental adaptations, sensory modulation, positive behavioral support, and physical self-regulation strategies. FAB Strategies can be used by…

  12. The design, construction and performance of the MICE target

    International Nuclear Information System (INIS)

    Booth, C N; Hodgson, P; Howlett, L; Nicholson, R; Overton, E; Robinson, M; Smith, P J; Apollonio, M; Barber, G; Dobbs, A; Leaver, J; Long, K R; Shepherd, B; Adams, D; Capocci, E; McCarron, E; Tarrant, J

    2013-01-01

    The pion-production target that serves the MICE Muon Beam consists of a titanium cylinder that is dipped into the halo of the ISIS proton beam. The design and construction of the MICE target system are described along with the quality-assurance procedures, electromagnetic drive and control systems, the readout electronics, and the data-acquisition system. The performance of the target is presented together with the particle rates delivered to the MICE Muon Beam. Finally, the beam loss in ISIS generated by the operation of the target is evaluated as a function of the particle rate, and the operating parameters of the target are derived.

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

    Directory of Open Access Journals (Sweden)

    Xiaowen Zhang

    2018-02-01

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

  14. New schools design: Acoustics as main target

    Science.gov (United States)

    Maffei, Luigi; Lembo, Paola

    2005-04-01

    The effects of poor intelligibility and high background noise levels on the cognitive development of school children and on the dissatisfaction of teachers has been largely investigated. National standards have been implemented and attempts to harmonize these standards in international guidelines are ongoing. All these activities have led to the awareness that design of new schools must be centered on the achievement of a good acoustic environment. At this point a strong research effort to study and implement best solutions must be conducted, in collaboration, by architects, acousticians, pedagogues, psychologists, builders and acoustic materials producers. Recently an international competition for the planning of new primary schools in Rome, Italy has been announced. The aim of the competition is to study new architectural and running features of primary schools to obtain, among other parameters such as lighting, low cost energy solutions and air quality, the control of reverberation time, sound insulation and mechanical equipments noise. In these school buildings, as innovative requirement, children must be also able to elaborate interpretative hypothesis of physical phenomena such as sound emission and perception and be aware of their influence on these phenomena. Different possible solutions are presented.

  15. The binding parameters of radiolabelled monoclonal F (ab')2 and Fab' fragments relative to immunoglobulin G in reactions with surface-bound antigens

    International Nuclear Information System (INIS)

    Fjeld, J.G.; Nustad, K.; Michaelsen, T.E.

    1992-01-01

    The binding parameters of iodine-125-labelled intact monoclonal immunoglobulin G (IgG), F(ab') 2 and Fab' fragments were compared. The study was carried out with the two monoclonal antibodies (MoAbs) K13 and K16 specific for human Ig light chains κ and λ, respectively. When testing the 125 I-MoAbs against monodisperse polymer particles coated with the specific antigens, the K a for the F(ab') 2 fragments were similar to that for IgG, while the K a for the Fab' fragments were reduced to 10%-20% of that for IgG. The number N of effective target sites revealed with Fab' was higher than with F(ab') and IgG, presumably because less surface area is occupied by the small Fab' molecules. The immunoreactive fraction F ranged according to IgG>F(ab') 2 >Fab'. The explanation of the moderate difference between the K a of the monoclonal Fab' and the divalent IgG and F(ab') 2 was that the divalent molecules were not divalently attached to the particles. When testing the same antibody preparations against humanlymphoma cells producing Ig with light chains κ or λ, the binding results were less reliable than when particles were utilised, presumably due to antigen shedding. Different MoAbs vary in their loss of immunoreactivity due to enzymatic degradation and the radiolabelling procedure. The preparation of the radiolabelled fragments should therefore be optimized for each MoAb, and evaluation is necessary before injection. Artificial targets with a low leakage of antigen, like the monodisperse polymer particles here applied, are recommended for the in vitro evaluation of the immunoreactivity of labelled MoAb preparations. (orig.)

  16. Target based drug design - a reality in virtual sphere.

    Science.gov (United States)

    Verma, Saroj; Prabhakar, Yenamandra S

    2015-01-01

    The target based drug design approaches are a series of computational procedures, including visualization tools, to support the decision systems of drug design/discovery process. In the essence of biological targets shaping the potential lead/drug molecules, this review presents a comprehensive position of different components of target based drug design which include target identification, protein modeling, molecular dynamics simulations, binding/catalytic sites identification, docking, virtual screening, fragment based strategies, substructure treatment of targets in tackling drug resistance, in silico ADMET, structural vaccinology, etc along with the key issues involved therein and some well investigated case studies. The concepts and working of these procedures are critically discussed to arouse interest and to advance the drug research.

  17. Design of a cryogenic deuterium gas target for neutron therapy

    International Nuclear Information System (INIS)

    Kuchnir, F.T.; Waterman, F.M.; Forsthoff, H.; Skaggs, L.S.; Vander Arend, P.C.; Stoy, S.

    1976-01-01

    A cryogenic deuterium gas target operating at 80 0 K and 10 atm pressure has been designed for use with a small cyclotron; the D(d,n) reaction is used to produce a neutron beam suitable for radiation therapy. The target is cooled by circulation of the gas in a closed loop between the target and an external heat exchanger immersed in liquid nitrogen

  18. Design and Fabrication of Titanium Target for Portable Neutron Generator

    International Nuclear Information System (INIS)

    Lee, Cheol Ho; Oh, Byunghoon; Chang, Daesik; Jang, Dohyun; In Sang Yeol; Park, Jaewon; Hong, Kwangpyo

    2014-01-01

    For the neutron generator to produce a neutron flux of the above order, a target that produces fast neutrons in the generator plays an important role, and the target is used and applied to develop the generator due to its simplicity and inexpensive. Making suitable targets for neutron production, especially mono-energy neutrons, has always been of interest. These targets have been used for neutron production reaction studies, calibration of detectors, and neutron therapy. Different studies have been carried out on deuterium and tritium for making solid targets to produce mono-energy neutron from D-D and D-T reactions. A lot of investigations have been carried out on solid target properties such as lifetime, thermal stability, neutron yield, and energy. Vaporized zirconium and titanium layers on a high thermal conductivity substrate (Cu, Mo, Ag) have been used as deuterium and tritium absorbing metals. The density of titanium is smaller than zirconium and the range of charged particles in the titanium targets is more than that in zirconium targets. Thus, titanium targets have more neutron yield than zirconium targets in a low energy beam and titanium is usually used to make a target. The titanium target was designed and simulated to determine the suitable thickness of the target. As a result of the simulation, the target was fabricated to generate fast neutrons by the reaction. The thickness of the target was measured using a profiler. The thickness of the two targets is 2.108 and 2.190 μm. The target will be applied to produce neutrons in a neutron generator

  19. Design of ignition targets for the National Ignition Facility

    International Nuclear Information System (INIS)

    Haan, S.W.; Dittrich, T.R.; Marinak, M.M.; Hinkel, D.E.

    1999-01-01

    This is a brief update on the work being done to design ignition targets for the National Ignition Facility. Updates are presented on three areas of current activity : improvements in modeling, work on a variety of targets spanning the parameter space of possible ignition targets ; and the setting of specifications for target fabrication and diagnostics. Highlights of recent activity include : a simulation of the Rayleigh-Taylor instability growth on an imploding capsule, done in 3D on a 72degree by 72degree wedge, with enough zones to resolve modes out to 100 ; and designs of targets at 250eV and 350eV, as well as the baseline 300 eV ; and variation of the central DT gas density, which influences both the Rayleigh-Taylor growth and the smoothness of the DT ice layer

  20. Functional Dissection of the Blocking and Bypass Activities of the Fab-8 Boundary in the Drosophila Bithorax Complex.

    Science.gov (United States)

    Kyrchanova, Olga; Mogila, Vladic; Wolle, Daniel; Deshpande, Girish; Parshikov, Alexander; Cléard, Fabienne; Karch, Francois; Schedl, Paul; Georgiev, Pavel

    2016-07-01

    Functionally autonomous regulatory domains direct the parasegment-specific expression of the Drosophila Bithorax complex (BX-C) homeotic genes. Autonomy is conferred by boundary/insulator elements that separate each regulatory domain from its neighbors. For six of the nine parasegment (PS) regulatory domains in the complex, at least one boundary is located between the domain and its target homeotic gene. Consequently, BX-C boundaries must not only block adventitious interactions between neighboring regulatory domains, but also be permissive (bypass) for regulatory interactions between the domains and their gene targets. To elucidate how the BX-C boundaries combine these two contradictory activities, we have used a boundary replacement strategy. We show that a 337 bp fragment spanning the Fab-8 boundary nuclease hypersensitive site and lacking all but 83 bp of the 625 bp Fab-8 PTS (promoter targeting sequence) fully rescues a Fab-7 deletion. It blocks crosstalk between the iab-6 and iab-7 regulatory domains, and has bypass activity that enables the two downstream domains, iab-5 and iab-6, to regulate Abdominal-B (Abd-B) transcription in spite of two intervening boundary elements. Fab-8 has two dCTCF sites and we show that they are necessary both for blocking and bypass activity. However, CTCF sites on their own are not sufficient for bypass. While multimerized dCTCF (or Su(Hw)) sites have blocking activity, they fail to support bypass. Moreover, this bypass defect is not rescued by the full length PTS. Finally, we show that orientation is critical for the proper functioning the Fab-8 replacement. Though the inverted Fab-8 boundary still blocks crosstalk, it disrupts the topology of the Abd-B regulatory domains and does not support bypass. Importantly, altering the orientation of the Fab-8 dCTCF sites is not sufficient to disrupt bypass, indicating that orientation dependence is conferred by other factors.

  1. Optimum design of exploding pusher target to produce maximum neutrons

    International Nuclear Information System (INIS)

    Kitagawa, Y.; Miyanaga, N.; Kato, Y.; Nakatsuka, M.; Nishiguchi, A.; Yabe, T.; Yamanaka, C.

    1985-03-01

    Exploding pusher target experiments have been conducted with the 1.052-μm GEKKO MII two-beam glass laser system to design an optimum target, which couples to the incident laser light most effectively to produce the maximum neutrons. Since hot electrons preheat the shell entirely in spite of strongly nonuniform irradiation, a simple model can design the optimum target, of which the shell/fuel interface is accelerated to 0.5 to 0.7 times the initial radius within a laser pulse. A 2-dimensional computer simulation supports this target design. The scaling of the neutron yield N with the laser power P is N ∝ P 2.4±0.4 . (author)

  2. LBNF 1.2 MW TARGET: CONCEPTUAL DESIGN & FABRICATION

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-06-29

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

  3. LBNF 1.2 MW Target: Conceptual Design & Fabrication

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-06-01

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

  4. Design and Characterization of High Power Targets for RIB Generation

    International Nuclear Information System (INIS)

    Zhang, Y.

    2001-01-01

    In this article, thermal modeling techniques are used to simulate ISOL targets irradiated with high power proton beams. Beam scattering effects, nuclear reactions and beam power deposition distributions in the target were computed with the Monte Carlo simulation code, GEANT4. The power density information was subsequently used as input to the finite element thermal analysis code, ANSYS, for extracting temperature distribution information for a variety of target materials. The principal objective of the studies was to evaluate techniques for more uniformly distributing beam deposited heat over the volumes of targets to levels compatible with their irradiation with the highest practical primary-beam power, and to use the preferred technique to design high power ISOL targets. The results suggest that radiation cooling, in combination, with primary beam manipulation, can be used to control temperatures in practically sized targets, to levels commensurate with irradiation with 1 GeV, 100 kW proton beams

  5. Test Information Targeting Strategies for Adaptive Multistage Testing Designs.

    Science.gov (United States)

    Luecht, Richard M.; Burgin, William

    Adaptive multistage testlet (MST) designs appear to be gaining popularity for many large-scale computer-based testing programs. These adaptive MST designs use a modularized configuration of preconstructed testlets and embedded score-routing schemes to prepackage different forms of an adaptive test. The conditional information targeting (CIT)…

  6. Water-cooled target-box design at LAMPF

    International Nuclear Information System (INIS)

    Grisham, D.; Lambert, J.

    1983-01-01

    The target boxes in the main experimental beam line (Line A) at the Clinton P. Anderson Meson Physics Facility (LAMPF) have operated since 1976. A program of replacing the boxes is underway. This paper will present past history, design considerations, calculational results and the final box design

  7. Trastuzumab- and Fab' fragment-modified curcumin PEG-PLGA nanoparticles: preparation and evaluation in vitro and in vivo.

    Science.gov (United States)

    Duan, Dongyu; Wang, Aiping; Ni, Ling; Zhang, Liping; Yan, Xiuju; Jiang, Ying; Mu, Hongjie; Wu, Zimei; Sun, Kaoxiang; Li, Youxin

    2018-01-01

    Nanoparticles (NPs) modified with bio-ligands represent a promising strategy for active targeted drug delivery to tumour. However, many targeted ligands, such as trastuzumab (TMAB), have high molecular weight, limiting their application for targeting. In this study, we prepared Fab' (antigen-binding fragments cut from TMAB)-modified NPs (Fab'-NPs) with curcumin (Cur) as a model drug for more effective targeting of human epidermal growth factor receptor 2 (HER2/ErbB2/Neu), which is overexpressed on breast cancer cells. The release kinetics was conducted by dialysis bags. The ability to kill HER2-overexpressing BT-474 cells of Fab'-Cur-NPs compared with TMAB-Cur-NPs was conducted by cytotoxicity experiments. Qualitative and quantitative cell uptake studies using coumarin-6 (fluorescent probe)-loaded NPs were performed by fluorescence microscopy and flow cytometry. Pharmacokinetics and biodistribution experiments in vivo were assessed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The release kinetics showed that both Fab'-Cur-NPs and TMAB-Cur-NPs provided continuous, slow release of curcumin for 72 h, with no significant difference. In vitro cytotoxicity experiments showed that Fab'-Cur-NPs manifested prominent ability to kill HER2-overexpressing BT-474 cells compared with TMAB-Cur-NPs. Qualitative and quantitative cell uptake studies indicated that the accumulation of Fab'-NPs was greater than that of TMAB-NPs in BT-474 (HER2+) cells; However, there was no significant difference in MDA-MB-231 (HER2-) cells. Pharmacokinetics and biodistribution experiments in vivo demonstrated that the half-life (t1/2) and area under the blood concentration-time curve (AUC0-t) of Fab'-Cur-NPs increased 5.30-fold and 1.76-fold relative to those of TMAB-Cur-NPs, respectively. Furthermore, the tumor accumulation of Fab'-Cur-NPs was higher than that of TMAB-Cur-NPs. Fab' fragment has greater capacity than the intact antibody to achieve tumor targeting through NP

  8. Preliminary conceptual design of target system. Pt. 1. System configuration

    Energy Technology Data Exchange (ETDEWEB)

    Hino, Ryutaro; Haga, Katsuhiro; Kaminaga, Masanori [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment] [and others

    1997-07-01

    In the 21st century, neutron is expected to play a very important role in the fields of structural biology, nuclear physics, material science if a very high-intensity neutron source will be built because of its superior nature as an probe to investigate material structure and its function. The Japan Atomic Energy Research Institute has launched the Neutron Science Project for construction and utilization of a high-intensity spallation neutron source coupled with a proton accelerator. In the project, a neutron scattering facility is planned to be constructed in an early stage. Development of a 5MW spallation neutron source is one of the most difficult technical challenges in this project. A two-step development plan of the target was established to construct a 5MW-target station In the 1st step, a 1.5MW target will be constructed to develop 5MW target technology. The preliminary conceptual design was conducted to clarify the specifications of the target system of 1.5MW and 5MW including system layout, scale etc. This report describes (1) a design policy, (2) a layout of system consisting of the target, remote-handling devices, bio-shieldings etc., (3) specifications of components and facilities such as cooling systems for target and moderators, beam-port shutter and air conditioning system, (4) overhaul procedures by remote-handling devices, (5) safety assessment, and (6) necessary R and D items derived from the design activity. (author)

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

    Science.gov (United States)

    Pan, Qihe; Narayanan, Ram M

    2011-01-01

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

  10. Shortening User Interface Design Iterations through Realtime Visualisation of Design Actions on the Target Device

    OpenAIRE

    MESKENS, Jan; LUYTEN, Kris; CONINX, Karin

    2009-01-01

    In current mobile user interface design tools, it is time consuming to export a design to the target device. This makes it hard for designers to iterate over the user interfaces they are creating. We propose Gummy-live, a GUI builder for mobile devices allowing designers to test and observe immediately on the target device each step they take in the GUI builder. This way, designers are stimulated to iteratively test and refine user interface prototypes in order to take the target device charac...

  11. Present status of the conceptual design of IFMIF target facility

    International Nuclear Information System (INIS)

    Katsuta, H.; Kato, Y.; Konishi, S.; Miyauchi, Y.; Smith, D.; Hua, T.; Green, L.; Benamati, G.; Cevolani, S.; Roehrig, H.; Schutz, W.

    1998-01-01

    The conceptual design activity (CDA) for the international fusion materials irradiation facility (IFMIF) has been conducted. For the IFMIF target facility, the conceptual designs of the following two main components have been performed. The design concept of IFMIF utilizes a high energy deuteron beam of 30-40 MeV and total current of 250 mA, impinging on a flowing lithium jet to produce high energy neutrons for irradiation of candidate fusion materials. (1) The target assembly: The kinetic energy of the deuteron beam is deposited on a Li-jet target and neutrons are produced through the d-Li stripping reaction in this target. The assembly is designed to get a stable lithium jet and to prevent the onset of lithium boiling. For 40-MeV deuteron beam (total current of 250 mA) and a beam footprint of 5 x 20 cm 2 lithium jet dimensions are designed to be 2.5 cm thick and 26 cm wide. The lithium jet parameters are given. (2) Lithium loop: The loop circulates the lithium to and from the target assembly and removes the heat deposited by the deuteron beam containing systems for maintaining the-high purity of the lithium required for radiological safety and to minimize corrosion. The maximum lithium flow rate is 130 l/s and the total lithium inventory is about 21 m 3 . The IFMIF policy requires that the lithium loop system be designed to guarantee no combustion of lithium in the event of a lithium leak. This can be achieved by use of multiple confinement of the lithium carrying components. The radioactive waste generated by the target facilities is estimated. (orig.)

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

    Science.gov (United States)

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

    2017-10-01

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

  13. A novel antibody-drug conjugate anti-CD19(Fab)-LDM in the treatment of B-cell non-Hodgkin lymphoma xenografts with enhanced anticancer activity.

    Science.gov (United States)

    Jiang, Linlin; Yang, Ming; Zhang, Xiaoyun; Bao, Shiqi; Ma, Li; Fan, Dongmei; Zhou, Yuan; Xiong, Dongsheng; Zhen, Yongsu

    2016-01-01

    Rituximab is widely used in clinical setting for the treatment of B malignant lymphoma and has achieved remarkable success. However, in most patients, the disease ultimately relapses and become resistant to rituximab. To overcome the limitation, there is still a need to find novel strategy for improving therapeutic efficacy. To construct genetically engineered antibody anti-CD19(Fab)-LDM, and verify the anticancer activity targeted toward B-lymphoma. The anticancer activity of anti-CD19(Fab)-LDM in vitro and in vivo was examined. In vitro, the binding activity and internalization of anti-CD19(Fab)-LDP were measured. Using comet assay and apoptosis, the cytotoxicity of energized fusion proteins was observed. From in vivo experiments, targeting of therapeutic effect and anticancer efficacy bythe fusion protein was verified. Data showed that anti-CD19(Fab)-LDM does not only binding the cell surface but is also internalized into the cell. The energized fusion proteins anti-CD19(Fab)-LDM can induce DNA damage. Furthermore, significant in vivo therapeutic efficacy was observed. The present study demonstrated that the genetically engineered antibody anti-CD19(Fab)-LDM exhibited enhanced cytotoxicity compared to LDM alone. One of the most powerful advantages of anti-CD19(Fab)-LDM, however, is that it can be internalized within the cells and carry out cytotoxic effects. Therefore, anti-CD19(Fab)-LDM may be as a useful targeted therapy for B-cell lymphoma.

  14. Reorienting the Fab Domains of Trastuzumab Results in Potent HER2 Activators

    Science.gov (United States)

    Scheer, Justin M.; Sandoval, Wendy; Elliott, J. Michael; Shao, Lily; Luis, Elizabeth; Lewin-Koh, Sock-Cheng; Schaefer, Gabriele; Vandlen, Richard

    2012-01-01

    The structure of the Fab region of antibodies is critical to their function. By introducing single cysteine substitutions into various positions of the heavy and light chains of the Fab region of trastuzumab, a potent antagonist of HER2, and using thiol chemistry to link the different Fabs together, we produced a variety of monospecific F(ab′)2-like molecules with activities spanning from activation to inhibition of breast tumor cell growth. These isomers (or bis-Fabs) of trastuzumab, with varying relative spatial arrangements between the Fv-regions, were able to either promote or inhibit cell-signaling activities through the PI3K/AKT and MAPK pathways. A quantitative phosphorylation mapping of HER2 indicated that the agonistic isomers produced a distinct phosphorylation pattern associated with activation. This study suggests that antibody geometric isomers, found both in nature and during synthetic antibody development, can have profoundly different biological activities independent of their affinities for their target molecules. PMID:23284778

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

    Directory of Open Access Journals (Sweden)

    Avinaba Mukherjee

    2016-03-01

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

  16. The Fatty Acid Biosynthesis Enzyme FabI Plays a Key Role In the Development of Liver Stage Malarial Parasites

    Science.gov (United States)

    Yu, Min; Santha Kumar, T. R.; Nkrumah, Louis J.; Coppi, Alida; Retzlaff, Silke; Li, Celeste D.; Kelly, Brendan J.; Moura, Pedro A.; Lakshmanan, Viswanathan; Freundlich, Joel S.; Valderramos, Juan-Carlos; Vilcheze, Catherine; Siedner, Mark; Tsai, Jennifer H.-C.; Falkard, Brie; Sidhu, Amar bir Singh; Purcell, Lisa A.; Gratraud, Paul; Kremer, Laurent; Waters, Andy P.; Schiehser, Guy; Jacobus, David P.; Janse, Chris J.; Ager, Arba; Jacobs, William R.; Sacchettini, James C.; Heussler, Volker; Sinnis, Photini; Fidock, David A.

    2008-01-01

    SUMMARY Fatty acid biosynthesis has been viewed as an important biological function of and therapeutic target for Plasmodium falciparum asexual blood stage infection. This apicoplast-resident type II pathway, distinct from the mammalian type I process, includes FabI. Here, we report synthetic chemistry and transfection studies concluding that Plasmodium FabI is not the target of the antimalarial activity of the bacterial FabI inhibitor triclosan. Disruption of fabI in P. falciparum or the rodent parasite P. berghei does not impede blood stage growth. In contrast, mosquito-derived fabI-deficient P. berghei sporozoites are markedly less infective for mice and typically fail to complete liver stage development in vitro. This is characterized by an inability to form intra-hepatic merosomes that normally initiate blood stage infections. These data illuminate key differences between liver and blood stage parasites in their requirements for host versus de novo synthesized fatty acids, and create new prospects for stage-specific antimalarial interventions. PMID:19064257

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

    DEFF Research Database (Denmark)

    Jørgensen, Bo

    2005-01-01

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

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

    CERN Document Server

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

    2007-01-01

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

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

    CERN Document Server

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

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

  20. Design choices and issues in fixed-target B experiments

    International Nuclear Information System (INIS)

    Camilleri, L.

    1993-01-01

    The main priority of any experiment on B physics in the years to come will be an endeavour to observe CP violation in the B sector. Such measurements imply the following requirements of the experiment. Trigger: a muon trigger will be sensitive to J/ψ reactions and muon tags; an electron trigger will double the number of lepton events; in order to include kaon tags and self-tagging reactions, the experiment must not rely entirely on lepton triggers. Secondary Vertex triggers and hadron p T triggers should be included in order to have the maximum flexibility. Detector: vertex detector; particle identification; good momentum resolution; electromagnetic and hadronic calorimeters; muon detector. In addition the following issues have to be addressed: Collider or fixed-target mode? If fixed target, extracted beam or internal target? If internal target, gas jet or wire target? If a gas jet, hydrogen or a heavy gas? Beam pipe design. Silicon microvertex design and radiation damage. K s 0 decay path. Particle identification. Momentum resolution. Order of detectors. No single method stands out as the open-quotes obvious one.close quotes An extracted beam yields better vertex resolution and an internal target easier triggering. A flexible and diverse triggering scheme is of prime importance in order to be sensitive to as many reactions as possible, the experiment should not be limited to lepton triggers only. Proposed experiments (P867, HERA B) at existing machines will be invaluable for testing new devices and strategies for the LHC and SSC experiments

  1. Bringing optics to Fab Labs in Europe

    Science.gov (United States)

    Adam, Aurèle; Zuidwijk, Thim; Urbach, Paul

    2017-08-01

    The Optics Group of Delft University of Technology plays a major role in teaching optics to bachelor and master students. In addition, the group has a long record of introducing, demonstrating and teaching optics to quite diverse groups of people from outside of the university. We will describe some of these activities and focus on a recently started project funded by the European Commission called Phablabs 4.0, which aims to bring photonics to European Fab labs.

  2. Massively parallel de novo protein design for targeted therapeutics

    KAUST Repository

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

    2017-01-01

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

  3. Massively parallel de novo protein design for targeted therapeutics

    KAUST Repository

    Chevalier, Aaron

    2017-09-26

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

  4. Massively parallel de novo protein design for targeted therapeutics

    Science.gov (United States)

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

    2018-01-01

    De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37–43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing. PMID:28953867

  5. Design considerations for foil windows for PET radioisotope targets

    International Nuclear Information System (INIS)

    Hughey, B.J.; Shefer, R.E.; Klinkowstein, R.E.; Welch, M.J.

    1992-01-01

    This paper describes the results of a study performed at SRL to develop analytical and computational techniques for optimizing the design of conduction-cooled foil windows for PET targets. Single foil conduction cooled windows have been found to be good target entrance windows for both low energy accelerators and medium energy cyclotrons. Detailed thermal analysis has given an approximate analytical expression for the maximum temperature reached in a foil window under conditions of realistic ion beam bombardment. The effects of 'hot spots' in the beam density profile were investigated. It was shown that a factor of two safety margin in window design should be adequate to compensate for any possible beam hot spots. In addition, the reduction of foil stress by slack mounting was verified by experiments. The properties of conventional and novel foil materials were investigated for use in conduction cooled windows. Novel foil materials include two-component Al/Ti and Al/Havar foil. Results on the testing of candidate foil materials for thermal conductivity and mechanical strength at elevated temperature were presented. Two optimum foil window geometries were analyzed: a high aspect ratio window and a multiply slotted window. The multiply slotted window combines the advantages of a high aspect ratio foil window with a circular beam strike and is a promising window design for both TCA and cyclotron targets. A multiply slotted window for a N 2 gas target for 15 O production was designed using the methodologies discussed above. This prototype target was successfully tested using the TCA beam at SRL. (author) 6 figs., 3 tabs., 10 refs

  6. Some Aspects on Filter Design for Target Tracking

    Directory of Open Access Journals (Sweden)

    Bertil Ekstrand

    2012-01-01

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

  7. Radioiodinated iodobenzoyl conjugates of a monoclonal antibody Fab fragment. In vivo comparisons with chloramine-T-labeled Fab

    International Nuclear Information System (INIS)

    Wilbur, D.S.; Hadley, S.W.; Grant, L.M.; Hylarides, M.D.

    1991-01-01

    A comparative investigation of the biodistributions of radioiodinated p- and m-iodobenzoyl conjugates of a monoclonal antibody Fab fragment, NR-LU-10 Fab, and the same antibody Fab fragment radioiodinated by the chloramine-T (ChT) method has been carried out in mice. Coinjected, dual-isotope studies in athymic mice with tumor xenografts have demonstrated that there are only minor differences in the in vivo distributions of the iodobenzoyl-labeled Fabs, except in the excretory organs, kidneys, and intestines, where major differences were observed. Similarly, coinjection of either the p-iodobenzoyl or m-iodobenzoyl conjugate of NR-LU-10 Fab with the Fab radioiodinated with ChT/radioiodide into BALB/c mice provided additional data that indicated that the two iodobenzoyl conjugates distributed similar in a number of selected tissues. The tissue-distribution differences of the regioisomeric iodobenzoyl conjugates in relation to the ChT-radioiodinated Fab were large for the stomach and neck, consistent with previous studies. The most notable difference between the two iodobenzoyl conjugates was the kidney activity, where the m-iodobenzoyl conjugate was similar to the directly labeled Fab, but the p-iodobenzoyl-conjugated Fab was higher by nearly a factor of 2

  8. Introduction to spallation physics and spallation-target design

    Energy Technology Data Exchange (ETDEWEB)

    Russell, G.J.; Pitcher, E.J.; Daemen, L.L. [Los Alamos National Laboratory, NM (United States)

    1995-10-01

    When coupled with the spallation process in appropriate target materials, high-power accelerators can be used to produce large numbers of neutrons, thus providing an alternate method to the use of nuclear reactors for this purpose. Spallation offers exciting new possibilities for generating intense neutron fluxes for a variety of applications, including: (a) spallation-neutron sources for materials science research; (b) accelerator-based production of tritium; (c) accelerator-based transmutation of waste; (d) accelerator-based destruction of plutonium; and (e) radioisotope production for medical and energy applications. Target design plays a key role in these applications, with neutron production/leakage being strongly dependent on the incident particle type and energy, and target material and geometry.

  9. Optimum nuclear design of target fuel rod for Mo-99 production in HANARO

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Myung Hyun [Kyung Hee University, Seoul (Korea)

    1998-04-01

    Nuclear target design for Mo-99 production in HANARO was performed, KAERI proposed target design was analyzed and its feasibility was shown. Three commercial target designs of Cintichem, ANL and KAERI were tested for the HANARO irradiation an d they all satisfied with design specification. A parametric study was done for target design options and Mo-99 yields ratio and surface heat flux were compared. Tested parameters were target fuel thickness, irradiation location, target axial length, packing density of powder fuel, size of target radius, target geometry, fuel enrichment, fuel composition, and cladding material. Optimized target fuel was designed for both LEU and HEU options. (author). 17 refs., 33 figs., 42 tabs.

  10. Radiolabeled F(ab')2-cetuximab for theranostic purposes in colorectal and skin tumor-bearing mice models.

    Science.gov (United States)

    Bellaye, P-S; Moreau, M; Raguin, O; Oudot, A; Bernhard, C; Vrigneaud, J-M; Dumont, L; Vandroux, D; Denat, F; Cochet, A; Brunotte, F; Collin, B

    2018-05-17

    This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, 111 In and 177 Lu, respectively. We designed F(ab') 2 -fragments of cetuximab radiolabeled with 111 In and 177 Lu. 111 In-F(ab') 2 -cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111 In-F(ab') 2 -cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on 177 Lu-F(ab') 2 -cetuximab was evaluated in SWISS nude mice bearing A431 tumors. Radiolabeling procedure did not change F(ab') 2 -cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. 111 In-DOTAGA-F(ab') 2 -cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab') 2 -cetuximab. SPECT imaging of 111 In-DOTAGA-F(ab') 2 -cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, 177 Lu-DOTAGA-F(ab') 2 -cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses. 111 In-DOTAGA-F(ab') 2 -cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. 177 Lu-DOTAGA-F(ab') 2 -cetuximab is an interesting theranostic tool allowing therapy and imaging.

  11. A collagen-binding EGFR antibody fragment targeting tumors with a collagen-rich extracellular matrix

    OpenAIRE

    Hui Liang; Xiaoran Li; Bin Wang; Bing Chen; Yannan Zhao; Jie Sun; Yan Zhuang; Jiajia Shi; He Shen; Zhijun Zhang; Jianwu Dai

    2016-01-01

    Many tumors over-express collagen, which constitutes the physical scaffold of tumor microenvironment. Collagen has been considered to be a target for cancer therapy. The collagen-binding domain (CBD) is a short peptide, which could bind to collagen and achieve the sustained release of CBD-fused proteins in collagen scaffold. Here, a collagen-binding EGFR antibody fragment was designed and expressed for targeting the collagen-rich extracellular matrix in tumors. The antibody fragment (Fab) of ...

  12. Rare isotope accelerator—conceptual design of target areas

    Science.gov (United States)

    Bollen, Georg; Baek, Inseok; Blideanu, Valentin; Lawton, Don; Mantica, Paul F.; Morrissey, David J.; Ronningen, Reginald M.; Sherrill, Bradley S.; Zeller, Albert; Beene, James R.; Burgess, Tom; Carter, Kenneth; Carrol, Adam; Conner, David; Gabriel, Tony; Mansur, Louis; Remec, Igor; Rennich, Mark; Stracener, Dan; Wendel, Mark; Ahle, Larry; Boles, Jason; Reyes, Susana; Stein, Werner; Heilbronn, Lawrence

    2006-06-01

    The planned rare isotope accelerator facility RIA in the US would become the most powerful radioactive beam facility in the world. RIA's driver accelerator will be a device capable of providing beams from protons to uranium at energies of at least 400 MeV per nucleon, with beam power up to 400 kW. Radioactive beam production relies on both the in-flight separation of fast beam fragments and on the ISOL technique. In both cases the high beam power poses major challenges for target technology and handling and on the design of the beam production areas. This paper will give a brief overview of RIA and discuss aspects of ongoing conceptual design work for the RIA target areas.

  13. Rare Isotope Accelerator - Conceptual Design of Target Areas

    Energy Technology Data Exchange (ETDEWEB)

    Bollen, Georg [Michigan State University, East Lansing; Baek, Inseok [Michigan State University, East Lansing; Blideanu, Valentin [CEA, Saclay, France; Lawton, Don [Michigan State University, East Lansing; Mantica, Paul F. [Michigan State University, East Lansing; Morrissey, David J. [Michigan State University, East Lansing; Ronningen, Reginald M. [Michigan State University, East Lansing; Sherrill, Bradley S. [Michigan State University, East Lansing; Zeller, Albert [Michigan State University, East Lansing; Beene, James R [ORNL; Burgess, Tom [Oak Ridge National Laboratory (ORNL); Carter, Kenneth [Oak Ridge National Laboratory (ORNL); Carrol, Adam [Oak Ridge National Laboratory (ORNL); Conner, David [ORNL; Gabriel, Tony A [ORNL; Mansur, Louis K [ORNL; Remec, Igor [ORNL; Rennich, Mark J [ORNL; Stracener, Daniel W [ORNL; Wendel, Mark W [ORNL; Ahle, Larry [Lawrence Livermore National Laboratory (LLNL); Boles, Jason [Lawrence Livermore National Laboratory (LLNL); Reyes, Susana [Lawrence Livermore National Laboratory (LLNL); Stein, Werner [Lawrence Livermore National Laboratory (LLNL); Heilbronn, Lawrence [Lawrence Berkeley National Laboratory (LBNL)

    2006-01-01

    The planned rare isotope accelerator facility RIA in the US would become the most powerful radioactive beam facility in the world. RIA s driver accelerator will be a device capable of providing beams from protons to uranium at energies of at least 400MeV per nucleon, with beam power up to 400 kW. Radioactive beam production relies on both the in-flight separation of fast beam fragments and on the ISOL technique. In both cases the high beam power poses major challenges for target technology and handling and on the design of the beam production areas. This paper will give a brief overview of RIA and discuss aspects of ongoing conceptual design work for the RIA target areas.

  14. New designs of LMJ targets for early ignition experiments

    International Nuclear Information System (INIS)

    Clerouin, C; Bonnefille, M; Dattolo, E; Fremerye, P; Galmiche, D; Gauthier, P; Giorla, J; Laffite, S; Liberatore, S; Loiseau, P; Malinie, G; Masse, L; Poggi, F; Seytor, P

    2008-01-01

    The LMJ experimental plans include the attempt of ignition and burn of an ICF capsule with 40 laser quads, delivering up to 1.4MJ and 380TW. New targets needing reduced laser energy with only a small decrease in robustness are then designed for this purpose. A first strategy is to use scaled-down cylindrical hohlraums and capsules, taking advantage of our better understanding of the problem, set on theoretical modelling, simulations and experiments. Another strategy is to work specifically on the coupling efficiency parameter, i.e. the ratio of the energy absorbed by the capsule to the laser energy, which is with parametric instabilities a crucial drawback of indirect drive. An alternative design is proposed, made up of the nominal 60 quads capsule, named A1040, in a rugby-shaped hohlraum. Robustness evaluations of these different targets are in progress

  15. New designs of LMJ targets for early ignition experiments

    Energy Technology Data Exchange (ETDEWEB)

    Clerouin, C; Bonnefille, M; Dattolo, E; Fremerye, P; Galmiche, D; Gauthier, P; Giorla, J; Laffite, S; Liberatore, S; Loiseau, P; Malinie, G; Masse, L; Poggi, F; Seytor, P [Commissariat a l' Energie Atomique, DAM-Ile de France, BP 12 91680 Bruyeres-le-Chatel (France)], E-mail: catherine.cherfils@cea.fr

    2008-05-15

    The LMJ experimental plans include the attempt of ignition and burn of an ICF capsule with 40 laser quads, delivering up to 1.4MJ and 380TW. New targets needing reduced laser energy with only a small decrease in robustness are then designed for this purpose. A first strategy is to use scaled-down cylindrical hohlraums and capsules, taking advantage of our better understanding of the problem, set on theoretical modelling, simulations and experiments. Another strategy is to work specifically on the coupling efficiency parameter, i.e. the ratio of the energy absorbed by the capsule to the laser energy, which is with parametric instabilities a crucial drawback of indirect drive. An alternative design is proposed, made up of the nominal 60 quads capsule, named A1040, in a rugby-shaped hohlraum. Robustness evaluations of these different targets are in progress.

  16. Rare isotope accelerator - conceptual design of target areas

    International Nuclear Information System (INIS)

    Bollen, Georg; Baek, Inseok; Blideanu, Valentin; Lawton, Don; Mantica, Paul F.; Morrissey, David J.; Ronningen, Reginald M.; Sherrill, Bradley S.; Zeller, Albert; Beene, James R; Burgess, Tom; Carter, Kenneth; Carrol, Adam; Conner, David; Gabriel, Tony A; Mansur, Louis K; Remec, Igor; Rennich, Mark J; Stracener, Daniel W; Wendel, Mark W; Ahle, Larry; Boles, Jason; Reyes, Susana; Stein, Werner; Heilbronn, Lawrence

    2006-01-01

    The planned rare isotope accelerator facility RIA in the US would become the most powerful radioactive beam facility in the world. RIA's driver accelerator will be a device capable of providing beams from protons to uranium at energies of at least 400MeV per nucleon, with beam power up to 400 kW. Radioactive beam production relies on both the in-flight separation of fast beam fragments and on the ISOL technique. In both cases the high beam power poses major challenges for target technology and handling and on the design of the beam production areas. This paper will give a brief overview of RIA and discuss aspects of ongoing conceptual design work for the RIA target areas

  17. Rare isotope accelerator-conceptual design of target areas

    Energy Technology Data Exchange (ETDEWEB)

    Bollen, Georg [National Superconducting Cyclotron Laboratory, Michigan State University, East Lansing, MI 48824 (United States)]. E-mail: bollen@nscl.msu.edu; Baek, Inseok; Blideanu, Valentin; Lawton, Don; Mantica, Paul F.; Morrissey, David J.; Ronningen, Reginald M.; Sherrill, Bradley S.; Zeller, Albert [National Superconducting Cyclotron Laboratory, Michigan State University, East Lansing, MI 48824 (United States); Beene, James R.; Burgess, Tom; Carter, Kenneth; Carrol, Adam; Conner, David; Gabriel, Tony; Mansur, Louis; Remec, Igor; Rennich, Mark; Stracener, Dan; Wendel, Mark [Oak Ridge National Laboratory, Oak Ridge, TN 37830 (United States); Ahle, Larry; Boles, Jason; Reyes, Susana; Stein, Werner [Lawrence Livermore Laboratory, Livermore, CA 94550 (United States); Heilbronn, Lawrence [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States)

    2006-06-23

    The planned rare isotope accelerator facility RIA in the US would become the most powerful radioactive beam facility in the world. RIA's driver accelerator will be a device capable of providing beams from protons to uranium at energies of at least 400 MeV per nucleon, with beam power up to 400 kW. Radioactive beam production relies on both the in-flight separation of fast beam fragments and on the ISOL technique. In both cases the high beam power poses major challenges for target technology and handling and on the design of the beam production areas. This paper will give a brief overview of RIA and discuss aspects of ongoing conceptual design work for the RIA target areas.

  18. Spallation neutron source target design for radioactive waste transmutation

    International Nuclear Information System (INIS)

    Beard, C.A.

    1992-01-01

    The disposal of high-level radioactive waste has long been one of the most serious problems facing the nuclear industry. Transmutation of this waste through particle bombardment has been suggested numerous times as a possible method of enhancing the waste management process. Due to advances in accelerator technology, the feasibility of an accelerator based transmutation system has increased enough to allow serious investigation of this process. Therefore, in pursuit of this goal, an accelerator target was designed for use in an accelerator based transmutation system. The target design consists of an array of tantalum rods, cooled by liquid sodium, which are arranged in a cylindrical configuration 40 cm in diameter and 125 cm in height. Tantalum was chosen as the target material over tungsten, lead, bismuth, and a lead-bismuth alloy (55 w/o bismuth) due to a large neutron yield, low activation, low chemical toxicity, and the fact that it does not produce significant amounts of long-lived isotopes through spallation or activation. The target yields a neutron source of 29.7 neutrons/proton when exposed to a 1600 MeV proton beam, and is suitable for use with both thermal or fast spectrum transmutation systems

  19. Design and implementation of typical target image database system

    International Nuclear Information System (INIS)

    Qin Kai; Zhao Yingjun

    2010-01-01

    It is necessary to provide essential background data and thematic data timely in image processing and application. In fact, application is an integrating and analyzing procedure with different kinds of data. In this paper, the authors describe an image database system which classifies, stores, manages and analyzes database of different types, such as image database, vector database, spatial database, spatial target characteristics database, its design and structure. (authors)

  20. Observations on the Biology of Callosobruchus maculatus (Fab ...

    African Journals Online (AJOL)

    Observations on the biology of Callosobruchus maculatus( Fab.) were carried out under ambient laboratory conditions. Pattern of oviposition, female adult longevity and F1 progeny emergence in Callosobruchus maculatus ( Fab. ) were observed. The results showed that over 60% of the total number of eggs was laid during ...

  1. Benchmarking CRISPR on-target sgRNA design.

    Science.gov (United States)

    Yan, Jifang; Chuai, Guohui; Zhou, Chi; Zhu, Chenyu; Yang, Jing; Zhang, Chao; Gu, Feng; Xu, Han; Wei, Jia; Liu, Qi

    2017-02-15

    CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-based gene editing has been widely implemented in various cell types and organisms. A major challenge in the effective application of the CRISPR system is the need to design highly efficient single-guide RNA (sgRNA) with minimal off-target cleavage. Several tools are available for sgRNA design, while limited tools were compared. In our opinion, benchmarking the performance of the available tools and indicating their applicable scenarios are important issues. Moreover, whether the reported sgRNA design rules are reproducible across different sgRNA libraries, cell types and organisms remains unclear. In our study, a systematic and unbiased benchmark of the sgRNA predicting efficacy was performed on nine representative on-target design tools, based on six benchmark data sets covering five different cell types. The benchmark study presented here provides novel quantitative insights into the available CRISPR tools. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. Structures of Pseudomonas aeruginosa β-ketoacyl-(acyl-carrier-protein) synthase II (FabF) and a C164Q mutant provide templates for antibacterial drug discovery and identify a buried potassium ion and a ligand-binding site that is an artefact of the crystal form

    Energy Technology Data Exchange (ETDEWEB)

    Baum, Bernhard [Johannes Gutenberg-Universität, Staudinger Weg 5, 55128 Mainz (Germany); Lecker, Laura S. M.; Zoltner, Martin [University of Dundee, Dundee DD1 4EH, Scotland (United Kingdom); Jaenicke, Elmar [Johannes Gutenberg-Universität, Jakob Welder Weg 26, 55128 Mainz (Germany); Schnell, Robert [Karolinska Institutet, 17 177 Stockholm (Sweden); Hunter, William N., E-mail: w.n.hunter@dundee.ac.uk [University of Dundee, Dundee DD1 4EH, Scotland (United Kingdom); Brenk, Ruth, E-mail: w.n.hunter@dundee.ac.uk [Johannes Gutenberg-Universität, Staudinger Weg 5, 55128 Mainz (Germany)

    2015-07-28

    Three crystal structures of recombinant P. aeruginosa FabF are reported: the apoenzyme, an active-site mutant and a complex with a fragment of a natural product inhibitor. The characterization provides reagents and new information to support antibacterial drug discovery. Bacterial infections remain a serious health concern, in particular causing life-threatening infections of hospitalized and immunocompromised patients. The situation is exacerbated by the rise in antibacterial drug resistance, and new treatments are urgently sought. In this endeavour, accurate structures of molecular targets can support early-stage drug discovery. Here, crystal structures, in three distinct forms, of recombinant Pseudomonas aeruginosa β-ketoacyl-(acyl-carrier-protein) synthase II (FabF) are presented. This enzyme, which is involved in fatty-acid biosynthesis, has been validated by genetic and chemical means as an antibiotic target in Gram-positive bacteria and represents a potential target in Gram-negative bacteria. The structures of apo FabF, of a C164Q mutant in which the binding site is altered to resemble the substrate-bound state and of a complex with 3-(benzoylamino)-2-hydroxybenzoic acid are reported. This compound mimics aspects of a known natural product inhibitor, platensimycin, and surprisingly was observed binding outside the active site, interacting with a symmetry-related molecule. An unusual feature is a completely buried potassium-binding site that was identified in all three structures. Comparisons suggest that this may represent a conserved structural feature of FabF relevant to fold stability. The new structures provide templates for structure-based ligand design and, together with the protocols and reagents, may underpin a target-based drug-discovery project for urgently needed antibacterials.

  3. Structures of Pseudomonas aeruginosa β-ketoacyl-(acyl-carrier-protein) synthase II (FabF) and a C164Q mutant provide templates for antibacterial drug discovery and identify a buried potassium ion and a ligand-binding site that is an artefact of the crystal form

    International Nuclear Information System (INIS)

    Baum, Bernhard; Lecker, Laura S. M.; Zoltner, Martin; Jaenicke, Elmar; Schnell, Robert; Hunter, William N.; Brenk, Ruth

    2015-01-01

    Three crystal structures of recombinant P. aeruginosa FabF are reported: the apoenzyme, an active-site mutant and a complex with a fragment of a natural product inhibitor. The characterization provides reagents and new information to support antibacterial drug discovery. Bacterial infections remain a serious health concern, in particular causing life-threatening infections of hospitalized and immunocompromised patients. The situation is exacerbated by the rise in antibacterial drug resistance, and new treatments are urgently sought. In this endeavour, accurate structures of molecular targets can support early-stage drug discovery. Here, crystal structures, in three distinct forms, of recombinant Pseudomonas aeruginosa β-ketoacyl-(acyl-carrier-protein) synthase II (FabF) are presented. This enzyme, which is involved in fatty-acid biosynthesis, has been validated by genetic and chemical means as an antibiotic target in Gram-positive bacteria and represents a potential target in Gram-negative bacteria. The structures of apo FabF, of a C164Q mutant in which the binding site is altered to resemble the substrate-bound state and of a complex with 3-(benzoylamino)-2-hydroxybenzoic acid are reported. This compound mimics aspects of a known natural product inhibitor, platensimycin, and surprisingly was observed binding outside the active site, interacting with a symmetry-related molecule. An unusual feature is a completely buried potassium-binding site that was identified in all three structures. Comparisons suggest that this may represent a conserved structural feature of FabF relevant to fold stability. The new structures provide templates for structure-based ligand design and, together with the protocols and reagents, may underpin a target-based drug-discovery project for urgently needed antibacterials

  4. Preliminary design implications of SSC fixed-target operation

    International Nuclear Information System (INIS)

    Zisman, M.S.

    1984-06-01

    This paper covers some of the accelerator physics issues relevant to a possible fixed-target operating mode for the Superconducting Super Collider (SSC). In the brief time available, no attempt has been made to design this capability into the SSC. Rather, I have tried to evaluate what the performance of such a machine might be, and to indicate the hardware implications and extraction considerations that would be part of an actual design study. Where appropriate, parameters and properties of the present LBL design for the SSC have been used; these should be taken as being representative of the general class of small-aperture, high-field colliders being considered by the accelerator physics community. Thus, the numerical examples given here must ultimately be reexamined in light of the actual parameters of the particular accelerator being considered

  5. Target designs for energetics experiments on the National Ignition Facility

    International Nuclear Information System (INIS)

    Meezan, N B; Glenzer, S H; Suter, L J

    2008-01-01

    The goal of the first hohlraum energetics experiments on the National Ignition Facility (NIF) [G. H. Miller et al, Optical Eng. 43, 2841 (2004)] is to select the hohlraum design for the first ignition experiments. Sub-scale hohlraums heated by 96 of the 192 laser beams on the NIF are used to emulate the laser-plasma interaction behavior of ignition hohlraums. These 'plasma emulator' targets are 70% scale versions of the 1.05 MJ, 300 eV ignition hohlraum and have the same energy-density as the full-scale ignition designs. Radiation-hydrodynamics simulations show that the sub-scale target is a good emulator of plasma conditions inside the ignition hohlraum, reproducing density n e within 10% and temperature T e within 15% along a laser beam path. Linear backscatter gain analysis shows the backscatter risk to be comparable to that of the ignition target. A successful energetics campaign will allow the National Ignition Campaign to focus its efforts on optimizing ignition hohlraums with efficient laser coupling

  6. Een inventarisatie naar de bekendheid van Functionele Agrobiodiversiteit (FAB) en de mogelijkheden om FAB met andere agroranden te combineren

    NARCIS (Netherlands)

    Geerts, R.H.E.M.; Meerburg, B.G.

    2011-01-01

    Op dit moment zijn er regio's waar het FAB concept al breed wordt toegepast en goed is ingebed (West-Brabant/Zeeland), waar het in opmars is (Flevoland en Zuid-Holland) en enkele regio's waar het FAB gedachtegoed slechts matig aanwezig is (Groningen / Drenthe).

  7. Efficacy of IgG, Fab, and F(ab')2 fragments of horse antivenom in the ...

    African Journals Online (AJOL)

    The ability of horse antivenoms, consisting of immunoglobulin G (IgG) and its fragments F(ab')2 and Fab were comparatively studied in mice to neutralize several effects of Cerastes cerastes venom. The three antivenoms were produced from the same batch of hyperimmune horse plasma. Neutralization was only partial ...

  8. Modern design of far-field target motion simulators

    Science.gov (United States)

    Hauser, Robin; Swamp, Michael; Havlicsek, Howard

    2006-05-01

    Target Motion Simulators (TMS) are often used in conjunction with Flight Motion Simulators (FMS) to provide a realistic simulation of tracking and target engagement. For near-field applications, the TMS has typically been implemented with two additional gimbals around the FMS. For far-field applications, such as a radar, the TMS has traditionally been implemented with curvilinear X-Y Frames. A curvilinear frame placed at the proper distance from the FMS has the benefit of always pointing the Target back to the FMS intersection of axes. In most cases the curvilinear TMS provides good results. However, the curvilinear TMS lacks the possibility to change the distance between Target and Seeker, which is needed for operation with different radar wavelengths. Acutronic has developed a new approach using a flat frame (X-Y) TMS coupled with a gimballed payload mount that has the possibility of being used at various distances without losing the functionality of continuous pointing back to the seeker. This paper describes the electro-mechanical design and gives an overview of the Computer and Controllers used. It further addresses the problem of coordination transformation that is needed to obtain the correct pointing.

  9. IFMIF target and test cell - design and integration

    International Nuclear Information System (INIS)

    Heinzel, V.

    2007-01-01

    The International Fusion Material Irradiation Facility (IFMIF) aims at the qualification of appropriate materials for a Demonstration Fusion Power Plant (DEMO) to a fluence of up to 150 dpa (displacement per atom) at a DEMO typical neutron spectrum. It comprises two accelerators each providing a deuteron beam with 125 mA and 40 MeV. The deuterons strike a lithium target and create via stripping reactions neutrons. The neutrons are mainly forward directed into the High-Flux-Test-Module (HFTM). The Medium Flux-Test-Modules (MFTM) and the Low-Flux-Test-Modules (LFTM) are arranged in beam direction behind. In the HFTM a damage rate in steel of more than 20 dpa/fpy (displacement per atome per full power year) will be provide in a volume of 0.5 litre. The neutron spectrum is prone to produce helium and tritium in steel like in the first wall of a DEMO reactor. The Medium- Flux-Test-Modules are designed for creep fatigues in situ and tritium release test. The test modules are cooled with helium. The target is a lithium jet with a free surface towards the deuteron beams. The jet follows a concave curved so called back wall. Centrifugal forces increase the static pressure, which prevents lithium boiling at the beam tube pressure and the power release of 10 MW due to the deuteron beams. The target and Test Cell (TTC) houses the target and the test modules as well as the lithium supply tubes and a quench tank into which the lithium splashes after the target. The lithium containing components have a temperature of 250 to 350 C. Nuclear reactions mainly in beam direction contribute to heat releases in TTC components. The TTC is filled with a noble gas with almost atmospheric pressure. Natural convection transfers heat to the walls but also mitigates temperature peaks. The Forschungszentrum Karlsruhe (FZK) has developed or validated tools for: - The extended Monte Carlo Code McDeLicious for calculations of the neutron source term, dpa rates in the material specimens, activation

  10. ImmunoPET of tissue factor expression in triple-negative breast cancer with a radiolabeled antibody Fab fragment

    International Nuclear Information System (INIS)

    Shi, Sixiang; Hong, Hao; Orbay, Hakan; Yang, Yunan; Ohman, Jakob D.; Graves, Stephen A.; Nickles, Robert J.; Liu, Bai; Wong, Hing C.; Cai, Weibo

    2015-01-01

    To date, there is no effective therapy for triple-negative breast cancer (TNBC), which has a dismal clinical outcome. Upregulation of tissue factor (TF) expression leads to increased patient morbidity and mortality in many solid tumor types, including TNBC. Our goal was to employ the Fab fragment of ALT-836, a chimeric anti-human TF mAb, for PET imaging of TNBC, which can be used to guide future TNBC therapy. ALT-836-Fab was generated by enzymatic papain digestion. SDS-PAGE and FACS studies were performed to evaluate the integrity and TF binding affinity of ALT-836-Fab before NOTA conjugation and 64 Cu-labeling. Serial PET imaging and biodistribution studies were carried out to evaluate the tumor targeting efficacy and pharmacokinetics in the MDA-MB-231 TNBC model, which expresses high levels of TF on the tumor cells. Blocking studies, histological assessment, as well as RT-PCR were performed to confirm TF specificity of 64 Cu-NOTA-ALT-836-Fab. ALT-836-Fab was produced with high purity, which exhibited superb TF binding affinity and specificity. Serial PET imaging revealed rapid and persistent tumor uptake of 64 Cu-NOTA-ALT-836-Fab (5.1 ± 0.5 %ID/g at 24 h post-injection; n = 4) and high tumor/muscle ratio (7.0 ± 1.2 at 24 h post-injection; n = 4), several-fold higher than that of the blocking group and tumor models that do not express significant level of TF, which was confirmed by biodistribution studies. TF specificity of the tracer was also validated by histology and RT-PCR. 64 Cu-NOTA-ALT-836-Fab exhibited prominent tissue factor targeting efficiency in MDA-MB-231 TNBC model. The use of a Fab fragment led to fast tumor uptake and good tissue/muscle ratio, which may be translated into same-day immunoPET imaging in the clinical setting to improve TNBC patient management. (orig.)

  11. ImmunoPET of tissue factor expression in triple-negative breast cancer with a radiolabeled antibody Fab fragment.

    Science.gov (United States)

    Shi, Sixiang; Hong, Hao; Orbay, Hakan; Graves, Stephen A; Yang, Yunan; Ohman, Jakob D; Liu, Bai; Nickles, Robert J; Wong, Hing C; Cai, Weibo

    2015-07-01

    To date, there is no effective therapy for triple-negative breast cancer (TNBC), which has a dismal clinical outcome. Upregulation of tissue factor (TF) expression leads to increased patient morbidity and mortality in many solid tumor types, including TNBC. Our goal was to employ the Fab fragment of ALT-836, a chimeric anti-human TF mAb, for PET imaging of TNBC, which can be used to guide future TNBC therapy. ALT-836-Fab was generated by enzymatic papain digestion. SDS-PAGE and FACS studies were performed to evaluate the integrity and TF binding affinity of ALT-836-Fab before NOTA conjugation and (64)Cu-labeling. Serial PET imaging and biodistribution studies were carried out to evaluate the tumor targeting efficacy and pharmacokinetics in the MDA-MB-231 TNBC model, which expresses high levels of TF on the tumor cells. Blocking studies, histological assessment, as well as RT-PCR were performed to confirm TF specificity of (64)Cu-NOTA-ALT-836-Fab. ALT-836-Fab was produced with high purity, which exhibited superb TF binding affinity and specificity. Serial PET imaging revealed rapid and persistent tumor uptake of (64)Cu-NOTA-ALT-836-Fab (5.1 ± 0.5 %ID/g at 24 h post-injection; n = 4) and high tumor/muscle ratio (7.0 ± 1.2 at 24 h post-injection; n = 4), several-fold higher than that of the blocking group and tumor models that do not express significant level of TF, which was confirmed by biodistribution studies. TF specificity of the tracer was also validated by histology and RT-PCR. (64)Cu-NOTA-ALT-836-Fab exhibited prominent tissue factor targeting efficiency in MDA-MB-231 TNBC model. The use of a Fab fragment led to fast tumor uptake and good tissue/muscle ratio, which may be translated into same-day immunoPET imaging in the clinical setting to improve TNBC patient management.

  12. ImmunoPET of tissue factor expression in triple-negative breast cancer with a radiolabeled antibody Fab fragment

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Sixiang [University of Wisconsin, Materials Science Program, Madison, WI (United States); Hong, Hao; Orbay, Hakan; Yang, Yunan; Ohman, Jakob D. [University of Wisconsin, Department of Radiology, Madison, WI (United States); Graves, Stephen A.; Nickles, Robert J. [University of Wisconsin, Department of Medical Physics, Madison, WI (United States); Liu, Bai; Wong, Hing C. [Altor BioScience, Miramar, FL (United States); Cai, Weibo [University of Wisconsin, Materials Science Program, Madison, WI (United States); University of Wisconsin, Department of Radiology, Madison, WI (United States); University of Wisconsin, Department of Medical Physics, Madison, WI (United States); University of Wisconsin Carbone Cancer Center, Madison, WI (United States); University of Wisconsin, Departments of Radiology and Medical Physics, Madison, WI (United States)

    2015-07-15

    To date, there is no effective therapy for triple-negative breast cancer (TNBC), which has a dismal clinical outcome. Upregulation of tissue factor (TF) expression leads to increased patient morbidity and mortality in many solid tumor types, including TNBC. Our goal was to employ the Fab fragment of ALT-836, a chimeric anti-human TF mAb, for PET imaging of TNBC, which can be used to guide future TNBC therapy. ALT-836-Fab was generated by enzymatic papain digestion. SDS-PAGE and FACS studies were performed to evaluate the integrity and TF binding affinity of ALT-836-Fab before NOTA conjugation and {sup 64}Cu-labeling. Serial PET imaging and biodistribution studies were carried out to evaluate the tumor targeting efficacy and pharmacokinetics in the MDA-MB-231 TNBC model, which expresses high levels of TF on the tumor cells. Blocking studies, histological assessment, as well as RT-PCR were performed to confirm TF specificity of {sup 64}Cu-NOTA-ALT-836-Fab. ALT-836-Fab was produced with high purity, which exhibited superb TF binding affinity and specificity. Serial PET imaging revealed rapid and persistent tumor uptake of {sup 64}Cu-NOTA-ALT-836-Fab (5.1 ± 0.5 %ID/g at 24 h post-injection; n = 4) and high tumor/muscle ratio (7.0 ± 1.2 at 24 h post-injection; n = 4), several-fold higher than that of the blocking group and tumor models that do not express significant level of TF, which was confirmed by biodistribution studies. TF specificity of the tracer was also validated by histology and RT-PCR. {sup 64}Cu-NOTA-ALT-836-Fab exhibited prominent tissue factor targeting efficiency in MDA-MB-231 TNBC model. The use of a Fab fragment led to fast tumor uptake and good tissue/muscle ratio, which may be translated into same-day immunoPET imaging in the clinical setting to improve TNBC patient management. (orig.)

  13. The cosmology of the Fab-Four

    International Nuclear Information System (INIS)

    Copeland, Edmund J.; Padilla, Antonio; Saffin, Paul M.

    2012-01-01

    We have recently proposed a novel self tuning mechanism to alleviate the famous cosmological constant problem, based on the general scalar tensor theory proposed by Horndeski. The self-tuning model ends up consisting of four geometric terms in the action, with each term containing a free potential function of the scalar field; the four together being labeled as the Fab-Four. In this paper we begin the important task of deriving the cosmology associated with the Fab-Four Lagrangian. Performing a phase plane analysis of the system we are able to obtain a number of fixed points for the system, with some remarkable new solutions emerging from the trade-off between the various potentials. As well as obtaining inflationary solutions we also find conventional radiation/matter-like solutions, but in regimes where the energy density is dominated by a cosmological constant, and where we do not have any explicit forms of radiation or matter. Stability conditions for matter solutions are obtained and we show how it is possible for there to exist an extended period of 'matter domination' opening up the possibility that we can generate cosmological structures, and recover a consistent cosmology even in the presence of a large cosmological constant

  14. Fab the coming revolution on your desktop : from personal computers to personal fabrication

    CERN Document Server

    Gershenfeld, Neil

    2005-01-01

    What if you could someday put the manufacturing power of an automobile plant on your desktop? According to Neil Gershenfeld, the renowned MIT scientist and inventor, the next big thing is personal fabrication-the ability to design and produce your own products, in your own home, with a machine that combines consumer electronics and industrial tools. Personal fabricators are about to revolutionize the world just as personal computers did a generation ago, and Fab shows us how.

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

    Directory of Open Access Journals (Sweden)

    WANG Jian

    2017-10-01

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

  16. Mock Target Window OTR and IR Design and Testing

    Energy Technology Data Exchange (ETDEWEB)

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

    2017-09-19

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

  17. Target design for materials processing very far from equilibrium

    Science.gov (United States)

    Barnard, John J.; Schenkel, Thomas

    2016-10-01

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

  18. Relative stabilities of IgG1 and IgG4 Fab domains: Influence of the light–heavy interchain disulfide bond architecture

    Science.gov (United States)

    Heads, James T; Adams, Ralph; D'Hooghe, Lena E; Page, Matt J T; Humphreys, David P; Popplewell, Andrew G; Lawson, Alastair D; Henry, Alistair J

    2012-01-01

    The stability of therapeutic antibodies is a prime pharmaceutical concern. In this work we examined thermal stability differences between human IgG1 and IgG4 Fab domains containing the same variable regions using the thermofluor assay. It was found that the IgG1 Fab domain is up to 11°C more stable than the IgG4 Fab domain containing the same variable region. We investigated the cause of this difference with the aim of developing a molecule with the enhanced stability of the IgG1 Fab and the biological properties of an IgG4 Fc. We found that replacing the seven residues, which differ between IgG1 CH1 and IgG4 CH1 domains, while retaining the native IgG1 light-heavy interchain disulfide (L–H) bond, did not affect thermal stability. Introducing the IgG1 type L–H interchain disulfide bond (DSB) into the IgG4 Fab resulted in an increase in thermal stability to levels observed in the IgG1 Fab with the same variable region. Conversely, replacement of the IgG1 L–H interchain DSB with the IgG4 type L–H interchain DSB reduced the thermal stability. We utilized the increased stability of the IgG1 Fab and designed a hybrid antibody with an IgG1 CH1 linked to an IgG4 Fc via an IgG1 hinge. This construct has the expected biophysical properties of both the IgG4 Fc and IgG1 Fab domains and may therefore be a pharmaceutically relevant format. PMID:22761163

  19. In-Situ Ion Source Cleaning: Review of Chemical Mechanisms and Evaluation Data at Production Fabs

    International Nuclear Information System (INIS)

    Kaim, R.; Bishop, S.; Byl, O.; Eldridge, D.; Marganski, P.; Mayer, J.; Sweeney, J.; Yedave, S.; Fuchs, D.; Spreitzer, S.; Vogel, J.; Dunn, J.; Lundquist, P.; Rolland, J.; Romig, T.; Newman, D.; Mitchell, M.; Ditzler, K.

    2008-01-01

    Since the concept of chemical in-situ ion implanter cleaning was introduced at IIT2006 [1], evaluations of the XeF 2 cleaning technology have taken place or are ongoing at more than 40 production fabs worldwide. Testing has been focused on assessing effects of cleaning in the source arc chamber and extraction regions. In this paper we describe use of the cleaning technology in a production environment and summarize evaluation data showing advantages of the technology for improving ion source life, reducing glitching, improving beam auto-tuning and avoiding species cross-contamination. More details of the evaluations are given in several separate papers submitted to this Conference. We have supplemented the fab production data with laboratory experiments designed to investigate the reactivity of XeF 2 and fundamental aspects of the source deposition and cleaning processes. These experiments are summarized here, and more details can be found in separate papers submitted to this Conference

  20. Semiconductor industry wafer fab exhaust management

    CERN Document Server

    Sherer, Michael J

    2005-01-01

    Given the myriad exhaust compounds and the corresponding problems that they can pose in an exhaust management system, the proper choice of such systems is a complex task. Presenting the fundamentals, technical details, and general solutions to real-world problems, Semiconductor Industry: Wafer Fab Exhaust Management offers practical guidance on selecting an appropriate system for a given application. Using examples that provide a clear understanding of the concepts discussed, Sherer covers facility layout, support facilities operations, and semiconductor process equipment, followed by exhaust types and challenges. He reviews exhaust point-of-use devices and exhaust line requirements needed between process equipment and the centralized exhaust system. The book includes information on wet scrubbers for a centralized acid exhaust system and a centralized ammonia exhaust system and on centralized equipment to control volatile organic compounds. It concludes with a chapter devoted to emergency releases and a separ...

  1. How fabulous is Fab 5 cosmology?

    International Nuclear Information System (INIS)

    Linder, Eric V.

    2013-01-01

    Extended gravity origins for cosmic acceleration can solve some fine tuning issues and have useful characteristics, but generally have little to say regarding the cosmological constant problem. Fab 5 gravity can be ghost free and stable, have attractor solutions in the past and future, and possess self tuning that solves the original cosmological constant problem. Here we show however it does not possess all these qualities at the same time. We also demonstrate that the self tuning is so powerful that it not only cancels the cosmological constant but also all other energy density, and we derive the scalings of its approach to a renormalized de Sitter cosmology. While this strong cancellation is bad for the late universe, it greatly eases early universe inflation

  2. How fabulous is Fab 5 cosmology?

    Energy Technology Data Exchange (ETDEWEB)

    Linder, Eric V., E-mail: evlinder@lbl.gov [Berkeley Center for Cosmological Physics and Berkeley Lab, University of California, Berkeley, CA, 94720 (United States)

    2013-12-01

    Extended gravity origins for cosmic acceleration can solve some fine tuning issues and have useful characteristics, but generally have little to say regarding the cosmological constant problem. Fab 5 gravity can be ghost free and stable, have attractor solutions in the past and future, and possess self tuning that solves the original cosmological constant problem. Here we show however it does not possess all these qualities at the same time. We also demonstrate that the self tuning is so powerful that it not only cancels the cosmological constant but also all other energy density, and we derive the scalings of its approach to a renormalized de Sitter cosmology. While this strong cancellation is bad for the late universe, it greatly eases early universe inflation.

  3. Modern Prodrug Design for Targeted Oral Drug Delivery

    Directory of Open Access Journals (Sweden)

    Arik Dahan

    2014-10-01

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

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

    Directory of Open Access Journals (Sweden)

    Luc Calvin Owono Owono

    2013-01-01

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

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

    International Nuclear Information System (INIS)

    Crescenzi, Fabio; Bachmann, C.; Richou, M.; Roccella, S.; Visca, E.; You, J.-H.

    2015-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-10-15

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

  7. Rasch Analysis of the Fullerton Advanced Balance (FAB) Scale

    OpenAIRE

    Klein, Penelope J.; Fiedler, Roger C.; Rose, Debra J.

    2011-01-01

    Purpose: This cross-sectional study explores the psychometric properties and dimensionality of the Fullerton Advanced Balance (FAB) Scale, a multi-item balance test for higher-functioning older adults.

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

    KAUST Repository

    Jardak, Seifallah

    2014-04-01

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

  9. Designer interface peptide grafts target estrogen receptor alpha dimerization

    International Nuclear Information System (INIS)

    Chakraborty, S.; Asare, B.K.; Biswas, P.K.; Rajnarayanan, R.V.

    2016-01-01

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

  10. Designer interface peptide grafts target estrogen receptor alpha dimerization

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-09-09

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

  11. National Ignition Facility subsystem design requirements target positioning subsystem SSDR 1.8.2

    International Nuclear Information System (INIS)

    Pittenger, L.

    1996-01-01

    This Subsystem Design Requirement document is a development specification that establishes the performance, design, development and test requirements for the target positioner subsystem (WBS 1.8.2) of the NIF Target Experimental System (WBS 1.8)

  12. Structural and biophysical characterization of an epitope-specific engineered Fab fragment and complexation with membrane proteins: implications for co-crystallization.

    Science.gov (United States)

    Johnson, Jennifer L; Entzminger, Kevin C; Hyun, Jeongmin; Kalyoncu, Sibel; Heaner, David P; Morales, Ivan A; Sheppard, Aly; Gumbart, James C; Maynard, Jennifer A; Lieberman, Raquel L

    2015-04-01

    Crystallization chaperones are attracting increasing interest as a route to crystal growth and structure elucidation of difficult targets such as membrane proteins. While strategies to date have typically employed protein-specific chaperones, a peptide-specific chaperone to crystallize multiple cognate peptide epitope-containing client proteins is envisioned. This would eliminate the target-specific chaperone-production step and streamline the co-crystallization process. Previously, protein engineering and directed evolution were used to generate a single-chain variable (scFv) antibody fragment with affinity for the peptide sequence EYMPME (scFv/EE). This report details the conversion of scFv/EE to an anti-EE Fab format (Fab/EE) followed by its biophysical characterization. The addition of constant chains increased the overall stability and had a negligible impact on the antigen affinity. The 2.0 Å resolution crystal structure of Fab/EE reveals contacts with larger surface areas than those of scFv/EE. Surface plasmon resonance, an enzyme-linked immunosorbent assay, and size-exclusion chromatography were used to assess Fab/EE binding to EE-tagged soluble and membrane test proteins: namely, the β-barrel outer membrane protein intimin and α-helical A2a G protein-coupled receptor (A2aR). Molecular-dynamics simulation of the intimin constructs with and without Fab/EE provides insight into the energetic complexities of the co-crystallization approach.

  13. The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites.

    Science.gov (United States)

    Yu, Min; Kumar, T R Santha; Nkrumah, Louis J; Coppi, Alida; Retzlaff, Silke; Li, Celeste D; Kelly, Brendan J; Moura, Pedro A; Lakshmanan, Viswanathan; Freundlich, Joel S; Valderramos, Juan-Carlos; Vilcheze, Catherine; Siedner, Mark; Tsai, Jennifer H-C; Falkard, Brie; Sidhu, Amar Bir Singh; Purcell, Lisa A; Gratraud, Paul; Kremer, Laurent; Waters, Andrew P; Schiehser, Guy; Jacobus, David P; Janse, Chris J; Ager, Arba; Jacobs, William R; Sacchettini, James C; Heussler, Volker; Sinnis, Photini; Fidock, David A

    2008-12-11

    The fatty acid synthesis type II pathway has received considerable interest as a candidate therapeutic target in Plasmodium falciparum asexual blood-stage infections. This apicoplast-resident pathway, distinct from the mammalian type I process, includes FabI. Here, we report synthetic chemistry and transfection studies concluding that Plasmodium FabI is not the target of the antimalarial activity of triclosan, an inhibitor of bacterial FabI. Disruption of fabI in P. falciparum or the rodent parasite P. berghei does not impede blood-stage growth. In contrast, mosquito-derived, FabI-deficient P. berghei sporozoites are markedly less infective for mice and typically fail to complete liver-stage development in vitro. This defect is characterized by an inability to form intrahepatic merosomes that normally initiate blood-stage infections. These data illuminate key differences between liver- and blood-stage parasites in their requirements for host versus de novo synthesized fatty acids, and create new prospects for stage-specific antimalarial interventions.

  14. Aerial image measurement technique for automated reticle defect disposition (ARDD) in wafer fabs

    Science.gov (United States)

    Zibold, Axel M.; Schmid, Rainer M.; Stegemann, B.; Scheruebl, Thomas; Harnisch, Wolfgang; Kobiyama, Yuji

    2004-08-01

    The Aerial Image Measurement System (AIMS)* for 193 nm lithography emulation has been brought into operation successfully worldwide. A second generation system comprising 193 nm AIMS capability, mini-environment and SMIF, the AIMS fab 193 plus is currently introduced into the market. By adjustment of numerical aperture (NA), illumination type and partial illumination coherence to match the conditions in 193 nm steppers or scanners, it can emulate the exposure tool for any type of reticles like binary, OPC and PSM down to the 65 nm node. The system allows a rapid prediction of wafer printability of defects or defect repairs, and critical features, like dense patterns or contacts on the masks without the need to perform expensive image qualification consisting of test wafer exposures followed by SEM measurements. Therefore, AIMS is a mask quality verification standard for high-end photo masks and established in mask shops worldwide. The progress on the AIMS technology described in this paper will highlight that besides mask shops there will be a very beneficial use of the AIMS in the wafer fab and we propose an Automated Reticle Defect Disposition (ARDD) process. With smaller nodes, where design rules are 65 nm or less, it is expected that smaller defects on reticles will occur in increasing numbers in the wafer fab. These smaller mask defects will matter more and more and become a serious yield limiting factor. With increasing mask prices and increasing number of defects and severability on reticles it will become cost beneficial to perform defect disposition on the reticles in wafer production. Currently ongoing studies demonstrate AIMS benefits for wafer fab applications. An outlook will be given for extension of 193 nm aerial imaging down to the 45 nm node based on emulation of immersion scanners.

  15. SNS Target Test Facility for remote handling design and verification

    International Nuclear Information System (INIS)

    Spampinato, P.T.; Graves, V.B.; Schrock, S.L.

    1998-01-01

    The Target Test Facility will be a full-scale prototype of the Spallation Neutron Source Target Station. It will be used to demonstrate remote handling operations on various components of the mercury flow loop and for thermal/hydraulic testing. This paper describes the remote handling aspects of the Target Test Facility. Since the facility will contain approximately 1 cubic meter of mercury for the thermal/hydraulic tests, an enclosure will also be constructed that matches the actual Target Test Cell

  16. Conjugation of 10 kDa Linear PEG onto Trastuzumab Fab' Is Sufficient to Significantly Enhance Lymphatic Exposure while Preserving in Vitro Biological Activity.

    Science.gov (United States)

    Chan, Linda J; Ascher, David B; Yadav, Rajbharan; Bulitta, Jürgen B; Williams, Charlotte C; Porter, Christopher J H; Landersdorfer, Cornelia B; Kaminskas, Lisa M

    2016-04-04

    The lymphatic system is a major conduit by which many diseases spread and proliferate. There is therefore increasing interest in promoting better lymphatic drug targeting. Further, antibody fragments such as Fabs have several advantages over full length monoclonal antibodies but are subject to rapid plasma clearance, which can limit the lymphatic exposure and activity of Fabs against lymph-resident diseases. This study therefore explored ideal PEGylation strategies to maximize biological activity and lymphatic exposure using trastuzumab Fab' as a model. Specifically, the Fab' was conjugated with single linear 10 or 40 kDa PEG chains at the hinge region. PEGylation led to a 3-4-fold reduction in binding affinity to HER2, but antiproliferative activity against HER2-expressing BT474 cells was preserved. Lymphatic pharmacokinetics were then examined in thoracic lymph duct cannulated rats after intravenous and subcutaneous dosing at 2 mg/kg, and the data were evaluated via population pharmacokinetic modeling. The Fab' displayed limited lymphatic exposure, but conjugation of 10 kDa PEG improved exposure by approximately 11- and 5-fold after intravenous (15% dose collected in thoracic lymph over 30 h) and subcutaneous (9%) administration, respectively. Increasing the molecular weight of the PEG to 40 kDa, however, had no significant impact on lymphatic exposure after intravenous (14%) administration and only doubled lymphatic exposure after subcutaneous administration (18%) when compared to 10 kDa PEG-Fab'. The data therefore suggests that minimal PEGylation has the potential to enhance the exposure and activity of Fab's against lymph-resident diseases, while no significant benefit is achieved with very large PEGs.

  17. Designing block copolymer architectures for targeted membrane performance

    KAUST Repository

    Dorin, Rachel Mika

    2014-01-01

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

  18. Structure of the Francisella tularensis enoyl-acyl carrier protein reductase (FabI) in complex with NAD+ and triclosan

    International Nuclear Information System (INIS)

    Mehboob, Shahila; Truong, Kent; Santarsiero, Bernard D.; Johnson, Michael E.

    2010-01-01

    Structure of the ternary complex of F. tularensis enoyl-acyl carrier protein reductase reveals the structure of the substrate binding loop whose electron density was missing in an earlier structure, and demonstrates a shift in the position of the NAD + cofactor. Enoyl-acyl carrier protein reductase (FabI) catalyzes the last rate-limiting step in the elongation cycle of the fatty-acid biosynthesis pathway and has been validated as a potential antimicrobial drug target in Francisella tularensis. The development of new antibiotic therapies is important both to combat potential drug-resistant bioweapons and to address the broader societal problem of increasing antibiotic resistance among many pathogenic bacteria. The crystal structure of FabI from F. tularensis (FtuFabI) in complex with the inhibitor triclosan and the cofactor NAD + has been solved to a resolution of 2.1 Å. Triclosan is known to effectively inhibit FabI from different organisms. Precise characterization of the mode of triclosan binding is required to develop highly specific inhibitors. Comparison of our structure with the previously determined FtuFabI structure which is bound to only NAD + reveals the conformation of the substrate-binding loop, electron density for which was missing in the earlier structure, and demonstrates a shift in the conformation of the NAD + cofactor. This shift in the position of the phosphate groups allows more room in the active site for substrate or inhibitor to bind and be better accommodated. This information will be crucial for virtual screening studies to identify novel scaffolds for development into new active inhibitors

  19. Specific Conjugation of the Hinge Region for Homogeneous Preparation of Antibody Fragment-Drug Conjugate: A Case Study for Doxorubicin-PEG-anti-CD20 Fab' Synthesis.

    Science.gov (United States)

    Zhou, Zhan; Zhang, Jing; Zhang, Yan; Ma, Guanghui; Su, Zhiguo

    2016-01-20

    Conventional preparation strategies for antibody-drug conjugates (ADCs) result in heterogeneous products with various molecular sizes and species. In this study, we developed a homogeneous preparation strategy by site-specific conjugation of the anticancer drug with an antibody fragment. The model drug doxorubicin (DOX) was coupled to the Fab' fragment of anti-CD20 IgG at its permissive sites through a heterotelechelic PEG linker, generating an antibody fragment-drug conjugate (AFDC). Anti-CD20 IgG was digested and reduced specifically with β-mercaptoethylamine to generate the Fab' fragment with two free mercapto groups in its hinge region. Meanwhile, DOX was conjugated with α-succinimidylsuccinate ω-maleimide polyethylene glycol (NHS-PEG-MAL) to form MAL-PEG-DOX, which was subsequently linked to the free mercapto containing Fab' fragment to form a Fab'-PEG-DOX conjugate. The dual site-specific bioconjugation was achieved through the combination of highly selective reduction of IgG and introduction of heterotelechelic PEG linker. The resulting AFDC provides an utterly homogeneous product, with a definite ratio of one fragment to two drugs. Laser confocal microscopy and cell ELISA revealed that the AFDC could accumulate in the antigen-positive Daudi tumor cell. In addition, the Fab'-PEG-DOX retained appreciable targeting ability and improved antitumor activity, demonstrating an excellent therapeutic effect on the lymphoma mice model for better cure rate and significantly reduced side effects.

  20. Conceptual design studies for the liquid metal target META:LIC

    International Nuclear Information System (INIS)

    Class, A.G.; Fazio, C.; Fetzer, J.R.; Gordeev, S.

    2014-01-01

    When the construction of ESS (European Spallation Source) in Sweden was initiated, the target station concept selection group decided to reevaluate a variety of target designs to respect new developments in their selection process. The META:LIC (MEgawatt TArget:Lead bIsmuth Cooled) target concept was developed following an extensive analysis of existing and new proposed designs and reached the level of proof of principle within only 2 years. ESS selected META:LIC as comparative target option for licensing purposes during the design update phase of ESS. The present work describes the design motivation of META:LIC referring to properties and design features of other targets. Therefore, META:LIC design is an evolutionary target which incorporates the extensive experience of liquid metal targets. The modular LBE (Lead Bismuth Eutectic) target concept with focus on the target module is introduced. Both, a window target option for the start of operation and a windowless option with extended lifetime are foreseen. Thermohydraulic simulations show that adequate window cooling can be realized. The stability of the free surface in the windowless option has been shown. Robust target module instrumentation based on free surface levels and the MEGAPIE experience is proposed for target control. Since the META:LIC concept foresees a horizontal extraction for both moderators and target from the monolith a safety concept based on the SNS and JSNS experience is proposed

  1. Extending the half-life of a fab fragment through generation of a humanized anti-human serum albumin Fv domain: An investigation into the correlation between affinity and serum half-life.

    Science.gov (United States)

    Adams, Ralph; Griffin, Laura; Compson, Joanne E; Jairaj, Mark; Baker, Terry; Ceska, Tom; West, Shauna; Zaccheo, Oliver; Davé, Emma; Lawson, Alastair Dg; Humphreys, David P; Heywood, Sam

    2016-10-01

    We generated an anti-albumin antibody, CA645, to link its Fv domain to an antigen-binding fragment (Fab), thereby extending the serum half-life of the Fab. CA645 was demonstrated to bind human, cynomolgus, and mouse serum albumin with similar affinity (1-7 nM), and to bind human serum albumin (HSA) when it is in complex with common known ligands. Importantly for half-life extension, CA645 binds HSA with similar affinity within the physiologically relevant range of pH 5.0 - pH 7.4, and does not have a deleterious effect on the binding of HSA to neonatal Fc receptor (FcRn). A crystal structure of humanized CA645 Fab in complex with HSA was solved and showed that CA645 Fab binds to domain II of HSA. Superimposition with the crystal structure of FcRn bound to HSA confirmed that CA645 does not block HSA binding to FcRn. In mice, the serum half-life of humanized CA645 Fab is 84.2 h. This is a significant extension in comparison with Fab variant. The Fab-HSA structure was used to design a series of mutants with reduced affinity to investigate the correlation between the affinity for albumin and serum half-life. Reduction in the affinity for MSA by 144-fold from 2.2 nM to 316 nM had no effect on serum half-life. Strikingly, despite a reduction in affinity to 62 µM, an extension in serum half-life of 26.4 h was still obtained. CA645 Fab and the CA645 Fab-HSA complex have been deposited in the Protein Data Bank (PDB) with accession codes, 5FUZ and 5FUO, respectively.

  2. 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).

  3. Re-188 labelling of DD-3B6/22 Fab' monoclonal antibody fragment for radio immuno therapy

    International Nuclear Information System (INIS)

    Schmidt, P.F.; Smith, S.V.; Bundesen, P.

    1996-01-01

    The chemical similarity of technetium and rhenium has created much interest in the nuclear medicine field to make a 'matched pair' of radiopharmaceuticals for radioimmuno- diagnosis and therapy. Clinical trials with the 99 mTc-DD-3B6/22 Fab' has shown promise in the diagnosis of ovarian cancer. The design of the analogous therapeutic agent with rhenium-188 (155 keV γ 15 % abundant, β E max 2.1 MeV, T 1/2 17 h) is under investigation. The present study describes the approach taken for direct radiolabelling of the DD-3B6/22 Fab' with carrier-free 188 Re and its biological evaluation in balb/c and nude mice. The effect of temperature, pH and antibody concentration on the amount and rate of transchelation was also evaluated. The final product had a specific activity of 35 mCi/mg with an immunoreactive fraction of 77%. Stability of the product was assessed under various conditions: temperature, presence and absence of an inert atmosphere and presence of ascorbic acid (stabilised). Pharmacokinetics of the final product was evaluated in balb/c and nude mice transplanted with both D-dimer (+Ve) and Glycine (-Ve) beads. Results show that 188 Re DD-3B6/22 Fab' clears rapidly from the blood (α = 2.4 hr, β = 3.5 hr) and is excreted through the renal system. Localisation to subcutaneous antigen beads shows specific uptake to the D-dimer (antigen) beads was achieved within 6 h (0.23% ID) and was maintained for 24 hour post injection. Specificity to antigen implants was 5:1 (P 99m Tc DD-3B6/22 Fab' in mice. The radiolabelling procedures are congenial for therapeutic levels and hence the authors believe that the 188 Re DD-3B6/22 Fab' has some potential for use in treatment of ovarian cancer

  4. 20 CFR 30.316 - How does the FAB issue a final decision on a claim?

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false How does the FAB issue a final decision on a... Adjudicatory Process Hearings and Final Decisions on Claims § 30.316 How does the FAB issue a final decision on... waives any objections to all or part of the recommended decision, the FAB may issue a final decision...

  5. 21 CFR 866.5520 - Immunoglobulin G (Fab fragment specific) immunological test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Immunoglobulin G (Fab fragment specific... Test Systems § 866.5520 Immunoglobulin G (Fab fragment specific) immunological test system. (a) Identification. An immunoglobulin G (Fab fragment specific) immunological test system is a device that consists...

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

    International Nuclear Information System (INIS)

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

    1982-03-01

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

  7. Novel target design for enhanced laser driven proton acceleration

    Directory of Open Access Journals (Sweden)

    Malay Dalui

    2017-09-01

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

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

    International Nuclear Information System (INIS)

    Latge, Ch.; Laffont, G.; Groeschel, F.; Thomsen, K.; Wagner, W.; Agostini, P.; Dierckx, M.; Fazio, C.; Kirchner, T.; Kurata, Y.; Song, T.; Woloshun, K.

    2006-01-01

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

  9. Changing paradigm from one target one ligand towards multi target directed ligand design for key drug targets of Alzheimer disease: An important role of Insilco methods in multi target directed ligands design.

    Science.gov (United States)

    Kumar, Akhil; Tiwari, Ashish; Sharma, Ashok

    2018-03-15

    Alzheimer disease (AD) is now considered as a multifactorial neurodegenerative disorder and rapidly increasing to an alarming situation and causing higher death rate. One target one ligand hypothesis is not able to provide complete solution of AD due to multifactorial nature of disease and one target one drug seems to fail to provide better treatment against AD. Moreover, current available treatments are limited and most of the upcoming treatments under clinical trials are based on modulating single target. So the current AD drug discovery research shifting towards new approach for better solution that simultaneously modulate more than one targets in the neurodegenerative cascade. This can be achieved by network pharmacology, multi-modal therapies, multifaceted, and/or the more recently proposed term "multi-targeted designed drugs. Drug discovery project is tedious, costly and long term project. Moreover, multi target AD drug discovery added extra challenges such as good binding affinity of ligands for multiple targets, optimal ADME/T properties, no/less off target side effect and crossing of the blood brain barrier. These hurdles may be addressed by insilico methods for efficient solution in less time and cost as computational methods successfully applied to single target drug discovery project. Here we are summarizing some of the most prominent and computationally explored single target against AD and further we discussed successful example of dual or multiple inhibitors for same targets. Moreover we focused on ligand and structure based computational approach to design MTDL against AD. However is not an easy task to balance dual activity in a single molecule but computational approach such as virtual screening docking, QSAR, simulation and free energy are useful in future MTDLs drug discovery alone or in combination with fragment based method. However, rational and logical implementations of computational drug designing methods are capable of assisting AD drug

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

    Directory of Open Access Journals (Sweden)

    Obrey K.

    2013-11-01

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

  11. Membrane Transporters: Structure, Function and Targets for Drug Design

    Science.gov (United States)

    Ravna, Aina W.; Sager, Georg; Dahl, Svein G.; Sylte, Ingebrigt

    Current therapeutic drugs act on four main types of molecular targets: enzymes, receptors, ion channels and transporters, among which a major part (60-70%) are membrane proteins. This review discusses the molecular structures and potential impact of membrane transporter proteins on new drug discovery. The three-dimensional (3D) molecular structure of a protein contains information about the active site and possible ligand binding, and about evolutionary relationships within the protein family. Transporters have a recognition site for a particular substrate, which may be used as a target for drugs inhibiting the transporter or acting as a false substrate. Three groups of transporters have particular interest as drug targets: the major facilitator superfamily, which includes almost 4000 different proteins transporting sugars, polyols, drugs, neurotransmitters, metabolites, amino acids, peptides, organic and inorganic anions and many other substrates; the ATP-binding cassette superfamily, which plays an important role in multidrug resistance in cancer chemotherapy; and the neurotransmitter:sodium symporter family, which includes the molecular targets for some of the most widely used psychotropic drugs. Recent technical advances have increased the number of known 3D structures of membrane transporters, and demonstrated that they form a divergent group of proteins with large conformational flexibility which facilitates transport of the substrate.

  12. Thrombus imaging with indium-111 and iodine-131-labeled fibrin-specific monoclonal antibody and its F(ab')2 and Fab fragments

    International Nuclear Information System (INIS)

    Rosebrough, S.F.; Grossman, Z.D.; McAfee, J.G.

    1988-01-01

    We have previously reported successful imaging of fresh (2-4 hr old) and aged (1-5 days old) canine thrombi with 131 I-labeled intact monoclonal antibody (MAb) specific for fibrin. We now report thrombus imaging with 131 I-labeled F(ab')2 and Fab and 111 In-labeled intact MAb, F(ab')2, and Fab. Indium-111-labeled F(ab')2 proved to be the best imaging agent due to less nonspecific binding in the liver than whole IgG. Image quality was improved by the higher administered dose permissible with 111 In and its better physical characteristics for imaging, compared to 131 I. Immunofluorescence of fresh human histologic sections showed intact MAb and F(ab')2 binding to thrombi, pulmonary emboli, and atherosclerotic plaques, strengthening the feasibility of clinical thrombus imaging

  13. Pollution prevention opportunity assessment for MicroFab and SiFab facilities at Sandia National Laboratories.

    Energy Technology Data Exchange (ETDEWEB)

    Gerard, Morgan Evan

    2011-12-01

    This Pollution Prevention Opportunity Assessment (PPOA) was conducted for the MicroFab and SiFab facilities at Sandia National Laboratories/New Mexico in Fiscal Year 2011. The primary purpose of this PPOA is to provide recommendations to assist organizations in reducing the generation of waste and improving the efficiency of their processes and procedures. This report contains a summary of the information collected, the analyses performed, and recommended options for implementation. The Sandia National Laboratories Environmental Management System (EMS) and Pollution Prevention (P2) staff will continue to work with the organizations to implement the recommendations.

  14. Backward Design: Targeting Depth of Understanding for All Learners

    Science.gov (United States)

    Childre, Amy; Sands, Jennifer R.; Pope, Saundra Tanner

    2009-01-01

    Curriculum design is at the center of developing student ability to construct understanding. Without appropriately designed curriculum, instruction can be ineffective at scaffolding understanding. Often students with disabilities need more explicit instruction or guidance in applying their schema to new information. Thus, instruction must not only…

  15. Direct labelling of monomeric antibody fragments Fab' with 99mTc

    International Nuclear Information System (INIS)

    Li Jun; Wang Shizhen; Yang Ziyi

    1994-01-01

    Direct labelling method and conditions of monomeric antibody Fab' with 99m Tc were investigated. Polyclonal antibody IgG was digested with ficin to produce dimeric fragments F(ab') 2 , which was subsequently reduced to monomeric fragments Fab' with 2-mercaptoethylamine. Finally, Fab' was incubated with sodium gluconate (Sn(II)) kit solution and 99m TcO 4 - eluted at room temperature to form 99m Tc-Fab'. The labelling efficiency was 85%-95%. The stability of labelled products was satisfactory and the elimination rate was faster than 99m Tc-IgG

  16. 20 CFR 30.319 - May a claimant request reconsideration of a final decision of the FAB?

    Science.gov (United States)

    2010-04-01

    ... final decision of the FAB? 30.319 Section 30.319 Employees' Benefits OFFICE OF WORKERS' COMPENSATION... reconsideration of a final decision of the FAB? (a) A claimant may request reconsideration of a final decision of the FAB by filing a written request with the FAB within 30 days from the date of issuance of such...

  17. Seismic design and evaluation criteria based on target performance goals

    International Nuclear Information System (INIS)

    Murray, R.C.; Nelson, T.A.; Kennedy, R.P.; Short, S.A.

    1994-04-01

    The Department of Energy utilizes deterministic seismic design/evaluation criteria developed to achieve probabilistic performance goals. These seismic design and evaluation criteria are intended to apply equally to the design of new facilities and to the evaluation of existing facilities. In addition, the criteria are intended to cover design and evaluation of buildings, equipment, piping, and other structures. Four separate sets of seismic design/evaluation criteria have been presented each with a different performance goal. In all these criteria, earthquake loading is selected from seismic hazard curves on a probabilistic basis but seismic response evaluation methods and acceptable behavior limits are deterministic approaches with which design engineers are familiar. For analytical evaluations, conservatism has been introduced through the use of conservative inelastic demand-capacity ratios combined with ductile detailing requirements, through the use of minimum specified material strengths and conservative code capacity equations, and through the use of a seismic scale factor. For evaluation by testing or by experience data, conservatism has been introduced through the use of an increase scale factor which is applied to the prescribed design/evaluation input motion

  18. 1L Mark-IV Target Design Review

    Energy Technology Data Exchange (ETDEWEB)

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

    2017-11-16

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

  19. Design strategies for self-assembly of discrete targets

    International Nuclear Information System (INIS)

    Madge, Jim; Miller, Mark A.

    2015-01-01

    Both biological and artificial self-assembly processes can take place by a range of different schemes, from the successive addition of identical building blocks to hierarchical sequences of intermediates, all the way to the fully addressable limit in which each component is unique. In this paper, we introduce an idealized model of cubic particles with patterned faces that allows self-assembly strategies to be compared and tested. We consider a simple octameric target, starting with the minimal requirements for successful self-assembly and comparing the benefits and limitations of more sophisticated hierarchical and addressable schemes. Simulations are performed using a hybrid dynamical Monte Carlo protocol that allows self-assembling clusters to rearrange internally while still providing Stokes-Einstein-like diffusion of aggregates of different sizes. Our simulations explicitly capture the thermodynamic, dynamic, and steric challenges typically faced by self-assembly processes, including competition between multiple partially completed structures. Self-assembly pathways are extracted from the simulation trajectories by a fully extendable scheme for identifying structural fragments, which are then assembled into history diagrams for successfully completed target structures. For the simple target, a one-component assembly scheme is most efficient and robust overall, but hierarchical and addressable strategies can have an advantage under some conditions if high yield is a priority

  20. Design of a cone target for fast ignition

    Directory of Open Access Journals (Sweden)

    Sunahara Atsushi

    2013-11-01

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

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

    KAUST Repository

    Jardak, Seifallah

    2014-01-01

    outperformed the phased array radar by providing better parametric identifiability, achieving higher spatial resolution, and designing complex beampatterns. To avoid jamming and enhance the signal to noise ratio, it is often interesting to maximize

  2. Improved Fab presentation on phage surface with the use of molecular chaperone coplasmid system.

    Science.gov (United States)

    Loh, Qiuting; Leong, Siew Wen; Tye, Gee Jun; Choong, Yee Siew; Lim, Theam Soon

    2015-05-15

    The low presentation efficiency of Fab (fragment antigen binding) fragments during phage display is largely due to the complexity of disulphide bond formation. This can result in the presentation of Fab fragments devoid of a light chain during phage display. Here we propose the use of a coplasmid system encoding several molecular chaperones (DsbA, DsbC, FkpA, and SurA) to improve Fab packaging. A comparison was done using the Fab fragment from IgG and IgD. We found that the use of the coplasmid during phage packaging was able to improve the presentation efficiency of the Fab fragment on phage surfaces. A modified version of panning using the coplasmid system was evaluated and was successful at enriching Fab binders. Therefore, the coplasmid system would be an attractive alternative for improved Fab presentation for phage display. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Protein crystallization with microseed matrix screening: application to human germline antibody Fabs

    International Nuclear Information System (INIS)

    Obmolova, Galina; Malia, Thomas J.; Teplyakov, Alexey; Sweet, Raymond W.; Gilliland, Gary L.

    2014-01-01

    The power of microseed matrix screening is demonstrated in the crystallization of a panel of antibody Fab fragments. The crystallization of 16 human antibody Fab fragments constructed from all pairs of four different heavy chains and four different light chains was enabled by employing microseed matrix screening (MMS). In initial screening, diffraction-quality crystals were obtained for only three Fabs, while many Fabs produced hits that required optimization. Application of MMS, using the initial screens and/or refinement screens, resulted in diffraction-quality crystals of these Fabs. Five Fabs that failed to give hits in the initial screen were crystallized by cross-seeding MMS followed by MMS optimization. The crystallization protocols and strategies that resulted in structure determination of all 16 Fabs are presented. These results illustrate the power of MMS and provide a basis for developing future strategies for macromolecular crystallization

  4. Improved radioimaging and tumor localization with monoclonal F(ab')2

    International Nuclear Information System (INIS)

    Wahl, R.L.; Parker, C.W.; Philpott, G.W.

    1983-01-01

    Monoclonal anti-tumor antibodies have great promise for radioimmunodetection and localization of tumors. Fab and F(ab')2 fragments, which lack the Fc fragment of antibody (Ab), are cleared more rapidly from the circulation and may have less nonspecific tissue binding than intact Ab. In radioimaging studies using a murine monoclonal antibody to carcinoembryonic antigen in a human colon carcinoma xenografted into hamsters, F(ab')2 fragments were shown superior to Fab fragments and intact antibody for scintiscanning. In double-label experiments with anti-CEA antibody and control monoclonal IgG, F(ab')2 fragments were found to give better and more rapid specific tumor localization than intact antibody or Fab fragments. F(ab')2 fragments offer significant promise for tumor imaging and possibly therapy

  5. Opening the Arms: The FAB Projects and Digital Resilience

    Science.gov (United States)

    Longden, Alison; Monaghan, Tom; Mycroft, Lou; Kelly, Claire

    2018-01-01

    A chance observation in a staff training session led to a series of action research projects, which dug into why some educators are digitally resistant whilst others, however experienced, are not. The Education and Training Foundation-funded "FAB Projects" have so far spanned three years and three small-scale research investigations and…

  6. Scatterometry on pelliclized masks: an option for wafer fabs

    Science.gov (United States)

    Gallagher, Emily; Benson, Craig; Higuchi, Masaru; Okumoto, Yasuhiro; Kwon, Michael; Yedur, Sanjay; Li, Shifang; Lee, Sangbong; Tabet, Milad

    2007-03-01

    Optical scatterometry-based metrology is now widely used in wafer fabs for lithography, etch, and CMP applications. This acceptance of a new metrology method occurred despite the abundance of wellestablished CD-SEM and AFM methods. It was driven by the desire to make measurements faster and with a lower cost of ownership. Over the last year, scatterometry has also been introduced in advanced mask shops for mask measurements. Binary and phase shift masks have been successfully measured at all desired points during photomask production before the pellicle is mounted. There is a significant benefit to measuring masks with the pellicle in place. From the wafer fab's perspective, through-pellicle metrology would verify mask effects on the same features that are characterized on wafer. On-site mask verification would enable quality control and trouble-shooting without returning the mask to a mask house. Another potential application is monitoring changes to mask films once the mask has been delivered to the fab (haze, oxide growth, etc.). Similar opportunities apply to the mask metrologist receiving line returns from a wafer fab. The ability to make line-return measurements without risking defect introduction is clearly attractive. This paper will evaluate the feasibility of collecting scatterometry data on pelliclized masks. We explore the effects of several different pellicle types on scatterometry measurements made with broadband light in the range of 320-780 nm. The complexity introduced by the pellicles' optical behavior will be studied.

  7. Mechanism of immunoglobulin G4 Fab-arm exchange

    NARCIS (Netherlands)

    Rispens, Theo; Ooijevaar-de Heer, Pleuni; Bende, Onno; Aalberse, Rob C.

    2011-01-01

    Immunoglobulin G (IgG) antibodies are symmetrical molecules that may be regarded as covalent dimers of 2 half-molecules, each consisting of a light chain and a heavy chain. Human IgG4 is an unusually dynamic antibody, with half-molecule exchange ("Fab-arm exchange") resulting in asymmetrical,

  8. National Ignition Facility subsystem design requirements target diagnostics subsystem SSDR 1.8.3

    International Nuclear Information System (INIS)

    Lee, D.

    1996-01-01

    This SSDR establishes the performance, design, development and test requirements for the Target Experimental System's Diagnostic, WBS 1.8. 3. This includes the individual diagnostic components, the Target Diagnostic Data Acquisition System (Target DAS), the diagnostic vacuum system, the timing/fiducial system, and the EMI protection system

  9. RNAblueprint: flexible multiple target nucleic acid sequence design.

    Science.gov (United States)

    Hammer, Stefan; Tschiatschek, Birgit; Flamm, Christoph; Hofacker, Ivo L; Findeiß, Sven

    2017-09-15

    Realizing the value of synthetic biology in biotechnology and medicine requires the design of molecules with specialized functions. Due to its close structure to function relationship, and the availability of good structure prediction methods and energy models, RNA is perfectly suited to be synthetically engineered with predefined properties. However, currently available RNA design tools cannot be easily adapted to accommodate new design specifications. Furthermore, complicated sampling and optimization methods are often developed to suit a specific RNA design goal, adding to their inflexibility. We developed a C ++  library implementing a graph coloring approach to stochastically sample sequences compatible with structural and sequence constraints from the typically very large solution space. The approach allows to specify and explore the solution space in a well defined way. Our library also guarantees uniform sampling, which makes optimization runs performant by not only avoiding re-evaluation of already found solutions, but also by raising the probability of finding better solutions for long optimization runs. We show that our software can be combined with any other software package to allow diverse RNA design applications. Scripting interfaces allow the easy adaption of existing code to accommodate new scenarios, making the whole design process very flexible. We implemented example design approaches written in Python to demonstrate these advantages. RNAblueprint , Python implementations and benchmark datasets are available at github: https://github.com/ViennaRNA . s.hammer@univie.ac.at, ivo@tbi.univie.ac.at or sven@tbi.univie.ac.at. Supplementary data are available at Bioinformatics online. © The Author(s) 2017. Published by Oxford University Press.

  10. TRPV1: A Target for Rational Drug Design

    Directory of Open Access Journals (Sweden)

    Vincenzo Carnevale

    2016-08-01

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

  11. Flat cladding and pellets in the design of an irradiation target

    International Nuclear Information System (INIS)

    Yorio, Daniel; Denis, Alicia C.; Soba, Alejandro; Beuter, Oscar; Marajofsky, Adolfo

    2003-01-01

    The design of an enriched uranium irradiation target made of flat pellets and cladding is proposed in order to improve the fission Mo 99 production. The variation range of each one of the parameters is studied and the basic design of the target is given

  12. High gain direct drive target designs and supporting experiments with KrF

    International Nuclear Information System (INIS)

    Karasik, Max; Bates, Jason W.; Aglitskiy, Yefim

    2013-01-01

    Krypton-fluoride laser is an attractive inertial fusion energy driver from the standpoint of target physics. Target designs taking advantage of zooming, shock ignition, and favorable physics with KrF reach energy gains of 200 with sub-MJ laser energy. The designs are robust under 2D simulations. Experiments on the Nike KrF laser support the physics basis. (author)

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

    Science.gov (United States)

    Li, Benjamin; Xu, Deyin

    2001-10-01

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

  14. In silico design of targeted SRM-based experiments

    Directory of Open Access Journals (Sweden)

    Nahnsen Sven

    2012-11-01

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

  15. Representing Targets of Measurement within Evidence-Centered Design

    Science.gov (United States)

    Ewing, Maureen; Packman, Sheryl; Hamen, Cynthia; Thurber, Allison Clark

    2010-01-01

    In the last few years, the Advanced Placement (AP) Program[R] has used evidence-centered assessment design (ECD) to articulate the knowledge, skills, and abilities to be taught in the course and measured on the summative exam for four science courses, three history courses, and six world language courses; its application to calculus and English…

  16. Experimental study of liquid-metal target designs of accelerating-controlled systems

    International Nuclear Information System (INIS)

    Iarmonov, Mikhail; Makhov, Kirill; Novozhilova, Olga; Meluzov, A.G.; Beznosov, A.V.

    2011-01-01

    Models of a liquid-metal target of an accelerator-controlled system have been experimentally studied at the Nizhny Novgorod State Technical University to develop an optimal design of the flow part of the target. The main explored variants of liquid-metal targets are: Design with a diaphragm (firm-and-impervious plug) mounted on the pipe tap of particle transport from the accelerator cavity to the working cavity of the liquid-metal target. Design without a diaphragm on the pipe tab of particle transport from the accelerator. The study was carried out in a high-temperature liquid-metal test bench under the conditions close to full-scale ones: the temperature of the eutectic lead-bismuth alloy was 260degC - 400degC, the coolant mass flow was 5-80 t/h, and the rarefaction in the gas cavity was 10 5 Pa, the coefficient of geometric similarity equal to 1. The experimental studies of hydrodynamic characteristics of flow parts in the designs of targets under full-scale conditions indicated high efficiency of a target in triggering, operating, and deactivating modes. Research and technology instructions for designs of the flow part of the liquid-metal target, the target design as a whole, and the target circuit of accelerator-controlled systems were formulated as a result of the studies. (author)

  17. Dual Constant Domain-Fab: A novel strategy to improve half-life and potency of a Met therapeutic antibody.

    Science.gov (United States)

    Cignetto, Simona; Modica, Chiara; Chiriaco, Cristina; Fontani, Lara; Milla, Paola; Michieli, Paolo; Comoglio, Paolo M; Vigna, Elisa

    2016-06-01

    The kinase receptor encoded by the Met oncogene is a sensible target for cancer therapy. The chimeric monovalent Fab fragment of the DN30 monoclonal antibody (MvDN30) has an odd mechanism of action, based on cell surface removal of Met via activation of specific plasma membrane proteases. However, the short half-life of the Fab, due to its low molecular weight, is a severe limitation for the deployment in therapy. This issue was addressed by increasing the Fab molecular weight above the glomerular filtration threshold through the duplication of the constant domains, in tandem (DCD-1) or reciprocally swapped (DCD-2). The two newly engineered molecules showed biochemical properties comparable to the original MvDN30 in vitro, acting as full Met antagonists, impairing Met phosphorylation and activation of downstream signaling pathways. As a consequence, Met-mediated biological responses were inhibited, including anchorage-dependent and -independent cell growth. In vivo DCD-1 and DCD-2 showed a pharmacokinetic profile significantly improved over the original MvDN30, doubling the circulating half-life and reducing the clearance. In pre-clinical models of cancer, generated by injection of tumor cells or implant of patient-derived samples, systemic administration of the engineered molecules inhibited the growth of Met-addicted tumors. Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  18. Activation of Exogenous Fatty Acids to Acyl-Acyl Carrier Protein Cannot Bypass FabI Inhibition in Neisseria*

    Science.gov (United States)

    Yao, Jiangwei; Bruhn, David F.; Frank, Matthew W.; Lee, Richard E.; Rock, Charles O.

    2016-01-01

    Neisseria is a Gram-negative pathogen with phospholipids composed of straight chain saturated and monounsaturated fatty acids, the ability to incorporate exogenous fatty acids, and lipopolysaccharides that are not essential. The FabI inhibitor, AFN-1252, was deployed as a chemical biology tool to determine whether Neisseria can bypass the inhibition of fatty acid synthesis by incorporating exogenous fatty acids. Neisseria encodes a functional FabI that was potently inhibited by AFN-1252. AFN-1252 caused a dose-dependent inhibition of fatty acid synthesis in growing Neisseria, a delayed inhibition of growth phenotype, and minimal inhibition of DNA, RNA, and protein synthesis, showing that its mode of action is through inhibiting fatty acid synthesis. Isotopic fatty acid labeling experiments showed that Neisseria encodes the ability to incorporate exogenous fatty acids into its phospholipids by an acyl-acyl carrier protein-dependent pathway. However, AFN-1252 remained an effective antibacterial when Neisseria were supplemented with exogenous fatty acids. These results demonstrate that extracellular fatty acids are activated by an acyl-acyl carrier protein synthetase (AasN) and validate type II fatty acid synthesis (FabI) as a therapeutic target against Neisseria. PMID:26567338

  19. Fab-based inhibitors reveal ubiquitin independent functions for HIV Vif neutralization of APOBEC3 restriction factors.

    Directory of Open Access Journals (Sweden)

    Jennifer M Binning

    2018-01-01

    Full Text Available The lentiviral protein Viral Infectivity Factor (Vif counteracts the antiviral effects of host APOBEC3 (A3 proteins and contributes to persistent HIV infection. Vif targets A3 restriction factors for ubiquitination and proteasomal degradation by recruiting them to a multi-protein ubiquitin E3 ligase complex. Here, we describe a degradation-independent mechanism of Vif-mediated antagonism that was revealed through detailed structure-function studies of antibody antigen-binding fragments (Fabs to the Vif complex. Two Fabs were found to inhibit Vif-mediated A3 neutralization through distinct mechanisms: shielding A3 from ubiquitin transfer and blocking Vif E3 assembly. Combined biochemical, cell biological and structural studies reveal that disruption of Vif E3 assembly inhibited A3 ubiquitination but was not sufficient to restore its packaging into viral particles and antiviral activity. These observations establish that Vif can neutralize A3 family members in a degradation-independent manner. Additionally, this work highlights the potential of Fabs as functional probes, and illuminates how Vif uses a multi-pronged approach involving both degradation dependent and independent mechanisms to suppress A3 innate immunity.

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

    DEFF Research Database (Denmark)

    Heller, Alfred; Gianniou, Panagiota; Katsigiannis, Emmanouil

    2014-01-01

    that there are exposed solutions where synergy effects arise that unleash extra saving potentials. Based on the insight gained by the simulations, IT intelligence and cross-component communication are to be invented to control the components and hereby to optimize the total system performance. One main strategy in doing......Designing cities from an overall energy optimization system point of view, demands changes in engineering procedures. Traditionally the design was driven independently between the involved domains and energy system components. By modelling the whole energy system in one, it is expected...... so is, to move demands from high demand periods to low demand periods and hereby to avoid “peak” demands. This is called “flexibility” within the terminology of “smart grids”. In early solutions the search was for energy capacities within the domain of the electrical grid, hence car batteries where...

  1. Designing decision support tools for targeted N-regulation

    DEFF Research Database (Denmark)

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

    2017-01-01

    data model for land use data – the dNmark landscape model. Based on input data which is corrected and edited by workshop participants, the tool estimates the effect of potential land use scenarios on nutrient emissions. The tool was tested in 5 scenario workshops in case areas in Denmark in 2016...... in Denmark to develop and improve a functioning decision support tool for landscape scale N-management. The aim of the study is to evaluate how a decision support tool can best be designed in order to enable landscape scale strategic N-management practices. Methods: A prototype GIS-tool for capturing......, storing, editing, displaying and modelling landscape scale farming practices and associated emission consequences was developed. The tool was designed to integrate locally held knowledge with national scale datasets in live scenario situations through the implementation of a flexible, uniform and editable...

  2. Lumican Peptides: Rational Design Targeting ALK5/TGFBRI

    Science.gov (United States)

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

    2017-02-01

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

  3. A fully synthetic human Fab antibody library based on fixed VH/VL framework pairings with favorable biophysical properties

    Science.gov (United States)

    Tiller, Thomas; Schuster, Ingrid; Deppe, Dorothée; Siegers, Katja; Strohner, Ralf; Herrmann, Tanja; Berenguer, Marion; Poujol, Dominique; Stehle, Jennifer; Stark, Yvonne; Heßling, Martin; Daubert, Daniela; Felderer, Karin; Kaden, Stefan; Kölln, Johanna; Enzelberger, Markus; Urlinger, Stefanie

    2013-01-01

    This report describes the design, generation and testing of Ylanthia, a fully synthetic human Fab antibody library with 1.3E+11 clones. Ylanthia comprises 36 fixed immunoglobulin (Ig) variable heavy (VH)/variable light (VL) chain pairs, which cover a broad range of canonical complementarity-determining region (CDR) structures. The variable Ig heavy and Ig light (VH/VL) chain pairs were selected for biophysical characteristics favorable to manufacturing and development. The selection process included multiple parameters, e.g., assessment of protein expression yield, thermal stability and aggregation propensity in fragment antigen binding (Fab) and IgG1 formats, and relative Fab display rate on phage. The framework regions are fixed and the diversified CDRs were designed based on a systematic analysis of a large set of rearranged human antibody sequences. Care was taken to minimize the occurrence of potential posttranslational modification sites within the CDRs. Phage selection was performed against various antigens and unique antibodies with excellent biophysical properties were isolated. Our results confirm that quality can be built into an antibody library by prudent selection of unmodified, fully human VH/VL pairs as scaffolds. PMID:23571156

  4. TARGETED SEQUENTIAL DESIGN FOR TARGETED LEARNING INFERENCE OF THE OPTIMAL TREATMENT RULE AND ITS MEAN REWARD.

    Science.gov (United States)

    Chambaz, Antoine; Zheng, Wenjing; van der Laan, Mark J

    2017-01-01

    This article studies the targeted sequential inference of an optimal treatment rule (TR) and its mean reward in the non-exceptional case, i.e. , assuming that there is no stratum of the baseline covariates where treatment is neither beneficial nor harmful, and under a companion margin assumption. Our pivotal estimator, whose definition hinges on the targeted minimum loss estimation (TMLE) principle, actually infers the mean reward under the current estimate of the optimal TR. This data-adaptive statistical parameter is worthy of interest on its own. Our main result is a central limit theorem which enables the construction of confidence intervals on both mean rewards under the current estimate of the optimal TR and under the optimal TR itself. The asymptotic variance of the estimator takes the form of the variance of an efficient influence curve at a limiting distribution, allowing to discuss the efficiency of inference. As a by product, we also derive confidence intervals on two cumulated pseudo-regrets, a key notion in the study of bandits problems. A simulation study illustrates the procedure. One of the corner-stones of the theoretical study is a new maximal inequality for martingales with respect to the uniform entropy integral.

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

    International Nuclear Information System (INIS)

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

    1978-01-01

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

  6. Conceptual design considerations and neutronics of lithium fall laser target chambers

    International Nuclear Information System (INIS)

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

    1978-01-01

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

  7. NIF target area design support. Final summary report

    International Nuclear Information System (INIS)

    Tokheim, R.E.; Seaman, L.; Curran, D.R.

    1996-02-01

    SRI International continued support work for the National Ignition Facility, Chamber Dynamics Group at Lawrence Livermore National Laboratory (LLNL). The work entailed computational modeling of shrapnel and debris generation from copper shine shields, hohlraum, and stainless steel cryogenic support tubes for 1.8 MJ and 1.0 MJ no-yield and 20 MJ yield shots. Also, the authors addressed the effects of shrapnel at the first wall. Computations for 1.8 MJ showed an ionized gold hohlraum, but about half solid and half ionized copper shine shields, when material cell phase boundaries were maintained. This debris generation represents a potential threat to the first wall and debris shields. Further work is required to translate these results into particle size distributions based on computed strain rates. The authors used simple algorithms for x-ray loading of frost layers protecting the target support to compute peak stress attenuation. They developed algorithmic formulas for predicting damage in candidate first wall materials and they found damage algorithms for fused-silica debris shield material. They obtained very preliminary computational results at 20 MJ for predicting shrapnel mass and particle density at the first wall in spherical polar coordinate space with the hohlraum axis as the polar direction

  8. Conceptual design of the handling and storage system for spent target vessel

    Energy Technology Data Exchange (ETDEWEB)

    Adachi, Junichi; Sasaki, Shinobu; Kaminaga, Masanori; Hino, Ryutaro [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment

    2001-03-01

    A conceptual design of a handling and storage system for spent target vessels has been carried out, in order to establish spent target technology for the neutron scattering facility. The spent target vessels must be treated remotely with high reliability and safety, since they are highly activated and contain the poisonous mercury. The system is composed of a target exchange trolley to exchange the target vessel, remote handling equipment such as manipulators, airtight casks for the spent target vessel, storage pits and so on. This report presents the results of conceptual design study on a basic plan, a handling procedure, main devices and their arrangement of a handling and storage system for the spent target vessels. (author)

  9. Design and features of the target tracker of the Opera's target: study of the electron channel events

    International Nuclear Information System (INIS)

    Chon-Sen, N.

    2009-01-01

    Neutrino oscillations are now well acknowledged, the purpose of the Opera experiment is to show how ν τ appear in a ν μ beam. The ν μ beam is produced at CERN and crosses the earth crust on a distance of 732 km before being detected in the Gran-Sasso underground laboratory. The Opera experiment uses the technique of the photographic emulsion. The detector target is a series of walls of lead bricks, each brick being made of photographic emulsions intercalated with lead sheets. A target tracker enables the localization of the brick in which the neutrino interaction has happened. As soon as the brick is found, the brick is removed from the detector and the emulsion is developed and analysed. the target tracker is made up of plastic scintillator bars on which optic fibers are stuck to collect photons and send them to photomultipliers. The main purpose of this work is the calibration of the target tracker. The first chapter introduces the standard model, the neutrino and the neutrino oscillation phenomenon. The second chapter reviews the neutrino experiments worldwide. The third chapter describes the Opera experiment while chapter 4 and 5 are dedicated to the design and operation of the target tracker. The last chapter studies through simulation the behaviour of the target tracker when submitted to an electron beam in order to use it as a complementary tool for the identification of the τ → e channel. (A.C.)

  10. Introduction of a glycosylation site in the constant region decreases the aggregation of adalimumab Fab.

    Science.gov (United States)

    Nakamura, Hitomi; Oda-Ueda, Naoko; Ueda, Tadashi; Ohkuri, Takatoshi

    2018-06-18

    The production of therapeutic monoclonal antibodies is costly; therefore, antigen-binding fragments (Fabs) can be used instead. However, their tendency toward aggregation can reduce the half-life in the plasma and the therapeutic effectiveness. To examine the effect of glycosylation on the properties of the Fab of a therapeutic antibody, an N-glycosylation site was introduced at position 178 of the H-chain constant region of adalimumab Fab through site-directed mutagenesis of L178 N (H:L178 N Fab), and then H:L178 N Fab was expressed in Pichia pastoris. SDS-PAGE analysis with treatment of N-glycosidase F or periodic acid-Schiff reagent showed that H:L178 N Fab contained a relatively low glycan level. Moreover, the H:L178 N mutation did not decrease the binding activity and thermal stability of Fab, and H:L178 N Fab was more resistant to protease digestion than wild-type Fab. The aggregation of Fab induced by pH-shift stress was measured by monitoring the optical density at 350 nm. Although the wild-type Fab showed a large increase in optical density with an increase of protein concentration, no such increase of turbidity during aggregation was found in H:L178 N Fab. These results demonstrated that glycosylation at position 178 of the H-chain constant region of adalimumab Fab can prevent protein aggregation, and therefore serve as a potentially effective platform for drug development. Copyright © 2018. Published by Elsevier Inc.

  11. Target station design for a 1 MW pulsed spallation neutron source

    International Nuclear Information System (INIS)

    Russell, G.J.; Baker, G.D.; Brewton, R.J.

    1993-01-01

    Target stations are vital components of the 1 MW, next generation spallation neutron source proposed for LANSCE. By and large, target stations design determines the overall performance of the facility. Many traditional concepts will probably have to be rethought, and many new concepts will have to be put forward to meet the 1 MW challenge. This article gives a brief overview of the proposed neutron spallation source from the target station viewpoint, as well as the general philosophy adopted for the design of the LANSCE-II target stations. Some of the saliant concepts and features envisioned for LANSCE-II are briefly described

  12. Safety and environmental requirements and design targets for TIBER-II

    International Nuclear Information System (INIS)

    Piet, S.J.

    1987-09-01

    A consistent set of safety and environmental requirements and design targets was proposed and adopted for the TIBER-II (Tokamak Ignition/Burn Experimental Reactor) design effort. TIBER-II is the most recent US version of a fusion experimental test reactor (ETR). These safety and environmental design targets were one contribution of the Fusion Safety Program in the TIBER-II design effort. The other contribution, safety analyses, is documented in the TIBER-II design report. The TIBER-II approach, described here, concentrated on logical development of, first, a complete and consistent set of safety and environmental requirements that are likely appropriate for an ETR, and, second, an initial set of design targets to guide TIBER-II. Because of limited time in the TIBER-II design effort, the iterative process only included one iteration - one set of targets and one design. Future ETR design efforts should therefore build on these design targets and the associated safety analyses. 29 refs., 5 figs., 3 tabs

  13. Evaluation of strategies to control Fab light chain dimer during mammalian expression and purification: A universal one-step process for purification of correctly assembled Fab.

    Science.gov (United States)

    Spooner, Jennifer; Keen, Jenny; Nayyar, Kalpana; Birkett, Neil; Bond, Nicholas; Bannister, David; Tigue, Natalie; Higazi, Daniel; Kemp, Benjamin; Vaughan, Tristan; Kippen, Alistair; Buchanan, Andrew

    2015-07-01

    Fabs are an important class of antibody fragment as both research reagents and therapeutic agents. There are a plethora of methods described for their recombinant expression and purification. However, these do not address the issue of excessive light chain production that forms light chain dimers nor do they describe a universal purification strategy. Light chain dimer impurities and the absence of a universal Fab purification strategy present persistent challenges for biotechnology applications using Fabs, particularly around the need for bespoke purification strategies. This study describes methods to address light chain dimer formation during Fab expression and identifies a novel CH 1 affinity resin as a simple and efficient one-step purification for correctly assembled Fab. © 2015 Wiley Periodicals, Inc.

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

    Science.gov (United States)

    Lim, Brian Y.

    1991-01-01

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

  15. A Fab fragment directed against the neural cell adhesion molecule L1 enhances functional recovery after injury of the adult mouse spinal cord.

    Science.gov (United States)

    Loers, Gabriele; Cui, Yi-Fang; Neumaier, Irmgard; Schachner, Melitta; Skerra, Arne

    2014-06-15

    Lack of permissive mechanisms and abundance of inhibitory molecules in the lesioned central nervous system of adult mammals contribute to the failure of functional recovery, which leads to severe disabilities in motor functions or pain. Previous studies have indicated that the neural cell adhesion molecule L1 constitutes a viable target to promote regeneration. In the present study, we describe the cloning, functional expression in Escherichia coli cells and purification of a recombinant αL1 Fab fragment that binds to L1 with comparable activity as the function-triggering monoclonal antibody 557.B6 and induces neurite outgrowth and neuronal survival in cultured neurons, despite its monovalent function. Infusion of αL1 Fab into the lesioned spinal cord of mice enhanced functional recovery after thoracic spinal cord compression injury. αL1 Fab treatment resulted in reduced scar volume, enhanced number of tyrosine hydroxylase-positive axons and increased linear density of VGLUT1 (vesicular glutamate transporter 1) on motoneurons. Furthermore, the number and soma size of ChAT (choline acetyltransferase)-positive motoneurons and the linear density of ChAT-positive boutons on motoneurons as well as parvalbumin-positive interneurons in the lumbar spinal cord were elevated. Stimulation of endogenous L1 by application of the αL1 Fab opens new avenues for recombinant antibody technology, offering prospects for therapeutic applications after traumatic nervous system lesions.

  16. Conceptual design of a high current ISOL target area at TRIUMF

    International Nuclear Information System (INIS)

    Beveridge, J.L.; Buchmann, L.; Clark, G.S.; Sprenger, H.; Thorson, I.; Vincent, J.; D'Auria, J.M.; Dombsky, M.

    1993-05-01

    Two similar conceptual designs for the handling of highly activated components at the target area of a high current radioactive beam facility have been investigated. The proposed designs are sufficiently flexible that practical detailed designs could be realized. Personnel exposure to radiation during the handling procedures is expected to be minimal. (author) 3 refs., 4 figs

  17. Target designs for the Brookhaven National Laboratory 5-MW pulsed spallation neutron source

    International Nuclear Information System (INIS)

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

    1996-01-01

    A feasibility study of a compact high power density target for a spallation neutron source was under-taken. The target arrangement consists primarily of heavy metal, with appropriate cooling passages. A high intensity proton beam of intermediate energy is directed at the target, where it interacts with the heavy metal nuclei. The subsequent spallation reactions produce several neutrons per proton resulting in an intense neutron source. The proton beam is assumed to havean energy of 5 MW, and to be cyclic with a repetition rate of 10Hz and 50Hz. The study was divided into two broad sections. First, an analysis of preliminary target designs was undertaken to ensure the overall feasibility of the concepts involved in the design and eventual construction of such a high power density target. Second, two proposed target designs, based on the first set of analyses, are investigated in more detail. Special care is taken to ensure that the neutron fluxes in the moderator are at the desired level no material compatibility problems exist,and the target is able to operate in a reliable and safe manner. Several target materials, coolant types, and target arrangements are investigated in the first section. The second section concentrates on a single target material and geometric arrangement. However, several structural material choices continue to be investigated with the aim of minimizing the effects of structural heating, and associated thermally induced stresses. In the final section the conclusions of this preliminary study are summarized

  18. Immobilization and functional reconstitution of antibody Fab fragment by solid-phase refolding.

    Science.gov (United States)

    Kumada, Yoichi; Hamasaki, Kyoto; Nakagawa, Aya; Sasaki, Eiju; Shirai, Tatsunori; Okumura, Masahiro; Inoue, Manami; Kishimoto, Michimasa

    2013-12-31

    In this study, we demonstrated the successful preparation of a Fab antibody-immobilized hydrophilic polystyrene (phi-PS) plate via one- and two-step solid-phase refolding methods. Both polystyrene-binding peptide (PS-tag)-fused Fd fragment of heavy chain (Fab H-PS) and full-length of light-chain (Fab L-PS) were individually produced in insoluble fractions of Escherichia coli cells, and they were highly purified in the presence of 8M of urea. Antigen-binding activities of Fab antibody immobilized were correctly recovered by the one-step solid-phase refolding method that a mixture of Fab H-PS and Fab L-PS was immobilized in the presence of 0.5-2M urea, followed by surface washing of the phi-PS plate with PBST. These results indicate that by genetic fusion of a PS-tag, a complex between Fab H and Fab L was efficiently immobilized on the surface of a phi-PS plate even in the presence of a low concentration of urea, and was then correctly refolded to retain its high antigen-binding activity via removal of the urea. A two-step solid-phase refolding method whereby Fab H-PS and Fab L-PS were successively refolded on the surface of a phi-PS plate also resulted in Fab antibody formation on the plate. Furthermore, both the binding affinity and the specificity of the Fab antibody produced by the two-step method were highly maintained, according to the results of sandwich ELISA and competitive ELISA using Fab antibody-immobilized plate via two-step solid-phase refolding. Thus, the solid-phase refolding method demonstrated in this study should be quite useful for the preparation of a Fab antibody-immobilized PS surface with high efficiency from individually produced Fab H-PS and Fab L-PS. This method will be applicable to the preparation of a large Fab antibody library on the surface of a PS plate for use in antibody screening. © 2013. Published by Elsevier B.V. All rights reserved.

  19. A pilot pharmacokinetic study of tricyclic antidepressant ovine Fab for TCA poisoning in children.

    Science.gov (United States)

    Yalindağ-Oztürk, Nilüfer; Goto, Collin S; Shepherd, Greene; Torres, Olivia Nayeli; Giroir, Brett

    2010-06-01

    A pilot study of tricyclic antidepressant (TCA)-specific antibody fragments (TCA Fab) in TCA-intoxicated adults showed a marked increase in serum total TCA concentrations following TCA Fab infusion with no worsening signs of TCA toxicity. TCA Fab pharmacokinetics (PK) was not described in this adult study. The objective of this study was to evaluate the PK of TCA Fab in children with TCA poisoning. This was an open-label, single-center, dose escalation pilot trial of three patients. Inclusion criteria were documented TCA ingestion with at least one serious complication (QRS prolongation, dysrhythmia, hypotension, seizure, or coma). Patients were assigned to either a low-dose intravenous TCA Fab regimen (15, 30, and 60 mg/kg) or a high-dose regimen (30, 60, and 120 mg/kg) as needed to reverse TCA toxicity. Following the administration of TCA Fab, samples of blood and urine were obtained for PK evaluations. The outcomes of interest were serum and urine TCA concentrations (free and total), serum and urine Fab concentrations, improvement or worsening of TCA toxicity, and adverse effects. Three study patients were 11, 11, and 14 years of age. Two patients received 15 mg/kg of TCA Fab and one patient received a total of 90 mg/kg of TCA Fab (30 + 60 mg/kg). Serum-bound TCA increased significantly following TCA Fab administration with concomitant enhanced urinary elimination. Serum-free TCA concentrations were minimal to undetectable. Fab data were available for two patients. The serum TCA Fab area under the curve was 306.12 mg/L/h for the 15 mg/kg dose and 2,198.10 mg/L/h for the 90 mg/kg dose of TCA Fab. Maximum Fab concentrations correlated with maximum bound TCA in serum. The volume of distribution (V(D)) of TCA Fab was 0.2-0.3 L/kg. The clearance was 0.036-0.05 L/kg/h and the elimination half-life was 4 h. No adverse effects were observed. The limited PK data from this study are consistent with binding of TCA to TCA Fab and redistribution of TCA from the tissue to

  20. Design of a tripartite network for the prediction of drug targets

    Science.gov (United States)

    Kunimoto, Ryo; Bajorath, Jürgen

    2018-02-01

    Drug-target networks have aided in many target prediction studies aiming at drug repurposing or the analysis of side effects. Conventional drug-target networks are bipartite. They contain two different types of nodes representing drugs and targets, respectively, and edges indicating pairwise drug-target interactions. In this work, we introduce a tripartite network consisting of drugs, other bioactive compounds, and targets from different sources. On the basis of analog relationships captured in the network and so-called neighbor targets of drugs, new drug targets can be inferred. The tripartite network was found to have a stable structure and simulated network growth was accompanied by a steady increase in assortativity, reflecting increasing correlation between degrees of connected nodes leading to even network connectivity. Local drug environments in the tripartite network typically contained neighbor targets and revealed interesting drug-compound-target relationships for further analysis. Candidate targets were prioritized. The tripartite network design extends standard drug-target networks and provides additional opportunities for drug target prediction.

  1. Translating Genetic Research into Preventive Intervention: The Baseline Target Moderated Mediator Design.

    Science.gov (United States)

    Howe, George W; Beach, Steven R H; Brody, Gene H; Wyman, Peter A

    2015-01-01

    In this paper we present and discuss a novel research approach, the baseline target moderated mediation (BTMM) design, that holds substantial promise for advancing our understanding of how genetic research can inform prevention research. We first discuss how genetically informed research on developmental psychopathology can be used to identify potential intervention targets. We then describe the BTMM design, which employs moderated mediation within a longitudinal study to test whether baseline levels of intervention targets moderate the impact of the intervention on change in that target, and whether change in those targets mediates causal impact of preventive or treatment interventions on distal health outcomes. We next discuss how genetically informed BTMM designs can be applied to both microtrials and full-scale prevention trials. We use simulated data to illustrate a BTMM, and end with a discussion of some of the advantages and limitations of this approach.

  2. Translating genetic research into preventive intervention: The baseline target moderated mediator design

    Directory of Open Access Journals (Sweden)

    George W. Howe

    2016-01-01

    Full Text Available In this paper we present and discuss a novel research approach, the baseline target moderated mediation (BTMM design, that holds substantial promise for advancing our understanding of how genetic research can inform prevention research. We first discuss how genetically informed research on developmental psychopathology can be used to identify potential intervention targets. We then describe the BTMM design, which employs moderated mediation within a longitudinal study to test whether baseline levels of intervention targets moderate the impact of the intervention on change in that target, and whether change in those targets mediates causal impact of preventive or treatment interventions on distal health outcomes. We next discuss how genetically informed BTMM designs can be applied to both microtrials and full-scale prevention trials. We end with a discussion of some of the advantages and limitations of this approach.

  3. 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...

  4. Directions for reactor target design based on the US heavy ion fusion systems assessment

    International Nuclear Information System (INIS)

    Wilson, D.C.; Dudziak, D.; Magelssen, G.; Zuckerman, D.; Dreimeyer, D.

    1986-01-01

    We studied areas of major uncertainty in target design using the cost of electricity as our figure of merit. Net electric power from the plant was fixed at 1000 MW to eliminate large effects due to economies of scale. The system is relatively insensitive to target gain. Factors of three changes in gain cause only 8 to 12% changes in electricity cost. An increase in the peak power needed to drive targets poses only a small cost risk, but requires many more beamlets be transported to the target. A shortening of the required ion range causes both cost and beamlet difficulties. A factor of 4 decrease in the required range at a fixed driver energy increases electricity cost by 44% and raises the number of beamlets to 240. Finally, the heavy ion fusion system can accommodate large increases in target costs. To address the major uncertainties, target design should concentrate on the understanding requirements for ion range and peak driver power

  5. National Ignition Facility subsystem design requirements target area auxiliary subsystem SSDR 1.8.6

    International Nuclear Information System (INIS)

    Reitz, T.

    1996-01-01

    This Subsystem Design Requirement (SSDR) establishes the performance, design, development, and test requirements for the Target Area Auxiliary Subsystems (WBS 1.8.6), which is part of the NIF Target Experimental System (WBS 1.8). This document responds directly to the requirements detailed in NIF Target Experimental System SDR 003 document. Key elements of the Target Area Auxiliary Subsystems include: WBS 1.8.6.1 Local Utility Services; WBS 1.8.6.2 Cable Trays; WBS 1.8.6.3 Personnel, Safety, and Occupational Access; WBS 1.8.6.4 Assembly, Installation, and Maintenance Equipment; WBS 1.8.6.4.1 Target Chamber Service System; WBS 1.8.6.4.2 Target Bay Service Systems

  6. Wind Fab: Manufacturer of water pumping windmills in India

    International Nuclear Information System (INIS)

    Gurumoorthy, S.

    1991-01-01

    Wind Fab is one of the four manufacturers appointed recently by the Indian government to produce a classic gear type wind pump for deep well pumping (H = 50-100 meter). In various regions, the ground water table has been lowering considerably and a deep well wind pump is required. Wind Fab is still producing the 12PU500 windmill. The main problem is that the wind pumps are applied in a wide range of climatological, hydrological and agricultural conditions. Different types of windmills suitable for the different application ranges should be produced. It is explained that the drawings of the 12PU500 windmills were easily available and consequently the windmills were produced all over the country. There was no quality control and the 12PU500 was applied under low lift to high lift conditions. 5 figs., 5 tabs

  7. Spherical cows in the sky with fab four

    Energy Technology Data Exchange (ETDEWEB)

    Kaloper, Nemanja; Sandora, McCullen, E-mail: kaloper@physics.ucdavis.edu, E-mail: mesandora@ucdavis.edu [Department of Physics, University of California, Davis, CA 95616 (United States)

    2014-05-01

    We explore spherically symmetric static solutions in a subclass of unitary scalar-tensor theories of gravity, called the 'Fab Four' models. The weak field large distance solutions may be phenomenologically viable, but only if the Gauss-Bonnet term is negligible. Only in this limit will the Vainshtein mechanism work consistently. Further, classical constraints and unitarity bounds constrain the models quite tightly. Nevertheless, in the limits where the range of individual terms at large scales is respectively Kinetic Braiding, Horndeski, and Gauss-Bonnet, the horizon scale effects may occur while the theory satisfies Solar system constraints and, marginally, unitarity bounds. On the other hand, to bring the cutoff down to below a millimeter constrains all the couplings scales such that 'Fab Fours' can't be heard outside of the Solar system.

  8. A novel bispecific antibody, S-Fab, induces potent cancer cell killing.

    Science.gov (United States)

    Li, Li; He, Ping; Zhou, Changhua; Jing, Li; Dong, Bin; Chen, Siqi; Zhang, Ning; Liu, Yawei; Miao, Ji; Wang, Zhong; Li, Qing

    2015-01-01

    Bispecific antibodies that engage immune cells to kill cancer cells have been actively studied in cancer immunotherapy. In this study, we present a novel bispecific format, S-Fab, fabricated by linking a single-domain anti-carcinoembryonic antigen VHH to a conventional anti-CD3 Fab. In contrast to most bispecific antibodies, the S-Fab bispecific antibody can be efficiently expressed and purified from bacteria. The purified S-Fab is stable in serum and is able to recruit T cells to drive potent cancer cell killing. In xenograft models, the S-Fab antibody suppresses tumor growth in the presence of human immune cells. Our study suggested that the bispecific S-Fab format can be applied to a wide range of immunotherapies.

  9. Fab Four self-interaction in quantum regime

    Science.gov (United States)

    Arbuzov, A. B.; Latosh, B. N.

    2017-10-01

    Quantum behavior of the John Lagrangian from the Fab Four class of covariant Galileons is studied. We consider one-loop corrections to the John interaction due to cubic scalar field interaction. Counter terms are calculated, one appears because of massless scalar field theory infrared issues, another one lies in the George class, and the rest of them can be reduced to the initial Lagrangian up to surface terms. The role of quantum corrections in the context of cosmological applications is discussed.

  10. Fab Four self-interaction in quantum regime

    Energy Technology Data Exchange (ETDEWEB)

    Arbuzov, A.B.; Latosh, B.N. [JINR, Bogoliubov Laboratory for Theoretical Physics, Dubna (Russian Federation); Dubna State University, Dubna, Moscow Region (Russian Federation)

    2017-10-15

    Quantum behavior of the John Lagrangian from the Fab Four class of covariant Galileons is studied. We consider one-loop corrections to the John interaction due to cubic scalar field interaction. Counter terms are calculated, one appears because of massless scalar field theory infrared issues, another one lies in the George class, and the rest of them can be reduced to the initial Lagrangian up to surface terms. The role of quantum corrections in the context of cosmological applications is discussed. (orig.)

  11. Detection of experimental myocarditis by monoclonal antimyosin antibody, Fab fragment

    Energy Technology Data Exchange (ETDEWEB)

    Rezkalla, S.; Kloner, R.A.; Khaw, B.A.; Haber, E.; Fallon, J.T.; Smith, F.E.; Khatib, R.

    1989-02-01

    The purpose of this study was to determine whether monoclonal antimyosin Fab (antigen binding fragment) was capable of labeling hearts with experimental coxsackievirus myocarditis, and to determine whether Fab could be used for detecting myocardial damage in either early or chronic phases of the disease. Sixty-five, 3-week-old cesarean-derived 1 (CD 1) mice were divided into two groups: group I (noninfected animals) and group II (infected with coxsackievirus B3). Mice from each group were killed on days 7, 17, 30, or 90 of infection. Forty-eight hours before killing, mice were injected with monoclonal I-125 antimyosin, Fab (25 microCi/injection) and radioactivity was counted in the heart. Selected heart sections were also examined by autoradiography. Heart radioactivity, count/m/mg (m +/- SEM) on days 7, 17, 30, and 90 of infection was 10.8 +/- 1.7, 21.3 +/- 1.1, 11.2 +/- 3.4, and 12.4 +/- 1.5 for group I, versus 36.7 +/- 8.0 (p less than 0.01), 50.0 +/- 4.5 (p less than 0.001), 33.4 +/- 16.1 (p = NS), and 40.6 +/- 8.5 (p less than 0.01) for group II, respectively. Autoradiography revealed focal uptake within areas of necrotic myocardium. We conclude that I125 Fab may be useful in detecting myocardial damage in the experimental model of murine myocarditis up to day 90 of infection.

  12. Detection of experimental myocarditis by monoclonal antimyosin antibody, Fab fragment

    International Nuclear Information System (INIS)

    Rezkalla, S.; Kloner, R.A.; Khaw, B.A.; Haber, E.; Fallon, J.T.; Smith, F.E.; Khatib, R.

    1989-01-01

    The purpose of this study was to determine whether monoclonal antimyosin Fab (antigen binding fragment) was capable of labeling hearts with experimental coxsackievirus myocarditis, and to determine whether Fab could be used for detecting myocardial damage in either early or chronic phases of the disease. Sixty-five, 3-week-old cesarean-derived 1 (CD 1) mice were divided into two groups: group I (noninfected animals) and group II (infected with coxsackievirus B3). Mice from each group were killed on days 7, 17, 30, or 90 of infection. Forty-eight hours before killing, mice were injected with monoclonal I-125 antimyosin, Fab (25 microCi/injection) and radioactivity was counted in the heart. Selected heart sections were also examined by autoradiography. Heart radioactivity, count/m/mg (m +/- SEM) on days 7, 17, 30, and 90 of infection was 10.8 +/- 1.7, 21.3 +/- 1.1, 11.2 +/- 3.4, and 12.4 +/- 1.5 for group I, versus 36.7 +/- 8.0 (p less than 0.01), 50.0 +/- 4.5 (p less than 0.001), 33.4 +/- 16.1 (p = NS), and 40.6 +/- 8.5 (p less than 0.01) for group II, respectively. Autoradiography revealed focal uptake within areas of necrotic myocardium. We conclude that I125 Fab may be useful in detecting myocardial damage in the experimental model of murine myocarditis up to day 90 of infection

  13. Design principles for target stations and methods of remote handling at PSI

    International Nuclear Information System (INIS)

    Steiner, E.W.

    1992-01-01

    Two design concepts for target stations used at Paul Scherrer Institute (PSI) are shown. The method of the remote handling of activated elements is described and some conclusions with respect to a radioactive beam facility are given

  14. Double-shell target designs for the Los Alamos Scientific Laboratory eight-beam laser system

    International Nuclear Information System (INIS)

    Kindel, J.M.; Stroscio, M.A.

    1978-03-01

    We investigate two double-pusher laser fusion targets, one that incorporates an outer exploding pusher shell and another that uses velocity multiplication. Specific designs are presented for the Los Alamos Scientific Laboratory Eight-Beam Laser System

  15. Rasch Analysis of the Fullerton Advanced Balance (FAB) Scale

    Science.gov (United States)

    Fiedler, Roger C.; Rose, Debra J.

    2011-01-01

    ABSTRACT Purpose: This cross-sectional study explores the psychometric properties and dimensionality of the Fullerton Advanced Balance (FAB) Scale, a multi-item balance test for higher-functioning older adults. Methods: Participants (n=480) were community-dwelling adults able to ambulate independently. Data gathering consisted of survey and balance performance assessment. Psychometric properties were assessed using Rasch analysis. Results: Mean age of participants was 76.4 (SD=7.1) years. Mean FAB Scale scores were 24.7/40 (SD=7.5). Analyses for scale dimensionality showed that 9 of the 10 items fit a unidimensional measure of balance. Item 10 (Reactive Postural Control) did not fit the model. The reliability of the scale to separate persons was 0.81 out of 1.00; the reliability of the scale to separate items in terms of their difficulty was 0.99 out of 1.00. Cronbach's alpha for a 10-item model was 0.805. Items of differing difficulties formed a useful ordinal hierarchy for scaling patterns of expected balance ability scoring for a normative population. Conclusion: The FAB Scale appears to be a reliable and valid tool to assess balance function in higher-functioning older adults. The test was found to discriminate among participants of varying balance abilities. Further exploration of concurrent validity of Rasch-generated expected item scoring patterns should be undertaken to determine the test's diagnostic and prescriptive utility. PMID:22210989

  16. Rasch Analysis of the Fullerton Advanced Balance (FAB) Scale.

    Science.gov (United States)

    Klein, Penelope J; Fiedler, Roger C; Rose, Debra J

    2011-01-01

    This cross-sectional study explores the psychometric properties and dimensionality of the Fullerton Advanced Balance (FAB) Scale, a multi-item balance test for higher-functioning older adults. Participants (n=480) were community-dwelling adults able to ambulate independently. Data gathering consisted of survey and balance performance assessment. Psychometric properties were assessed using Rasch analysis. Mean age of participants was 76.4 (SD=7.1) years. Mean FAB Scale scores were 24.7/40 (SD=7.5). Analyses for scale dimensionality showed that 9 of the 10 items fit a unidimensional measure of balance. Item 10 (Reactive Postural Control) did not fit the model. The reliability of the scale to separate persons was 0.81 out of 1.00; the reliability of the scale to separate items in terms of their difficulty was 0.99 out of 1.00. Cronbach's alpha for a 10-item model was 0.805. Items of differing difficulties formed a useful ordinal hierarchy for scaling patterns of expected balance ability scoring for a normative population. The FAB Scale appears to be a reliable and valid tool to assess balance function in higher-functioning older adults. The test was found to discriminate among participants of varying balance abilities. Further exploration of concurrent validity of Rasch-generated expected item scoring patterns should be undertaken to determine the test's diagnostic and prescriptive utility.

  17. The reliability and validity of the Turkish version of Fullerton Advanced Balance (FAB-T) scale.

    Science.gov (United States)

    Iyigun, Gozde; Kirmizigil, Berkiye; Angin, Ender; Oksuz, Sevim; Can, Filiz; Eker, Levent; Rose, Debra J

    2018-06-04

    The aim of this study was to evaluate the reliability and validity of the Turkish version of the FAB(FAB-T) scale in the older Turkish adults. The reliability and validity of the scale was tested on 200 community-dwelling older adults. FAB-T scale was scored by different physiotherapists on different days to evaluate inter-rater and intrarater reliability. The Berg Balance Scale (BBS) was used for the evaluation of convergent validity, and the content validity of the FAB-T scale was investigated. The FAB-T scale showed very high inter- and intra-rater reliability. For inter-rater agreement, on the individual test items and total score ICC values were 0.92 (95 %CI; 0.90-0.94) and 0.96 (95% CI; 0.95-0.97) respectively. The intra-rater agreement, on the individual test items and total score ICC values were 0.93 (95 %CI; 0.91- 0.95) and 0.96 (95% CI; 0.95- 0.97) respectively. There was a good agreement between the FAB-T and BBS scales. A high correlation was found between the BBS and FAB-T scales [rho = 0.70 (%95 CI; 0.62-0.76)] indicating good convergent validity. Considering the content validity of the FAB-T scale, no floor (floor score: 0%) or ceiling (ceiling score: 6.5%) effect was detected. The FAB-T scale was successfully translated from the original English version (FAB) and demonstrated strong psychometric features. It was found that the FAB-T scale has very high inter-rater and intra-rater reliability. Considering the convergent validity, the scale has high correlation with the BBS. The FAB-T has no floor and ceiling effect. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. Complex Binding of the FabR Repressor of Bacterial Unsaturated Fatty Acid Biosynthesis to its Cognate Promoters

    OpenAIRE

    Feng, Youjun; Cronan, John E.

    2011-01-01

    Two transcriptional regulators, the FadR activator and the FabR repressor control biosynthesis of unsaturated fatty acids in Escherichia coli. FabR represses expression of the two genes, fabA and fabB, required for unsaturated fatty acid synthesis and has been reported to require the presence of an unsaturated thioester (of either acyl carrier protein or CoA) in order to bind the fabA and fabB promoters in vitro. We report in vivo experiments in which unsaturated fatty acid synthesis was bloc...

  19. Assessment of Digoxin-Specific Fab Fragment Dosages in Digoxin Poisoning.

    Science.gov (United States)

    Nordt, Sean Patrick; Clark, Richard F; Machado, Carol; Cantrell, F Lee

    2016-01-01

    Digoxin poisoning still remains a common cause of morbidity and mortality. Fortunately, digoxin-specific Fab fragments are commercially available as an antidote. However, these Fab fragments are several thousand dollars per vial. There is a standardized formula to calculate appropriate Fab fragment dosage based on the serum digoxin concentration. This can greatly reduce the amount of Fab fragment administered. There is also an empiric dosing guideline recommending 6-10 vials be given; however, this may result in higher amounts of Fab fragments being administered than required. We performed this study to assess the amounts of digoxin-specific Fab fragments administered in the treatment of digoxin poisonings recorded in a poison control system database from January 1, 2000, to December 31, 2009, in which digoxin serum concentrations were available. This was a retrospective study of 278 patients, 107 with acute poisonings (group A) and 171 following chronic poisoning (group B). In group A, the calculated Fab dose was higher than the calculated dose based on available concentrations in 39 (36%) of group A and 15 (9%) of group B patients. The average wholesale price cost of the excessive dosages ranged from $4818 to as high as $50,589 per patient. Our data suggests that clinician education on digoxin poisoning and the use of the standardized formula to calculate the Fab dose may decrease over utilization and decrease costs associated with the administration of digoxin-specific Fab fragments in the treatment of digoxin poisonings.

  20. Frontal assessment battery (FAB) performance following traumatic brain injury hospitalized in an acute care setting.

    Science.gov (United States)

    Rojas, Natalia; Laguë-Beauvais, Maude; Belisle, Arielle; Lamoureux, Julie; AlSideiri, Ghusn; Marcoux, Judith; Maleki, Mohammed; Alturki, Abdulrahman Y; Anchouche, Sonia; Alquraini, Hanan; Feyz, Mitra; Guise, Elaine de

    2018-01-19

    The Frontal Assessment Battery (FAB) has been shown to be useful in several clinical settings. The aim of the present study was to examine the performance of patients with traumatic brain injury (TBI) on the FAB and to predict their acute outcome. The FAB was administered to 89 patients with mild (27 = uncomplicated and 39 = complicated) and moderate (n = 23) TBI during hospitalization in an acute care setting. The length of stay in days (LOS), Glasgow Outcome Scale-Revised score (GOSE) and Disability Rating Scale (DRS) score were collected. Results showed no significant differences between the three groups on the FAB score, but age and education were significantly associated with the FAB score. Parietal lesions were associated with lower total FAB score, and with the Similarities, Motor series and Conflicting instructions subscales, while frontal lesions were associated with lower performance on the Motor series and Conflicting instructions subscales. Total FAB score was significantly correlated with all outcome measures, and together the FAB total score and the Glasgow Coma Scale (GCS) score explained 30.8% of the variance in the DRS score. The FAB may be useful clinically to acutely assess frontal and parietal lobe functions at bedside in patients with TBI and, in combination with the GCS score to measure TBI severity, can enable clinicians to predict early outcome.

  1. Efficient production of Trastuzumab Fab antibody fragments in Brevibacillus choshinensis expression system.

    Science.gov (United States)

    Mizukami, Makoto; Onishi, Hiromasa; Hanagata, Hiroshi; Miyauchi, Akira; Ito, Yuji; Tokunaga, Hiroko; Ishibashi, Matsujiro; Arakawa, Tsutomu; Tokunaga, Masao

    2018-10-01

    The Brevibacillus expression system has been successfully employed for the efficient productions of a variety of recombinant proteins, including enzymes, cytokines, antigens and antibody fragments. Here, we succeeded in secretory expression of Trastuzumab Fab antibody fragments using B. choshinensis/BIC (Brevibacillus in vivocloning) expression system. In the fed-batch high-density cell culture, recombinant Trastuzumab Fab with amino-terminal His-tag (His-BcFab) was secreted at high level, 1.25 g/liter, and Fab without His-tag (BcFab) at ∼145 mg/L of culture supernatant. His-BcFab and BcFab were purified to homogeneity using combination of conventional column chromatographies with a yield of 10-13%. This BcFab preparation exhibited native structure and functions evaluated by enzyme-linked immunosorbent assay, surface plasmon resonance, circular dichroism measurements and size exclusion chromatography. To our knowledge, this is the highest production of Fab antibody fragments in gram-positive bacterial expression/secretion systems. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. The design status of the liquid lithium target facility of IFMIF at the end of the engineering design activities

    Energy Technology Data Exchange (ETDEWEB)

    Nitti, F.S., E-mail: francesco.nitti@enea.it [IFMIF/EVEDA Project Team, Rokkasho Japan (Japan); Ibarra, A. [CIEMAT, Madrid (Spain); Ida, M. [IHI Corporation, Tokyo (Japan); Favuzza, P. [ENEA Research Center Firenze (Italy); Furukawa, T. [JAEA Research Center, Tokai-mura, Ibaraki (Japan); Groeschel, F. [KIT Research Center, Karlsruhe (Germany); Heidinger, R. [F4E Research Center, Garching (Germany); Kanemura, T. [JAEA Research Center, Tokai-mura, Ibaraki (Japan); Knaster, J. [IFMIF/EVEDA Project Team, Rokkasho Japan (Japan); Kondo, H. [JAEA Research Center, Tokai-mura, Ibaraki (Japan); Micchiche, G. [ENEA Research Center, Brasimone (Italy); Sugimoto, M. [JAEA Research Center, Rokkasho Japan (Japan); Wakai, E. [JAEA Research Center, Tokai-mura, Ibaraki (Japan)

    2015-11-15

    Highlights: • Results of validation and design activity for the Li loop facility of IFMIF. • Demonstration of Li target stability, with surface disturbance <1 mm. • Demonstration of start-up and shut down procedures of Li loop. • Complete design of the heat removal system and C and O purification system. • Conceptual design of N and H isotopes purification systems. - Abstract: The International Fusion Material Irradiation Facility (IFMIF) is an experimental facility conceived for qualifying and characterizing structural materials for nuclear fusion applications. The Engineering Validation and Engineering Design Activity (EVEDA) is a fundamental step towards the final design. It presented two mandates: the Engineering Validation Activities (EVA), still on-going, and the Engineering Design Activities (EDA) accomplished on schedule in June 2013. Five main facilities are identified in IFMIF, among which the Lithium Target Facility constituted a technological challenge overcome thanks to the success of the main validation challenges impacting the design. The design of the liquid Lithium Target Facility at the end of the EDA phase is here detailed.

  3. The design status of the liquid lithium target facility of IFMIF at the end of the engineering design activities

    International Nuclear Information System (INIS)

    Nitti, F.S.; Ibarra, A.; Ida, M.; Favuzza, P.; Furukawa, T.; Groeschel, F.; Heidinger, R.; Kanemura, T.; Knaster, J.; Kondo, H.; Micchiche, G.; Sugimoto, M.; Wakai, E.

    2015-01-01

    Highlights: • Results of validation and design activity for the Li loop facility of IFMIF. • Demonstration of Li target stability, with surface disturbance <1 mm. • Demonstration of start-up and shut down procedures of Li loop. • Complete design of the heat removal system and C and O purification system. • Conceptual design of N and H isotopes purification systems. - Abstract: The International Fusion Material Irradiation Facility (IFMIF) is an experimental facility conceived for qualifying and characterizing structural materials for nuclear fusion applications. The Engineering Validation and Engineering Design Activity (EVEDA) is a fundamental step towards the final design. It presented two mandates: the Engineering Validation Activities (EVA), still on-going, and the Engineering Design Activities (EDA) accomplished on schedule in June 2013. Five main facilities are identified in IFMIF, among which the Lithium Target Facility constituted a technological challenge overcome thanks to the success of the main validation challenges impacting the design. The design of the liquid Lithium Target Facility at the end of the EDA phase is here detailed.

  4. Aerial imaging for FABs: productivity and yield aspects

    Science.gov (United States)

    Englard, Ilan; Cohen, Yaron; Elblinger, Yair; Attal, Shay; Berns, Neil; Shoval, Lior; Ben-Yishai, Michael; Mangan, Shmoolik

    2009-03-01

    The economy of wafer fabs is changing faster for 3x geometry requirements and below. Mask set and exposure tool costs are almost certain to increase the overall cost per die requiring manufacturers to develop productivity and yield improvements to defray the lithography cell economic burden. Lithography cell cost effectiveness can be significantly improved by increasing mask availability while reducing the amount of mask sets needed during a product life cycle. Further efficiency can be gained from reducing send-ahead wafers and qualification cycle time, and elimination of inefficient metrology. Yield is the overriding die cost modulator and is significantly more sensitive to lithography as a result of masking steps required to fabricate the integrated circuit. Thus, for productivity to increase with minimal yield risk, the sample space of reticle induced source of variations should be large, with shortest measurement acquisition time possible. This paper presents the latest introduction of mask aerial imaging technology for the fab, Aera2TM for Lithography with IntenCTM, as an enabler for efficient lithography manufacturing. IntenCD is a high throughput, high density mask-based critical dimension (CD) mapping technology, with the potential for increasing productivity and yield in a wafer production environment. Connecting IntenCD to a feed forward advance process control (APC) reduces significantly the amount of traditional CD metrology required for robust wafer CD uniformity (CDU) correction and increases wafer CD uniformity. This in turn improves the lithography process window and yield and contributes to cost reduction and cycle time reduction of new reticles qualification. Advanced mask technology has introduced a new challenge. Exposure to 193nm wavelength stimulates haze growth on the mask and imposes a regular cleaning schedule. Cleaning eventually causes mask degradation. Haze growth impacts mask CD uniformity and induce global transmission fingerprint

  5. Verification of the hydraulic design of the FMIT liquid lithium target

    International Nuclear Information System (INIS)

    Miles, R.R.; Annese, C.E.; Ingham, J.G.

    1983-01-01

    A liquid lithium target is being developed to generate a neutron flux for material testing in a fusion-like environment. The target consists of a thin, high speed, curved wall jet of lithium which is formed by an asymmetric nozzle. A prototype target was designed using potential flow analysis and was tested in water. Measurements of jet thickness and velocity in water and thickness in lithium were compared with isothermal design predictions and were shown to match within 1% for thickness and 5% for jet velocity

  6. Generic study on the design and operation of high power targets

    Directory of Open Access Journals (Sweden)

    A. Ahmad

    2014-02-01

    Full Text Available With the move towards beam power in the range of 1–10 MW, a thorough understanding of the response of target materials and auxiliary systems to high power densities and intense radiation fields is required. This paper provides insight into three major aspects related to the design and operation of high power solid targets: thermal stresses, coolant performance, and radiation damage. Where appropriate, a figure-of-merit approach is followed to facilitate the comparison between different target or coolant candidates. The section on radiation damage reports total and spatial variations of displacement-per-atom and helium production levels in different target materials.

  7. Design and Optimization for the Windowless Target of the China Nuclear Waste Transmutation Reactor

    Directory of Open Access Journals (Sweden)

    Desheng Cheng

    2016-04-01

    Full Text Available A windowless spallation target can provide a neutron source and maintain neutron chain reaction for a subcritical reactor, and is a key component of China's nuclear waste transmutation of coupling accelerator and subcritical reactor. The main issue of the windowless target design is to form a stable and controllable free surface that can ensure that energy spectrum distribution is acquired for the neutron physical design when the high energy proton beam beats the lead–bismuth eutectic in the spallation target area. In this study, morphology and flow characteristics of the free surface of the windowless target were analyzed through the volume of fluid model using computational fluid dynamics simulation, and the results show that the outlet cross section size of the target is the key to form a stable and controllable free surface, as well as the outlet with an arc transition. The optimization parameter of the target design, in which the radius of outlet cross section is 60 ± 1 mm, is verified to form a stable and controllable free surface and to reduce the formation of air bubbles. This work can function as a reference for carrying out engineering design of windowless target and for verification experiments.

  8. Acute hypersensitivity reaction to Crotalidae polyvalent immune Fab (CroFab) as initial presentation of galactose-α-1,3-galactose (α-gal) allergy.

    Science.gov (United States)

    Rizer, Justin; Brill, Kaitlin; Charlton, Nathan; King, Joshua

    2017-08-01

    Crotalidae polyvalent immune Fab antivenom (CroFab), commonly used for the treatment of clinically significant North American crotalinae envenomation, is generally well-tolerated. A novel form of anaphylaxis due to an IgE antibody response to the mammalian oligosaccharide galactose-α-1,3-galactose (α-gal) has been established following red-meat consumption as well as IV administration of cetuximab, which contain the α-gal epitope. We present a case of α-gal allergy discovered after acute hypersensitivity reaction to FabAV. A 61-year-old healthy female was bitten on her left ankle by Agkistrodon contortrix. Given the patient's rapid progression of pain and swelling, she was given FabAV. During infusion of FabAV, she developed diffuse hives over her entire body and itching, but denied respiratory or gastrointestinal symptoms and her vital signs remained stable. The FabAV was immediately discontinued and she received intravenous diphenhydramine and famotidine with gradual resolution of symptoms. On further discussion, she denied a history of α-gal or papaya allergy but rarely ate red meat and endorsed sustaining frequent tick bites. Subsequent antibody testing was significant for an α-1,3-galactose IgE concentration of 45,000 U/L (normal allergy. To our knowledge, this is the first report of FabAV hypersensitivity associated with an underlying α-gal allergy.

  9. Design and Preliminary Testing of the International Docking Adapter's Peripheral Docking Target

    Science.gov (United States)

    Foster, Christopher W.; Blaschak, Johnathan; Eldridge, Erin A.; Brazzel, Jack P.; Spehar, Peter T.

    2015-01-01

    The International Docking Adapter's Peripheral Docking Target (PDT) was designed to allow a docking spacecraft to judge its alignment relative to the docking system. The PDT was designed to be compatible with relative sensors using visible cameras, thermal imagers, or Light Detection and Ranging (LIDAR) technologies. The conceptual design team tested prototype designs and materials to determine the contrast requirements for the features. This paper will discuss the design of the PDT, the methodology and results of the tests, and the conclusions pertaining to PDT design that were drawn from testing.

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

    International Nuclear Information System (INIS)

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

    1991-12-01

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

  11. RobOKoD: microbial strain design for (over)production of target compounds.

    Science.gov (United States)

    Stanford, Natalie J; Millard, Pierre; Swainston, Neil

    2015-01-01

    Sustainable production of target compounds such as biofuels and high-value chemicals for pharmaceutical, agrochemical, and chemical industries is becoming an increasing priority given their current dependency upon diminishing petrochemical resources. Designing these strains is difficult, with current methods focusing primarily on knocking-out genes, dismissing other vital steps of strain design including the overexpression and dampening of genes. The design predictions from current methods also do not translate well-into successful strains in the laboratory. Here, we introduce RobOKoD (Robust, Overexpression, Knockout and Dampening), a method for predicting strain designs for overproduction of targets. The method uses flux variability analysis to profile each reaction within the system under differing production percentages of target-compound and biomass. Using these profiles, reactions are identified as potential knockout, overexpression, or dampening targets. The identified reactions are ranked according to their suitability, providing flexibility in strain design for users. The software was tested by designing a butanol-producing Escherichia coli strain, and was compared against the popular OptKnock and RobustKnock methods. RobOKoD shows favorable design predictions, when predictions from these methods are compared to a successful butanol-producing experimentally-validated strain. Overall RobOKoD provides users with rankings of predicted beneficial genetic interventions with which to support optimized strain design.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2017-06-12

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

  13. Neutron Reflection Study of Surface Adsorption of Fc, Fab, and the Whole mAb.

    Science.gov (United States)

    Li, Zongyi; Li, Ruiheng; Smith, Charles; Pan, Fang; Campana, Mario; Webster, John R P; van der Walle, Christopher F; Uddin, Shahid; Bishop, Steve M; Narwal, Rojaramani; Warwicker, Jim; Lu, Jian Ren

    2017-07-12

    Characterizing the influence of fragment crystallization (Fc) and antigen-binding fragment (Fab) on monoclonal antibody (mAb) adsorption at the air/water interface is an important step to understanding liquid mAb drug product stability during manufacture, shipping, and storage. Here, neutron reflection is used to study the air/water adsorption of a mAb and its Fc and Fab fragments. By varying the isotopic contrast, the adsorbed amount, thickness, orientation, and immersion of the adsorbed layers could be determined unambiguously. While Fc adsorption reached saturation within the hour, its surface adsorbed amount showed little variation with bulk concentration. In contrast, Fab adsorption was slower and the adsorbed amount was concentration dependent. The much higher Fc adsorption, as compared to Fab, was linked to its lower surface charge. Time and concentration dependence of mAb adsorption was dominated by Fab behavior, although both Fab and Fc behaviors contributed to the amount of mAb adsorbed. Changing the pH from 5.5 to 8.8 did not much perturb the adsorbed amount of Fc, Fab, or mAb. However, a small decrease in adsorption was observed for the Fc over pH 8-8.8 and vice versa for the Fab and mAb, consistent with a dominant Fab behavior. As bulk concentration increased from 5 to 50 ppm, the thicknesses of the Fc layers were almost constant at 40 Å, while Fab and mAb layers increased from 45 to 50 Å. These results imply that the adsorbed mAb, Fc, and Fab all retained their globular structures and were oriented with their short axial lengths perpendicular to the interface.

  14. Conceptual design report for the University of Rochester cryogenic target delivery system

    Energy Technology Data Exchange (ETDEWEB)

    Fagaly, R.L.; Alexander, N.B.; Bourque, R.F.; Dahms, C.F.; Lindgren, J.R.; Miller, W.J. (General Atomics, San Diego, CA (United States)); Bittner, D.N.; Hendricks, C.D. (W.J. Schafer Associates, Livermore, CA (United States))

    1993-05-01

    The upgrade of the Omega laser at the University of Rochester's Laboratory for Laser Energetics (UR/LLE) will result in a need for large targets filled with D[sub 2] or Dt and maintained at cryogenic temperatures. This mandates a cryogenic target delivery system capable of filling, layering, characterizing and delivering cryogenic targets to the Omega Upgrade target chamber. The program goal is to design, construct, and test the entire target delivery system by June 1996. When completed (including an operational demonstration), the system will be shipped to Rochester for reassembly and commissioning in time for the Omega Upgrade cryogenic campaign, scheduled to start in 1998. General Atomics has been assigned the task of developing the conceptual design for the cryogenic target delivery system. Design and fabrication activities will be closely coordinated with the University of Rochester, Lawrence Livermore National laboratory (LLNL) and Los Alamos National Laboratory (LANL), drawing upon their knowledge base in fuel layering and cryogenic characterization. The development of a target delivery system for Omega could also benefit experiments at Lawrence Livermore National Laboratory and the other ICF Laboratories in that the same technologies could be applied to NOVA, the National Ignition Facility or the future Laboratory Microfusion Facility.

  15. Conceptual design report for the University of Rochester cryogenic target delivery system

    Energy Technology Data Exchange (ETDEWEB)

    Fagaly, R.L.; Alexander, N.B.; Bourque, R.F.; Dahms, C.F.; Lindgren, J.R.; Miller, W.J. [General Atomics, San Diego, CA (United States); Bittner, D.N.; Hendricks, C.D. [W.J. Schafer Associates, Livermore, CA (US)

    1993-05-01

    The upgrade of the Omega laser at the University of Rochester`s Laboratory for Laser Energetics (UR/LLE) will result in a need for large targets filled with D{sub 2} or Dt and maintained at cryogenic temperatures. This mandates a cryogenic target delivery system capable of filling, layering, characterizing and delivering cryogenic targets to the Omega Upgrade target chamber. The program goal is to design, construct, and test the entire target delivery system by June 1996. When completed (including an operational demonstration), the system will be shipped to Rochester for reassembly and commissioning in time for the Omega Upgrade cryogenic campaign, scheduled to start in 1998. General Atomics has been assigned the task of developing the conceptual design for the cryogenic target delivery system. Design and fabrication activities will be closely coordinated with the University of Rochester, Lawrence Livermore National laboratory (LLNL) and Los Alamos National Laboratory (LANL), drawing upon their knowledge base in fuel layering and cryogenic characterization. The development of a target delivery system for Omega could also benefit experiments at Lawrence Livermore National Laboratory and the other ICF Laboratories in that the same technologies could be applied to NOVA, the National Ignition Facility or the future Laboratory Microfusion Facility.

  16. Conceptual design report for the University of Rochester cryogenic target delivery system

    International Nuclear Information System (INIS)

    Fagaly, R.L.; Alexander, N.B.; Bourque, R.F.; Dahms, C.F.; Lindgren, J.R.; Miller, W.J.; Bittner, D.N.; Hendricks, C.D.

    1993-05-01

    The upgrade of the Omega laser at the University of Rochester's Laboratory for Laser Energetics (UR/LLE) will result in a need for large targets filled with D 2 or Dt and maintained at cryogenic temperatures. This mandates a cryogenic target delivery system capable of filling, layering, characterizing and delivering cryogenic targets to the Omega Upgrade target chamber. The program goal is to design, construct, and test the entire target delivery system by June 1996. When completed (including an operational demonstration), the system will be shipped to Rochester for reassembly and commissioning in time for the Omega Upgrade cryogenic campaign, scheduled to start in 1998. General Atomics has been assigned the task of developing the conceptual design for the cryogenic target delivery system. Design and fabrication activities will be closely coordinated with the University of Rochester, Lawrence Livermore National laboratory (LLNL) and Los Alamos National Laboratory (LANL), drawing upon their knowledge base in fuel layering and cryogenic characterization. The development of a target delivery system for Omega could also benefit experiments at Lawrence Livermore National Laboratory and the other ICF Laboratories in that the same technologies could be applied to NOVA, the National Ignition Facility or the future Laboratory Microfusion Facility

  17. Designing multi-targeted agents: An emerging anticancer drug discovery paradigm.

    Science.gov (United States)

    Fu, Rong-Geng; Sun, Yuan; Sheng, Wen-Bing; Liao, Duan-Fang

    2017-08-18

    The dominant paradigm in drug discovery is to design ligands with maximum selectivity to act on individual drug targets. With the target-based approach, many new chemical entities have been discovered, developed, and further approved as drugs. However, there are a large number of complex diseases such as cancer that cannot be effectively treated or cured only with one medicine to modulate the biological function of a single target. As simultaneous intervention of two (or multiple) cancer progression relevant targets has shown improved therapeutic efficacy, the innovation of multi-targeted drugs has become a promising and prevailing research topic and numerous multi-targeted anticancer agents are currently at various developmental stages. However, most multi-pharmacophore scaffolds are usually discovered by serendipity or screening, while rational design by combining existing pharmacophore scaffolds remains an enormous challenge. In this review, four types of multi-pharmacophore modes are discussed, and the examples from literature will be used to introduce attractive lead compounds with the capability of simultaneously interfering with different enzyme or signaling pathway of cancer progression, which will reveal the trends and insights to help the design of the next generation multi-targeted anticancer agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  18. The design of a lead-bismuth target system with a dual injection tube

    International Nuclear Information System (INIS)

    Cho, C.H.; Kim, Y.; Song, T.Y.; Park, W.S.

    2005-01-01

    A spallation target system is a key component to be developed for an accelerator driven system (ADS). It is known that a 15 ∼ 25 MW spallation target is required for a practical 1000 MWth ADS. The design of a 20 MW spallation target is very challenging because more than 60% of the beam power is deposited as heat in a small volume of the target system. In the present work, a numerical design study was performed to obtain the optimal design parameters for a 20 MW spallation target for a 1000 MW ADS. A dual injection tube was proposed for the reduction of the LBE flow rate at the target channel. The results of the present study show that a 30 cm wide proton beam with a uniform beam distribution should be adopted for the spallation target of a 20 MW power. When the dual LBE injection tube is employed, the LBE flow rate could be reduced by a factor of 4 without reducing the maximum allowable beam current. (authors)

  19. Autonomous Rover Traverse and Precise Arm Placement on Remotely Designated Targets

    Science.gov (United States)

    Felder, Michael; Nesnas, Issa A.; Pivtoraiko, Mihail; Kelly, Alonzo; Volpe, Richard

    2011-01-01

    Exploring planetary surfaces typically involves traversing challenging and unknown terrain and acquiring in-situ measurements at designated locations using arm-mounted instruments. We present field results for a new implementation of an autonomous capability that enables a rover to traverse and precisely place an arm-mounted instrument on remote targets. Using point-and-click mouse commands, a scientist designates targets in the initial imagery acquired from the rover's mast cameras. The rover then autonomously traverse the rocky terrain for a distance of 10 - 15 m, tracks the target(s) of interest during the traverse, positions itself for approaching the target, and then precisely places an arm-mounted instrument within 2-3 cm from the originally designated target. The rover proceeds to acquire science measurements with the instrument. This work advances what has been previously developed and integrated on the Mars Exploration Rovers by using algorithms that are capable of traversing more rock-dense terrains, enabling tight thread-the-needle maneuvers. We integrated these algorithms on the newly refurbished Athena Mars research rover and fielded them in the JPL Mars Yard. We conducted 43 runs with targets at distances ranging from 5 m to 15 m and achieved a success rate of 93% for placement of the instrument within 2-3 cm.

  20. European DEMO divertor target: Operational requirements and material-design interface

    Directory of Open Access Journals (Sweden)

    J.H. You

    2016-12-01

    Full Text Available Recently, an integrated program of conceptual design activities for the European DEMO reactor was launched in the framework of the EUROfusion Consortium, where reliable power handling capability was identified as one of the most critical scientific as well as technological challenges for a DEMO reactor. The divertor is the key in-vessel plasma-facing component being in charge of power exhaust and removal of impurity particles. The DEMO divertor target will have to withstand extreme thermal loads where the local peak heat flux is expected to reach up to 20 MW/m2 during slow transient events in DEMO. To assure sufficient heat removal capability of the divertor target against normal and transient operational scenarios under expected cumulative neutron dose of up to 13 dpa is one of the fundamental engineering challenges imposed on target design. To develop the design of the DEMO divertor and related technologies, an R&D work package ‘Divertor’ has been set up in this consortium. The subproject ‘Target Development’ is devoted to the development of the conceptual design and the core technologies of the plasma-facing target. Devising and implementing novel structural heat sink materials (e.g. W/Cu composites to advanced target design concepts is one of the major objectives of this subproject. In this paper, the underlying design requirements imposed by the envisaged power exhaust goal and the prominent material-design interface issues are discussed. In addition, the candidate design concepts being currently considered are presented together with the related material issues. Finally, the first results achieved so far are presented.

  1. Structure of anti-FLAG M2 Fab domain and its use in the stabilization of engineered membrane proteins

    International Nuclear Information System (INIS)

    Roosild, Tarmo P.; Castronovo, Samantha; Choe, Senyon

    2006-01-01

    The X-ray crystallographic analysis of anti-FLAG M2 Fab is reported and the implications of the structure on FLAG epitope binding are described as a first step in the development of a tool for the structural and biophysical study of membrane proteins. The inherent difficulties of stabilizing detergent-solubilized integral membrane proteins for biophysical or structural analysis demand the development of new methodologies to improve success rates. One proven strategy is the use of antibody fragments to increase the ‘soluble’ portion of any membrane protein, but this approach is limited by the difficulties and expense associated with producing monoclonal antibodies to an appropriate exposed epitope on the target protein. Here, the stabilization of a detergent-solubilized K + channel protein, KvPae, by engineering a FLAG-binding epitope into a known loop region of the protein and creating a complex with Fab fragments from commercially available anti-FLAG M2 monoclonal antibodies is reported. Although well diffracting crystals of the complex have not yet been obtained, during the course of crystallization trials the structure of the anti-FLAG M2 Fab domain was solved to 1.86 Å resolution. This structure, which should aid future structure-determination efforts using this approach by facilitating molecular-replacement phasing, reveals that the binding pocket appears to be specific only for the first four amino acids of the traditional FLAG epitope, namely DYKD. Thus, the use of antibody fragments for improving the stability of target proteins can be rapidly applied to the study of membrane-protein structure by placing the short DKYD motif within a predicted peripheral loop of that protein and utilizing commercially available anti-FLAG M2 antibody fragments

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-10-15

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

  3. A Study of the Charge Trap Transistor (CTT) for Post-Fab Modification of Wafers

    Science.gov (United States)

    2018-04-01

    AFRL-RY-WP-TR-2018-0030 A STUDY OF THE CHARGE TRAP TRANSISTOR (CTT) FOR POST- FAB MODIFICATION OF WAFERS Subramanian S. Iyer University of California...Final 13 June 2016 – 13 December 2017 4. TITLE AND SUBTITLE A STUDY OF THE CHARGE TRAP TRANSISTOR (CTT) FOR POST- FAB MODIFICATION OF WAFERS 5a. CONTRACT

  4. Phage-display libraries of murine and human antibody Fab fragments

    DEFF Research Database (Denmark)

    Engberg, J; Andersen, P S; Nielsen, L K

    1996-01-01

    We provide efficient and detailed procedures for construction, expression, and screening of comprehensive libraries of murine or human antibody Fab fragments displayed on the surface of filamentous phage. In addition, protocols for producing and using ultra-electrocompetent cells, for producing Fab...

  5. 75 FR 9438 - Samsung Austin Semiconductor, LLC, DRAM Fab 1, a Subsidiary of Samsung Electronics Corporation...

    Science.gov (United States)

    2010-03-02

    ... Semiconductor, LLC, DRAM Fab 1, a Subsidiary of Samsung Electronics Corporation, Including On-Site Leased... Semiconductor, LLC, a subsidiary of Samsung Electronics Corporation, DRAM Fab 1, including on-site leased.... The workers are engaged in activities related to the production of DRAM chips for use in electronics...

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

    Directory of Open Access Journals (Sweden)

    Jameel Ahmad Khan

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

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

    Directory of Open Access Journals (Sweden)

    Hossein Rezaei Dolatabadi

    2013-01-01

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

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

    DEFF Research Database (Denmark)

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

    2017-01-01

    encoded into molecular mechanics force fields. Cheminformatics analyses of binding data show EGFR to be dissimilar to ALK and MET, but its structure shows how it may be co-targeted with the addition of a covalent trap. This suggests a strategy for the design of a focussed chemical library based on a pan......Drug design of protein kinase inhibitors is now greatly enabled by thousands of publicly available X-ray structures, extensive ligand binding data, and optimized scaffolds coming off patent. The extensive data begin to enable design against a spectrum of targets (polypharmacology); however...... consider polypharmacological targeting of protein kinases ALK, MET, and EGFR (and its drug resistant mutant T790M) in non small cell lung cancer as an example. Both EGFR and ALK represent sources of primary oncogenic lesions, while drug resistance arises from MET amplification and EGFR mutation. A drug...

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

    Science.gov (United States)

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

    2014-02-21

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

  10. Designing and modeling a centrifugal microfluidic device to separate target blood cells

    International Nuclear Information System (INIS)

    Shamloo, Amir; Selahi, AmirAli; Madadelahi, Masoud

    2016-01-01

    The objective of this study is to design a novel and efficient portable lab-on-a-CD (LOCD) microfluidic device for separation of specific cells (target cells) using magnetic beads. In this study the results are shown for neutrophils as target cells. However, other kinds of target cells can be separated in a similar approach. The designed microfluidics can be utilized as a point of care system for neutrophil detection. This microfluidic system employs centrifugal and magnetic forces for separation. After model validation by the experimental data in the literature (that may be used as a design tool for developing centrifugo-magnetophoretic devices), two models are presented for separation of target cells using magnetic beads. The first model consists of one container in the inlet section and two containers in the outlets. Initially, the inlet container is filled with diluted blood sample which is a mixture of red blood cells (RBCs) plus neutrophils which are attached to Magnetic beads. It is shown that by using centrifugal and magnetic forces, this model can separate all neutrophils with recovery factor of ∼100%. In the second model, due to excess of magnetic beads in usual experimental analysis (to ensure that all target cells are attached to them) the geometry is improved by adding a third outlet for these free magnetic beads. It is shown that at angular velocity of 45 rad s −1 , recovery factor of 100% is achievable for RBCs, free magnetic beads and neutrophils as target cells. (paper)

  11. Designing and modeling a centrifugal microfluidic device to separate target blood cells

    Science.gov (United States)

    Shamloo, Amir; Selahi, AmirAli; Madadelahi, Masoud

    2016-03-01

    The objective of this study is to design a novel and efficient portable lab-on-a-CD (LOCD) microfluidic device for separation of specific cells (target cells) using magnetic beads. In this study the results are shown for neutrophils as target cells. However, other kinds of target cells can be separated in a similar approach. The designed microfluidics can be utilized as a point of care system for neutrophil detection. This microfluidic system employs centrifugal and magnetic forces for separation. After model validation by the experimental data in the literature (that may be used as a design tool for developing centrifugo-magnetophoretic devices), two models are presented for separation of target cells using magnetic beads. The first model consists of one container in the inlet section and two containers in the outlets. Initially, the inlet container is filled with diluted blood sample which is a mixture of red blood cells (RBCs) plus neutrophils which are attached to Magnetic beads. It is shown that by using centrifugal and magnetic forces, this model can separate all neutrophils with recovery factor of ~100%. In the second model, due to excess of magnetic beads in usual experimental analysis (to ensure that all target cells are attached to them) the geometry is improved by adding a third outlet for these free magnetic beads. It is shown that at angular velocity of 45 rad s-1, recovery factor of 100% is achievable for RBCs, free magnetic beads and neutrophils as target cells.

  12. 20 CFR 30.908 - How will the FAB evaluate new medical evidence submitted to challenge the impairment...

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false How will the FAB evaluate new medical... Medical Evidence of Impairment § 30.908 How will the FAB evaluate new medical evidence submitted to... impairment evaluation that differs from the impairment evaluation relied upon by the district office, the FAB...

  13. Characterization of deamidation at Asn138 in L-chain of recombinant humanized Fab expressed from Pichia pastoris.

    Science.gov (United States)

    Ohkuri, Takatoshi; Murase, Eri; Sun, Shu-Lan; Sugitani, Jun; Ueda, Tadashi

    2013-10-01

    A method was previously established for evaluating Asn deamidation by matrix-assisted laser desorption/ionization time of flight-mass spectrometry using endoproteinase Asp-N. In this study, we demonstrated that this method could be applied to the identification of the deamidation site of the humanized fragment antigen-binding (Fab). First, a system for expressing humanized Fab from methylotrophic yeast Pichia pastoris was constructed, resulting in the preparation of ∼30 mg of the purified humanized Fab from 1 l culture. Analysis of the L-chain derived from recombinant humanized Fab that was heated at pH 7 and 100°C for 1 h showed the deamidation at Asn138 in the constant region. Then, we prepared L-N138D Fab and L-N138A Fab and examined their properties. The circular dichroism (CD) spectrum of the L-N138D Fab was partially different from that of the wild-type Fab. The measurement of the thermostability showed that L-N138D caused a significant decrease in the thermostability of Fab. On the other hand, the CD spectrum and thermostability of L-N138A Fab showed the same behaviour as the wild-type Fab. Thus, it was suggested that the introduction of a negative charge at position 138 in the L-chain by the deamidation significantly affected the stability of humanized Fab.

  14. 20 CFR 30.320 - Can a claim be reopened after the FAB has issued a final decision?

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false Can a claim be reopened after the FAB has... AMENDED Adjudicatory Process Reopening Claims § 30.320 Can a claim be reopened after the FAB has issued a final decision? (a) At any time after the FAB has issued a final decision pursuant to § 30.316, and...

  15. 75 FR 21353 - Intel Corporation, Fab 20 Division, Including On-Site Leased Workers From Volt Technical...

    Science.gov (United States)

    2010-04-23

    ... DEPARTMENT OF LABOR Employment and Training Administration [TA-W-73,642] Intel Corporation, Fab 20... of Intel Corporation, Fab 20 Division, including on-site leased workers of Volt Technical Resources... Precision, Inc. were employed on-site at the Hillsboro, Oregon location of Intel Corporation, Fab 20...

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

    International Nuclear Information System (INIS)

    Ludwig, S.B.

    2003-01-01

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

  17. Design and fabrication of foam-insulated cryogenic target for wet-wall laser fusion reactor

    International Nuclear Information System (INIS)

    Norimatsu, T.; Takeda, T.; Nagai, K.; Mima, K.; Yamanaka, T.

    2003-01-01

    A foam insulated cryogenic target was proposed for use in a future laser fusion reactor with a wet wall. This scheme can protect the solid DT layer from melting due to surface heating by adsorption of metal vapor without significant reduction in the target gain. Design spaces for the injection velocity and the acceptable vapor pressure in the reactor are discussed. Basic technology to fabricate such structure was demonstrated by emulsion process. Concept of a cryogenic fast-ignition target with a gold guiding cone was proposed together with direct injection filling of liquid DT. (author)

  18. EURISOL-DS Overall Design of the Multi-MW Target Station

    CERN Document Server

    Olivier Choisnet, Cyril Kharoua, Yacine Kadi, Karel Samec (CERN)

    The EURISOL Design Study investigated the feasibility of a complex instrument to push back the boundaries of current physics knowledge amidst today’s ever-increasing need for realism due to constraints imposed by safety, performance and, not least, budgetary responsibility.In order to attend to these concerns, the EURISOL Multi-Megawatt converter target, its associated fission targets and the three 100 kW direct targets are all integrated into a single facility housing the ancillary equipment as well. The overall layout of the facility, its functional break-down and the main modes of operation are presented in the current report.

  19. Shielding design for the target room of the proton accelerator research center

    International Nuclear Information System (INIS)

    Min, Y. S.; Lee, C. W.; Mun, K. J.; Nam, J.; Kim, J. Y.

    2010-01-01

    The Proton Engineering Frontier Project (PEFP) has been developing a 100-MeV proton linear accelerator. Also, PEFP has been designing the Proton Accelerator Research Center (PARC). In the Accelerator Tunnel and Beam Experiment Hall in PARC, 10 target rooms for the 20- and 100-MeV beamline facilities exist in the Beam Experiment Hall. For the 100-MeV target rooms during 100-MeV proton beam extraction, a number of high energy neutrons, ranging up to 100-MeV, are produced. Because of the high beam current and space limitations of each target room, the shielding design of each target room should be considered seriously. For the shielding design of the 100-MeV target rooms of the PEFP, a permanent and removable local shield structure was adopted. To optimize shielding performance, we evaluated four different shield materials (concrete, HDPE, lead, iron). From the shielding calculation results, we confirmed that the proposed shielding design made it possible to keep the dose rate below the 'as low as reasonably achievable (ALARA)' objective.

  20. Glycoprotein CD98 as a receptor for colitis-targeted delivery of nanoparticle.

    Science.gov (United States)

    Xiao, Bo; Yang, Yang; Viennois, Emilie; Zhang, Yuchen; Ayyadurai, Saravanan; Baker, Mark; Laroui, Hamed; Merlin, Didier

    2014-03-21

    Treatment strategies for inflammatory bowel disease have been constrained by limited therapeutic efficacy and serious adverse effects owing to a lack of receptor for targeted drug delivery to the inflamed colon. Upon inflammation, CD98 expression is highly elevated in colonic epithelial cells and infiltrating immune cells. To investigate whether CD98 can be used as a colitis-targeted delivery receptor, we constructed CD98 Fab'-bearing quantum dots (QDs)-loaded nanoparticles (Fab'-NPs). The resultant Fab'-NPs had desired particle size (~458 nm) with a narrow size distribution and zeta-potential (approximately +19 mV), low cytotoxicity, and excellent fluorescence properties. Electron microscopy images provided direct evidence for the well-dispersed distribution of QDs within spherical Fab'-NPs. Cellular uptake experiments demonstrated that Fab'-NPs were efficiently internalized into Colon-26 and RAW 264.7 cells through the CD98-mediated endocytosis pathway, and showed that the targeting effect of CD98 Fab' markedly increased their cellular uptake efficiency compared with control pegylated QDs-loaded NPs (PEG-NPs). Furthermore, ex vivo studies showed much more effective accumulation of Fab'-NPs in colitis tissue than that of PEG-NPs. These findings suggest that because of inflammation-dependent over-expression of CD98, active colitis-targeted delivery can be accomplished using NPs decorated with CD98 antibody.

  1. Locking the Elbow: Improved Antibody Fab Fragments as Chaperones for Structure Determination.

    Science.gov (United States)

    Bailey, Lucas J; Sheehy, Kimberly M; Dominik, Pawel K; Liang, Wenguang G; Rui, Huan; Clark, Michael; Jaskolowski, Mateusz; Kim, Yejoon; Deneka, Dawid; Tang, Wei-Jen; Kossiakoff, Anthony A

    2018-02-02

    Antibody Fab fragments have been exploited with significant success to facilitate the structure determination of challenging macromolecules as crystallization chaperones and as molecular fiducial marks for single particle cryo-electron microscopy approaches. However, the inherent flexibility of the "elbow" regions, which link the constant and variable domains of the Fab, can introduce disorder and thus diminish their effectiveness. We have developed a phage display engineering strategy to generate synthetic Fab variants that significantly reduces elbow flexibility, while maintaining their high affinity and stability. This strategy was validated using previously recalcitrant Fab-antigen complexes where introduction of an engineered elbow region enhanced crystallization and diffraction resolution. Furthermore, incorporation of the mutations appears to be generally portable to other synthetic antibodies and may serve as a universal strategy to enhance the success rates of Fabs as structure determination chaperones. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. The Emerging Importance of IgG Fab Glycosylation in Immunity.

    Science.gov (United States)

    van de Bovenkamp, Fleur S; Hafkenscheid, Lise; Rispens, Theo; Rombouts, Yoann

    2016-02-15

    Human IgG is the most abundant glycoprotein in serum and is crucial for protective immunity. In addition to conserved IgG Fc glycans, ∼15-25% of serum IgG contains glycans within the variable domains. These so-called "Fab glycans" are primarily highly processed complex-type biantennary N-glycans linked to N-glycosylation sites that emerge during somatic hypermutation. Specific patterns of Fab glycosylation are concurrent with physiological and pathological conditions, such as pregnancy and rheumatoid arthritis. With respect to function, Fab glycosylation can significantly affect stability, half-life, and binding characteristics of Abs and BCRs. Moreover, Fab glycans are associated with the anti-inflammatory activity of IVIgs. Consequently, IgG Fab glycosylation appears to be an important, yet poorly understood, process that modulates immunity. Copyright © 2016 by The American Association of Immunologists, Inc.

  3. Isolation of Osteosarcoma-Associated Human Antibodies from a Combinatorial Fab Phage Display Library

    Directory of Open Access Journals (Sweden)

    Carmela Dantas-Barbosa

    2009-01-01

    Full Text Available Osteosarcoma, a highly malignant disease, is the most common primary bone tumor and is frequently found in children and adolescents. In order to isolate antibodies against osteosarcoma antigens, a combinatorial osteosarcoma Fab library displayed on the surface of phages was used. After three rounds of selection on the surface of tumor cells, several osteosarcoma-reactive Fabs were detected. From these Fabs, five were better characterized, and despite having differences in their VH (heavy chain variable domain and Vκ (kappa chain variable domain regions, they all bound to a protein with the same molecular mass. Further analysis by cell ELISA and immunocytochemistry suggested that the Fabs recognize a membrane-associated tumor antigen expressed in higher amounts in neoplasic cells than in normal tissue. These results suggest that the human Fabs selected in this work are a valuable tool for the study of this neoplasia.

  4. Optimal expression of a Fab-effector fusion protein in Escherichia coli by removing the cysteine residues responsible for an interchain disulfide bond of a Fab molecule.

    Science.gov (United States)

    Kang, Hyeon-Ju; Kim, Hye-Jin; Jung, Mun-Sik; Han, Jae-Kyu; Cha, Sang-Hoon

    2017-04-01

    Development of novel bi-functional or even tri-functional Fab-effector fusion proteins would have a great potential in the biomedical sciences. However, the expression of Fab-effector fusion proteins in Escherichia coli is problematic especially when a eukaryotic effector moiety is genetically linked to a Fab due to the lack of proper chaperone proteins and an inappropriate physicochemical environment intrinsic to the microbial hosts. We previously reported that a human Fab molecule, referred to as SL335, reactive to human serum albumin has a prolonged in vivo serum half-life in rats. We, herein, tested six discrete SL335-human growth hormone (hGH) fusion constructs as a model system to define an optimal Fab-effector fusion format for E. coli expression. We found that one variant, referred to as HserG/Lser, outperformed the others in terms of a soluble expression yield and functionality in that HserG/Lser has a functional hGH bioactivity and possesses an serum albumin-binding affinity comparable to SL335. Our results clearly demonstrated that the genetic linkage of an effector domain to the C-terminus of Fd (V H +C H1 ) and the removal of cysteine (Cys) residues responsible for an interchain disulfide bond (IDB) ina Fab molecule optimize the periplasmic expression of a Fab-effector fusion protein in E. coli. We believe that our approach can contribute the development of diverse bi-functional Fab-effector fusion proteins by providing a simple strategy that enables the reliable expression of a functional fusion proteins in E. coli. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  5. DigDesFab15 Research Pavilion

    Directory of Open Access Journals (Sweden)

    Andrei Gheorghe

    2017-09-01

    Full Text Available This full-scale research pavilion exercises the application of timber and polymer concrete in architectural production (Figure 1. It attempts to develop and test a new hybrid construction technique using composite joints [as introduced in Schober et al. (2014] within a modular geometric system and no need for formwork. The structure was designed and erected by students and instructors of the Digital Design and Full-Scale Fabrication seminar taught at the Institute of Architecture, University of Applied Arts Vienna. CNC milled, 3-layer spruce laminated timber boards are used for construction, which are temporarily fixed, then rigidized with polymer concrete. The cured composite node proves high structural capabilities, as polymer concrete withstands both pressure and tensile forces, and the bond between the materials is as strong as the wood itself. Compared to traditional timber construction, no metal bolting is needed for the creation of the node, while at the same time, the node geometry becomes more flexible, meaning any three-dimensional layout can be produced, as long as a temporary containment and fixation can be implemented until the chemical curing process is completed (Schober et al., 2016. The geometry is developed as an interpretation of the Zollinger (Menges et al., 2016 grid, where members originally are of twice the grid length (Figure 2 and reciprocally reliant on each other (Figure 3. Instead, every second grid cell is made a joint node when cast out with concrete, making the structural members a lost formwork at the same time (Figure 4. Double-layering each member (see detail explanation of the construction process in Section “Construction Method” below makes it possible to cast all 122 nodes of the pavilion structure separately and flat-bolt them together on-site with metal screws. Alternative fixation techniques (i.e., glue of the nodes can be tested in future. The software plugin RhinoVault is used as a design tool to

  6. Ligand design for riboswitches, an emerging target class for novel antibiotics.

    Science.gov (United States)

    Rekand, Illimar Hugo; Brenk, Ruth

    2017-09-01

    Riboswitches are cis-acting gene regulatory elements and constitute potential targets for new antibiotics. Recent studies in this field have started to explore these targets for drug discovery. New ligands found by fragment screening, design of analogs of the natural ligands or serendipitously by phenotypic screening have shown antibacterial effects in cell assays against a range of bacteria strains and in animal models. In this review, we highlight the most advanced drug design work of riboswitch ligands and discuss the challenges in the field with respect to the development of antibiotics with a new mechanism of action.

  7. Radioimmunoimaging using F(ab')2 fragment of monoclonal antibodies against human alpha-fetoprotein

    International Nuclear Information System (INIS)

    Sakahara, Harumi; Endo, Keigo; Nakashima, Tetsuo; Koizumi, Mitsuru; Ohta, Hitoya; Torizuka, Kanji; Okada, Kenichiro; Yoshida, Osamu; Nishi, Shinzo.

    1985-01-01

    Using monoclonal antibodies against human α-fetoprotein (AFP), radioiodinated F(ab') 2 fragments were compared with whole IgG as a radiotracer for radioimmunoimaging of cancer. F(ab') 2 fragments were obtained by pepsin digestion of whole IgG (IgGl). IgG and F(ab') 2 were labeled with 125 I or 131 I by the chloramine-T method with almost full retention of antibody activity. F(ab') 2 fragments were cleared more rapidly from the circulation in normal mice with a half life of 6.3 hours than whole IgG with a half life of 5.5 days. Radioactivity of F(ab') 2 in various organs also decreased faster than IgG. In nude mice transplanted with AFP-producing human testicular tumor, F(ab') 2 fragments demonstrated superior scintigrams to whole IgG at 2 days after the injection, because of the fast disappearance of background radioactivity. Although absolute accumulation of 131 I labeled F(ab') 2 in the tumor was less than that of 131 I labeled IgG, tumor to other organ ratios were much higher with F(ab') 2 than those of IgG. The tumor to blood ratio of 131 I labeled F(ab') 2 was 1.04 at day 2, whereas tumor to blood ratio of 131 I labeled IgG was 0.55 at day 2 and 0.92 at day 4, respectively. These results indicated that for the radiolabeling of monoclonal antibodies, F(ab') 2 fragments would be superior to whole IgG in the radioimmunoimaging of cancer. (author)

  8. Comparing domain interactions within antibody Fabs with kappa and lambda light chains.

    Science.gov (United States)

    Toughiri, Raheleh; Wu, Xiufeng; Ruiz, Diana; Huang, Flora; Crissman, John W; Dickey, Mark; Froning, Karen; Conner, Elaine M; Cujec, Thomas P; Demarest, Stephen J

    2016-10-01

    IgG antibodies are multi-domain proteins with complex inter-domain interactions. Human IgG heavy chains (HCs) associate with light chains (LCs) of the κ or λ isotype to form mature antibodies capable of binding antigen. The HC/LC interaction involves 4 domains: VH and CH1 from the HC and VL and CL from the LC. Human Fabs with κ LCs have been well characterized for their unfolding behaviors and demonstrate a significant level of cooperativity and stabilization when all 4 domains are intact. Very little is known regarding the thermodynamic properties of human Fabs with λ LCs. Here, we dissect the domain contributions to Fab stability for both κ and λ LC-containing Fabs. We find the cooperativity of unfolding between the constant domains, CH1/Cλ, and variable domains, VH/Vλ, within λ LC-containing Fabs is significantly weaker than that of κ LC-containing Fabs. The data suggests there may not be an evolutionary necessity for strong variable/constant domain cooperativity within λ LC-containing Fabs. After investigating the biophysical properties of Fabs with mismatched variable and constant domain subunits (e.g., VH/Vκ paired with CH1/Cλ or T cell receptor Cα/Cβ), the major role of the constant domains for both κ- and λ-containing Fabs may be to reduce the hydrophobic exposure at the VH/VL interface. Even though Fabs with these non-native pairings were thermodynamically less stable, they secreted well from mammalian cells as well behaved monodisperse proteins, which was in contrast to what was observed with the VH/Vκ and VH/Vλ scFvs that secreted as a mixture of monomer and aggregates.

  9. Clinical trial of an F(ab')(2) polyvalent equine antivenom for African snake bites in Benin

    OpenAIRE

    Chippaux, Jean-Philippe; Massougbodji, A.; Stock, R. P.; Alagon, A.

    2007-01-01

    We report the results of a trial designed to measure the safety and efficacy of African Antivipmyn((R)), a new freeze-dried polyvalent equine F(ab')(2)-based antivenom. We tested 289 envenomations. After treatment, 19% of treated patients had undesirable events, all benign. A possible adverse effect was attributed to this antivenom in 11% of the patients. Bleeding was observed in 48% of the patients; it stopped within 2 hours after treatment with antivenom in 60% of the patients. Blood incoag...

  10. A novel graphical technique for Pinch Analysis applications: Energy Targets and grassroots design

    International Nuclear Information System (INIS)

    Gadalla, Mamdouh A.

    2015-01-01

    Graphical abstract: A new HEN graphical design. - Highlights: • A new graphical technique for heat exchanger networks design. • Pinch Analysis principles and design rules are better interpreted. • Graphical guidelines for optimum heat integration. • New temperature-based graphs provide user-interactive features. - Abstract: Pinch Analysis is for decades a leading tool to energy integration for retrofit and design. This paper presents a new graphical technique, based on Pinch Analysis, for the grassroots design of heat exchanger networks. In the new graph, the temperatures of hot streams are plotted versus those of the cold streams. The temperature–temperature based graph is constructed to include temperatures of hot and cold streams as straight lines, horizontal lines for hot streams, and vertical lines for cold streams. The graph is applied to determine the pinch temperatures and Energy Targets. It is then used to synthesise graphically a complete exchanger network, achieving the Energy Targets. Within the new graph, exchangers are represented by inclined straight lines, whose slopes are proportional to the ratio of heat capacities and flows. Pinch Analysis principles for design are easily interpreted using this new graphical technique to design a complete exchanger network. Network designs achieved by the new technique can guarantee maximum heat recovery. The new technique can also be employed to simulate basic designs of heat exchanger networks. The strengths of the new tool are that it is simply applied using computers, requires no commercial software, and can be used for academic purposes/engineering education

  11. An investigative approach to explore optimum assembly process design for annular targets carrying LEU foil

    Science.gov (United States)

    Hoyer, Annemarie

    Technetium-99m is the most widely used nuclear isotope in the medical field, with nearly 80 to 85% of all diagnostic imaging procedures. The daughter isotope of molybdenum-99 is currently produced using weapons-grade uranium. A suggested design for aluminum targets carrying low-enriched uranium (LEU) foil is presented for the fulfillment of eliminating highly enriched uranium (HEU) for medical isotope production. The assembly process that this research focuses on is the conventional draw-plug process which is currently used and lastly the sealing process. The research is unique in that it is a systematic approach to explore the optimal target assembly process to produce those targets with the required quality and integrity. Conducting 9 parametric experiments, aluminum tubes with a nickel foil fission-barrier and a surrogate stainless steel foil are assembled, welded and then examined to find defects, to determine residual stresses, and to find the best cost-effective target dimensions. The experimental design consists of 9 assembly combinations that were found through orthogonal arrays in order to explore the significance of each factor. Using probabilistic modeling, the parametric study is investigated using the Taguchi method of robust analysis. Depending on the situation, optimal conditions may be a nominal, a minimized or occasionally a maximized condition. The results will provide the best target design and will give optimal quality with little or no assembly defects.

  12. Defect reduction in different periods of a fab's life

    Science.gov (United States)

    Kallis, Norbert

    1997-08-01

    The reduction of yield loss caused by particles is a key topic of productivity enhancement. It deals with many components of a fab's structure: (1) Cultural mindset of managers, engineers, and operators -- to have champions for that mission, (2) selection of defect metrology tools -- with high throughput and reliable data, (3) single equipment characterization -- to set challenging specs according to the best performing tool, (4) inline reaction procedures -- to transfer knowledge and responsibility to the operators, (5) statistical evaluation of large datasets -- including correlation to electrical yield, (6) and to trace back the way to the single tools or the low performing processes. This paper discusses some topics to be considered during process and equipment planning, ramp up, and mature production. It has been proven to be successful during a very aggressive ramp up in wafer starts and an even more convincing yield increase of a fab, that now started the production of DRAM's in quarter micron technology. It will conclude in an understanding, that besides a reliable statistical methodology the human performance is the key: can we really integrate people of different groups and levels of responsibility and motivate them to take joint actions for yield goals?

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

    International Nuclear Information System (INIS)

    Nakamura, Hiroo; Ida, Mizuho; Sugimoto, Masayoshi; Takeuchi, Hiroshi; Yutani, Toshiaki

    2001-01-01

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

  14. Target/blanket conceptual design for the Los Alamos ATW concept

    International Nuclear Information System (INIS)

    Ames, K.; Cappiello, M.; Ireland, J.; Sapir, J.; Farnum, G.

    1992-01-01

    The Los Alamos Accelerator Transmutation of Waste (ATW) concept has many potential applications that include defense waste transmutation, defense material production (i.e., tritium and 238 Pu), and the transmutation of hazardous nuclear wastes from commercial nuclear reactors (fission products and actinides). A more advanced long-term Los Alamos effort is investigating the potential of an accelerator- driven system to produce fission energy with a minimal nuclear waste stream. All applications employ a high-energy (800- to 1600-MeV), high-current (25--250 mA) proton linear accelerator as the driver. In this report, we discuss only the target/blanket conceptual design for the commercial nuclear waste application. A conceptual design for the target/blanket of the Los Alamos ATW concept has been presented. The neutronics, mechanical design, and heat transfer have been investigated in some detail for the base-case design. Much more work needs to be done, but at this point it appears that the design is feasible and will approach the design goal of supporting two commercial power reactors with each target/blanket module

  15. Fabrication of Quench Condensed Thin Films Using an Integrated MEMS Fab on a Chip

    Science.gov (United States)

    Lally, Richard; Reeves, Jeremy; Stark, Thomas; Barrett, Lawrence; Bishop, David

    Atomic calligraphy is a microelectromechanical systems (MEMS)-based dynamic stencil nanolithography technique. Integrating MEMS devices into a bonded stacked array of three die provides a unique platform for conducting quench condensed thin film mesoscopic experiments. The atomic calligraphy Fab on a Chip process incorporates metal film sources, electrostatic comb driven stencil plate, mass sensor, temperature sensor, and target surface into one multi-die assembly. Three separate die are created using the PolyMUMPs process and are flip-chip bonded together. A die containing joule heated sources must be prepared with metal for evaporation prior to assembly. A backside etch of the middle/central die exposes the moveable stencil plate allowing the flux to pass through the stencil from the source die to the target die. The chip assembly is mounted in a cryogenic system at ultra-high vacuum for depositing extremely thin films down to single layers of atoms across targeted electrodes. Experiments such as the effect of thin film alloys or added impurities on their superconductivity can be measured in situ with this process.

  16. Experimental study of lithium free-surface flow for IFMIF target design

    International Nuclear Information System (INIS)

    Kondo, H.; Fujisato, A.; Yamaoka, N.; Inoue, S.; Miyamoto, S.; Iida, T.; Nakamura, H.; Ida, M.; Matushita, I.; Muroga, T.; Horiike, H.

    2006-01-01

    Lithium free-surface flow experiments to verify the design of IFMIF target have been carried out at Osaka University. The present report summarizes experimental results of surface phenomena, and cavitation characteristics of the loop, so as to try to apply these results to design parameters. Waves on the lithium flow surface is similar to that on water, and can be predicted by a linear stability theory. The wave amplitude is measured by an electro-contact probe. Surface roughness on a target nozzle, caused for example by attached chemical compounds and/or wastages by erosion and corrosion, can lead to a significant loss of target flow stability as well as surface wakes. The need of a polishing manipulator or exchange of the nozzle may be anticipated. Cavitation characteristic of the loop was measured by an accelerometer. From the results, a friction factor could be estimated fort he lithium flow

  17. The experimental study on biodistribution and radioimmunoimaging of 131I labeled anti-lymphoma Fab antibody in nude mice bearing human B cell lymphoma

    International Nuclear Information System (INIS)

    Yang Xiaochun; Zhang Meihua; Shen Junkang; Shen Yongmei; Shi Yizhen; Liu Zengli

    2008-01-01

    Objective: Radioimmunoimaging is still an interesting study in the domain of nuclear medicine. The aim of this study was to evaluate the biodistribution and radioimmunoimaging of 131 I-Fab anti- body in nude mice beating human B cell lymphoma. Methods: The immunoreactivity of Fab antibody to Raji cells was analyzed by immunohistochemistry and flow cytometry. Fab antibody and CD20 monoclonal antibody (as control) were labeled with 131 I using Iodogen method. 131 I-Fab antibody or 131 I-CD20 was injected into nude mice bearing B cell lymphoma via tail veins. The biodistribution and radioimmunoimaging results were obtained at 2, 4, 8 and 24 h postinjection, respectively. Results: The results of immunohistochemistry and flow cytometry indicated that both Fab antibody and 131 I-Fab antibody could bind strongly with membrane antigens on Raji cells, and the binding rate reached above 87%. Clear tumor image was obtained at 8 h after injection with 131 I-Fab and elimination was observed at 24 h postinjection. The clear tumor image for 131 I-CD20 antibody was obtained at 24 h post injection. The biodistribution in vivo showed that the percentage activities of injection dose per gram of tumor (% ID/g) of 131 I-Fab group at 2, 4, 8 h postinjection were higher than that of 131 I-CD20 antibody [(1.37±0.28), (1.84±0.13), (2.21±0.15)% ID/g vs (0.33±0.06), (0.62±0.08), (1.46±0.24)% ID/g, respectively; F=52.22, 278.42 and 29.00, all P 131 I-Fad and 131 I-CD20 groups at 2, 4, 8 and 24 h were [(0.22±0.03)-(5.44± 0.31)] vs[(0.04±0.01)-(3.10±0.29)], [(0.43±0.11) - (21.01±3.97)] vs [(0.11±0.05) - (7.99±1.81)], [(1.09±0.07) -(20.28±2.77)] vs [(0.48±0.06) - (23.55±1.69)], [(1.12± 0.02) - (10.29±1.78)] vs [(2.32 ± 0.34) - (33.23±6.83)], respectively. Conclusion: 131 I-Fab anti- body has advantages of small molecular weight, excellent targeting characteristics, early imaging and fast elimination, which indicates the potential application value in diagnosing B cell

  18. EDRP public local inquiry, UKAEA/BNFL precognition on: Risk targets and EDRP design

    International Nuclear Information System (INIS)

    Brown, M.L.

    1986-06-01

    A full description is presented of the extent to which risk is controlled by the targets to be implemented in the proposed EDRP design, including a discussion of a particular accident sequence. Risk expressions and the usefulness of risk criteria are reviewed. Details are given of the accident consequence modelling as used by the UKAEA. Terrorist attack and sabotage are briefly discussed. (UK)

  19. Design of block-copolymer-based micelles for active and passive targeting

    NARCIS (Netherlands)

    Lebouille, Jérôme G J L; Leermakers, Frans A M; Cohen Stuart, Martien A.; Tuinier, Remco

    2016-01-01

    A self-consistent field study is presented on the design of active and passive targeting block-copolymeric micelles. These micelles form in water by self-assembly of triblock copolymers with a hydrophilic middle block and two hydrophobic outer blocks. A minority amount of diblock copolymers with the

  20. Design of block-copolymer-based micelles for active and passive targeting

    NARCIS (Netherlands)

    Lebouille, Jérôme G.J.L.; Leermakers, Frans A.M.; Cohen Stuart, Martien A.; Tuinier, Remco

    2016-01-01

    A self-consistent field study is presented on the design of active and passive targeting block-copolymeric micelles. These micelles form in water by self-assembly of triblock copolymers with a hydrophilic middle block and two hydrophobic outer blocks. A minority amount of diblock copolymers with

  1. Design of a deuterium and tritium-ablator shock ignition target for the National Ignition Facility

    International Nuclear Information System (INIS)

    Terry, Matthew R.; Perkins, L. John; Sepke, Scott M.

    2012-01-01

    Shock ignition presents a viable path to ignition and high gain on the National Ignition Facility (NIF). In this paper, we describe the development of the 1D design of 0.5 MJ class, all-deuterium and tritium (fuel and ablator) shock ignition target that should be reasonably robust to Rayleigh-Taylor fluid instabilities, mistiming, and hot electron preheat. The target assumes “day one” NIF hardware and produces a yield of 31 MJ with reasonable allowances for laser backscatter, absorption efficiency, and polar drive power variation. The energetics of polar drive laser absorption require a beam configuration with half of the NIF quads dedicated to launching the ignitor shock, while the remaining quads drive the target compression. Hydrodynamic scaling of the target suggests that gains of 75 and yields 70 MJ may be possible.

  2. Shock ignition: a brief overview and progress in the design of robust targets

    International Nuclear Information System (INIS)

    Atzeni, S; Marocchino, A; Schiavi, A

    2015-01-01

    Shock ignition is a laser direct-drive inertial confinement fusion (ICF) scheme in which the stages of compression and hot spot formation are partly separated. The fuel is first imploded at a lower velocity than in conventional ICF, reducing the threats due to Rayleigh–Taylor instability. Close to stagnation, an intense laser spike drives a strong converging shock, which contributes to hot spot formation. This paper starts with a brief overview of the theoretical studies, target design and experimental results on shock ignition. The second part of the paper illustrates original work aiming at the design of robust targets and computation of the relevant gain curves. Following Chang et al (2010 Phys. Rev. Lett. 104 135002) a safety factor for high gain, ITF* (analogous to the ignition threshold factor ITF introduced by Clark et al (2008 Phys. Plasmas 15 056305)), is evaluated by means of parametric 1D simulations with artificially reduced reactivity. SI designs scaled as in Atzeni et al (2013 New J. Phys. 15 045004) are found to have nearly the same ITF*. For a given target, such ITF* increases with implosion velocity and laser spike power. A gain curve with a prescribed ITF* can then be simply generated by upscaling a reference target with that value of ITF*. An interesting option is scaling in size by reducing the implosion velocity to keep the ratio of implosion velocity to self-ignition velocity constant. At a given total laser energy, targets with higher ITF* are driven to higher implosion velocity and achieve a somewhat lower gain. However, a 1D gain higher than 100 is achieved at an (incident) energy below 1 MJ, an implosion velocity below 300 km s −1 and a peak incident power below 400 TW. 2D simulations of mispositioned targets show that targets with a higher ITF* indeed tolerate larger displacements. (paper)

  3. Target design for high fusion yield with the double Z-pinch-driven hohlraum

    International Nuclear Information System (INIS)

    Vesey, R. A.; Herrmann, M. C.; Lemke, R. W.; Desjarlais, M. P.; Cuneo, M. E.; Stygar, W. A.; Bennett, G. R.; Campbell, R. B.; Christenson, P. J.; Mehlhorn, T. A.; Porter, J. L.; Slutz, S. A.

    2007-01-01

    A key demonstration on the path to inertial fusion energy is the achievement of high fusion yield (hundreds of MJ) and high target gain. Toward this goal, an indirect-drive high-yield inertial confinement fusion (ICF) target involving two Z-pinch x-ray sources heating a central secondary hohlraum is described by Hammer et al. [Phys. Plasmas 6, 2129 (1999)]. In subsequent research at Sandia National Laboratories, theoretical/computational models have been developed and an extensive series of validation experiments have been performed to study hohlraum energetics, capsule coupling, and capsule implosion symmetry for this system. These models have been used to design a high-yield Z-pinch-driven ICF target that incorporates the latest experience in capsule design, hohlraum symmetry control, and x-ray production by Z pinches. An x-ray energy output of 9 MJ per pinch, suitably pulse-shaped, is sufficient for this concept to drive 0.3-0.5 GJ capsules. For the first time, integrated two-dimensional (2D) hohlraum/capsule radiation-hydrodynamics simulations have demonstrated adequate hohlraum coupling, time-dependent radiation symmetry control, and the successful implosion, ignition, and burn of a high-yield capsule in the double Z-pinch hohlraum. An important new feature of this target design is mode-selective symmetry control: the use of burn-through shields offset from the capsule that selectively tune certain low-order asymmetry modes (P 2 ,P 4 ) without significantly perturbing higher-order modes and without a significant energy penalty. This paper will describe the capsule and hohlraum design that have produced 0.4-0.5 GJ yields in 2D simulations, provide a preliminary estimate of the Z-pinch load and accelerator requirements necessary to drive the system, and suggest future directions for target design work

  4. Isolation of a human anti-epidermal growth factor receptor Fab antibody, EG-19-11, with subnanomolar affinity from naïve immunoglobulin repertoires using a hierarchical antibody library system.

    Science.gov (United States)

    Hur, Byung-ung; Yoon, Jae-bong; Liu, Li-Kun; Cha, Sang-hoon

    2010-11-30

    Specific antibodies that possess a subnanomolar affinity are very difficult to obtain from human naïve immunoglobulin repertoires without the use of lengthy affinity optimization procedures. Here, we designed a hierarchical phage-displayed antibody library system to generate an enormous diversity of combinatorial Fab fragments (6×10(17)) and attempted to isolate high-affinity Fabs against the human epidermal growth factor receptor (EGFR). A primary antibody library, designated HuDVFab-8L, comprising 4.5×10(9) human naïve heavy chains and eight unspecified human naïve light chains was selected against the EGFR-Fc protein by biopanning, and four anti-EGFR Fab clones were isolated. Because one of the Fab clones, denoted EG-L2-11, recognized a native EGFR expressed on A431 cells, the heavy chain of the Fab was shuffled with a human naïve light chain repertoire with a diversity of 1.4×10(8) and selected a second time against the EGFR-Fc protein again. One EG-L2-11 variant, denoted EG-19-11, recognized an EGFR epitope that was almost the same as that bound by cetuximab and had a K(D) of approximately 540 pM for soluble EGFR, which is about 7-fold higher than that of the FabC225 derived from cetuximab. This variant was also internalized by A431 cells, likely via receptor-mediated endocytosis, and it efficiently inhibited EGF-mediated tyrosine phosphorylation of the EGFR. These results demonstrate that the use of our hierarchical antibody library system is advantageous in generating fully human antibodies especially with a therapeutic purpose. Copyright © 2010 Elsevier B.V. All rights reserved.

  5. Proton-beam window design for a transmutation facility operating with a liquid lead target

    Energy Technology Data Exchange (ETDEWEB)

    Jansen, C.; Lypsch, F.; Lizana, P. [Institute for Safety Research and Reactor Technology, Juelich (Germany)] [and others

    1995-10-01

    The proton beam target of an accelerator-driven transmutation facility can be designed as a vertical liquid lead column. To prevent lead vapor from entering the accelerator vacuum, a proton-beam window has to separate the area above the lead surface from the accelerator tube. Two radiation-cooled design alternatives have been investigated which should withstand a proton beam of 1.6 GeV and 25 mA. Temperature calculations based on energy deposition calculations with the Monte Carlo code HETC, stability analysis and spallation-induced damage calculations have been performed showing the applicability of both designs.

  6. Statistical inference on censored data for targeted clinical trials under enrichment design.

    Science.gov (United States)

    Chen, Chen-Fang; Lin, Jr-Rung; Liu, Jen-Pei

    2013-01-01

    For the traditional clinical trials, inclusion and exclusion criteria are usually based on some clinical endpoints; the genetic or genomic variability of the trial participants are not totally utilized in the criteria. After completion of the human genome project, the disease targets at the molecular level can be identified and can be utilized for the treatment of diseases. However, the accuracy of diagnostic devices for identification of such molecular targets is usually not perfect. Some of the patients enrolled in targeted clinical trials with a positive result for the molecular target might not have the specific molecular targets. As a result, the treatment effect may be underestimated in the patient population truly with the molecular target. To resolve this issue, under the exponential distribution, we develop inferential procedures for the treatment effects of the targeted drug based on the censored endpoints in the patients truly with the molecular targets. Under an enrichment design, we propose using the expectation-maximization algorithm in conjunction with the bootstrap technique to incorporate the inaccuracy of the diagnostic device for detection of the molecular targets on the inference of the treatment effects. A simulation study was conducted to empirically investigate the performance of the proposed methods. Simulation results demonstrate that under the exponential distribution, the proposed estimator is nearly unbiased with adequate precision, and the confidence interval can provide adequate coverage probability. In addition, the proposed testing procedure can adequately control the size with sufficient power. On the other hand, when the proportional hazard assumption is violated, additional simulation studies show that the type I error rate is not controlled at the nominal level and is an increasing function of the positive predictive value. A numerical example illustrates the proposed procedures. Copyright © 2013 John Wiley & Sons, Ltd.

  7. Fab glycosylation of immunoglobulin G does not associate with improvement of rheumatoid arthritis during pregnancy.

    Science.gov (United States)

    Bondt, Albert; Wuhrer, Manfred; Kuijper, T Martijn; Hazes, Johanna M W; Dolhain, Radboud J E M

    2016-11-25

    Changes in immunoglobulin G (IgG) constant domain (Fc) glycosylation are associated with changes in rheumatoid arthritis (RA) disease activity in response to pregnancy. Here, we sought to determine whether the same holds true for variable domain (Fab) glycosylation. IgGs were captured from RA and control sera obtained before (RA only), during and after pregnancy, followed by Fc and Fab separation, glycan release, and mass spectrometric detection. In parallel, glycans from intact IgG were analysed. The data was used to calculate glycosylation traits, and to estimate the level of Fab glycosylation. The overall level of Fab glycosylation was increased in RA patients compared to controls, while no differences in Fab glycosylation patterns were found. For the Fc and intact IgG (Total) previously observed differences in galactosylation and bisection were confirmed. Furthermore, increased galactosylation of Fc and Total were associated with lower disease activity and autoantibody positivity. In addition, the change in Fc galactosylation associated with the change in disease activity during pregnancy and after delivery, while this was not the case for Fab. In contrast to changes in Fc glycosylation, changes in Fab glycosylation are not associated with improvement of RA during pregnancy and arthritis flare after delivery.

  8. 'Zipbody' leucine zipper-fused Fab in E. coli in vitro and in vivo expression systems.

    Science.gov (United States)

    Ojima-Kato, Teruyo; Fukui, Kansuke; Yamamoto, Hiroaki; Hashimura, Dai; Miyake, Shiro; Hirakawa, Yuki; Yamasaki, Tomomi; Kojima, Takaaki; Nakano, Hideo

    2016-04-01

    A small antibody fragment, fragment of antigen binding (Fab), is favorable for various immunological assays. However, production efficiency of active Fab in microorganisms depends considerably on the clones. In this study, leucine zipper-peptide pairs that dimerize in parallel (ACID-p1 (LZA)/BASE-p1 (LZB) or c-Jun/c-Fos) were fused to the C-terminus of heavy chain (Hc, VH-CH1) and light chain (Lc, VL-CL), respectively, to accelerate the association of Hc and Lc to form Fab in Escherichia coli in vivo and in vitro expression systems. The leucine zipper-fused Fab named 'Zipbody' was constructed using anti-E. coli O157 monoclonal antibody obtained from mouse hybridoma and produced in both in vitro and in vivo expression systems in an active form, whereas Fab without the leucine zipper fusion was not. Similarly, Zipbody of rabbit monoclonal antibody produced in in vitro expression showed significant activity. The purified, mouse Zipbody produced in the E. coli strain Shuffle T7 Express had specificity toward the antigen; in bio-layer interferometry analysis, the KD value was measured to be 1.5-2.0 × 10(-8) M. These results indicate that leucine zipper fusion to Fab C-termini markedly enhances active Fab formation in E. coli. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  9. Isolation of human anti-serum albumin Fab antibodies with an extended serum-half life.

    Science.gov (United States)

    Kang, Hyeon-Ju; Kim, Hye-Jin; Cha, Sang-Hoon

    2016-01-01

    The serum albumin (SA) has been exploited to generate long-acting biotherapeutics by taking advantage of the FcRn-mediated recycling mechanism in a direct or an indirect way. Since Fab fragments have been proven to be clinically safe for human usage, we assumed that human anti-SA Fab antibodies could have a great potential as a carrier molecule to extend the serum half-life of therapeutic proteins. We, herein, had attempted to isolate anti-SA Fab antibodies from HuDVFab-8L antibody library via a phage display technology, and identified eight discrete human Fab antibodies. One of the Fab antibodies, SL335, showed the strongest binding reactivity to human SA with nM range of affinity at both pH 6 and pH 7.4, and cross-reacted to SAs from various species including rat, mouse, canine and monkey. The in vivo pharmacokinetic assay using a rat model indicated that SL335 has approximately 10 fold longer serum half-life and 26 to 44-fold increase in AUC0 → ∞ compared to the negative control Fab molecule in both intravenous and subcutaneous administrations. Knowing that Fabs have proven to be safe in clinics for a long time, SL335 seems to have a great potential in generating long-acting protein drugs by tagging effector molecules with either chemical conjugation or genetic fusion. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Structural features of Fab fragments of rheumatoid factor IgM-RF in solution

    International Nuclear Information System (INIS)

    Volkov, V. V.; Lapuk, V. A.; Shtykova, E. V.; Stepina, N. D.; Dembo, K. A.; Sokolova, A. V.; Amarantov, S. V.; Timofeev, V. P.; Ziganshin, R. Kh.; Varlamova, E. Yu.

    2008-01-01

    The structural features of the Fab fragments of monoclonal (Waldenstroem's disease) immunoglobulin M (IgM) and rheumatoid immunoglobulin M (IgM-RF) were studied by a complex of methods, including small-angle X-ray scattering (SAXS), electron spin resonance (ESR), and mass spectrometry (MS). The Fab-RF fragment was demonstrated to be much more flexible in the region of interdomain contacts, the molecular weights and the shapes of the Fab and Fab-RF macromolecules in solution being only slightly different. According to the ESR data, the rotational correlation time for a spin label introduced into the peptide sequence for Fab is twice as large as that for Fab-RF (21±2 and 11±1 ns, respectively), whereas the molecular weights of these fragments differ by only 0.5% (mass-spectrometric data), which correlates with the results of molecular-shape modeling by small-angle X-ray scattering. The conclusion about the higher flexibility of the Fab-RF fragment contributes to an understanding of the specificity of interactions between the rheumatoid factor and the antigens of the own organism.

  11. Mechanistic and quantitative insight into cell surface targeted molecular imaging agent design.

    Science.gov (United States)

    Zhang, Liang; Bhatnagar, Sumit; Deschenes, Emily; Thurber, Greg M

    2016-05-05

    Molecular imaging agent design involves simultaneously optimizing multiple probe properties. While several desired characteristics are straightforward, including high affinity and low non-specific background signal, in practice there are quantitative trade-offs between these properties. These include plasma clearance, where fast clearance lowers background signal but can reduce target uptake, and binding, where high affinity compounds sometimes suffer from lower stability or increased non-specific interactions. Further complicating probe development, many of the optimal parameters vary depending on both target tissue and imaging agent properties, making empirical approaches or previous experience difficult to translate. Here, we focus on low molecular weight compounds targeting extracellular receptors, which have some of the highest contrast values for imaging agents. We use a mechanistic approach to provide a quantitative framework for weighing trade-offs between molecules. Our results show that specific target uptake is well-described by quantitative simulations for a variety of targeting agents, whereas non-specific background signal is more difficult to predict. Two in vitro experimental methods for estimating background signal in vivo are compared - non-specific cellular uptake and plasma protein binding. Together, these data provide a quantitative method to guide probe design and focus animal work for more cost-effective and time-efficient development of molecular imaging agents.

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

    Science.gov (United States)

    Macfarlane, Joseph; Golovkin, Igor; Sebald, James

    2017-10-01

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

  13. Single-reagent one-step procedures for the purification of ovine IgG, F(ab')2 and Fab antivenoms by caprylic acid.

    Science.gov (United States)

    Al-Abdulla, Ibrahim; Casewell, Nicholas R; Landon, John

    2014-01-15

    Antivenoms are typically produced in horses or sheep and often purified using salt precipitation of immunoglobulins or F(ab')2 fragments. Caprylic (octanoic) acid fractionation of antiserum has the advantage of not precipitating the desired antibodies, thereby avoiding potential degradation that can lead to the formation of aggregates, which may be the cause of some adverse reactions to antivenoms. Here we report that when optimising the purification of immunoglobulins from ovine antiserum raised against snake venom, caprylic acid was found to have no effect on the activity of the enzymes pepsin and papain, which are employed in antivenom manufacturing to digest immunoglobulins to obtain F(ab')2 and Fab fragments, respectively. A "single-reagent" method was developed for the production of F(ab')2 antivenom whereby whole ovine antiserum was mixed with both caprylic acid and pepsin and incubated for 4h at 37°C. For ovine Fab antivenom production from whole antiserum, the "single reagent" comprised of caprylic acid, papain and l-cysteine; after incubation at 37°C for 18-20h, iodoacetamide was added to stop the reaction. Caprylic acid facilitated the precipitation of albumin, resulting in a reduced protein load presented to the digestion enzymes, culminating in substantial reductions in processing time. The ovine IgG, F(ab')2 and Fab products obtained using these novel caprylic acid methods were comparable in terms of yield, purity and specific activity to those obtained by multi-step conventional salt fractionation with sodium sulphate. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Fab fragments of ovine antibody to colchicine enhance its clearance in the rat.

    Science.gov (United States)

    Peake, Philip W; Pianta, Timothy J; Succar, Lena; Fernando, Mangalee; Buckley, Nicholas A; Endre, Zoltan H

    2015-06-01

    Colchicine is an anti-inflammatory alkaloid used for the treatment of acute gout, but has a narrow therapeutic index. Colchicine overdoses are relatively rare, but have high mortality requiring rapid treatment. To evaluate the ability of a newly available ovine fragment antigen-binding (Fab) antibody to colchicine (ColchiFab(™)) to protect rats against renal and other injury 24 h after colchicine ingestion. Rats were gavaged with colchicine (5 mg/kg), then 2 h later injected intraperitoneally with 5 ml of sterile saline, or Fab anti-colchicine, a newly available ovine antibody to colchicine. Samples of blood were taken at 1, 2, 5 and 24 h after gavage, and urine was collected from 5 to 24 h after gavage. Concentrations of colchicine in tissue, blood and urine were measured by liquid chromatography/mass spectrometry, concentrations of Fab anti-colchicine, urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 or KIM-1 by enzyme-linked immunosorbent assay or ELISA, while concentrations of creatine kinase and creatinine (Cr) were measured enzymatically. Colchicine equilibrated rapidly throughout the body and increased serum creatine kinase. Fab anti-colchicine also rapidly redistributed to the blood and remained at high concentrations over 24 h. Fab anti-colchicine caused a rapid 7.1-fold increase in serum colchicine level, followed by excretion of both colchicine and Fab anti-colchicine through the urine. This was associated with the accumulation of colchicine in the kidney, a reversal of colchicine-induced diarrhoea, and increasing urinary NGAL level; from 168 ± 48 to 477 ± 255 ng/mmol Cr [mean ± standard deviation or SD]. Fab anti-colchicine greatly increased the clearance of colchicine, although increasing NGAL level suggested the presence of mild kidney damage. These data suggest clinical utility for Fab anti-colchicine in the treatment of colchicine overdose.

  15. Assistant in design of tissue targeting leads with radio-combinatorial screening vivo

    International Nuclear Information System (INIS)

    Liu Ciyi; Zeng Jun; Xie Wenhui; Hu Silong; Jin Muxiu

    2004-01-01

    The diagnostic and therapeutic efficiency of drug depends highly on the drug distribution in target tissues (tumor for example) both specifically and accumulatively. We report here a powerful approach in design of tissue targeting leads with the assistant of radio-combinatorial screening technique developed in our laboratory. Methods: The C-terminal amide tripeptide libraries were synthesized on Rink Amide-MBHA resin in the OXX aO1OXaO1O2O positional scanning format and iterative protoco. A technetium (V) oxo core[(TcO)3+] was bound to the N4-triligands of tripeptide libraries via four deprotonated anfide nitrogen atoms to form a structure of 99Tcm-tripeptoid libraries. The radio-combinatorial screening (RCS) in vivo was then carried out after SD rats and A549 tumor bearing mice received i.v. with 99Tcm-tripeptoid libraries. Results: Signals of tissue distribution and metabolism of libraries were recorded by g counting or imaging. From library of 8,000 99Tcm-tripeptoid members, the tissue targeting leads had been identified by RCS. Those included 99Tcm-DSG (RES), 99Tcm-VAA, and 99Tcm-VIG that had specific tissue targeting in kidney, stomach, and liver respectively. The percent injected dose per gram tissue (%ID/g) of 99Tcm labeled leads in their target tissues was highly structure-dependent The discovery of 99Tcm-VAA and 99Tcm-VIG indicates that side chain methyl at positionl and 2 are crucial for stomach and liver accumulating 99Tcm-tripeptoids. In the case of kidney targeting, Ser in the position 2 and 3 is crucial for 99Tcm-tripeptoids renal excretion and accumulation characteristics respectively. Conclusion: RCS in vivo is a powerful tool for design of tissue targeting leads. (authors)

  16. Design of a tensor polarized deuterium target polarized by spin-exchange with optically pumped NA

    International Nuclear Information System (INIS)

    Green, M.C.

    1984-01-01

    A proposed design for a tensor polarized deuterium target (approx. 10 15 atoms/cm 2 ) for nuclear physics studies in an electron storage ring accelerator is presented. The deuterium atoms undergo electron spin exchange with a highly polarized sodium vapor; this polarization is transferred to the deuterium nuclei via the hyperfine interaction. The deuterium nuclei obtain their tensor polarization through repeated electron spin exchange/hyperfine interactions. The sodium vapor polarization is maintained by standard optical pumping techniques. Model calculations are presented in detail leading to a discussion of the expected performance and the technical obstacles to be surmounted in the development of such a target

  17. Design of a tensor polarized deuterium target polarized by spin-exchange with optically pumped NA

    International Nuclear Information System (INIS)

    Green, M.C.

    1984-05-01

    A proposed design for a tensor polarized deuterium target (approx. 10 15 atoms/cm 2 ) for nuclear physics studies in an electron storage ring accelerator is presented. The deuterium atoms undergo electron spin exchange with a highly polarized sodium vapor; this polarization is transferred to the deuterium nuclei via the hyperfine interaction. The deuterium nuclei obtain their tensor polarization through repeated electron spin exchange/hyperfine interactions. The sodium vapor polarization is maintained by standard optical pumping techniques. Model calculations are presented in detail leading to a discussion of the expected performance and the technical obstacles to be surmounted in the development of such a target. 15 references, 10 figures

  18. Validation of a new design of tellurium dioide-irradiated target

    Energy Technology Data Exchange (ETDEWEB)

    Fllaoui, Aziz; Ghamad, Younes; Zoubir, Brahim; Ayaz, Zinel Abidine; El Morabiti, Aissam; Amayoud, Hafid [Centre National de l' Energie des Sciences et des Techniques Nucleaires, Rabat (Morocco); Chakir, El Mahjoub [Nuclear Physics Department, University Ibn Toufail, Kenitra (Morocco)

    2016-10-15

    Production of iodine-131 by neutron activation of tellurium in tellurium dioxide (TeO{sub 2}) material requires a target that meets the safety requirements. In a radiopharmaceutical production unit, a new lid for a can was designed, which permits tight sealing of the target by using tungsten inert gas welding. The leakage rate of all prepared targets was assessed using a helium mass spectrometer. The accepted leakage rate is ≤ 10 - 4 mbr.L/s, according to the approved safety report related to iodine-131 production in the TRIGA Mark II research reactor (TRIGA: Training, Research, Isotopes, General Atomics). To confirm the resistance of the new design to the irradiation conditions in the TRIGA Mark II research reactor's central thimble, a study of heat effect on the sealed targets for 7 hours in an oven was conducted and the leakage rates were evaluated. The results show that the tightness of the targets is ensured up to 600 .deg. C with the appearance of deformations on lids beyond 450 .deg. C. The study of heat transfer through the target was conducted by adopting a one-dimensional approximation, under consideration of the three transfer modes-convection, conduction, and radiation. The quantities of heat generated by gamma and neutron heating were calculated by a validated computational model for the neutronic simulation of the TRIGA Mark II research reactor using the Monte Carlo N-Particle transport code. Using the heat transfer equations according to the three modes of heat transfer, the thermal study of I-131 production by irradiation of the target in the central thimble showed that the temperatures of materials do not exceed the corresponding melting points. To validate this new design, several targets have been irradiated in the central thimble according to a preplanned irradiation program, going from 4 hours of irradiation at a power level of 0.5 MW up to 35 hours (7 h/d for 5 days a week) at 1.5 MW. The results show that the irradiated targets are

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

    Directory of Open Access Journals (Sweden)

    Aziz Fllaoui

    2016-10-01

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

  20. Family of Advanced Beyond Line-of-Sight Terminals (FAB-T)

    Science.gov (United States)

    2015-12-01

    Selected Acquisition Report (SAR) RCS: DD-A&T(Q&A)823-199 Family of Advanced Beyond Line-of-Sight Terminals ( FAB -T) As of FY 2017 President’s...Budget Defense Acquisition Management Information Retrieval (DAMIR) March 21, 2016 15:24:15 UNCLASSIFIED FAB -T December 2015 SAR March 21, 2016 15:24...Operational Requirements Document OSD - Office of the Secretary of Defense O&S - Operating and Support PAUC - Program Acquisition Unit Cost FAB -T December 2015

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

    International Nuclear Information System (INIS)

    Laffite, S.; Loiseau, P.

    2010-01-01

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

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

    Science.gov (United States)

    Laffite, S.; Loiseau, P.

    2010-10-01

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

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

    Science.gov (United States)

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

    2017-06-12

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

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

    Directory of Open Access Journals (Sweden)

    Ana Giménez

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

  5. Design of the fill/transfer station cryostat for the OMEGA cryogenic target system

    International Nuclear Information System (INIS)

    Gibson, C.R.; Charmin, C.M.; Del Bene, J.V.; Hoffmann, E.H.; Besenbruch, G.E.; Anteby, I.

    1997-09-01

    General Atomics is designing, testing and fabricating a system for supplying cryogenic targets for the University of Rochester's OMEGA laser system. A prototype system has demonstrated the filling of 1 mm diameter, 3 microm wall plastic spheres to 111 MPa (1,100 atm) with deuterium and then cooling to 18 K to condense the fuel. The production design must be capable of routinely filling and cooling targets with a 50/50 mix of deuterium and tritium and transferring them to a device which places the targets into the focus of 60 laser beams. This paper discusses the design and analysis of the production Fill/Transfer Station cryostat. The cryostat has two major components, a fixed base and a removable dome. The joint between the base and the dome is similar to a bayonet fitting and is sealed by a room temperature elastomeric o-ring. Since the cryostat must be housed in a glovebox, its design is driven strongly by maintenance requirements. To reach the equipment inside the cryostat, the dome is simply unbolted and lifted. The inside of the cryostat is maintained at 16 K by a closed loop helium flow system. Gaseous helium at about 1.4 MPa (200 psi) flows through tubes which are brazed to the inner walls. Cooling is provided by several cryocoolers which are located external to the cryostat. Liquid nitrogen is used as a heat intercept and to precool the helium gas

  6. Primary design of Si cooling arm structure in ICF cryogenic target

    International Nuclear Information System (INIS)

    Zhang Yong; Yi Yong; Tang Changhuan; Zhang Jicheng

    2013-01-01

    According to the requirement of the cryogenic target system to the Si cooling arm structure, the Si cooling arm was primarily designed based on the USA National Ignition Facility (NIF) target. A new three-dimensional model of Si cooling arm was developed by SolidWorks software, and the simulation and analysis of Si cooling arm in aspect of mechanical property, thermal response and assembly were made based on the model. A law about the effect of the arm length of Si cooling arm and the width and the length of bifurcation on Si cooling arm was achieved. The research may provide the theoretical foundation and reference for the further improvement of cryogenic target. (authors)

  7. A Study on Control System Design Based on ARM Sea Target Search System

    Directory of Open Access Journals (Sweden)

    Lin Xinwei

    2015-01-01

    Full Text Available The infrared detector is used for sea target search, which can assist humans in searching suspicious objects at night and under poor visibility conditions, and improving search efficiency. This paper applies for interrupt and stack technology to solve problems of data losses that may be caused by one-to-many multi-byte protocol communication. Meanwhile, this paper implements hardware and software design of the system based on industrial-grade ARM control chip and uC / OS-II embedded operating system. The control system in the sea target search system is an information exchange and control center of the whole system, which solves the problem of controlling over the shooting angle of the infrared detector in the process of target search. After testing, the control system operates stably and reliably, and realizes rotation and control functions of the pan/tilt platform during automatic search, manual search and track.

  8. TRAC analysis of design basis events for the accelerator production of tritium target/blanket

    International Nuclear Information System (INIS)

    Lin, J.C.; Elson, J.

    1997-01-01

    A two-loop primary cooling system with a residual heat removal system was designed to mitigate the heat generated in the tungsten neutron source rods inside the rungs of the ladders and the shell of the rungs. The Transient Reactor Analysis Code (TRAC) was used to analyze the thermal-hydraulic behavior of the primary cooling system during a pump coastdown transient; a cold-leg, large-break loss-of-coolant accident (LBLOCA); a hot-leg LBLOCA; and a target downcomer LBLOCA. The TRAC analysis results showed that the heat generated in the tungsten neutron source rods can be mitigated by the primary cooling system for the pump coastdown transient and all the LBLOCAs except the target downcomer LBLOCA. For the target downcomer LBLOCA, a cavity flood system is required to fill the cavity with water at a level above the large fixed headers

  9. Matching the Decay Half-Life with the Biological Half-Life: ImmunoPET Imaging with 44Sc-Labeled Cetuximab Fab Fragment

    Science.gov (United States)

    2015-01-01

    Scandium-44 (t1/2 = 3.9 h) is a relatively new radioisotope of potential interest for use in clinical positron emission tomography (PET). Herein, we report, for the first time, the room-temperature radiolabeling of proteins with 44Sc for in vivo PET imaging. For this purpose, the Fab fragment of Cetuximab, a monoclonal antibody that binds with high affinity to epidermal growth factor receptor (EGFR), was generated and conjugated with N-[(R)-2-amino-3-(para-isothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N′,N″,N″-pentaacetic acid (CHX-A″-DTPA). The high purity of Cetuximab-Fab was confirmed by SDS-PAGE and mass spectrometry. The potential of the bioconjugate for PET imaging of EGFR expression in human glioblastoma (U87MG) tumor-bearing mice was investigated after 44Sc labeling. PET imaging revealed rapid tumor uptake (maximum uptake of ∼12% ID/g at 4 h postinjection) of 44Sc–CHX-A″-DTPA–Cetuximab-Fab with excellent tumor-to-background ratio, which might allow for same day PET imaging in future clinical studies. Immunofluorescence staining was conducted to correlate tracer uptake in the tumor and normal tissues with EGFR expression. This successful strategy for immunoPET imaging of EGFR expression using 44Sc–CHX-A″-DTPA–Cetuximab-Fab can make clinically translatable advances to select the right population of patients for EGFR-targeted therapy and also to monitor the therapeutic efficacy of anti-EGFR treatments. PMID:25389697

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

    International Nuclear Information System (INIS)

    Tanaka, F.; Hibiki, T.; Saito, Y.; Takeda, T.; Mishima, K.

    2001-01-01

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

  11. Conceptual design of low activation target chamber and components for the National Ignition Facility

    International Nuclear Information System (INIS)

    Streckert, H.H.; Schultz, K.R.; Sager, G.T.; Kantner, R.D.

    1996-01-01

    The baseline design for the target chamber and chamber components for the National Ignition Facility (NIF) consists of aluminum alloy structural material. Low activation composite chamber and components have important advantages including enhanced environmental and safety characteristics and improved accessibility due to reduced neutron-induced radioactivity. A low activation chamber can be fabricated from carbon fiber reinforced epoxy using thick wall laminate technology similar to submarine bow dome fabrication for the U.S. Navy. A risk assessment analysis indicates that a composite chamber has a reasonably high probability of success, but that an aluminum alloy chamber represents a lower risk. Use of low activation composite materials for several chamber components such as the final optics assemblies, the target positioner and inserter, the diagnostics manipulator tubes, and the optics beam tubes would offer an opportunity to make significant reductions in post-shot radiation dose rate with smaller, less immediate impact on the NIF design. 7 refs., 3 figs

  12. Design of a control system for HIRFL-CSRe internal target facility in Lanzhou

    International Nuclear Information System (INIS)

    Wang Yanyu; Liu Wufeng; Shao Caojie; Lin Feiyu; Zhang Jianchuan; Xiao Wenjun

    2010-01-01

    It is described in this paper the design of the control system for HIRFL-CSRe internal target facility, in which there are many different kinds of units need to be monitored and controlled. The control system is composed of several subsystems which are designed to control the gas-jet temperature, chamber vacuum, valves and molecular pumps. A human-computer interaction interface is also realized to do the data acquisition, data processing and display. The whole system has been working stably and safely, it fully meets the requirements of physical experiments in the internal target facility. In January of 2010, the first physics experiment of the radioactive electron capture was finished successfully with the aids of this control system. (authors)

  13. Automated reticle inspection data analysis for wafer fabs

    Science.gov (United States)

    Summers, Derek; Chen, Gong; Reese, Bryan; Hutchinson, Trent; Liesching, Marcus; Ying, Hai; Dover, Russell

    2009-04-01

    To minimize potential wafer yield loss due to mask defects, most wafer fabs implement some form of reticle inspection system to monitor photomask quality in high-volume wafer manufacturing environments. Traditionally, experienced operators review reticle defects found by an inspection tool and then manually classify each defect as 'pass, warn, or fail' based on its size and location. However, in the event reticle defects are suspected of causing repeating wafer defects on a completed wafer, potential defects on all associated reticles must be manually searched on a layer-by-layer basis in an effort to identify the reticle responsible for the wafer yield loss. This 'problem reticle' search process is a very tedious and time-consuming task and may cause extended manufacturing line-down situations. Often times, Process Engineers and other team members need to manually investigate several reticle inspection reports to determine if yield loss can be tied to a specific layer. Because of the very nature of this detailed work, calculation errors may occur resulting in an incorrect root cause analysis effort. These delays waste valuable resources that could be spent working on other more productive activities. This paper examines an automated software solution for converting KLA-Tencor reticle inspection defect maps into a format compatible with KLA-Tencor's Klarity Defect(R) data analysis database. The objective is to use the graphical charting capabilities of Klarity Defect to reveal a clearer understanding of defect trends for individual reticle layers or entire mask sets. Automated analysis features include reticle defect count trend analysis and potentially stacking reticle defect maps for signature analysis against wafer inspection defect data. Other possible benefits include optimizing reticle inspection sample plans in an effort to support "lean manufacturing" initiatives for wafer fabs.

  14. LH2 Target Design & Position Survey Techniques for the MUSE experiment for Precise Proton Radius Measurement

    Science.gov (United States)

    Le Pottier, Luc; Roy, Pryiashee; Lorenzon, Wolfgang; Raymond, Richard; Steinberg, Noah; Rossi de La Fuente, Erick; MUSE (MUon proton Scattering Experiment) Collaboration

    2017-09-01

    The proton radius puzzle is a currently unresolved problem which has intrigued the scientific community, dealing with a 7 σ discrepancy between the proton radii determined from muonic hydrogen spectroscopy and electron scattering measurements. The MUon Scattering Experiment (MUSE) aims to resolve this puzzle by performing the first simultaneous elastic scattering measurements of both electrons and muons on the proton, which will allow the comparison of the radii from the two interactions with reduced systematic uncertainties. The data from this experiment is expected to provide the best test of lepton universality to date. The experiment will take place at the Paul Scherrer Institute in Switzerland in 2018. An essential component of the experiment is a liquid hydrogen (LH2) cryotarget system. Our group at the University of Michigan is responsible for the design, fabrication and installation of this system. Here we present our LH2 target cell design and fabrication techniques for successful operation at 20 K and 1 atm, and our computer vision-based target position survey system which will determine the position of the target, installed inside a vacuum chamber, with 0.01 mm or better precision at the height of the liquid hydrogen target and along the beam direction during the experiment.

  15. The Design of New HIV-IN Tethered Bifunctional Inhibitors using Multiple Microdomain Targeted Docking.

    Science.gov (United States)

    Ciubotaru, Mihai; Musat, Mihaela Georgiana; Surleac, Marius; Ionita, Elena; Petrescu, Andrei Jose; Abele, Edgars; Abele, Ramona

    2018-04-05

    Currently used antiretroviral HIV therapy drugs exclusively target critical groups in the enzymes essential for the viral life cycle. Increased mutagenesis of their genes, changes these viral enzymes which once mutated can evade therapeutic targeting, effects which confer drug resistance. To circumvent this, our review addresses a strategy to design and derive HIV-Integrase (HIV-IN) inhibitors which simultaneously target two IN functional domains, rendering it inactive even if the enzyme accumulates many mutations. First we review the enzymatic role of IN to insert the copied viral DNA into a chromosome of the host T lymphocyte, highlighting its main functional and structural features to be subjected to inhibitory action. From a functional and structural perspective we present all classes of HIV-IN inhibitors with their most representative candidates. For each chosen compound we also explain its mechanism of IN inhibition. We use the recently resolved cryo EM IN tetramer intasome DNA complex [1] onto which we dock various reference IN inhibitory chemical scaffolds such as to target adjacent functional IN domains. Pairing compounds with complementary activity, which dock in the vicinity of a IN structural microdomain, we design bifunctional new drugs which may not only be more resilient to IN mutations but also may be more potent inhibitors than their original counterparts. In the end of our review we propose synthesis pathways to link such paired compounds with enhanced synergistic IN inhibitory effects. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Beams configuration design in target area with successive quadratic programming method

    International Nuclear Information System (INIS)

    Shi Zhiquan; Tan Jichun; Wei Xiaofeng; Man Jongzai; Zhang Xiaomin; Yuan Jing; Yuan Xiaodong

    1998-01-01

    The author describes the application of successive quadratic programming method (SQP) to design laser beam configuration in target area. Based on the requirement of ICF experiment physics, a math model of indirect-driver beam geometry is given. A 3D wire-frame is plotted, in which support lines represent 60 laser entireties and 240 turning points of support lines' segments stand for the spatial positions of reflectors

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

    Science.gov (United States)

    DSouza, Christopher; Weeks, Michael

    2010-01-01

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

  18. Design challenges in nanoparticle-based platforms: Implications for targeted drug delivery systems

    Science.gov (United States)

    Mullen, Douglas Gurnett

    Characterization and control of heterogeneous distributions of nanoparticle-ligand components are major design challenges for nanoparticle-based platforms. This dissertation begins with an examination of poly(amidoamine) (PAMAM) dendrimer-based targeted delivery platform. A folic acid targeted modular platform was developed to target human epithelial cancer cells. Although active targeting was observed in vitro, active targeting was not found in vivo using a mouse tumor model. A major flaw of this platform design was that it did not provide for characterization or control of the component distribution. Motivated by the problems experienced with the modular design, the actual composition of nanoparticle-ligand distributions were examined using a model dendrimer-ligand system. High Pressure Liquid Chromatography (HPLC) resolved the distribution of components in samples with mean ligand/dendrimer ratios ranging from 0.4 to 13. A peak fitting analysis enabled the quantification of the component distribution. Quantified distributions were found to be significantly more heterogeneous than commonly expected and standard analytical parameters, namely the mean ligand/nanoparticle ratio, failed to adequately represent the component heterogeneity. The distribution of components was also found to be sensitive to particle modifications that preceded the ligand conjugation. With the knowledge gained from this detailed distribution analysis, a new platform design was developed to provide a system with dramatically improved control over the number of components and with improved batch reproducibility. Using semi-preparative HPLC, individual dendrimer-ligand components were isolated. The isolated dendrimer with precise numbers of ligands were characterized by NMR and analytical HPLC. In total, nine different dendrimer-ligand components were obtained with degrees of purity ≥80%. This system has the potential to serve as a platform to which a precise number of functional molecules

  19. Design and implement of infrared small target real-time detection system based on pipeline technology

    Science.gov (United States)

    Sun, Lihui; Wang, Yongzhong; He, Yongqiang

    2007-01-01

    The detection for motive small target in infrared image sequence has become a hot topic nowadays. Background suppress algorithm based on minim gradient median filter and temporal recursion target detection algorithm are introduced. On the basis of contents previously mentioned, a four stages pipeline structure infrared small target detection process system, which aims at characters of algorithm complexity, large amounts of data to process, high frame frequency and exigent real-time character in this kind of application, is designed and implemented. The logical structure of the system was introduced and the function and signals flows are programmed. The system is composed of two FPGA chips and two DSP chips of TI. According to the function of each part, the system is divided into image preprocess stage, target detection stage, track relation stage and image output stage. The experiment of running algorithms on the system presented in this paper proved that the system could meet acquisition and process of 50Hz 240x320 digital image and the system could real time detect small target with a signal-noise ratio more than 3 reliably. The system achieves the characters of large amount of memory, high real-time processing, excellent extension and favorable interactive interface.

  20. Optimized beryllium target design for indirectly driven inertial confinement fusion experiments on the National Ignition Facility

    Energy Technology Data Exchange (ETDEWEB)

    Simakov, Andrei N., E-mail: simakov@lanl.gov; Wilson, Douglas C.; Yi, Sunghwan A.; Kline, John L.; Batha, Steven H. [Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, New Mexico 87545 (United States); Clark, Daniel S.; Milovich, Jose L.; Salmonson, Jay D. [Lawrence Livermore National Laboratory, P.O. Box 808, Livermore, California 94551 (United States)

    2014-02-15

    For indirect drive inertial confinement fusion, Beryllium (Be) ablators offer a number of important advantages as compared with other ablator materials, e.g., plastic and high density carbon. In particular, the low opacity and relatively high density of Be lead to higher rocket efficiencies giving a higher fuel implosion velocity for a given X-ray drive; and to higher ablation velocities providing more ablative stabilization and reducing the effect of hydrodynamic instabilities on the implosion performance. Be ablator advantages provide a larger target design optimization space and can significantly improve the National Ignition Facility (NIF) [J. D. Lindl et al., Phys. Plasmas 11, 339 (2004)] ignition margin. Herein, we summarize the Be advantages, briefly review NIF Be target history, and present a modern, optimized, low adiabat, Revision 6 NIF Be target design. This design takes advantage of knowledge gained from recent NIF experiments, including more realistic levels of laser-plasma energy backscatter, degraded hohlraum-capsule coupling, and the presence of cross-beam energy transfer.

  1. Rational Design of Cancer-Targeted Benzoselenadiazole by RGD Peptide Functionalization for Cancer Theranostics.

    Science.gov (United States)

    Yang, Liye; Li, Wenying; Huang, Yanyu; Zhou, Yangliang; Chen, Tianfeng

    2015-09-01

    A cancer-targeted conjugate of the selenadiazole derivative BSeC (benzo[1,2,5] selenadiazole-5-carboxylic acid) with RGD peptide as targeting molecule and PEI (polyethylenimine) as a linker is rationally designed and synthesized in the present study. The results show that RGD-PEI-BSeC forms nanoparticles in aqueous solution with a core-shell nanostructure and high stability under physiological conditions. This rational design effectively enhances the selective cellular uptake and cellular retention of BSeC in human glioma cells, and increases its selectivity between cancer and normal cells. The nanoparticles enter the cells through receptor-mediated endocytosis via clathrin-mediated and nystatin-dependent lipid raft-mediated pathways. Internalized nanoparticles trigger glioma cell apoptosis by activation of ROS-mediated p53 phosphorylation. Therefore, this study provides a strategy for the rational design of selenium-containing cancer-targeted theranostics. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Reclassification of leukemia among A-bomb survivors by French-American-British (FAB) classification, 1

    International Nuclear Information System (INIS)

    Matsuo, Tatsuki; Tomonaga, Masao; Bennett, J.M.

    1987-09-01

    The concordance rate for the French-American-British (FAB) reclassification diagnoses of atomic bomb-related cases of leukemia in Nagasaki was determined by a group of RERF hematologists and one of the members of the FAB cooperative gruop. The peripheral blood and/or bone marrow smears from 193 persons with leukemia or related disorder were reviewed. There was 85% agreement in the identification of leukemia types and subtypes. There was almost complete agreement for the diagnosis of non-FAB disorders (chronic myeloid leukemia and others) resulting in overall concordance of 88.2%. The conclusion from this remarkably high rate of concordance is that it is feasible to accurately apply the FAB classification system to the cases of A-bomb-related leukemia. These preliminary observations suggest that the previously established leukemia types for about a quarter of the cases of acute leukemia and related disorders should be changed. (author)

  3. Target selection and mass estimation for manned NEO exploration using a baseline mission design

    Science.gov (United States)

    Boden, Ralf C.; Hein, Andreas M.; Kawaguchi, Junichiro

    2015-06-01

    In recent years Near-Earth Objects (NEOs) have received an increased amount of interest as a target for human exploration. NEOs offer scientifically interesting targets, and at the same time function as a stepping stone for achieving future Mars missions. The aim of this research is to identify promising targets from the large number of known NEOs that qualify for a manned sample-return mission with a maximum duration of one year. By developing a baseline mission design and a mass estimation model, mission opportunities are evaluated based on on-orbit mass requirements, safety considerations, and the properties of the potential targets. A selection of promising NEOs is presented and the effects of mission requirements and restrictions are discussed. Regarding safety aspects, the use of free-return trajectories provides the lowest on-orbit mass, when compared to an alternative design that uses system redundancies to ensure return of the spacecraft to Earth. It is discovered that, although a number of targets are accessible within the analysed time frame, no NEO offers both easy access and high incentive for its exploration. Under the discussed aspects a first human exploration mission going beyond the vicinity of Earth will require a trade off between targets that provide easy access and those that are of scientific interest. This lack of optimal mission opportunities can be seen in the small number of only 4 NEOs that meet all requirements for a sample-return mission and remain below an on-orbit mass of 500 metric Tons (mT). All of them require a mass between 315 and 492 mT. Even less ideal, smaller asteroids that are better accessible require an on-orbit mass that exceeds the launch capability of future heavy lift vehicles (HLV) such as SLS by at least 30 mT. These mass requirements show that additional efforts are necessary to increase the number of available targets and reduce on-orbit mass requirements through advanced mission architectures. The need for on

  4. Comparative imaging and biodistribution studies with an anti-CEA monoclonal antibody and its F(ab)2 and Fab fragments in mice with colon carcinoma xenografts

    International Nuclear Information System (INIS)

    Andrew, S.M.; Pimm, M.V.; Baldwin, R.W.; Perkins, A.C.

    1986-01-01

    An IgG1 mouse monoclonal antibody directed against CEA has been digested with papain to yield F(ab) 2 and Fab fragments. Following radioiodination, intact antibody and fragments showed specific binding to cells of a CEA-producing tumour, although the immune reactivities of the fragments were lower than that of intact antibody. Gamma scintigraphy of nude mice bearing CEA producing human tumour xenografts and injected with 131 I-labelled fragments showed earlier and superior imaging of tumours than did 131 I-intact antibody, and this was most marked with the Fab fragment. Sequential dissection analyses showed that this was due to earlier and higher tumour-to-blood ratios with fragments than with intact antibody, but in absolute terms the degree of localization of both fragment types was significantly lower than that of intact antibody. (orig.)

  5. Near-Atomic Resolution Structure of a Highly Neutralizing Fab Bound to Canine Parvovirus.

    Science.gov (United States)

    Organtini, Lindsey J; Lee, Hyunwook; Iketani, Sho; Huang, Kai; Ashley, Robert E; Makhov, Alexander M; Conway, James F; Parrish, Colin R; Hafenstein, Susan

    2016-11-01

    Canine parvovirus (CPV) is a highly contagious pathogen that causes severe disease in dogs and wildlife. Previously, a panel of neutralizing monoclonal antibodies (MAb) raised against CPV was characterized. An antibody fragment (Fab) of MAb E was found to neutralize the virus at low molar ratios. Using recent advances in cryo-electron microscopy (cryo-EM), we determined the structure of CPV in complex with Fab E to 4.1 Å resolution, which allowed de novo building of the Fab structure. The footprint identified was significantly different from the footprint obtained previously from models fitted into lower-resolution maps. Using single-chain variable fragments, we tested antibody residues that control capsid binding. The near-atomic structure also revealed that Fab binding had caused capsid destabilization in regions containing key residues conferring receptor binding and tropism, which suggests a mechanism for efficient virus neutralization by antibody. Furthermore, a general technical approach to solving the structures of small molecules is demonstrated, as binding the Fab to the capsid allowed us to determine the 50-kDa Fab structure by cryo-EM. Using cryo-electron microscopy and new direct electron detector technology, we have solved the 4 Å resolution structure of a Fab molecule bound to a picornavirus capsid. The Fab induced conformational changes in regions of the virus capsid that control receptor binding. The antibody footprint is markedly different from the previous one identified by using a 12 Å structure. This work emphasizes the need for a high-resolution structure to guide mutational analysis and cautions against relying on older low-resolution structures even though they were interpreted with the best methodology available at the time. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  6. Optimum design of beam window's diameter and thickness of Hyper target system

    International Nuclear Information System (INIS)

    Cho, C. H.; Tak, N. I.; Song, T. Y.; Park, W. S.

    2002-01-01

    HYPER is designed to transmute long-lived TRU and fission products such as Tc-99 and I-129. Pb-Bi is used as the coolant and spallation target material at the same time. HYPER is expected to need about 20mA proton beam to sustain a 1000MW th power level. The cylindrical beam tube and spherical window is adopted as the basic window shape of HYPER. The window diameter and the window thickness are varied to find the maximum allowable current based on the design criteria : Pb-Bi temperature < 500 .deg. C, window temperature < 600 .deg. C, Pb-Bi velocity < 2m/s and window stress < 160MPa. The LAHET code is used to simulate heat generation. CFX is also used for the thermal-hydraulics calculation. Based on our design criteria, the maximum allowable current is calculated to be about 9.2mA, which is smaller than the required current. Therefore, an upgrade of the target system design is required

  7. Design of the solid target structure and the study on the coolant flow distribution in the solid target using the 2-dimensional flow analysis

    International Nuclear Information System (INIS)

    Haga, Katsuhiro; Terada, Atsuhiko; Ishikura, Shuichi; Teshigawara, Makoto; Kinoshita, Hidetaka; Kobayashi, Kaoru; Kaminaga, Masaki; Hino, Ryutaro; Susuki, Akira

    1999-11-01

    A solid target cooled by heavy water is presently under development under the Neutron Science Research Project of the Japan Atomic Energy Research Institute (JAERI). Target plates of several millimeters thickness made of heavy metal are used as the spallation target material and they are put face to face in a row with one to two millimeters gaps in between though which heavy water flows, as the coolant. Based on the design criteria regarding the target plate cooling, the volume percentage of the coolant, and the thermal stress produced in the target plates, we conducted thermal and hydraulic analysis with a one dimensional target plate model. We choosed tungsten as the target material, and decided on various target plate thicknesses. We then calculated the temperature and the thermal stress in the target plates using a two dimensional model, and confirmed the validity of the target plate thicknesses. Based on these analytical results, we proposed a target structure in which forty target plates are divided into six groups and each group is cooled using a single pass of coolant. In order to investigate the relationship between the distribution of the coolant flow, the pressure drop, and the coolant velocity, we conducted a hydraulic analysis using the general purpose hydraulic analysis code. As a result, we realized that an uniform coolant flow distribution can be achieved under a wide range of flow velocity conditions in the target plate cooling channels from 1 m/s to 10 m/s. The pressure drop along the coolant path was 0.09 MPa and 0.17 MPa when the coolant flow velocity was 5 m/s and 7 m/s respectively, which is required to cool the 1.5 MW and 2.5 MW solid targets. (author)

  8. Design, construction, and characterization of high-performance membrane fusion devices with target-selectivity.

    Science.gov (United States)

    Kashiwada, Ayumi; Yamane, Iori; Tsuboi, Mana; Ando, Shun; Matsuda, Kiyomi

    2012-01-31

    Membrane fusion proteins such as the hemagglutinin glycoprotein have target recognition and fusion accelerative domains, where some synergistically working elements are essential for target-selective and highly effective native membrane fusion systems. In this work, novel membrane fusion devices bearing such domains were designed and constructed. We selected a phenylboronic acid derivative as a recognition domain for a sugar-like target and a transmembrane-peptide (Leu-Ala sequence) domain interacting with the target membrane, forming a stable hydrophobic α-helix and accelerating the fusion process. Artificial membrane fusion behavior between the synthetic devices in which pilot and target liposomes were incorporated was characterized by lipid-mixing and inner-leaflet lipid-mixing assays. Consequently, the devices bearing both the recognition and transmembrane domains brought about a remarkable increase in the initial rate for the membrane fusion compared with the devices containing the recognition domain alone. In addition, a weakly acidic pH-responsive device was also constructed by replacing three Leu residues in the transmembrane-peptide domain by Glu residues. The presence of Glu residues made the acidic pH-dependent hydrophobic α-helix formation possible as expected. The target-selective liposome-liposome fusion was accelerated in a weakly acidic pH range when the Glu-substituted device was incorporated in pilot liposomes. The use of this pH-responsive device seems to be a potential strategy for novel applications in a liposome-based delivery system. © 2011 American Chemical Society

  9. A universal phage display system for the seamless construction of Fab libraries.

    Science.gov (United States)

    Nelson, Renae S; Valadon, Philippe

    2017-11-01

    The construction of Fab phage libraries requires the cloning of domains from both the light and the heavy chain of antibodies. Despite the advent of powerful strategies such as splicing-by-overlap extension PCR, obtaining high quality libraries with excellent coverage remains challenging. Here, we explored the use of type IIS restriction enzymes for the seamless cloning of Fab libraries. We analyzed human, murine and rabbit germline antibody repertoires and identified combinations of restriction enzymes that exhibit very few or no recognition sites in the antibody sequences. We describe three phagemid vectors, pUP-22Hb, pUP-22Mc and pUP-22Rc, which were employed for cloning the Fab repertoire of these hosts using BsmBI and SapI (human) or SapI alone (mouse and rabbit). Using human serum albumin as a model immunization, we built a mouse/human chimeric Fab library and a mouse Fab library in a single step ligation and successfully panned multiple cognate antibodies. The overall process is highly scalable and faster than PCR-based techniques, with a Fab insertion success rate of around 80%. By using carefully chosen overhangs on each end of the antibody domains, this approach paves the way to the universal, sequence- and vector-independent cloning and reformatting of antibody libraries. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Fab is the most efficient format to express functional antibodies by yeast surface display.

    Science.gov (United States)

    Sivelle, Coline; Sierocki, Raphaël; Ferreira-Pinto, Kelly; Simon, Stéphanie; Maillere, Bernard; Nozach, Hervé

    2018-04-30

    Multiple formats are available for engineering of monoclonal antibodies (mAbs) by yeast surface display, but they do not all lead to efficient expression of functional molecules. We therefore expressed four anti-tumor necrosis factor and two anti-IpaD mAbs as single-chain variable fragment (scFv), antigen-binding fragment (Fab) or single-chain Fabs and compared their expression levels and antigen-binding efficiency. Although the scFv and scFab formats are widely used in the literature, 2 of 6 antibodies were either not or weakly expressed. In contrast, all 6 antibodies expressed as Fab revealed strong binding and high affinity, comparable to that of the soluble form. We also demonstrated that the variations in expression did not affect Fab functionality and were due to variations in light chain display and not to misfolded dimers. Our results suggest that Fab is the most versatile format for the engineering of mAbs.

  11. Effect of DNA sequence of Fab fragment on yield characteristics and cell growth of E. coli.

    Science.gov (United States)

    Kulmala, Antti; Huovinen, Tuomas; Lamminmäki, Urpo

    2017-06-19

    Codon usage is one of the factors influencing recombinant protein expression. We were interested in the codon usage of an antibody Fab fragment gene exhibiting extreme toxicity in the E. coli host. The toxic synthetic human Fab gene contained domains optimized by the "one amino acid-one codon" method. We redesigned five segments of the Fab gene with a "codon harmonization" method described by Angov et al. and studied the effects of these changes on cell viability, Fab yield and display on filamentous phage using different vectors and bacterial strains. The harmonization considerably reduced toxicity, increased Fab expression from negligible levels to 10 mg/l, and restored the display on phage. Testing the impact of the individual redesigned segments revealed that the most significant effects were conferred by changes in the constant domain of the light chain. For some of the Fab gene variants, we also observed striking differences in protein yields when cloned from a chloramphenicol resistant vector into an identical vector, except with ampicillin resistance. In conclusion, our results show that the expression of a heterodimeric secretory protein can be improved by harmonizing selected DNA segments by synonymous codons and reveal additional complexity involved in heterologous protein expression.

  12. Functional Requirements for Fab-7 Boundary Activity in the Bithorax Complex

    Science.gov (United States)

    Wolle, Daniel; Cleard, Fabienne; Aoki, Tsutomu; Deshpande, Girish; Karch, Francois

    2015-01-01

    Chromatin boundaries are architectural elements that determine the three-dimensional folding of the chromatin fiber and organize the chromosome into independent units of genetic activity. The Fab-7 boundary from the Drosophila bithorax complex (BX-C) is required for the parasegment-specific expression of the Abd-B gene. We have used a replacement strategy to identify sequences that are necessary and sufficient for Fab-7 boundary function in the BX-C. Fab-7 boundary activity is known to depend on factors that are stage specific, and we describe a novel ∼700-kDa complex, the late boundary complex (LBC), that binds to Fab-7 sequences that have insulator functions in late embryos and adults. We show that the LBC is enriched in nuclear extracts from late, but not early, embryos and that it contains three insulator proteins, GAF, Mod(mdg4), and E(y)2. Its DNA binding properties are unusual in that it requires a minimal sequence of >65 bp; however, other than a GAGA motif, the three Fab-7 LBC recognition elements display few sequence similarities. Finally, we show that mutations which abrogate LBC binding in vitro inactivate the Fab-7 boundary in the BX-C. PMID:26303531

  13. Functional Requirements for Fab-7 Boundary Activity in the Bithorax Complex.

    Science.gov (United States)

    Wolle, Daniel; Cleard, Fabienne; Aoki, Tsutomu; Deshpande, Girish; Schedl, Paul; Karch, Francois

    2015-11-01

    Chromatin boundaries are architectural elements that determine the three-dimensional folding of the chromatin fiber and organize the chromosome into independent units of genetic activity. The Fab-7 boundary from the Drosophila bithorax complex (BX-C) is required for the parasegment-specific expression of the Abd-B gene. We have used a replacement strategy to identify sequences that are necessary and sufficient for Fab-7 boundary function in the BX-C. Fab-7 boundary activity is known to depend on factors that are stage specific, and we describe a novel ∼700-kDa complex, the late boundary complex (LBC), that binds to Fab-7 sequences that have insulator functions in late embryos and adults. We show that the LBC is enriched in nuclear extracts from late, but not early, embryos and that it contains three insulator proteins, GAF, Mod(mdg4), and E(y)2. Its DNA binding properties are unusual in that it requires a minimal sequence of >65 bp; however, other than a GAGA motif, the three Fab-7 LBC recognition elements display few sequence similarities. Finally, we show that mutations which abrogate LBC binding in vitro inactivate the Fab-7 boundary in the BX-C. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  14. Human recombinant Fab fragment from combinatorial libraries of a B-cell lymphoma patient recognizes core protein of chondroitin sulphate proteoglycan 4.

    Science.gov (United States)

    Egami, Yoko; Narushima, Yuta; Ohshima, Motohiro; Yoshida, Akira; Yoneta, Naruki; Masaki, Yasufumi; Itoh, Kunihiko

    2018-01-01

    CD antigens are well known as therapeutic targets of B-cell lymphoma. To isolate therapeutic antibodies that recognize novel targets other than CD antigens, we constructed a phage display combinatorial antibody Fab library from bone marrow lymphocytes of B-cell lymphoma patient. To eliminate antibodies reactive with known B-cell lymphoma antigen, non-hematopoietic and patient's sera reactive HeLaS3 cells was selected as a target of whole cell panning. Five rounds of panning against live HeLaS3 cells retrieved single Fab clone, termed AHSA (Antibody to HeLa Surface Antigen). Using phage display random peptide library, LSYLEP was identified as an epitope sequence of AHSA. LC-MS/MS analysis of AHSA-precipitated HeLaS3 cell lysates detected several fragments corresponding to the sequence of chondroitin sulphate proteoglycan 4 (CSPG4) core protein. Since LSYLEP sequence was at the position of 313-318 of CSPG4, we considered that CSPG4 was AHSA-associated antigen. Double staining of CSPG4-postive MDA-MB-435S cells with AHSA and anti-CSPG4 rabbit antibody showed identical staining position, and reduced AHSA reactivity was observed in CSPG4-siRNA treated MDA-MB-435S cells. In conclusion, we retrieved a human Fab from antibody library of B-cell lymphoma patient, and identified CSPG4 as a recognizing antigen. AHSA may have potential benefits for development of CSPG4-targeting theranostics for B-cell lymphoma. © The Authors 2017. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

  15. Preconceptual engineering design for the APT 3He Target/Blanket concept

    International Nuclear Information System (INIS)

    Mensink, D.L.

    1994-01-01

    A preconceptual engineering design has been developed for the 3 He Target/Blanket (T/B) System for the Accelerator Production of Tritium Project. This concept uses an array of pressure tubes containing tungsten rods for the neutron spallation source and 3 He gas contained in a metal tank and blanket tubes as the tritium production material. The engineering design is based on a physics model optimized for efficient tritium production. Principle engineering consideration were: provisions for cooling all materials including the 3 He gas; containment of the gas and radionuclides; remote handling; material compatibility; minimization of 3 He, D 2 O, and activated waste; modularity; and manufacturability. The design provides a basis for estimating the cost to implement the system

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

    Science.gov (United States)

    Lund, Glenn

    1993-01-01

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

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

    Science.gov (United States)

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

    2017-11-01

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

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

    Science.gov (United States)

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

    2017-11-15

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

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

    CERN Document Server

    Charitonidis, Nikolaos; Rivkin, Leonid

    2014-06-13

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

  20. Recycling issues facing target and RTL materials of inertial fusion designs

    International Nuclear Information System (INIS)

    El-Guebaly, L.; Wilson, P.; Sawan, M.; Henderson, D.; Varuttamaseni, A.

    2005-01-01

    Designers of heavy ion (HI) and Z-pinch inertial fusion power plants have explored the potential of recycling the target and recyclable transmission line (RTL) materials as an alternate option to disposal in a geological repository. This work represents the first time a comprehensive recycling assessment was performed on both machines with an exact pulse history. Our results offer two divergent conclusions on the recycling issue. For the HI concept, target recycling is not a 'must' requirement and the preferred option is the one-shot use scenario as target materials represent a small waste stream, less than 1% of the total nuclear island waste. We recommend using low-cost hohlraum materials once-through and then disposing of them instead of recycling expensive materials such as Au and Gd. On the contrary, RTL recycling is a 'must' requirement for the Z-pinch concept in order to minimize the RTL inventory and enhance the economics. The RTLs meet the low level waste and recycling dose requirements with a wide margin when recycled for the entire plant life even without a cooling period. While recycling offers advantages to the Z-pinch system, it adds complexity and cost to the HI designs

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

    International Nuclear Information System (INIS)

    Aguilar, A.; Sordo, F.; Mora, T.; Mena, L.; Mancisidor, M.; Aguilar, J.; Bakedano, G.; Herranz, I.; Luna, P.; Magan, M.; Vivanco, R.; Jimenez-Villacorta, F.; Sjogreen, K.; Oden, U.; Perlado, J.M.

    2017-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2017-06-01

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

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

    Science.gov (United States)

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

    2008-01-01

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

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

    Science.gov (United States)

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

    2018-03-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-06-15

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

  6. Lujan Center Mark-IV Target Neutronics Design Internal Review Report

    Energy Technology Data Exchange (ETDEWEB)

    Lisowski, Paul W. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Gallmeier, Franz [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Guber, Klaus [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2018-02-26

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

  7. Target Channel Visiting Order Design Using Particle Swarm Optimization for Spectrum Handoff in Cognitive Radio Networks

    Directory of Open Access Journals (Sweden)

    Shilian Zheng

    2014-08-01

    Full Text Available In a dynamic spectrum access network, when a primary user (licensed user reappears on the current channel, cognitive radios (CRs need to vacate the channel and reestablish a communications link on some other channel to avoid interference to primary users, resulting in spectrum handoff. This paper studies the problem of designing target channel visiting order for spectrum handoff to minimize expected spectrum handoff delay. A particle swarm optimization (PSO based algorithm is proposed to solve the problem. Simulation results show that the proposed algorithm performs far better than random target channel visiting scheme. The solutions obtained by PSO are very close to the optimal solution which further validates the effectiveness of the proposed method.

  8. Heterogeneity in head and neck IMRT target design and clinical practice

    International Nuclear Information System (INIS)

    Hong, Theodore S.; Tomé, Wolfgang A.; Harari, Paul M.

    2012-01-01

    Purpose: To assess patterns of H and N IMRT practice with particular emphasis on elective target delineation. Materials and methods: Twenty institutions with established H and N IMRT expertise were solicited to design clinical target volumes for the identical H and N cancer case. To limit contouring variability, a primary tonsil GTV and ipsilateral level II node were pre-contoured. Participants were asked to accept this GTV, and contour their recommended CTV and PTV. Dose prescriptions, contouring time, and recommendations regarding chemotherapy were solicited. Results: All 20 institutions responded. Remarkable heterogeneity in H and N IMRT design and practice was identified. Seventeen of 20 centers recommended treatment of bilateral necks whereas 3/20 recommended treatment of the ipsilateral neck only. The average CTV volume was 250 cm 3 (range 37–676 cm 3 ). Although there was high concordance in coverage of ipsilateral neck levels II and III, substantial variation was identified for levels I, V, and the contralateral neck. Average CTV expansion was 4.1 mm (range 0–15 mm). Eight of 20 centers recommended chemotherapy (cisplatin), whereas 12/20 recommended radiation alone. Responders prescribed on average 69 and 68 Gy to the tumor and metastatic node GTV, respectively. Average H and N target volume contouring time was 102.5 min (range 60–210 min). Conclusion: This study identifies substantial heterogeneity in H and N IMRT target definition, prescription, neck treatment, and use of chemotherapy among practitioners with established H and N IMRT expertise. These data suggest that continued efforts to standardize and simplify the H and N IMRT process are desirable for the safe and effective global advancement of H and N IMRT practice.

  9. Targeting the dopamine D3 receptor: an overview of drug design strategies.

    Science.gov (United States)

    Cortés, Antoni; Moreno, Estefanía; Rodríguez-Ruiz, Mar; Canela, Enric I; Casadó, Vicent

    2016-07-01

    Dopamine is a neurotransmitter widely distributed in both the periphery and the central nervous system (CNS). Its physiological effects are mediated by five closely related G protein-coupled receptors (GPCRs) that are divided into two major subclasses: the D1-like (D1, D5) and the D2-like (D2, D3, D4) receptors. D3 receptors (D3Rs) have the highest density in the limbic areas of the brain, which are associated with cognitive and emotional functions. These receptors are therefore attractive targets for therapeutic management. This review summarizes the functional and pharmacological characteristics of D3Rs, including the design and clinical relevance of full agonists, partial agonists and antagonists, as well as the capacity of these receptors to form active homodimers, heterodimers or higher order receptor complexes as pharmacological targets in several neurological and neurodegenerative disorders. The high sequence homology between D3R and the D2-type challenges the development of D3R-selective compounds. The design of new D3R-preferential ligands with improved physicochemical properties should provide a better pharmacokinetic/bioavailability profile and lesser toxicity than is found with existing D3R ligands. It is also essential to optimize D3R affinity and, especially, D3R vs. D2-type binding and functional selectivity ratios. Developing allosteric and bitopic ligands should help to improve the D3R selectivity of these drugs. As most evidence points to the ability of GPCRs to form homomers and heteromers, the most promising therapeutic strategy in the future is likely to involve the application of heteromer-selective drugs. These selective ligands would display different affinities for a given receptor depending on the receptor partners within the heteromer. Therefore, designing novel compounds that specifically target and modulate D1R-D3R heteromers would be an interesting approach for the treatment of levodopa (L-DOPA)-induced dyskinesias.

  10. Epitope-based peptide vaccine design and target site depiction against Ebola viruses: an immunoinformatics study.

    Science.gov (United States)

    Khan, M A; Hossain, M U; Rakib-Uz-Zaman, S M; Morshed, M N

    2015-07-01

    Ebola viruses (EBOVs) have been identified as an emerging threat in recent year as it causes severe haemorrhagic fever in human. Epitope-based vaccine design for EBOVs remains a top priority because a mere progress has been made in this regard. Another reason is the lack of antiviral drug and licensed vaccine although there is a severe outbreak in Central Africa. In this study, we aimed to design an epitope-based vaccine that can trigger a significant immune response as well as to prognosticate inhibitor that can bind with potential drug target sites using various immunoinformatics and docking simulation tools. The capacity to induce both humoral and cell-mediated immunity by T cell and B cell was checked for the selected protein. The peptide region spanning 9 amino acids from 42 to 50 and the sequence TLASIGTAF were found as the most potential B and T cell epitopes, respectively. This peptide could interact with 12 HLAs and showed high population coverage up to 80.99%. Using molecular docking, the epitope was further appraised for binding against HLA molecules to verify the binding cleft interaction. In addition with this, the allergenicity of the epitopes was also evaluated. In the post-therapeutic strategy, docking study of predicted 3D structure identified suitable therapeutic inhibitor against targeted protein. However, this computational epitope-based peptide vaccine designing and target site prediction against EBOVs open up a new horizon which may be the prospective way in Ebola viruses research; the results require validation by in vitro and in vivo experiments. © 2015 John Wiley & Sons Ltd.

  11. High-resolution imaging and target designation through clouds or smoke

    Science.gov (United States)

    Perry, Michael D.

    2003-01-01

    A method and system of combining gated intensifiers and advances in solid-state, short-pulse laser technology, compact systems capable of producing high resolution (i.e., approximately less than 20 centimeters) optical images through a scattering medium such as dense clouds, fog, smoke, etc. may be achieved from air or ground based platforms. Laser target designation through a scattering medium is also enabled by utilizing a short pulse illumination laser and a relatively minor change to the detectors on laser guided munitions.

  12. Crystallization and preliminary X-ray analysis of the complexes between a Fab and two forms of human insulin-like growth factor II

    International Nuclear Information System (INIS)

    Newman, Janet; Cohen, Edward H.; Cosgrove, Leah; Kopacz, Kris; Dransfield, Daniel T.; Adams, Timothy E.; Peat, Thomas S.

    2009-01-01

    Complexes of both hIGF-II and hIGF-IIE with a Fab have been crystallized and investigated by X-ray analysis. Elevated expression of insulin-like growth factor II (IGF-II) is frequently observed in a variety of human malignancies, including breast, colon and liver cancer. As IGF-II can deliver a mitogenic signal through both the type 1 insulin-like growth factor receptor (IGF-IR) and an alternately spliced form of the insulin receptor (IR-A), neutralizing the biological activity of this growth factor directly is an attractive therapeutic option. One method of doing this would be to find antibodies that bind tightly and specifically to the peptide, which could be used as protein therapeutics to lower the peptide levels in vivo and/or to block the peptide from binding to the IGF-IR or IR-A. To address this, Fabs were selected from a phage-display library using a biotinylated precursor form of the growth factor known as IGF-IIE as a target. Fabs were isolated that were specific for the E-domain C-terminal extension and for mature IGF-II. Four Fabs selected from the library were produced, complexed with IGF-II and set up in crystallization trials. One of the Fab–IGF-II complexes (M64-F02–IGF-II) crystallized readily, yielding crystals that diffracted to 2.2 Å resolution and belonged to space group P2 1 2 1 2 1 , with unit-cell parameters a = 50.7, b = 106.9, c = 110.7 Å. There was one molecule of the complete complex in the asymmetric unit. The same Fab was also crystallized with a longer form of the growth factor, IGF-IIE. This complex crystallized in space group P2 1 2 1 2 1 , with unit-cell parameters a = 50.7, b = 107, c = 111.5 Å, and also diffracted X-rays to 2.2 Å resolution

  13. Design, synthesis, and evaluation of an alpha-helix mimetic library targeting protein-protein interactions.

    Science.gov (United States)

    Shaginian, Alex; Whitby, Landon R; Hong, Sukwon; Hwang, Inkyu; Farooqi, Bilal; Searcey, Mark; Chen, Jiandong; Vogt, Peter K; Boger, Dale L

    2009-04-22

    The design and solution-phase synthesis of an alpha-helix mimetic library as an integral component of a small-molecule library targeting protein-protein interactions are described. The iterative design, synthesis, and evaluation of the candidate alpha-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 x 20 x 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an alpha-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead alpha-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an alpha-helix mediated protein-protein interaction) and define the key residues and their characteristics responsible for recognition.

  14. Conversion of a Mouse Fab into a Whole Humanized IgG Antibody for Detecting Botulinum Toxin

    National Research Council Canada - National Science Library

    Palys, Thomas J; Schmid, Kara E; Scherer, John M; Schoepp, Randal J

    2006-01-01

    Antibodies serve as the gold standard in most immunodiagnostic assays. Recent advances in recombinant DNA technology have offered the production of antibody fragments or Fabs as promising alternatives...

  15. Phage Fab Display Selection In Vitro and In Vivo: Novel Means to Identify New Breast Cancer Avid Compounds

    National Research Council Canada - National Science Library

    Meighan, Mark

    2001-01-01

    .... In this annual report we present preliminary results on the isolation of antibody fragments (Fabs), isolated from phage display libraries, when affinity selected against breast cancer cell lines...

  16. Effect of polyethylene glycol conjugation on conformational and colloidal stability of a monoclonal antibody antigen-binding fragment (Fab').

    Science.gov (United States)

    Roque, Cristopher; Sheung, Anthony; Rahman, Nausheen; Ausar, S Fernando

    2015-02-02

    We have investigated the effects of site specific "hinge" polyethylene glycol conjugation (PEGylation) on thermal, pH, and colloidal stability of a monoclonal antibody antigen-binding fragment (Fab') using a variety of biophysical techniques. The results obtained by circular dichroism (CD), ultraviolet (UV) absorbance, and fluorescence spectroscopy suggested that the physical stability of the Fab' is maximized at pH 6-7 with no apparent differences due to PEGylation. Temperature-induced aggregation experiments revealed that PEGylation was able to increase the transition temperature, as well as prevent the formation of visible and subvisible aggregates. Statistical comparison of the three-index empirical phase diagram (EPD) revealed significant differences in thermal and pH stability signatures between Fab' and PEG-Fab'. Upon mechanical stress, micro-flow imaging (MFI) and measurement of the optical density at 360 nm showed that the PEG-Fab' had significantly higher resistance to surface-induced aggregation compared to the Fab'. Analysis of the interaction parameter, kD, indicated repulsive intermolecular forces for PEG-Fab' and attractive forces for Fab'. In conclusion, PEGylation appears to protect Fab' against thermal and mechanical stress-induced aggregation, likely due to a steric hindrance mechanism.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1997-11-01

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

  18. Design of a distributed radiator target for inertial fusion driven from two sides with heavy ion beams

    International Nuclear Information System (INIS)

    Tabak, M.; Callahan-Miller, D.

    1997-01-01

    We describe the status of a distributed radiator heavy ion target design. In integrated calculations this target ignited and produced 390-430 MJ of yieldwhen driven with 5.8-6.5 MJ of 3-4 GeV Pb ions. The target has cylindrical symmetry with disk endplates. The ions uniformly illuminate these endplates in a 5mm radius spot. We discuss the considerations which led to this design together with some previously unused design features: low density hohlraum walls in approximate pressure balance with internal low-Z fill materials, radiationsymmetry determined by the position of the radiator materials and particle ranges, and early time pressure symmetry possibly influenced by radiation shims. We discuss how this target scales to lower input energy or to lower beam power. Variant designs with more realistic beam focusing strategies are also discussed. We show the tradeoffs required for targets which accept higher particle energies

  19. Optimal Design of Gradient Materials and Bi-Level Optimization of Topology Using Targets (BOTT)

    Science.gov (United States)

    Garland, Anthony

    The objective of this research is to understand the fundamental relationships necessary to develop a method to optimize both the topology and the internal gradient material distribution of a single object while meeting constraints and conflicting objectives. Functionally gradient material (FGM) objects possess continuous varying material properties throughout the object, and they allow an engineer to tailor individual regions of an object to have specific mechanical properties by locally modifying the internal material composition. A variety of techniques exists for topology optimization, and several methods exist for FGM optimization, but combining the two together is difficult. Understanding the relationship between topology and material gradient optimization enables the selection of an appropriate model and the development of algorithms, which allow engineers to design high-performance parts that better meet design objectives than optimized homogeneous material objects. For this research effort, topology optimization means finding the optimal connected structure with an optimal shape. FGM optimization means finding the optimal macroscopic material properties within an object. Tailoring the material constitutive matrix as a function of position results in gradient properties. Once, the target macroscopic properties are known, a mesostructure or a particular material nanostructure can be found which gives the target material properties at each macroscopic point. This research demonstrates that topology and gradient materials can both be optimized together for a single part. The algorithms use a discretized model of the domain and gradient based optimization algorithms. In addition, when considering two conflicting objectives the algorithms in this research generate clear 'features' within a single part. This tailoring of material properties within different areas of a single part (automated design of 'features') using computational design tools is a novel benefit

  20. Mechanical design of experimental apparatus for FIREX cryo-target cooling

    Science.gov (United States)

    Iwamoto, A.; Norimatsu, T.; Nakai, M.; Sakagami, H.; Fujioka, S.; Shiraga, H.; Azechi, H.

    2016-05-01

    Mechanical design of an experimental apparatus for FIREX cryo-target cooling is described. Gaseous helium (GHe) sealing system at a cryogenic environment is an important issue for laser fusion experiments. The dedicated loading system was designed for a metal gasket. We take U-TIGHTSEAL® (Usui Kokusai Sangyo Kaisha. Ltd.) with an indium plated copper jacket as an example. According to its specification, a linear load of 110 N/m along its circumference is the optimum compression; however a lower load would still maintain helium (He) leak below the required level. Its sealing performance was investigated systematically. Our system demanded 27 N/mm of the load to keep He leak tightness in a cryogenic environment. Once leak tightness was obtained, it could be reduced to 9.5 N/mm.

  1. Design improvement of the target elements of Wendelstein 7-X divertor

    International Nuclear Information System (INIS)

    Boscary, J.; Peacock, A.; Friedrich, T.; Greuner, H.; Böswirth, B.; Tittes, H.; Schulmeyer, W.; Hurd, F.

    2012-01-01

    Highlights: ► Improvement of the cooling structure design. ► Improvement of the CFC tile arrangement at the element end. ► Design and fabrication validated with high heat flux testing. ► Selected solution removes stationary heat load of 5 MW/m 2 and 2 MW/m 2 on the top and on the side facing the pumping gap of the element, respectively. - Abstract: The actively cooled high-heat flux divertor of the Wendelstein 7-X stellarator consists of individual target elements made of a water-cooled CuCrZr copper alloy heat sink armored with CFC tiles. The so-called “bi-layer” technology developed in collaboration with the company Plansee for the bonding of the tiles onto the heat sink has reliably demonstrated the removal of the specified heat load of 10 MW/m 2 in the central area of the divertor. However, due to geometrical constraints, the loading performance at the ends of the elements is reduced compared to the central part. Design modifications compatible with industrial processes have been made to improve the cooling capabilities at this location. These changes have been validated during test campaigns of full-scale prototypes carried out in the neutral beam test facility GLADIS. The tested solution can remove reliably the stationary heat load of 5 MW/m 2 and 2 MW/m 2 on the top and on the side of the element, respectively. The results of the testing allowed the release of the design and fabrication processes for the next manufacturing phase of the target elements.

  2. Colon-targeted oral drug delivery systems: design trends and approaches.

    Science.gov (United States)

    Amidon, Seth; Brown, Jack E; Dave, Vivek S

    2015-08-01

    Colon-specific drug delivery systems (CDDS) are desirable for the treatment of a range of local diseases such as ulcerative colitis, Crohn's disease, irritable bowel syndrome, chronic pancreatitis, and colonic cancer. In addition, the colon can be a potential site for the systemic absorption of several drugs to treat non-colonic conditions. Drugs such as proteins and peptides that are known to degrade in the extreme gastric pH, if delivered to the colon intact, can be systemically absorbed by colonic mucosa. In order to achieve effective therapeutic outcomes, it is imperative that the designed delivery system specifically targets the drugs into the colon. Several formulation approaches have been explored in the development colon-targeted drug delivery systems. These approaches involve the use of formulation components that interact with one or more aspects of gastrointestinal (GI) physiology, such as the difference in the pH along the GI tract, the presence of colonic microflora, and enzymes, to achieve colon targeting. This article highlights the factors influencing colon-specific drug delivery and colonic bioavailability, and the limitations associated with CDDS. Further, the review provides a systematic discussion of various conventional, as well as relatively newer formulation approaches/technologies currently being utilized for the development of CDDS.

  3. Activation loop targeting strategy for design of receptor-interacting protein kinase 2 (RIPK2) inhibitors.

    Science.gov (United States)

    Suebsuwong, Chalada; Pinkas, Daniel M; Ray, Soumya S; Bufton, Joshua C; Dai, Bing; Bullock, Alex N; Degterev, Alexei; Cuny, Gregory D

    2018-02-15

    Development of selective kinase inhibitors remains a challenge due to considerable amino acid sequence similarity among family members particularly in the ATP binding site. Targeting the activation loop might offer improved inhibitor selectivity since this region of kinases is less conserved. However, the strategy presents difficulties due to activation loop flexibility. Herein, we report the design of receptor-interacting protein kinase 2 (RIPK2) inhibitors based on pan-kinase inhibitor regorafenib that aim to engage basic activation loop residues Lys169 or Arg171. We report development of CSR35 that displayed >10-fold selective inhibition of RIPK2 versus VEGFR2, the target of regorafenib. A co-crystal structure of CSR35 with RIPK2 revealed a resolved activation loop with an ionic interaction between the carboxylic acid installed in the inhibitor and the side-chain of Lys169. Our data provides principle feasibility of developing activation loop targeting type II inhibitors as a complementary strategy for achieving improved selectivity. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  4. Current therapeutic molecules and targets in neurodegenerative diseases based on in silico drug design.

    Science.gov (United States)

    Sehgal, Sheikh Arslan; Hammad, Mirza A; Tahir, Rana Adnan; Akram, Hafiza Nisha; Ahmad, Faheem

    2018-03-15

    As the number of elderly persons increases, neurodegenerative diseases are becoming ubiquitous. There is currently a great need for knowledge concerning management of old-age neurodegenerative diseases; the most important of which are: Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's disease. To summarize the potential of computationally predicted molecules and targets against neurodegenerative diseases. Review of literature published since 1997 against neurodegenerative diseases, utilizing as keywords: in silico, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis ALS, and Huntington's disease. Due to the costs associated with experimentation and current ethical law, performing experiments directly on living organisms has become much more difficult. In this scenario, in silico techniques have been successful and have become powerful tools in the search to cure disease. Researchers use the Computer Aided Drug Design pipeline which: 1) generates 3-dimensional structures of target proteins through homology modeling 2) achieves stabilization through molecular dynamics simulation, and 3) exploits molecular docking through large compound libraries. Next generation sequencing is continually producing enormous amounts of raw sequence data while neuroimaging is producing a multitude of raw image data. To solve such pressing problems, these new tools and algorithms are required. This review elaborates precise in silico tools and techniques for drug targets, active molecules, and molecular docking studies, together with future prospects and challenges concerning possible breakthroughs in Alzheimer's, Parkinson's, Amyotrophic Lateral Sclerosis, and Huntington's disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

    CERN Document Server

    Montano, J; Gottberg, A

    2013-01-01

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

  6. Deep Extragalactic VIsible Legacy Survey (DEVILS): Motivation, Design and Target Catalogue

    Science.gov (United States)

    Davies, L. J. M.; Robotham, A. S. G.; Driver, S. P.; Lagos, C. P.; Cortese, L.; Mannering, E.; Foster, C.; Lidman, C.; Hashemizadeh, A.; Koushan, S.; O'Toole, S.; Baldry, I. K.; Bilicki, M.; Bland-Hawthorn, J.; Bremer, M. N.; Brown, M. J. I.; Bryant, J. J.; Catinella, B.; Croom, S. M.; Grootes, M. W.; Holwerda, B. W.; Jarvis, M. J.; Maddox, N.; Meyer, M.; Moffett, A. J.; Phillipps, S.; Taylor, E. N.; Windhorst, R. A.; Wolf, C.

    2018-06-01

    The Deep Extragalactic VIsible Legacy Survey (DEVILS) is a large spectroscopic campaign at the Anglo-Australian Telescope (AAT) aimed at bridging the near and distant Universe by producing the highest completeness survey of galaxies and groups at intermediate redshifts (0.3 < z < 1.0). Our sample consists of ˜60,000 galaxies to Y<21.2 mag, over ˜6 deg2 in three well-studied deep extragalactic fields (Cosmic Origins Survey field, COSMOS, Extended Chandra Deep Field South, ECDFS and the X-ray Multi-Mirror Mission Large-Scale Structure region, XMM-LSS - all Large Synoptic Survey Telescope deep-drill fields). This paper presents the broad experimental design of DEVILS. Our target sample has been selected from deep Visible and Infrared Survey Telescope for Astronomy (VISTA) Y-band imaging (VISTA Deep Extragalactic Observations, VIDEO and UltraVISTA), with photometry measured by PROFOUND. Photometric star/galaxy separation is done on the basis of NIR colours, and has been validated by visual inspection. To maximise our observing efficiency for faint targets we employ a redshift feedback strategy, which continually updates our target lists, feeding back the results from the previous night's observations. We also present an overview of the initial spectroscopic observations undertaken in late 2017 and early 2018.

  7. Effects of Fab' fragments of specific egg yolk antibody (IgY-Fab') against Shewanella putrefaciens on the preservation of refrigerated turbot.

    Science.gov (United States)

    Zhang, Qian; Lin, Hong; Sui, Jianxin; Wang, Jingxue; Cao, Limin

    2015-01-01

    In our previous studies the specific egg yolk antibody (IgY) against Shewanella putrefaciens (one of the specific spoilage organisms for marine products during aerobic chilling storage) demonstrated significant activity to prolong the shelf life of refrigerated fish. The exploitation of the antigen-binding fragment plus the hinge region (IgY-Fab') is now considered a promising method for improving the efficiency of such natural antimicrobial agents. The antimicrobial activity of IgY-Fab' against S. putrefaciens was investigated using refrigerated turbot as samples. By microbial, chemical and sensory tests, it was shown to be able to effectively inhibit bacterial growth and prolong the shelf life of samples, with an efficiency evaluated significantly higher than that of whole IgY with the same molarity. The interaction between IgY agents and S. putrefaciens cells was also investigated, and the IgY-Fab' showed a much greater ability to damage cell membranes than the whole IgY. Compared to whole IgY with the same molarity, IgY-Fab' demonstrated higher and more durable antimicrobial efficiency. Such a result was assumed to be closely related to its structural properties (such as the much lower molecular weight), which may enhance its ability to influence physiological activities of antigen bacteria, especially the property or/and structure of cell membranes. © 2014 Society of Chemical Industry.

  8. Management of Tissue Loss After Agkistrodon Snakebite: Appropriate Use of Crotalidae-Fab Antivenin.

    Science.gov (United States)

    Larson, Kenneth W; Schaefer, Keith R; Austin, Cindy; Norton, Rhy; Finley, Phillip J

    2016-01-01

    Although initially created for the treatment of rattlesnake (genus: Crotalus) bites, Crotalidae-Fab antivenin is used to treat many different pit viper envenomations. However, the efficacy of Crotalidae-Fab in preventing tissue loss from copperhead (Agkistrodon contortrix) or cottonmouth (Agkistrodon piscivorus) snakebites remains unclear. Recent reports show that Agkistrodon-related bites rarely require treatment beyond simple observation and pain control. The purpose of this study was to examine the amount of tissue loss in patients who received Crotalidae-Fab compared with those who did not after an Agkistrodon bite. After institutional review board approval, a retrospective study was completed at a Level 1 trauma center. Between 2009 and 2013, a total of 57 snakebites were identified. Of the 57 bites, the snake species was documented in 36 cases including 31 copperheads, 1 cottonmouth, and 4 rattlesnakes. The other 21 bites were from unknown or nonvenomous species. Of the 32 Agkistrodon-related bites, 15 patients received Crotalidae-Fab (average of 3 vials administered) and 17 did not receive Crotalidae-Fab. None of the 32 patients, regardless of treatment option, had tissue loss or required surgical interventions. Only 1 patient received Crotalidae-Fab and debridement of a vesicle associated with the bite. No clinically significant differences were observed between the groups. These findings support previous literature that failed to show added benefit of Crotalidae-Fab treatment for Agkistrodon bites beyond patient comfort and pain control. Evaluation of current protocols for Agkistrodon envenomations is warranted. Snakebite wound education in trauma physicians and nurses may decrease unnecessary use of antivenom medication.

  9. Molecular design and nanoparticle-mediated intracellular delivery of functional proteins to target cellular pathways

    Science.gov (United States)

    Shah, Dhiral Ashwin

    Intracellular delivery of specific proteins and peptides represents a novel method to influence stem cells for gain-of-function and loss-of-function. Signaling control is vital in stem cells, wherein intricate control of and interplay among critical pathways directs the fate of these cells into either self-renewal or differentiation. The most common route to manipulate cellular function involves the introduction of genetic material such as full-length genes and shRNA into the cell to generate (or prevent formation of) the target protein, and thereby ultimately alter cell function. However, viral-mediated gene delivery may result in relatively slow expression of proteins and prevalence of oncogene insertion into the cell, which can alter cell function in an unpredictable fashion, and non-viral delivery may lead to low efficiency of genetic delivery. For example, the latter case plagues the generation of induced pluripotent stem cells (iPSCs) and hinders their use for in vivo applications. Alternatively, introducing proteins into cells that specifically recognize and influence target proteins, can result in immediate deactivation or activation of key signaling pathways within the cell. In this work, we demonstrate the cellular delivery of functional proteins attached to hydrophobically modified silica (SiNP) nanoparticles to manipulate specifically targeted cell signaling proteins. In the Wnt signaling pathway, we have targeted the phosphorylation activity of glycogen synthase kinase-3beta (GSK-3beta) by designing a chimeric protein and delivering it in neural stem cells. Confocal imaging indicates that the SiNP-chimeric protein conjugates were efficiently delivered to the cytosol of human embryonic kidney cells and rat neural stem cells, presumably via endocytosis. This uptake impacted the Wnt signaling cascade, indicated by the elevation of beta-catenin levels, and increased transcription of Wnt target genes, such as c-MYC. The results presented here suggest that

  10. Maximizing in vivo target clearance by design of pH-dependent target binding antibodies with altered affinity to FcRn.

    Science.gov (United States)

    Yang, Danlin; Giragossian, Craig; Castellano, Steven; Lasaro, Marcio; Xiao, Haiguang; Saraf, Himanshu; Hess Kenny, Cynthia; Rybina, Irina; Huang, Zhong-Fu; Ahlberg, Jennifer; Bigwarfe, Tammy; Myzithras, Maria; Waltz, Erica; Roberts, Simon; Kroe-Barrett, Rachel; Singh, Sanjaya

    2017-10-01

    Antibodies with pH-dependent binding to both target antigens and neonatal Fc receptor (FcRn) provide an alternative tool to conventional neutralizing antibodies, particularly for therapies where reduction in antigen level is challenging due to high target burden. However, the requirements for optimal binding kinetic framework and extent of pH dependence for these antibodies to maximize target clearance from circulation are not well understood. We have identified a series of naturally-occurring high affinity antibodies with pH-dependent target binding properties. By in vivo studies in cynomolgus monkeys, we show that pH-dependent binding to the target alone is not sufficient for effective target removal from circulation, but requires Fc mutations that increase antibody binding to FcRn. Affinity-enhanced pH-dependent FcRn binding that is double-digit nM at pH 7.4 and single-digit nM at pH 6 achieved maximal target reduction when combined with similar target binding affinities in reverse pH directions. Sustained target clearance below the baseline level was achieved 3 weeks after single-dose administration at 1.5 mg/kg. Using the experimentally derived mechanistic model, we demonstrate the essential kinetic interplay between target turnover and antibody pH-dependent binding during the FcRn recycling, and identify the key components for achieving maximal target clearance. These results bridge the demand for improved patient dosing convenience with the "know-how" of therapeutic modality by design.

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

    National Research Council Canada - National Science Library

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

    2006-01-01

    .... Additionally, incorporating sustainability into the range designs should remain a high priority to meet environmental compliance regulations and provide a durable long-lasting structure useful...

  12. IFMIF Li target back-plate design integration and thermo-mechanical analysis

    International Nuclear Information System (INIS)

    Riccardi, B.; Roccella, S.; Micciche, G.

    2006-01-01

    The International Fusion Materials Irradiation Facility (IFMIF) is an accelerator-driven intense neutron source where fusion reactor candidate materials will be tested. The neutron flux is produced by means of a deuteron beam (current 250 mA, energy 40 MeV) that strikes a liquid lithium target circulating in a lithium loop. The support on which the liquid lithium flows, i.e. the back-plate, is the most heavily exposed component to neutron flux. A '' bayonet '' concept solution for the back-plate was proposed by ENEA with the objectives of improving the back-plate reliability and simplifying the remote handling procedures. On the base of this concept, a back-plate mock-up was fabricated and validated. Starting from the findings of the mock up design, a back-plate design integration exercise was carried out in order to check if the back-plate geometrical features are compatible with the target assembly and the Vertical Test Assemblies (VTA). The work carried out has demonstrated that even with the changes operated for the design integration (increase of in-plane dimensions and reduction of thickness) the bayonet concept is able to guarantee a tight connection to the target assembly. A thermo-mechanical analysis of the back-plate has been carried out by means of ABAQUS code. The thermal load used as input for the calculations, i.e. the neutron heat generation, has been estimated by means of Monte Carlo Mc-Delicious code. The two boundary constraint cases (full and minimum contact with target assembly) considered for each back-plate geometry option represent the extreme cases of the real operating condition of the plate. The influence of the contact heat exchange coefficient and the back-plate thickness has been also evaluated. For all these reasons, the results of the analysis can be considered as the domain of variability of the real working conditions. The results show that AISI 316L steel is not suitable as black-plate material: the stress induced in the plate, in

  13. Fab Four: When John and George Play Gravitation and Cosmology

    Directory of Open Access Journals (Sweden)

    J.-P. Bruneton

    2012-01-01

    Full Text Available Scalar-tensor theories of gravitation attract again a great interest since the discovery of the Chameleon mechanism and of the Galileon models. The former allows reconciling the presence of a scalar field with the constraints from Solar System experiments. The latter leads to inflationary models that do not need ad hoc potentials. Further generalizations lead to a tensor-scalar theory, dubbed the “Fab Four,” with only first and second order derivatives of the fields in the equations of motion that self-tune to a vanishing cosmological constant. This model needs to be confronted with experimental data in order to constrain its large parameter space. We present some results regarding a subset of this theory named “John,” which corresponds to a nonminimal derivative coupling between the scalar field and the Einstein tensor in the action. We show that this coupling gives rise to an inflationary model with very unnatural initial conditions. Thus, we include the term named “George,” namely, a nonminimal, but nonderivative, coupling between the scalar field and Ricci scalar. We find a more natural inflationary model, and, by performing a post-Newtonian analysis, we derive the set of equations that constrain the parameter space with data from experiments in the Solar System.

  14. Computer-aided Molecular Design of Compounds Targeting Histone Modifying Enzymes

    Science.gov (United States)

    Andreoli, Federico; Del Rio, Alberto

    2015-01-01

    Growing evidences show that epigenetic mechanisms play crucial roles in the genesis and progression of many physiopathological processes. As a result, research in epigenetic grew at a fast pace in the last decade. In particular, the study of histone post-translational modifications encountered an extraordinary progression and many modifications have been characterized and associated to fundamental biological processes and pathological conditions. Histone modifications are the catalytic result of a large set of enzyme families that operate covalent modifications on specific residues at the histone tails. Taken together, these modifications elicit a complex and concerted processing that greatly contribute to the chromatin remodeling and may drive different pathological conditions, especially cancer. For this reason, several epigenetic targets are currently under validation for drug discovery purposes and different academic and industrial programs have been already launched to produce the first pre-clinical and clinical outcomes. In this scenario, computer-aided molecular design techniques are offering important tools, mainly as a consequence of the increasing structural information available for these targets. In this mini-review we will briefly discuss the most common types of known histone modifications and the corresponding operating enzymes by emphasizing the computer-aided molecular design approaches that can be of use to speed-up the efforts to generate new pharmaceutically relevant compounds. PMID:26082827

  15. Optimization of LDL targeted nanostructured lipid carriers of 5-FU by a full factorial design

    Directory of Open Access Journals (Sweden)

    Sare Andalib

    2012-01-01

    Full Text Available Background: Nanostructured lipid carriers (NLC are a mixture of solid and liquid lipids or oils as colloidal carrier systems that lead to an imperfect matrix structure with high ability for loading water soluble drugs. The aim of this study was to find the best proportion of liquid and solid lipids of different types for optimization of the production of LDL targeted NLCs used in carrying 5-Fu by the emulsification-solvent evaporation method. Materials and Methods: The influence of the lipid type, cholesterol or cholesteryl stearate for targeting LDL receptors, oil type (oleic acid or octanol, lipid and oil% on particle size, surface charge, drug loading efficiency, and drug released percent from the NLCs were studied by a full factorial design. Results: The NLCs prepared by 54.5% cholesterol and 25% of oleic acid, showed optimum results with particle size of 105.8 nm, relatively high zeta potential of −25 mV, drug loading efficiency of 38% and release efficiency of about 40%. Scanning electron microscopy of nanoparticles confirmed the results of dynamic light scattering method used in measuring the particle size of NLCs. Conclusions: The optimization method by a full factorial statistical design is a useful optimization method for production of nanostructured lipid carriers.

  16. An optimized target-field method for MRI transverse biplanar gradient coil design

    International Nuclear Information System (INIS)

    Zhang, Rui; Xu, Jing; Huang, Kefu; Zhang, Jue; Fang, Jing; Fu, Youyi; Li, Yangjing

    2011-01-01

    Gradient coils are essential components of magnetic resonance imaging (MRI) systems. In this paper, we present an optimized target-field method for designing a transverse biplanar gradient coil with high linearity, low inductance and small resistance, which can well satisfy the requirements of permanent-magnet MRI systems. In this new method, the current density is expressed by trigonometric basis functions with unknown coefficients in polar coordinates. Following the standard procedures, we construct an objective function with respect to the total square errors of the magnetic field at all target-field points with the penalty items associated with the stored magnetic energy and the dissipated power. By adjusting the two penalty factors and minimizing the objective function, the appropriate coefficients of the current density are determined. Applying the stream function method to the current density, the specific winding patterns on the planes can be obtained. A novel biplanar gradient coil has been designed using this method to operate in a permanent-magnet MRI system. In order to verify the validity of the proposed approach, the gradient magnetic field generated by the resulted current density has been calculated via the Biot–Savart law. The results have demonstrated the effectiveness and advantage of this proposed method

  17. Optimization of LDL targeted nanostructured lipid carriers of 5-FU by a full factorial design.

    Science.gov (United States)

    Andalib, Sare; Varshosaz, Jaleh; Hassanzadeh, Farshid; Sadeghi, Hojjat

    2012-01-01

    Nanostructured lipid carriers (NLC) are a mixture of solid and liquid lipids or oils as colloidal carrier systems that lead to an imperfect matrix structure with high ability for loading water soluble drugs. The aim of this study was to find the best proportion of liquid and solid lipids of different types for optimization of the production of LDL targeted NLCs used in carrying 5-Fu by the emulsification-solvent evaporation method. The influence of the lipid type, cholesterol or cholesteryl stearate for targeting LDL receptors, oil type (oleic acid or octanol), lipid and oil% on particle size, surface charge, drug loading efficiency, and drug released percent from the NLCs were studied by a full factorial design. The NLCs prepared by 54.5% cholesterol and 25% of oleic acid, showed optimum results with particle size of 105.8 nm, relatively high zeta potential of -25 mV, drug loading efficiency of 38% and release efficiency of about 40%. Scanning electron microscopy of nanoparticles confirmed the results of dynamic light scattering method used in measuring the particle size of NLCs. The optimization method by a full factorial statistical design is a useful optimization method for production of nanostructured lipid carriers.

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

    Directory of Open Access Journals (Sweden)

    Fatemeh Torkashvand

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

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

    International Nuclear Information System (INIS)

    Rennoll, Sherri A.; Scott, Samantha A.; Yochum, Gregory S.

    2014-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-04-18

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

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

    Science.gov (United States)

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

    2016-09-30

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

  2. Coagulation parameters in copperhead compared to other Crotalinae envenomation: secondary analysis of the F(ab')2 versus Fab antivenom trial.

    Science.gov (United States)

    Gerardo, Charles J; Vissoci, Joao R Nickenig; Brown, Michael W J; Bush, Sean P

    2017-02-01

    Coagulation derangements in copperhead envenomation are considered less severe than other crotaline envenomations, resulting in recommendations to limit both coagulation testing and antivenom treatment. A prospective, blinded, multicenter, randomized clinical trial comparing the effectiveness of F(ab') 2 versus Fab antivenom in crotaline envenomation patients was completed in 2011. We determined the difference between coagulation parameters in copperhead compared to other crotaline envenomations. We performed a post hoc analysis comparing the coagulation parameters (platelets and fibrinogen) prospectively obtained in the aforementioned trial. All the patients received antivenom in one of three treatment arms [F(ab') 2 with maintenance, F(ab') 2 with placebo maintenance, or Fab with maintenance]. Coagulation parameters were measured at pretreatment baseline, during acute hospitalization, day 5, day 8, and day 15 post-envenomation. Mean platelet count and fibrinogen levels for the copperhead and other crotaline groups were compared. The platelet and fibrinogen point estimates with distribution are presented graphically over time. 122 patients were enrolled in the study. There were 22 patients with copperhead envenomation, 93 with other crotaline envenomations, and 7 that could not be definitively determined. The mean age was 42 (SD 20) years. There was a minor pretreatment difference in mean baseline platelet count between the copperhead group (246 × 109/L 95% CI 215, 277) compared to other crotaline envenomation patients (184 × 109/L 95% CI 167, 202). There was a modest pretreatment difference in mean fibrinogen level between copperhead patients (345 mg/dL 95% CI 277, 415) and other crotaline patients (261mg/dL 95% CI 241, 281). Pretreatment coagulation parameter means were normal and converged post treatment. On average, copperhead envenomations have less severe initial coagulation derangements. However, in mild envenomations, differences in laboratory

  3. Design and verification experiments for the windowless spallation target of the ADS prototype Myrrha

    International Nuclear Information System (INIS)

    Kantrien Van, Tichelen; Kupschus, P.; Arien, B.; Ait Abderrahim, H.

    2003-01-01

    SCKxCEN, the Belgian Nuclear Research Centre, works on the conceptual design and basic engineering of a multipurpose ADS for R and D, dubbed MYRRHA, a small high-performance irradiation facility with fast neutron fluxes up to 1.10 15 n/cm 2 /s to start operation in about 2010. Specific to the MYRRHA ADS system is the choice for a windowless spallation target at the centre of the subcritical core. Apart from the space limitations and material property short-comings, the current and power density figures would make the design of a solid window for the spallation source next to impossible: the chosen 5 mA at the relative low energy of 350 MeV leads to a current density of order 150 μA/cm 2 (as far as we know at least a factor of 3 higher than any window design that has been attempted to meet). This is the main reason for adopting the windowless design for MYRRHA which has as a consequence that the free surface ultimately has to be compatible with the vacuum requirements of the beam transport system of the accelerator. The total beam energy will be dumped into a volume of ca 0.5 1 leading to a heating power density of ca 3 kW/cm 3 . In order to remove this heat from the LM with an average temperature increase of 100 deg C on top of the temperature of the inlet flow of 240 deg C a total flow rate of 101/s at an average flow speed of 2.5 m/s is required. It is suggested from estimates that the evaporation from 'hot spots' with elevated temperatures beyond the average 340 deg C - close to the free surface in the re-circulation zone - is then still acceptable. The design investigations are therefore directed to assess and minimise the re-circulation zone inherent in the free surface formation under the geometry and flow requirements. This paper will summarize the design programme for the windowless design of the spallation source at the centre of the subcritical core. It will include the main findings reported in (Van Tichelen, 2000) and (Van Tichelen, 2001) and the

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

    Directory of Open Access Journals (Sweden)

    Dimitrios Vlachakis

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

  5. Contribution of Antibody Hydrodynamic Size to Vitreal Clearance Revealed through Rabbit Studies Using a Species-Matched Fab.

    Science.gov (United States)

    Shatz, Whitney; Hass, Philip E; Mathieu, Mary; Kim, Hok Seon; Leach, Kim; Zhou, Michelle; Crawford, Yongping; Shen, Amy; Wang, Kathryn; Chang, Debby P; Maia, Mauricio; Crowell, Susan R; Dickmann, Leslie; Scheer, Justin M; Kelley, Robert F

    2016-09-06

    We have developed a tool Fab fragment of a rabbit monoclonal antibody that is useful for early evaluation in rabbit models of technologies for long acting delivery (LAD) of proteins to the eye. Using this Fab we show that vitreal clearance can be slowed through increased hydrodynamic size. Fab (G10rabFab) and Fab' (G10rabFab') fragments of a rabbit monoclonal antibody (G10rabIgG) were expressed in Chinese hamster ovary (CHO) cells and purified using antigen-based affinity chromatography. G10rabFab retains antigen-binding upon thermal stress (37 °C) for 8 weeks in phosphate-buffered saline (PBS) and can be detected in rabbit tissues using an antigen-based ELISA. Hydrodynamic radius, measured using quasi-elastic light scattering (QELS), was increased through site-specific modification of the G10rabFab' free cysteine with linear methoxy-polyethylene glycol(PEG)-maleimide of 20000 or 40000 molecular weight. Pharmacokinetic studies upon intravitreal dosing in New Zealand white rabbits were conducted on the G10rabFab and PEGylated G10rabFab'. Results of single and multidose pharmacokinetic experiments yield reproducible results and a vitreal half-life for G10rabFab of 3.2 days. Clearance from the eye is slowed through increased hydrodynamic size, with vitreal half-life showing a linear dependence on hydrodynamic radius (RH). A linear dependence of vitreal half-life on RH suggests that molecule diffusivity makes an important contribution to vitreal clearance. A method for prediction of vitreal half-life from RH measurements is proposed.

  6. The Ubx Polycomb response element bypasses an unpaired Fab-8 insulator via cis transvection in Drosophila.

    Science.gov (United States)

    Lu, Danfeng; Li, Zhuoran; Li, Lingling; Yang, Liping; Chen, Guijun; Yang, Deying; Zhang, Yue; Singh, Vikrant; Smith, Sheryl; Xiao, Yu; Wang, Erlin; Ye, Yunshuang; Zhang, Wei; Zhou, Lei; Rong, Yikang; Zhou, Jumin

    2018-01-01

    Chromatin insulators or boundary elements protect genes from regulatory activities from neighboring genes or chromatin domains. In the Drosophila Abdominal-B (Abd-B) locus, the deletion of such elements, such as Frontabdominal-7 (Fab-7) or Fab-8 led to dominant gain of function phenotypes, presumably due to the loss of chromatin barriers. Homologous chromosomes are paired in Drosophila, creating a number of pairing dependent phenomena including transvection, and whether transvection may affect the function of Polycomb response elements (PREs) and thus contribute to the phenotypes are not known. Here, we studied the chromatin barrier activity of Fab-8 and how it is affected by the zygosity of the transgene, and found that Fab-8 is able to block the silencing effect of the Ubx PRE on the DsRed reporter gene in a CTCF binding sites dependent manner. However, the blocking also depends on the zygosity of the transgene in that the barrier activity is present when the transgene is homozygous, but absent when the transgene is heterozygous. To analyze this effect, we performed chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR) experiments on homozygous transgenic embryos, and found that H3K27me3 and H3K9me3 marks are restricted by Fab-8, but they spread beyond Fab-8 into the DsRed gene when the two CTCF binding sites within Fab-8 were mutated. Consistent with this, the mutation reduced H3K4me3 and RNA Pol II binding to the DsRed gene, and consequently, DsRed expression. Importantly, in heterozygous embryos, Fab-8 is unable to prevent the spread of H3K27me3 and H3K9me3 marks from crossing Fab-8 into DsRed, suggesting an insulator bypass. These results suggest that in the Abd-B locus, deletion of the insulator in one copy of the chromosome could lead to the loss of insulator activity on the homologous chromosome, and in other loci where chromosomal deletion created hemizygous regions of the genome, the chromatin barrier could be compromised. This study highlights

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

    National Research Council Canada - National Science Library

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

    2006-01-01

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

  8. /sup 99m/Tc labeling of antibodies to cardiac myosin Fab and to human fibrinogen

    International Nuclear Information System (INIS)

    Khaw, B.A.; Strauss, H.W.; Carvalho, A.; Locke, E.; Gold, H.K.; Haber, E.

    1982-01-01

    We have developed a method of labeling biologically active labile macromolecules, such as human fibrinogen (HF) and anticardiac-myosin Fab (AM-Fab), with /sup 99m/Tc at neutral pH. This method uses dithionite reduction of pertechnetate and subsequent labeling, to test the method with acid-labile macromolecules. Complexes of diethylene triamine pentaacetic acid with macromolecules such as human fibrinogen (D-HF) and anticardiac-myosin Fab (D-AM-Fab) were labeled and utilized in in vitro and in vivo studies. In biodistribution studies, the /sup 99m/Tc D-HF had a two-component blood clearance (half-times 1 hr and 15 hr) and was 80--88% coagulable. The /sup 99m/Tc AM-Fab retained its immunoreactivity as tested by affinity chromatography; also during in vivo localization in experimental myocardial infarction. This labeling technique provides an easy and efficient approach to the /sup 99m/Tc labeling of other biologically active and acid-labile macromolecules

  9. Technetium-99m labeling of antibodies to cardiac myosin Fab and to human fibrinogen

    International Nuclear Information System (INIS)

    Khaw, B.A.; Strauss, H.W.; Carvalho, A.; Locke, E.; Gold, H.K.; Haber, E.

    1982-01-01

    A method of labeling biologically active labile macromolecules, such as human fibrinogen (HF) and anticardiac-myosin Fab (AM-Fab), with Tc-99m at neutral pH was developed. This method uses dithionite reduction of pertechnetate and subsequent labeling to test the method with acid-labile macromolecules. Complexes of diethylene triamine pentaacetic acid with macromolecules such as human fibrinogen (D-HF) and anticardiac-myosin Fab (D-AM-Fab) were labeled and utilized in in vitro and in vivo studies. In biodistribution studies, the Tc-99m D-HF had a two-component blood clearance (half-times 1 hr and 15 hr) and was 80-88% coagulable. The Tc-99m AM-Fab retained its immunoreactivity as tested by affinity chromatography; also during in vivo localization in experimental myocardial infarction. This labeling technique provides an easy and efficient approach to the Tc-99m labeling of other biologically active and acid-labile macromolecules

  10. Cyclization strategies of meditopes: affinity and diffraction studies of meditope–Fab complexes

    International Nuclear Information System (INIS)

    Bzymek, Krzysztof P.; Ma, Yuelong; Avery, Kendra A.; Horne, David A.; Williams, John C.

    2016-01-01

    An overview of cyclization strategies of a Fab-binding peptide to maximize affinity. Recently, a unique binding site for a cyclic 12-residue peptide was discovered within a cavity formed by the light and heavy chains of the cetuximab Fab domain. In order to better understand the interactions that drive this unique complex, a number of variants including the residues within the meditope peptide and the antibody, as well as the cyclization region of the meditope peptide, were created. Here, multiple crystal structures of meditope peptides incorporating different cyclization strategies bound to the central cavity of the cetuximab Fab domain are presented. The affinity of each cyclic derivative for the Fab was determined by surface plasmon resonance and correlated to structural differences. Overall, it was observed that the disulfide bond used to cyclize the peptide favorably packs against a hydrophobic ‘pocket’ and that amidation and acetylation of the original disulfide meditope increased the overall affinity ∼2.3-fold. Conversely, replacing the terminal cysteines with serines and thus creating a linear peptide reduced the affinity over 50-fold, with much of this difference being reflected in a decrease in the on-rate. Other cyclization methods, including the formation of a lactam, reduced the affinity but not to the extent of the linear peptide. Collectively, the structural and kinetic data presented here indicate that small perturbations introduced by different cyclization strategies can significantly affect the affinity of the meditope–Fab complex

  11. Fast conversion of scFv to Fab antibodies using type IIs restriction enzymes.

    Science.gov (United States)

    Sanmark, Hanna; Huovinen, Tuomas; Matikka, Tero; Pettersson, Tiina; Lahti, Maria; Lamminmäki, Urpo

    2015-11-01

    Single chain variable fragment (scFv) antibody libraries are widely used for developing novel bioaffinity reagents, although Fab or IgG molecules are the preferred antibody formats in many final applications. Therefore, rapid conversion methods for combining multiple DNA fragments are needed to attach constant domains to the scFv derived variable domains. In this study we describe a fast and easy cloning method for the conversion of single framework scFv fragments to Fab fragments using type IIS restriction enzymes. All cloning steps excluding plating of the Fab transformants can be done in 96 well plates and the procedure can be completed in one working day. The concept was tested by converting 69 scFv clones into Fab format on 96 well plates, which resulted in 93% success rate. The method is particularly useful as a high-throughput tool for the conversion of the chosen scFv clones into Fab molecules in order to analyze them as early as possible, as the conversion can significantly affect the binding properties of the chosen clones. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Cyclization strategies of meditopes: affinity and diffraction studies of meditope–Fab complexes

    Energy Technology Data Exchange (ETDEWEB)

    Bzymek, Krzysztof P.; Ma, Yuelong; Avery, Kendra A.; Horne, David A.; Williams, John C., E-mail: jcwilliams@coh.org [Beckman Research Institute of City of Hope, 1710 Flower Street, Duarte, CA 91010 (United States)

    2016-05-23

    An overview of cyclization strategies of a Fab-binding peptide to maximize affinity. Recently, a unique binding site for a cyclic 12-residue peptide was discovered within a cavity formed by the light and heavy chains of the cetuximab Fab domain. In order to better understand the interactions that drive this unique complex, a number of variants including the residues within the meditope peptide and the antibody, as well as the cyclization region of the meditope peptide, were created. Here, multiple crystal structures of meditope peptides incorporating different cyclization strategies bound to the central cavity of the cetuximab Fab domain are presented. The affinity of each cyclic derivative for the Fab was determined by surface plasmon resonance and correlated to structural differences. Overall, it was observed that the disulfide bond used to cyclize the peptide favorably packs against a hydrophobic ‘pocket’ and that amidation and acetylation of the original disulfide meditope increased the overall affinity ∼2.3-fold. Conversely, replacing the terminal cysteines with serines and thus creating a linear peptide reduced the affinity over 50-fold, with much of this difference being reflected in a decrease in the on-rate. Other cyclization methods, including the formation of a lactam, reduced the affinity but not to the extent of the linear peptide. Collectively, the structural and kinetic data presented here indicate that small perturbations introduced by different cyclization strategies can significantly affect the affinity of the meditope–Fab complex.

  13. Identification of 2-aminothiazole-4-carboxylate derivatives active against Mycobacterium tuberculosis H37Rv and the beta-ketoacyl-ACP synthase mtFabH.

    Directory of Open Access Journals (Sweden)

    Qosay Al-Balas

    Full Text Available BACKGROUND: Tuberculosis (TB is a disease which kills two million people every year and infects approximately over one-third of the world's population. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance and co-infection with HIV/AIDS. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration. METHODOLOGY/PRINCIPAL FINDINGS: Our approach was to modify the naturally occurring and synthetically challenging antibiotic thiolactomycin (TLM to the more tractable 2-aminothiazole-4-carboxylate scaffold to generate compounds that mimic TLM's novel mode of action. We report here the identification of a series of compounds possessing excellent activity against M. tuberculosis H(37R(v and, dissociatively, against the beta-ketoacyl synthase enzyme mtFabH which is targeted by TLM. Specifically, methyl 2-amino-5-benzylthiazole-4-carboxylate was found to inhibit M. tuberculosis H(37R(v with an MIC of 0.06 microg/ml (240 nM, but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido-5-(3-chlorophenylthiazole-4-carboxylate inhibited mtFabH with an IC(50 of 0.95+/-0.05 microg/ml (2.43+/-0.13 microM but was not active against the whole cell organism. CONCLUSIONS/SIGNIFICANCE: These findings clearly identify the 2-aminothiazole-4-carboxylate scaffold as a promising new template towards the discovery of a new class of anti-tubercular agents.

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

    NARCIS (Netherlands)

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

    2011-01-01

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

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

    National Research Council Canada - National Science Library

    Harclerode, Eric

    2008-01-01

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

  16. Role of fibronectin in collagen deposition: Fab' to the gelatin-binding domain of fibronectin inhibits both fibronectin and collagen organization in fibroblast extracellular matrix

    OpenAIRE

    1982-01-01

    We report the effect of Fab' (anti-60k) to a 60,000 mol wt gelatin binding domain of fibronectin (1981, J. Biol. Chem. 256:5583) on diploid fibroblast (IMR-90) extracellular fibronectin and collagen organization. Anti-60k Fab' did not inhibit IMR-90 attachment or proliferation in fibronectin-depleted medium. Fibroblasts cultured with preimmune Fab' deposited a dense extracellular network of fibronectin and collagen detectable by immunofluorescence, while anti-60k Fab' prevented extracellular ...

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

    Science.gov (United States)

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

    2016-10-01

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

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

    CERN Document Server

    Hirakawa, Akihiro; Daimon, Takashi; Matsui, Shigeyuki

    2018-01-01

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

  19. A design concept of target-moderator-reflector assemblies for KENS-II

    International Nuclear Information System (INIS)

    Watanabe, N.

    1991-01-01

    A design concept of KENS-II target-moderator-reflector assemblies is described. One of the assemblies is dedicated to the cold neutron source, and the other, to the thermal and epithermal neutron source. A flux-trap type moderator-configuration was adopted with a vertical proton-beam injection scheme. All moderators for the cold neutron source are coupled liquid hydrogen moderators with premoderators. A new scheme of proton beam delivery is proposed. The new system can provide several times higher total performance than a reference system based on a traditional single assembly with all decoupled moderators in a wing geometry and with a horizontal proton-beam injection scheme. (author)

  20. A trajectory design method via target practice for air-breathing hypersonic vehicle

    Science.gov (United States)

    Kong, Xue; Yang, Ming; Ning, Guodong; Wang, Songyan; Chao, Tao

    2017-11-01

    There are strong coupling interactions between aerodynamics and scramjet, this kind of aircraft also has multiple restrictions, such as the range and difference of dynamic pressure, airflow, and fuel. On the one hand, we need balance the requirement between maneuverability of vehicle and stabilization of scramjet. On the other hand, we need harmonize the change of altitude and the velocity. By describing aircraft's index system of climbing capability, acceleration capability, the coupling degree in aerospace, this paper further propose a rapid design method which based on target practice. This method aimed for reducing the coupling degree, it depresses the coupling between aircraft and engine in navigation phase, satisfy multiple restriction conditions to leave some control buffer and create good condition for control implementation. According to the simulation, this method could be used for multiple typical fly commissions such as climbing, acceleration or both.

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

    Science.gov (United States)

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

    2016-10-01

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

  2. Preliminary shielding analysis in support of the CSNS target station shutter neutron beam stop design

    Institute of Scientific and Technical Information of China (English)

    ZHANG Bin; CHEN Yi-Xue; WANG Wei-Jin; YANG Shou-Hai; WU Jun; YIN Wen; LIANG Tian-Jiao; JIA Xue-Jun

    2011-01-01

    The construction of China Spallation Neutron Source (CSNS) has been initiated in Dongguan,Guangdong, China.Thus a detailed radiation transport analysis of the shutter neutron beam stop is of vital importance. The analyses are performed using the coupled Monte Carlo and multi-dimensional discrete ordinates method. The target of calculations is to optimize the neutron beamline shielding design to guarantee personal safety and minimize cost. Successful elimination of the primary ray effects via the two-dimensional uncollided flux and the first collision source methodology is also illustrated. Two-dimensional dose distribution is calculated. The dose at the end of the neutron beam line is less than 2.5μSv/h. The models have ensured that the doses received by the hall staff members are below the standard limit required.

  3. Oral heparin delivery: design and in vivo evaluation of a stomach-targeted mucoadhesive delivery system.

    Science.gov (United States)

    Schmitz, Thierry; Leitner, Verena M; Bernkop-Schnürch, Andreas

    2005-05-01

    Low molecular weight heparin (LMWH) is an agent of choice in the anti-coagulant therapy and prophylaxis of thrombosis and coronary syndromes. However, the therapeutic use is partially limited due to a poor oral bioavailability. It was therefore the aim of this study to design and evaluate a highly efficient stomach-targeted oral delivery system for LMWH. In order to appraise the influence of the molecular weight on the oral bioavailability, mini-tablets comprising 3 kDa (279 IU) and 6 kDa (300 IU) LMWH, respectively, were generated and tested in vivo in rats. The potential of the test formulations based on thiolated polycarbophil, was evaluated in comparison to hydroxyethylcellulose (HEC) as control carrier matrix. The plasma levels of LMWH after oral versus subcutaneous administration were determined in order to calculate the relative bioavailability. With the delivery system containing 3 kDa LMWH (279 IU) a relative bioavailability of 19.1% was achieved, offering a significantly (p thiolated polymers are a promising tool for the non-invasive stomach-targeted systemic delivery of LMWH as model for a hydrophilic macromolecular polysaccharide. Copyright 2005 Wiley-Liss, Inc

  4. Designs of contraction nozzle and concave back-wall for IFMIF target

    Energy Technology Data Exchange (ETDEWEB)

    Ida, Mizuho E-mail: ida@ifmif.tokai.jaeri.go.jp; Nakamura, Hideo; Nakamura, Hiroo; Takeuchi, Hiroshi

    2004-02-01

    For the liquid lithium flow target of International Fusion Materials Irradiation Facility (IFMIF), the double reducer (two-step contraction) nozzle with a high-contraction ratio of 10 which generated high-speed uniform jet flows up to 20 m/s was proposed. Multi-dimensional hydraulic analyses were carried out to verify the performance of the proposed nozzle. The analytical results showed that the double reducer nozzle would well generate high-speed uniform flow, while one-step contraction nozzle generated non-uniform flow and resulted in flow thickening at the beam footprint. For the target design, the range of the concave back-wall radius with no lithium boiling due to the centrifugal force and proper component arrangement in the irradiation test cell was determined by the thermal-hydraulic analysis of a free-surface flow. It was verified that the back-wall radius from 0.25 to 10 m was acceptable in the velocity range of 10-20 m/s.

  5. Designs of contraction nozzle and concave back-wall for IFMIF target

    International Nuclear Information System (INIS)

    Ida, Mizuho; Nakamura, Hideo; Nakamura, Hiroo; Takeuchi, Hiroshi

    2004-01-01

    For the liquid lithium flow target of International Fusion Materials Irradiation Facility (IFMIF), the double reducer (two-step contraction) nozzle with a high-contraction ratio of 10 which generated high-speed uniform jet flows up to 20 m/s was proposed. Multi-dimensional hydraulic analyses were carried out to verify the performance of the proposed nozzle. The analytical results showed that the double reducer nozzle would well generate high-speed uniform flow, while one-step contraction nozzle generated non-uniform flow and resulted in flow thickening at the beam footprint. For the target design, the range of the concave back-wall radius with no lithium boiling due to the centrifugal force and proper component arrangement in the irradiation test cell was determined by the thermal-hydraulic analysis of a free-surface flow. It was verified that the back-wall radius from 0.25 to 10 m was acceptable in the velocity range of 10-20 m/s

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

    Directory of Open Access Journals (Sweden)

    Daniel Ken Inaoka

    2015-07-01

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

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

    Science.gov (United States)

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

    2015-07-07

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

  8. Design criteria for a high energy Compton Camera and possible application to targeted cancer therapy

    Science.gov (United States)

    Conka Nurdan, T.; Nurdan, K.; Brill, A. B.; Walenta, A. H.

    2015-07-01

    The proposed research focuses on the design criteria for a Compton Camera with high spatial resolution and sensitivity, operating at high gamma energies and its possible application for molecular imaging. This application is mainly on the detection and visualization of the pharmacokinetics of tumor targeting substances specific for particular cancer sites. Expected high resolution (animals with a human tumor xenograft which is one of the first steps in evaluating the potential utility of a candidate gene. The additional benefit of high sensitivity detection will be improved cancer treatment strategies in patients based on the use of specific molecules binding to cancer sites for early detection of tumors and identifying metastasis, monitoring drug delivery and radionuclide therapy for optimum cell killing at the tumor site. This new technology can provide high resolution, high sensitivity imaging of a wide range of gamma energies and will significantly extend the range of radiotracers that can be investigated and used clinically. The small and compact construction of the proposed camera system allows flexible application which will be particularly useful for monitoring residual tumor around the resection site during surgery. It is also envisaged as able to test the performance of new drug/gene-based therapies in vitro and in vivo for tumor targeting efficacy using automatic large scale screening methods.

  9. Analytical study of narrow channel flow for a spallation target system design

    Energy Technology Data Exchange (ETDEWEB)

    Islam, Md. Shafiqul; Monde, Masanori [Saga Univ., Saga (Japan); Terada, Atsuhiko; Kinoshita, Hidetaka; Hino, Ryutaro [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment

    2001-07-01

    Heat transfer and pressure drop characteristics under fully developed turbulent water flow condition were analyzed over a two-dimensional narrow rectangular channel whose height is H=1.2 mm. The channel configuration and water flow condition simulate forced convection cooling of a spallation target system components design such as a solid target and a proton beam window. The high-Reynolds number form of the standard k - {epsilon} and RNG k - {epsilon} models employing wall functions for the Reynolds number (Re) range of 7,000 to 22,000 were used in the analyses. As for heat transfer characteristics of a smooth channel, the Nusselt number obtained by the standard k - {epsilon} model agreed very well with the Dittus-Boelter correlation. No significant differences in friction factors for the smooth channel were observed for these two models, which agreed well with the Blasius correlation. However, the standard k - {epsilon} model could not predict friction factors well for the rib-roughened channel. (author)

  10. Analytical study of narrow channel flow for a spallation target system design

    International Nuclear Information System (INIS)

    Islam, Md. Shafiqul; Monde, Masanori; Terada, Atsuhiko; Kinoshita, Hidetaka; Hino, Ryutaro

    2001-07-01

    Heat transfer and pressure drop characteristics under fully developed turbulent water flow condition were analyzed over a two-dimensional narrow rectangular channel whose height is H=1.2 mm. The channel configuration and water flow condition simulate forced convection cooling of a spallation target system components design such as a solid target and a proton beam window. The high-Reynolds number form of the standard k - ε and RNG k - ε models employing wall functions for the Reynolds number (Re) range of 7,000 to 22,000 were used in the analyses. As for heat transfer characteristics of a smooth channel, the Nusselt number obtained by the standard k - ε model agreed very well with the Dittus-Boelter correlation. No significant differences in friction factors for the smooth channel were observed for these two models, which agreed well with the Blasius correlation. However, the standard k - ε model could not predict friction factors well for the rib-roughened channel. (author)

  11. A Rationally Designed Agonist Defines Subfamily IIIA Abscisic Acid Receptors As Critical Targets for Manipulating Transpiration.

    Science.gov (United States)

    Vaidya, Aditya S; Peterson, Francis C; Yarmolinsky, Dmitry; Merilo, Ebe; Verstraeten, Inge; Park, Sang-Youl; Elzinga, Dezi; Kaundal, Amita; Helander, Jonathan; Lozano-Juste, Jorge; Otani, Masato; Wu, Kevin; Jensen, Davin R; Kollist, Hannes; Volkman, Brian F; Cutler, Sean R

    2017-11-17

    Increasing drought and diminishing freshwater supplies have stimulated interest in developing small molecules that can be used to control transpiration. Receptors for the plant hormone abscisic acid (ABA) have emerged as key targets for this application, because ABA controls the apertures of stomata, which in turn regulate transpiration. Here, we describe the rational design of cyanabactin, an ABA receptor agonist that preferentially activates Pyrabactin Resistance 1 (PYR1) with low nanomolar potency. A 1.63 Å X-ray crystallographic structure of cyanabactin in complex with PYR1 illustrates that cyanabactin's arylnitrile mimics ABA's cyclohexenone oxygen and engages the tryptophan lock, a key component required to stabilize activated receptors. Further, its sulfonamide and 4-methylbenzyl substructures mimic ABA's carboxylate and C6 methyl groups, respectively. Isothermal titration calorimetry measurements show that cyanabactin's compact structure provides ready access to high ligand efficiency on a relatively simple scaffold. Cyanabactin treatments reduce Arabidopsis whole-plant stomatal conductance and activate multiple ABA responses, demonstrating that its in vitro potency translates to ABA-like activity in vivo. Genetic analyses show that the effects of cyanabactin, and the previously identified agonist quinabactin, can be abolished by the genetic removal of PYR1 and PYL1, which form subclade A within the dimeric subfamily III receptors. Thus, cyanabactin is a potent and selective agonist with a wide spectrum of ABA-like activities that defines subfamily IIIA receptors as key target sites for manipulating transpiration.

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

    Directory of Open Access Journals (Sweden)

    Maryam M Shanechi

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

  13. Localization of 131I-labeled p97-specific Fab fragments in human melanoma as a basis for radiotherapy

    International Nuclear Information System (INIS)

    Larson, S.M.; Carrasquillo, J.A.; Krohn, K.A.

    1983-01-01

    33 patients with advanced malignant melanoma were studied after intravenous administration of 131 I-labeled Fab fragments specific for p97, an oncofetal glycoprotein of human melanoma. In all, 47 gamma camera imaging studies were performed for the purpose of localization of metastatic deposits. In addition to tumor, 131 I-Fab uptake was also seen in liver and kidney. 20 of these studies included simultaneous administration of both an 131 I-labeled Fab specific for p97, and an 125 I-labeled Fab not specific for p97. Blood clearance of p97-specific Fab was significantly more rapid than for nonspecific Fab. Eight of these patients had biopsies of subcutaneous nodules at 48 and 72 h postinjection in order to assess whether localization of radioactivity was antigen specific. Antigen-specific localization was observed with average ratios of specific/nonspecific uptake of 3.7 (48 h) and 3.4 (72 h); uptake was strongly correlated with tumor p97 concentration (r . 0.81, P less than 0.01). Also, imaging studies of the bio-distribution of 131 I-labeled anti-p97 Fab in patients selected for high p97 tumor concentration showed avid tumor uptake and more prolonged retention of labeled Fab in tumor than in normal tissues. Based on these studies, we estimated that total 131 I doses of 500 mCi could be safely given to patients before dose-limiting toxicity would be observed

  14. Enoyl-Acyl Carrier Protein Reductase I (FabI) Is Essential for the Intracellular Growth of Listeria monocytogenes

    Science.gov (United States)

    Ericson, Megan E.; Frank, Matthew W.

    2016-01-01

    Enoyl-acyl carrier protein reductase catalyzes the last step in each elongation cycle of type II bacterial fatty acid synthesis and is a key regulatory protein in bacterial fatty acid synthesis. Genes of the facultative intracellular pathogen Listeria monocytogenes encode two functional enoyl-acyl carrier protein isoforms based on their ability to complement the temperature-sensitive growth phenotype of Escherichia coli strain JP1111 [fabI(Ts)]. The FabI isoform was inactivated by the FabI selective inhibitor AFN-1252, but the FabK isoform was not affected by the drug, as expected. Inhibition of FabI by AFN-1252 decreased endogenous fatty acid synthesis by 80% and lowered the growth rate of L. monocytogenes in laboratory medium. Robust exogenous fatty acid incorporation was not detected in L. monocytogenes unless the pathway was partially inactivated by AFN-1252 treatment. However, supplementation with exogenous fatty acids did not restore normal growth in the presence of AFN-1252. FabI inactivation prevented the intracellular growth of L. monocytogenes, showing that neither FabK nor the incorporation of host cellular fatty acids was sufficient to support the intracellular growth of L. monocytogenes. Our results show that FabI is the primary enoyl-acyl carrier protein reductase of type II bacterial fatty acid synthesis and is essential for the intracellular growth of L. monocytogenes. PMID:27736774

  15. Conversion of a Mouse Fab into a Whole Humanized IgG Antibody for Detecting Botulinum Toxin

    National Research Council Canada - National Science Library

    Palys, Thomas J; Schmid, Kara E; Scherer, John M; Schoepp, Randal J

    2006-01-01

    .... Therefore we sought to convert a murine Fab into a whole humanized IgG. The variable regions from an anti-botulinum Fab were cloned into human IgG heavy and light chain vectors and produced in myeloma cells...

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

    Science.gov (United States)

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

    2015-05-15

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

  17. Mapping the conformational space accessible to BACE2 using surface mutants and cocrystals with Fab fragments, Fynomers and Xaperones.

    Science.gov (United States)

    Banner, David W; Gsell, Bernard; Benz, Jörg; Bertschinger, Julian; Burger, Dominique; Brack, Simon; Cuppuleri, Simon; Debulpaep, Maja; Gast, Alain; Grabulovski, Dragan; Hennig, Michael; Hilpert, Hans; Huber, Walter; Kuglstatter, Andreas; Kusznir, Eric; Laeremans, Toon; Matile, Hugues; Miscenic, Christian; Rufer, Arne C; Schlatter, Daniel; Steyaert, Jan; Stihle, Martine; Thoma, Ralf; Weber, Martin; Ruf, Armin

    2013-06-01

    The aspartic protease BACE2 is responsible for the shedding of the transmembrane protein Tmem27 from the surface of pancreatic β-cells, which leads to inactivation of the β-cell proliferating activity of Tmem27. This role of BACE2 in the control of β-cell maintenance suggests BACE2 as a drug target for diabetes. Inhibition of BACE2 has recently been shown to lead to improved control of glucose homeostasis and to increased insulin levels in insulin-resistant mice. BACE2 has 52% sequence identity to the well studied Alzheimer's disease target enzyme β-secretase (BACE1). High-resolution BACE2 structures would contribute significantly to the investigation of this enzyme as either a drug target or anti-target. Surface mutagenesis, BACE2-binding antibody Fab fragments, single-domain camelid antibody VHH fragments (Xaperones) and Fyn-kinase-derived SH3 domains (Fynomers) were used as crystallization helpers to obtain the first high-resolution structures of BACE2. Eight crystal structures in six different packing environments define an ensemble of low-energy conformations available to the enzyme. Here, the different strategies used for raising and selecting BACE2 binders for cocrystallization are described and the crystallization success, crystal quality and the time and resources needed to obtain suitable crystals are compared.

  18. Development of 90Y-DOTA-nimotuzumab Fab fragment for radioimmunotherapy

    International Nuclear Information System (INIS)

    Alonso Martinez, L.M.; Marylaine Perez-Malo Cruz; Rene Leyva Montana; Calzada Falcon, V.N.; Minely Zamora Barrabi; Alejandro Arbesu Valdivia; Ignacio Hernandez Gonzalez; Mariela Leon Perez

    2014-01-01

    Yttrium-90-( 90 Y) labeled monoclonal antibodies prepared with a chelating agent, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), have been used for radioimmunotherapy of cancer. In the present work, the Fab fragment of anti-EGFR monoclonal antibody nimotuzumab was prepared with high purity, integrity and biological activity. The Fab fragment with high specific recognition of EGFR in NCI-H125 human lung adenocarcinoma cells was derivatized with DOTA-NHS applying a simple procedure. DOTA-nimotuzumab Fab fragment was successfully radiolabeled with 90 Y with high radiochemical yield. The in vitro stability of labeled product was optimal over 24 h in buffered solution at 37 deg C. Biodistribution and pharmacokinetic studies correctly evaluated the in vivo non-tumor uptake, dosage regimen and excretion pathway in normal Wistar rats. (author)

  19. 3D printing in social education: Eki-Fab and student PBL

    Science.gov (United States)

    Makino, Masato; Saito, Azusa; Kodama, Mai; Takamatsu, Kyuuichiro; Tamate, Hideaki; Sakai, Kazuyuki; Wada, Masato; Khosla, Ajit; Kawakami, Masaru; Furukawa, Hidemitsu

    2017-04-01

    Additive manufacturing or 3D printer is one of the most innovative material processing methods. We are considering that human resources for 3D printing would be needed in the future. To educate the abilities of the digital fabrication, we have the public digital fabrication space "Eki-Fab" for junior and high school students and Project Based Learning (PBL) class for undergraduate students. Eki-Fab is held on every Saturday at the Yonezawa train station. In the "Eki-Fab", anybody can study the utilizing of 3D printer and modeling technics under the instruction of staff in Yamagata University. In the PBL class, we have the class every Thursday. The students get the techniques of the digital fabrication through the PBL.

  20. 20 CFR 30.312 - What will the FAB do if the claimant objects to the recommended decision but does not request a...

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false What will the FAB do if the claimant objects....312 What will the FAB do if the claimant objects to the recommended decision but does not request a... period of time allotted in § 30.310 but does not request a hearing, the FAB will consider any objections...

  1. 20 CFR 30.318 - Can the FAB consider objections to HHS's reconstruction of a radiation dose or to the guidelines...

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false Can the FAB consider objections to HHS's... OF 2000, AS AMENDED Adjudicatory Process Hearings and Final Decisions on Claims § 30.318 Can the FAB... to HHS's reconstruction of the radiation dose to which the employee was exposed, the FAB will...

  2. 20 CFR 30.317 - Can the FAB request a further response from the claimant or return a claim to the district office?

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false Can the FAB request a further response from....317 Can the FAB request a further response from the claimant or return a claim to the district office? At any time before the issuance of its final decision, the FAB may request that the claimant submit...

  3. Crotaline Fab antivenom appears to be effective in cases of severe North American pit viper envenomation: An integrative review

    Directory of Open Access Journals (Sweden)

    Mlynarchek Sara L

    2009-06-01

    Full Text Available Abstract Background In 2000, the United States Food and Drug Administration approved Crotalidae Polyvalent Immune Fab (Ovine (hereafter, FabAV, "for the management of patients with minimal to moderate North American Crotalid envenomation." Because whole-IgG pit viper antivenom is no longer available in the United States, FabAV is currently the only specific treatment option available to United States clinicians treating snakebite victims of any severity. No clinical trial data are available concerning the effectiveness of FabAV for treatment of severe snakebite, but several published articles describe its use in this setting. Methods We performed a comprehensive review of the English-language medical literature to identify all publications (1996 to July, 2008 containing data about the administration of FabAV. Two trained reviewers separately extracted case-level data concerning the administration of FabAV to patients with severe envenomation by North American crotaline snakes to a standardized form. Descriptive statistics were used. In addition, we hand-searched the US National Poison Data System reports for the years 2000–2006 to identify and describe any reports of death that occurred after FabAV administration. Results The literature review found 147 unique publications regarding FabAV. Twenty-four evaluable cases of severe human envenomation treated with FabAV were identified in 19 publications. Seven cases were described in five cohort studies, and 17 cases were described in 14 single patient case reports or non-cohort case series. Sixty-five specific severe venom effects were reported in these 24 patients, of which 50 effects (77% improved or resolved after FabAV therapy. Initial control of all severe venom effects was achieved in 12 patients (50%. The rate at which initial control was achieved was significantly higher among patients reported in the cohort series than in the case series and non-cohort reports (100% vs. 29%, P = 0

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

    Science.gov (United States)

    Kievit, Forrest M.

    2011-07-01

    Nanotechnology provides a flexible platform for the development of effective therapeutic nanomaterials that can interact specifically with a target in a biological system and provoke a desired biological respons