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Sample records for broadly neutralizing anti-hiv-1

  1. Neutralizing Activity of Broadly Neutralizing Anti-HIV-1 Antibodies against Clade B Clinical Isolates Produced in Peripheral Blood Mononuclear Cells.

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    Cohen, Yehuda Z; Lorenzi, Julio C C; Seaman, Michael S; Nogueira, Lilian; Schoofs, Till; Krassnig, Lisa; Butler, Allison; Millard, Katrina; Fitzsimons, Tomas; Daniell, Xiaoju; Dizon, Juan P; Shimeliovich, Irina; Montefiori, David C; Caskey, Marina; Nussenzweig, Michel C

    2018-03-01

    HIV-1 epidemic. Antibodies with exceptional neutralizing activity against HIV-1 may provide several advantages to traditional HIV drugs, including an improved side-effect profile, a reduced dosing frequency, and immune enhancement. The activity of these antibodies has been established in vitro by utilizing HIV-1 Env-pseudotyped viruses derived from circulating viruses but produced in 293T cells by pairing Env proteins with a backbone vector. We tested PBMC-produced circulating viruses against five anti-HIV-1 antibodies currently in clinical development. We found that the activity of these antibodies against PBMC isolates is significantly less than that against 293T Env-pseudotyped viruses. This decline varied among the antibodies tested, with some demonstrating moderate reductions in activity and others showing an almost 100-fold reduction. As the development of these antibodies progresses, it will be critical to determine how the results of different in vitro tests correspond to performance in the clinic. Copyright © 2018 Cohen et al.

  2. Lignosulfonic acid exhibits broadly anti-HIV-1 activity--potential as a microbicide candidate for the prevention of HIV-1 sexual transmission.

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    Min Qiu

    Full Text Available Some secondary metabolites from plants show to have potent inhibitory activities against microbial pathogens, such as human immunodeficiency virus (HIV, herpes simplex virus (HSV, Treponema pallidum, Neisseria gonorrhoeae, etc. Here we report that lignosulfonic acid (LSA, a polymeric lignin derivative, exhibits potent and broad activity against HIV-1 isolates of diverse subtypes including two North America strains and a number of Chinese clinical isolates values ranging from 21.4 to 633 nM. Distinct from other polyanions, LSA functions as an entry inhibitor with multiple targets on viral gp120 as well as on host receptor CD4 and co-receptors CCR5/CXCR4. LSA blocks viral entry as determined by time-of-drug addiction and cell-cell fusion assays. Moreover, LSA inhibits CD4-gp120 interaction by blocking the binding of antibodies specific for CD4-binding sites (CD4bs and for the V3 loop of gp120. Similarly, LSA interacts with CCR5 and CXCR4 via its inhibition of specific anti-CCR5 and anti-CXCR4 antibodies, respectively. Interestingly, the combination of LSA with AZT and Nevirapine exhibits synergism in viral inhibition. For the purpose of microbicide development, LSA displays low in vitro cytotoxicity to human genital tract epithelial cells, does not stimulate NF-κB activation and has no significant up-regulation of IL-1α/β and IL-8 as compared with N-9. Lastly, LSA shows no adverse effect on the epithelial integrity and the junctional protein expression. Taken together, our findings suggest that LSA can be a potential candidate for tropical microbicide.

  3. Broadly neutralizing antibodies for treatment and prevention of HIV-1 infection.

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    Cohen, Yehuda Z; Caskey, Marina

    2018-04-24

    Several anti-HIV-1 broadly neutralizing antibodies (bNAbs) with exceptional breadth and potency that target different HIV-1 envelope epitopes have been identified. bNAbs are an attractive new strategy for HIV-1 prevention and therapy, and potentially, for long-term remission or cure. Here, we discuss findings from early clinical studies that have evaluated these novel bNAbs. Phase 1 studies of bNAbs targeting two distinct HIV-1 envelope epitopes have demonstrated their favorable safety and pharmacokinetic profile. Single bNAb infusions led to significant, but transient, decline in viremia with selection of escape variants. A single bNAb also delayed viral rebound in ART-treated participants who discontinued ART. Importantly, in-vivo efficacy was related to antibody potency and to the level of preexisting resistance. Studies in animal models showed that bNAbs can clear HIV-infected cells and modulate host immune responses. These findings suggest that bNAbs may target the latent HIV reservoir in humans and could contribute to long-term remission of HIV-1 infection. bNAbs may offer advantages over traditional ART for both the prevention and treatment of HIV-1 infection. In addition, bNAbs may target the latent viral reservoir. bNAb combinations and bNAbs engineered for prolonged half-life and increased potency are currently undergoing clinical evaluation.

  4. Prolonged expression of an anti-HIV-1 gp120 minibody to the female rhesus macaque lower genital tract by AAV gene transfer.

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    Abdel-Motal, U M; Harbison, C; Han, T; Pudney, J; Anderson, D J; Zhu, Q; Westmoreland, S; Marasco, W A

    2014-09-01

    Topical microbicides are a leading strategy for prevention of HIV mucosal infection to women; however, numerous pharmacokinetic limitations associated with coitally related dosing strategy have contributed to their limited success. Here we test the hypothesis that adeno-associated virus (AAV) mediated delivery of the b12 human anti-HIV-1 gp120 minibody gene to the lower genital tract of female rhesus macaques (Rh) can provide prolonged expression of b12 minibodies in the cervical-vaginal secretions. Gene transfer studies demonstrated that, of various green fluorescent protein (GFP)-expressing AAV serotypes, AAV-6 most efficiently transduced freshly immortalized and primary genital epithelial cells (PGECs) of female Rh in vitro. In addition, AAV-6-b12 minibody transduction of Rh PGECs led to inhibition of SHIV162p4 transmigration and virus infectivity in vitro. AAV-6-GFP could also successfully transduce vaginal epithelial cells of Rh when applied intravaginally, including p63+ epithelial stem cells. Moreover, intravaginal application of AAV-6-b12 to female Rh resulted in prolonged minibody detection in their vaginal secretions throughout the 79-day study period. These data provide proof of principle that AAV-6-mediated delivery of anti-HIV broadly neutralizing antibody (BnAb) genes to the lower genital tract of female Rh results in persistent minibody detection for several months. This strategy offers promise that an anti-HIV-1 genetic microbicide strategy may be possible in which topical application of AAV vector, with periodic reapplication as needed, may provide sustained local BnAb expression and protection.

  5. Anti-HIV-1 B cell responses are dependent on B cell precursor frequency and antigen-binding affinity.

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    Dosenovic, Pia; Kara, Ervin E; Pettersson, Anna-Klara; McGuire, Andrew T; Gray, Matthew; Hartweger, Harald; Thientosapol, Eddy S; Stamatatos, Leonidas; Nussenzweig, Michel C

    2018-04-16

    The discovery that humans can produce potent broadly neutralizing antibodies (bNAbs) to several different epitopes on the HIV-1 spike has reinvigorated efforts to develop an antibody-based HIV-1 vaccine. Antibody cloning from single cells revealed that nearly all bNAbs show unusual features that could help explain why it has not been possible to elicit them by traditional vaccination and instead would require a sequence of different immunogens. This idea is supported by experiments with genetically modified immunoglobulin (Ig) knock-in mice. Sequential immunization with a series of specifically designed immunogens was required to shepherd the development of bNAbs. However, knock-in mice contain superphysiologic numbers of bNAb precursor-expressing B cells, and therefore how these results can be translated to a more physiologic setting remains to be determined. Here we make use of adoptive transfer experiments using knock-in B cells that carry a synthetic intermediate in the pathway to anti-HIV-1 bNAb development to examine how the relationship between B cell receptor affinity and precursor frequency affects germinal center (GC) B cell recruitment and clonal expansion. Immunization with soluble HIV-1 antigens can recruit bNAb precursor B cells to the GC when there are as few as 10 such cells per mouse. However, at low precursor frequencies, the extent of clonal expansion is directly proportional to the affinity of the antigen for the B cell receptor, and recruitment to GCs is variable and dependent on recirculation.

  6. Antiviral Therapy by HIV-1 Broadly Neutralizing and Inhibitory Antibodies

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    Zhiqing Zhang

    2016-11-01

    Full Text Available Human immunodeficiency virus type 1 (HIV-1 infection causes acquired immune deficiency syndrome (AIDS, a global epidemic for more than three decades. HIV-1 replication is primarily controlled through antiretroviral therapy (ART but this treatment does not cure HIV-1 infection. Furthermore, there is increasing viral resistance to ART, and side effects associated with long-term therapy. Consequently, there is a need of alternative candidates for HIV-1 prevention and therapy. Recent advances have discovered multiple broadly neutralizing antibodies against HIV-1. In this review, we describe the key epitopes on the HIV-1 Env protein and the reciprocal broadly neutralizing antibodies, and discuss the ongoing clinical trials of broadly neutralizing and inhibitory antibody therapy as well as antibody combinations, bispecific antibodies, and methods that improve therapeutic efficacy by combining broadly neutralizing antibodies (bNAbs with latency reversing agents. Compared with ART, HIV-1 therapeutics that incorporate these broadly neutralizing and inhibitory antibodies offer the advantage of decreasing virus load and clearing infected cells, which is a promising prospect in HIV-1 prevention and treatment.

  7. Photo-translocation of anti-HIV-1 drugs into TZM-bl cells

    CSIR Research Space (South Africa)

    Khanyile, T

    2013-04-01

    Full Text Available Targeted drug delivery into HIV-1 infected cells offers a reduction in toxicity and side effect. Using a femtosecond (fs) laser of different beam shapes anti-HIV-1 drugs are efficiently delivered into TZM-bl cells....

  8. Short communication: Anti-HIV-1 envelope immunoglobulin Gs in blood and cervicovaginal samples of Beninese commercial sex workers.

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    Batraville, Laurie-Anne; Richard, Jonathan; Veillette, Maxime; Labbé, Annie-Claude; Alary, Michel; Guédou, Fernand; Kaufmann, Daniel E; Poudrier, Johanne; Finzi, Andrés; Roger, Michel

    2014-11-01

    Characterization of the immune correlates of protection against HIV infection is crucial for the development of preventive strategies. This study examined HIV-1 envelope (Env) glycoproteins, specifically immunoglobulin G (IgG), in systemic and mucosal compartments of female Beninese commercial sex workers (CSWs). Samples of 23 HIV-1-positive and 20 highly exposed HIV-1-seronegative (HESN) CSWs were studied. HIV-1 Env-specific IgG detection in sera and cervicovaginal lavages (CVLs) from the study population was done by cell-based ELISA. The HIV neutralizing activity was evaluated with a neutralization assay. The HIV-1-specific antibody-dependent cellular cytotoxicity (ADCC) response of the cohort was measured with a FACS-based assay evaluating the ADCC-mediated elimination of gp120-coated target cells. No anti-HIV-1 Env-specific IgG neutralizing or ADCC activities were detected in samples from HESN CSWs. Samples from HIV-1-infected CSWs presented ADCC activity in both sera and CVLs. Anti-Env IgG from sera and CVLs from HIV-1-infected CSWs preferentially recognized Env in its CD4-bound conformation. HIV-1-infected CSWs have ADCC-mediating IgG that preferentially recognizes Env in its CD4-bound conformation at the mucosal site.

  9. 7,8-secolignans from Schisandra neglecta and their anti-HIV-1 activities

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    Gao, Xuemei; Mu, Huaixue; Hu, Qiufen, E-mail: huqiufena@yahoo.com.cn [Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan University of Nationalities (China); Wang, Ruirui; Yang, Liumeng; Zheng, Yongtang [Kunming Institute of Zoology, Chinese Academy of Sciences (China); Sun, Handong; Xiao, Weilie, E-mail: xwl@mail.kib.ac.cn [State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming (China)

    2012-10-15

    Four new 7,8-secolignans (neglectahenols A-D), together with two known 7,8-secolignans, were isolated from leaves and stems of Schisandra neglecta. The structures were elucidated by spectroscopic methods, including extensive one and two dimension NMR (nuclear magnetic resonance) techniques. 7,8-Secolignans and neglectahenols A-D were also tested for their anti-HIV-1 (human immunodeficiency virus type 1) activities, and all of them showed modest activities. (author)

  10. Towards HIV-1 remission: potential roles for broadly neutralizing antibodies.

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    Halper-Stromberg, Ariel; Nussenzweig, Michel C

    2016-02-01

    Current antiretroviral drug therapies do not cure HIV-1 because they do not eliminate a pool of long-lived cells harboring immunologically silent but replication-competent proviruses - termed the latent reservoir. Eliminating this reservoir and stimulating the immune response to control infection in the absence of therapy remain important but unsolved goals of HIV-1 cure research. Recently discovered broadly neutralizing antibodies (bNAbs) exhibit remarkable breadth and potency in their ability to neutralize HIV-1 in vitro, and recent studies have demonstrated new therapeutic applications for passively administered bNAbs in vivo. This Review discusses the roles bNAbs might play in HIV-1 treatment regimens, including prevention, therapy, and cure.

  11. Llama Antibody Fragments Recognizing Various Epitopes of the CD4bs Neutralize a Broad Range of HIV-1 Subtypes A, B and C

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    Aasa-Chapman, Marlèn; Gorlani, Andrea; Forsman Quigley, Anna; Hulsik, David Lutje; Chen, Lei; Weiss, Robin; de Haard, Hans; Verrips, Theo

    2012-01-01

    Many of the neutralising antibodies, isolated to date, display limited activities against the globally most prevalent HIV-1 subtypes A and C. Therefore, those subtypes are considered to be an important target for antibody-based therapy. Variable domains of llama heavy chain antibodies (VHH) have some superior properties compared with classical antibodies. Therefore we describe the application of trimeric forms of envelope proteins (Env), derived from HIV-1 of subtype A and B/C, for a prolonged immunization of two llamas. A panel of VHH, which interfere with CD4 binding to HIV-1 Env were selected with use of panning. The results of binding and competition assays to various Env, including a variant with a stabilized CD4-binding state (gp120Ds2), cross-competition experiments, maturation analysis and neutralisation assays, enabled us to classify the selected VHH into three groups. The VHH of group I were efficient mainly against viruses of subtype A, C and B′/C. The VHH of group II resemble the broadly neutralising antibody (bnmAb) b12, neutralizing mainly subtype B and C viruses, however some had a broader neutralisation profile. A representative of the third group, 2E7, had an even higher neutralization breadth, neutralizing 21 out of the 26 tested strains belonging to the A, A/G, B, B/C and C subtypes. To evaluate the contribution of certain amino acids to the potency of the VHH a small set of the mutants were constructed. Surprisingly this yielded one mutant with slightly improved neutralisation potency against 92UG37.A9 (subtype A) and 96ZM651.02 (subtype C). These findings and the well-known stability of VHH indicate the potential application of these VHH as anti-HIV-1 microbicides. PMID:22438910

  12. Enhanced anti-HIV-1 activity of G-quadruplexes comprising locked nucleic acids and intercalating nucleic acids

    DEFF Research Database (Denmark)

    Pedersen, Erik Bjerregaard; Nielsen, Jakob Toudahl; Nielsen, Claus

    2011-01-01

    Two G-quadruplex forming sequences, 50-TGGGAG and the 17-mer sequence T30177, which exhibit anti-HIV-1 activity on cell lines, were modified using either locked nucleic acids (LNA) or via insertions of (R)-1-O-(pyren-1-ylmethyl)glycerol (intercalating nucleic acid, INA) or (R)-1-O-[4-(1......-pyrenylethynyl)phenylmethyl]glycerol (twisted intercalating nucleic acid, TINA). Incorporation of LNA or INA/TINA monomers provide as much as 8-fold improvement of anti-HIV-1 activity. We demonstrate for the first time a detailed analysis of the effect the incorporation of INA/TINA monomers in quadruplex forming...

  13. Role of seminal plasma in the anti-HIV-1 activity of candidate microbicides

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    Li Yun-Yao

    2006-10-01

    Full Text Available Abstract Background Evaluation of microbicides for prevention of HIV-1 infection in macaque models for vaginal infection has indicated that the concentrations of active compounds needed for protection by far exceed levels sufficient for complete inhibition of infection in vitro. These experiments were done in the absence of seminal plasma (SP, a vehicle for sexual transmission of the virus. To gain insight into the possible effect of SP on the performance of selected microbicides, their anti-HIV-1 activity in the presence, and absence of SP, was determined. Methods The inhibitory activity of compounds against the X4 virus, HIV-1 IIIB, and the R5 virus, HIV-1 BaL was determined using TZM-bl indicator cells and quantitated by measuring β-galactosidase induced by infection. The virucidal properties of cellulose acetate 1,2-benzene-dicarboxylate (CAP, the only microbicide provided in water insoluble, micronized form, in the presence of SP was measured. Results The HIV-1 inhibitory activity of the polymeric microbicides, poly(naphthalene sulfonate, cellulose sulfate, carrageenan, CAP (in soluble form and polystyrene sulfonate, respectively, was considerably (range ≈ 4 to ≈ 73-fold diminished in the presence of SP (33.3%. Formulations of micronized CAP, providing an acidic buffering system even in the presence of an SP volume excess, effectively inactivated HIV-1 infectivity. Conclusion The data presented here suggest that the in vivo efficacy of polymeric microbicides, acting as HIV-1 entry inhibitors, might become at least partly compromised by the inevitable presence of SP. These possible disadvantages could be overcome by combining the respective polymers with acidic pH buffering systems (built-in for formulations of micronized CAP or with other anti-HIV-1 compounds, the activity of which is not affected by SP, e.g. reverse transcriptase and zinc finger inhibitors.

  14. Synthesis of single- and double-chain fluorocarbon and hydrocarbon galactosyl amphiphiles and their anti-HIV-1 activity.

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    Faroux-Corlay, B; Clary, L; Gadras, C; Hammache, D; Greiner, J; Santaella, C; Aubertin, A M; Vierling, P; Fantini, J

    2000-07-24

    Galactosylceramide (GalCer) is an alternative receptor allowing HIV-1 entry into CD4(-)/GalCer(+) cells. This glycosphingolipid recognizes the V3 loop of HIV gp120, which plays a key role in the fusion of the HIV envelope and cellular membrane. To inhibit HIV uptake and infection, we designed and synthesized analogs of GalCer. These amphiphiles and bolaamphiphiles consist of single and double hydrocarbon and/or fluorocarbon chain beta-linked to galactose and galactosamine. They derive from serine (GalSer), cysteine (GalCys), and ethanolamine (GalAE). The anti-HIV activity and cytotoxicity of these galactolipids were evaluated in vitro on CEM-SS (a CD4(+) cell line), HT-29, a CD4(-) cell line expressing high levels of GalCer receptor, and/or HT29 genetically modified to express CD4. GalSer and GalAE derivatives, tested in aqueous medium or as part of liposome preparation, showed moderate anti-HIV-1 activities (IC50 in the 20-220 microM range), whereas none of the GalCys derivatives was found to be active. Moreover, only some of these anti-HIV active analogs inhibited the binding of [3H]suramin (a polysulfonyl compound which displays a high affinity for the V3 loop) to SPC3, a synthetic peptide which contains the conserved GPGRAF region of the V3 loop. Our results most likely indicate that the neutralization of the virion through masking of this conserved V3 loop region is not the only mechanism involved in the HIV-1 antiviral activity of our GalCer analogs.

  15. Comparative pharmacokinetic, immunologic and hematologic studies on the anti-HIV-1/2 compounds aconitylated and succinylated HSA

    NARCIS (Netherlands)

    Swart, P J; Beljaars, E; Smit, C; Pasma, A; Schuitemaker, H; Meijer, D K

    1996-01-01

    Charge modification by succinylation or cis-aconitylation of the terminal epsilon NH2 functions of the amino acid lysine in human serum albumin, resulted in polyanionic compounds with an anti-HIV-1 activity in the low nanomolar concentration range. After iv injections in rats of the negatively

  16. Aaptamine Derivatives with Antifungal and Anti-HIV-1 Activities from the South China Sea Sponge Aaptos aaptos

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    Hao-Bing Yu

    2014-12-01

    Full Text Available Five new alkaloids of aaptamine family, compounds (1–5 and three known derivatives (6–8, have been isolated from the South China Sea sponge Aaptos aaptos. The structures of all compounds were unambiguously elucidated by spectroscopic analyses, as well as by comparison with the literature data. Compounds 1–2 are characterized with triazapyrene lactam skeleton, whereas compounds 4–5 share an imidazole-fused aaptamine moiety. These compounds were evaluated in antifungal and anti-HIV-1 assays. Compounds 3, 7, and 8 showed antifungal activity against six fungi, with MIC values in the range of 4 to 64 μg/mL. Compounds 7–8 exhibited anti-HIV-1 activity, with inhibitory rates of 88.0% and 72.3%, respectively, at a concentration of 10 μM.

  17. 3D printed, controlled release, tritherapeutic tablet matrix for advanced anti-HIV-1 drug delivery.

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    Siyawamwaya, Margaret; du Toit, Lisa C; Kumar, Pradeep; Choonara, Yahya E; Kondiah, Pierre P P D; Pillay, Viness

    2018-04-12

    A 3D-Bioplotter® was employed to 3D print (3DP) a humic acid-polyquaternium 10 (HA-PQ10) controlled release fixed dose combination (FDC) tablet comprising of the anti-HIV-1 drugs, efavirenz (EFV), tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). Chemical interactions, surface morphology and mechanical strength of the FDC were ascertained. In vitro drug release studies were conducted in biorelevant media followed by in vivo study in the large white pigs, in comparison with a market formulation, Atripla®. In vitro-in vivo correlation of results was undertaken. EFV, TDF and FTC were successfully entrapped in the 24-layered rectangular prism-shaped 3DP FDC with a loading of ∼12.5 mg/6.3 mg/4 mg of EFV/TDF/FTC respectively per printed layer. Hydrogen bonding between the EFV/TDF/FTC and HA-PQ10 was detected which was indicative of possible drug solubility enhancement. The overall surface of the tablet exhibited a fibrilla structure and the 90° inner pattern was determined to be optimal for 3DP of the FDC. In vitro and in vivo drug release profiles from the 3DP FDC demonstrated that intestinal-targeted and controlled drug release was achieved. A 3DP FDC was successfully manufactured with the aid of a 3D-Bioplotter in a single step process. The versatile HA-PQ10 entrapped all drugs and achieved an enhanced relative bioavailability of EFV, TDF, and FTC compared to the market formulation for potentially enhanced HIV treatment. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. Naturally selected hepatitis C virus polymorphisms confer broad neutralizing antibody resistance.

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    Bailey, Justin R; Wasilewski, Lisa N; Snider, Anna E; El-Diwany, Ramy; Osburn, William O; Keck, Zhenyong; Foung, Steven K H; Ray, Stuart C

    2015-01-01

    For hepatitis C virus (HCV) and other highly variable viruses, broadly neutralizing mAbs are an important guide for vaccine development. The development of resistance to anti-HCV mAbs is poorly understood, in part due to a lack of neutralization testing against diverse, representative panels of HCV variants. Here, we developed a neutralization panel expressing diverse, naturally occurring HCV envelopes (E1E2s) and used this panel to characterize neutralizing breadth and resistance mechanisms of 18 previously described broadly neutralizing anti-HCV human mAbs. The observed mAb resistance could not be attributed to polymorphisms in E1E2 at known mAb-binding residues. Additionally, hierarchical clustering analysis of neutralization resistance patterns revealed relationships between mAbs that were not predicted by prior epitope mapping, identifying 3 distinct neutralization clusters. Using this clustering analysis and envelope sequence data, we identified polymorphisms in E2 that confer resistance to multiple broadly neutralizing mAbs. These polymorphisms, which are not at mAb contact residues, also conferred resistance to neutralization by plasma from HCV-infected subjects. Together, our method of neutralization clustering with sequence analysis reveals that polymorphisms at noncontact residues may be a major immune evasion mechanism for HCV, facilitating viral persistence and presenting a challenge for HCV vaccine development.

  19. Diarylpyrimidine-dihydrobenzyloxopyrimidine hybrids: new, wide-spectrum anti-HIV-1 agents active at (sub)-nanomolar level.

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    Rotili, Dante; Tarantino, Domenico; Artico, Marino; Nawrozkij, Maxim B; Gonzalez-Ortega, Emmanuel; Clotet, Bonaventura; Samuele, Alberta; Esté, José A; Maga, Giovanni; Mai, Antonello

    2011-04-28

    Here, we describe a novel small series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine peculiar structural features of diarylpyrimidines (DAPYs) and dihydro-alkoxy-benzyl-oxopyrimidines (DABOs). These DAPY-DABO hybrids (1-4) showed a characteristic SAR profile and a nanomolar anti-HIV-1 activity at both enzymatic and cellular level. In particular, the two compounds 4d and 2d, with a (sub)nanomolar activity against wild-type and clinically relevant HIV-1 mutant strains, were selected as lead compounds for next optimization studies.

  20. Molecular evolution of broadly neutralizing Llama antibodies to the CD4-binding site of HIV-1.

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    McCoy, Laura E; Rutten, Lucy; Frampton, Dan; Anderson, Ian; Granger, Luke; Bashford-Rogers, Rachael; Dekkers, Gillian; Strokappe, Nika M; Seaman, Michael S; Koh, Willie; Grippo, Vanina; Kliche, Alexander; Verrips, Theo; Kellam, Paul; Fassati, Ariberto; Weiss, Robin A

    2014-12-01

    To date, no immunization of humans or animals has elicited broadly neutralizing sera able to prevent HIV-1 transmission; however, elicitation of broad and potent heavy chain only antibodies (HCAb) has previously been reported in llamas. In this study, the anti-HIV immune responses in immunized llamas were studied via deep sequencing analysis using broadly neutralizing monoclonal HCAbs as a guides. Distinct neutralizing antibody lineages were identified in each animal, including two defined by novel antibodies (as variable regions called VHH) identified by robotic screening of over 6000 clones. The combined application of five VHH against viruses from clades A, B, C and CRF_AG resulted in neutralization as potent as any of the VHH individually and a predicted 100% coverage with a median IC50 of 0.17 µg/ml for the panel of 60 viruses tested. Molecular analysis of the VHH repertoires of two sets of immunized animals showed that each neutralizing lineage was only observed following immunization, demonstrating that they were elicited de novo. Our results show that immunization can induce potent and broadly neutralizing antibodies in llamas with features similar to human antibodies and provide a framework to analyze the effectiveness of immunization protocols.

  1. Molecular cloning and anti-HIV-1 activities of APOBEC3s from northern pig-tailed macaques (Macaca leonina

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    Xiao-Liang ZHANG

    2016-07-01

    Full Text Available Northern pig-tailed macaques (NPMs, Macaca leonina are susceptible to HIV-1 infection largely due to the loss of HIV-1-restricting factor TRIM5α. However, great impediments still exist in the persistent replication of HIV-1 in vivo, suggesting some viral restriction factors are reserved in this host. The APOBEC3 proteins have demonstrated a capacity to restrict HIV-1 replication, but their inhibitory effects in NPMs remain elusive. In this study, we cloned the NPM A3A-A3H genes, and determined by BLAST searching that their coding sequences (CDSs showed 99% identity to the corresponding counterparts from rhesus and southern pig-tailed macaques. We further analyzed the anti-HIV-1 activities of the A3A-A3H genes, and found that A3G and A3F had the greatest anti-HIV-1 activity compared with that of other members. The results of this study indicate that A3G and A3F might play critical roles in limiting HIV-1 replication in NPMs in vivo. Furthermore, this research provides valuable information for the optimization of monkey models of HIV-1 infection.

  2. [Isolation, idetification and anti-HIV-1 integrase activity of culturable endophytic fungi from Tibetan medicinal plant Phlomis younghusbandii Mukerjee].

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    Zhang, Da-Wei; Zhao, Ming-Ming; Chen, Juan; Li, Chao; Guo, Shun-Xing

    2013-05-01

    A total of 52 endophytic fungi were isolated from roots and stems of Tibetan medicinal plant Phlomis younghusbandii Mukerjee. These fungal isolates were molecularly identified based on ITS sequnces and 28S sequences distributed to 12 genera, including Phoma, Chaetosphaeronema, Fusarium and Leptosphaeria, etc. Among them, the dominant genus was Phoma. Extracts of all strains were evaluated for anti-HIV-1 integrase activity by using soluable integrase expressed in E. coli BL21 (DE3). The results showed that seven samples from five fungal endophytes PHY-24, PHY-38, PHY-40, PHY-51, PHY-53, which belonged to genus Chaetosphaeronema, inhibited strand transfer reaction catalyzed by HIV-1 integrase with IC50 values, of 6.60, 5.20, 2.86, 7.86, 4.47, 4.56 and 3.23 microg x mL(-1) respectively. In conclusion, the endophytic fungi of Phlomis younghusbandii Mukerjee are valuable for further screening anti-HIV-1 integrase agents.

  3. Broadly Neutralizing Antibody Responses in a Large Longitudinal Sub-Saharan HIV Primary Infection Cohort.

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    Elise Landais

    2016-01-01

    Full Text Available Broadly neutralizing antibodies (bnAbs are thought to be a critical component of a protective HIV vaccine. However, designing vaccines immunogens able to elicit bnAbs has proven unsuccessful to date. Understanding the correlates and immunological mechanisms leading to the development of bnAb responses during natural HIV infection is thus critical to the design of a protective vaccine. The IAVI Protocol C program investigates a large longitudinal cohort of primary HIV-1 infection in Eastern and South Africa. Development of neutralization was evaluated in 439 donors using a 6 cross-clade pseudo-virus panel predictive of neutralization breadth on larger panels. About 15% of individuals developed bnAb responses, essentially between year 2 and year 4 of infection. Statistical analyses revealed no influence of gender, age or geographical origin on the development of neutralization breadth. However, cross-clade neutralization strongly correlated with high viral load as well as with low CD4 T cell counts, subtype-C infection and HLA-A*03(- genotype. A correlation with high overall plasma IgG levels and anti-Env IgG binding titers was also found. The latter appeared not associated with higher affinity, suggesting a greater diversity of the anti-Env responses in broad neutralizers. Broadly neutralizing activity targeting glycan-dependent epitopes, largely the N332-glycan epitope region, was detected in nearly half of the broad neutralizers while CD4bs and gp41-MPER bnAb responses were only detected in very few individuals. Together the findings suggest that both viral and host factors are critical for the development of bnAbs and that the HIV Env N332-glycan supersite may be a favorable target for vaccine design.

  4. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus

    Science.gov (United States)

    Liao, Hua-Xin; Lynch, Rebecca; Zhou, Tongqing; Gao, Feng; Alam, S. Munir; Boyd, Scott D.; Fire, Andrew Z.; Roskin, Krishna M.; Schramm, Chaim A.; Zhang, Zhenhai; Zhu, Jiang; Shapiro, Lawrence; Mullikin, James C.; Gnanakaran, S.; Hraber, Peter; Wiehe, Kevin; Kelsoe, Garnett; Yang, Guang; Xia, Shi-Mao; Montefiori, David C.; Parks, Robert; Lloyd, Krissey E.; Scearce, Richard M.; Soderberg, Kelly A.; Cohen, Myron; Kaminga, Gift; Louder, Mark K.; Tran, Lillan M.; Chen, Yue; Cai, Fangping; Chen, Sheri; Moquin, Stephanie; Du, Xiulian; Joyce, Gordon M.; Srivatsan, Sanjay; Zhang, Baoshan; Zheng, Anqi; Shaw, George M.; Hahn, Beatrice H.; Kepler, Thomas B.; Korber, Bette T.M.; Kwong, Peter D.; Mascola, John R.; Haynes, Barton F.

    2013-01-01

    Current HIV-1 vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in ~20% of HIV-1-infected individuals, and details of their generation could provide a roadmap for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from time of infection. The mature antibody, CH103, neutralized ~55% of HIV-1 isolates, and its co-crystal structure with gp120 revealed a novel loop-based mechanism of CD4-binding site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the CH103-lineage unmutated common ancestor avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data elucidate the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies and provide insights into strategies to elicit similar antibodies via vaccination. PMID:23552890

  5. Screening of anti-HIV-1 inophyllums by HPLC-DAD of Calophyllum inophyllum leaf extracts from French Polynesia Islands.

    Science.gov (United States)

    Laure, Frédéric; Raharivelomanana, Phila; Butaud, Jean-François; Bianchini, Jean-Pierre; Gaydou, Emile M

    2008-08-22

    Various pyranocoumarins, calophyllolide, inophyllums B, C, G(1), G(2) and P, from Calophyllum inophyllum (Clusiaceae) leaves of French Polynesia (Austral, Marquesas, Society and Tuamotu archipelagos) have been determined in 136 leaf extracts using a high pressure liquid chromatography-UV-diode array detection (HPLC-UV-DAD) technique. Results show a wide range in chemical composition within trees growing on eighteen islands. The use of multivariate statistical analyses (PCA) shows geographical distribution of inophyllums and indicate those rich in HIV-1 active (+)-inophyllums. Inophyllum B and P contents (0.0-39.0 and 0.0-21.8 mg kg(-1), respectively) confirm the chemodiversity of this species within the large area of French Polynesia. The study suggests the presence of interesting chemotypes which could be used as plant source for anti-HIV-1 drugs.

  6. Modeling neutralization kinetics of HIV by broadly neutralizing monoclonal antibodies in genital secretions coating the cervicovaginal mucosa.

    Directory of Open Access Journals (Sweden)

    Scott A McKinley

    Full Text Available Eliciting broadly neutralizing antibodies (bnAb in cervicovaginal mucus (CVM represents a promising "first line of defense" strategy to reduce vaginal HIV transmission. However, it remains unclear what levels of bnAb must be present in CVM to effectively reduce infection. We approached this complex question by modeling the dynamic tally of bnAb coverage on HIV. This analysis introduces a critical, timescale-dependent competition: to protect, bnAb must accumulate at sufficient stoichiometry to neutralize HIV faster than virions penetrate CVM and reach target cells. We developed a model that incorporates concentrations and diffusivities of HIV and bnAb in semen and CVM, kinetic rates for binding (kon and unbinding (koff of select bnAb, and physiologically relevant thicknesses of CVM and semen layers. Comprehensive model simulations lead to robust conclusions about neutralization kinetics in CVM. First, due to the limited time virions in semen need to penetrate CVM, substantially greater bnAb concentrations than in vitro estimates must be present in CVM to neutralize HIV. Second, the model predicts that bnAb with more rapid kon, almost independent of koff, should offer greater neutralization potency in vivo. These findings suggest the fastest arriving virions at target cells present the greatest likelihood of infection. It also implies the marked improvements in in vitro neutralization potency of many recently discovered bnAb may not translate to comparable reduction in the bnAb dose needed to confer protection against initial vaginal infections. Our modeling framework offers a valuable tool to gaining quantitative insights into the dynamics of mucosal immunity against HIV and other infectious diseases.

  7. Modeling neutralization kinetics of HIV by broadly neutralizing monoclonal antibodies in genital secretions coating the cervicovaginal mucosa.

    Science.gov (United States)

    McKinley, Scott A; Chen, Alex; Shi, Feng; Wang, Simi; Mucha, Peter J; Forest, M Gregory; Lai, Samuel K

    2014-01-01

    Eliciting broadly neutralizing antibodies (bnAb) in cervicovaginal mucus (CVM) represents a promising "first line of defense" strategy to reduce vaginal HIV transmission. However, it remains unclear what levels of bnAb must be present in CVM to effectively reduce infection. We approached this complex question by modeling the dynamic tally of bnAb coverage on HIV. This analysis introduces a critical, timescale-dependent competition: to protect, bnAb must accumulate at sufficient stoichiometry to neutralize HIV faster than virions penetrate CVM and reach target cells. We developed a model that incorporates concentrations and diffusivities of HIV and bnAb in semen and CVM, kinetic rates for binding (kon) and unbinding (koff) of select bnAb, and physiologically relevant thicknesses of CVM and semen layers. Comprehensive model simulations lead to robust conclusions about neutralization kinetics in CVM. First, due to the limited time virions in semen need to penetrate CVM, substantially greater bnAb concentrations than in vitro estimates must be present in CVM to neutralize HIV. Second, the model predicts that bnAb with more rapid kon, almost independent of koff, should offer greater neutralization potency in vivo. These findings suggest the fastest arriving virions at target cells present the greatest likelihood of infection. It also implies the marked improvements in in vitro neutralization potency of many recently discovered bnAb may not translate to comparable reduction in the bnAb dose needed to confer protection against initial vaginal infections. Our modeling framework offers a valuable tool to gaining quantitative insights into the dynamics of mucosal immunity against HIV and other infectious diseases.

  8. Anti-HIV-1 activity of flavonoid myricetin on HIV-1 infection in a dual-chamber in vitro model.

    Directory of Open Access Journals (Sweden)

    Silvana Pasetto

    Full Text Available HIV infection by sexual transmission remains an enormous global health concern. More than 1 million new infections among women occur annually. Microbicides represent a promising prevention strategy that women can easily control. Among emerging therapies, natural small molecules such as flavonoids are an important source of new active substances. In this study we report the in vitro cytotoxicity and anti-HIV-1 and microbicide activity of the following flavonoids: Myricetin, Quercetin and Pinocembrin. Cytotoxicity tests were conducted on TZM-bl, HeLa, PBMC, and H9 cell cultures using 0.01-100 µM concentrations. Myricetin presented the lowest toxic effect, with Quercetin and Pinocembrin relatively more toxic. The anti-HIV-1 activity was tested with TZM-bl cell plus HIV-1 BaL (R5 tropic, H9 and PBMC cells plus HIV-1 MN (X4 tropic, and the dual tropic (X4R5 HIV-1 89.6. All flavonoids showed anti-HIV activity, although Myricetin was more effective than Quercetin or Pinocembrin. In TZM-bl cells, Myricetin inhibited ≥90% of HIV-1 BaL infection. The results were confirmed by quantification of HIV-1 p24 antigen in supernatant from H9 and PBMC cells following flavonoid treatment. In H9 and PBMC cells infected by HIV-1 MN and HIV-1 89.6, Myricetin showed more than 80% anti-HIV activity. Quercetin and Pinocembrin presented modest anti-HIV activity in all experiments. Myricetin activity was tested against HIV-RT and inhibited the enzyme by 49%. Microbicide activities were evaluated using a dual-chamber female genital tract model. In the in vitro microbicide activity model, Myricetin showed promising results against different strains of HIV-1 while also showing insignificant cytotoxic effects. Further studies of Myricetin should be performed to identify its molecular targets in order to provide a solid biological foundation for translational research.

  9. Association between HIV-1 coreceptor usage and resistance to broadly neutralizing antibodies.

    Science.gov (United States)

    Pfeifer, Nico; Walter, Hauke; Lengauer, Thomas

    2014-10-01

    Recently discovered broadly neutralizing antibodies have revitalized hopes of developing a universal vaccine against HIV-1. Mainly responsible for new infections are variants only using CCR5 for cell entry, whereas CXCR4-using variants can become dominant in later infection stages. We performed a statistical analysis on two different previously published data sets. The first data set was a panel of 199 diverse HIV-1 isolates for which IC50 neutralization titers were determined for the broadly neutralizing antibodies VRC01, VRC-PG04, PG9, and PG16. The second data set contained env sequences of viral variants extracted from HIV-1-infected humanized mice treated with the antibody PGT128 and from untreated control mice. For the panel of 199 diverse HIV-1 isolates, we found a statistically significant association between viral resistance to PG9 and PG16 and CXCR4 coreceptor usage (P = 0.0011 and P = 0.0010, respectively). Our analysis of viral variants from HIV-1-infected humanized mice under treatment with the broadly neutralizing antibody PGT128 indicated that certain antibodies might drive a viral population toward developing CXCR4 coreceptor usage capability (P = 0.0011 for the comparison between PGT128 and control measurement). These analyses highlight the importance of accounting for a possible coreceptor usage bias pertaining to the effectiveness of an HIV vaccine and to passive antibody transfer as therapeutic approach.

  10. Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies.

    Directory of Open Access Journals (Sweden)

    S Gnanakaran

    Full Text Available A steady increase in knowledge of the molecular and antigenic structure of the gp120 and gp41 HIV-1 envelope glycoproteins (Env is yielding important new insights for vaccine design, but it has been difficult to translate this information to an immunogen that elicits broadly neutralizing antibodies. To help bridge this gap, we used phylogenetically corrected statistical methods to identify amino acid signature patterns in Envs derived from people who have made potently neutralizing antibodies, with the hypothesis that these Envs may share common features that would be useful for incorporation in a vaccine immunogen. Before attempting this, essentially as a control, we explored the utility of our computational methods for defining signatures of complex neutralization phenotypes by analyzing Env sequences from 251 clonal viruses that were differentially sensitive to neutralization by the well-characterized gp120-specific monoclonal antibody, b12. We identified ten b12-neutralization signatures, including seven either in the b12-binding surface of gp120 or in the V2 region of gp120 that have been previously shown to impact b12 sensitivity. A simple algorithm based on the b12 signature pattern was predictive of b12 sensitivity/resistance in an additional blinded panel of 57 viruses. Upon obtaining these reassuring outcomes, we went on to apply these same computational methods to define signature patterns in Env from HIV-1 infected individuals who had potent, broadly neutralizing responses. We analyzed a checkerboard-style neutralization dataset with sera from 69 HIV-1-infected individuals tested against a panel of 25 different Envs. Distinct clusters of sera with high and low neutralization potencies were identified. Six signature positions in Env sequences obtained from the 69 samples were found to be strongly associated with either the high or low potency responses. Five sites were in the CD4-induced coreceptor binding site of gp120, suggesting an

  11. Hepatitis C virus resistance to broadly neutralizing antibodies measured using replication-competent virus and pseudoparticles.

    Science.gov (United States)

    Wasilewski, Lisa N; Ray, Stuart C; Bailey, Justin R

    2016-11-01

    A better understanding of natural variation in neutralization resistance and fitness of diverse hepatitis C virus (HCV) envelope (E1E2) variants will be critical to guide rational development of an HCV vaccine. This work has been hindered by inadequate genetic diversity in viral panels and by a lack of standardization of HCV entry assays. Neutralization assays generally use lentiviral pseudoparticles expressing HCV envelope proteins (HCVpp) or chimeric full-length viruses that are replication competent in cell culture (HCVcc). There have been few systematic comparisons of specific infectivities of E1E2-matched HCVcc and HCVpp, and to our knowledge, neutralization of E1E2-matched HCVpp and HCVcc has never been compared using a diverse panel of human broadly neutralizing monoclonal antibodies (bNAbs) targeting distinct epitopes. Here, we describe an efficient method for introduction of naturally occurring E1E2 genes into a full-length HCV genome, producing replication-competent chimeric HCVcc. We generated diverse panels of E1E2-matched HCVcc and HCVpp and measured the entry-mediating fitness of E1E2 variants using the two systems. We also compared neutralization of E1E2-matched HCVcc and HCVpp by a diverse panel of human bNAbs targeting epitopes across E1E2. We found no correlation between specific infectivities of E1E2-matched HCVcc versus HCVpp, but found a very strong positive correlation between relative neutralization resistance of these same E1E2-matched HCVcc and HCVpp variants. These results suggest that quantitative comparisons of neutralization resistance of E1E2 variants can be made with confidence using either HCVcc or HCVpp, allowing the use of either or both systems to maximize diversity of neutralization panels.

  12. Novel Synthesis and Anti-HIV-1 Activity of 2-Arylthio-6-benzyl-2,3-dihydro-1H-pyrimidin-4-ones (Aryl S-DABOs)

    DEFF Research Database (Denmark)

    Aly, Youssef L.; Pedersen, Erik Bjerreg.; La Colla, Paolo

    2007-01-01

    The synthesis and the anti-HIV-1 activity of a series of 2-arylthio-6-benzyl-2,3-dihydro-1H-pyrimidin-4-ones (aryl S-DABOs) are reported. These compounds were synthesized via a coupling reaction of the corresponding 6-benzyl-2-thiouracils with aryl iodides in the presence of neocuproine hydrate...

  13. Prediction of HIV-1 sensitivity to broadly neutralizing antibodies shows a trend towards resistance over time.

    Science.gov (United States)

    Hake, Anna; Pfeifer, Nico

    2017-10-01

    Treatment with broadly neutralizing antibodies (bNAbs) has proven effective against HIV-1 infections in humanized mice, non-human primates, and humans. Due to the high mutation rate of HIV-1, resistance testing of the patient's viral strains to the bNAbs is still inevitable. So far, bNAb resistance can only be tested in expensive and time-consuming neutralization experiments. Here, we introduce well-performing computational models that predict the neutralization response of HIV-1 to bNAbs given only the envelope sequence of the virus. Using non-linear support vector machines based on a string kernel, the models learnt even the important binding sites of bNAbs with more complex epitopes, i.e., the CD4 binding site targeting bNAbs, proving thereby the biological relevance of the models. To increase the interpretability of the models, we additionally provide a new kind of motif logo for each query sequence, visualizing those residues of the test sequence that influenced the prediction outcome the most. Moreover, we predicted the neutralization sensitivity of around 34,000 HIV-1 samples from different time points to a broad range of bNAbs, enabling the first analysis of HIV resistance to bNAbs on a global scale. The analysis showed for many of the bNAbs a trend towards antibody resistance over time, which had previously only been discovered for a small non-representative subset of the global HIV-1 population.

  14. Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus

    DEFF Research Database (Denmark)

    Giang, Erick; Dorner, Marcus; Prentoe, Jannick C

    2012-01-01

    , and an effective vaccine should target conserved T- and B-cell epitopes of the virus. Conserved B-cell epitopes overlapping the CD81 receptor-binding site (CD81bs) on the E2 viral envelope glycoprotein have been reported previously and provide promising vaccine targets. In this study, we isolated 73 human m......Abs recognizing five distinct antigenic regions on the virus envelope glycoprotein complex E1E2 from an HCV-immune phage-display antibody library by using an exhaustive-panning strategy. Many of these mAbs were broadly neutralizing. In particular, the mAb AR4A, recognizing a discontinuous epitope outside the CD81......bs on the E1E2 complex, has an exceptionally broad neutralizing activity toward diverse HCV genotypes and protects against heterologous HCV challenge in a small animal model. The mAb panel will be useful for the design and development of vaccine candidates to elicit broadly neutralizing antibodies...

  15. Structural Basis for Recognition of Human Enterovirus 71 by a Bivalent Broadly Neutralizing Monoclonal Antibody.

    Directory of Open Access Journals (Sweden)

    Xiaohua Ye

    2016-03-01

    Full Text Available Enterovirus 71 (EV71 is the main pathogen responsible for hand, foot and mouth disease with severe neurological complications and even death in young children. We have recently identified a highly potent anti-EV71 neutralizing monoclonal antibody, termed D5. Here we investigated the structural basis for recognition of EV71 by the antibody D5. Four three-dimensional structures of EV71 particles in complex with IgG or Fab of D5 were reconstructed by cryo-electron microscopy (cryo-EM single particle analysis all at subnanometer resolutions. The most critical EV71 mature virion-Fab structure was resolved to a resolution of 4.8 Å, which is rare in cryo-EM studies of virus-antibody complex so far. The structures reveal a bivalent binding pattern of D5 antibody across the icosahedral 2-fold axis on mature virion, suggesting that D5 binding may rigidify virions to prevent their conformational changes required for subsequent RNA release. Moreover, we also identified that the complementary determining region 3 (CDR3 of D5 heavy chain directly interacts with the extremely conserved VP1 GH-loop of EV71, which was validated by biochemical and virological assays. We further showed that D5 is indeed able to neutralize a variety of EV71 genotypes and strains. Moreover, D5 could potently confer protection in a mouse model of EV71 infection. Since the conserved VP1 GH-loop is involved in EV71 binding with its uncoating receptor, the scavenger receptor class B, member 2 (SCARB2, the broadly neutralizing ability of D5 might attribute to its inhibition of EV71 from binding SCARB2. Altogether, our results elucidate the structural basis for the binding and neutralization of EV71 by the broadly neutralizing antibody D5, thereby enhancing our understanding of antibody-based protection against EV71 infection.

  16. Plant-based anti-HIV-1 strategies: vaccine molecules and antiviral approaches.

    Science.gov (United States)

    Scotti, Nunzia; Buonaguro, Luigi; Tornesello, Maria Lina; Cardi, Teodoro; Buonaguro, Franco Maria

    2010-08-01

    The introduction of highly active antiretroviral therapy has drastically changed HIV infection from an acute, very deadly, to a chronic, long-lasting, mild disease. However, this requires continuous care management, which is difficult to implement worldwide, especially in developing countries. Sky-rocketing costs of HIV-positive subjects and the limited success of preventive recommendations mean that a vaccine is urgently needed, which could be the only effective strategy for the real control of the AIDS pandemic. To be effective, vaccination will need to be accessible, affordable and directed against multiple antigens. Plant-based vaccines, which are easy to produce and administer, and require no cold chain for their heat stability are, in principle, suited to such a strategy. More recently, it has been shown that even highly immunogenic, enveloped plant-based vaccines can be produced at a competitive and more efficient rate than conventional strategies. The high variability of HIV epitopes and the need to stimulate both humoral neutralizing antibodies and cellular immunity suggest the importance of using the plant system: it offers a wide range of possible strategies, from single-epitope to multicomponent vaccines, modulators of the immune response (adjuvants) and preventive molecules (microbicides), either alone or in association with plant-derived monoclonal antibodies, besides the potential use of the latter as therapeutic agents. Furthermore, plant-based anti-HIV strategies can be administered not only parenterally but also by the more convenient and safer oral route, which is a more suitable approach for possible mass vaccination.

  17. Heterotypic Protection and Induction of a Broad Heterotypic Neutralization Response by Rotavirus-Like Particles

    Science.gov (United States)

    Crawford, Sue E.; Estes, Mary K.; Ciarlet, Max; Barone, Christopher; O’Neal, Christine M.; Cohen, Jean; Conner, Margaret E.

    1999-01-01

    The recognition that rotaviruses are the major cause of life-threatening diarrheal disease and significant morbidity in young children has focused efforts on disease prevention and control of these viruses. Although the correlates of protection in children remain unclear, some studies indicate that serotype-specific antibody is important. Based on this premise, current live attenuated reassortant rotavirus vaccines include the four predominant serotypes of virus. We are evaluating subunit rotavirus vaccines, 2/6/7-VLPs and 2/4/6/7-VLPs, that contain only a single VP7 of serotype G1 or G3. In mice immunized parenterally twice, G3 virus-like particles (VLPs) induced a homotypic, whereas G1 VLPs induced a homotypic and heterotypic (G3) serum neutralizing immune response. Administration of three doses of G1 or G3 VLPs induced serum antibodies that neutralized five of seven different serotype test viruses. The inclusion of VP4 in the VLPs was not essential for the induction of heterotypic neutralizing antibody in mice. To confirm these results in another species, rabbits were immunized parenterally with two doses of 2/4/6/7-VLPs containing a G3 or G1 VP7, sequentially with G3 VLPs followed by G1 (G3/G1) VLPs, or with live or psoralen-inactivated SA11. High-titer homotypic serum neutralizing antibody was induced in all rabbits, and low-level heterotypic neutralizing antibody was induced in a subset of rabbits. The rabbits immunized with the G1 or G3/G1 VLPs in QS-21 were challenged orally with live G3 ALA rotavirus. Protection levels were similar in rabbits immunized with homotypic G3 2/4/6/7-VLPs, heterotypic G1 2/4/6/7-VLPs, or G3/G1 2/4/6/7-VLPs. Therefore, G1 2/4/6/7-VLPs can induce protective immunity against a live heterotypic rotavirus challenge in an adjuvant with potential use in humans. Following challenge, broad serum heterotypic neutralizing antibody responses were detected in rabbits parenterally immunized with G1, G3/G1, or G3 VLPs but not with SA11

  18. Broad neutralizing human monoclonal antibodies against influenza virus from vaccinated healthy donors

    Energy Technology Data Exchange (ETDEWEB)

    Kubota-Koketsu, Ritsuko; Mizuta, Hiroyuki [Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871 (Japan); Oshita, Masatoshi; Ideno, Shoji [Osaka Research Laboratory, Benesis Corporation, Yodogawa-ku, Osaka 532-6505 (Japan); Yunoki, Mikihiro [Osaka Research Laboratory, Benesis Corporation, Yodogawa-ku, Osaka 532-6505 (Japan); Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871 (Japan); Kuhara, Motoki [Ina Laboratory, Medical and Biological Laboratories Corporation, Ltd., Ina, Nagano 396-0002 (Japan); Yamamoto, Naomasa [Department of Biochemistry, School of Pharmaceutical Sciences, Ohu University, Koriyama, Fukushima 963-8611 (Japan); Okuno, Yoshinobu [Kanonji Institute, The Research Foundation for Microbial Diseases of Osaka University, Kanonji, Kagawa 768-0061 (Japan); Ikuta, Kazuyoshi, E-mail: ikuta@biken.osaka-u.ac.jp [Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871 (Japan)

    2009-09-11

    Human monoclonal antibodies (HuMAbs) prepared from patients with viral infections could provide information on human epitopes important for the development of vaccines as well as potential therapeutic applications. Through the fusion of peripheral blood mononuclear cells from a total of five influenza-vaccinated volunteers, with newly developed murine-human chimera fusion partner cells, named SPYMEG, we obtained 10 hybridoma clones stably producing anti-influenza virus antibodies: one for influenza A H1N1, four for influenza A H3N2 and five for influenza B. Surprisingly, most of the HuMAbs showed broad reactivity within subtype and four (two for H3N2 and two for B) showed broad neutralizing ability. Importantly, epitope mapping revealed that the two broad neutralizing antibodies to H3N2 derived from different donors recognized the same epitope located underneath the receptor-binding site of the hemagglutinin globular region that is highly conserved among H3N2 strains.

  19. Broad neutralizing human monoclonal antibodies against influenza virus from vaccinated healthy donors

    International Nuclear Information System (INIS)

    Kubota-Koketsu, Ritsuko; Mizuta, Hiroyuki; Oshita, Masatoshi; Ideno, Shoji; Yunoki, Mikihiro; Kuhara, Motoki; Yamamoto, Naomasa; Okuno, Yoshinobu; Ikuta, Kazuyoshi

    2009-01-01

    Human monoclonal antibodies (HuMAbs) prepared from patients with viral infections could provide information on human epitopes important for the development of vaccines as well as potential therapeutic applications. Through the fusion of peripheral blood mononuclear cells from a total of five influenza-vaccinated volunteers, with newly developed murine-human chimera fusion partner cells, named SPYMEG, we obtained 10 hybridoma clones stably producing anti-influenza virus antibodies: one for influenza A H1N1, four for influenza A H3N2 and five for influenza B. Surprisingly, most of the HuMAbs showed broad reactivity within subtype and four (two for H3N2 and two for B) showed broad neutralizing ability. Importantly, epitope mapping revealed that the two broad neutralizing antibodies to H3N2 derived from different donors recognized the same epitope located underneath the receptor-binding site of the hemagglutinin globular region that is highly conserved among H3N2 strains.

  20. Fluorine Substituted 1,2,4-Triazinones as Potential Anti-HIV-1 and CDK2 Inhibitors

    Directory of Open Access Journals (Sweden)

    Mohammed S. I. Makki

    2014-01-01

    Full Text Available Fluorine substituted 1,2,4-triazinones have been synthesized via alkylation, amination, and/or oxidation of 6-(2-amino-5-fluorophenyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H-one 1 and 4-fluoro-N-(4-fluoro-2-(5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-ylphenylbenzamide 5 as possible anti-HIV-1 and CDK2 inhibitors. Alkylation on positions 2 and 4 in 1,2,4-triazinone gave compounds 6–8. Further modification was performed by selective alkylation and amination on position 3 to form compounds 9–15. However oxidation of 5 yielded compounds 16–18. Structures of the target compounds have been established by spectral analysis data. Five compounds (5, 11, 14, 16, and 17 have shown very good anti-HIV activity in MT-4 cells. Similarly, five compounds (1, 3, and 14–16 have exhibited very significant CDK2 inhibition activity. Compounds 14 and 16 were found to have dual anti-HIV and anticancer activities.

  1. Qualitative and quantitative intravaginal targeting: key to anti-HIV-1 microbicide delivery from test tube to in vivo success.

    Science.gov (United States)

    Pillay, Viness; Mashingaidze, Felix; Choonara, Yahya E; Du Toit, Lisa C; Buchmann, Eckhart; Maharaj, Vinesh; Ndesendo, Valence M K; Kumar, Pradeep

    2012-06-01

    The past decade has seen several effective anti-HIV-1 agent discoveries, yet microbicides continue to disappoint clinically. Our review expounds the view that unsatisfactory microbicide failures may be a result of inefficient delivery systems employed. We hereby propose a thorough scientific qualitative and quantitative investigation of important aspects involved in HIV-1 transmission as a prerequisite for microbicide delivery. Intravaginal targeting of HIV-1 increases the chances of microbicide success, wherein vaginal microenvironmental factors including pH should be maintained at HIV-1 prohibitive acidic levels simultaneously to ward off other sexually transmitted diseases, which compromise vaginal epithelial barrier properties. Furthermore, choice of receptors to target both on HIV-1 and on target cells is vital in deterring transmission. Appropriate modeling of virus-target cell interactions as well as targeting early stages of the HIV-1 infection accompanied by computation and delivery of appropriate microbicide quantities could revolutionize microbicide research, ultimately delivering a female-controlled HIV-1 prevention modality appropriately. Copyright © 2012 Wiley Periodicals, Inc.

  2. Development of an anti-HIV vaccine eliciting broadly neutralizing antibodies.

    Science.gov (United States)

    Ahmed, Yousuf; Tian, Meijuan; Gao, Yong

    2017-09-12

    The extreme HIV diversity posts a great challenge on development of an effective anti-HIV vaccine. To solve this problem, it is crucial to discover an appropriate immunogens and strategies that are able to prevent the transmission of the diverse viruses that are circulating in the world. Even though there have been a number of broadly neutralizing anti-HIV antibodies (bNAbs) been discovered in recent years, induction of such antibodies to date has only been observed in HIV-1 infection. Here, in this mini review, we review the progress in development of HIV vaccine in eliciting broad immune response, especially production of bNAbs, discuss possible strategies, such as polyvalent sequential vaccination, that facilitates B cell maturation leading to bNAb response.

  3. Development of Broadly Neutralizing Antibody Mimitopes for Characterization of CRF01_AE HIV-1 Antibody Responses

    Directory of Open Access Journals (Sweden)

    Jesse V. Schoen

    2017-10-01

    Full Text Available Mapping humoral immune responses to HIV-1 over the course of natural infection is important in understanding epitope exposure in relation to elicitation of broadly neutralizing antibodies (bNAbs, which is considered imperative for effective vaccine design. When analyzing HIV-specific immune responses, the antibody binding profiles may be a correlate for functional antibody activity. In this study, we utilized phage display technology to identify novel mimitopes that may represent Env epitope structures bound by bNAbs directed at V1V2 and V3 domains, CD4 binding site (CD4bs and the membrane proximal external region (MPER of Env. Mimitope sequence motifs were determined for each bNAb epitope. Given the ongoing vaccine development efforts in Thailand, these mimitopes that represent CD4bs and MPER epitopes were used to map immune responses of HIV-1 CRF01_AE-infected individuals with known neutralizing responses from two distinct time periods, 1996-98 and 2012-15. The more contemporary cohort showed an increase in binding breadth with binding observed for all MPER and CD4bs mimitopes, while the older cohort showed only 75% recognition of the CD4bs mimitopes and no MPER mimotope binding. Furthermore, mimitope binding profiles correlated significantly with magnitude (p=0.0036 and breadth (p=0.0358 of neutralization of a multi-subtype Tier 1 panel of pseudoviruses. These results highlight the utility of this mimitope mapping approach for detecting human plasma IgG-specificities that target known neutralizing antibody epitopes, and may also provide an indication of the plasticity of antibody binding within HIV-1 Env neutralization determinants.

  4. Development and characterization of novel chimeric monoclonal antibodies for broad spectrum neutralization of rabies virus.

    Directory of Open Access Journals (Sweden)

    Pan Kyeom Kim

    Full Text Available Current post-exposure prophylaxis for rabies virus infection has several limitations in terms of supply, cost, safety, and efficacy. Attempts to replace human or equine rabies immune globulins (HRIG or ERIG have been made by several companies and institutes. We developed potent monoclonal antibodies to neutralize a broad spectrum of rabies viruses by screening hybridomas received from the U.S. Centers for Disease Control and Prevention (CDC. Two kinds of chimeric human antibodies (chimeric #7 and #17 were constructed by cloning the variable regions from selected hybridomas and the constant region of a human antibody. Two antibodies were bound to antigenic site III and I/IV, respectively, and were able to neutralize 51 field isolates of rabies virus that were isolated at different times and places such as Asia, Africa, North America, South America, and Australia. These two antibodies neutralize rabies viruses with high efficacy in an in vivo test using Syrian hamster and mouse models and show low risk for adverse immunogenicity.

  5. Development and characterization of novel chimeric monoclonal antibodies for broad spectrum neutralization of rabies virus.

    Science.gov (United States)

    Kim, Pan Kyeom; Keum, Sun Ju; Osinubi, Modupe O V; Franka, Richard; Shin, Ji Young; Park, Sang Tae; Kim, Man Su; Park, Mi Jung; Lee, Soo Young; Carson, William; Greenberg, Lauren; Yu, Pengcheng; Tao, Xiaoyan; Lihua, Wang; Tang, Qing; Liang, Guodong; Shampur, Madhusdana; Rupprecht, Charles E; Chang, Shin Jae

    2017-01-01

    Current post-exposure prophylaxis for rabies virus infection has several limitations in terms of supply, cost, safety, and efficacy. Attempts to replace human or equine rabies immune globulins (HRIG or ERIG) have been made by several companies and institutes. We developed potent monoclonal antibodies to neutralize a broad spectrum of rabies viruses by screening hybridomas received from the U.S. Centers for Disease Control and Prevention (CDC). Two kinds of chimeric human antibodies (chimeric #7 and #17) were constructed by cloning the variable regions from selected hybridomas and the constant region of a human antibody. Two antibodies were bound to antigenic site III and I/IV, respectively, and were able to neutralize 51 field isolates of rabies virus that were isolated at different times and places such as Asia, Africa, North America, South America, and Australia. These two antibodies neutralize rabies viruses with high efficacy in an in vivo test using Syrian hamster and mouse models and show low risk for adverse immunogenicity.

  6. Affinity maturation in an HIV broadly neutralizing B-cell lineage through reorientation of variable domains.

    Science.gov (United States)

    Fera, Daniela; Schmidt, Aaron G; Haynes, Barton F; Gao, Feng; Liao, Hua-Xin; Kepler, Thomas B; Harrison, Stephen C

    2014-07-15

    Rapidly evolving pathogens, such as human immunodeficiency and influenza viruses, escape immune defenses provided by most vaccine-induced antibodies. Proposed strategies to elicit broadly neutralizing antibodies require a deeper understanding of antibody affinity maturation and evolution of the immune response to vaccination or infection. In HIV-infected individuals, viruses and B cells evolve together, creating a virus-antibody "arms race." Analysis of samples from an individual designated CH505 has illustrated the interplay between an antibody lineage, CH103, and autologous viruses at various time points. The CH103 antibodies, relatively broad in their neutralization spectrum, interact with the CD4 binding site of gp120, with a contact dominated by CDRH3. We show by analyzing structures of progenitor and intermediate antibodies and by correlating them with measurements of binding to various gp120s that there was a shift in the relative orientation of the light- and heavy-chain variable domains during evolution of the CH103 lineage. We further show that mutations leading to this conformational shift probably occurred in response to insertions in variable loop 5 (V5) of the HIV envelope. The shift displaced the tips of the light chain away from contact with V5, making room for the inserted residues, which had allowed escape from neutralization by the progenitor antibody. These results, which document the selective mechanism underlying this example of a virus-antibody arms race, illustrate the functional significance of affinity maturation by mutation outside the complementarity determining region surface of the antibody molecule.

  7. Methamphetamine inhibits HIV-1 replication in CD4+ T cells by modulating anti-HIV-1 miRNA expression.

    Science.gov (United States)

    Mantri, Chinmay K; Mantri, Jyoti V; Pandhare, Jui; Dash, Chandravanu

    2014-01-01

    Methamphetamine is the second most frequently used illicit drug in the United States. Methamphetamine abuse is associated with increased risk of HIV-1 acquisition, higher viral loads, and enhanced HIV-1 pathogenesis. Although a direct link between methamphetamine abuse and HIV-1 pathogenesis remains to be established in patients, methamphetamine has been shown to increase HIV-1 replication in macrophages, dendritic cells, and cells of HIV transgenic mice. Intriguingly, the effects of methamphetamine on HIV-1 replication in human CD4(+) T cells that serve as the primary targets of infection in vivo are not clearly understood. Therefore, we examined HIV-1 replication in primary CD4(+) T cells in the presence of methamphetamine in a dose-dependent manner. Our results demonstrate that methamphetamine had a minimal effect on HIV-1 replication at concentrations of 1 to 50 μmol/L. However, at concentrations >100 μmol/L, it inhibited HIV-1 replication in a dose-dependent manner. We also discovered that methamphetamine up-regulated the cellular anti-HIV-1 microRNAs (miR-125b, miR-150, and miR-28-5p) in CD4(+) T cells. Knockdown experiments illustrated that up-regulation of the anti-HIV miRNAs inhibited HIV-1 replication. These results are contrary to the paradigm that methamphetamine accentuates HIV-1 pathogenesis by increasing HIV-1 replication. Therefore, our findings underline the complex interaction between drug use and HIV-1 and necessitate comprehensive understanding of the effects of methamphetamine on HIV-1 pathogenesis. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  8. Structural Basis for Escape of Human Astrovirus from Antibody Neutralization: Broad Implications for Rational Vaccine Design

    Energy Technology Data Exchange (ETDEWEB)

    Bogdanoff, Walter A.; Perez, Edmundo I.; López, Tomás; Arias, Carlos F.; DuBois, Rebecca M. (UNAM-Mexico); (UCSC)

    2017-10-25

    ABSTRACT

    Human astroviruses are recognized as a leading cause of viral diarrhea worldwide in children, immunocompromised patients, and the elderly. There are currently no vaccines available to prevent astrovirus infection; however, antibodies developed by healthy individuals during previous infection correlate with protection from reinfection, suggesting that an effective vaccine could be developed. In this study, we investigated the molecular mechanism by which several strains of human astrovirus serotype 2 (HAstV-2) are resistant to the potent HAstV-2-neutralizing monoclonal antibody PL-2 (MAb PL-2). Sequencing of the HAstV-2 capsid genes reveals mutations in the PL-2 epitope within the capsid's spike domain. To understand the molecular basis for resistance from MAb PL-2 neutralization, we determined the 1.35-Å-resolution crystal structure of the capsid spike from one of these HAstV-2 strains. Our structure reveals a dramatic conformational change in a loop within the PL-2 epitope due to a serine-to-proline mutation, locking the loop in a conformation that sterically blocks binding and neutralization by MAb PL-2. We show that mutation to serine permits loop flexibility and recovers MAb PL-2 binding. Importantly, we find that HAstV-2 capsid spike containing a serine in this loop is immunogenic and elicits antibodies that neutralize all HAstV-2 strains. Taken together, our results have broad implications for rational selection of vaccine strains that do not contain prolines in antigenic loops, so as to elicit antibodies against diverse loop conformations.

    IMPORTANCEHuman astroviruses (HAstVs) infect nearly every person in the world during childhood and cause diarrhea, vomiting, and fever. In this study, we investigated how several strains of HAstV are resistant to a virus-neutralizing monoclonal antibody. We determined the crystal structure of the capsid protein spike domain from one of these HAstV strains and found that

  9. Tandem bispecific broadly neutralizing antibody - a novel approach to HIV-1 treatment.

    Science.gov (United States)

    Ferrari, Guido

    2018-04-23

    The last decade has led to a significant advance in our knowledge of HIV-1 latency and immunity. However, we are still not close to finding a cure for HIV-1. Although combination antiretroviral therapy (cART) has led to increased survival, almost close to that of the general population, it is still not curative. In the current issue of the JCI, Wu et al. studied the prophylactic and therapeutic potential of an engineered tandem bispecific broadly neutralizing antibody (bs-bnAb), BiIA-SG. This bnAb's breadth and potency were highly effective in protection and treatment settings, as measured by complete viremia control following direct infusion, as well as elimination of infected cells and delay in viral rebound when delivered with a recombinant vector. These observations underscore the need for the clinical development of BiIA-SG for the prevention of HIV-1.

  10. HIV-specific Fc effector function early in infection predicts the development of broadly neutralizing antibodies.

    Directory of Open Access Journals (Sweden)

    Simone I Richardson

    2018-04-01

    Full Text Available While the induction of broadly neutralizing antibodies (bNAbs is a major goal of HIV vaccination strategies, there is mounting evidence to suggest that antibodies with Fc effector function also contribute to protection against HIV infection. Here we investigated Fc effector functionality of HIV-specific IgG plasma antibodies over 3 years of infection in 23 individuals, 13 of whom developed bNAbs. Antibody-dependent cellular phagocytosis (ADCP, complement deposition (ADCD, cellular cytotoxicity (ADCC and cellular trogocytosis (ADCT were detected in almost all individuals with levels of activity increasing over time. At 6 months post-infection, individuals with bNAbs had significantly higher levels of ADCD and ADCT that correlated with antibody binding to C1q and FcγRIIa respectively. In addition, antibodies from individuals with bNAbs showed more IgG subclass diversity to multiple HIV antigens which also correlated with Fc polyfunctionality. Germinal center activity represented by CXCL13 levels and expression of activation-induced cytidine deaminase (AID was found to be associated with neutralization breadth, Fc polyfunctionality and IgG subclass diversity. Overall, multivariate analysis by random forest classification was able to group bNAb individuals with 85% sensitivity and 80% specificity based on the properties of their antibody Fc early in HIV infection. Thus, the Fc effector function profile predicted the development of neutralization breadth in this cohort, suggesting that intrinsic immune factors within the germinal center provide a mechanistic link between the Fc and Fab of HIV-specific antibodies.

  11. HIV-specific Fc effector function early in infection predicts the development of broadly neutralizing antibodies.

    Science.gov (United States)

    Richardson, Simone I; Chung, Amy W; Natarajan, Harini; Mabvakure, Batsirai; Mkhize, Nonhlanhla N; Garrett, Nigel; Abdool Karim, Salim; Moore, Penny L; Ackerman, Margaret E; Alter, Galit; Morris, Lynn

    2018-04-01

    While the induction of broadly neutralizing antibodies (bNAbs) is a major goal of HIV vaccination strategies, there is mounting evidence to suggest that antibodies with Fc effector function also contribute to protection against HIV infection. Here we investigated Fc effector functionality of HIV-specific IgG plasma antibodies over 3 years of infection in 23 individuals, 13 of whom developed bNAbs. Antibody-dependent cellular phagocytosis (ADCP), complement deposition (ADCD), cellular cytotoxicity (ADCC) and cellular trogocytosis (ADCT) were detected in almost all individuals with levels of activity increasing over time. At 6 months post-infection, individuals with bNAbs had significantly higher levels of ADCD and ADCT that correlated with antibody binding to C1q and FcγRIIa respectively. In addition, antibodies from individuals with bNAbs showed more IgG subclass diversity to multiple HIV antigens which also correlated with Fc polyfunctionality. Germinal center activity represented by CXCL13 levels and expression of activation-induced cytidine deaminase (AID) was found to be associated with neutralization breadth, Fc polyfunctionality and IgG subclass diversity. Overall, multivariate analysis by random forest classification was able to group bNAb individuals with 85% sensitivity and 80% specificity based on the properties of their antibody Fc early in HIV infection. Thus, the Fc effector function profile predicted the development of neutralization breadth in this cohort, suggesting that intrinsic immune factors within the germinal center provide a mechanistic link between the Fc and Fab of HIV-specific antibodies.

  12. Evolution of Neutralization Response in HIV-1 Subtype C-Infected Individuals Exhibiting Broad Cross-Clade Neutralization of HIV-1 Strains

    Directory of Open Access Journals (Sweden)

    Narayanaiah Cheedarla

    2018-03-01

    Full Text Available Strain-specific neutralizing antibodies develop in all human immunodeficiency virus type 1 (HIV-1-infected individuals. However, only 10–30% of infected individuals produce broadly neutralizing antibodies (bNAbs. Identification and characterization of these bNAbs and understanding their evolution dynamics are critical for obtaining useful clues for the development of an effective HIV vaccine. Very recently, we published a study in which we identified 12 HIV-1 subtype C-infected individuals from India whose plasma showed potent and broad cross-clade neutralization (BCN ability (1. In the present study, we report our findings on the evolution of host bNAb response over a period of 4 years in a subset of these individuals. Three of the five individuals (NAB033, NAB059, and NAB065 demonstrated a significant increase (p < 0.05 in potency. Interestingly, two of the three samples also showed a significant increase in CD4 binding site-specific antibody response, maintained stable CD4+ T cell counts (>350 cells/mm3 and continued to remain ART-naïve for more than 10 years after initial diagnosis, implying a strong clinical correlation with the development and evolution of broadly neutralizing antibody response against HIV-1.

  13. Broadly-Reactive Neutralizing and Non-neutralizing Antibodies Directed against the H7 Influenza Virus Hemagglutinin Reveal Divergent Mechanisms of Protection.

    Directory of Open Access Journals (Sweden)

    Gene S Tan

    2016-04-01

    Full Text Available In the early spring of 2013, Chinese health authorities reported several cases of H7N9 influenza virus infections in humans. Since then the virus has established itself at the human-animal interface in Eastern China and continues to cause several hundred infections annually. In order to characterize the antibody response to the H7N9 virus we generated several mouse monoclonal antibodies against the hemagglutinin of the A/Shanghai/1/13 (H7N9 virus. Of particular note are two monoclonal antibodies, 1B2 and 1H5, that show broad reactivity to divergent H7 hemagglutinins. Monoclonal antibody 1B2 binds to viruses of the Eurasian and North American H7 lineages and monoclonal antibody 1H5 reacts broadly to virus isolates of the Eurasian lineage. Interestingly, 1B2 shows broad hemagglutination inhibiting and neutralizing activity, while 1H5 fails to inhibit hemagglutination and demonstrates no neutralizing activity in vitro. However, both monoclonal antibodies were highly protective in an in vivo passive transfer challenge model in mice, even at low doses. Experiments using mutant antibodies that lack the ability for Fc/Fc-receptor and Fc/complement interactions suggest that the protection provided by mAb 1H5 is, at least in part, mediated by the Fc-fragment of the mAb. These findings highlight that a protective response to a pathogen may not only be due to neutralizing antibodies, but can also be the result of highly efficacious non-neutralizing antibodies not readily detected by classical in vitro neutralization or hemagglutination inhibition assays. This is of interest because H7 influenza virus vaccines induce only low hemagglutination inhibiting antibody titers while eliciting robust antibody titers as measured by ELISA. Our data suggest that these binding but non-neutralizing antibodies contribute to protection in vivo.

  14. Synergistic activity profile of carbosilane dendrimer G2-STE16 in combination with other dendrimers and antiretrovirals as topical anti-HIV-1 microbicide.

    Science.gov (United States)

    Sepúlveda-Crespo, Daniel; Lorente, Raquel; Leal, Manuel; Gómez, Rafael; De la Mata, Francisco J; Jiménez, José Luis; Muñoz-Fernández, M Ángeles

    2014-04-01

    Polyanionic carbosilane dendrimers represent opportunities to develop new anti-HIV microbicides. Dendrimers and antiretrovirals (ARVs) acting at different stages of HIV replication have been proposed as compounds to decrease new HIV infections. Thus, we determined the potential use of our G2-STE16 carbosilane dendrimer in combination with other carbosilane dendrimers and ARVs for the use as topical microbicide against HIV-1. We showed that these combinations obtained 100% inhibition and displayed a synergistic profile against different HIV-1 isolates in our model of TZM.bl cells. Our results also showed their potent activity in the presence of an acidic vaginal or seminal fluid environment and did not activate an inflammatory response. This study is the first step toward exploring the use of different anionic carbosilane dendrimers in combination and toward making a safe microbicide. Therefore, our results support further studies on dendrimer/dendrimer or dendrimer/ARV combinations as topical anti-HIV-1 microbicide. This paper describes the first steps toward the use of anionic carbosilane dendrimers in combination with antivirals to address HIV-1, paving the way to further studies on dendrimer/dendrimer or dendrimer/ARV combinations as topical anti-HIV-1 microbicides. © 2014.

  15. Characterization of broadly neutralizing antibody responses to HIV-1 in a cohort of long term non-progressors.

    Science.gov (United States)

    González, Nuria; McKee, Krisha; Lynch, Rebecca M; Georgiev, Ivelin S; Jimenez, Laura; Grau, Eulalia; Yuste, Eloísa; Kwong, Peter D; Mascola, John R; Alcamí, José

    2018-01-01

    Only a small fraction of HIV-1-infected patients develop broadly neutralizing antibodies (bNAbs), a process generally associated to chronic antigen stimulation. It has been described that rare aviremic HIV-1-infected patients can generate bNAbs but this issue remains controversial. To address this matter we have assessed bNAb responses in a large cohort of long-term non-progressors (LTNPs) with low or undetectable viremia. Samples from the LTNP cohort of the Spanish AIDS Research Network (87 elite and 42 viremic controllers) and a control population of 176 viremic typical-progressors (TPs) were screened for bNAbs using Env-recombinant viruses. bNAb specificities were studied by ELISA using mutated gp120, neutralization assays with mutated viruses, and peptide competition. Epitope specificities were also elucidated from the serum pattern of neutralization against a panel of diverse HIV-1 isolates. Broadly neutralizing sera were found among 9.3% LTNPs, both elite (7%) and viremic controllers (14%). Within the broadly neutralizing sera, CD4 binding site antibodies were detected by ELISA in 4/12 LTNPs (33%), and 16/33 of TPs (48%). Anti-MPER antibodies were detected in 6/12 LTNPs (50%) and 14/33 TPs (42%) whereas glycan-dependent HIV-1 bNAbs were more frequent in LTNPs (11/12, 92%) as compared to TPs (12/33, 36%). A good concordance between standard serum mapping and neutralization-based mapping was observed. LTNPs, both viremic and elite controllers, showed broad humoral immune responses against HIV-1, including activity against many major epitopes involved in bNAbs-mediated protection.

  16. Broadly Neutralizing Activity of Zika Virus-Immune Sera Identifies a Single Viral Serotype

    Directory of Open Access Journals (Sweden)

    Kimberly A. Dowd

    2016-08-01

    Full Text Available Recent epidemics of Zika virus (ZIKV have been associated with congenital malformation during pregnancy and Guillain-Barré syndrome. There are two ZIKV lineages (African and Asian that share >95% amino acid identity. Little is known regarding the ability of neutralizing antibodies elicited against one lineage to protect against the other. We investigated the breadth of the neutralizing antibody response following ZIKV infection by measuring the sensitivity of six ZIKV strains to neutralization by ZIKV-confirmed convalescent human serum or plasma samples. Contemporary Asian and early African ZIKV strains were similarly sensitive to neutralization regardless of the cellular source of virus. Furthermore, mouse immune serum generated after infection with African or Asian ZIKV strains was capable of neutralizing homologous and heterologous ZIKV strains equivalently. Because our study only defines a single ZIKV serotype, vaccine candidates eliciting robust neutralizing antibody responses should inhibit infection of both ZIKV lineages, including strains circulating in the Americas.

  17. The Presence and Anti-HIV-1 Function of Tenascin C in Breast Milk and Genital Fluids.

    Directory of Open Access Journals (Sweden)

    Robin G Mansour

    Full Text Available Tenascin-C (TNC is a newly identified innate HIV-1-neutralizing protein present in breast milk, yet its presence and potential HIV-inhibitory function in other mucosal fluids is unknown. In this study, we identified TNC as a component of semen and cervical fluid of HIV-1-infected and uninfected individuals, although it is present at a significantly lower concentration and frequency compared to that of colostrum and mature breast milk, potentially due to genital fluid protease degradation. However, TNC was able to neutralize HIV-1 after exposure to low pH, suggesting that TNC could be active at low pH in the vaginal compartment. As mucosal fluids are complex and contain a number of proteins known to interact with the HIV-1 envelope, we further studied the relationship between the concentration of TNC and neutralizing activity in breast milk. The amount of TNC correlated only weakly with the overall innate HIV-1-neutralizing activity of breast milk of uninfected women and negatively correlated with neutralizing activity in milk of HIV-1 infected women, indicating that the amount of TNC in mucosal fluids is not adequate to impede HIV-1 transmission. Moreover, the presence of polyclonal IgG from milk of HIV-1 infected women, but not other HIV-1 envelope-binding milk proteins or monoclonal antibodies, blocked the neutralizing activity of TNC. Finally, as exogenous administration of TNC would be necessary for it to mediate measurable HIV-1 neutralizing activity in mucosal compartments, we established that recombinantly produced TNC has neutralizing activity against transmitted/founder HIV-1 strains that mimic that of purified TNC. Thus, we conclude that endogenous TNC concentration in mucosal fluids is likely inadequate to block HIV-1 transmission to uninfected individuals.

  18. Limited naturally occurring escape in broadly neutralizing antibody epitopes in hepatitis C glycoprotein E2 and constrained sequence usage in acute infection

    NARCIS (Netherlands)

    Rodrigo, Chaturaka; Walker, Melanie R.; Leung, Preston; Eltahla, Auda A.; Grebely, Jason; Dore, Gregory J.; Applegate, Tanya; Page, Kimberly; Dwivedi, Sunita; Bruneau, Julie; Morris, Meghan D.; Cox, Andrea L.; Osburn, William; Kim, Arthur Y.; Schinkel, Janke; Shoukry, Naglaa H.; Lauer, Georg M.; Maher, Lisa; Hellard, Margaret; Prins, Maria; Luciani, Fabio; Lloyd, Andrew R.; Bull, Rowena A.

    2017-01-01

    Broadly neutralizing antibodies have been associated with spontaneous clearance of the hepatitis C infection as well as viral persistence by immune escape. Further study of neutralizing antibody epitopes is needed to unravel pathways of resistance to virus neutralization, and to identify conserved

  19. A Cinnamon-Derived Procyanidin Compound Displays Anti-HIV-1 Activity by Blocking Heparan Sulfate- and Co-Receptor- Binding Sites on gp120 and Reverses T Cell Exhaustion via Impeding Tim-3 and PD-1 Upregulation.

    Directory of Open Access Journals (Sweden)

    Bridgette Janine Connell

    Full Text Available Amongst the many strategies aiming at inhibiting HIV-1 infection, blocking viral entry has been recently recognized as a very promising approach. Using diverse in vitro models and a broad range of HIV-1 primary patient isolates, we report here that IND02, a type A procyanidin polyphenol extracted from cinnamon, that features trimeric and pentameric forms displays an anti-HIV-1 activity against CXCR4 and CCR5 viruses with 1-7 μM ED50 for the trimer. Competition experiments, using a surface plasmon resonance-based binding assay, revealed that IND02 inhibited envelope binding to CD4 and heparan sulphate (HS as well as to an antibody (mAb 17b directed against the gp120 co-receptor binding site with an IC50 in the low μM range. IND02 has thus the remarkable property of simultaneously blocking gp120 binding to its major host cell surface counterparts. Additionally, the IND02-trimer impeded up-regulation of the inhibitory receptors Tim-3 and PD-1 on CD4+ and CD8+ cells, thereby demonstrating its beneficial effect by limiting T cell exhaustion. Among naturally derived products significantly inhibiting HIV-1, the IND02-trimer is the first component demonstrating an entry inhibition property through binding to the viral envelope glycoprotein. These data suggest that cinnamon, a widely consumed spice, could represent a novel and promising candidate for a cost-effective, natural entry inhibitor for HIV-1 which can also down-modulate T cell exhaustion markers Tim-3 and PD-1.

  20. Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-gp120 interface

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Jinghe; Kang, Byong H.; Pancera, Marie; Lee, Jeong Hyun; Tong, Tommy; Feng, Yu; Imamichi, Hiromi; Georgiev, Ivelin S.; Chuang, Gwo-Yu; Druz, Aliaksandr; Doria-Rose, Nicole A.; Laub, Leo; Sliepen, Kwinten; van Gils, Marit J.; de la Peña, Alba Torrents; Derking, Ronald; Klasse, Per-Johan; Migueles, Stephen A.; Bailer, Robert T.; Alam, Munir; Pugach, Pavel; Haynes, Barton F.; Wyatt, Richard T.; Sanders, Rogier W.; Binley, James M.; Ward, Andrew B.; Mascola, John R.; Kwong, Peter D.; Connors, Mark [NIH

    2015-10-15

    The isolation of human monoclonal antibodies is providing important insights into the specificities that underlie broad neutralization of HIV-1 (reviewed in ref. 1). Here we report a broad and extremely potent HIV-specific monoclonal antibody, termed 35O22, which binds a novel HIV-1 envelope glycoprotein (Env) epitope. 35O22 neutralized 62% of 181 pseudoviruses with a half-maximum inhibitory concentration (IC50) <50 μg ml-1. The median IC50 of neutralized viruses was 0.033 μg ml-1, among the most potent thus far described. 35O22 did not bind monomeric forms of Env tested, but did bind the trimeric BG505 SOSIP.664. Mutagenesis and a reconstruction by negative-stain electron microscopy of the Fab in complex with trimer revealed that it bound to a conserved epitope, which stretched across gp120 and gp41. The specificity of 35O22 represents a novel site of vulnerability on HIV Env, which serum analysis indicates to be commonly elicited by natural infection. Binding to this new site of vulnerability may thus be an important complement to current monoclonal-antibody-based approaches to immunotherapies, prophylaxis and vaccine design.

  1. Broadly neutralizing antibodies targeted to mucin-type carbohydrate epitopes of human immunodeficiency virus

    DEFF Research Database (Denmark)

    Hansen, J E; Nielsen, C; Arendrup, M

    1991-01-01

    . This inhibition was found in infection of both lymphocytic cells and monocytoid cells. Viruses tested included six HIV-1 and five HIV-2 isolates propagated in different cells, as well as infectious plasma from AIDS patients. The antiviral effect of anti-Tn MAbs occurred by specific binding of the MAb to the virus......; this binding was inhibitable by pure Tn antigen, and indications were found that this inhibition occurred at a pre-entry step. Boosting the naturally occurring low-titer anti-Tn activity may be of prophylactic value, as suggested by the in vitro neutralization found in this study....

  2. Rapid High-Level Production of Functional HIV Broadly Neutralizing Monoclonal Antibodies in Transient Plant Expression Systems

    Science.gov (United States)

    Rosenberg, Yvonne; Sack, Markus; Montefiori, David; Forthal, Donald; Mao, Lingjun; -Abanto, Segundo Hernandez; Urban, Lori; Landucci, Gary; Fischer, Rainer; Jiang, Xiaoming

    2013-01-01

    Passive immunotherapy using anti-HIV broadly neutralizing monoclonal antibodies (mAbs) has shown promise as an HIV treatment, reducing mother-to-child-transmission (MTCT) of simian/human immunodeficiency virus (SHIV) in non-human primates and decreasing viral rebound in patients who ceased receiving anti-viral drugs. In addition, a cocktail of potent mAbs may be useful as mucosal microbicides and provide an effective therapy for post-exposure prophylaxis. However, even highly neutralizing HIV mAbs used today may lose their effectiveness if resistance occurs, requiring the rapid production of new or engineered mAbs on an ongoing basis in order to counteract the viral resistance or the spread of a certain HIV-1 clade in a particular region or patient. Plant-based expression systems are fast, inexpensive and scalable and are becoming increasingly popular for the production of proteins and monoclonal antibodies. In the present study, Agrobacterium-mediated transient transfection of plants, utilizing two species of Nicotiana, have been tested to rapidly produce high levels of an HIV 89.6PΔ140env and several well-studied anti-HIV neutralizing monoclonal antibodies (b12, 2G12, 2F5, 4E10, m43, VRC01) or a single chain antibody construct (m9), for evaluation in cell-based viral inhibition assays. The protein-A purified plant-derived antibodies were intact, efficiently bound HIV envelope, and were equivalent to, or in one case better than, their counterparts produced in mammalian CHO or HEK-293 cells in both neutralization and antibody dependent viral inhibition assays. These data indicate that transient plant-based transient expression systems are very adaptable and could rapidly generate high levels of newly identified functional recombinant HIV neutralizing antibodies when required. In addition, they warrant detailed cost-benefit analysis of prolonged incubation in plants to further increase mAb production. PMID:23533588

  3. Rapid high-level production of functional HIV broadly neutralizing monoclonal antibodies in transient plant expression systems.

    Directory of Open Access Journals (Sweden)

    Yvonne Rosenberg

    Full Text Available Passive immunotherapy using anti-HIV broadly neutralizing monoclonal antibodies (mAbs has shown promise as an HIV treatment, reducing mother-to-child-transmission (MTCT of simian/human immunodeficiency virus (SHIV in non-human primates and decreasing viral rebound in patients who ceased receiving anti-viral drugs. In addition, a cocktail of potent mAbs may be useful as mucosal microbicides and provide an effective therapy for post-exposure prophylaxis. However, even highly neutralizing HIV mAbs used today may lose their effectiveness if resistance occurs, requiring the rapid production of new or engineered mAbs on an ongoing basis in order to counteract the viral resistance or the spread of a certain HIV-1 clade in a particular region or patient. Plant-based expression systems are fast, inexpensive and scalable and are becoming increasingly popular for the production of proteins and monoclonal antibodies. In the present study, Agrobacterium-mediated transient transfection of plants, utilizing two species of Nicotiana, have been tested to rapidly produce high levels of an HIV 89.6PΔ140env and several well-studied anti-HIV neutralizing monoclonal antibodies (b12, 2G12, 2F5, 4E10, m43, VRC01 or a single chain antibody construct (m9, for evaluation in cell-based viral inhibition assays. The protein-A purified plant-derived antibodies were intact, efficiently bound HIV envelope, and were equivalent to, or in one case better than, their counterparts produced in mammalian CHO or HEK-293 cells in both neutralization and antibody dependent viral inhibition assays. These data indicate that transient plant-based transient expression systems are very adaptable and could rapidly generate high levels of newly identified functional recombinant HIV neutralizing antibodies when required. In addition, they warrant detailed cost-benefit analysis of prolonged incubation in plants to further increase mAb production.

  4. An anti-HIV-1 compound that increases steady-state expression of apoplipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G.

    Science.gov (United States)

    Ejima, Tomohiko; Hirota, Mayuko; Mizukami, Tamio; Otsuka, Masami; Fujita, Mikako

    2011-10-01

    Human apoplipoprotein B mRNA-editing enzyme-catalytic polypeptide-like (APOBEC) 3G (A3G) is an antiviral protein that blocks HIV-1 replication. However, the antiviral activity of A3G is overcome by the HIV-1 protein Vif. This inhibitory function of Vif is related to its ability to degrade A3G in the proteasome. This finding prompted us to examine the activities of 4-(dimethylamino)-2,6-bis[(N-(2-[(2-nitrophenyl)dithio]ethyl)amino)methyl]pyridine (SN-2) and SN-3. We found that 5 µM SN-2 increases the expression of A3G to a level much higher than that observed in the absence of Vif, without affecting the level of Vif expression. The proteasome inhibitor MG-132 increased the level of both A3G and Vif expression. These results demonstrate that A3G is ubiquitinated and degraded in the proteasome by a factor other than Vif, and that SN-2 selectively inhibits these processes. Furthermore, 5 µM SN-2 significantly inhibited the MAGI cell infectivity of wild-type HIV-1. These findings may contribute to the development of a novel anti-HIV-1 drug.

  5. 9G4 autoreactivity is increased in HIV-infected patients and correlates with HIV broadly neutralizing serum activity.

    Directory of Open Access Journals (Sweden)

    James J Kobie

    Full Text Available The induction of a broadly neutralizing antibody (BNAb response against HIV-1 would be a desirable feature of a protective vaccine. Vaccine strategies thus far have failed to elicit broadly neutralizing antibody responses; however a minority of HIV-infected patients do develop circulating BNAbs, from which several potent broadly neutralizing monoclonal antibodies (mAbs have been isolated. The findings that several BNmAbs exhibit autoreactivity and that autoreactive serum antibodies are observed in some HIV patients have advanced the possibility that enforcement of self-tolerance may contribute to the rarity of BNAbs. To examine the possible breakdown of tolerance in HIV patients, we utilized the 9G4 anti-idiotype antibody system, enabling resolution of both autoreactive VH4-34 gene-expressing B cells and serum antibodies. Compared with healthy controls, HIV patients had significantly elevated 9G4+ serum IgG antibody concentrations and frequencies of 9G4+ B cells, a finding characteristic of systemic lupus erythematosus (SLE patients, both of which positively correlated with HIV viral load. Compared to the global 9G4-IgD--memory B cell population, the 9G4+IgD--memory fraction in HIV patients was dominated by isotype switched IgG+ B cells, but had a more prominent bias toward "IgM only" memory. HIV envelope reactivity was observed both in the 9G4+ serum antibody and 9G4+ B cell population. 9G4+ IgG serum antibody levels positively correlated (r = 0.403, p = 0.0019 with the serum HIV BNAbs. Interestingly, other serum autoantibodies commonly found in SLE (anti-dsDNA, ANA, anti-CL did not correlate with serum HIV BNAbs. 9G4-associated autoreactivity is preferentially expanded in chronic HIV infection as compared to other SLE autoreactivities. Therefore, the 9G4 system provides an effective tool to examine autoreactivity in HIV patients. Our results suggest that the development of HIV BNAbs is not merely a consequence of a general breakdown in

  6. Variable epitope libraries: new vaccine immunogens capable of inducing broad human immunodeficiency virus type 1-neutralizing antibody response.

    Science.gov (United States)

    Charles-Niño, Claudia; Pedroza-Roldan, Cesar; Viveros, Monica; Gevorkian, Goar; Manoutcharian, Karen

    2011-07-18

    The extreme antigenic variability of human immunodeficiency virus (HIV) leads to immune escape of the virus, representing a major challenge in the design of effective vaccine. We have developed a novel concept for immunogen construction based on introduction of massive mutations within the epitopes targeting antigenically variable pathogens and diseases. Previously, we showed that these immunogens carrying large combinatorial libraries of mutated epitope variants, termed as variable epitope libraries (VELs), induce potent, broad and long lasting CD8+IFN-γ+ T-cell response. Moreover, we demonstrated that these T cells recognize more than 50% of heavily mutated variants (5 out of 10 amino acid positions were mutated in each epitope variant) of HIV-1 gp120 V3 loop-derived cytotoxic T lymphocyte epitope (RGPGRAFVTI) in mice. The constructed VELs had complexities of 10000 and 12500 individual members, generated as plasmid DNA or as M13 phage display combinatorial libraries, respectively, and with structural composition RGPGXAXXXX or XGXGXAXVXI, where X is any of 20 natural amino acids. Here, we demonstrated that sera from mice immunized with these VELs are capable of neutralizing 5 out of 10 viral isolates from Tier 2 reference panel of subtype B envelope clones, including HIV-1 isolates which are known to be resistant to neutralization by several potent monoclonal antibodies, described previously. These data indicate the feasibility of the application of immunogens based on VEL concept as an alternative approach for the development of molecular vaccines against antigenically variable pathogens. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. In vivo evaluation of a mucoadhesive polymeric caplet for intravaginal anti-HIV-1 delivery and development of a molecular mechanistic model for thermochemical characterization.

    Science.gov (United States)

    Ndesendo, Valence M K; Choonara, Yahya E; Meyer, Leith C R; Kumar, Pradeep; Tomar, Lomas K; Tyagi, Charu; du Toit, Lisa C; Pillay, Viness

    2015-01-01

    The aim of this study was to develop, characterize and evaluate a mucoadhesive caplet resulting from a polymeric blend (polymeric caplet) for intravaginal anti-HIV-1 delivery. Poly(lactic-co-glycolic) acid, ethylcellulose, poly(vinylalcohol), polyacrylic acid and modified polyamide 6, 10 polymers were blended and compressed to a caplet-shaped device, with and without two model drugs 3'-azido-3'-deoxythymidine (AZT) and polystyrene sulfonate (PSS). Thermal analysis, infrared spectroscopy and microscopic analysis were carried out on the caplets employing temperature-modulated DSC (TMDSC), Fourier transform infra-red (FTIR) spectrometer and scanning electron microscope, respectively. In vitro and in vivo drug release analyses as well as the histopathological toxicity studies were carried out on the drug-loaded caplets. Furthermore, molecular mechanics (MM) simulations were carried out on the drug-loaded caplets to corroborate the experimental findings. There was a big deviation between the Tg of the polymeric caplet from the Tg's of the constituent polymers indicating a strong interaction between constituent polymers. FTIR spectroscopy confirmed the presence of specific ionic and non-ionic interactions within the caplet. A controlled near zero-order drug release was obtained for AZT (20 d) and PSS (28 d). In vivo results, i.e. the drug concentration in plasma ranged between 0.012-0.332 mg/mL and 0.009-0.256 mg/mL for AZT and PSS over 1-28 d. The obtained results, which were corroborated by MM simulations, attested that the developed system has the potential for effective delivery of anti-HIV-agents.

  8. Targeting N-Glycan Cryptic Sugar Moieties for Broad-Spectrum Virus Neutralization: Progress in Identifying Conserved Molecular Targets in Viruses of Distinct Phylogenetic Origins

    Directory of Open Access Journals (Sweden)

    Denong Wang

    2015-03-01

    Full Text Available Identifying molecular targets for eliciting broadly virus-neutralizing antibodies is one of the key steps toward development of vaccines against emerging viral pathogens. Owing to genomic and somatic diversities among viral species, identifying protein targets for broad-spectrum virus neutralization is highly challenging even for the same virus, such as HIV-1. However, viruses rely on host glycosylation machineries to synthesize and express glycans and, thereby, may display common carbohydrate moieties. Thus, exploring glycan-binding profiles of broad-spectrum virus-neutralizing agents may provide key information to uncover the carbohydrate-based virus-neutralizing epitopes. In this study, we characterized two broadly HIV-neutralizing agents, human monoclonal antibody 2G12 and Galanthus nivalis lectin (GNA, for their viral targeting activities. Although these agents were known to be specific for oligomannosyl antigens, they differ strikingly in virus-binding activities. The former is HIV-1 specific; the latter is broadly reactive and is able to neutralize viruses of distinct phylogenetic origins, such as HIV-1, severe acute respiratory syndrome coronavirus (SARS-CoV, and human cytomegalovirus (HCMV. In carbohydrate microarray analyses, we explored the molecular basis underlying the striking differences in the spectrum of anti-virus activities of the two probes. Unlike 2G12, which is strictly specific for the high-density Man9GlcNAc2Asn (Man9-clusters, GNA recognizes a number of N-glycan cryptic sugar moieties. These include not only the known oligomannosyl antigens but also previously unrecognized tri-antennary or multi-valent GlcNAc-terminating N-glycan epitopes (Tri/m-Gn. These findings highlight the potential of N-glycan cryptic sugar moieties as conserved targets for broad-spectrum virus neutralization and suggest the GNA-model of glycan-binding warrants focused investigation.

  9. Quantitative analyses reveal distinct sensitivities of the capture of HIV-1 primary viruses and pseudoviruses to broadly neutralizing antibodies.

    Science.gov (United States)

    Kim, Jiae; Jobe, Ousman; Peachman, Kristina K; Michael, Nelson L; Robb, Merlin L; Rao, Mangala; Rao, Venigalla B

    2017-08-01

    Development of vaccines capable of eliciting broadly neutralizing antibodies (bNAbs) is a key goal to controlling the global AIDS epidemic. To be effective, bNAbs must block the capture of HIV-1 to prevent viral acquisition and establishment of reservoirs. However, the role of bNAbs, particularly during initial exposure of primary viruses to host cells, has not been fully examined. Using a sensitive, quantitative, and high-throughput qRT-PCR assay, we found that primary viruses were captured by host cells and converted into a trypsin-resistant form in less than five minutes. We discovered, unexpectedly, that bNAbs did not block primary virus capture, although they inhibited the capture of pseudoviruses/IMCs and production of progeny viruses at 48h. Further, viruses escaped bNAb inhibition unless the bNAbs were present in the initial minutes of exposure of virus to host cells. These findings will have important implications for HIV-1 vaccine design and determination of vaccine efficacy. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Investigation of Sequence Clipping and Structural Heterogeneity of an HIV Broadly Neutralizing Antibody by a Comprehensive LC-MS Analysis

    Science.gov (United States)

    Ivleva, Vera B.; Schneck, Nicole A.; Gollapudi, Deepika; Arnold, Frank; Cooper, Jonathan W.; Lei, Q. Paula

    2018-05-01

    CAP256 is one of the highly potent, broadly neutralizing monoclonal antibodies (bNAb) designed for HIV-1 therapy. During the process development of one of the constructs, an unexpected product-related impurity was observed via microfluidics gel electrophoresis. A panel of complementary LC-MS analyses was applied for the comprehensive characterization of CAP256 which included the analysis of the intact and reduced protein, the middle-up approach, and a set of complementary peptide mapping techniques and verification of the disulfide bonds. The designed workflow allowed to identify a clip within a protruding acidic loop in the CDR-H3 region of the heavy chain, which can lead to the decrease of bNAb potency. This characterization explained the origin of the additional species reflected by the reducing gel profile. An intra-loop disulfide bond linking the two fragments was identified, which explained why the non-reducing capillary electrophoresis (CE) profile was not affected. The extensive characterization of CAP256 post-translational modifications was performed to investigate a possible cause of CE profile complexity and to illustrate other structural details related to this molecule's biological function. Two sites of the engineered Tyr sulfation were verified in the antigen-binding loop, and pyroglutamate formation was used as a tool for monitoring the extent of antibody clipping. Overall, the comprehensive LC-MS study was crucial to (1) identify the impurity as sequence clipping, (2) pinpoint the clipping location and justify its susceptibility relative to the molecular structure, (3) lead to an upstream process optimization to mitigate product quality risk, and (4) ultimately re-engineer the sequence to be clip-resistant. [Figure not available: see fulltext.

  11. Measles Virus Hemagglutinin epitopes immunogenic in natural infection and vaccination are targeted by broad or genotype-specific neutralizing monoclonal antibodies.

    Science.gov (United States)

    Muñoz-Alía, Miguel Angel; Casasnovas, José M; Celma, María Luisa; Carabaña, Juan; Liton, Paloma B; Fernandez-Muñoz, Rafael

    2017-05-15

    Measles virus (MV) remains a leading cause of vaccine-preventable deaths in children. Protection against MV is associated with neutralizing antibodies that preferentially recognize the viral hemagglutinin (MV-H), and to a lesser extent, the fusion protein (MV-F). Although MV is serologically monotypic, 24 genotypes have been identified. Here we report three neutralization epitopes conserved in the more prevalent circulating MV genotypes, two located in the MV-H receptor binding site (RBS) (antigenic site III) and a third in MV-H/MV-F interphase (antigenic site Ia) which are essential for MV multiplication. In contrast, two MV-H neutralization epitopes, showed a genotype-specific neutralization escape due to a single amino acid change, that we mapped in the "noose" antigenic site, or an enhanced neutralization epitope (antigenic site IIa). The monoclonal antibody (mAb) neutralization potency correlated with its binding affinity and was mainly driven by kinetic dissociation rate (k off ). We developed an immunoassay for mAb binding to MV-H in its native hetero-oligomeric structure with MV-F on the surface of a MV productive steady-state persistently infected (p.i.) human cell lines, and a competitive-binding assay with serum from individuals with past infection by different MV genotypes. Binding assays revealed that a broad neutralization epitope, in RBS antigenic site, a genotype specific neutralization epitopes, in noose and IIa sites, were immunogenic in natural infection and vaccination and may elicit long-lasting humoral immunity that might contribute to explain MV immunogenic stability. These results support the design of improved measles vaccines, broad-spectrum prophylactic or therapeutic antibodies and MV-used in oncolytic therapies. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Isolation and characterization of broadly neutralizing human monoclonal antibodies to the e1 glycoprotein of hepatitis C virus

    DEFF Research Database (Denmark)

    Meunier, Jean-Christophe; Russell, Rodney S.; Goossens, Vera

    2008-01-01

    The relative importance of humoral and cellular immunity in the prevention or clearance of hepatitis C virus (HCV) infection is poorly understood. However, there is considerable evidence that neutralizing antibodies are involved in disease control. Here we describe the detailed analysis of human...... monoclonal antibodies (MAbs) directed against HCV glycoprotein E1, which may have the potential to control HCV infection. We have identified two MAbs that can strongly neutralize HCV-pseudotyped particles (HCVpp) bearing the envelope glycoproteins of genotypes 1a, 1b, 4a, 5a, and 6a and less strongly...... neutralize HCVpp bearing the envelope glycoproteins of genotype 2a. Genotype 3a was not neutralized. The epitopes for both MAbs were mapped to the region encompassing amino acids 313 to 327. In addition, robust neutralization was also observed against cell culture-adapted viruses of genotypes 1a and 2a...

  13. MABGEL 1: first phase 1 trial of the anti-HIV-1 monoclonal antibodies 2F5, 4E10 and 2G12 as a vaginal microbicide.

    Directory of Open Access Journals (Sweden)

    Georgina C Morris

    Full Text Available BACKGROUND: Monoclonal antibodies (mAbs which potently neutralize a broad range of HIV isolates are potential microbicide candidates. To date, topical application of mAbs in humans and their stability in vaginal secretions has not been studied. OBJECTIVES: To assess the pharmacokinetics and safety of the mAbs 2F5, 4E10 and 2G12 when applied vaginally in women. DESIGN: A randomized, double-blind, placebo-controlled phase 1 trial. METHODS: Twenty-eight healthy, sexually abstinent women administered 2.5 g of gel daily for 12 days containing either 10 or 20 mg/g of each mAb (MABGEL or placebo. Main clinical evaluations and sampling occurred at baseline, 1, 8, and 24 hours post-1st dose and 12 and 36 hours post-12th dose. RESULTS: After adjustment for dilution factors, median levels of 2F5, 4E10 and 2G12 in vaginal secretions at 1 hour post high-dose MABGEL were 7.74, 5.28 and 7.48 mg/ml respectively. Levels of 2F5 and 4E10 declined exponentially thereafter with similar estimated half-lives (4.6 and 4.3 hours. In contrast, 2G12 levels declined more rapidly in the first 8 hours, with an estimated half-life of 1.4 hours during this period. There was no evidence of systemic absorption. There were no significant differences in local or systemic adverse event rates or vaginal flora changes (by qPCR between active and placebo gel arms. Whilst at least 1 adverse event was recorded in 96% of participants, 95% were mild and none were serious. CONCLUSIONS: Vaginal application of 50 mg of each mAb daily was safe over a 12 day period. Median mAb concentrations detected at 8 hours post dose were potentially sufficient to block HIV transmission.2G12 exhibited more rapid elimination from the human vagina than 4E10 and 2F5, likely due to poor stability of 2G12 in acidic human vaginal secretions. Further research is needed to develop mAb-based vaginal microbicides and delivery systems. TRIAL REGISTRATION: ISRCTN 64808733 UK CRN Portfolio 6470.

  14. Broad antibody mediated cross-neutralization and preclinical immunogenicity of new codon-optimized HIV-1 clade CRF02_AG and G primary isolates.

    Directory of Open Access Journals (Sweden)

    Simon M Agwale

    Full Text Available Creation of an effective vaccine for HIV has been an elusive goal of the scientific community for almost 30 years. Neutralizing antibodies are assumed to be pivotal to the success of a prophylactic vaccine but previous attempts to make an immunogen capable of generating neutralizing antibodies to primary "street strain" isolates have resulted in responses of very limited breadth and potency. The objective of the study was to determine the breadth and strength of neutralizing antibodies against autologous and heterologous primary isolates in a cohort of HIV-1 infected Nigerians and to characterize envelopes from subjects with particularly broad or strong immune responses for possible use as vaccine candidates in regions predominated by HIV-1 CRF02_AG and G subtypes. Envelope vectors from a panel of primary Nigerian isolates were constructed and tested with plasma/sera from the same cohort using the PhenoSense HIV neutralizing antibody assay (Monogram Biosciences Inc, USA to assess the breadth and potency of neutralizing antibodies. The immediate goal of this study was realized by the recognition of three broadly cross-neutralizing sera: (NG2-clade CRF02_AG, NG3-clade CRF02_AG and NG9- clade G. Based on these findings, envelope gp140 sequences from NG2 and NG9, complemented with a gag sequence (Clade G and consensus tat (CRF02_AG and G antigens have been codon-optimized, synthesized, cloned and evaluated in BALB/c mice. The intramuscular administration of these plasmid DNA constructs, followed by two booster DNA immunizations, induced substantial specific humoral response against all constructs and strong cellular responses against the gag and tat constructs. These preclinical findings provide a framework for the design of candidate vaccine for use in regions where the HIV-1 epidemic is driven by clades CRF02_AG and G.

  15. Broad antibody mediated cross-neutralization and preclinical immunogenicity of new codon-optimized HIV-1 clade CRF02_AG and G primary isolates.

    Science.gov (United States)

    Agwale, Simon M; Forbi, Joseph C; Notka, Frank; Wrin, Terri; Wild, Jens; Wagner, Ralf; Wolf, Hans

    2011-01-01

    Creation of an effective vaccine for HIV has been an elusive goal of the scientific community for almost 30 years. Neutralizing antibodies are assumed to be pivotal to the success of a prophylactic vaccine but previous attempts to make an immunogen capable of generating neutralizing antibodies to primary "street strain" isolates have resulted in responses of very limited breadth and potency. The objective of the study was to determine the breadth and strength of neutralizing antibodies against autologous and heterologous primary isolates in a cohort of HIV-1 infected Nigerians and to characterize envelopes from subjects with particularly broad or strong immune responses for possible use as vaccine candidates in regions predominated by HIV-1 CRF02_AG and G subtypes. Envelope vectors from a panel of primary Nigerian isolates were constructed and tested with plasma/sera from the same cohort using the PhenoSense HIV neutralizing antibody assay (Monogram Biosciences Inc, USA) to assess the breadth and potency of neutralizing antibodies. The immediate goal of this study was realized by the recognition of three broadly cross-neutralizing sera: (NG2-clade CRF02_AG, NG3-clade CRF02_AG and NG9- clade G). Based on these findings, envelope gp140 sequences from NG2 and NG9, complemented with a gag sequence (Clade G) and consensus tat (CRF02_AG and G) antigens have been codon-optimized, synthesized, cloned and evaluated in BALB/c mice. The intramuscular administration of these plasmid DNA constructs, followed by two booster DNA immunizations, induced substantial specific humoral response against all constructs and strong cellular responses against the gag and tat constructs. These preclinical findings provide a framework for the design of candidate vaccine for use in regions where the HIV-1 epidemic is driven by clades CRF02_AG and G.

  16. A hepatitis C virus (HCV) vaccine comprising envelope glycoproteins gpE1/gpE2 derived from a single isolate elicits broad cross-genotype neutralizing antibodies in humans

    DEFF Research Database (Denmark)

    Law, John Lok Man; Chen, Chao; Wong, Jason

    2013-01-01

    of genotype 1a). Cross neutralization was tested in Huh-7.5 human hepatoma cell cultures using infectious recombinant HCV (HCVcc) expressing structural proteins of heterologous HCV strains from all known major genotypes, 1-7. Vaccination induced significant neutralizing antibodies against heterologous HCV...... genotype 1a virus which represents the most common genotype in North America. Of the 16 vaccinees tested, 3 were selected on the basis of strong 1a virus neutralization for testing of broad cross-neutralizing responses. At least 1 vaccinee was shown to elicit broad cross-neutralization against all HCV...

  17. Isolation and characterization of broadly neutralizing human monoclonal antibodies to the e1 glycoprotein of hepatitis C virus

    DEFF Research Database (Denmark)

    Meunier, Jean-Christophe; Russell, Rodney S; Goossens, Vera

    2008-01-01

    monoclonal antibodies (MAbs) directed against HCV glycoprotein E1, which may have the potential to control HCV infection. We have identified two MAbs that can strongly neutralize HCV-pseudotyped particles (HCVpp) bearing the envelope glycoproteins of genotypes 1a, 1b, 4a, 5a, and 6a and less strongly...

  18. Ectopic expression of anti-HIV-1 shRNAs protects CD8{sup +} T cells modified with CD4ζ CAR from HIV-1 infection and alleviates impairment of cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Kamata, Masakazu, E-mail: masa3k@ucla.edu [Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Kim, Patrick Y. [Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Ng, Hwee L. [Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Ringpis, Gene-Errol E.; Kranz, Emiko; Chan, Joshua; O' Connor, Sean [Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Yang, Otto O. [Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); UCLA AIDS Institute, Los Angeles, CA (United States); AIDS Healthcare Foundation, Los Angeles, CA (United States); Chen, Irvin S.Y. [Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); UCLA AIDS Institute, Los Angeles, CA (United States)

    2015-07-31

    Chimeric antigen receptors (CARs) are artificially engineered receptors that confer a desired specificity to immune effector T cells. As an HIV-1-specific CAR, CD4ζ CAR has been extensively tested in vitro as well as in clinical trials. T cells modified with this CAR mediated highly potent anti-HIV-1 activities in vitro and were well-tolerated in vivo, but exerted limited effects on viral load and reservoir size due to poor survival and/or functionality of the transduced cells in patients. We hypothesize that ectopic expression of CD4ζ on CD8{sup +} T cells renders them susceptible to HIV-1 infection, resulting in poor survival of those cells. To test this possibility, highly purified CD8{sup +} T cells were genetically modified with a CD4ζ-encoding lentiviral vector and infected with HIV-1. CD8{sup +} T cells were vulnerable to HIV-1 infection upon expression of CD4ζ as evidenced by elevated levels of p24{sup Gag} in cells and culture supernatants. Concurrently, the number of CD4ζ-modified CD8{sup +} T cells was reduced relative to control cells upon HIV-1 infection. To protect these cells from HIV-1 infection, we co-expressed two anti-HIV-1 shRNAs previously developed by our group together with CD4ζ. This combination vector was able to suppress HIV-1 infection without impairing HIV-1-dependent effector activities of CD4ζ. In addition, the number of CD4ζ-modified CD8{sup +} T cells maintained similar levels to that of the control even under HIV-1 infection. These results suggest that protecting CD4ζ-modified CD8{sup +} T cells from HIV-1 infection is required for prolonged HIV-1-specific immune surveillance. - Highlights: • Ectopic expression of CD4ζ CAR in CD8{sup +} T cells renders them susceptible to HIV-1 infection. • Co-expression of two anti-HIV-1 shRNAs protects CD4ζ CAR-modified CD8{sup +} T cells from HIV-1 infection. • Protecting CD4ζ CAR-modified CD8{sup +} T cells from HIV-1 infection suppresses its cytopathic effect.

  19. Ectopic expression of anti-HIV-1 shRNAs protects CD8+ T cells modified with CD4ζ CAR from HIV-1 infection and alleviates impairment of cell proliferation

    International Nuclear Information System (INIS)

    Kamata, Masakazu; Kim, Patrick Y.; Ng, Hwee L.; Ringpis, Gene-Errol E.; Kranz, Emiko; Chan, Joshua; O'Connor, Sean; Yang, Otto O.; Chen, Irvin S.Y.

    2015-01-01

    Chimeric antigen receptors (CARs) are artificially engineered receptors that confer a desired specificity to immune effector T cells. As an HIV-1-specific CAR, CD4ζ CAR has been extensively tested in vitro as well as in clinical trials. T cells modified with this CAR mediated highly potent anti-HIV-1 activities in vitro and were well-tolerated in vivo, but exerted limited effects on viral load and reservoir size due to poor survival and/or functionality of the transduced cells in patients. We hypothesize that ectopic expression of CD4ζ on CD8 + T cells renders them susceptible to HIV-1 infection, resulting in poor survival of those cells. To test this possibility, highly purified CD8 + T cells were genetically modified with a CD4ζ-encoding lentiviral vector and infected with HIV-1. CD8 + T cells were vulnerable to HIV-1 infection upon expression of CD4ζ as evidenced by elevated levels of p24 Gag in cells and culture supernatants. Concurrently, the number of CD4ζ-modified CD8 + T cells was reduced relative to control cells upon HIV-1 infection. To protect these cells from HIV-1 infection, we co-expressed two anti-HIV-1 shRNAs previously developed by our group together with CD4ζ. This combination vector was able to suppress HIV-1 infection without impairing HIV-1-dependent effector activities of CD4ζ. In addition, the number of CD4ζ-modified CD8 + T cells maintained similar levels to that of the control even under HIV-1 infection. These results suggest that protecting CD4ζ-modified CD8 + T cells from HIV-1 infection is required for prolonged HIV-1-specific immune surveillance. - Highlights: • Ectopic expression of CD4ζ CAR in CD8 + T cells renders them susceptible to HIV-1 infection. • Co-expression of two anti-HIV-1 shRNAs protects CD4ζ CAR-modified CD8 + T cells from HIV-1 infection. • Protecting CD4ζ CAR-modified CD8 + T cells from HIV-1 infection suppresses its cytopathic effect

  20. Structure and function of broadly reactive antibody PG16 reveal an H3 subdomain that mediates potent neutralization of HIV-1

    Energy Technology Data Exchange (ETDEWEB)

    Pejchal, Robert; Walker, Laura M.; Stanfield, Robyn L.; Phogat, Sanjay K.; Koff, Wayne C.; Poignard, Pascal; Burton, Dennis R.; Wilson, Ian A. (Scripps); (IAVI)

    2010-11-15

    Development of an effective vaccine against HIV-1 will likely require elicitation of broad and potent neutralizing antibodies against the trimeric surface envelope glycoprotein (Env). Monoclonal antibodies (mAbs) PG9 and PG16 neutralize {approx}80% of HIV-1 isolates across all clades with extraordinary potency and target novel epitopes preferentially expressed on Env trimers. As these neutralization properties are ideal for a vaccine-elicited antibody response to HIV-1, their structural basis was investigated. The crystal structure of the antigen-binding fragment (Fab) of PG16 at 2.5 {angstrom} resolution revealed its unusually long, 28-residue, complementarity determining region (CDR) H3 forms a unique, stable subdomain that towers above the antibody surface. A 7-residue 'specificity loop' on the 'hammerhead' subdomain was identified that, when transplanted from PG16 to PG9 and vice versa, accounted for differences in the fine specificity and neutralization of these two mAbs. The PG16 electron density maps also revealed that a CDR H3 tyrosine was sulfated, which was confirmed for both PG9 (doubly) and PG16 (singly) by mass spectral analysis. We further showed that tyrosine sulfation plays a role in binding and neutralization. An N-linked glycan modification is observed in the variable light chain, but not required for antigen recognition. Further, the crystal structure of the PG9 light chain at 3.0 {angstrom} facilitated homology modeling to support the presence of these unusual features in PG9. Thus, PG9 and PG16 use unique structural features to mediate potent neutralization of HIV-1 that may be of utility in antibody engineering and for high-affinity recognition of a variety of therapeutic targets.

  1. Extra-epitopic hepatitis C virus polymorphisms confer resistance to broadly neutralizing antibodies by modulating binding to scavenger receptor B1.

    Science.gov (United States)

    El-Diwany, Ramy; Cohen, Valerie J; Mankowski, Madeleine C; Wasilewski, Lisa N; Brady, Jillian K; Snider, Anna E; Osburn, William O; Murrell, Ben; Ray, Stuart C; Bailey, Justin R

    2017-02-01

    Broadly-neutralizing monoclonal antibodies (bNAbs) may guide vaccine development for highly variable viruses including hepatitis C virus (HCV), since they target conserved viral epitopes that could serve as vaccine antigens. However, HCV resistance to bNAbs could reduce the efficacy of a vaccine. HC33.4 and AR4A are two of the most potent anti-HCV human bNAbs characterized to date, binding to highly conserved epitopes near the amino- and carboxy-terminus of HCV envelope (E2) protein, respectively. Given their distinct epitopes, it was surprising that these bNAbs showed similar neutralization profiles across a panel of natural HCV isolates, suggesting that some viral polymorphisms may confer resistance to both bNAbs. To investigate this resistance, we developed a large, diverse panel of natural HCV envelope variants and a novel computational method to identify bNAb resistance polymorphisms in envelope proteins (E1 and E2). By measuring neutralization of a panel of HCV pseudoparticles by 10 μg/mL of each bNAb, we identified E1E2 variants with resistance to one or both bNAbs, despite 100% conservation of the AR4A binding epitope across the panel. We discovered polymorphisms outside of either binding epitope that modulate resistance to both bNAbs by altering E2 binding to the HCV co-receptor, scavenger receptor B1 (SR-B1). This study is focused on a mode of neutralization escape not addressed by conventional analysis of epitope conservation, highlighting the contribution of extra-epitopic polymorphisms to bNAb resistance and presenting a novel mechanism by which HCV might persist even in the face of an antibody response targeting multiple conserved epitopes.

  2. Broad neutralization of calcium-permeable amyloid pore channels with a chimeric Alzheimer/Parkinson peptide targeting brain gangliosides.

    Science.gov (United States)

    Di Scala, Coralie; Yahi, Nouara; Flores, Alessandra; Boutemeur, Sonia; Kourdougli, Nazim; Chahinian, Henri; Fantini, Jacques

    2016-02-01

    Growing evidence supports a role for brain gangliosides in the pathogenesis of neurodegenerative diseases including Alzheimer's and Parkinson's. Recently we deciphered the ganglioside-recognition code controlling specific ganglioside binding to Alzheimer's β-amyloid (Aβ1-42) peptide and Parkinson's disease-associated protein α-synuclein. Cracking this code allowed us to engineer a short chimeric Aβ/α-synuclein peptide that recognizes all brain gangliosides. Here we show that ganglioside-deprived neural cells do no longer sustain the formation of zinc-sensitive amyloid pore channels induced by either Aβ1-42 or α-synuclein, as assessed by single-cell Ca(2+) fluorescence microscopy. Thus, amyloid channel formation, now considered a key step in neurodegeneration, is a ganglioside-dependent process. Nanomolar concentrations of chimeric peptide competitively inhibited amyloid pore formation induced by Aβ1-42 or α-synuclein in cultured neural cells. Moreover, this peptide abrogated the intracellular calcium increases induced by Parkinson's-associated mutant forms of α-synuclein (A30P, E46K and A53T). The chimeric peptide also prevented the deleterious effects of Aβ1-42 on synaptic vesicle trafficking and decreased the Aβ1-42-induced impairment of spontaneous activity in rat hippocampal slices. Taken together, these data show that the chimeric peptide has broad anti-amyloid pore activity, suggesting that a common therapeutic strategy based on the prevention of amyloid-ganglioside interactions is a reachable goal for both Alzheimer's and Parkinson's diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Hidden Lineage Complexity of Glycan-Dependent HIV-1 Broadly Neutralizing Antibodies Uncovered by Digital Panning and Native-Like gp140 Trimer

    Directory of Open Access Journals (Sweden)

    Linling He

    2017-08-01

    Full Text Available Germline precursors and intermediates of broadly neutralizing antibodies (bNAbs are essential to the understanding of humoral response to HIV-1 infection and B-cell lineage vaccine design. Using a native-like gp140 trimer probe, we examined antibody libraries constructed from donor-17, the source of glycan-dependent PGT121-class bNAbs recognizing the N332 supersite on the HIV-1 envelope glycoprotein. To facilitate this analysis, a digital panning method was devised that combines biopanning of phage-displayed antibody libraries, 900 bp long-read next-generation sequencing, and heavy/light (H/L-paired antibodyomics. In addition to single-chain variable fragments resembling the wild-type bNAbs, digital panning identified variants of PGT124 (a member of the PGT121 class with a unique insertion in the heavy chain complementarity-determining region 1, as well as intermediates of PGT124 exhibiting notable affinity for the native-like trimer and broad HIV-1 neutralization. In a competition assay, these bNAb intermediates could effectively compete with mouse sera induced by a scaffolded BG505 gp140.681 trimer for the N332 supersite. Our study thus reveals previously unrecognized lineage complexity of the PGT121-class bNAbs and provides an array of library-derived bNAb intermediates for evaluation of immunogens containing the N332 supersite. Digital panning may prove to be a valuable tool in future studies of bNAb diversity and lineage development.

  4. Hidden Lineage Complexity of Glycan-Dependent HIV-1 Broadly Neutralizing Antibodies Uncovered by Digital Panning and Native-Like gp140 Trimer.

    Science.gov (United States)

    He, Linling; Lin, Xiaohe; de Val, Natalia; Saye-Francisco, Karen L; Mann, Colin J; Augst, Ryan; Morris, Charles D; Azadnia, Parisa; Zhou, Bin; Sok, Devin; Ozorowski, Gabriel; Ward, Andrew B; Burton, Dennis R; Zhu, Jiang

    2017-01-01

    Germline precursors and intermediates of broadly neutralizing antibodies (bNAbs) are essential to the understanding of humoral response to HIV-1 infection and B-cell lineage vaccine design. Using a native-like gp140 trimer probe, we examined antibody libraries constructed from donor-17, the source of glycan-dependent PGT121-class bNAbs recognizing the N332 supersite on the HIV-1 envelope glycoprotein. To facilitate this analysis, a digital panning method was devised that combines biopanning of phage-displayed antibody libraries, 900 bp long-read next-generation sequencing, and heavy/light (H/L)-paired antibodyomics. In addition to single-chain variable fragments resembling the wild-type bNAbs, digital panning identified variants of PGT124 (a member of the PGT121 class) with a unique insertion in the heavy chain complementarity-determining region 1, as well as intermediates of PGT124 exhibiting notable affinity for the native-like trimer and broad HIV-1 neutralization. In a competition assay, these bNAb intermediates could effectively compete with mouse sera induced by a scaffolded BG505 gp140.681 trimer for the N332 supersite. Our study thus reveals previously unrecognized lineage complexity of the PGT121-class bNAbs and provides an array of library-derived bNAb intermediates for evaluation of immunogens containing the N332 supersite. Digital panning may prove to be a valuable tool in future studies of bNAb diversity and lineage development.

  5. Immunization of rabbits with highly purified, soluble, trimeric human immunodeficiency virus type 1 envelope glycoprotein induces a vigorous B cell response and broadly cross-reactive neutralization.

    Directory of Open Access Journals (Sweden)

    Gerald V Quinnan

    Full Text Available Previously we described induction of cross-reactive HIV-1 neutralizing antibody responses in rabbits using a soluble HIV-1 gp140 envelope glycoprotein (Env in an adjuvant containing monophosphoryl lipid A (MPL and QS21 (AS02A. Here, we compared different forms of the same HIV-1 strain R2 Env for antigenic and biophysical characteristics, and in rabbits characterized the extent of B cell induction for specific antibody expression and secretion and neutralizing responses. The forms of this Env that were produced in and purified from stably transformed 293T cells included a primarily dimeric gp140, a trimeric gp140 appended to a GCN4 trimerization domain (gp140-GCN4, gp140-GCN4 with a 15 amino acid flexible linker between the gp120 and gp41 ectodomain (gp140-GCN4-L, also trimeric, and a gp140 with the flexible linker purified from cell culture supernatants as either dimer (gp140-L(D or monomer (gp140-L(M. Multimeric states of the Env proteins were assessed by native gel electrophoresis and analytical ultracentrifugation. The different forms of gp140 bound broadly cross-reactive neutralizing (BCN human monoclonal antibodies (mAbs similarly in ELISA and immunoprecipitation assays. All Envs bound CD4i mAbs in the presence and absence of sCD4, as reported for the R2 Env. Weak neutralization of some strains of HIV-1 was seen after two additional doses in AS02A. Rabbits that were given a seventh dose of gp140-GCN4-L developed BCN responses that were weak to moderate, similar to our previous report. The specificity of these responses did not appear similar to that of any of the known BCN human mAbs. Induction of spleen B cell and plasma cells producing immunoglobulins that bound trimeric gp140-GCN4-L was vigorous, based on ELISpot and flow cytometry analyses. The results demonstrate that highly purified gp140-GCN4-L trimer in adjuvant elicits BCN responses in rabbits accompanied by vigorous B cell induction.

  6. A glycoconjugate antigen based on the recognition motif of a broadly neutralizing human immunodeficiency virus antibody, 2G12, is immunogenic but elicits antibodies unable to bind to the self glycans of gp120

    DEFF Research Database (Denmark)

    Astronomo, Rena D; Lee, Hing-Ken; Scanlan, Christopher N

    2008-01-01

    The glycan shield of human immunodeficiency virus type 1 (HIV-1) gp120 contributes to viral evasion from humoral immune responses. However, the shield is recognized by the HIV-1 broadly neutralizing antibody (Ab), 2G12, at a relatively conserved cluster of oligomannose glycans. The discovery of 2G......12 raises the possibility that a carbohydrate immunogen may be developed that could elicit 2G12-like neutralizing Abs and contribute to an AIDS vaccine. We have previously dissected the fine specificity of 2G12 and reported that the synthetic tetramannoside (Man(4)) that corresponds to the D1 arm...

  7. Fully human broadly neutralizing monoclonal antibodies against influenza A viruses generated from the memory B cells of a 2009 pandemic H1N1 influenza vaccine recipient

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Weibin [Molecular Virus Unit, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025 (China); Chen, Aizhong [Key Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031 (China); Miao, Yi [Shanghai Xuhui Central Hospital, Shanghai 200031 (China); Xia, Shengli [Center for Disease Control and Prevention of Henan Province, Zhengzhou 450016 (China); Ling, Zhiyang; Xu, Ke; Wang, Tongyan [Molecular Virus Unit, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025 (China); Xu, Ying; Cui, Jun; Wu, Hongqiang; Hu, Guiyu; Tian, Lin; Wang, Lingling [Key Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031 (China); Shu, Yuelong [Chinese Center for Disease Control and Prevention, Beijing 102206 (China); Ma, Xiaowei [Hualan Biological Bacterin Company, Xinxiang 453003 (China); Xu, Bianli; Zhang, Jin [Center for Disease Control and Prevention of Henan Province, Zhengzhou 450016 (China); Lin, Xiaojun, E-mail: linxiaojun@hualan.com [Hualan Biological Bacterin Company, Xinxiang 453003 (China); Bian, Chao, E-mail: cbian@sibs.ac.cn [Key Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031 (China); Sun, Bing, E-mail: bsun@sibs.ac.cn [Molecular Virus Unit, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025 (China); Key Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031 (China)

    2013-01-20

    Whether the 2009 pandemic H1N1 influenza vaccine can induce heterosubtypic cross-protective anti-hemagglutinin (HA) neutralizing antibodies is an important issue. We obtained a panel of fully human monoclonal antibodies from the memory B cells of a 2009 pandemic H1N1 influenza vaccine recipient. Most of the monoclonal antibodies targeted the HA protein but not the HA1 fragment. Among the analyzed antibodies, seven mAbs exhibited neutralizing activity against several influenza A viruses of different subtypes. The conserved linear epitope targeted by the neutralizing mAbs (FIEGGWTGMVDGWYGYHH) is part of the fusion peptide on HA2. Our work suggests that a heterosubtypic neutralizing antibody response primarily targeting the HA stem region exists in recipients of the 2009 pandemic H1N1 influenza vaccine. The HA stem region contains various conserved neutralizing epitopes with the fusion peptide as an important one. This work may aid in the design of a universal influenza A virus vaccine.

  8. Fully human broadly neutralizing monoclonal antibodies against influenza A viruses generated from the memory B cells of a 2009 pandemic H1N1 influenza vaccine recipient

    International Nuclear Information System (INIS)

    Hu, Weibin; Chen, Aizhong; Miao, Yi; Xia, Shengli; Ling, Zhiyang; Xu, Ke; Wang, Tongyan; Xu, Ying; Cui, Jun; Wu, Hongqiang; Hu, Guiyu; Tian, Lin; Wang, Lingling; Shu, Yuelong; Ma, Xiaowei; Xu, Bianli; Zhang, Jin; Lin, Xiaojun; Bian, Chao; Sun, Bing

    2013-01-01

    Whether the 2009 pandemic H1N1 influenza vaccine can induce heterosubtypic cross-protective anti-hemagglutinin (HA) neutralizing antibodies is an important issue. We obtained a panel of fully human monoclonal antibodies from the memory B cells of a 2009 pandemic H1N1 influenza vaccine recipient. Most of the monoclonal antibodies targeted the HA protein but not the HA1 fragment. Among the analyzed antibodies, seven mAbs exhibited neutralizing activity against several influenza A viruses of different subtypes. The conserved linear epitope targeted by the neutralizing mAbs (FIEGGWTGMVDGWYGYHH) is part of the fusion peptide on HA2. Our work suggests that a heterosubtypic neutralizing antibody response primarily targeting the HA stem region exists in recipients of the 2009 pandemic H1N1 influenza vaccine. The HA stem region contains various conserved neutralizing epitopes with the fusion peptide as an important one. This work may aid in the design of a universal influenza A virus vaccine.

  9. Host-Primed Ebola Virus GP Exposes a Hydrophobic NPC1 Receptor-Binding Pocket, Revealing a Target for Broadly Neutralizing Antibodies.

    Science.gov (United States)

    Bornholdt, Zachary A; Ndungo, Esther; Fusco, Marnie L; Bale, Shridhar; Flyak, Andrew I; Crowe, James E; Chandran, Kartik; Saphire, Erica Ollmann

    2016-02-23

    The filovirus surface glycoprotein (GP) mediates viral entry into host cells. Following viral internalization into endosomes, GP is cleaved by host cysteine proteases to expose a receptor-binding site (RBS) that is otherwise hidden from immune surveillance. Here, we present the crystal structure of proteolytically cleaved Ebola virus GP to a resolution of 3.3 Å. We use this structure in conjunction with functional analysis of a large panel of pseudotyped viruses bearing mutant GP proteins to map the Ebola virus GP endosomal RBS at molecular resolution. Our studies indicate that binding of GP to its endosomal receptor Niemann-Pick C1 occurs in two distinct stages: the initial electrostatic interactions are followed by specific interactions with a hydrophobic trough that is exposed on the endosomally cleaved GP1 subunit. Finally, we demonstrate that monoclonal antibodies targeting the filovirus RBS neutralize all known filovirus GPs, making this conserved pocket a promising target for the development of panfilovirus therapeutics. Ebola virus uses its glycoprotein (GP) to enter new host cells. During entry, GP must be cleaved by human enzymes in order for receptor binding to occur. Here, we provide the crystal structure of the cleaved form of Ebola virus GP. We demonstrate that cleavage exposes a site at the top of GP and that this site binds the critical domain C of the receptor, termed Niemann-Pick C1 (NPC1). We perform mutagenesis to find parts of the site essential for binding NPC1 and map distinct roles for an upper, charged crest and lower, hydrophobic trough in cleaved GP. We find that this 3-dimensional site is conserved across the filovirus family and that antibody directed against this site is able to bind cleaved GP from every filovirus tested and neutralize viruses bearing those GPs. Copyright © 2016 Bornholdt et al.

  10. Host-Primed Ebola Virus GP Exposes a Hydrophobic NPC1 Receptor-Binding Pocket, Revealing a Target for Broadly Neutralizing Antibodies

    Directory of Open Access Journals (Sweden)

    Zachary A. Bornholdt

    2016-02-01

    Full Text Available The filovirus surface glycoprotein (GP mediates viral entry into host cells. Following viral internalization into endosomes, GP is cleaved by host cysteine proteases to expose a receptor-binding site (RBS that is otherwise hidden from immune surveillance. Here, we present the crystal structure of proteolytically cleaved Ebola virus GP to a resolution of 3.3 Å. We use this structure in conjunction with functional analysis of a large panel of pseudotyped viruses bearing mutant GP proteins to map the Ebola virus GP endosomal RBS at molecular resolution. Our studies indicate that binding of GP to its endosomal receptor Niemann-Pick C1 occurs in two distinct stages: the initial electrostatic interactions are followed by specific interactions with a hydrophobic trough that is exposed on the endosomally cleaved GP1 subunit. Finally, we demonstrate that monoclonal antibodies targeting the filovirus RBS neutralize all known filovirus GPs, making this conserved pocket a promising target for the development of panfilovirus therapeutics.

  11. Human monoclonal antibodies derived from a patient infected with 2009 pandemic influenza A virus broadly cross-neutralize group 1 influenza viruses

    International Nuclear Information System (INIS)

    Pan, Yang; Sasaki, Tadahiro; Kubota-Koketsu, Ritsuko; Inoue, Yuji; Yasugi, Mayo; Yamashita, Akifumi; Ramadhany, Ririn; Arai, Yasuha; Du, Anariwa; Boonsathorn, Naphatsawan; Ibrahim, Madiha S.

    2014-01-01

    Highlights: • Influenza infection can elicit heterosubtypic antibodies to group 1 influenza virus. • Three human monoclonal antibodies were generated from an H1N1-infected patient. • The antibodies predominantly recognized α-helical stem of viral hemagglutinin (HA). • The antibodies inhibited HA structural activation during the fusion process. • The antibodies are potential candidates for future antibody therapy to influenza. - Abstract: Influenza viruses are a continuous threat to human public health because of their ability to evolve rapidly through genetic drift and reassortment. Three human monoclonal antibodies (HuMAbs) were generated in this study, 1H11, 2H5 and 5G2, and they cross-neutralize a diverse range of group 1 influenza A viruses, including seasonal H1N1, 2009 pandemic H1N1 (H1N1pdm) and avian H5N1 and H9N2. The three HuMAbs were prepared by fusing peripheral blood lymphocytes from an H1N1pdm-infected patient with a newly developed fusion partner cell line, SPYMEG. All the HuMAbs had little hemagglutination inhibition activity but had strong membrane-fusion inhibition activity against influenza viruses. A protease digestion assay showed the HuMAbs targeted commonly a short α-helix region in the stalk of the hemagglutinin. Furthermore, Ile45Phe and Glu47Gly double substitutions in the α-helix region made the HA unrecognizable by the HuMAbs. These two amino acid residues are highly conserved in the HAs of H1N1, H5N1 and H9N2 viruses. The HuMAbs reported here may be potential candidates for the development of therapeutic antibodies against group 1 influenza viruses

  12. Human monoclonal antibodies derived from a patient infected with 2009 pandemic influenza A virus broadly cross-neutralize group 1 influenza viruses

    Energy Technology Data Exchange (ETDEWEB)

    Pan, Yang [Research Institute for Microbial Diseases, Osaka University, Suita, Osaka (Japan); Sasaki, Tadahiro [Research Institute for Microbial Diseases, Osaka University, Suita, Osaka (Japan); JST/JICA, Science and Technology Research Partnership for Sustainable Development (SATREPS), Tokyo (Japan); Kubota-Koketsu, Ritsuko [Research Institute for Microbial Diseases, Osaka University, Suita, Osaka (Japan); Kanonji Institute, The Research Foundation for Microbial Diseases of Osaka University, Kanonji, Kagawa (Japan); JST/JICA, Science and Technology Research Partnership for Sustainable Development (SATREPS), Tokyo (Japan); Inoue, Yuji [Research Institute for Microbial Diseases, Osaka University, Suita, Osaka (Japan); JST/JICA, Science and Technology Research Partnership for Sustainable Development (SATREPS), Tokyo (Japan); Yasugi, Mayo [Research Institute for Microbial Diseases, Osaka University, Suita, Osaka (Japan); Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano, Osaka (Japan); JST/JICA, Science and Technology Research Partnership for Sustainable Development (SATREPS), Tokyo (Japan); Yamashita, Akifumi; Ramadhany, Ririn; Arai, Yasuha [Research Institute for Microbial Diseases, Osaka University, Suita, Osaka (Japan); Du, Anariwa [Research Institute for Microbial Diseases, Osaka University, Suita, Osaka (Japan); JST/JICA, Science and Technology Research Partnership for Sustainable Development (SATREPS), Tokyo (Japan); Boonsathorn, Naphatsawan [Research Institute for Microbial Diseases, Osaka University, Suita, Osaka (Japan); Department of Medical Sciences, Ministry of Public Health, Muang, Nonthaburi (Thailand); JST/JICA, Science and Technology Research Partnership for Sustainable Development (SATREPS), Tokyo (Japan); Ibrahim, Madiha S. [Research Institute for Microbial Diseases, Osaka University, Suita, Osaka (Japan); Department of Microbiology and Immunology, Faculty of Veterinary Medicine, Damanhour University, Damanhour (Egypt); and others

    2014-07-18

    Highlights: • Influenza infection can elicit heterosubtypic antibodies to group 1 influenza virus. • Three human monoclonal antibodies were generated from an H1N1-infected patient. • The antibodies predominantly recognized α-helical stem of viral hemagglutinin (HA). • The antibodies inhibited HA structural activation during the fusion process. • The antibodies are potential candidates for future antibody therapy to influenza. - Abstract: Influenza viruses are a continuous threat to human public health because of their ability to evolve rapidly through genetic drift and reassortment. Three human monoclonal antibodies (HuMAbs) were generated in this study, 1H11, 2H5 and 5G2, and they cross-neutralize a diverse range of group 1 influenza A viruses, including seasonal H1N1, 2009 pandemic H1N1 (H1N1pdm) and avian H5N1 and H9N2. The three HuMAbs were prepared by fusing peripheral blood lymphocytes from an H1N1pdm-infected patient with a newly developed fusion partner cell line, SPYMEG. All the HuMAbs had little hemagglutination inhibition activity but had strong membrane-fusion inhibition activity against influenza viruses. A protease digestion assay showed the HuMAbs targeted commonly a short α-helix region in the stalk of the hemagglutinin. Furthermore, Ile45Phe and Glu47Gly double substitutions in the α-helix region made the HA unrecognizable by the HuMAbs. These two amino acid residues are highly conserved in the HAs of H1N1, H5N1 and H9N2 viruses. The HuMAbs reported here may be potential candidates for the development of therapeutic antibodies against group 1 influenza viruses.

  13. Nef decreases HIV-1 sensitivity to neutralizing antibodies that target the membrane-proximal external region of TMgp41.

    Directory of Open Access Journals (Sweden)

    Rachel P J Lai

    2011-12-01

    discovered activity for Nef has important implications for anti-HIV-1 immunity and AIDS pathogenesis.

  14. Novel Clostridium difficile Anti-Toxin (TcdA and TcdB Humanized Monoclonal Antibodies Demonstrate In Vitro Neutralization across a Broad Spectrum of Clinical Strains and In Vivo Potency in a Hamster Spore Challenge Model.

    Directory of Open Access Journals (Sweden)

    Hongyu Qiu

    Full Text Available Clostridium difficile (C. difficile infection (CDI is the main cause of nosocomial antibiotic-associated colitis and increased incidence of community-associated diarrhea in industrialized countries. At present, the primary treatment of CDI is antibiotic administration, which is effective but often associated with recurrence, especially in the elderly. Pathogenic strains produce enterotoxin, toxin A (TcdA, and cytotoxin, toxin B (TcdB, which are necessary for C. difficile induced diarrhea and gut pathological changes. Administration of anti-toxin antibodies provides an alternative approach to treat CDI, and has shown promising results in preclinical and clinical studies. In the current study, several humanized anti-TcdA and anti-TcdB monoclonal antibodies were generated and their protective potency was characterized in a hamster infection model. The humanized anti-TcdA (CANmAbA4 and anti-TcdB (CANmAbB4 and CANmAbB1 antibodies showed broad spectrum in vitro neutralization of toxins from clinical strains and neutralization in a mouse toxin challenge model. Moreover, co-administration of humanized antibodies (CANmAbA4 and CANmAbB4 cocktail provided a high level of protection in a dose dependent manner (85% versus 57% survival at day 22 for 50 mg/kg and 20 mg/kg doses, respectively in a hamster gastrointestinal infection (GI model. This study describes the protective effects conferred by novel neutralizing anti-toxin monoclonal antibodies against C. difficile toxins and their potential as therapeutic agents in treating CDI.

  15. Performance comparison of the 4th generation Bio-Rad Laboratories GS HIV Combo Ag/Ab EIA on the EVOLIS™ automated system versus Abbott ARCHITECT HIV Ag/Ab Combo, Ortho Anti-HIV 1+2 EIA on Vitros ECi and Siemens HIV-1/O/2 enhanced on Advia Centaur.

    Science.gov (United States)

    Mitchell, Elizabeth O; Stewart, Greg; Bajzik, Olivier; Ferret, Mathieu; Bentsen, Christopher; Shriver, M Kathleen

    2013-12-01

    A multisite study was conducted to evaluate the performance of the Bio-Rad 4th generation GS HIV Combo Ag/Ab EIA versus Abbott 4th generation ARCHITECT HIV Ag/Ab Combo. The performance of two 3rd generation EIAs, Ortho Diagnostics Anti-HIV 1+2 EIA and Siemens HIV 1/O/2 was also evaluated. Study objective was comparison of analytical HIV-1 p24 antigen detection, sensitivity in HIV-1 seroconversion panels, specificity in blood donors and two HIV false reactive panels. Analytical sensitivity was evaluated with International HIV-1 p24 antigen standards, the AFFSAPS (pg/mL) and WHO 90/636 (IU/mL) standards; sensitivity in acute infection was compared on 55 seroconversion samples, and specificity was evaluated on 1000 negative blood donors and two false reactive panels. GS HIV Combo Ag/Ab demonstrated better analytical HIV antigen sensitivity compared to ARCHITECT HIV Ag/Ab Combo: 0.41 IU/mL versus 1.2 IU/mL (WHO) and 12.7 pg/mL versus 20.1 pg/mL (AFSSAPS); GS HIV Combo Ag/Ab EIA also demonstrated slightly better specificity compared to ARCHITECT HIV Ag/Ab Combo (100% versus 99.7%). The 4th generation HIV Combo tests detected seroconversion 7-11 days earlier than the 3rd generation HIV antibody only EIAs. Both 4th generation immunoassays demonstrated excellent performance in sensitivity, with the reduction of the serological window period (7-11 days earlier detection than the 3rd generation HIV tests). However, GS HIV Combo Ag/Ab demonstrated improved HIV antigen analytical sensitivity and slightly better specificity when compared to ARCHITECT HIV Ag/Ab Combo assay, with higher positive predictive values (PPV) for low prevalence populations. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. The anti-HIV-1 effect of scutellarin

    International Nuclear Information System (INIS)

    Zhang Gaohong; Wang Qian; Chen Jijun; Zhang Xuemei; Tam, S.-C.; Zheng Yongtang

    2005-01-01

    Scutellarin was purified from the plant Erigeron breviscapus (Vant.) Hand.-Mazz. The activity against 3 strains of human immunodeficiency virus (HIV) was determined in vitro in this study. These were laboratory-derived virus (HIV-1 IIIB ), drug-resistant virus (HIV-1 74V ), and low-passage clinical isolated virus (HIV-1 KM018 ). From syncytia inhibition study, the EC 50 of scutellarin against HIV-1 IIIB direct infection in C8166 cells was 26 μM with a therapeutic index of 36. When the mode of infection changed from acute infection to cell-to-cell infection, this compound became even more potent and the EC 50 reduced to 15 μM. This suggested that cell fusion might be affected by this compound. By comparing the inhibitory effects on p24 antigen, scutellarin was also found to be active against HIV-1 74V (EC 50 253 μM) and HIV-1 KM018 (EC 50 136 μM) infection with significant difference in potency. The mechanism of its action was also explored in this study. At a concentration of 433 μM, scutellarin inhibited 48% of the cell free recombinant HIV-1 RT activity. It also caused 82% inhibition of HIV-1 particle attachment and 45% inhibition of fusion at the concentrations of 54 μM. In summary, scutellarin was found to inhibit several strains of HIV-1 replication with different potencies. It appeared to inhibit HIV-1 RT activity, HIV-1 particle attachment and cell fusion. These are essential activities for viral transmission and replication

  17. Induction of human immunodeficiency virus neutralizing antibodies using fusion complexes.

    Science.gov (United States)

    Zipeto, Donato; Matucci, Andrea; Ripamonti, Chiara; Scarlatti, Gabriella; Rossolillo, Paola; Turci, Marco; Sartoris, Silvia; Tridente, Giuseppe; Bertazzoni, Umberto

    2006-05-01

    Human immunodeficiency virus-1 (HIV-1) infects cells by membrane fusion that is mediated by the envelope proteins gp120/gp41 and the cellular receptors CD4 and CCR5. During this process, some conserved viral epitopes are temporarily exposed and may induce a neutralizing antibody response when fixed in the fusogenic conformation. These transient structures are conserved and may be effective antigens for use in an anti-HIV-1 vaccine. In this study we tested different conditions of preparation of fusion complexes inducing neutralizing antibodies against both R5 and X4 tropic HIV-1 strains. Cell lines expressing HIV-1 gp120/gp41 and CD4-CCR5 were prepared and conditions for producing fusion complexes were tested. Complexes produced at different temperature and fixative combinations were used to immunize mice. Results indicated that (a) fusion complexes prepared at either 21 degrees C, 30 degrees C or 37 degrees C were immunogenic and induced neutralizing antibodies against both R5 and X4 HIV-1 heterologous isolates; (b) after extensive purification of antibodies there was no cytotoxic effect; (c) complexes prepared at 37 degrees C were more immunogenic and induced higher titers of neutralizing antibodies than complexes prepared at either 21 degrees C or 30 degrees C; (d) the fixative used did not affect the titer of neutralizing antibodies except for glutaraldehyde which was ineffective; (e) the neutralizing activity was retained after CD4-CCR5 antibody removal. The production of higher titers of neutralizing antibody with fusion complexes prepared at 37 degrees C, as compared to lower temperatures, may be related to the induction of antibodies against many different conformation intermediates that subsequently act synergistically at different steps in the fusion process.

  18. A replicating modified vaccinia tiantan strain expressing an avian-derived influenza H5N1 hemagglutinin induce broadly neutralizing antibodies and cross-clade protective immunity in mice.

    Directory of Open Access Journals (Sweden)

    Haixia Xiao

    Full Text Available To combat the possibility of a zoonotic H5N1 pandemic in a timely fashion, it is necessary to develop a vaccine that would confer protection against homologous and heterologous human H5N1 influenza viruses. Using a replicating modified vaccinia virus Tian Tan strain (MVTT as a vaccine vector, we constructed MVTTHA-QH and MVTTHA-AH, which expresses the H5 gene of a goose-derived Qinghai strain A/Bar-headed Goose/Qinghai/1/2005 or human-derived Anhui Strain A/Anhui/1/2005. The immunogenicity profiles of both vaccine candidates were evaluated. Vaccination with MVTTHA-QH induced a significant level of neutralizing antibodies (Nabs against a homologous strain and a wide range of H5N1 pseudoviruses (clades 1, 2.1, 2.2, 2.3.2, and 2.3.4. Neutralization tests (NT and Haemagglutination inhibition (HI antibodies inhibit the live autologous virus as well as a homologous A/Xingjiang/1/2006 and a heterologous A/Vietnam/1194/2004, representing two human isolates from clade 2.2 and clade 1, respectively. Importantly, mice vaccinated with intranasal MVTTHA-QH were completely protected from challenge with lethal dosages of A/Bar-headed Goose/Qinghai/1/2005 and the A/Viet Nam/1194/2004, respectively, but not control mice that received a mock MVTTS vaccine. However, MVTTHA-AH induced much lower levels of NT against its autologous strain. Our results suggest that it is feasible to use the H5 gene from A/Bar-headed Goose/Qinghai/1/2005 to construct an effective vaccine, when using MVTT as a vector, to prevent infections against homologous and genetically divergent human H5N1 influenza viruses.

  19. Neutral currents

    International Nuclear Information System (INIS)

    Paschos, E.A.

    1977-01-01

    It is stated that over the past few years considerable progress has been made in the field of weak interactions. The existence of neutral currents involving leptons and hadrons has been established and some of the questions concerning their detailed structure have been answered. This imposes constraints on the gauge theories and has eliminated large classes of models. New questions have also been raised, one of which concerns the conservation laws obeyed by neutral currents. The wide range of investigations is impressive and is expected to continue with new results from particle, nuclear, and atomic physics. Headings include - various aspects of a gauge theory (choice of group, the symmetry breaking scheme, representation assignments for fermion fields); space-time structure; isospin structure; leptonic neutral currents; and atomic experiments. (U.K.)

  20. Neutral currents

    International Nuclear Information System (INIS)

    Aubert, B.

    1994-11-01

    The evidence for the existence of weak neutral current has been a very controverted topics in the early 1970's, as well as the muon did in the 1930's. The history is very rich considering the evolution of the experimental techniques in high energy particle physics. The history of the discovery and the study of weak neutral current is reviewed. Later the quest of the intermediate vector boson continues with the decision of the community to build a large proton antiproton collider. (K.A.). 14 refs., 1 fig

  1. Broad-spectrum inhibition of HIV-1 by a monoclonal antibody directed against a gp120-induced epitope of CD4.

    Science.gov (United States)

    Burastero, Samuele E; Frigerio, Barbara; Lopalco, Lucia; Sironi, Francesca; Breda, Daniela; Longhi, Renato; Scarlatti, Gabriella; Canevari, Silvana; Figini, Mariangela; Lusso, Paolo

    2011-01-01

    To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs) directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env) bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Κ) was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T-cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1.

  2. Broad-spectrum inhibition of HIV-1 by a monoclonal antibody directed against a gp120-induced epitope of CD4.

    Directory of Open Access Journals (Sweden)

    Samuele E Burastero

    Full Text Available To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Κ was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T-cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1.

  3. The 2010 Broad Prize

    Science.gov (United States)

    Education Digest: Essential Readings Condensed for Quick Review, 2011

    2011-01-01

    A new data analysis, based on data collected as part of The Broad Prize process, provides insights into which large urban school districts in the United States are doing the best job of educating traditionally disadvantaged groups: African-American, Hispanics, and low-income students. Since 2002, The Eli and Edythe Broad Foundation has awarded The…

  4. Broad spectrum bioactive sunscreens.

    Science.gov (United States)

    Velasco, Maria Valéria Robles; Sarruf, Fernanda Daud; Salgado-Santos, Idalina Maria Nunes; Haroutiounian-Filho, Carlos Alberto; Kaneko, Telma Mary; Baby, André Rolim

    2008-11-03

    The development of sunscreens containing reduced concentration of chemical UV filters, even though, possessing broad spectrum effectiveness with the use of natural raw materials that improve and infer UV absorption is of great interest. Due to the structural similarities between polyphenolic compounds and organic UV filters, they might exert photoprotection activity. The objective of the present research work was to develop bioactive sunscreen delivery systems containing rutin, Passiflora incarnata L. and Plantago lanceolata extracts associated or not with organic and inorganic UV filters. UV transmission of the sunscreen delivery system films was performed by using diffuse transmittance measurements coupling to an integrating sphere. In vitro photoprotection efficacy was evaluated according to the following parameters: estimated sun protection factor (SPF); Boot's Star Rating category; UVA/UVB ratio; and critical wavelength (lambda(c)). Sunscreen delivery systems obtained SPF values ranging from 0.972+/-0.004 to 28.064+/-2.429 and bioactive compounds interacted with the UV filters positive and negatively. This behavior may be attributed to: the composition of the delivery system; the presence of inorganic UV filter and quantitative composition of the organic UV filters; and the phytochemical composition of the P. incarnata L. and P. lanceolata extracts. Among all associations of bioactive compounds and UV filters, we found that the broad spectrum sunscreen was accomplished when 1.68% (w/w) P. incarnata L. dry extract was in the presence of 7.0% (w/w) ethylhexyl methoxycinnamate, 2.0% (w/w) benzophenone-3 and 2.0% (w/w) TiO(2). It was demonstrated that this association generated estimated SPF of 20.072+/-0.906 and it has improved the protective defense against UVA radiation accompanying augmentation of the UVA/UVB ratio from 0.49 to 0.52 and lambda(c) from 364 to 368.6nm.

  5. Anti-HIV-1 activity of anionic polymers: a comparative study of candidate microbicides

    Directory of Open Access Journals (Sweden)

    Li Yun-Yao

    2002-11-01

    Full Text Available Abstract Background Cellulose acetate phthalate (CAP in soluble form blocks coreceptor binding sites on the virus envelope glycoprotein gp120 and elicits gp41 six-helix bundle formation, processes involved in virus inactivation. CAP is not soluble at pH Methods Enzyme linked immunosorbent assays (ELISA were used to (1 study HIV-1 IIIB and BaL binding to micronized CAP; (2 detect virus disintegration; and (3 measure gp41 six-helix bundle formation. Cells containing integrated HIV-1 LTR linked to the β-gal gene and expressing CD4 and coreceptors CXCR4 or CCR5 were used to measure virus infectivity. Results 1 HIV-1 IIIB and BaL, respectively, effectively bound to micronized CAP. 2 The interaction between HIV-1 and micronized CAP led to: (a gp41 six-helix bundle formation; (b virus disintegration and shedding of envelope glycoproteins; and (c rapid loss of infectivity. Polymers other than CAP, except Carbomer 974P, elicited gp41 six-helix bundle formation in HIV-1 IIIB but only poly(napthalene sulfonate, in addition to CAP, had this effect on HIV-1 BaL. These polymers differed with respect to their virucidal activities, the differences being more pronounced for HIV-1 BaL. Conclusions Micronized CAP is the only candidate topical microbicide with the capacity to remove rapidly by adsorption from physiological fluids HIV-1 of both the X4 and R5 biotypes and is likely to prevent virus contact with target cells. The interaction between micronized CAP and HIV-1 leads to rapid virus inactivation. Among other anionic polymers, cellulose sulfate, BufferGel and aryl sulfonates appear most effective in this respect.

  6. The C-terminal sequence of IFITM1 regulates its anti-HIV-1 activity.

    Directory of Open Access Journals (Sweden)

    Rui Jia

    Full Text Available The interferon-inducible transmembrane (IFITM proteins inhibit a wide range of viruses. We previously reported the inhibition of human immunodeficiency virus type 1 (HIV-1 strain BH10 by human IFITM1, 2 and 3. It is unknown whether other HIV-1 strains are similarly inhibited by IFITMs and whether there exists viral countermeasure to overcome IFITM inhibition. We report here that the HIV-1 NL4-3 strain (HIV-1NL4-3 is not restricted by IFITM1 and its viral envelope glycoprotein is partly responsible for this insensitivity. However, HIV-1NL4-3 is profoundly inhibited by an IFITM1 mutant, known as Δ(117-125, which is deleted of 9 amino acids at the C-terminus. In contrast to the wild type IFITM1, which does not affect HIV-1 entry, the Δ(117-125 mutant diminishes HIV-1NL4-3 entry by 3-fold. This inhibition correlates with the predominant localization of Δ(117-125 to the plasma membrane where HIV-1 entry occurs. In spite of strong conservation of IFITM1 among most species, mouse IFITM1 is 19 amino acids shorter at its C-terminus as compared to human IFITM1 and, like the human IFITM1 mutant Δ(117-125, mouse IFITM1 also inhibits HIV-1 entry. This is the first report illustrating the role of viral envelope protein in overcoming IFITM1 restriction. The results also demonstrate the importance of the C-terminal region of IFITM1 in modulating the antiviral function through controlling protein subcellular localization.

  7. Anti-HIV-1 integrase activity of medicinal plants used as self medication by AIDS patients

    Directory of Open Access Journals (Sweden)

    Sopa Kummee

    2006-07-01

    Full Text Available The extracts of selected medicinal plants used as self medication by AIDS patients were investigated for their inhibitory activities against HIV-1 integrase (HIV-1 IN using the multiplate integration assay (MIA. Of these, the water extract of Eclipta prostrata (whole plant exhibited the most potent inhibitory activity with an IC50 value of 4.8 μg/ml, followed by the methanol extract of Eclipta prostrata (whole plant, IC50 = 21.1 μg/ ml, the water extract of Barleria lupulina (stem, IC50 = 26.4 μg/ml, the chloroform extract of Barleria lupulina (stem, IC50 = 33.0 μg/ml, the methanol extract of Barleria lupulina (stem, IC50 = 38.2 μg/ml and the chloroform extract of Piper betle (leaf, IC50 = 39.3 μg/ml, respectively.

  8. Interferon-Inducible CD169/Siglec1 Attenuates Anti-HIV-1 Effects of Alpha Interferon

    Science.gov (United States)

    Akiyama, Hisashi; Ramirez, Nora-Guadalupe Pina; Gibson, Gregory; Kline, Christopher; Watkins, Simon; Ambrose, Zandrea

    2017-01-01

    ABSTRACT A hallmark of human immunodeficiency virus type 1 (HIV-1) infection in vivo is chronic immune activation concomitant with type I interferon (IFN) production. Although type I IFN induces an antiviral state in many cell types, HIV-1 can replicate in vivo via mechanisms that have remained unclear. We have recently identified a type I IFN-inducible protein, CD169, as the HIV-1 attachment factor on dendritic cells (DCs) that can mediate robust infection of CD4+ T cells in trans. Since CD169 expression on macrophages is also induced by type I IFN, we hypothesized that type I IFN-inducible CD169 could facilitate productive HIV-1 infection in myeloid cells in cis and CD4+ T cells in trans and thus offset antiviral effects of type I IFN. In support of this hypothesis, infection of HIV-1 or murine leukemia virus Env (MLV-Env)-pseudotyped HIV-1 particles was enhanced in IFN-α-treated THP-1 monocytoid cells, and this enhancement was primarily dependent on CD169-mediated enhancement at the virus entry step, a phenomenon phenocopied in HIV-1 infections of IFN-α-treated primary monocyte-derived macrophages (MDMs). Furthermore, expression of CD169, a marker of type I IFN-induced immune activation in vivo, was enhanced in lymph nodes from pigtailed macaques infected with simian immunodeficiency virus (SIV) carrying HIV-1 reverse transcriptase (RT-SHIV), compared to uninfected macaques, and interestingly, there was extensive colocalization of p27gag and CD169, suggesting productive infection of CD169+ myeloid cells in vivo. While cell-free HIV-1 infection of IFN-α-treated CD4+ T cells was robustly decreased, initiation of infection in trans via coculture with CD169+ IFN-α-treated DCs restored infection, suggesting that HIV-1 exploits CD169 in cis and in trans to attenuate a type I IFN-induced antiviral state. IMPORTANCE HIV-1 infection in humans causes immune activation characterized by elevated levels of proinflammatory cytokines, including type I interferons (IFN). Although type I IFN induces an antiviral state in many cell types in vitro, HIV-1 can replicate in vivo via mechanisms that have remained unclear. In this study, we tested the hypothesis that CD169, a type I IFN-inducible HIV-1 attachment factor, offsets antiviral effects of type I IFN. Infection of HIV-1 was rescued in IFN-α-treated myeloid cells via upregulation of CD169 and a subsequent increase in CD169-dependent virus entry. Furthermore, extensive colocalization of viral Gag and CD169 was observed in lymph nodes of infected pigtailed macaques, suggesting productive infection of CD169+ cells in vivo. Treatment of dendritic cell (DC)-T cell cocultures with IFN-α upregulated CD169 expression on DCs and rescued HIV-1 infection of CD4+ T cells in trans, suggesting that HIV-1 exploits CD169 to attenuate type I IFN-induced restrictions. PMID:28794041

  9. New findings on the d(TGGGAG) sequence: Surprising anti-HIV-1 activity.

    Science.gov (United States)

    Romanucci, Valeria; Zarrelli, Armando; Liekens, Sandra; Noppen, Sam; Pannecouque, Christophe; Di Fabio, Giovanni

    2018-02-10

    The biological relevance of tetramolecular G-quadruplexes especially as anti-HIV agents has been extensively reported in the literature over the last years. In the light of our recent results regarding the slow G-quadruplex folding kinetics of ODNs based on d(TGGGAG) sequence, here we report a systematic anti-HIV screening to investigate the impact of the G-quadruplex folding on their anti-HIV activity. In particular, varying the single stranded concentrations of ODNs, it has been tested a pool of ODN sample solutions with different G-quadruplex concentrations. The anti-HIV assays have been designed favouring the limited kinetics involved in the tetramolecular G4-association based on the d(TGGGAG) sequence. Aiming to determine the stoichiometry of G-quadruplex structures in the same experimental conditions of the anti-HIV assays, a native gel electrophoresis was performed. The gel confirmed the G-quadruplex formation for almost all sample solutions while showing the formation of high order G4 structures for the more concentrated ODNs solutions. The most significant result is the discovery of a potent anti-HIV activity of the G-quadruplex formed by the natural d(TGGGAG) sequence (IC 50  = 14 nM) that, until now, has been reported to be completely inactive against HIV infection. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  10. Synthesis and Anti-HIV-1 Evaluation of New Sonogashira-Modified Emivirine (MKC-442) Analogues

    DEFF Research Database (Denmark)

    Danel, Krzystof; Jørgensen, Per Trolle; La Colla, Paolo

    2009-01-01

    The MKC-442 analogue 6-(3,5-dimethylbenzyl)-5-ethyluracil substituted with a (propargyloxo)methyl group at N(1) has previously been found highly active against HIV-1. The C C bond in the substituent at N(1) is here utilized in a series of chemical reactions in order to develop new agents with hig......The MKC-442 analogue 6-(3,5-dimethylbenzyl)-5-ethyluracil substituted with a (propargyloxo)methyl group at N(1) has previously been found highly active against HIV-1. The C C bond in the substituent at N(1) is here utilized in a series of chemical reactions in order to develop new agents...... with higher activity against HIV-1-resistant mutants. The syntheses involved Pd-catalyzed C,C-coupling reactions, addition of disulfides, and click chemistry on the terminal C C bond as well as addition of bromine to the so formed internal C C bonds. Sonogashira coupling were performed with silyl...

  11. New anti-HIV-1, antimalarial, and antifungal compounds from Terminalia bellerica

    DEFF Research Database (Denmark)

    Valsaraj, R; Pushpangadan, P; Smitt, U W

    1997-01-01

    A bioactivity-guided fractionation of an extract of Terminalia bellerica fruit rind led to the isolation of two new lignans named termilignan (1) and thannilignan (2), together with 7-hydroxy-3',4'-(methylenedioxy)flavan (3) and anolignan B (4). All four compounds possessed demonstrable anti-HIV-......, antimalarial, and antifungal activity in vitro....

  12. Anti-HIV-1 activities of the extracts from the medicinal plant Linum grandiflorum Desf

    DEFF Research Database (Denmark)

    Mohammed, Magdy M. D.; Christensen, Lars Porskjær; Ibrahim, Nabaweya A.

    2009-01-01

    As part of our screening of anti-AIDS agents from natural sources e.g. Ixora undulata, Paulownia tomentosa, Fortunella margarita, Aegle marmelos and Erythrina abyssinica, the different organic and aqueous extracts of Linum grandiflorum leaves and seeds were evaluated in vitro by the microculture...... tetrazolium (MTT) assay. The activity of the tested extracts against multiplication of HIV-1 wild type IIIB, N119, A17, and EFVR in acutely infected cells was based on inhibition of virus-induced cytopathicity in MT-4 cells. Results revealed that both the MeOH and the CHCl3 extracts of L. grandiflorum have...... significant inhibitory effects against HIV-1 induced infection with MT-4 cells. The MeOH extract of the leaves is more potent than other extracts against MT-4 cell cultures infected with the wild type HIV-1, strain IIIB with an ED50 of 46 ± 6 µM, while the CHCl3 extract of the seeds is more potent than other...

  13. Feline Immunodeficiency Virus (FIV Neutralization: A Review

    Directory of Open Access Journals (Sweden)

    Margaret J. Hosie

    2011-10-01

    Full Text Available One of the major obstacles that must be overcome in the design of effective lentiviral vaccines is the ability of lentiviruses to evolve in order to escape from neutralizing antibodies. The primary target for neutralizing antibodies is the highly variable viral envelope glycoprotein (Env, a glycoprotein that is essential for viral entry and comprises both variable and conserved regions. As a result of the complex trimeric nature of Env, there is steric hindrance of conserved epitopes required for receptor binding so that these are not accessible to antibodies. Instead, the humoral response is targeted towards decoy immunodominant epitopes on variable domains such as the third hypervariable loop (V3 of Env. For feline immunodeficiency virus (FIV, as well as the related human immunodeficiency virus-1 (HIV-1, little is known about the factors that lead to the development of broadly neutralizing antibodies. In cats infected with FIV and patients infected with HIV-1, only rarely are plasma samples found that contain antibodies capable of neutralizing isolates from other clades. In this review we examine the neutralizing response to FIV, comparing and contrasting with the response to HIV. We ask whether broadly neutralizing antibodies are induced by FIV infection and discuss the comparative value of studies of neutralizing antibodies in FIV infection for the development of more effective vaccine strategies against lentiviral infections in general, including HIV-1.

  14. Neutral atom traps of radioactives

    International Nuclear Information System (INIS)

    Behr, J.A.

    2003-01-01

    Neutral atoms trapped with modern laser cooling techniques offer the promise of improving several broad classes of experiments with radioactive isotopes. In nuclear β decay, neutrino spectroscopy from beta-recoil coincidences, along with highly polarized samples, enable experiments to search for non-Standard Model interactions, test whether parity symmetry is maximally violated, and search for new sources of time reversal violation. Ongoing efforts at TRIUMF, Los Alamos and Berkeley will be highlighted. The traps also offer bright sources for Doppler-free spectroscopy, particularly in high-Z atoms where precision measurements could measure the strength of weak neutral nucleon-nucleon and electron-nucleon interactions. Physics with francium atoms has been vigorously pursued at Stony Brook. Several facilities plan work with radioactive atom traps; concrete plans and efforts at KVI Groningen and Legnaro will be among those summarized. Contributions to the multidisciplinary field of trace analysis will be left up to other presenters

  15. Neutral atom traps of radioactives

    CERN Document Server

    Behr, J A

    2003-01-01

    Neutral atoms trapped with modern laser cooling techniques offer the promise of improving several broad classes of experiments with radioactive isotopes. In nuclear beta decay, neutrino spectroscopy from beta-recoil coincidences, along with highly polarized samples, enable experiments to search for non-Standard Model interactions, test whether parity symmetry is maximally violated, and search for new sources of time reversal violation. Ongoing efforts at TRIUMF, Los Alamos and Berkeley will be highlighted. The traps also offer bright sources for Doppler-free spectroscopy, particularly in high-Z atoms where precision measurements could measure the strength of weak neutral nucleon-nucleon and electron-nucleon interactions. Physics with francium atoms has been vigorously pursued at Stony Brook. Several facilities plan work with radioactive atom traps; concrete plans and efforts at KVI Groningen and Legnaro will be among those summarized. Contributions to the multidisciplinary field of trace analysis will be left...

  16. Neutral Buoyancy Laboratory (NBL)

    Data.gov (United States)

    Federal Laboratory Consortium — The Neutral Buoyancy Laboratory (NBL) is an astronaut training facility and neutral buoyancy pool operated by NASA and located at the Sonny Carter Training Facility,...

  17. Broad band exciplex dye lasers

    International Nuclear Information System (INIS)

    Dienes, A.; Shank, C.V.; Trozzolo, A.M.

    1975-01-01

    The disclosure is concerned with exciplex dye lasers, i.e., lasers in which the emitting species is a complex formed only from a constituent in an electronically excited state. Noting that an exciplex laser, favorable from the standpoint of broad tunability, results from a broad shift in the peak emission wavelength for the exciplex relative to the unreacted species, a desirable class resulting in such broad shift is described. Preferred classes of laser media utilizing specified resonant molecules are set forth. (auth)

  18. Study of neutral particles

    International Nuclear Information System (INIS)

    Bartel, W.; Bulos, F.; Eisner, A.

    1975-01-01

    The range of physics problems for which a detector emphasizing neutrals is most suitable is discussed. The primary goals are the all neutrals cross section, sigma/sub o/ (e + e - → neutrals), the characterization of the neutral energy in multi-hadronic events, the search for monoenergetic photons, and good sensitivity in the difficult region of low energy photons. Those features of multi-hadronic events which are most relevant to a neutral detector were calculated using a jet model with parameters extrapolated from SPEAR energies. These distributions are presented and discussed

  19. Neutral theory and the species abundance distribution: recent developments and prospects for unifying niche and neutral perspectives

    Science.gov (United States)

    Matthews, Thomas J; Whittaker, Robert J

    2014-01-01

    Published in 2001, The Unified Neutral Theory of Biodiversity and Biogeography (UNTB) emphasizes the importance of stochastic processes in ecological community structure, and has challenged the traditional niche-based view of ecology. While neutral models have since been applied to a broad range of ecological and macroecological phenomena, the majority of research relating to neutral theory has focused exclusively on the species abundance distribution (SAD). Here, we synthesize the large body of work on neutral theory in the context of the species abundance distribution, with a particular focus on integrating ideas from neutral theory with traditional niche theory. First, we summarize the basic tenets of neutral theory; both in general and in the context of SADs. Second, we explore the issues associated with neutral theory and the SAD, such as complications with fitting and model comparison, the underlying assumptions of neutral models, and the difficultly of linking pattern to process. Third, we highlight the advances in understanding of SADs that have resulted from neutral theory and models. Finally, we focus consideration on recent developments aimed at unifying neutral- and niche-based approaches to ecology, with a particular emphasis on what this means for SAD theory, embracing, for instance, ideas of emergent neutrality and stochastic niche theory. We put forward the argument that the prospect of the unification of niche and neutral perspectives represents one of the most promising future avenues of neutral theory research. PMID:25360266

  20. Neutral theory and the species abundance distribution: recent developments and prospects for unifying niche and neutral perspectives.

    Science.gov (United States)

    Matthews, Thomas J; Whittaker, Robert J

    2014-06-01

    Published in 2001, The Unified Neutral Theory of Biodiversity and Biogeography (UNTB) emphasizes the importance of stochastic processes in ecological community structure, and has challenged the traditional niche-based view of ecology. While neutral models have since been applied to a broad range of ecological and macroecological phenomena, the majority of research relating to neutral theory has focused exclusively on the species abundance distribution (SAD). Here, we synthesize the large body of work on neutral theory in the context of the species abundance distribution, with a particular focus on integrating ideas from neutral theory with traditional niche theory. First, we summarize the basic tenets of neutral theory; both in general and in the context of SADs. Second, we explore the issues associated with neutral theory and the SAD, such as complications with fitting and model comparison, the underlying assumptions of neutral models, and the difficultly of linking pattern to process. Third, we highlight the advances in understanding of SADs that have resulted from neutral theory and models. Finally, we focus consideration on recent developments aimed at unifying neutral- and niche-based approaches to ecology, with a particular emphasis on what this means for SAD theory, embracing, for instance, ideas of emergent neutrality and stochastic niche theory. We put forward the argument that the prospect of the unification of niche and neutral perspectives represents one of the most promising future avenues of neutral theory research.

  1. On neutral plasma oscillations

    International Nuclear Information System (INIS)

    Shadwick, B.A.; Morrison, P.J.

    1993-06-01

    We examine the conditions for the existence of spectrally stable neutral modes in a Vlasov-Poisson plasma and show that for stable equilibria of systems that have unbounded spatial domain, the only possible neutral modes are those with phase velocities that correspond to stationary inflection points of the equilibrium distribution function. It is seen that these neutral modes can possess positive or negative free energy

  2. Neutral beam monitoring

    International Nuclear Information System (INIS)

    Fink, J.H.

    1979-01-01

    A neutral beam generated by passing accelerated ions through a walled cell containing a low energy neutral gas, such that charge exchange partially neutralizes the high energy beam, is monitored by detecting the current flowing through the cell wall produced by low energy ions which drift to the wall after the charge exchange. By segmenting the wall into radial and longitudinal segments various beam conditions are identified. (U.K.)

  3. On neutral plasma oscillations

    International Nuclear Information System (INIS)

    Shadwick, B.A.; Texas Univ., Austin; Morrison, P.J.; Texas Univ., Austin

    1994-01-01

    We examine the conditions for the existence of spectrally stable neutral modes in a Vlasov-Poisson plasma and show that for stable equilibria of systems that have unbounded spatial domain, the only possible neutral modes are those with phase velocities that correspond to stationary inflection points of the equilibrium distribution function. It is seen that these neutral modes can posses positive or negative free energy. (orig.)

  4. Search for neutral leptons

    International Nuclear Information System (INIS)

    Perl, M.L.

    1984-12-01

    At present we know of three kinds of neutral leptons: the electron neutrino, the muon neutrino, and the tau neutrino. This paper reviews the search for additional neutral leptons. The method and significance of a search depends upon the model used for the neutral lepton being sought. Some models for the properties and decay modes of proposed neutral leptons are described. Past and present searches are reviewed. The limits obtained by some completed searches are given, and the methods of searches in progress are described. Future searches are discussed. 41 references

  5. Neutralized transport experiment

    International Nuclear Information System (INIS)

    Roy, P.K.; Yu, S.S.; Eylon, S.; Henestroza, E.; Anders, A.; Gilson, E.P.; Bieniosek, F.M.; Greenway, W.G.; Logan, B.G.; Waldron, W.L.; Shuman, D.B.; Vanecek, D.L.; Welch, D.R.; Rose, D.V.; Thoma, C.; Davidson, R.C.; Efthimion, P.C.; Kaganovich, I.; Sefkow, A.B.; Sharp, W.M.

    2005-01-01

    Experimental details on providing active neutralization of high brightness ion beam have been demonstrated for Heavy Ion Fusion program. A K + beam was extracted from a variable-perveance injector and transported through 2.4 m long quadrupole lattice for final focusing. Neutralization was provided by a localized cathode arc plasma plug and a RF volume plasma system. Effects of beam perveance, emittance, convergence focusing angle, and axial focusing position on neutralization have been investigated. Good agreement has been observed with theory and experiment throughout the study

  6. Are "Market Neutral" Hedge Funds Really Market Neutral?

    OpenAIRE

    Andrew J. Patton

    2009-01-01

    Using a variety of different definitions of "neutrality," this study presents significant evidence against the neutrality to market risk of hedge funds in a range of style categories. I generalize standard definitions of "market neutrality," and propose five different neutrality concepts. I suggest statistical tests for each neutrality concept, and apply these tests to a database of monthly returns on 1423 hedge funds from five style categories. For the "market neutral" style, approximately o...

  7. Bunched beam neutralization

    International Nuclear Information System (INIS)

    Gammel, G.M.; Maschke, A.W.; Mobley, R.M.

    1979-01-01

    One of the steps involved in producing an intense ion beam from conventional accelerators for Heavy Ion Fusion (HIF) is beam bunching. To maintain space charge neutralized transport, neutralization must occur more quickly as the beam bunches. It has been demonstrated at BNL that a 60 mA proton beam from a 750 kV Cockcroft--Walton can be neutralized within a microsecond. The special problem in HIF is that the neutralization must occur in a time scale of nanoseconds. To study neutralization on a faster time scale, a 40 mA, 450 kV proton beam was bunched at 16 MHz. A biased Faraday cup sampled the bunched beam at the position where maximum bunching was nominally expected, about 2.5 meters from the buncher. Part of the drift region, about 1.8 meters, was occupied by a series of Gabor lenses. In addition to enhancing beam transport by transverse focussing, the background cloud of electrons in the lenses provided an extra degree of neutralization. With no lens, the best bunch factor was at least 20. Bunch factor is defined here as the ratio of the distance between bunches to the FWHM bunch length. With the lens, it was hoped that the increased plasma frequency would decrease the neutralization time and cause an increase in the bunch factor. In fact, with the lens, the instantaneous current increased about three times, but the bunch factor dropped to about 10. Even with the lens, the FWHM of the bunches at the position of maximum bunching was still comparable to or less than the oscillation period of the surrounding electron plasma. Thus, the electron density in the lens must increase before neutralization could be effective in this case, or bunching should be done at a lower frequency

  8. Formation of broad Balmer wings in symbiotic stars

    International Nuclear Information System (INIS)

    Chang, Seok-Jun; Heo, Jeong-Eun; Hong, Chae-Lin; Lee, Hee-Won

    2016-01-01

    Symbiotic stars are binary systems composed of a hot white dwarf and a mass losing giant. In addition to many prominent emission lines symbiotic stars exhibit Raman scattered O VI features at 6825 and 7088 Å. Another notable feature present in the spectra of many symbiotics is the broad wings around Balmer lines. Astrophysical mechanisms that can produce broad wings include Thomson scattering by free electrons and Raman scattering of Ly,β and higher series by neutral hydrogen. In this poster presentation we produce broad wings around Hα and H,β adopting a Monte Carlo techinique in order to make a quantitative comparison of these two mechanisms. Thomson wings are characterized by the exponential cutoff given by the termal width whereas the Raman wings are dependent on the column density and continuum shape in the far UV region. A brief discussion is provided. (paper)

  9. Evolution of the HIV-1 Envelope Glycoprotein Genes and Neutralizing Antibody Response in an Individual with Broadly Cross Neutralizing Antibodies

    Science.gov (United States)

    2010-08-31

    1994, 140: 1 05-130. 51. Pantaleo G, Graziosi C, Demarest JF, Butini L, Montroni M, Fox CH, Orenstein JM, Kotler DP, Fauci AS: HIV infection is...Pizzo PA, Schnittman SM, Kotler DP, Fauci AS: Lymphoid organs function as major reservoirs for human immunodeficiency virus. Proc Natl Acad Sci US

  10. Neutral beam development plan

    International Nuclear Information System (INIS)

    Staten, H.S.

    1980-08-01

    The national plan is presented for developing advanced injection systems for use on upgrades of existing experiments, and use on future facilities such as ETF, to be built in the late 1980's or early 90's where power production from magnetic fusion will move closer to a reality. Not only must higher power and longer pulse length systems be developed , but they must operate reliably; they must be a tool for the experimenter, not the experiment itself. Neutral beam systems handle large amounts of energy and as such, they often are as complicated as the plasma physics experiment itself. This presents a significant challenge to the neutral beam developer

  11. Neutral beam program

    International Nuclear Information System (INIS)

    Anon.

    1979-01-01

    The structure of the beam injection program for the Doublet-3 device is discussed. The design considerations for the beam line and design parameters for the Doublet-3 ion souce are given. Major components of the neutral beam injector system are discussed in detail. These include the neutralizer, magnetic shielding, reflecting magnets, vacuum system, calorimeter and beam dumps, and drift duct. The planned location of the two-injector system for Doublet-3 is illustrated and site preparation is considered. The status of beamline units 1 and 2 and the future program schedule are discussed

  12. Neutral Community Dynamics and the Evolution of Species Interactions.

    Science.gov (United States)

    Coelho, Marco Túlio P; Rangel, Thiago F

    2018-04-01

    A contemporary goal in ecology is to determine the ecological and evolutionary processes that generate recurring structural patterns in mutualistic networks. One of the great challenges is testing the capacity of neutral processes to replicate observed patterns in ecological networks, since the original formulation of the neutral theory lacks trophic interactions. Here, we develop a stochastic-simulation neutral model adding trophic interactions to the neutral theory of biodiversity. Without invoking ecological differences among individuals of different species, and assuming that ecological interactions emerge randomly, we demonstrate that a spatially explicit multitrophic neutral model is able to capture the recurrent structural patterns of mutualistic networks (i.e., degree distribution, connectance, nestedness, and phylogenetic signal of species interactions). Nonrandom species distribution, caused by probabilistic events of migration and speciation, create nonrandom network patterns. These findings have broad implications for the interpretation of niche-based processes as drivers of ecological networks, as well as for the integration of network structures with demographic stochasticity.

  13. Mod en neutral seksualitet!

    DEFF Research Database (Denmark)

    Leer, Jonatan

    2013-01-01

    Towards a Neutral Sexuality! or Roland Barthes as a Queer Thinker? This article argues that the work of Roland Barthes has interesting perspectives in common with the queer theory. This argument will be put forward by using his concept of ‘the neutral’ that Barthes defines as “that which outplays...

  14. Issues in neutral currents

    International Nuclear Information System (INIS)

    Sehgal, L.M.

    1980-01-01

    The experimental results on low energy confirming the structure of the effective Lagrangian of the weak neutral current processes as predicted by the Salam-Weinberg model are reviewed. Some possible modifications of the effective Lagrangian and the feasibility of their experimental verification are also considered. (P.L.)

  15. ITER neutral beam system

    International Nuclear Information System (INIS)

    Mondino, P.L.; Di Pietro, E.; Bayetti, P.

    1999-01-01

    The Neutral Beam (NB) system for the International Thermonuclear Experimental Reactor (ITER) has reached a high degree of integration with the tokamak and with the rest of the plant. Operational requirements and maintainability have been considered in the design. The paper considers the integration with the tokamak, discusses design improvements which appear necessary and finally notes R and D progress in key areas. (author)

  16. Neutral theory of chemical reaction networks

    International Nuclear Information System (INIS)

    Lee, Sang Hoon; Holme, Petter; Minnhagen, Petter; Bernhardsson, Sebastian; Kim, Beom Jun

    2012-01-01

    To what extent do the characteristic features of a chemical reaction network reflect its purpose and function? In general, one argues that correlations between specific features and specific functions are key to understanding a complex structure. However, specific features may sometimes be neutral and uncorrelated with any system-specific purpose, function or causal chain. Such neutral features are caused by chance and randomness. Here we compare two classes of chemical networks: one that has been subjected to biological evolution (the chemical reaction network of metabolism in living cells) and one that has not (the atmospheric planetary chemical reaction networks). Their degree distributions are shown to share the very same neutral system-independent features. The shape of the broad distributions is to a large extent controlled by a single parameter, the network size. From this perspective, there is little difference between atmospheric and metabolic networks; they are just different sizes of the same random assembling network. In other words, the shape of the degree distribution is a neutral characteristic feature and has no functional or evolutionary implications in itself; it is not a matter of life and death. (paper)

  17. Broad-Application Test Reactor

    International Nuclear Information System (INIS)

    Motloch, C.G.

    1992-05-01

    This report is about a new, safe, and operationally efficient DOE reactor of nuclear research and testing proposed for the early to mid- 21st Century. Dubbed the Broad-Application Test Reactor (BATR), the proposed facility incorporates a multiple-application, multiple-mission design to support DOE programs such as naval reactors and space power and propulsion, as well as research in medical, science, isotope, and electronics arenas. DOE research reactors are aging, and implementing major replacement projects requires long lead times. Primary design drivers include safety, low risk, minimum operation cost, mission flexibility, waste minimization, and long life. Scientists and engineers at the Idaho National Engineering Laboratory are evaluating possible fuel forms, structural materials, reactor geometries, coolants, and moderators

  18. Broad-band beam buncher

    International Nuclear Information System (INIS)

    Goldberg, D.A.; Flood, W.S.; Arthur, A.A.; Voelker, F.

    1986-01-01

    This patent describes a broad-band beam buncher. This beam buncher consists of: a housing adapted to be eacuated, an electron gun in the housing for producing a beam of electrons, buncher means in the housing forming a buncher cavity which has an entrance opening for receiving the electron beam and an exit opening through which the electron beam passes out of the buncher cavity, a drift tube electrode in the buncher cavity and disposed between the entrance opening and the exit opening with first and second gaps between the drift tube electrode and the entrance and exit openings, the drift tube electrode which has a first drift space through which the electron beam passes in traveling between the entrance and exit openings, modulating means for supplying an ultrahigh frequeny modulating signal to the drift tube electrode for producing velocity modulation of the electrons in the electron beam as the electrons pass through the buncher cavity and the drift tube electrode between the entrance opening and the exit opening, drift space means in the housing forming a second drift space for receiving the velocity modulated electron beam from the exit opening, the velocity modulated electron beam being bunched as it passes along the second drift space, the drift space means has a discharge opening through which the electron beam is discharged from the second drift space after being bunched therein, the modulating means containing a signal source for producing an ultrahigh frequency signal, a transmission line connected between the signal source and the drift tube electrode, and terminating means connected to the drift tube electrode for terminating the transmission line in approximately its characteristic impedance to afford a broad response band with minimum 6 variations therein

  19. Antihypertensive neutral lipid

    Science.gov (United States)

    Snyder, F.L.; Blank, M.L.

    1984-10-26

    The invention relates to the discovery of a class of neutral acetylated either-linked glycerolipids having the capacity to lower blood presure in warm-blooded animals. This physiological effect is structure sensitive requiring a long chain alkyl group at the sn-1 position and a short carbon chain acyl group (acetyl or propionyl) at the sn-2 position, and a hydroxyl group at the sn-3 position.

  20. Exercise Equipment: Neutral Buoyancy

    Science.gov (United States)

    Shackelford, Linda; Valle, Paul

    2016-01-01

    Load Bearing Equipment for Neutral Buoyancy (LBE-NB) is an exercise frame that holds two exercising subjects in position as they apply counter forces to each other for lower extremity and spine loading resistance exercises. Resistance exercise prevents bone loss on ISS, but the ISS equipment is too massive for use in exploration craft. Integrating the human into the load directing, load generating, and motion control functions of the exercise equipment generates safe exercise loads with less equipment mass and volume.

  1. Neutral beams for mirrors

    International Nuclear Information System (INIS)

    Fink, J.H.

    1983-01-01

    An important demonstration of negative ion technology is proposed for FY92 in the MFTF-α+T, an upgrade of the Mirror Fusion Test Facility at the Lawrence Livermore National Laboratory. This facility calls for 200-keV negative ions to form neutral beams that generate sloshing ions in the reactor end plugs. Three different beam lines are considered for this application. Their advantages and disadvantages are discussed

  2. Gargamelle: neutral current event

    CERN Multimedia

    1973-01-01

    This event shows real tracks of particles from the 1200 litre Gargamelle bubble chamber that ran on the PS from 1970 to 1976 and on the SPS from 1976 to 1979. In this image a neutrino passes close to a nucleon and reemerges as a neutrino. Such events are called neutral curent, as they are mediated by the Z0 boson which has no electric charge.

  3. Excitation of the inner 4d shell of neutral iodine

    Energy Technology Data Exchange (ETDEWEB)

    Pettini, M; Tozzi, G P [Osservatorio Astrofisico di Arcetri, Florence (Italy); Mazzoni, M [Florence Univ. (Italy). Ist. di Astronomia

    1981-03-23

    The absorption spectrum of neutral atomic iodine has been photographed in the EUV region and three strong autoionized resonances have been identified. A broad absorption feature has been observed and is ascribed to a collective exitation of the 4d inner shell.

  4. Climate Neutral Campus Key Terms and Definitions | Climate Neutral Research

    Science.gov (United States)

    Campuses | NREL Neutral Campus Key Terms and Definitions Climate Neutral Campus Key Terms and Definitions The term climate neutral evolved along with net zero and a number of other "green" and accuracy in these areas lets research campuses know exactly how close they are to climate

  5. Synthesis and Anti-HIV-1 Activity of New MKC-442 Analogues with an Alkynyl-Substituted 6-Benzyl Group

    DEFF Research Database (Denmark)

    Aly, Youssef L.; Pedersen, Erik Bjerreg.; La Colla, Paolo

    2007-01-01

    Synthesis and antiviral activities are reported of a series of 6-(3-alkynyl benzyl)-substituted analogues of MKC-442 (6-benzyl-1-(ethoxymethyl)-5-isopropyluracil), a highly potent agent against HIV. The 3-alkynyl group is assumed to give a better stacking of the substituted benzyl group to reverse...... transcriptase (RT) and this was believed to improve antiviral activity against HIV-1. The bromo derivatives, 5-alkyl-6-(3-bromo-benzyl)-1-ethoxymethyl derivatives 7a, b and 5-alkyl-6-(3-bromobenzyl)-1-allyloxymethyl derivatives 9a, b, showed activity against HIV on the same level as their corresponding...

  6. Detection of anti-HIV-1 IgG antibodies in whole saliva by GACELISA and Western blot assays.

    Science.gov (United States)

    Matee, M I; Lyamuya, E F; Simon, E; Mbena, E C; Kagoma, C; Samaranayake, L P; Scheutz, F

    1996-05-01

    The present study, based on 158 HIV seropositives and 167 HIV seronegatives, demonstrates that saliva collected with the Omni-SAL device and tested with GACELISA (an IgG antibody capture ELISA) is an effective non-invasive alternative to serum for anti-HIV IgG antibody screening. The study also shows that a conventional serum Western blot kit can be used, with slight modifications, for confirmatory testing of saliva specimens. Collecting saliva with the Omni-SAL device had a very good acceptance rate among Tanzanian subjects, and although this diagnostic method is not yet known by the general public, 65% of the study participants preferred to give saliva instead of blood for HIV testing.

  7. A trypsin inhibitor from rambutan seeds with antitumor, anti-HIV-1 reverse transcriptase, and nitric oxide-inducing properties.

    Science.gov (United States)

    Fang, Evandro Fei; Ng, Tzi Bun

    2015-04-01

    Nephelium lappaceum L., commonly known as "rambutan," is a typical tropical tree and is well known for its juicy and sweet fruit which has an exotic flavor. Chemical studies on rambutan have led to the identification of various components such as monoterpene lactones and volatile compounds. Here, a 22.5-kDa trypsin inhibitor (N . lappaceum trypsin inhibitor (NLTI)) was isolated from fresh rambutan seeds using liquid chromatographical techniques. NLTI reduced the proteolytic activities of both trypsin and α-chymotrypsin. Dithiothreitol reduced the trypsin inhibitory activity of NLTI at a concentration of 1 mM, indicating that an intact disulfide bond is essential to the activity. NLTI inhibited HIV-1 reverse transcriptase with an IC50 of 0.73 μM. In addition, NLTI manifested a time- and dose-dependent inhibitory effect on growth in many tumor cells. NLTI is one of the few trypsin inhibitors with nitric oxide-inducing activity and may find application in tumor therapy.

  8. Qualitative and quantitative intravaginal targeting: Key to anti-HIV-1 microbicide delivery from test tube to in vivo success

    CSIR Research Space (South Africa)

    Pillay, V

    2012-06-01

    Full Text Available employed. We hereby propose a thorough scientific qualitative and quantitative investigation of important aspects involved in HIV-1 transmission as a prerequisite for microbicide delivery. Intravaginal targeting of HIV-1 increases the chances of microbicide...

  9. Arzanol, an anti-inflammatory and anti-HIV-1 phloroglucinol alpha-Pyrone from Helichrysum italicum ssp. microphyllum.

    Science.gov (United States)

    Appendino, Giovanni; Ottino, Michela; Marquez, Nieves; Bianchi, Federica; Giana, Anna; Ballero, Mauro; Sterner, Olov; Fiebich, Bernd L; Munoz, Eduardo

    2007-04-01

    An acetone extract of Helichrysum italicum ssp. microphyllum afforded the phloroglucinol alpha-pyrone arzanol (1a) as a potent NF-kappaB inhibitor. Arzanol is identical with homoarenol (2a), whose structure should be revised. The phloroglucinol-type structure of arzanol and the 1,2,4-trihydroxyphenyl-type structure of the base-induced fragmentation product of homoarenol could be reconciled in light of a retro-Fries-type fragmentation that triggers a change of the hydroxylation pattern of the aromatic moiety. On the basis of these findings, the structure of arenol, the major constituent of the clinically useful antibiotic arenarin, should be revised from 2b to 1b, solving a long-standing puzzle over its biogenetic derivation. An alpha-pyrone (micropyrone, 7), the monoterpene rac-E-omega-oleoyloxylinalol (10), four known tremetones (9a-d), and the dimeric pyrone helipyrone (8) were also obtained. Arzanol inhibited HIV-1 replication in T cells and the release of pro-inflammatory cytokines in LPS-stimulated primary monocytes, qualifying as a novel plant-derived anti-inflammatory and antiviral chemotype worth further investigation.

  10. Anti-HIV-1 and cytotoxicity of a new dimeric thiazepine alkaloid isolated from Ixora undulata Roxb. leaves

    DEFF Research Database (Denmark)

    Mohammed, Magdy M.D.; Mohamed, Khaled M.

    2017-01-01

    The crude alkaloidal extract of Ixora undulata Roxb. leaves recorded a cytotoxicity of IC50 = 125 µg/mL against EL4 and revealed a reduction with CC50 = 47 µg/mL in the viability of MT-4 cells, beside a 50% protection with EC50 > 47 µg/mL against HIV-1IIIB. Bioassay guided fractionation...

  11. Broad Neutralization of Ebolaviruses via a Fusion Loop Epitope Elicited by Immunization

    Science.gov (United States)

    2017-03-31

    abnormalities as well as petechial rash at the time of death (Kozak et al., 2016). We show that two doses of the CA45/FVM04 cocktail were fully protective...Schmaljohn, C., and Huggins, J. (1999). A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever . J Infect Dis 179 Suppl...assessment. Genome Res 21, 1746-1756. Feldmann, H., and Geisbert, T.W. (2011). Ebola haemorrhagic fever . Lancet 377, 849-862. Flyak, A.I., Shen, X

  12. Bremsstrahlung and neutral currents

    International Nuclear Information System (INIS)

    Ellis, R.G.; McKellar, B.H.J.

    1979-01-01

    The utility of the bremsstrahlung process in detecting parity violations from V-A weak neutral current interference is analysed in two ways. Firstly, bremsstrahlung from polarized lepton-nucleus scattering has an asymmetry with respect to the polarization of the incident leptons, and secondly, bremsstrahlung from unpolarized lepton nucleus scattering has a small circular polarization. The magnitude of each effect is calculated. The ratio of the parity violating contribution and the parity conserving contribution to the cross section is shown to be a misleading measure of the utility of these experiments. A parameter, the figure of merit, is introduced and used to discuss the feasibility of possible experiments

  13. 78 FR 20119 - Broad Stakeholder Survey

    Science.gov (United States)

    2013-04-03

    ... DEPARTMENT OF HOMELAND SECURITY [Docket No. DHS-2012-0042] Broad Stakeholder Survey AGENCY... concerning the Broad Stakeholder Survey. DHS previously published this ICR in the Federal Register on August... across the Nation. The Broad Stakeholder Survey is designed to gather stakeholder feedback on the...

  14. Plasma neutralizer for H- beams

    International Nuclear Information System (INIS)

    Grossman, M.W.

    1977-01-01

    Neutralization of H - beams by a hydrogen plasma is discussed. Optimum target thickness and maximum neutralization efficiency as a function of the fraction of the hydrogen target gas ionized is calculated for different H - beam energies. Also, the variation of neutralization efficiency with respect to target thickness for different H - beam energies is computed. The dispersion of the neutralized beam by a magnetic field for different energies and different values of B . z is found. Finally, a type of plasma jet is proposed, which may be suitable for a compact H - neutralizer

  15. Neutral helium beam probe

    Science.gov (United States)

    Karim, Rezwanul

    1999-10-01

    This article discusses the development of a code where diagnostic neutral helium beam can be used as a probe. The code solves numerically the evolution of the population densities of helium atoms at their several different energy levels as the beam propagates through the plasma. The collisional radiative model has been utilized in this numerical calculation. The spatial dependence of the metastable states of neutral helium atom, as obtained in this numerical analysis, offers a possible diagnostic tool for tokamak plasma. The spatial evolution for several hypothetical plasma conditions was tested. Simulation routines were also run with the plasma parameters (density and temperature profiles) similar to a shot in the Princeton beta experiment modified (PBX-M) tokamak and a shot in Tokamak Fusion Test Reactor tokamak. A comparison between the simulation result and the experimentally obtained data (for each of these two shots) is presented. A good correlation in such comparisons for a number of such shots can establish the accurateness and usefulness of this probe. The result can possibly be extended for other plasma machines and for various plasma conditions in those machines.

  16. Spectroscopy of neutral radium

    Energy Technology Data Exchange (ETDEWEB)

    Mol, Aran; De, Subhadeep; Jungmann, Klaus; Wilschut, Hans; Willmann, Lorenz [KVI, University of Groningen, Groningen (Netherlands)

    2008-07-01

    The heavy alkaline earth atoms radium is uniquely sensitive towards parity and time reversal symmetry violations due to a large enhancement of an intrinsic permanent electric dipole moment of the nucleous or the electron. Furthermore, radium is sensitive to atomic parity violation and the nuclear anapole moment. To prepare such experiments spectroscopy of relevant atomic states need to be done. At a later stage we will build a neutral atom trap for radium. We have built an atomic beam of the short lived isotope {sup 225}Ra with a flux of several 10{sup 4} atoms/sec. We are preparing the laser spectroscopy using this beam setup. In the preparation for efficient laser cooling and trapping we have successfully trapped barium, which is similar in it's requirements for laser cooling. The techniques which we have developed with barium can be used to trap rare radium isotopes. We report on the progress of the experiments.

  17. Neutralization potential as an assay of alkalinity of environmental solids

    International Nuclear Information System (INIS)

    Grube, W.E.Jr.; Ammons, J.T.

    1993-01-01

    The method to determine neutralizing equivalence of agricultural limestone has been applied to quantify the amount of bases present in a broad diversity of mineral materials, solid reagents, and products involved in environmental processes. The capacity to neutralize native or imposed acidity must be known in many processes in order to preserve near-neutral material. The standard method for assaying agricultural limestones was adapted to quantify native alkalinity in calcareous rocks exposed by coal surface mining. Data from these analyses continue to provide the surface mining industry and regulating agencies with a measure of the extent to which acidic mine drainage may be neutralized by the natural components of surrounding rock strata and disturbed materials. This approach to determine base content has also been applied to commercially available industrial byproducts added to soils or wastes. Kiln dust, fly ash, sludge, and other additives have been evaluated routinely to measure their alkalinity contribution and also batch-to-batch uniformity. The application of this technique to monitor amounts of reagents added to neutralize acid waste materials by adding alkalis is discussed. Use of this procedure to evaluate different materials is documented with exemplary data. Results of analyses of a broad variety of rock and soil materials, amended soils, soil additives or amendments, industrial waste byproducts, sludge, and treated wastes are presented. Utility of the procedure for routine quality control in soil treatment, amendment uniformity, and product analysis is discussed

  18. Net neutrality and audiovisual services

    OpenAIRE

    van Eijk, N.; Nikoltchev, S.

    2011-01-01

    Net neutrality is high on the European agenda. New regulations for the communication sector provide a legal framework for net neutrality and need to be implemented on both a European and a national level. The key element is not just about blocking or slowing down traffic across communication networks: the control over the distribution of audiovisual services constitutes a vital part of the problem. In this contribution, the phenomenon of net neutrality is described first. Next, the European a...

  19. LADEE Neutral Mass Spectrometer Data

    Data.gov (United States)

    National Aeronautics and Space Administration — This bundle contains the data collected by the Neutral Mass Spectrometer (NMS) instrument aboard the Lunar Atmosphere and Dust Environment Explorer (LADEE)...

  20. Phenomenology of neutral current interactions

    International Nuclear Information System (INIS)

    Sakurai, J.J.

    1978-01-01

    Neutral-current interactions are discussed within a rather general phenomenological framework without commitment to any particular theoretical model. Three points are kept in mind: what various experiments really measure; the performing of complete experiments to determine the neutral-current couplings; and the testing of models in an objective, emotionally uninvolved manner. The following topics are considered: neutrino-electron scattering, hadronic currents and models, neutrino-induced inclusive hadronic reactions, neutrino-induced exclusive hadronic reactions, and neutral-current phenomena without neutrinos. In conclusion, what has actually been learned about neutral-current interactions is summarized. 9 figures, 2 tables

  1. HIV-1 binding and neutralizing antibodies of injecting drug users

    Directory of Open Access Journals (Sweden)

    E.P. Ouverney

    2005-09-01

    Full Text Available Previous studies have demonstrated a stronger seroreactivity against some synthetic peptides responsible for inducing neutralizing antibodies in injecting drug users (IDU compared to that of individuals sexually infected with HIV-1 (S, but the effectiveness in terms of the neutralizing ability of these antibodies has not been evaluated. Our objective was to study the humoral immune response of IDU by determining the specificity of their antibodies and the presence of neutralizing antibodies. The neutralization capacity against the HIV-1 isolate MN (genotype B, the primary HIV-1 isolate 95BRRJ021 (genotype F, and the seroreactivity with peptides known to induce neutralizing antibodies, from the V2 and V3 loops of different HIV-1 subtypes, were analyzed. Seroreactivity indicates that IDU plasma are more likely to recognize a broader range of peptides than S plasma, with significantly higher titers, especially of V3 peptides. Similar neutralization frequencies of the MN isolate were observed in plasma of the IDU (16/47 and S (20/60 groups in the 1:10 dilution. The neutralization of the 95BRRJ021 isolate was more frequently observed for plasma from the S group (15/23 than from the IDU group (15/47, P = 0.0108. No correlation between neutralization and seroreactivity with the peptides tested was observed. These results suggest that an important factor responsible for the extensive and broad humoral immune response observed in IDU is their infection route. There was very little difference in neutralizing antibody response between the IDU and S groups despite their differences in seroreactivity and health status.

  2. On becoming neutral: effects of experimental neutralizing reconsidered.

    Science.gov (United States)

    van den Hout, M; van Pol, M; Peters, M

    2001-12-01

    Behaviour Research and Therapy 34 (1996) 889-898 found that writing out a negative thought produced anxiety and an urge to neutralize the thought, that instructing participants to neutralize the thought reduced anxiety/neutralization urge in the short run (i.e. within 2 min), but that in the control group 20 min without instruction was attended by the same reduction in anxiety/urge to neutralize ("natural decay"). The observations were made with pariticipants who scored high on "thought action fusion" and the experiment was set up as exerimental model of obsessions. We repeated the study with participants that were not selected on thought action fusion. All the findings reported by Behaviour Research and Therapy 34 (1996) 889-898 were replicated. Correlational analysis indicated that the strength of the effect was not related to scores on scales measuring "thought action fusion". Behaviour Research and Therapy 34 (1996) 889-898 did not assess whether non-neutralizing was followed by immediate reductions in distress. We did assess this and found that the larger part of the immediate reduction of distress after neutralization also occurs when no neutralization instruction is given. The effects of neutralization instructions in the present type of experiment are considerably less powerful than suggested earlier.

  3. CO2-neutral fuels

    Directory of Open Access Journals (Sweden)

    Goede A. P. H.

    2015-01-01

    Full Text Available The need for storage of renewable energy (RE generated by photovoltaic, concentrated solar and wind arises from the fact that supply and demand are ill-matched both geographically and temporarily. This already causes problems of overcapacity and grid congestion in countries where the fraction of RE exceeds the 20% level. A system approach is needed, which focusses not only on the energy source, but includes conversion, storage, transport, distribution, use and, last but not least, the recycling of waste. Furthermore, there is a need for more flexibility in the energy system, rather than relying on electrification, integration with other energy systems, for example the gas network, would yield a system less vulnerable to failure and better adapted to requirements. For example, long-term large-scale storage of electrical energy is limited by capacity, yet needed to cover weekly to seasonal demand. This limitation can be overcome by coupling the electricity net to the gas system, considering the fact that the Dutch gas network alone has a storage capacity of 552 TWh, sufficient to cover the entire EU energy demand for over a month. This lecture explores energy storage in chemicals bonds. The focus is on chemicals other than hydrogen, taking advantage of the higher volumetric energy density of hydrocarbons, in this case methane, which has an approximate 3.5 times higher volumetric energy density. More importantly, it allows the ready use of existing gas infrastructure for energy storage, transport and distribution. Intermittent wind electricity generated is converted into synthetic methane, the Power to Gas (P2G scheme, by splitting feedstock CO2 and H2O into synthesis gas, a mixture of CO and H2. Syngas plays a central role in the synthesis of a range of hydrocarbon products, including methane, diesel and dimethyl ether. The splitting is accomplished by innovative means; plasmolysis and high-temperature solid oxygen electrolysis. A CO2-neutral fuel

  4. Anti-gp120 minibody gene transfer to female genital epithelial cells protects against HIV-1 virus challenge in vitro.

    Directory of Open Access Journals (Sweden)

    Ussama M Abdel-Motal

    Full Text Available Although cervico-vaginal epithelial cells of the female lower genital tract provide the initial defense system against HIV-1 infection, the protection is sometimes incomplete. Thus, enhancing anti-HIV-1 humoral immunity at the mucosal cell surface by local expression of anti-HIV-1 broadly neutralizing antibodies (BnAb that block HIV-1 entry would provide an important new intervention that could slow the spread of HIV/AIDS.This study tested the hypothesis that adeno-associated virus (AAV-BnAb gene transfer to cervico-vaginal epithelial cells will lead to protection against HIV-1. Accordingly, a recombinant AAV vector that encodes human b12 anti-HIV gp120 BnAb as a single-chain variable fragment Fc fusion (scFvFc, or "minibody" was constructed. The secreted b12 minibody was shown to be biologically functional in binding to virus envelope protein, neutralizing HIV-1 and importantly, blocking transfer and infectivity of HIV-1(bal in an organotypic human vaginal epithelial cell (VEC model. Furthermore, cervico-vaginal epithelial stem cells were found to be efficiently transduced by the optimal AAV serotype mediated expression of GFP.This study provides the foundation for a novel microbicide strategy to protect against sexual transmission of HIV-1 by AAV transfer of broadly neutralizing antibody genes to cervico-vaginal epithelial stem cells that could replenish b12 BnAb secreting cells through multiple menstrual cycles.

  5. Electromagnetic radiation optimum neutralizer

    International Nuclear Information System (INIS)

    Smirnov, Igor

    2002-01-01

    This particular article relates to subtle electrical effects, and provides some evidence of a fundamental nature on how subtle low frequency electromagnetic fields might be utilized to protect human body against harmful effects of high frequencies electromagnetic radiation. I have focused my efforts on definite polar polymer compound named EMRON which is patented in the USA. This polar polymer compound can be excited by external high frequencies electromagnetic fields to generate subtle low frequency oscillations that are beneficial for cellular life structures. This concept is based on the possibility of existence of resonance phenomenon between polar polymers and biopolymers such as proteins, nucleic acids, lipids, etc. Low frequency patterns generated by defined polar polymer compound can interact with biostructures and transmit the signals that support and improve cellular functions in the body. The mechanism of this process was confirmed by number of studies. The animal (including human) brain is affected by electromagnetic waves to the extent that production of Alpha or Theta waves can be directly induced into brain by carrying an ELF (extremely low frequency, 5-12 Hz) signal on a microwave carrier frequency. EMRON does not reduce the power of electromagnetic fields. It 'shields' the cellular structures of the body against the harmful effects of EMR. The radiation is still entering the body but the neutralizing effect of EMRON renders the radiation harmless

  6. Is science metaphysically neutral?

    Science.gov (United States)

    Fry, Iris

    2012-09-01

    This paper challenges the claim that science is metaphysically neutral upheld by contenders of the separation of peacefully co-existent science and religion and by evolutionary theists. True, naturalistic metaphysical claims can neither be refuted nor proved and are thus distinct from empirical hypotheses. However, metaphysical assumptions not only regulate the theoretical and empirical study of nature, but are increasingly supported by the growing empirical body of science. This historically evolving interaction has contributed to the development of a naturalistic worldview that renounces the necessity of a transcendent god and of purposeful design. The thesis presented here differs not only from the claims of the "separatists" and of evolutionary theists. In pointing to the metaphysical aspects of science, I also criticize the failure of some evolutionary naturalists to distinguish between empirical and metaphysical contentions. Most important, based on the examination of science suggested here, creationists' false accusation that science is only a naturalistic dogma is refuted. Finally, the difficulties involved in the position endorsed here for the public support of evolution are acknowledged, taking into account the high religious profile of the American society and the social and political context in the US and in other countries. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. The merits of neutral theory

    NARCIS (Netherlands)

    Alonso, D.; Etienne, R.S.; McKane, A.J.

    2006-01-01

    Hubbell's neutral theory of biodiversity has challenged the classic niche-based view of ecological community structure. Although there have been many attempts to falsify Hubbell's theory, we argue that falsification should not lead to rejection, because there is more to the theory than neutrality

  8. Neutral evolution of mutational robustness

    NARCIS (Netherlands)

    Nimwegen, Erik van; Crutchfield, James P.; Huynen, Martijn

    1999-01-01

    We introduce and analyze a general model of a population evolving over a network of selectively neutral genotypes. We show that the population s limit distribution on the neutral network is solely determined by the network topology and given by the principal eigenvector of the network

  9. Net neutrality and audiovisual services

    NARCIS (Netherlands)

    van Eijk, N.; Nikoltchev, S.

    2011-01-01

    Net neutrality is high on the European agenda. New regulations for the communication sector provide a legal framework for net neutrality and need to be implemented on both a European and a national level. The key element is not just about blocking or slowing down traffic across communication

  10. Broad Prize: Do the Successes Spread?

    Science.gov (United States)

    Samuels, Christina A.

    2011-01-01

    When the Broad Prize for Urban Education was created in 2002, billionaire philanthropist Eli Broad said he hoped the awards, in addition to rewarding high-performing school districts, would foster healthy competition; boost the prestige of urban education, long viewed as dysfunctional; and showcase best practices. Over the 10 years the prize has…

  11. 77 FR 50144 - Broad Stakeholder Survey

    Science.gov (United States)

    2012-08-20

    ... DEPARTMENT OF HOMELAND SECURITY [Docket No. DHS-2012-0042] Broad Stakeholder Survey AGENCY... Information Collection Request: 1670-NEW. SUMMARY: The Department of Homeland Security (DHS), National... (Pub. L. 104-13, 44 U.S.C. Chapter 35). NPPD is soliciting comments concerning the Broad Stakeholder...

  12. 76 FR 34087 - Broad Stakeholder Survey

    Science.gov (United States)

    2011-06-10

    ... DEPARTMENT OF HOMELAND SECURITY [Docket No. DHS-2011-0027] Broad Stakeholder Survey AGENCY... Information Collection Request: 1670-NEW. SUMMARY: The Department of Homeland Security (DHS), National... (Pub. L. 104-13, 44 U.S.C. Chapter 35). NPPD is soliciting comments concerning the Broad Stakeholder...

  13. Is an inequality-neutral flat tax reform really neutral?

    OpenAIRE

    Juan Prieto Rodríguez; Juan Gabriel Rodríguez; Rafael Salas

    2004-01-01

    . Let us assume a revenue- and inequality-neutral flat tax reform shifting from a graduated-rate tax. Is this reform really neutral in terms of the income distribution? Traditionally, there has been a bias toward the inequality analysis, forgetting other relevant aspects of the income distribution. This kind of reforms implies a set of composite transfers, both progressive and regressive, even though inequality remains unchanged. This paper shows that polarization is a useful tool for charact...

  14. Neutrality Versus Materiality: A Thermodynamic Theory of Neutral Surfaces

    Directory of Open Access Journals (Sweden)

    Rémi Tailleux

    2016-09-01

    Full Text Available In this paper, a theory for constructing quasi-neutral density variables γ directly in thermodynamic space is formulated, which is based on minimising the absolute value of a purely thermodynamic quantity J n . Physically, J n has a dual dynamic/thermodynamic interpretation as the quantity controlling the energy cost of adiabatic and isohaline parcel exchanges on material surfaces, as well as the dependence of in-situ density on spiciness, in a description of water masses based on γ, spiciness and pressure. Mathematically, minimising | J n | in thermodynamic space is showed to be equivalent to maximising neutrality in physical space. The physics of epineutral dispersion is also reviewed and discussed. It is argued, in particular, that epineutral dispersion is best understood as the aggregate effect of many individual non-neutral stirring events (being understood here as adiabatic and isohaline events with non-zero buoyancy, so that it is only the net displacement aggregated over many events that is approximately neutral. This new view resolves an apparent paradox between the focus in neutral density theory on zero-buoyancy motions and the overwhelming evidence that lateral dispersion in the ocean is primarily caused by non-zero buoyancy processes such as tides, residual currents and sheared internal waves. The efficiency by which a physical process contributes to lateral dispersion can be characterised by its energy signature, with those processes releasing available potential energy (negative energy cost being more efficient than purely neutral processes with zero energy cost. The latter mechanism occurs in the wedge of instability, and its source of energy is the coupling between baroclinicity, thermobaricity, and density compensated temperature/salinity anomalies. Such a mechanism, which can only exist in a salty ocean, is speculated to be important for dissipating spiciness anomalies and neutral helicity. The paper also discusses potential

  15. Net Neutrality: Background and Issues

    National Research Council Canada - National Science Library

    Gilroy, Angele A

    2006-01-01

    .... The move to place restrictions on the owners of the networks that compose and provide access to the Internet, to ensure equal access and nondiscriminatory treatment, is referred to as "net neutrality...

  16. Weak neutral-current interactions

    International Nuclear Information System (INIS)

    Barnett, R.M.

    1978-08-01

    The roles of each type of experiment in establishing uniquely the values of the the neutral-current couplings of u and d quarks are analyzed together with their implications for gauge models of the weak and electromagnetic interactions. An analysis of the neutral-current couplings of electrons and of the data based on the assumption that only one Z 0 boson exists is given. Also a model-independent analysis of parity violation experiments is discussed. 85 references

  17. Assessment of effects of neutrals on the power threshold for L to H transitions in DIII-D

    International Nuclear Information System (INIS)

    Owen, L.W.; Carreras, B.A.; Maingi, R.; Mioduszewski, P.K.; Carlstrom, T.N.; Groebner, R.J.

    1998-01-01

    To assess the effect of edge neutrals on the low-to-high confinement transition threshold, a broad range of plasma discharges has been analyzed. From this analysis, the transition power divided by the density, at constant magnetic field, appears to be a function of a single parameter measuring the neutrals' effect. This results suggest that there is a missing parameter linked to the neutrals in the power threshold scaling laws

  18. Doppler-shifted neutral beam line shape and beam transmission

    International Nuclear Information System (INIS)

    Kamperschroer, J.H.; Grisham, L.R.; Kokatnur, N.; Lagin, L.J.; Newman, R.A.; O'Connor, T.E.; Stevenson, T.N.; von Halle, A.

    1994-04-01

    Analysis of Doppler-shifted Balmer-α line emission from the TFTR neutral beam injection systems has revealed that the line shape is well approximated by the sum of two Gaussians, or, alternatively, by a Lorentzian. For the sum of two Gaussians, the broad portion of the distribution contains 40% of the beam power and has a divergence five times that of the narrow part. Assuming a narrow 1/e- divergence of 1.3 degrees (based on fits to the beam shape on the calorimeter), the broad part has a divergence of 6.9 degrees. The entire line shape is also well approximated by a Lorentzian with a half-maximum divergence of 0.9 degrees. Up to now, fusion neutral beam modelers have assumed a single Gaussian velocity distribution, at the extraction plane, in each direction perpendicular to beam propagation. This predicts a beam transmission efficiency from the ion source to the calorimeter of 97%. Waterflow calorimetry data, however, yield a transmission efficiency of ∼75%, a value in rough agreement with predictions of the Gaussian or Lorentzian models presented here. The broad wing of the two Gaussian distribution also accurately predicts the loss in the neutralizer. An average angle of incidence for beam loss at the exit of the neutralizer is 2.2 degrees, rather than the 4.95 degrees subtended by the center of the ion source. This average angle of incidence, which is used in computing power densities on collimators, is shown to be a function of beam divergence

  19. Gas cell neutralizers (Fundamental principles)

    International Nuclear Information System (INIS)

    Fuehrer, B.

    1985-06-01

    Neutralizing an ion-beam of the size and energy levels involved in the neutral-particle-beam program represents a considerable extension of the state-of-the-art of neutralizer technology. Many different mediums (e.g., solid, liquid, gas, plasma, photons) can be used to strip the hydrogen ion of its extra electron. A large, multidisciplinary R and D effort will no doubt be required to sort out all of the ''pros and cons'' of these various techniques. The purpose of this particular presentation is to discuss some basic configurations and fundamental principles of the gas type of neutralizer cell. Particular emphasis is placed on the ''Gasdynamic Free-Jet'' neutralizer since this configuration has the potential of being much shorter than other type of gas cells (in the beam direction) and it could operate in nearly a continuous mode (CW) if necessary. These were important considerations in the ATSU design which is discussed in some detail in the second presentation entitled ''ATSU Point Design''

  20. Electromagnetic trapping of neutral atoms

    International Nuclear Information System (INIS)

    Metcalf, H.J.

    1986-01-01

    Cooling and trapping of neutral atoms is a new branch of applied physics that has potential for application in many areas. The authors present an introduction to laser cooling and magnetic trapping. Some basic ideas and fundamental limitations are discussed, and the first successful experiments are reviewed. Trapping a neutral object depends on the interaction between an inhomogeneous electromagnetic field and a multiple moment that results in the exchange of kinetic for potential energy. In neutral atom traps, the potential energy must be stored as internal atomic energy, resulting in two immediate and extremely important consequences. First, the atomic energy levels will necessarily shift as the atoms move in the trap, and, second, practical traps for ground state neutral atoms atr necessarily very shallow compared to thermal energy. This small depth also dictates stringent vacuum requirements because a trapped atom cannot survive a single collision with a thermal energy background gas molecule. Neutral trapping, therefore, depends on substantial cooling of a thermal atomic sample and is inextricably connected with the cooling process

  1. Evidence for a Broad Autism Phenotype

    NARCIS (Netherlands)

    K. de Groot (Kristel); J.W. van Strien (Jan)

    2017-01-01

    textabstractThe broad autism phenotype implies the existence of a continuum ranging from individuals displaying almost no autistic traits to severely impaired diagnosed individuals. Recent studies have linked this variation in autistic traits to several domains of functioning. However, studies

  2. 33 CFR 117.921 - Broad River.

    Science.gov (United States)

    2010-07-01

    ... OPERATION REGULATIONS Specific Requirements South Carolina § 117.921 Broad River. (a) The draw of the S170 bridge, mile 14.0 near Beaufort, shall open on signal if at least 24 hours notice is given. (b) The draw...

  3. Education and Broad Concepts of Agency

    Science.gov (United States)

    Winch, Christopher

    2014-01-01

    Drawing on recent debates about the relationship between propositional and practical knowledge, this article is concerned with broad concepts of agency. Specifically, it is concerned with agency that involves the forming and putting into effect of intentions over relatively extended periods, particularly in work contexts (called, for want of a…

  4. Measurement of plasma production and neutralization in gas neutralizers

    International Nuclear Information System (INIS)

    Maor, D.; Meron, M.; Johnson, B.; Jones, K.; Agagu, A.; Hu, B.

    1986-01-01

    In order to satisfy the need of experimental data for the designing of gas neutralizers we have started a project aimed at measuring all relevant cross sections for the charge exchange of H - , H 0 and H + projectiles, as well as the cross sections for the production of ions in the target. The expected results of these latter measurements are shown schematically

  5. Neutral currents in semileptonic reactions

    International Nuclear Information System (INIS)

    Paschos, E.A.

    1975-05-01

    The evidence for weak neutral currents is analyzed in semileptonic reactions with special emphasis on their Lorentz and internal symmetry structure. It is found that present observations are consistent with the expectations of gauge theories, but other possibilities can not be ruled out. Of particular interest in this respect is the presence of a large isoscalar component. The excitation of the Δ-resonance by neutral currents is analyzed, and pion-nucleon mass distributions are presented. Charge asymmetries sensitive to isoscalar-isovector interferences are discussed. (U.S.)

  6. Dust in the Diffuse Neutral Interstellar Medium

    Science.gov (United States)

    Sofia, Ulysses J.

    2008-05-01

    Studies of interstellar dust have always relied heavily upon Laboratory Astrophysics for interpretation. Laboratory values, in the broad sense that includes theory, are needed for the most basic act of measuring interstellar abundances, to the more complex determination of what grains are responsible for particular extinction. The symbiotic relationship between astronomical observations and Laboratory Astrophysics has prompted both fields to move forward, especially in the era of high-resolution ultraviolet spectroscopy when new elemental species could be interpreted and observations were able to show the limits of laboratory determinations. Thanks to this synergy, we currently have a good idea of the quantity of the most abundant elements incorporated into dust in diffuse neutral interstellar clouds: carbon, oxygen, iron, silicon and magnesium. Now the task is to figure out how, chemically and physically, those elements are integrated into interstellar grains. We can do this by comparing extinction curves to grain populations in radiative transfer models. The limitation at the present time is the availability of optical constants in the infrared through ultraviolet for species that are likely to exist in dust, i.e., those that are easy to form in the physical environments around stars and in molecular clouds. Extinction in some lines of sight can be fit within current abundance limits and with the optical constants that are available. However the inability to reproduce other extinction curves suggests that optical constants can be improved, either in quality for compounds that have been measured, or quantity in the sense of providing data for more materials. This talk will address the current state and the future of dust studies in the diffuse neutral interstellar medium. This work is supported by the grant HST-AR-10979.01-A from the Space Telescope Science Institute to Whitman College.

  7. Serum neutralizing activities from a Beijing homosexual male cohort infected with different subtypes of HIV-1 in China.

    Directory of Open Access Journals (Sweden)

    Mingshun Zhang

    Full Text Available Protective antibodies play a critical role in an effective HIV vaccine; however, eliciting antibodies to block infection by viruses from diverse genetic subtypes remains a major challenge. As the world's most populous country, China has been under the threat of at least three major subtypes of circulating HIV-1 viruses. Understanding the cross reactivity and specificities of serum antibody responses that mediate broad neutralization of the virus in HIV-1 infected Chinese patients will provide valuable information for the design of vaccines to prevent HIV-1 transmission in China. Sera from a cohort of homosexual men, who have been managed by a major HIV clinical center in Beijing, China, were analyzed for cross-sectional neutralizing activities against pseudotyped viruses expressing Env antigens of the major subtype viruses (AE, BC and B subtypes circulating in China. Neutralizing activities in infected patients' blood were most capable of neutralizing viruses in the homologous subtype; however, a subset of blood samples was able to achieve broad neutralizing activities across different subtypes. Such cross neutralizing activity took 1-2 years to develop and CD4 binding site antibodies were critical components in these blood samples. Our study confirmed the presence of broadly neutralizing sera in China's HIV-1 patient population. Understanding the specificity and breadth of these neutralizing activities can guide efforts for the development of HIV vaccines against major HIV-1 viruses in China.

  8. ITER Neutral Beam Injection System

    International Nuclear Information System (INIS)

    Ohara, Yoshihiro; Tanaka, Shigeru; Akiba, Masato

    1991-03-01

    A Japanese design proposal of the ITER Neutral Beam Injection System (NBS) which is consistent with the ITER common design requirements is described. The injection system is required to deliver a neutral deuterium beam of 75MW at 1.3MeV to the reactor plasma and utilized not only for plasma heating but also for current drive and current profile control. The injection system is composed of 9 modules, each of which is designed so as to inject a 1.3MeV, 10MW neutral beam. The most important point in the design is that the injection system is based on the utilization of a cesium-seeded volume negative ion source which can produce an intense negative ion beam with high current density at a low source operating pressure. The design value of the source is based on the experimental values achieved at JAERI. The utilization of the cesium-seeded volume source is essential to the design of an efficient and compact neutral beam injection system which satisfies the ITER common design requirements. The critical components to realize this design are the 1.3MeV, 17A electrostatic accelerator and the high voltage DC acceleration power supply, whose performances must be demonstrated prior to the construction of ITER NBI system. (author)

  9. Laser cooling of neutral atoms

    International Nuclear Information System (INIS)

    1993-01-01

    A qualitative description of laser cooling of neutral atoms is given. Two of the most important mechanisms utilized in laser cooling, the so-called Doppler Cooling and Sisyphus Cooling, are reviewed. The minimum temperature reached by the atoms is derived using simple arguments. (Author) 7 refs

  10. Climate Neutral Research Campuses | NREL

    Science.gov (United States)

    the background. Set an example for climate neutrality. Use NREL's climate action planning process and more. Climate Action Planning Process Identify the best technology options for a climate action plan . Climate Action Planning Tool Identify the best technology options for a climate action plan. Technology

  11. PLT neutral beam injection systems

    International Nuclear Information System (INIS)

    Menon, M.M.; Barber, G.C.; Blue, C.W.

    1979-01-01

    A brief description of the Princeton Large Torus (PLT) neutral beam injection system is given and its performance characteristics are outlined. A detailed operational procedure is included, as are some tips on troubleshooting. Proper operation of the source is shown to be a crucial factor in system performance

  12. Neutral Models with Generalised Speciation

    NARCIS (Netherlands)

    Haegeman, Bart; Etienne, Rampal S.

    Hubbell's neutral theory claims that ecological patterns such as species abundance distributions can be explained by a stochastic model based on simple assumptions. One of these assumptions, the point mutation assumption, states that every individual has the same probability to speciate. Etienne et

  13. Multimegawatt neutral beams for tokamaks

    International Nuclear Information System (INIS)

    Kunkel, W.B.

    1979-03-01

    Most of the large magnetic confinement experiments today and in the near future use high-power neutral-beam injectors to heat the plasma. This review briefly describes this remarkable technique and summarizes recent results as well as near term expectations. Progress has been so encouraging that it seems probable that tokamaks will achieve scientific breakeven before 1990

  14. Heavy neutral leptons at FASER

    Science.gov (United States)

    Kling, Felix; Trojanowski, Sebastian

    2018-05-01

    We study the prospects for discovering heavy neutral leptons at Forward Search Experiment (FASER), the newly proposed detector at the LHC. Previous studies showed that a relatively small detector with ˜10 m length and ≲1 m2 cross sectional area can probe large unconstrained parts of parameter space for dark photons and dark Higgs bosons. In this work, we show that FASER will also be sensitive to heavy neutral leptons that have mixing angles with the active neutrinos that are up to an order of magnitude lower than current bounds. In particular, this is true for heavy neutral leptons produced dominantly in B -meson decays, in which case FASER's discovery potential is comparable to the proposed SHiP detector. We also illustrate how the search for heavy neutral leptons at FASER will be complementary to ongoing searches in high-pT experiments at the LHC and can shed light on the nature of dark matter and the process of baryogenesis in the early Universe.

  15. Money neutrality: Rethinking the myth

    Directory of Open Access Journals (Sweden)

    Issaoui Fakhri

    2015-01-01

    Full Text Available Considered as an axiomatic basis of classical, neoclassical, and monetarist theories, the long-run money neutrality assumption does not always seem to be verified. Indeed, in our view, the money, in the sense of M2, can constitute a long-run channel of growth transmission. Thus, this paper examines the long-term relationship among money supply (M2, income (GDP, and prices (CPI. The subprime crisis in 2007 has shown that the demand for money does not only meet motives of transaction, precaution, and speculation but also of fictional or quasi-fictional future demands due to the fact that they are created without real counterparts. The capacity of production systems in developed countries to respond to increases in money supply by creating more wealth, involves the assumption of money neutrality in the long-run. However, in developing countries, the excess of money supply may lead to inflation trends. The present study has confirmed the long-term non-neutrality of money supply in the USA, and its neutrality in Gabon and Morocco.

  16. The manipulation of neutral particles

    International Nuclear Information System (INIS)

    Chu, S.

    1998-01-01

    The article is a translation of the lecture delivered on the occasion of the 1997 Nobel Prize awarding ceremony. The author's personal contribution to the discovery of laser cooling and trapping of neutral atoms is described, and applications of this phenomenon in atomic physics are highlighted. The article is completed by Mr. Steven Chu's autobiography

  17. Net Neutrality in the Netherlands

    NARCIS (Netherlands)

    van Eijk, N.

    2014-01-01

    The Netherlands is among the first countries that have put specific net neutrality standards in place. The decision to implement specific regulation was influenced by at least three factors. The first was the prevailing social and academic debate, partly due to developments in the United States. The

  18. Broad line regions in Seyfert-1 galaxies

    International Nuclear Information System (INIS)

    Groningen, E. van.

    1984-01-01

    To reproduce observed emission profiles of Seyfert galaxies, rotation in an accretion disk has been proposed. In this thesis, the profiles emitted by such an accretion disk are investigated. Detailed comparison with the observed profiles yields that a considerable fraction can be fitted with a power-law function, as predicted by the model. The author analyzes a series of high quality spectra of Seyfert galaxies, obtained with the 2.5m telescope at Las Campanas. He presents detailed analyses of two objects: Mkn335 and Akn120. In both cases, strong evidence is presented for the presence of two separate broad line zones. These zones are identified with an accretion disk and an outflowing wind. The disk contains gas with very high densities and emits predominantly the lower ionization lines. He reports on the discovery of very broad wings beneath the strong forbidden line 5007. (Auth.)

  19. Fourier evaluation of broad Moessbauer spectra

    International Nuclear Information System (INIS)

    Vincze, I.

    1981-01-01

    It is shown by the Fourier analysis of broad Moessbauer spectra that the even part of the distribution of the dominant hyperfine interaction (hyperfine field or quadrupole splitting) can be obtained directly without using least-square fitting procedures. Also the odd part of this distribution correlated with other hyperfine parameters (e.g. isomer shift) can be directly determined. Examples for amorphous magnetic and paramagnetic iron-based alloys are presented. (author)

  20. Fourier evaluation of broad Moessbauer spectra

    International Nuclear Information System (INIS)

    Vincze, I.

    1981-09-01

    It is shown by the Fourier analysis of broad Moessbauer spectra that the even part of the distribution of the dominant hyperfine interaction (hyperfine field or quadrupole splitting) can be obtained directly without using least-square fitting procedures. Also the odd part of this distribution correlated with other hyperfine parameters (e.g. isomer shift) can be directly determined. Examples covering the case of amorphous magnetic and paramagnetic iron-based alloys are presented. (author)

  1. Two wide-angle imaging neutral-atom spectrometers

    Energy Technology Data Exchange (ETDEWEB)

    McComas, D.J.

    1997-12-31

    The Two Wide-angle Imaging Neutral-atom Spectrometers (TWINS) mission provides a new capability for stereoscopically imaging the magnetosphere. By imaging the charge exchange neutral atoms over a broad energy range (1 < E , {approximately} 100 keV) using two identical instruments on two widely-spaced high-altitude, high-inclination spacecraft, TWINS will enable the 3-dimensional visualization and the resolution of large scale structures and dynamics within the magnetosphere for the first time. These observations will provide a leap ahead in the understanding of the global aspects of the terrestrial magnetosphere and directly address a number of critical issues in the ``Sun-Earth Connections`` science theme of the NASA Office of Space Science.

  2. Two wide-angle imaging neutral-atom spectrometers

    International Nuclear Information System (INIS)

    McComas, D.J.

    1997-01-01

    The Two Wide-angle Imaging Neutral-atom Spectrometers (TWINS) mission provides a new capability for stereoscopically imaging the magnetosphere. By imaging the charge exchange neutral atoms over a broad energy range (1 < E , ∼ 100 keV) using two identical instruments on two widely-spaced high-altitude, high-inclination spacecraft, TWINS will enable the 3-dimensional visualization and the resolution of large scale structures and dynamics within the magnetosphere for the first time. These observations will provide a leap ahead in the understanding of the global aspects of the terrestrial magnetosphere and directly address a number of critical issues in the ''Sun-Earth Connections'' science theme of the NASA Office of Space Science

  3. Complexation of metal ions with humic acid: charge neutralization model

    International Nuclear Information System (INIS)

    Kim, J.I.; Czerwinski, K.R.

    1995-01-01

    A number of different approaches are being used for describing the complexation equilibrium of actinide ions with humic or fulvic acid. The approach chosen and verified experimentally by Tu Muenchen will be discussed with notable examples from experiment. This approach is based on the conception that a given actinide ion is neutralized upon complexation with functional groups of humic or fulvic acid, e.g. carboxylic and phenolic groups, which are known as heterogeneously cross-linked polyelectrolytes. The photon energy transfer experiment with laser light excitation has shown that the actinide ion binding with the functional groups is certainly a chelation process accompanied by metal ion charge neutralization. This fact is in accordance with the experimental evidence of the postulated thermodynamic equilibrium reaction. The experimental results are found to be independent of origin of humic or fulvic acid and applicable for a broad range of pH. (authors). 23 refs., 7 figs., 1 tab

  4. Development of broad-spectrum human monoclonal antibodies for rabies post-exposure prophylaxis

    International Nuclear Information System (INIS)

    Benedictis, P. de; Minola, A.; Rota, E.; Aiello, R.; Zecchin, B.; Salomoni, A.; Foglierini, M.; Agatic, G.; Vanzetta, F.; Lavenir, R.; Lepelletier, A.; Bentley, E.; Weiss, R.; Cattoli, G.

    2016-01-01

    Full text: Currently available rabies post-exposure prophylaxis (PEP) for use in humans includes equine or human rabies immunoglobulins (RIG). The replacement of RIG with an equally or more potent and safer product is strongly encouraged due to the high costs and limited availability of existing RIG. In this study, we identified two broadly neutralizing human monoclonal antibodies that represent a valid and affordable alternative to RIG in rabies PEP. Memory B cells from four selected vaccinated donors were immortalized and monoclonal antibodies were tested for neutralizing activity and epitope specificity. Two antibodies, identified as RVC20 and RVC58 (binding to antigenic site I and III, respectively), were selected for their potency and broad-spectrum reactivity. In vitro, RVC20 and RVC58 were able to neutralize all 35 rabies virus (RABV) and 25 non-RABV lyssaviruses. They showed higher potency and breath compared to antibodies under clinical development (namely CR57, CR4098, and RAB1) and commercially available human RIG. In vivo, the RVC20–RVC58 cocktail protected Syrian hamsters from a lethal RABV challenge and did not affect the endogenous hamster post-vaccination antibody response. (author)

  5. Make the Alberta Carbon Levy Revenue Neutral

    Directory of Open Access Journals (Sweden)

    Kenneth J. McKenzie

    2016-04-01

    Full Text Available The new carbon levy of $30 per tonne, announced in November 2015 as part of the report issued by the Alberta government’s Climate Leadership Panel, is a positive move in the direction of pricing carbon emissions. The levy is expected to generate $3 billion in net revenue by 2018, and possibly as much as $5 billion by 2030. While there is some discussion in the report of what should be done with the revenues generated by the carbon levy, it is somewhat vague on the details, leaving a number of options open to the government. The purpose of this briefing paper is to argue that the revenues from the carbon levy should be used to lower existing taxes – the carbon tax should be revenue neutral, generating no new net revenue for the government. The basic argument is that the carbon levy can be viewed through two lenses. The first lens is the imposition of a price on carbon emissions which (at least partly reflects the social costs of emissions. Viewed through this price lens, the carbon levy plays an important role in incenting firms and individuals to change their behaviour and move towards less carbon intensive activities. The second lens is the role of a carbon tax as a part of the broad revenue system. Viewed through this tax lens, a carbon tax is not a very good, or efficient, way of generating revenue. The reason for this is somewhat nuanced, but the basic idea is that the carbon tax is applied to a narrower base than broader-based taxes. Broad based taxes generally impose lower costs on the economy than narrow based taxes. Moreover, carbon taxes interact with other taxes in the economy, exacerbating the economic costs associated with those taxes. And those costs are quite high – research shows that the total cost to the economy of raising an additional $1 in revenue through the corporate income tax in Alberta is $3.79; for the personal income tax the cost is $1.71. These taxes therefore impose higher costs on the economy than they raise

  6. Clinical Ethics Consultation After God: Implications for Advocacy and Neutrality.

    Science.gov (United States)

    Parker, J Clint

    2018-06-01

    In After God: Morality and Bioethics in a Secular Age, H. Tristram Engelhardt, Jr. explores the broad implications for moral reasoning once a culture has lost a God's-eye perspective. In this paper, I focus on the implications of Engelhardt's views for clinical ethics consultation. I begin by examining the question of whether clinical ethics consultants (CECs) should advocate a particular viewpoint and/or process during consultations or adopt a neutral stance. I then examine the implications of Engelhardt's views for this question. Finally, I discuss some of Engelhardt's foundational ontological, metaphysical, meta-ethical, and epistemological commitments and how these commitments connect to his views on clinical ethics consultation.

  7. Neutral particles identification at LHCb

    CERN Multimedia

    Quintana, Boris Julien

    2018-01-01

    Important analyses of the core LHCb physics program rely on calorimetry to identify photons, high-energy neutral pions and electrons. For this purpose, the LHCb calorimeter system is composed of a scintillating pad plane, a preshower detector, an electromagnetic and a hadronic sampling calorimeters. The interaction of a given particle in these detectors leaves a specific signature. This is exploited for particle identification (PID) by combining calorimeters and tracking information into multi-variate classifiers. In this contribution, we focus on the identification of photons against high-energy neutral pion and hadronic backgrounds. Performance on Run 1 data will be shown. Small discrepancies with simulation predictions are then discussed, with special emphasis on the methods to correctly estimate PID cut efficiencies by means of large calibration samples of abundant beauty and charm decays to final states with photons. Finally, the technical aspects of the collection of these samples in Run 2 are presented...

  8. Vendor neutral archive in PACS

    International Nuclear Information System (INIS)

    Agarwal, Tapesh Kumar; Sanjeev

    2012-01-01

    An archive is a location containing a collection of records, documents, or other materials of historical importance. An integral part of Picture Archiving and Communication System (PACS) is archiving. When a hospital needs to migrate a PACS vendor, the complete earlier data need to be migrated in the format of the newly procured PACS. It is both time and money consuming. To address this issue, the new concept of vendor neutral archive (VNA) has emerged. A VNA simply decouples the PACS and workstations at the archival layer. This is achieved by developing an application engine that receives, integrates, and transmits the data using the different syntax of a Digital Imaging and Communication in Medicine (DICOM) format. Transferring the data belonging to the old PACS to a new one is performed by a process called migration of data. In VNA, a number of different data migration techniques are available to facilitate transfer from the old PACS to the new one, the choice depending on the speed of migration and the importance of data. The techniques include simple DICOM migration, prefetch-based DICOM migration, medium migration, and the expensive non-DICOM migration. “Vendor neutral” may not be a suitable term, and “architecture neutral,” “PACS neutral,” “content neutral,” or “third-party neutral” are probably better and preferred terms. Notwithstanding this, the VNA acronym has come to stay in both the medical IT user terminology and in vendor nomenclature, and radiologists need to be aware of its impact in PACS across the globe

  9. Electromagnetic disturbance neutralizing radiation detector

    International Nuclear Information System (INIS)

    Gripentog, W.G.

    1975-01-01

    A radiation detector of the Neher-White type is described which automatically neutralizes induced negative charges on the electrometer tube control grid which shut off the electrometer tube. The detector includes means for establishing a voltage of one polarity in response to plate current and voltage of opposite polarity in response to an absence of plate current and means for connecting the control grid to a reference potential for draining the negative charge in response to the voltage of opposite polarity. (author)

  10. Boosting of HIV-1 neutralizing antibody responses by a distally related retroviral envelope protein

    DEFF Research Database (Denmark)

    Uchtenhagen, Hannes; Schiffner, Torben; Bowles, Emma

    2014-01-01

    Our knowledge of the binding sites for neutralizing Abs (NAb) that recognize a broad range of HIV-1 strains (bNAb) has substantially increased in recent years. However, gaps remain in our understanding of how to focus B cell responses to vulnerable conserved sites within the HIV-1 envelope glycop...

  11. Steady state neutral beam injector

    International Nuclear Information System (INIS)

    Mattoo, S.K.; Bandyopadhyay, M.; Baruah, U.K.; Bisai, N.; Chakbraborty, A.K.; Chakrapani, Ch.; Jana, M.R.; Bajpai, M.; Jaykumar, P.K.; Patel, D.; Patel, G.; Patel, P.J.; Prahlad, V.; Rao, N.V.M.; Rotti, C.; Singh, N.P.; Sridhar, B.

    2000-01-01

    Learning from operational reliability of neutral beam injectors in particular and various heating schemes including RF in general on TFTR, JET, JT-60, it has become clear that neutral beam injectors may find a greater role assigned to them for maintaining the plasma in steady state devices under construction. Many technological solutions, integrated in the present day generation of injectors have given rise to capability of producing multimegawatt power at many tens of kV. They have already operated for integrated time >10 5 S without deterioration in the performance. However, a new generation of injectors for steady state devices have to address to some basic issues. They stem from material erosion under particle bombardment, heat transfer > 10 MW/m 2 , frequent regeneration of cryopanels, inertial power supplies, data acquisition and control of large volume of data. Some of these engineering issues have been addressed to in the proposed neutral beam injector for SST-1 at our institute; the remaining shall have to wait for the inputs of the database generated from the actual experience with steady state injectors. (author)

  12. Neutral beams for magnetic fusion

    International Nuclear Information System (INIS)

    Hooper, B.

    1977-01-01

    Significant advances in forming energetic beams of neutral hydrogen and deuterium atoms have led to a breakthrough in magnetic fusion: neutral beams are now heating plasmas to thermonuclear temperatures, here at LLL and at other laboratories. For example, in our 2XIIB experiment we have injected a 500-A-equivalent current of neutral deuterium atoms at an average energy of 18 keV, producing a dense plasma (10 14 particles/cm 3 ) at thermonuclear energy (14 keV or 160 million kelvins). Currently, LLL and LBL are developing beam energies in the 80- to 120-keV range for our upcoming MFTF experiment, for the TFTR tokamak experiment at Princeton, and for the Doublet III tokamak experiment at General Atomic. These results increase our long-range prospects of producing high-intensity beams of energies in the hundreds or even thousands of kilo-electron-volts, providing us with optimistic extrapolations for realizing power-producing fusion reactors

  13. The broad utility of Trizac diamond tile

    Science.gov (United States)

    Gagliardi, John I.; Romero, Vincent D.; Sventek, Bruce; Zu, Lijun

    2017-10-01

    Sample finishing data from a broad range of materials — glasses, sapphire, silicon carbide, silicon, zirconium oxide, lithium tantalate, and flooring materials — are shown effectively processed with Trizact™ Diamond Tile (TDT). This data should provide the reader with an understanding of what to expect when using TDT on hard to grind or brittle materials. Keys to maintaining effective TDT pad wear rates, and therefore cost effect and stable processes, are described as managing 1) the proper lubricant flow rate for glasses and silicon-type materials and 2) the conditioning particle concentration for harder-to-grind materials

  14. Plasma/Neutral-Beam Etching Apparatus

    Science.gov (United States)

    Langer, William; Cohen, Samuel; Cuthbertson, John; Manos, Dennis; Motley, Robert

    1989-01-01

    Energies of neutral particles controllable. Apparatus developed to produce intense beams of reactant atoms for simulating low-Earth-orbit oxygen erosion, for studying beam-gas collisions, and for etching semiconductor substrates. Neutral beam formed by neutralization and reflection of accelerated plasma on metal plate. Plasma ejected from coaxial plasma gun toward neutralizing plate, where turned into beam of atoms or molecules and aimed at substrate to be etched.

  15. The Neutral Interest Rate: Estimates for Chile

    OpenAIRE

    Rodrigo Fuentes S; Fabián Gredig U.

    2008-01-01

    To estimate the neutral real interest rate for Chile, we use a variety of methods that can be classified into three categories: those derived from economic theory, the neutral rate implicit in financial assets, and statistical procedures using macroeconomic data. We conclude that the neutral rate is not constant over time, but it is closely related with—though not equivalent to—the potential GDP growth rate. The application of the different methods yields fairly similar results. The neutral r...

  16. Neutrality in mediation: an ambiguous ethical value

    OpenAIRE

    Bailey, Paul

    2014-01-01

    Mediator neutrality would appear, by definition, to be a necessary and required ethical principle for all mediators to practice. But what is meant by neutrality in mediation? Is it practically possible to be completely neutral between parties in mediation while at the same time being fair to both of them? This paper attempts to answer these two questions.

  17. Ion-beam Plasma Neutralization Interaction Images

    International Nuclear Information System (INIS)

    Igor D. Kaganovich; Edward Startsev; S. Klasky; Ronald C. Davidson

    2002-04-01

    Neutralization of the ion beam charge and current is an important scientific issue for many practical applications. The process of ion beam charge and current neutralization is complex because the excitation of nonlinear plasma waves may occur. Computer simulation images of plasma neutralization of the ion beam pulse are presented

  18. Ion-beam Plasma Neutralization Interaction Images

    Energy Technology Data Exchange (ETDEWEB)

    Igor D. Kaganovich; Edward Startsev; S. Klasky; Ronald C. Davidson

    2002-04-09

    Neutralization of the ion beam charge and current is an important scientific issue for many practical applications. The process of ion beam charge and current neutralization is complex because the excitation of nonlinear plasma waves may occur. Computer simulation images of plasma neutralization of the ion beam pulse are presented.

  19. The Net Neutrality Debate: The Basics

    Science.gov (United States)

    Greenfield, Rich

    2006-01-01

    Rich Greenfield examines the basics of today's net neutrality debate that is likely to be an ongoing issue for society. Greenfield states the problems inherent in the definition of "net neutrality" used by Common Cause: "Network neutrality is the principle that Internet users should be able to access any web content they choose and…

  20. Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals.

    Directory of Open Access Journals (Sweden)

    Davide Corti

    2010-01-01

    Full Text Available The isolation of human monoclonal antibodies (mAbs that neutralize a broad spectrum of primary HIV-1 isolates and the characterization of the human neutralizing antibody B cell response to HIV-1 infection are important goals that are central to the design of an effective antibody-based vaccine.We immortalized IgG(+ memory B cells from individuals infected with diverse clades of HIV-1 and selected on the basis of plasma neutralization profiles that were cross-clade and relatively potent. Culture supernatants were screened using various recombinant forms of the envelope glycoproteins (Env in multiple parallel assays. We isolated 58 mAbs that were mapped to different Env surfaces, most of which showed neutralizing activity. One mAb in particular (HJ16 specific for a novel epitope proximal to the CD4 binding site on gp120 selectively neutralized a multi-clade panel of Tier-2 HIV-1 pseudoviruses, and demonstrated reactivity that was comparable in breadth, but distinct in neutralization specificity, to that of the other CD4 binding site-specific neutralizing mAb b12. A second mAb (HGN194 bound a conserved epitope in the V3 crown and neutralized all Tier-1 and a proportion of Tier-2 pseudoviruses tested, irrespective of clade. A third mAb (HK20 with broad neutralizing activity, particularly as a Fab fragment, recognized a highly conserved epitope in the HR-1 region of gp41, but showed striking assay-dependent selectivity in its activity.This study reveals that by using appropriate screening methods, a large proportion of memory B cells can be isolated that produce mAbs with HIV-1 neutralizing activity. Three of these mAbs show unusual breadth of neutralization and therefore add to the current panel of HIV-1 neutralizing antibodies with potential for passive protection and template-based vaccine design.

  1. Broad ion beam serial section tomography

    Energy Technology Data Exchange (ETDEWEB)

    Winiarski, B., E-mail: b.winiarski@manchester.ac.uk [School of Materials, University of Manchester, Manchester M13 9PL (United Kingdom); Materials Division, National Physical Laboratory, Teddington TW11 0LW (United Kingdom); Gholinia, A. [School of Materials, University of Manchester, Manchester M13 9PL (United Kingdom); Mingard, K.; Gee, M. [Materials Division, National Physical Laboratory, Teddington TW11 0LW (United Kingdom); Thompson, G.E.; Withers, P.J. [School of Materials, University of Manchester, Manchester M13 9PL (United Kingdom)

    2017-01-15

    Here we examine the potential of serial Broad Ion Beam (BIB) Ar{sup +} ion polishing as an advanced serial section tomography (SST) technique for destructive 3D material characterisation for collecting data from volumes with lateral dimensions significantly greater than 100 µm and potentially over millimetre sized areas. Further, the associated low level of damage introduced makes BIB milling very well suited to 3D EBSD acquisition with very high indexing rates. Block face serial sectioning data registration schemes usually assume that the data comprises a series of parallel, planar slices. We quantify the variations in slice thickness and parallelity which can arise when using BIB systems comparing Gatan PECS and Ilion BIB systems for large volume serial sectioning and 3D-EBSD data acquisition. As a test case we obtain 3D morphologies and grain orientations for both phases of a WC-11%wt. Co hardmetal. In our case we have carried out the data acquisition through the manual transfer of the sample between SEM and BIB which is a very slow process (1–2 slice per day), however forthcoming automated procedures will markedly speed up the process. We show that irrespective of the sectioning method raw large area 2D-EBSD maps are affected by distortions and artefacts which affect 3D-EBSD such that quantitative analyses and visualisation can give misleading and erroneous results. Addressing and correcting these issues will offer real benefits when large area (millimetre sized) automated serial section BIBS is developed. - Highlights: • In this work we examine how microstructures can be reconstructed in three-dimensions (3D) by serial argon broad ion beam (BIB) milling, enabling much larger volumes (>250×250×100µm{sup 3}) to be acquired than by serial section focused ion beam-scanning electron microscopy (FIB-SEM). • The associated low level of damage introduced makes BIB milling very well suited to 3D-EBSD acquisition with very high indexing rates. • We explore

  2. Spectrophotometry of six broad absorption line QSOs

    Science.gov (United States)

    Junkkarinen, Vesa T.; Burbidge, E. Margaret; Smith, Harding E.

    1987-01-01

    Spectrophotometric observations of six broad absorption-line QSOs (BALQSOs) are presented. The continua and emission lines are compared with those in the spectra of QSOs without BALs. A statistically significant difference is found in the emission-line intensity ratio for (N V 1240-A)/(C IV 1549-A). The median value of (N V)/(C IV) for the BALQSOs is two to three times the median for QSOs without BALs. The absorption features of the BALQSOs are described, and the column densities and limits on the ionization structure of the BAL region are discussed. If the dominant ionization mechanism is photoionization, then it is likely that either the ionizing spectrum is steep or the abundances are considerably different from solar. Collisional ionization may be a significant factor, but it cannot totally dominate the ionization rate.

  3. Study on broad beam heavy ion CT

    International Nuclear Information System (INIS)

    Ohno, Yumiko; Kohno, Toshiyuki; Sasaki, Hitomi; Nanbu, S.; Kanai, Tatsuaki

    2003-01-01

    To achieve the heavy ion radiotherapy more precisely, it is important to know the distribution of the electron density in a human body, which is highly related to the range of charged particles. From a heavy ion CT image, we can directly obtain the 2-D distribution of the electron density in a sample. For this purpose, we have developed a broad beam heavy ion CT system. The electron density was obtained using some kinds of solutions targets. Also the dependence of the spatial resolution on the target size and the kinds of beams was estimated in this work using cylinders targets of 40, 60 and 80 mm in diameter, each of them has a hole of 10 mm in diameter at the center of it. (author)

  4. Broad Ligament Haematoma Following Normal Vaginal Delivery.

    Science.gov (United States)

    Ibrar, Faiza; Awan, Azra Saeed; Fatima, Touseef; Tabassum, Hina

    2017-01-01

    A 37-year-old, patient presented in emergency with history of normal vaginal delivery followed by development of abdominal distention, vomiting, constipation for last 3 days. She was para 4 and had normal vaginal delivery by traditional birth attendant at peripheral hospital 3 days back. Imaging study revealed a heterogeneous complex mass, ascites, pleural effusion, air fluid levels with dilatation gut loops. Based upon pelvic examination by senior gynaecologist in combination with ultrasound; a clinical diagnosis of broad ligament haematoma was made. However, vomiting and abdominal distention raised suspicion of intestinal obstruction. Due to worsening abdominal distention exploratory laparotomy was carried out. It was pseudo colonic obstruction and caecostomy was done. Timely intervention by multidisciplinary approach saved patient life with minimal morbidity.

  5. A broad view of model validation

    International Nuclear Information System (INIS)

    Tsang, C.F.

    1989-10-01

    The safety assessment of a nuclear waste repository requires the use of models. Such models need to be validated to ensure, as much as possible, that they are a good representation of the actual processes occurring in the real system. In this paper we attempt to take a broad view by reviewing step by step the modeling process and bringing out the need to validating every step of this process. This model validation includes not only comparison of modeling results with data from selected experiments, but also evaluation of procedures for the construction of conceptual models and calculational models as well as methodologies for studying data and parameter correlation. The need for advancing basic scientific knowledge in related fields, for multiple assessment groups, and for presenting our modeling efforts in open literature to public scrutiny is also emphasized. 16 refs

  6. Advanced neutral-beam technology

    International Nuclear Information System (INIS)

    Berkner, K.H.

    1980-09-01

    Extensive development will be required to achieve the 50- to 75-MW, 175- to 200-keV, 5- to 10-sec pulses of deuterium atoms envisioned for ETF and INTOR. Multi-megawatt injector systems are large (and expansive); they consist of large vacuum tanks with many square meters of cryogenic pumping panels, beam dumps capable of dissipating several megawatts of un-neutralized beam, bending magnets, electrical power systems capable of fast turnoff with low (capacity) stored energy, and, of course, the injector modules (ion sources and accelerators). The technology requirements associated with these components are described

  7. Plasma neutralizers for H- or D- beams

    International Nuclear Information System (INIS)

    Berkner, K.H.; Pyle, R.V.; Savas, S.E.; Stalder, K.R.

    1980-10-01

    Plasma neutralizers can produce higher conversion efficiencies than are obtainable with gas neutralizers for the production of high-energy neutral beams from negative hydrogen ions. Little attention has been paid to experimental neutralizer studies because of the more critical problems connected with the development of negative-ion sources. With the prospect of accelerating ampere dc beams from extrapolatable ion sources some time next year, we are re-examining plasma neutralizers. Some basic considerations, two introductory experiments, and a next-step experiment are described

  8. ORNL positive ion neutral beam program

    International Nuclear Information System (INIS)

    Whealton, J.H.; Haselton, H.H.; Barber, G.C.

    1978-01-01

    The neutral beam group at Oak Ridge National Laboratory has constructed neutral beam generators for the ORMAK and PLT devices, is presently constructing neutral beam devices for the ISX and PDX devices, and is contemplating the construction of neutral beam systems for the advanced TNS device. These neutral beam devices stem from the pioneering work on ion sources of G. G. Kelley and O. B. Morgan. We describe the ion sources under development at this Laboratory, the beam optics exhibited by these sources, as well as some theoretical considerations, and finally the remainder of the beamline design

  9. Soluble HIV-1 envelope immunogens derived from an elite neutralizer elicit cross-reactive V1V2 antibodies and low potency neutralizing antibodies.

    Directory of Open Access Journals (Sweden)

    Sara Carbonetti

    Full Text Available We evaluated four gp140 Envelope protein vaccine immunogens that were derived from an elite neutralizer, subject VC10042, whose plasma was able to potently neutralize a wide array of genetically distinct HIV-1 isolates. We sought to determine whether soluble Envelope proteins derived from the viruses circulating in VC10042 could be used as immunogens to elicit similar neutralizing antibody responses by vaccination. Each gp140 was tested in its trimeric and monomeric forms, and we evaluated two gp140 trimer vaccine regimens in which adjuvant was supplied at all four immunizations or at only the first two immunizations. Interestingly, all four Envelope immunogens elicited high titers of cross-reactive antibodies that recognize the variable regions V1V2 and are potentially similar to antibodies linked with a reduced risk of HIV-1 acquisition in the RV144 vaccine trial. Two of the four immunogens elicited neutralizing antibody responses that neutralized a wide array of HIV-1 isolates from across genetic clades, but those responses were of very low potency. There were no significant differences in the responses elicited by trimers or monomers, nor was there a significant difference between the two adjuvant regimens. Our study identified two promising Envelope immunogens that elicited anti-V1V2 antibodies and broad, but low potency, neutralizing antibody responses.

  10. Discrete symmetries with neutral mesons

    Science.gov (United States)

    Bernabéu, José

    2018-01-01

    Symmetries, and Symmetry Breakings, in the Laws of Physics play a crucial role in Fundamental Science. Parity and Charge Conjugation Violations prompted the consideration of Chiral Fields in the construction of the Standard Model, whereas CP-Violation needed at least three families of Quarks leading to Flavour Physics. In this Lecture I discuss the Conceptual Basis and the present experimental results for a Direct Evidence of Separate Reversal-in-Time T, CP and CPT Genuine Asymmetries in Decaying Particles like Neutral Meson Transitions, using Quantum Entanglement and the Decay as a Filtering Measurement. The eight transitions associated to the Flavour-CP eigenstate decay products of entangled neutral mesons have demonstrated with impressive significance a separate evidence of TRV and CPV in Bd-physics, whereas a CPTV asymmetry shows a 2σ effect interpreted as an upper limit. Novel CPTV observables are discussed for K physics at KLOE-2, including the difference between the semileptonic asymmetries from KL and KS, the ratios of double decay rate Intensities to Flavour-CP eigenstate decay products and the ω-effect. Their observation would lead to a change of paradigm beyond Quantum Field Theory, however there is nothing in Quantum Mechanics forbidding CPTV.

  11. A "Trojan horse" bispecific-antibody strategy for broad protection against ebolaviruses.

    Science.gov (United States)

    Wec, Anna Z; Nyakatura, Elisabeth K; Herbert, Andrew S; Howell, Katie A; Holtsberg, Frederick W; Bakken, Russell R; Mittler, Eva; Christin, John R; Shulenin, Sergey; Jangra, Rohit K; Bharrhan, Sushma; Kuehne, Ana I; Bornholdt, Zachary A; Flyak, Andrew I; Saphire, Erica Ollmann; Crowe, James E; Aman, M Javad; Dye, John M; Lai, Jonathan R; Chandran, Kartik

    2016-10-21

    There is an urgent need for monoclonal antibody (mAb) therapies that broadly protect against Ebola virus and other filoviruses. The conserved, essential interaction between the filovirus glycoprotein, GP, and its entry receptor Niemann-Pick C1 (NPC1) provides an attractive target for such mAbs but is shielded by multiple mechanisms, including physical sequestration in late endosomes. Here, we describe a bispecific-antibody strategy to target this interaction, in which mAbs specific for NPC1 or the GP receptor-binding site are coupled to a mAb against a conserved, surface-exposed GP epitope. Bispecific antibodies, but not parent mAbs, neutralized all known ebolaviruses by coopting viral particles themselves for endosomal delivery and conferred postexposure protection against multiple ebolaviruses in mice. Such "Trojan horse" bispecific antibodies have potential as broad antifilovirus immunotherapeutics. Copyright © 2016, American Association for the Advancement of Science.

  12. Crx broadly modulates the pineal transcriptome

    DEFF Research Database (Denmark)

    Rovsing, Louise; Clokie, Samuel; Bustos, Diego M

    2011-01-01

    Cone-rod homeobox (Crx) encodes Crx, a transcription factor expressed selectively in retinal photoreceptors and pinealocytes, the major cell type of the pineal gland. In this study, the influence of Crx on the mammalian pineal gland was studied by light and electron microscopy and by use of micro......Cone-rod homeobox (Crx) encodes Crx, a transcription factor expressed selectively in retinal photoreceptors and pinealocytes, the major cell type of the pineal gland. In this study, the influence of Crx on the mammalian pineal gland was studied by light and electron microscopy and by use......-type animals; only eight of these were also day/night expressed in the Crx-/- pineal gland. However, in the Crx-/- pineal gland 41 genes exhibited differential night/day expression that was not seen in wild-type animals. These findings indicate that Crx broadly modulates the pineal transcriptome and also...... influences differential night/day gene expression in this tissue. Some effects of Crx deletion on the pineal transcriptome might be mediated by Hoxc4 up-regulation....

  13. Detection of neutral current events

    International Nuclear Information System (INIS)

    Innocenti, P.G.

    1979-01-01

    The topics investigated in the course of the study can be broadly divided into three classes: (i) Inclusive measurements of the scattered electron for the determination of structure functions, scaling violations, deltaL/deltaT and weak interaction effects. (ii) Exclusive measurements of the current jet (momentum, energy, particle composition) for the study of fragmentation functions, for search of new particles, new quarks and QCD effects in the jet. (iii) Search for heavy leptons by detection and identification of their decay products. (orig.)

  14. Happy birthday, little neutral one

    International Nuclear Information System (INIS)

    Sutton, C.

    1990-01-01

    This article looks at the history of the neutrino particle, a tiny neutral particle which reacts only with the weak force. Its existence was originally postulated by Wolfgang Pauli in 1930, to explain beta decay energy conservation but because of the extreme experimental difficulties involved, neutrinos were not observed experimentally until 1956. Notwithstanding this the neutrino has become a valuable tool in high energy physics. Neutrino beams are used to probe matter and were used to reveal the existence of quarks within the particles once viewed as elementary, the proton and neutron. Cosmic neutrinos may be detected in the Deep Underwater Muon and Neutrino Detector off the coast of Hawaii and the Moon itself is a target for ultra high energy neutrinos in a Russian experiment to detect cascades of charge particles produced by these neutrinos in ice in the Antarctic. (UK)

  15. Gargamelle and the neutral currents

    International Nuclear Information System (INIS)

    Rousset, A.

    1996-06-01

    In order to simplify the description of forces, the physicists want to reduce the number of four interactions to a smaller one. They want to unify them. Einstein tried to unify the electromagnetic interaction and the gravitation interaction but it was probably the most difficult to unify. during the sixties, the American physicists Sheldon Glashow and Steven Weinberg and the Pakistani Abdus Salam ( each rewarded by the Nobel price of 1979) propose to unify the weak and electromagnetic interactions interactions under the form of an only interaction, the electro-weak interaction. To check the validity of this theory exist the demonstration by the weak neutral currents. In 1973, European physicians which analyzed photos taken in the bubble chamber called Gargamelle brought the experimental proof. This book tells the story of this discovery. (N.C.)

  16. $\\tau$ decays with neutral kaons

    CERN Document Server

    Abbiendi, G.; Akesson, P.F.; Alexander, G.; Allison, John; Anderson, K.J.; Arcelli, S.; Asai, S.; Ashby, S.F.; Axen, D.; Azuelos, G.; Bailey, I.; Ball, A.H.; Barberio, E.; Barlow, Roger J.; Batley, J.R.; Baumann, S.; Behnke, T.; Bell, Kenneth Watson; Bella, G.; Bellerive, A.; Bentvelsen, S.; Bethke, S.; Betts, S.; Biebel, O.; Biguzzi, A.; Bloodworth, I.J.; Bock, P.; Bohme, J.; Boeriu, O.; Bonacorsi, D.; Boutemeur, M.; Braibant, S.; Bright-Thomas, P.; Brigliadori, L.; Brown, Robert M.; Burckhart, H.J.; Capiluppi, P.; Carnegie, R.K.; Carter, A.A.; Carter, J.R.; Chang, C.Y.; Charlton, David G.; Chrisman, D.; Ciocca, C.; Clarke, P.E.L.; Clay, E.; Cohen, I.; Conboy, J.E.; Cooke, O.C.; Couchman, J.; Couyoumtzelis, C.; Coxe, R.L.; Cuffiani, M.; Dado, S.; Dallavalle, G.Marco; Dallison, S.; Davis, R.; de Roeck, A.; Dervan, P.; Desch, K.; Dienes, B.; Dixit, M.S.; Donkers, M.; Dubbert, J.; Duchovni, E.; Duckeck, G.; Duerdoth, I.P.; Estabrooks, P.G.; Etzion, E.; Fabbri, F.; Fanfani, A.; Fanti, M.; Faust, A.A.; Feld, L.; Ferrari, P.; Fiedler, F.; Fierro, M.; Fleck, I.; Frey, A.; Furtjes, A.; Futyan, D.I.; Gagnon, P.; Gary, J.W.; Gaycken, G.; Geich-Gimbel, C.; Giacomelli, G.; Giacomelli, P.; Gingrich, D.M.; Glenzinski, D.; Goldberg, J.; Gorn, W.; Grandi, C.; Graham, K.; Gross, E.; Grunhaus, J.; Gruwe, M.; Hajdu, C.; Hanson, G.G.; Hansroul, M.; Hapke, M.; Harder, K.; Harel, A.; Hargrove, C.K.; Harin-Dirac, M.; Hauschild, M.; Hawkes, C.M.; Hawkings, R.; Hemingway, R.J.; Herten, G.; Heuer, R.D.; Hildreth, M.D.; Hill, J.C.; Hobson, P.R.; Hocker, James Andrew; Hoffman, Kara Dion; Homer, R.J.; Honma, A.K.; Horvath, D.; Hossain, K.R.; Howard, R.; Huntemeyer, P.; Igo-Kemenes, P.; Imrie, D.C.; Ishii, K.; Jacob, F.R.; Jawahery, A.; Jeremie, H.; Jimack, M.; Jones, C.R.; Jovanovic, P.; Junk, T.R.; Kanaya, N.; Kanzaki, J.; Karapetian, G.; Karlen, D.; Kartvelishvili, V.; Kawagoe, K.; Kawamoto, T.; Kayal, P.I.; Keeler, R.K.; Kellogg, R.G.; Kennedy, B.W.; Kim, D.H.; Klier, A.; Kobayashi, T.; Kobel, M.; Kokott, T.P.; Kolrep, M.; Komamiya, S.; Kowalewski, Robert V.; Kress, T.; Krieger, P.; von Krogh, J.; Kuhl, T.; Kupper, M.; Kyberd, P.; Lafferty, G.D.; Landsman, H.; Lanske, D.; Lauber, J.; Lawson, I.; Layter, J.G.; Lellouch, D.; Letts, J.; Levinson, L.; Liebisch, R.; Lillich, J.; List, B.; Littlewood, C.; Lloyd, A.W.; Lloyd, S.L.; Loebinger, F.K.; Long, G.D.; Losty, M.J.; Lu, J.; Ludwig, J.; Macchiolo, A.; Macpherson, A.; Mader, W.; Mannelli, M.; Marcellini, S.; Marchant, T.E.; Martin, A.J.; Martin, J.P.; Martinez, G.; Mashimo, T.; Mattig, Peter; McDonald, W.John; McKenna, J.; Mckigney, E.A.; McMahon, T.J.; McPherson, R.A.; Meijers, F.; Mendez-Lorenzo, P.; Merritt, F.S.; Mes, H.; Meyer, I.; Michelini, A.; Mihara, S.; Mikenberg, G.; Miller, D.J.; Mohr, W.; Montanari, A.; Mori, T.; Nagai, K.; Nakamura, I.; Neal, H.A.; Nisius, R.; O'Neale, S.W.; Oakham, F.G.; Odorici, F.; Ogren, H.O.; Okpara, A.; Oreglia, M.J.; Orito, S.; Pasztor, G.; Pater, J.R.; Patrick, G.N.; Patt, J.; Perez-Ochoa, R.; Petzold, S.; Pfeifenschneider, P.; Pilcher, J.E.; Pinfold, J.; Plane, David E.; Poli, B.; Polok, J.; Przybycien, M.; Quadt, A.; Rembser, C.; Rick, H.; Robins, S.A.; Rodning, N.; Roney, J.M.; Rosati, S.; Roscoe, K.; Rossi, A.M.; Rozen, Y.; Runge, K.; Runolfsson, O.; Rust, D.R.; Sachs, K.; Saeki, T.; Sahr, O.; Sang, W.M.; Sarkisian, E.K.G.; Sbarra, C.; Schaile, A.D.; Schaile, O.; Scharff-Hansen, P.; Schieck, J.; Schmitt, S.; Schoning, A.; Schroder, Matthias; Schumacher, M.; Schwick, C.; Scott, W.G.; Seuster, R.; Shears, T.G.; Shen, B.C.; Shepherd-Themistocleous, C.H.; Sherwood, P.; Siroli, G.P.; Skuja, A.; Smith, A.M.; Snow, G.A.; Sobie, R.; Soldner-Rembold, S.; Spagnolo, S.; Sproston, M.; Stahl, A.; Stephens, K.; Stoll, K.; Strom, David M.; Strohmer, R.; Surrow, B.; Talbot, S.D.; Taras, P.; Tarem, S.; Teuscher, R.; Thiergen, M.; Thomas, J.; Thomson, M.A.; Torrence, E.; Towers, S.; Trefzger, T.; Trigger, I.; Trocsanyi, Z.; Tsur, E.; Turner-Watson, M.F.; Ueda, I.; Van Kooten, Rick J.; Vannerem, P.; Verzocchi, M.; Voss, H.; Wackerle, F.; Waller, D.; Ward, C.P.; Ward, D.R.; Watkins, P.M.; Watson, A.T.; Watson, N.K.; Wells, P.S.; Wengler, T.; Wermes, N.; Wetterling, D.; White, J.S.; Wilson, G.W.; Wilson, J.A.; Wyatt, T.R.; Yamashita, S.; Zacek, V.; Zer-Zion, D.

    2000-01-01

    The branching ratio of the tau lepton to a neutral K meson is measured from a sample of approximately 200,000 tau decays recorded by the OPAL detector at centre-of-mass energies near the Z0 resonance. The measurement is based on two samples which identify one-prong tau decays with KL and KS mesons. The combined branching ratios are measured to be B(tau- -->pi- K0bar nutau) = (9.33+-0.68+-0.49)x10^-3 B(tau- -->pi- K0bar [>=1pi0] nutau) = (3.24+-0.74+-0.66)x10^-3 B(tau- -->K- K0bar [>=0pi0] nutau) = (3.30+-0.55+-0.39)x10^-3 where the first error is statistical and the second systematic.

  17. Laser sputter neutral mass spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    King, B V; Clarke, M; Hu, H; Betz, [Newcastle Univ., NSW (Australia). Dept. of Physics

    1994-12-31

    Laser sputter neutral mass spectrometry (LSNMS) is an emerging technique for highly sensitive surface analysis. In this technique a target is bombarded with a pulsed beam of keV ions. The sputtered particles are intercepted by a high intensity pulsed laser beam above the surface and ionised with almost 100% efficiency. The photions may then be mass analysed using a quadrupole or, more commonly, using time of flight (TOF) techniques. In this method photoions are extracted from the ionisation region, accelerated to a known energy E{sub o} and strike a channelplate detector a distance `d` away. The flight time `t` of the photoions is then related to their mass by `d` {radical}m / {radical} 2E{sub o} so measurement of `t` allows mass spectra to be obtained. It is found that LSNMS is an emerging technique of great sensitivity and flexibility, useful for both applied analysis and to investigate basic sputtering processes. 4 refs., 3 figs.

  18. Laser sputter neutral mass spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    King, B.V.; Clarke, M.; Hu, H.; Betz [Newcastle Univ., NSW (Australia). Dept. of Physics

    1993-12-31

    Laser sputter neutral mass spectrometry (LSNMS) is an emerging technique for highly sensitive surface analysis. In this technique a target is bombarded with a pulsed beam of keV ions. The sputtered particles are intercepted by a high intensity pulsed laser beam above the surface and ionised with almost 100% efficiency. The photions may then be mass analysed using a quadrupole or, more commonly, using time of flight (TOF) techniques. In this method photoions are extracted from the ionisation region, accelerated to a known energy E{sub o} and strike a channelplate detector a distance `d` away. The flight time `t` of the photoions is then related to their mass by `d` {radical}m / {radical} 2E{sub o} so measurement of `t` allows mass spectra to be obtained. It is found that LSNMS is an emerging technique of great sensitivity and flexibility, useful for both applied analysis and to investigate basic sputtering processes. 4 refs., 3 figs.

  19. TFTR neutral beam power system

    International Nuclear Information System (INIS)

    Deitz, A.; Murray, H.; Winje, R.

    1977-01-01

    The TFTR NB System will be composed of four beam lines, each containing three ion sources presently being developed for TFTR by the Lawrence Berkeley Laboratories (LBL). The Neutral Beam Power System (NBPS) will provide the necessary power required to operate these Ion Sources in both an experimental or operational mode as well as test mode. This paper describes the technical as well as the administrative/management aspects involved in the development and building of this system. The NBPS will combine the aspects of HV pulse (120 kV) and long pulse width (0.5 sec) together to produce a high power system that is unique in the Electrical Engineering field

  20. Challenges to the development of vaccines to hepatitis C virus that elicit neutralizing antibodies.

    Directory of Open Access Journals (Sweden)

    Heidi Edelgard Drummer

    2014-07-01

    Full Text Available Despite 20 years of research, a vaccine to prevent hepatitis C virus (HCV infection has not been developed. A vaccine to prevent HCV will need to induce broadly reactive immunity able to prevent infection by the 7 genetically and antigenically distinct genotypes circulating world-wide. Hepatitis C virus encodes two surface exposed glycoproteins, E1 and E2 that function as a heterodimer to mediate viral entry. Neutralizing antibodies (NAbs to both E1 and E2 have been described with the major NAb target being E2. The function of E2 is to attach virions to host cells via cell surface receptors that include, but is not limited to, the tetraspanin CD81 and scavenger receptor B class I. However, E2 has developed a number of immune evasion strategies to limit the effectiveness of the NAb response and possibly limit the ability of the immune system to generate potent NAbs in natural infection. Hypervariable regions that shield the underlying core domain, subdominant neutralization epitopes and glycan shielding combine to make E2 a difficult target for the immune system. This review summarizes recent information on the role of neutralizing antibodies to prevent HCV infection, the targets of the neutralizing antibody response and structural information on glycoprotein E2 in complex with neutralizing antibodies. This new information should provide a framework for the rational design of new vaccine candidates that elicit highly potent broadly reactive NAbs to prevent HCV infection.

  1. Modeling Secondary Neutral Helium in the Heliosphere

    International Nuclear Information System (INIS)

    Müller, Hans-Reinhard; Möbius, Eberhard; Wood, Brian E.

    2016-01-01

    An accurate, analytic heliospheric neutral test-particle code for helium atoms from the interstellar medium (ISM) is coupled to global heliospheric models dominated by hydrogen and protons from the solar wind and the ISM. This coupling enables the forward-calculation of secondary helium neutrals from first principles. Secondaries are produced predominantly in the outer heliosheath, upwind of the heliopause, by charge exchange of helium ions with neutral atoms. The forward model integrates the secondary production terms along neutral trajectories and calculates the combined neutral helium phase space density in the innermost heliosphere where it can be related to in-situ observations. The phase space density of the secondary component is lower than that of primary neutral helium, but its presence can change the analysis of primaries and the ISM, and can yield valuable insight into the characteristics of the plasma in the outer heliosheath. (paper)

  2. Molecular clock on a neutral network.

    Science.gov (United States)

    Raval, Alpan

    2007-09-28

    The number of fixed mutations accumulated in an evolving population often displays a variance that is significantly larger than the mean (the overdispersed molecular clock). By examining a generic evolutionary process on a neutral network of high-fitness genotypes, we establish a formalism for computing all cumulants of the full probability distribution of accumulated mutations in terms of graph properties of the neutral network, and use the formalism to prove overdispersion of the molecular clock. We further show that significant overdispersion arises naturally in evolution when the neutral network is highly sparse, exhibits large global fluctuations in neutrality, and small local fluctuations in neutrality. The results are also relevant for elucidating aspects of neutral network topology from empirical measurements of the substitution process.

  3. Neutral particle beam alternative concept for ITER

    International Nuclear Information System (INIS)

    Sedgley, D.; Brook, J.; Luzzi, T.; Deutsch, L.

    1989-01-01

    An analysis of an ITER neutral particle beam system is presented. The analysis covers the neutralizer, ion dumps, pumping, and geometric aspects. The US beam concept for ITER consists of three or four clusters of beamlines delivering approximately 80 MW total of 1.6-MeV deuterium to three or four reactor ports. Each cluster has three self-contained beamlines featuring plasma neutralizers and electrostatic ion dumps. In this study, each of the beamlines has two source assemblies with separate gas neutralizers and magnetic ion dumps. Deuterium is injected into the gas neutralizers by a separate system. Saddle-shaped copper coils augment the tokamak poloidal field to turn the charged particles into the ion dumps. The gas flow from the source, neutralizer, and ion dump is pumped by regenerable cryopanels. The effect of the port between the TF coils and the beam injection angle on the plasma footprint was studied

  4. BEAMS3D Neutral Beam Injection Model

    Energy Technology Data Exchange (ETDEWEB)

    Lazerson, Samuel

    2014-04-14

    With the advent of applied 3D fi elds in Tokamaks and modern high performance stellarators, a need has arisen to address non-axisymmetric effects on neutral beam heating and fueling. We report on the development of a fully 3D neutral beam injection (NBI) model, BEAMS3D, which addresses this need by coupling 3D equilibria to a guiding center code capable of modeling neutral and charged particle trajectories across the separatrix and into the plasma core. Ionization, neutralization, charge-exchange, viscous velocity reduction, and pitch angle scattering are modeled with the ADAS atomic physics database [1]. Benchmark calculations are presented to validate the collisionless particle orbits, neutral beam injection model, frictional drag, and pitch angle scattering effects. A calculation of neutral beam heating in the NCSX device is performed, highlighting the capability of the code to handle 3D magnetic fields.

  5. Neutral-beam current drive in tokamaks

    International Nuclear Information System (INIS)

    Devoto, R.S.

    1986-01-01

    The theory of neutral-beam current drive in tokamaks is reviewed. Experiments are discussed where neutral beams have been used to drive current directly and also indirectly through neoclassical effects. Application of the theory to an experimental test reactor is described. It is shown that neutral beams formed from negative ions accelerated to 500 to 700 keV are needed for this device

  6. Neutral-beam current drive in tokamaks

    International Nuclear Information System (INIS)

    Devoto, R.S.

    1987-01-01

    The theory of neutral-beam current drive in tokamaks is reviewed. Experiments are discussed where neutral beams have been used to drive current directly and also indirectly through neoclassical effects. Application of the theory to an experimental test reactor is described. It is shown that neutral beams formed from negative ions accelerated to 500-700 keV are needed for this device

  7. Lipid raft-like liposomes used for targeted delivery of a chimeric entry-inhibitor peptide with anti-HIV-1 activity.

    Science.gov (United States)

    Gómara, María José; Pérez-Pomeda, Ignacio; Gatell, José María; Sánchez-Merino, Victor; Yuste, Eloisa; Haro, Isabel

    2017-02-01

    The work reports the design and synthesis of a chimeric peptide that is composed of the peptide sequences of two entry inhibitors which target different sites of HIV-1 gp41. The chimeric peptide offers the advantage of targeting two gp41 regions simultaneously: the fusion peptide and the loop both of which are membrane active and participate in the membrane fusion process. We therefore use lipid raft-like liposomes as a tool to specifically direct the chimeric inhibitor peptide to the membrane domains where the HIV-1 envelope protein is located. Moreover, the liposomes that mimic the viral membrane composition protect the chimeric peptide against proteolytic digestion thereby increasing the stability of the peptide. The described liposome preparations are suitable nanosystems for managing hydrophobic entry-inhibitor peptides as putative therapeutics. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. D77, one benzoic acid derivative, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular LEDGF/p75

    International Nuclear Information System (INIS)

    Du Li; Zhao Yaxue; Chen, Jing; Yang Liumeng; Zheng Yongtang; Tang Yun; Shen Xu; Jiang Hualiang

    2008-01-01

    Integration of viral-DNA into host chromosome mediated by the viral protein HIV-1 integrase (IN) is an essential step in the HIV-1 life cycle. In this process, Lens epithelium-derived growth factor (LEDGF/p75) is discovered to function as a cellular co-factor for integration. Since LEDGF/p75 plays an important role in HIV integration, disruption of the LEDGF/p75 interaction with IN has provided a special interest for anti-HIV agent discovery. In this work, we reported that a benzoic acid derivative, 4-[(5-bromo-4-{[2,4-dioxo-3-(2-oxo-2-phenylethyl) -1,3-thiazolidin-5-ylidene]methyl}-2-ethoxyphenoxy)methyl]benzoic acid (D77) could potently inhibit the IN-LEDGF/p75 interaction and affect the HIV-1 IN nuclear distribution thus exhibiting antiretroviral activity. Molecular docking with site-directed mutagenesis analysis and surface plasmon resonance (SPR) binding assays has clarified possible binding mode of D77 against HIV-1 integrase. As the firstly discovered small molecular compound targeting HIV-1 integrase interaction with LEDGF/p75, D77 might supply useful structural information for further anti-HIV agent discovery

  9. 5,6-Dihydro-5-aza-2’-deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors

    OpenAIRE

    Rawson, Jonathan M.; Heineman, Richard H.; Beach, Lauren B.; Martin, Jessica L.; Schnettler, Erica K.; Dapp, Michael J.; Patterson, Steven E.; Mansky, Louis M.

    2013-01-01

    The nucleoside analog 5,6-dihydro-5-aza-2’-deoxycytidine (KP-1212) has been investigated as a first-in-class lethal mutagen of human immunodeficiency virus type-1 (HIV-1). Since a prodrug monotherapy did not reduce viral loads in Phase II clinical trials, we tested if ribonucleotide reductase inhibitors (RNRIs) combined with KP-1212 would improve antiviral activity. KP-1212 potentiated the activity of gemcitabine and resveratrol and simultaneously increased the viral mutant frequency. G-to-C ...

  10. Improved scFv Anti-HIV-1 p17 Binding Affinity Guided from the Theoretical Calculation of Pairwise Decomposition Energies and Computational Alanine Scanning

    Directory of Open Access Journals (Sweden)

    Panthip Tue-ngeun

    2013-01-01

    Full Text Available Computational approaches have been used to evaluate and define important residues for protein-protein interactions, especially antigen-antibody complexes. In our previous study, pairwise decomposition of residue interaction energies of single chain Fv with HIV-1 p17 epitope variants has indicated the key specific residues in the complementary determining regions (CDRs of scFv anti-p17. In this present investigation in order to determine whether a specific side chain group of residue in CDRs plays an important role in bioactivity, computational alanine scanning has been applied. Molecular dynamics simulations were done with several complexes of original scFv anti-p17 and scFv anti-p17mutants with HIV-1 p17 epitope variants with a production run up to 10 ns. With the combination of pairwise decomposition residue interaction and alanine scanning calculations, the point mutation has been initially selected at the position MET100 to improve the residue binding affinity. The calculated docking interaction energy between a single mutation from methionine to either arginine or glycine has shown the improved binding affinity, contributed from the electrostatic interaction with the negative favorably interaction energy, compared to the wild type. Theoretical calculations agreed well with the results from the peptide ELISA results.

  11. Elucidating a Key Anti-HIV-1 and Cancer-Associated Axis: The Structure of CCL5 (Rantes) in Complex with CCR5

    Science.gov (United States)

    Tamamis, Phanourios; Floudas, Christodoulos A.

    2014-06-01

    CCL5 (RANTES) is an inflammatory chemokine which binds to chemokine receptor CCR5 and induces signaling. The CCL5:CCR5 associated chemotactic signaling is of critical biological importance and is a potential HIV-1 therapeutic axis. Several studies provided growing evidence for the expression of CCL5 and CCR5 in non-hematological malignancies. Therefore, the delineation of the CCL5:CCR5 complex structure can pave the way for novel CCR5-targeted drugs. We employed a computational protocol which is primarily based on free energy calculations and molecular dynamics simulations, and report, what is to our knowledge, the first computationally derived CCL5:CCR5 complex structure which is in excellent agreement with experimental findings and clarifies the functional role of CCL5 and CCR5 residues which are associated with binding and signaling. A wealth of polar and non-polar interactions contributes to the tight CCL5:CCR5 binding. The structure of an HIV-1 gp120 V3 loop in complex with CCR5 has recently been derived through a similar computational protocol. A comparison between the CCL5 : CCR5 and the HIV-1 gp120 V3 loop : CCR5 complex structures depicts that both the chemokine and the virus primarily interact with the same CCR5 residues. The present work provides insights into the blocking mechanism of HIV-1 by CCL5.

  12. Niclosamide is a proton carrier and targets acidic endosomes with broad antiviral effects.

    Science.gov (United States)

    Jurgeit, Andreas; McDowell, Robert; Moese, Stefan; Meldrum, Eric; Schwendener, Reto; Greber, Urs F

    2012-01-01

    Viruses use a limited set of host pathways for infection. These pathways represent bona fide antiviral targets with low likelihood of viral resistance. We identified the salicylanilide niclosamide as a broad range antiviral agent targeting acidified endosomes. Niclosamide is approved for human use against helminthic infections, and has anti-neoplastic and antiviral effects. Its mode of action is unknown. Here, we show that niclosamide, which is a weak lipophilic acid inhibited infection with pH-dependent human rhinoviruses (HRV) and influenza virus. Structure-activity studies showed that antiviral efficacy and endolysosomal pH neutralization co-tracked, and acidification of the extracellular medium bypassed the virus entry block. Niclosamide did not affect the vacuolar H(+)-ATPase, but neutralized coated vesicles or synthetic liposomes, indicating a proton carrier mode-of-action independent of any protein target. This report demonstrates that physico-chemical interference with host pathways has broad range antiviral effects, and provides a proof of concept for the development of host-directed antivirals.

  13. Niclosamide is a proton carrier and targets acidic endosomes with broad antiviral effects.

    Directory of Open Access Journals (Sweden)

    Andreas Jurgeit

    Full Text Available Viruses use a limited set of host pathways for infection. These pathways represent bona fide antiviral targets with low likelihood of viral resistance. We identified the salicylanilide niclosamide as a broad range antiviral agent targeting acidified endosomes. Niclosamide is approved for human use against helminthic infections, and has anti-neoplastic and antiviral effects. Its mode of action is unknown. Here, we show that niclosamide, which is a weak lipophilic acid inhibited infection with pH-dependent human rhinoviruses (HRV and influenza virus. Structure-activity studies showed that antiviral efficacy and endolysosomal pH neutralization co-tracked, and acidification of the extracellular medium bypassed the virus entry block. Niclosamide did not affect the vacuolar H(+-ATPase, but neutralized coated vesicles or synthetic liposomes, indicating a proton carrier mode-of-action independent of any protein target. This report demonstrates that physico-chemical interference with host pathways has broad range antiviral effects, and provides a proof of concept for the development of host-directed antivirals.

  14. MICROLENSING OF QUASAR BROAD EMISSION LINES: CONSTRAINTS ON BROAD LINE REGION SIZE

    Energy Technology Data Exchange (ETDEWEB)

    Guerras, E.; Mediavilla, E. [Instituto de Astrofisica de Canarias, Via Lactea S/N, La Laguna E-38200, Tenerife (Spain); Jimenez-Vicente, J. [Departamento de Fisica Teorica y del Cosmos, Universidad de Granada, Campus de Fuentenueva, E-18071 Granada (Spain); Kochanek, C. S. [Department of Astronomy and the Center for Cosmology and Astroparticle Physics, The Ohio State University, 4055 McPherson Lab, 140 West 18th Avenue, Columbus, OH 43221 (United States); Munoz, J. A. [Departamento de Astronomia y Astrofisica, Universidad de Valencia, E-46100 Burjassot, Valencia (Spain); Falco, E. [Center for Astrophysics, 60 Garden Street, Cambridge, MA 02138 (United States); Motta, V. [Departamento de Fisica y Astronomia, Universidad de Valparaiso, Avda. Gran Bretana 1111, Valparaiso (Chile)

    2013-02-20

    We measure the differential microlensing of the broad emission lines between 18 quasar image pairs in 16 gravitational lenses. We find that the broad emission lines are in general weakly microlensed. The results show, at a modest level of confidence (1.8{sigma}), that high ionization lines such as C IV are more strongly microlensed than low ionization lines such as H{beta}, indicating that the high ionization line emission regions are more compact. If we statistically model the distribution of microlensing magnifications, we obtain estimates for the broad line region size of r{sub s} = 24{sup +22} {sub -15} and r{sub s} = 55{sup +150} {sub -35} lt-day (90% confidence) for the high and low ionization lines, respectively. When the samples are divided into higher and lower luminosity quasars, we find that the line emission regions of more luminous quasars are larger, with a slope consistent with the expected scaling from photoionization models. Our estimates also agree well with the results from local reveberation mapping studies.

  15. On implicit abstract neutral nonlinear differential equations

    Energy Technology Data Exchange (ETDEWEB)

    Hernández, Eduardo, E-mail: lalohm@ffclrp.usp.br [Universidade de São Paulo, Departamento de Computação e Matemática, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto (Brazil); O’Regan, Donal, E-mail: donal.oregan@nuigalway.ie [National University of Ireland, School of Mathematics, Statistics and Applied Mathematics (Ireland)

    2016-04-15

    In this paper we continue our developments in Hernández and O’Regan (J Funct Anal 261:3457–3481, 2011) on the existence of solutions for abstract neutral differential equations. In particular we extend the results in Hernández and O’Regan (J Funct Anal 261:3457–3481, 2011) for the case of implicit nonlinear neutral equations and we focus on applications to partial “nonlinear” neutral differential equations. Some applications involving partial neutral differential equations are presented.

  16. Structural Basis for Differential Neutralization of Ebolaviruses

    Directory of Open Access Journals (Sweden)

    John M. Dye

    2012-04-01

    Full Text Available There are five antigenically distinct ebolaviruses that cause hemorrhagic fever in humans or non-human primates (Ebola virus, Sudan virus, Reston virus, Taï Forest virus, and Bundibugyo virus. The small handful of antibodies known to neutralize the ebolaviruses bind to the surface glycoprotein termed GP1,2. Curiously, some antibodies against them are known to neutralize in vitro but not protect in vivo, whereas other antibodies are known to protect animal models in vivo, but not neutralize in vitro. A detailed understanding of what constitutes a neutralizing and/or protective antibody response is critical for development of novel therapeutic strategies. Here, we show that paradoxically, a lower affinity antibody with restricted access to its epitope confers better neutralization than a higher affinity antibody against a similar epitope, suggesting that either subtle differences in epitope, or different characteristics of the GP1,2 molecules themselves, confer differential neutralization susceptibility. Here, we also report the crystal structure of trimeric, prefusion GP1,2 from the original 1976 Boniface variant of Sudan virus complexed with 16F6, the first antibody known to neutralize Sudan virus, and compare the structure to that of Sudan virus, variant Gulu. We discuss new structural details of the GP1-GP2 clamp, thermal motion of various regions in GP1,2 across the two viruses visualized, details of differential interaction of the crystallized neutralizing antibodies, and their relevance for virus neutralization.

  17. Minor Capsid Protein L2 Polytope Induces Broad Protection against Oncogenic and Mucosal Human Papillomaviruses.

    Science.gov (United States)

    Pouyanfard, Somayeh; Spagnoli, Gloria; Bulli, Lorenzo; Balz, Kathrin; Yang, Fan; Odenwald, Caroline; Seitz, Hanna; Mariz, Filipe C; Bolchi, Angelo; Ottonello, Simone; Müller, Martin

    2018-02-15

    The amino terminus of the human papillomavirus (HPV) minor capsid protein L2 contains a major cross-neutralization epitope which provides the basis for the development of a broadly protecting HPV vaccine. A wide range of protection against different HPV types would eliminate one of the major drawbacks of the commercial, L1-based prophylactic vaccines. Previously, we have reported that insertion of the L2 epitope into a scaffold composed of bacterial thioredoxin protein generates a potent antigen inducing comprehensive protection against different animal and human papillomaviruses. We also reported, however, that although protection is broad, some oncogenic HPV types escape the neutralizing antibody response, if L2 epitopes from single HPV types are used as immunogen. We were able to compensate for this by applying a mix of thioredoxin proteins carrying L2 epitopes from HPV16, -31, and -51. As the development of a cost-efficient HPV prophylactic vaccines is one of our objectives, this approach is not feasible as it requires the development of multiple good manufacturing production processes in combination with a complex vaccine formulation. Here, we report the development of a thermostable thioredoxin-based single-peptide vaccine carrying an L2 polytope of up to 11 different HPV types. The L2 polytope antigens have excellent abilities in respect to broadness of protection and robustness of induced immune responses. To further increase immunogenicity, we fused the thioredoxin L2 polytope antigen with a heptamerization domain. In the final vaccine design, we achieve protective responses against all 14 oncogenic HPV types that we have analyzed plus the low-risk HPVs 6 and 11 and a number of cutaneous HPVs. IMPORTANCE Infections by a large number of human papillomaviruses lead to malignant and nonmalignant disease. Current commercial vaccines based on virus-like particles (VLPs) effectively protect against some HPV types but fail to do so for most others. Further, only

  18. Validation, automatic generation and use of broad phonetic transcriptions

    NARCIS (Netherlands)

    Bael, Cristophe Patrick Jan Van

    2007-01-01

    Broad phonetic transcriptions represent the pronunciation of words as strings of characters from specifically designed symbol sets. In everyday life, broad phonetic transcriptions are often used as aids to pronounce (foreign) words. In addition, broad phonetic transcriptions are often used for

  19. Manta A New BroadBand OBS

    Science.gov (United States)

    Hello, Y.; Yegikyan, M.; Charvis, P.; Philippe, O.

    2017-12-01

    Manta is a new BroadBand OBS developed at Geoazur and commercialized by Osean. The design is inspired by 3-years autonomy MUG-OBS a Multiparameter Ocean Bottom System which carry a lot of sort of sensor types. As Mug-OBS, Manta-OBS rated 6000m is designed to resist a trawling. All the components are non corrosive such polyethylene, titanium and buoyancy is ensured by syntactic foam. Equipped in standard version with a Trillium compact OBS Manta has an autonomy of 18 months, but can accept on its 4 input channels any kind of signal as low as from an hydrophone or larger from other type of a seismometer or accelerometer. Tri-axial geophones unit (2 Hz or 4.5 Hz ) can replace the seismometer and will expend the lifespan for the instrument. The seismometer is encapsulated in a central well established by four panels of the main structure to protect it from sea current convection and is decoupled from main chassis. An health bulletin is recoverable by acoustic any time to facilitate the installation and during a visit when instrument is deployed. Main parameters for acquisition can be changed by acoustics command from surface at any time. Once at the bottom, release for the main sensor installation is programmed on a timer but controlled by the tilt of the OBS. If the tilt is too important based on programmed limits, sensor will not released automatically, but this can be forced by acoustic command after returning the tilt informations to the boat operator. Manta is equipped with flash light and AIS system for easy location at recovery, and can also send it's position by Iridium satellite in case of an unexpected ascent such caused by a possible trawling if deployed in shallow water. Clock drift calculation is automatically made against GPS time signal once the OBS return at the surface. The recovery of the OBS is initiated by an acoustic command. These new features made Manta a very versatile instrument for monitoring earthquakes.

  20. Liberal Neutrality : Constructivist, not foundationalist

    Directory of Open Access Journals (Sweden)

    Lendell Horne

    2009-06-01

    Full Text Available In defending the principle of neutrality, liberals have often appealed to a more general moral principle that forbids coercing persons in the name of reasons those persons themselves cannot reasonably be expected to share. Yet liberals have struggled to articulate a non-arbitrary, non-dogmatic distinction between the reasons that persons can reasonably be expected to share and those they cannot. The reason for this, I argue, is that what it means to “share a reason” is itself obscure. In this paper I articulate two different conceptions of what it is to share a reason; I call these conceptions “foundationalist” and “constructivist.” On the foundationalist view, two people “share” a reason just in the sense that the same reason applies to each of them independently. On this view, I argue, debates about the reasons we share collapse into debates about the reasons we have, moving us no closer to an adequate defense of neutrality. On the constructivist view, by contrast, “sharing reasons” is understood as a kind of activity, and the reasons we must share are just those reasons that make this activity possible. I argue that the constructivist conception of sharing reasons yields a better defense of the principle of neutrality. À travers leur défense du principe de neutralité, les libéraux ont souvent interpellé un principe moral plus général qui interdit de contraindre des personnes pour des raisons dont on ne peut raisonnablement attendre que ces personnes elles-mêmes les partagent. Les libéraux éprouvent cependant de la difficulté à articuler une distinction non-arbitraire et non-dogmatique entre les raisons dont on peut raisonnablement attendre que les personnes les partagent et celles dont on ne le peut pas. Je soutiens dans cet article que cette difficulté provient du fait que «partager une raison » est une notion obscure. Pour illustrer cela, je me pencherai sur deux conceptions distinctes de ce que veut dire

  1. The status of neutral currents

    International Nuclear Information System (INIS)

    Zwirner, F.

    1987-11-01

    The situation of particle physics today is quite puzzling. On the one hand, the Standard Model (SM) of strong and electroweak interactions is consistent with all confirmed experimental data but theoretically rather unsatisfactory. On the other hand, none of the many theoretical speculations which try to go beyond the SM has (yet) received the slightest experimental support. The solution to this dilemma can only come from new data: either from the detection of a new particle threshold at high energy colliders, or from the appearance of some small discrepancy in high-precision experiments. A crucial sector for testing the SM and its extensions is that of neutral currents (NC), where an impressive amount of data has been collected in recent years. While waiting for the next generation of experiments, it is certainly useful to take stock of our knowledge, determining the NC parameters as precisely as we can and putting limits on possible deviations from the SM. The present talk contains the results of a recent analysis along these lines: the first part illustrates how a set of 'model-independent' parameters can be extracted from the available NC data, the second part particularizes the analysis to the SM and to some superstring-inspired models with an additional Z' in their low-energy spectrum. 27 refs., 3 figs., 1 tab

  2. Auditors' Professional Skepticism: Neutrality versus Presumptive Doubt

    NARCIS (Netherlands)

    Groot, T.L.C.M.; Quadackers, L.M.; Wright, A.

    2014-01-01

    Although skepticism is widely viewed as essential to audit quality, there is a debate about what form is optimal. The two prevailing perspectives that have surfaced are "neutrality" and "presumptive doubt." With neutrality, auditors neither believe nor disbelieve client management. With presumptive

  3. 32 CFR 644.323 - Neutral language.

    Science.gov (United States)

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Neutral language. 644.323 Section 644.323 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE HANDBOOK Disposal § 644.323 Neutral language. Wherever the words “man”, “men”, or their related...

  4. 3He neutral current detectors at SNO

    International Nuclear Information System (INIS)

    Elliott, S.R.; Browne, M.C.; Doe, P.J.

    1998-01-01

    The flux of solar neutrinos measured via charged and neutral current interactions can provide a model independent test of neutrino oscillations. Since the Sudbury Neutrino Observatory uses heavy water as a target, it has a large sensitivity to both interactions. A technique for observing the neutral current breakup of the deuteron using 3 He proportional counters is described

  5. Photoproduction of neutral pions off protons

    NARCIS (Netherlands)

    Crede, V.; Sparks, N.; Wilson, A.; Anisovich, A. V.; Bacelar, J. C. S.; Bantes, R.; Bartholomy, O.; Bayadilov, D.; Beck, R.; Beloglazov, Y. A.; Castelijns, R.; Dutz, H.; Elsner, D.; Ewald, R.; Frommberger, F.; Funke, Chr; Gregor, R.; Gridnev, A.; Gutz, E.; Hillert, W.; Hoffmeister, P.; Jaegle, I.; Junkersfeld, J.; Kalinowsky, H.; Kammer, S.; Klein, Frank; Klein, Friedrich; Klempt, E.; Kotulla, M.; Krusche, B.; Löhner, H.; Lopatin, I. V.; Lugert, S.; Menze, D.; Mertens, T.; Messchendorp, J. G.; Metag, V.; Nanova, M.; Nikonov, V. A.; Novinski, D.; Novotny, R.; Ostrick, M.; Pant, L. M.; van Pee, H.; Pfeiffer, M.; Roy, A.; Sarantsev, A. V.; Schadmand, S.; Schmidt, C.; Schmieden, H.; Schoch, B.; Shende, S.; Sokhoyan, V.; Suele, A.; Sumachev, V. V.; Szczepanek, T.; Thoma, U.; Trnka, D.; Varma, R.; Walther, D.; Wendel, Ch

    2011-01-01

    Photoproduction of neutral pions has been studied with the CBELSA/TAPS detector in the reaction gamma p -> p pi(0) for photon energies between 0.85 and 2.50 GeV. The pi(0) mesons are observed in their dominant neutral decay mode: pi(0) -> gamma gamma. For the first time, the differential cross

  6. On the possible eigenoscillations of neutral sheets

    International Nuclear Information System (INIS)

    Almeida, W.A.; Costa, J.M. da; Aruquipa, E.G.; Sudano, J.P.

    1974-12-01

    A neutral sheet model with hyperbolic tangent equilibrium magnetic field and hyperbolic square secant density profiles is considered. It is shown that the equation for small oscillations takes the form of an eigenvalue oscillation problem. Computed eigenfrequencies of the geomagnetic neutral sheet were found to be in the range of the resonant frequencies of the geomagnetic plasma sheet computed by other authors

  7. Gender Neutrality: Women's Friend or Foe?

    Science.gov (United States)

    Steuernagel, Trudy

    Gender neutral public policies are those that are either silent on the question of the existence of significant gender differences or incorporate a perspective which mandates that such differences be ignored. Prominent voices today contend that gender neutrality favors males and have held the male standard as the one for which women should aspire.…

  8. Targets for high power neutral beams

    International Nuclear Information System (INIS)

    Kim, J.

    1980-01-01

    Stopping high-power, long-pulse beams is fast becoming an engineering challenge, particularly in neutral beam injectors for heating magnetically confined plasmas. A brief review of neutral beam target technology is presented along with heat transfer calculations for some selected target designs

  9. On plasma-neutral gas interaction

    International Nuclear Information System (INIS)

    Venkataramani, N.; Mattoo, S.K.

    1980-01-01

    The importance of plasma-neutral gas interaction layer has been emphasized by pointing out its application to a wide variety of physical phenomena. The interaction of a magnetised plasma stream penetrating a neutral gas cloud is discussed in the light of Alfven's critical velocity and Varma's threshold velocity on the ionising interaction. Interaction of a moving magnetised plasma with a stationary neutral gas has been studied and described. The device comprises of a plasma gun and an interaction region where neutral gas cloud is injected. The interaction region is provided with a transverse magnetic field of upto 1000 G. Several diagnostics deployed at the interaction region to make measurements on the macroscopic parameters of plasma and neutral gas are described. The parameters of discharge circuits are measured with high current and voltage probes. An interaction between a magnetised plasma stream and a neutral gas cloud is demonstrated. It is shown that this interaction does not have Varma's threshold on their relative velocity. The Alfven's critical velocity phenomenon is shown to depend on the integrated column neutral gas density that a plasma stream encounters while penetrating through it and not on the neutral gas density in the range of 10 17 -10 21 m -3 . (auth.)

  10. Net Neutrality and Inflation of Traffic

    NARCIS (Netherlands)

    Peitz, M.; Schütt, F.

    2015-01-01

    Under strict net neutrality Internet service providers (ISPs) are required to carry data without any differentiation and at no cost to the content provider. We provide a simple framework with a monopoly ISP to evaluate different net neutrality rules. Content differs in its sensitivity to delay.

  11. Net neutrality and inflation of traffic

    NARCIS (Netherlands)

    Peitz, M.; Schütt, Florian

    Under strict net neutrality Internet service providers (ISPs) are required to carry data without any differentiation and at no cost to the content provider. We provide a simple framework with a monopoly ISP to evaluate the short-run effects of different net neutrality rules. Content differs in its

  12. Neutralization of wastewater from nitrite passivation

    International Nuclear Information System (INIS)

    Pawlowski, L.; Mientki, B.; Wasag, H.

    1982-01-01

    A method for neutralization of wastewater formed in nitrite passivation has been presented. The method consists of introducing urea into wastewater and acidifying it with sulphuric acid. Wastewater is neutralized with lime. After clarification, wastewater can be drained outside the plant

  13. A neutral sampling formula for multiple samples and an `exact' test of neutrality

    NARCIS (Netherlands)

    Etienne, R.S.

    2007-01-01

    As the utility of the neutral theory of biodiversity is increasingly being recognized, there is also an increasing need for proper tools to evaluate the relative importance of neutral processes (dispersal limitation and stochasticity). One of the key features of neutral theory is its close link to

  14. A neutral sampling formula for multiple samples and an 'exact' test of neutrality

    NARCIS (Netherlands)

    Etienne, Rampal S.

    As the utility of the neutral theory of biodiversity is increasingly being recognized, there is also an increasing need for proper tools to evaluate the relative importance of neutral processes (dispersal limitation and stochasticity). One of the key features of neutral theory is its close link to

  15. Neutral beam in ALVAND IIC tokamak

    International Nuclear Information System (INIS)

    Ghrannevisse, M.; Moradshahi, M.; Avakian, M.

    1992-01-01

    Neutral beams have a wide application in tokamak experiments. It used to heat; fuel; adjust electric potentials in plasmas and diagnose particles densities and momentum distributions. It may be used to sustain currents in tokamaks to extend the pulse length. A 5 KV; 500 mA ion source has been constructed by plasma physics group, AEOI and it used to produce plasma and study the plasma parameters. Recently this ion source has been neutralized and it adapted to a neutral beam source; and it used to heat a cylindrical DC plasma and the plasma of ALVAND IIC Tokamak which is a small research tokamak with a minor radius of 12.6 cm, and a major radius of 45.5 cm. In this paper we report the neutralization of the ion beam and the results obtained by injection of this neutral beam into plasmas. (author) 2 refs., 4 figs

  16. Tax Neutrality on International Capital Investments

    Directory of Open Access Journals (Sweden)

    Gizem KAPUCU

    2017-07-01

    Full Text Available The tax policies which states follow with regard to developing technology and capital investments with raising mobility due to globalism are need to be discussed in its legal basis. The principle of tax neutrality has the aim of being legal foundation for these policies. According to this, the neutrality principle in taxation of international capital investments is provided with two measures, namely; not effecting the investment decision and not discriminate between investments. In this paper, initially focused on the conceptual framework and the foundations of the tax neutrality principle and later capital export neutrality and capital import neutrality are considered and explained with regard to international capital movements. Moreover, conformity and diversion to the principle of the current situation and regulations in OECD, EU and Turkey are examined.

  17. Sputtering of neutral and ionic indium clusters

    International Nuclear Information System (INIS)

    Ma, Z.; Coon, S.R.; Calaway, W.F.; Pellin, M.J.; Gruen, D.M.; Von Nagy-Felsobuki, E.I.

    1993-01-01

    Secondary neutral and secondary ion cluster yields were measured during the sputtering of a polycrystalline indium surface by normally incident ∼4 keV Ar + ions. In the secondary neutral mass spectra, indium clusters as large as In 32 were observed. In the secondary ion mass spectra, indium clusters up to In 18 + were recorded. Cluster yields obtained from both the neutral and ion channel exhibited a power law dependence on the number of constituent atoms, n, in the cluster, with the exponents measured to be -5.6 and -4. 1, respectively. An abundance drop was observed at n=8, 15, and 16 in both the neutral and ion yield distributions suggesting that the stability of the ion (either secondary ion or photoion) plays a significant role in the observed distributions. In addition, our experiments suggest that unimolecular decomposition of the neutral cluster may also plays an important role in the measured yield distributions

  18. Neutral-beam-heating applications and development

    International Nuclear Information System (INIS)

    Menon, M.M.

    1981-01-01

    The technique of heating the plasma in magnetically confined fusion devices by the injection of intense beams of neutral atoms is described. The basic principles governing the physics of neutral beam heating and considerations involved in determining the injection energy, power, and pulse length required for a fusion reactor are discussed. The pertinent experimental results from various fusion devices are surveyed to illustrate the efficacy of this technique. The second part of the paper is devoted to the technology of producing the neutral beams. A state-of-the-art account o the development of neutral injectors is presented, and the prospects for utilizing neutral injection to heat the plasma in a fusion reactor are examined

  19. ORNL neutral-beam program in 1978

    International Nuclear Information System (INIS)

    Whealton, J.H.

    1982-12-01

    This report was presented at the ion source workshop held at Culham Laboratory, Abingdon, Oxfordshire, in 1978. Because the proceedings of that conference are unavailable, and because the material in this report is still not to be found elsewhere, it is issued as a laboratory report. The neutral beam group at Oak Ridge National Laboratory has constructed neutral beam generators for the ORMAK and PLT devices, is presently constructing neutral beam devices for the ISX and PDX devices, and is contemplating the construction of neutral beam systems for the advanced TNS device. These neutral beam devices stem from the pioneering work on ion sources of G.G. Kelley and O.B. Morgan. We describe the ion sources under development at this laboratory, the beam optics exhibited by these sources, as well as some theoretical considerations, and finally the remainder of the beamline design

  20. Net Neutrality: Media Discourses and Public Perception

    Directory of Open Access Journals (Sweden)

    Christine Quail

    2010-01-01

    Full Text Available This paper analyzes media and public discourses surrounding net neutrality, with particular attention to public utility philosophy, from a critical perspective. The article suggests that further public education about net neutrality would be beneficial. The first portion of this paper provides a survey of the existing literature surrounding net neutrality, highlighting the contentious debate between market-based and public interest perspectives. In order to contextualize the debate, an overview of public utility philosophy is provided, shedding light on how the Internet can be conceptualized as a public good. Following this discussion, an analysis of mainstream media is presented, exploring how the media represents the issue of net neutrality and whether or not the Internet is discussed through the lens of public utility. To further examine how the net neutrality debate is being addressed, and to see the potential impacts of media discourses on the general public, the results of a focus group are reported and analyzed. Finally, a discussion assesses the implications of the net neutrality debate as presented through media discourses, highlighting the future of net neutrality as an important policy issue.

  1. Neutral Supersymmetric Higgs Boson Searches

    Energy Technology Data Exchange (ETDEWEB)

    Robinson, Stephen Luke [Imperial College, London (United Kingdom)

    2008-07-01

    In some Supersymmetric extensions of the Standard Model, including the Minimal Supersymmetric Standard Model (MSSM), the coupling of Higgs bosons to b-quarks is enhanced. This enhancement makes the associated production of the Higgs with b-quarks an interesting search channel for the Higgs and Supersymmetry at D0. The identification of b-quarks, both online and offline, is essential to this search effort. This thesis describes the author's involvement in the development of both types of b-tagging and in the application of these techniques to the MSSM Higgs search. Work was carried out on the Level-3 trigger b-tagging algorithms. The impact parameter (IP) b-tagger was retuned and the effects of increased instantaneous luminosity on the tagger were studied. An extension of the IP-tagger to use the z-tracking information was developed. A new b-tagger using secondary vertices was developed and commissioned. A tool was developed to allow the use of large multi-run samples for trigger studies involving b-quarks. Offline, a neural network (NN) b-tagger was trained combining the existing offline lifetime based b-tagging tools. The efficiency and fake rate of the NN b-tagger were measured in data and MC. This b-tagger was internally reviewed and certified by the Collaboration and now provides the official b-tagging for all analyses using the Run IIa dataset at D0. A search was performed for neutral MSSM Higgs bosons decaying to a b{bar b} pair and produced in association with one or more b-quarks. Limits are set on the cross-section times the branching ratio for such a process. The limits were interpreted in various MSSM scenarios. This analysis uses the NN b-tagger and was the first to use this tool. The analysis also relies on triggers using the Level-3 IP b-tagging tool described previously. A likelihood discriminant was used to improve the analysis and a neural network was developed to cross-check this technique. The result of the analysis has been submitted to PRL

  2. Evaluation of smallpox vaccines using variola neutralization.

    Science.gov (United States)

    Damon, Inger K; Davidson, Whitni B; Hughes, Christine M; Olson, Victoria A; Smith, Scott K; Holman, Robert C; Frey, Sharon E; Newman, Frances; Belshe, Robert B; Yan, Lihan; Karem, Kevin

    2009-08-01

    The search for a 'third'-generation smallpox vaccine has resulted in the development and characterization of several vaccine candidates. A significant barrier to acceptance is the absence of challenge models showing induction of correlates of protective immunity against variola virus. In this light, virus neutralization provides one of few experimental methods to show specific 'in vitro' activity of vaccines against variola virus. Here, we provide characterization of the ability of a modified vaccinia virus Ankara vaccine to induce variola virus-neutralizing antibodies, and we provide comparison with the neutralization elicited by standard Dryvax vaccination.

  3. Neutral currents, supernovae neutrinos, and nucleosynthesis

    International Nuclear Information System (INIS)

    Haxton, W.C.

    1988-01-01

    The inelastic interactions of neutrinos during stellar collapse and neutron star cooling are discussed. The primary mechanism for dissipative neutrino reactions is nuclear excitation by neutral current scattering, a process not included in standard descriptions of supernovae. Charge-current and neutral current ''preheating'' of iron lying outside the shock front appears to be significant in the few milliseconds near shock breakout. This could help produce a more energetic shock. During the cooling phase, the neutral current interactions of muon and taon neutrinos appear to be responsible for some interesting nucleosynthesis. I discuss two examples the production of fluorine and neutrino-induced r-process nucleosynthesis. 26 refs., 1 fig., 3 tabs

  4. Rare decays of neutral π and eta

    International Nuclear Information System (INIS)

    Poutissou, J.M.

    1983-09-01

    The decays of the pseudoscalar neutral mesons π degree and eta degree have provided a test of fundamental principles. The main branch, π degree → 2γ, was investigated in the late 60's in the context of current algebra and the decay rate calculated from the singular triangle diagram is in excellent agreement with experiment. Rare leptonic decays of the neutral pseudoscalar mesons are of interest because of the information they reveal about neutral currents or other exotic interactions between leptons and quarks. The author discusses recent information on the π degree → e + e - decay

  5. Soviet exoatmospheric neutral particle beam research

    International Nuclear Information System (INIS)

    Leiss, J.E.; Abrams, R.H.; Ehlers, K.W.; Farrell, J.A.; Gillespie, G.H.; Jameson, R.A.; Keefe, D.; Parker, R.K.

    1988-02-01

    This technical assessment was performed by a panel of eight U.S. scientists and engineers who are familiar with Soviet research through their own research experience, their knowledge of the published scientific literature and conference proceedings, and personal contacts with Soviet scientists and other foreign colleagues. Most of the technical components of a neutral particle beam generating system including the ion source, the accelerator, the accelerator radio frequency power supply, the beam conditioning and aiming system, and the beam neutralizer system are addressed. It does not address a number of other areas important to an exoatmospheric neutral beam system

  6. Fast Neutral Pressure Measurements in NSTX

    International Nuclear Information System (INIS)

    R. Raman; H.W. Kugel; T. Provost; R. Gernhardt; T.R. Jarboe; M.G. Bell

    2002-01-01

    Several fast neutral pressure gauges have been installed on NSTX [National Spherical Torus Experiment] to measure the vessel and divertor pressure during inductive and coaxial helicity injected (CHI) plasma operations. Modified, PDX [Poloidal Divertor Experiment]-type Penning gauges have been installed on the upper and lower divertors. Neutral pressure measurements during plasma operations from these and from two shielded fast Micro ion gauges at different toroidal locations on the vessel mid-plane are described. A new unshielded ion gauge, referred to as the In-vessel Neutral Pressure (INP) gauge is under development

  7. Negative ion formation and neutralization processes, (2)

    International Nuclear Information System (INIS)

    Sugiura, Toshio

    1982-09-01

    This review is 2nd part of the report published at January 1982 (JAERI-M-9902). A compilation includes the survey of the data of the cross sections of H - and D - ion formations and the neutralization of these ions. This is also presented new information about the photosensitization by laser beam in dissociative-resonance electron capture of sulfur hexafluoride reported by Chen et al., for reference to enhancement of D - ions in discharge. For neutralization, the data of mutual neutralization and photodetachment are also presented. (author)

  8. Neutral Color Semitransparent Microstructured Perovskite Solar Cells

    KAUST Repository

    Eperon, Giles E.; Burlakov, Victor M.; Goriely, Alain; Snaith, Henry J.

    2014-01-01

    Neutral-colored semitransparent solar cells are commercially desired to integrate solar cells into the windows and cladding of buildings and automotive applications. Here, we report the use of morphological control of perovskite thin films to form

  9. Charge neutralization of small ion beam clumps

    Energy Technology Data Exchange (ETDEWEB)

    Welch, D R [Mission Research Corp., Albuquerque, NM (United States); Olson, C L; Hanson, D L [Sandia National Labs., Albuquerque, NM (United States)

    1997-12-31

    The mega-ampere currents associated with light ion fusion (LIF) require excellent charge neutralization to prevent divergence growth. As the size and space-charge potential of a beam clump or `beamlet` become small (submillimeter size and kilovolt potentials), the neutralization becomes increasingly difficult. Linear theory predicts that plasma electrons cannot neutralize potentials < {phi}{sub crit} = (1/2)m{sub e}v{sub i}{sup 2}/e, where m{sub e} is the electron mass and v{sub i} is the ion beam velocity. A non-uniform beam would, therefore, have regions with potentials sufficient to add divergence to beam clumps. The neutralization of small beamlets produced on the SABLE accelerator and in numerical simulation has supported the theory, showing a plateau in divergence growths as the potential in the beamlet exceeds {phi}{sub crit}. (author). 1 tab., 2 figs., 4 refs.

  10. UV Ionizer for Neutral Wind Mass Spectrometers

    Data.gov (United States)

    National Aeronautics and Space Administration — Current neutral particle instrumentation relies on hot cathode filaments or an electron gun for ionizing the target medium.  These ionization sources represent a...

  11. Kinetics of neutralization of Po-218

    International Nuclear Information System (INIS)

    Chu, K.D.

    1987-01-01

    In a well-defined experimental system the neutralization of polonium-218 ions was investigated as a function of the physical and chemical properties of the controlled composition atmosphere. The mobilities of Po + and PoO 2 + are determined by combining experimental results with a computer model of the system. Three neutralization mechanisms were individually studied. The small ion recombination rate has been found to be proportional to the square root of radon concentration. The electron scavenging mechanism is responsible for the neutralization of Po + in NO 2 or H 2 O in nitrogen. When PoO 2 + is formed, the electron transfer mechanism dominates the neutralization process. The electron is transferred to PoO 2 + from molecules with lower ionization potentials. The ionization potential of PoO 2 + is also determined to be 10.44 +/- 0.05 eV

  12. An experimenter's history of neutral currents

    International Nuclear Information System (INIS)

    Sciulli, F.

    1979-01-01

    The history of the experimental study of neutral currents, defined as the class of weak interactions engaged in by lepton pairs of net zero charge, is traced under the headings; historical motivations, experimental searches, first positive indications, neutral currents corroborated, neutrino experiments on neutral currents and some general experimental comments. It is concluded that the neutral current does exist and predicted on the basis of gauge theory ideas, and though to connect the weak and electromagnetic interactions, its very general experimental properties are quite consistent with those ideas. Among these are flavor conserving complicated isospin structure, complicated V, A structure and a structure which depends on the type (or quantum numbers) of the target. 50 references. (UK)

  13. ITER neutral beam system US conceptual design

    International Nuclear Information System (INIS)

    Purgalis, P.

    1990-09-01

    In this document we present the US conceptual design of a neutral beam system for International Thermonuclear Experimental Reactor (ITER). The design incorporates a barium surface conversion D - source feeding a linear array of accelerator channels. The system uses a dc accelerator with electrostatic quadrupoles for strong focusing. A high voltage power supply that is integrated with the accelerator is presented as an attractive option. A gas neutralizer is used and residual ions exiting the neutralizer are deflected to water-cooled dumps. Cryopanels are located at the accelerator exit to pump excess gas from the source and the neutralizer, and in the ion dump cavity to pump re-neutralized ions and neutralizer gas. All the above components are packaged in compact identical, independent modules which can be removed for remote maintenance. The neutral beam system delivers 75 MW of DO at 1.3 MeV, into three ports with a total of 9 modules arranged in stacks of three modules per port . To increase reliability each module is designed to deliver up to 10 MW; this allows eight modules operating at partial capacity to deliver the required power in the event one module is out of service, and provides 20% excess capacity to improve availability. Radiation protection is provided by shielding and by locating critical components in the source and accelerator 46.5 m from the torus centerline. Neutron shielding in the drift duct and neutralizer provides the added feature of limiting conductance and thus reducing gas flow to and from the torus

  14. Neutral-particle-beam production and injection

    International Nuclear Information System (INIS)

    Post, D.; Pyle, R.

    1982-07-01

    This paper is divided into two sections: the first is a discussion of the interactions of neutral beams with confined plasmas, the second is concerned with the production and diagnosis of the neutral beams. In general we are dealing with atoms, molecules, and ions of the isotopes of hydrogen, but some heavier elements (for example, oxygen) will be mentioned. The emphasis will be on single-particle collisions; selected atomic processes on surfaces will be included

  15. Neutral signature Walker-VSI metrics

    International Nuclear Information System (INIS)

    Coley, A; McNutt, D; Musoke, N; Brooks, D; Hervik, S

    2014-01-01

    We will construct explicit examples of four-dimensional neutral signature Walker (but not necessarily degenerate Kundt) spaces for which all of the polynomial scalar curvature invariants vanish. We then investigate the properties of some particular subclasses of Ricci flat spaces. We also briefly describe some four-dimensional neutral signature Einstein spaces for which all of the polynomial scalar curvature invariants are constant. (paper)

  16. Nitrogen-neutrality: a step towards sustainability

    Science.gov (United States)

    Leip, Adrian; Leach, Allison; Musinguzi, Patrick; Tumwesigye, Trust; Olupot, Giregon; Tenywa, John Stephen; Mudiope, Joseph; Hutton, Olivia; Cordovil, Claudia M. d. S.; Bekunda, Mateete; Galloway, James

    2014-11-01

    We propose a novel indicator measuring one dimension of the sustainability of an entity in modern societies: Nitrogen-neutrality. N-neutrality strives to offset Nr releases an entity exerts on the environment from the release of reactive nitrogen (Nr) to the environment by reducing it and by offsetting the Nr releases elsewhere. N-neutrality also aims to increase awareness about the consequences of unintentional releases of nitrogen to the environment. N-neutrality is composed of two quantified elements: Nr released by an entity (e.g. on the basis of the N footprint) and Nr reduction from management and offset projects (N offset). It includes management strategies to reduce nitrogen losses before they occur (e.g., through energy conservation). Each of those elements faces specific challenges with regard to data availability and conceptual development. Impacts of Nr releases to the environment are manifold, and the impact profile of one unit of Nr release depends strongly on the compound released and the local susceptibility to Nr. As such, N-neutrality is more difficult to conceptualize and calculate than C-neutrality. We developed a workable conceptual framework for N-neutrality which was adapted for the 6th International Nitrogen Conference (N2013, Kampala, November 2013). Total N footprint of the surveyed meals at N2013 was 66 kg N. A total of US 3050 was collected from the participants and used to offset the conference’s N footprint by supporting the UN Millennium Village cluster Ruhiira in South-Western Uganda. The concept needs further development in particular to better incorporate the spatio-temporal variability of impacts and to standardize the methods to quantify the required N offset to neutralize the Nr releases impact. Criteria for compensation projects need to be sharply defined to allow the development of a market for N offset certificates.

  17. Γ-source Neutral Point Clamped Inverter

    DEFF Research Database (Denmark)

    Mo, Wei; Loh, Poh Chiang; Blaabjerg, Frede

    Transformer based Z-source inverters are recently proposed to achieve promising buck-boost capability. They have improved higher buck-boost capability, smaller size and less components count over Z-source inverters. On the other hand, neutral point clamped inverters have less switching stress...... and better output performance comparing with traditional two-level inverters. Integrating these two types of configurations can help neutral point inverters achieve enhanced votlage buck-boost capability....

  18. TFTR neutral beam injection system conceptual design

    International Nuclear Information System (INIS)

    1975-01-01

    Three subsystems are described in the following chapters: (1) Neutral Beam Injection Line; (2) Power Supplies; and (3) Controls. Each chapter contains two sections: (1) Functions and Design Requirements; this is a brief listing of the requirements of components of the subsystem. (2) Design Description; this section describes the design and cost estimates. The overall performance requirements of the neutral beam injection system are summarized. (MOW)

  19. Neutral currents without gauge theory prejudices

    International Nuclear Information System (INIS)

    Sakurai, J.J.

    1976-01-01

    The measurement of weak neutral current processes allows a determination of the space-time structure and the isospin structure of these currents. The inclusive production data and the elastic neutrino electron scattering rules out a pure V or A structure of the current. A pure isoscalar current is in disagreement with the experimental data for the one pion production off neutrinos. Further aspects of the neutral current can be determined in neutrino-nucleus-scattering experiments. (BJ) [de

  20. Negative ion formation and neutralization processes, (1)

    International Nuclear Information System (INIS)

    Sugiura, Toshio

    1982-01-01

    This review has been made preliminary for the purpose of contribute to the plasma heating by ''negative ion based neutral beam injection'' in the magnetic confinement fusion reactor. A compilation includes the survey of the general processes of negative ion formation, the data of the cross section of H - ion formation and the neutralization of H - ion, and some of new processes of H - ion formation. The data of cross section are mainly experimental, but partly include the results of theoretical calculation. (author)

  1. Nitrogen-neutrality: a step towards sustainability

    International Nuclear Information System (INIS)

    Leip, Adrian; Leach, Allison; Hutton, Olivia; Galloway, James; Musinguzi, Patrick; Tumwesigye, Trust; Olupot, Giregon; Stephen Tenywa, John; Mudiope, Joseph; Cordovil, Claudia M d S; Bekunda, Mateete

    2014-01-01

    We propose a novel indicator measuring one dimension of the sustainability of an entity in modern societies: Nitrogen-neutrality. N-neutrality strives to offset Nr releases an entity exerts on the environment from the release of reactive nitrogen (Nr) to the environment by reducing it and by offsetting the Nr releases elsewhere. N-neutrality also aims to increase awareness about the consequences of unintentional releases of nitrogen to the environment. N-neutrality is composed of two quantified elements: Nr released by an entity (e.g. on the basis of the N footprint) and Nr reduction from management and offset projects (N offset). It includes management strategies to reduce nitrogen losses before they occur (e.g., through energy conservation). Each of those elements faces specific challenges with regard to data availability and conceptual development. Impacts of Nr releases to the environment are manifold, and the impact profile of one unit of Nr release depends strongly on the compound released and the local susceptibility to Nr. As such, N-neutrality is more difficult to conceptualize and calculate than C-neutrality. We developed a workable conceptual framework for N-neutrality which was adapted for the 6th International Nitrogen Conference (N2013, Kampala, November 2013). Total N footprint of the surveyed meals at N2013 was 66 kg N. A total of US$ 3050 was collected from the participants and used to offset the conference’s N footprint by supporting the UN Millennium Village cluster Ruhiira in South-Western Uganda. The concept needs further development in particular to better incorporate the spatio-temporal variability of impacts and to standardize the methods to quantify the required N offset to neutralize the Nr releases impact. Criteria for compensation projects need to be sharply defined to allow the development of a market for N offset certificates. (paper)

  2. Applications of neutral beam and rf technologies

    International Nuclear Information System (INIS)

    Haselton, H.H.

    1987-04-01

    This presentation provides an update on the applications of neutral beams and radiofrequency (rf) power in the fusion program; highlights of the ion cyclotron heating (ICH) experiments now in progress, as well as the neutral beam experiments; and heating requirements of future devices and some of the available options. Some remarks on current drive are presented because this area of technology is one that is being considered for future devices

  3. Apparatus for neutralization of accelerated ions

    International Nuclear Information System (INIS)

    Fink, J.H.; Frank, A.M.

    1979-01-01

    Apparatus is described for neutralization of a beam of accelerated ions, such as hydrogen negative ions (H - ), using relatively efficient strip diode lasers which emit monochromatically at an appropriate wavelength (lambda = 8000 A for H - ions) to strip the excess electrons by photodetachment. A cavity, formed by two or more reflectors spaced apart, causes the laser beams to undergo multiple reflections within the cavity, thus increasing the efficiency and reducing the illumination required to obtain an acceptable percentage (approx. 85%) of neutralization

  4. Negative ion based neutral beams for plasma heating

    International Nuclear Information System (INIS)

    Prelec, K.

    1978-01-01

    Neutral beam systems based on negative ions have been considered because of a high expected power efficiency. Methods for the production, acceleration and neutralization of negative ions will be reviewed and possibilities for an application in neutral beam lines explored

  5. Design of the ITER Neutral Beam injectors

    International Nuclear Information System (INIS)

    Hemsworth, R.S.; Feist, J.; Hanada, M.; Heinemann, B.; Inoue, T.; Kuessel, E.; Kulygin, V.; Krylov, A.; Lotte, P.; Miyamoto, K.; Miyamoto, N.; Murdoch, D.; Nagase, A.; Ohara, Y.; Okumura, Y.; Pamela, J.; Panasenkov, A.; Shibata, K.; Tanii, M.

    1996-01-01

    This paper describes the Neutral Beam Injection system which is presently being designed in Europe, Japan and Russia, with co-ordination by the Joint Central Team of ITER at Naka, Japan. The proposed system consists of three negative ion based neutral injectors, delivering a total of 50 MW of 1 MeV D 0 to the ITER plasma for pulse length of ≥1000 s. The injectors each use a single caesiated volume arc discharge negative ion source, and a multi-grid, multi-aperture accelerator, to produce about 40 A of 1 MeV D - . This will be neutralized in a sub-divided gas neutralizer, which has a conversion efficiency of about 60%. The charged fraction of the beam emerging from the neutralizer is dumped in an electrostatic residual ion dump. A water cooled calorimeter can be moved into the beam path to intercept the neutral beam, allowing commissioning of the injector independent of ITER. copyright 1996 American Institute of Physics

  6. Neutral particle kinetics in fusion devices

    International Nuclear Information System (INIS)

    Tendler, M.; Heifetz, D.

    1986-05-01

    The theory of neutral particle kinetics treats the transport of mass, momentum, and energy in a plasma due to neutral particles which themselves are unaffected by magnetic fields. This transport affects the global power and particle balances in fusion devices, as well as profile control and plasma confinement quality, particle and energy fluxes onto device components, performance of pumping systems, and the design of diagnostics and the interpretation of their measurements. This paper reviews the development of analytic, numerical, and Monte Carlo methods of solving the time-independent Boltzmann equation describing neutral kinetics. These models for neutral particle behavior typically use adaptations of techniques developed originally for computing neutron transport, due to the analogy between the two phenomena, where charge-exchange corresponds to scattering and ionization to absorption. Progress in the field depends on developing multidimensional analytic methods, and obtaining experimental data for the physical processes of wall reflection, the neutral/plasma interaction, and for processes in fusion devices which are directly related to neutral transport, such as H/sub α/ emission rates, plenum pressures, and charge-exchange emission spectra

  7. Neutral particle kinetics in fusion devices

    Energy Technology Data Exchange (ETDEWEB)

    Tendler, M.; Heifetz, D.

    1986-05-01

    The theory of neutral particle kinetics treats the transport of mass, momentum, and energy in a plasma due to neutral particles which themselves are unaffected by magnetic fields. This transport affects the global power and particle balances in fusion devices, as well as profile control and plasma confinement quality, particle and energy fluxes onto device components, performance of pumping systems, and the design of diagnostics and the interpretation of their measurements. This paper reviews the development of analytic, numerical, and Monte Carlo methods of solving the time-independent Boltzmann equation describing neutral kinetics. These models for neutral particle behavior typically use adaptations of techniques developed originally for computing neutron transport, due to the analogy between the two phenomena, where charge-exchange corresponds to scattering and ionization to absorption. Progress in the field depends on developing multidimensional analytic methods, and obtaining experimental data for the physical processes of wall reflection, the neutral/plasma interaction, and for processes in fusion devices which are directly related to neutral transport, such as H/sub ..cap alpha../ emission rates, plenum pressures, and charge-exchange emission spectra.

  8. Automated Facial Coding Software Outperforms People in Recognizing Neutral Faces as Neutral from Standardized Datasets

    Directory of Open Access Journals (Sweden)

    Peter eLewinski

    2015-09-01

    Full Text Available Little is known about people’s accuracy of recognizing neutral faces as neutral. In this paper, I demonstrate the importance of knowing how well people recognize neutral faces. I contrasted human recognition scores of 100 typical, neutral front-up facial images with scores of an arguably objective judge – automated facial coding (AFC software. I hypothesized that the software would outperform humans in recognizing neutral faces because of the inherently objective nature of computer algorithms. Results confirmed this hypothesis. I provided the first-ever evidence that computer software (90% was more accurate in recognizing neutral faces than people were (59%. I posited two theoretical mechanisms, i.e. smile-as-a-baseline and false recognition of emotion, as possible explanations for my findings.

  9. Recognition of emotional facial expressions and broad autism phenotype in parents of children diagnosed with autistic spectrum disorder.

    Science.gov (United States)

    Kadak, Muhammed Tayyib; Demirel, Omer Faruk; Yavuz, Mesut; Demir, Türkay

    2014-07-01

    Research findings debate about features of broad autism phenotype. In this study, we tested whether parents of children with autism have problems recognizing emotional facial expression and the contribution of such an impairment to the broad phenotype of autism. Seventy-two parents of children with autistic spectrum disorder and 38 parents of control group participated in the study. Broad autism features was measured with Autism Quotient (AQ). Recognition of Emotional Face Expression Test was assessed with the Emotion Recognition Test, consisting a set of photographs from Ekman & Friesen's. In a two-tailed analysis of variance of AQ, there was a significant difference for social skills (F(1, 106)=6.095; p<.05). Analyses of variance revealed significant difference in the recognition of happy, surprised and neutral expressions (F(1, 106)=4.068, p=.046; F(1, 106)=4.068, p=.046; F(1, 106)=6.064, p=.016). According to our findings, social impairment could be considered a characteristic feature of BAP. ASD parents had difficulty recognizing neutral expressions, suggesting that ASD parents may have impaired recognition of ambiguous expressions as do autistic children. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Well separated trion and neutral excitons on superacid treated MoS{sub 2} monolayers

    Energy Technology Data Exchange (ETDEWEB)

    Cadiz, Fabian, E-mail: cadiz@insa-toulouse.fr; Tricard, Simon; Gay, Maxime; Lagarde, Delphine; Wang, Gang; Robert, Cedric; Renucci, Pierre; Urbaszek, Bernhard; Marie, Xavier [Université de Toulouse, INSA-CNRS-UPS, LPCNO, 135 Av. Rangueil, 31077 Toulouse (France)

    2016-06-20

    Developments in optoelectronics and spin-optronics based on transition metal dichalcogenide monolayers (MLs) need materials with efficient optical emission and well-defined transition energies. In as-exfoliated MoS{sub 2} MLs, the photoluminescence (PL) spectra even at low temperature consist typically of broad, overlapping contributions from neutral, charged excitons (trions) and localized states. Here, we show that in superacid treated MoS{sub 2} MLs, the PL intensity increases by up to 60 times at room temperature. The neutral and charged exciton transitions are spectrally well separated in PL and reflectivity at T = 4 K, with linewidth for the neutral exciton of 15 meV, but both transitions have similar intensities compared to the ones in as-exfoliated MLs at the same temperature. Time resolved experiments uncover picoseconds recombination dynamics analyzed separately for charged and neutral exciton emissions. Using the chiral interband selection rules, we demonstrate optically induced valley polarization for both complexes and valley coherence for only the neutral exciton.

  11. Individual differences in processing emotional images after reading disgusting and neutral sentences.

    Science.gov (United States)

    Hartigan, Alex; Richards, Anne

    2017-11-21

    The present study examined the extent to which Event Related Potentials (ERPs) evoked by disgusting, threatening and neutral photographic images were influenced by disgust propensity, disgust sensitivity and attentional control following exposure to disgusting information. Emotional cognition was manipulated by instructing participants to remember either disgusting or neutral sentences; participants in both groups then viewed emotional images while ERPs were recorded. Disgust propensity was associated with a reduced Late Positive Potential (LPP) gap between threatening and neutral stimuli (an effect driven by a rise in the LPP for neutral images) but only amongst individuals who were exposed to disgusting sentences. The typical LPP increase for disgust over neutral was reduced by attentional shifting capacity but only for individuals who were not previously exposed to disgust. There was also a persistent occipital shifted late positivity that was enhanced for disgust for the entire LPP window and was independent of exposure. Results suggest that emotion specific ERP effects can emerge within the broad unpleasant emotional category in conjunction with individual differences and prior emotional exposure. These results have important implications for the ways in which the perception of emotion is impacted by short term cognitive influences and longer term individual differences. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Neutralization resistance of hepatitis C virus can be overcome by recombinant human monoclonal antibodies

    DEFF Research Database (Denmark)

    Pedersen, Jannie L; Carlsen, Thomas H R; Prentoe, Jannick

    2013-01-01

    Immunotherapy and vaccine development for hepatitis C virus (HCV) will depend on broadly reactive neutralizing antibodies (NAbs). However, studies in infectious strain JFH1-based culture systems expressing patient-derived Core-NS2 proteins have suggested neutralization resistance for specific HCV...... demonstrated that the novel genotype 2 viruses as well as prototype strains J6/JFH1(2a) and J8/JFH1(2b), all with authentic envelope proteins, were resistant to neutralization by genotype 2a, 2b, 2c, 2j, 2i, and 2q patient sera. However, these patient sera had high titers of HCV-specific NAbs, because...... they efficiently reduced the infectivity of J6(2a) and J8(2b) with deleted hypervariable region 1. The genotype 2a, 2b, and 2c viruses, found resistant to polyclonal patient sera neutralization, were efficiently neutralized by two lead HMAbs (AR4A and HC84.26). Conclusion: Using novel 2a, 2b, and 2c cell...

  13. Maturation Pathways of Cross-Reactive HIV-1 Neutralizing Antibodies

    Directory of Open Access Journals (Sweden)

    Dimiter S. Dimitrov

    2009-11-01

    Full Text Available Several human monoclonal antibodies (hmAbs and antibody fragments, including the best characterized in terms of structure-function b12 and Fab X5, exhibit relatively potent and broad HIV-1 neutralizing activity. However, the elicitation of b12 or b12-like antibodies in vivo by vaccine immunogens based on the HIV-1 envelope glycoprotein (Env has not been successful. B12 is highly divergent from the closest corresponding germline antibody while X5 is less divergent. We have hypothesized that the relatively high degree of specific somatic hypermutations may preclude binding of the HIV-1 envelope glycoprotein (Env to closest germline antibodies, and that identifying antibodies that are intermediates in the pathways to maturation could help design novel vaccine immunogens to guide the immune system for their enhanced elicitation. In support of this hypothesis we have previously found that a germline-like b12 (monovalent and bivalent scFv as an Fc fusion protein or IgG lacks measurable binding to an Env as measured by ELISA with a sensitivity in the μM range [1]; here we present evidence confirming and expanding these findings for a panel of Envs. In contrast, a germline-like scFv X5 bound Env with high (nM affinity. To begin to explore the maturation pathways of these antibodies we identified several possible b12 intermediate antibodies and tested their neutralizing activity. These intermediate antibodies neutralized only some HIV-1 isolates and with relatively weak potency. In contrast, germline-like scFv X5 neutralized a subset of the tested HIV-1 isolates with comparable efficiencies to that of the mature X5. These results could help explain the relatively high immunogenicity of the coreceptor binding site on gp120 and the abundance of CD4-induced (CD4i antibodies in HIV-1-infected patients (X5 is a CD4i antibody as well as the maturation pathway of X5. They also can help identify antigens that can bind specifically to b12 germline and

  14. Galactic neutral hydrogen emission-absorption observations from Arecibo

    International Nuclear Information System (INIS)

    Dickey, J.M.; Salpeter, E.E.; Terzian, Y.

    1978-01-01

    We have observed the interstellar medium in the directions of 27 extragalactic sources at high and intermediate galactic latitudes (vertical-barb/sup ii/vertical-bar>5 0 ) at 21 cm wavelength with the upgraded Arecibo telescope (HPBW=3'.2, gainapprox.6 K Jy -1 ). The small beam greatly reduces the uncertainty in the derived on-source emission profile and increases confidence that it corresponds to the same material as the absorption spectrum. Each region has been observed for approximately 2 hours to tetect optical depths as low as 10 -2 in most cases. The data allow the derivation of optical depths, harmonic mean spin temperatures, and column densities for the neutral hydrogen as a function of velocity in the range -200 -1 (LSR) with resolution as fine as 0.25 km s -1 . Spin temperatures as high as 1000 K are evident with a significant fraction of the neutral hydrogen still hotter. The cooler material is distributed over all temperatures from 30 K to at least 800 K. At latitudes below vertical-barb/sup ii/vertical-bar 0 values for the harmonic mean temperature T/sub spin/ in the range 100 K to 300 K are most common.We have detected 66 separate absorption features, tentatively associated with neutral hydrogen clouds, with central temperatures ranging from 30 to 500 K. These features conform well to the relationship T/sub spin/=45(1-e/sup -tau/)/sup -0.5/ (K), over a broad range of values of the optical depth. The velocity distribution of these clouds shows a significant negative-velocity ''tail'' at high and intermediate latitudes. The mean square velocity of the clouds seems to depend on optical depth: v/sub rms/ is greater (approx.11 km s -1 ) for the optically thin clouds (tau -1 ). High-negative-velocity emission (v -1 ) has been detected in six directions; in two of these corresponding absorption features are evident, indicating cool neutral material

  15. Transient nature of long-term nonprogression and broad virus-specific proliferative T-cell responses with sustained thymic output in HIV-1 controllers.

    Directory of Open Access Journals (Sweden)

    Samantha J Westrop

    Full Text Available HIV-1(+ individuals who, without therapy, conserve cellular anti-HIV-1 responses, present with high, stable CD4(+ T-cell numbers, and control viral replication, facilitate analysis of atypical viro-immunopathology. In the absence of universal definition, immune function in such HIV controllers remains an indication of non-progression.CD4 T-cell responses to a number of HIV-1 proteins and peptide pools were assessed by IFN-gamma ELISpot and lymphoproliferative assays in HIV controllers and chronic progressors. Thymic output was assessed by sjTRECs levels. Follow-up of 41 HIV-1(+ individuals originally identified as "Long-term non-progressors" in 1996 according to clinical criteria, and longitudinal analysis of two HIV controllers over 22 years, was also performed. HIV controllers exhibited substantial IFN-gamma producing and proliferative HIV-1-specific CD4 T-cell responses to both recombinant proteins and peptide pools of Tat, Rev, Nef, Gag and Env, demonstrating functional processing and presentation. Conversely, HIV-specific T-cell responses were limited to IFN-gamma production in chronic progressors. Additionally, thymic output was approximately 19 fold higher in HIV controllers than in age-matched chronic progressors. Follow-up of 41 HIV-1(+ patients identified as LTNP in 1996 revealed the transitory characteristics of this status. IFN-gamma production and proliferative T-cell function also declines in 2 HIV controllers over 22 years.Although increased thymic output and anti-HIV-1 T-cell responses are observed in HIV controllers compared to chronic progressors, the nature of nonprogressor/controller status appears to be transitory.

  16. Serbia's Military Neutrality: Origins, effects and challenges

    Directory of Open Access Journals (Sweden)

    Ejdus Filip

    2014-10-01

    Full Text Available Serbia is the only state in the Western Balkans that is not seeking NATO membership. In December 2007, Serbia declared military neutrality and in spite of its EU membership aspirations, developed very close relations with Moscow. The objective of this paper is threefold. First, I argue that in order to understand why Serbia declared military neutrality, one has to look both at the discursive terrain and domestic power struggles. The key narrative that was strategically used by mnemonic entrepreneurs, most importantly by the former Prime Minister Vojislav Koštunica, to legitimize military neutrality was the trauma of NATO intervention in 1999 and the ensuing secession of Kosovo. In the second part of the paper, I discuss the operational consequences of the military neutrality policy for Serbia's relations with NATO and Russia, as well as for military reform and EU accession. Finally, I spell out the challenges ahead in Serbia's neutrality policy and argue that its decision makers will increasingly be caught between pragmatic foreign policy requirements on the one hand and deeply entrenched traumatic memories on the other.

  17. Kinetic Properties of the Neutral Solar Wind

    International Nuclear Information System (INIS)

    Florinski, V.; Heerikhuisen, J.

    2017-01-01

    Charge-exchange collisions between the solar wind protons and interstellar hydrogen produce a distinctive population of neutral hydrogen streaming radially at nearly the solar-wind speed. This tenuous population, known as the neutral solar wind (NSW) is thought to play a key role in the appearance of the Interplanetary Boundary EXplorer ribbon, a bright circular band in the sky that is the source of neutral hydrogen with energies near 1 keV. According to the leading model of the ribbon, the velocity distribution of NSW hydrogen is imparted on the pickup ions (PUIs) generated via charge exchange with the interstellar protons beyond the heliopause, and in this way controls the stability of the resulting ring distribution of PUIs against hydromagnetic wave generation. In this paper, we examine the velocity distributions of the NSW atoms in the heliosphere and the outer heliosheath regions by following the phase-space trajectories of the Boltzmann equation. It is demonstrated that these distributions are highly anisotropic, with the parallel (radial) temperature greatly exceeding the perpendicular temperature. Ions picked up near 90° from the anisotropic NSW would form a stable ring distribution capable of generating the ribbon flux. We also discuss a second population of neutrals born in charge transfer collisions with interstellar PUIs, the so-called neutralized pickup ion (NPI) component. Their high thermal velocities translate into large parallel velocity spread of the daughter ribbon PUIs, which would adversely affect plasma stability in local interstellar space.

  18. Kinetic Properties of the Neutral Solar Wind

    Science.gov (United States)

    Florinski, V.; Heerikhuisen, J.

    2017-03-01

    Charge-exchange collisions between the solar wind protons and interstellar hydrogen produce a distinctive population of neutral hydrogen streaming radially at nearly the solar-wind speed. This tenuous population, known as the neutral solar wind (NSW) is thought to play a key role in the appearance of the Interplanetary Boundary EXplorer ribbon, a bright circular band in the sky that is the source of neutral hydrogen with energies near 1 keV. According to the leading model of the ribbon, the velocity distribution of NSW hydrogen is imparted on the pickup ions (PUIs) generated via charge exchange with the interstellar protons beyond the heliopause, and in this way controls the stability of the resulting ring distribution of PUIs against hydromagnetic wave generation. In this paper, we examine the velocity distributions of the NSW atoms in the heliosphere and the outer heliosheath regions by following the phase-space trajectories of the Boltzmann equation. It is demonstrated that these distributions are highly anisotropic, with the parallel (radial) temperature greatly exceeding the perpendicular temperature. Ions picked up near 90° from the anisotropic NSW would form a stable ring distribution capable of generating the ribbon flux. We also discuss a second population of neutrals born in charge transfer collisions with interstellar PUIs, the so-called neutralized pickup ion (NPI) component. Their high thermal velocities translate into large parallel velocity spread of the daughter ribbon PUIs, which would adversely affect plasma stability in local interstellar space.

  19. Neutral axis as damage sensitive feature

    International Nuclear Information System (INIS)

    Sigurdardottir, D H; Glisic, B

    2013-01-01

    Structural health monitoring (SHM) is the process of continuously or periodically measuring structural parameters and the transformation of the collected data into information on real structural conditions. The centroid of stiffness is a universal parameter and its position in a cross-section can be evaluated for any load-carrying beam structure as the position of the neutral axis under conveniently chosen loads. Thus, a change in the position of the neutral axis within a cross-section can indicate a change in the position of the centroid of stiffness, i.e., unusual structural behaviors. This paper proposes a novel monitoring method based on deterministic and probabilistic determination of the position of the neutral axis under conveniently chosen conditions. Therefore, the method proposed in this paper is potentially applicable to a large variety of beam-like structures. Data from two existing structures were used to validate the method and assess its performance: Streicker Bridge at Princeton University and the US202/NJ23 highway overpass in Wayne, NJ. The results show that the neutral axis location is varying even when damage is not present. Reasons for this variation are determined and the accuracy in the evaluation assessed. This paper concludes that the position of the neutral axis can be evaluated with sufficient accuracy using static and dynamic strain measurements performed on appropriate time-scales and indicates its potential to be used as a damage sensitive feature. (paper)

  20. Neutral axis as damage sensitive feature

    Science.gov (United States)

    Sigurdardottir, D. H.; Glisic, B.

    2013-07-01

    Structural health monitoring (SHM) is the process of continuously or periodically measuring structural parameters and the transformation of the collected data into information on real structural conditions. The centroid of stiffness is a universal parameter and its position in a cross-section can be evaluated for any load-carrying beam structure as the position of the neutral axis under conveniently chosen loads. Thus, a change in the position of the neutral axis within a cross-section can indicate a change in the position of the centroid of stiffness, i.e., unusual structural behaviors. This paper proposes a novel monitoring method based on deterministic and probabilistic determination of the position of the neutral axis under conveniently chosen conditions. Therefore, the method proposed in this paper is potentially applicable to a large variety of beam-like structures. Data from two existing structures were used to validate the method and assess its performance: Streicker Bridge at Princeton University and the US202/NJ23 highway overpass in Wayne, NJ. The results show that the neutral axis location is varying even when damage is not present. Reasons for this variation are determined and the accuracy in the evaluation assessed. This paper concludes that the position of the neutral axis can be evaluated with sufficient accuracy using static and dynamic strain measurements performed on appropriate time-scales and indicates its potential to be used as a damage sensitive feature.

  1. A Measurement of Coherent Neutral Pion Production in Neutrino Neutral Current Interactions in NOMAD experiment

    CERN Document Server

    Kullenberg, C T

    2009-01-01

    We present a study of exclusive neutral pion production in neutrino-nucleus Neutral Current interactions using data from the NOMAD experiment at the CERN SPS. The data correspond to $1.44 \\times 10^6$ muon-neutrino Charged Current interactions in the energy range $2.5 \\leq E_{\

  2. Water migration of macroelements in coniferous-broad-leaved forests of Sikhote-Alin

    Directory of Open Access Journals (Sweden)

    N. K. Kozhevnikova

    2017-06-01

    Full Text Available In the paper, the natural water chemical composition spatial variability studies results in the mountain forest catchment are presented. It’s shown that the catchment biotic components’ impact upon water chemical composition is detected even at input as atmospheric precipitation. The input fluxes are acid, sulfate ones with high ratio of hydrogen, potassium and dissolved organic matter. Diversity of ecotopic conditions determines the further transformation of natural water chemical composition. The role of tree crowns in the transformation increases while the crown closure and stands’ age increase. According to macrocomponents transformation and rain acidity neutralization, forest associations form the sequence: mixed > coniferous > young deciduous ones. Dissolved organic carbon (DOC, potassium and calcium become the main components of water chemical composition, while sulfates dominate among anions. For vegetation period, 9–11 kg/ha of sulfates come below tree crown. Biogenic elements transport is gradually limited in soil profile at the migration stage. Sulfate-potassium composition throughfall in spruce-fir and secondary forests community transforms into sulfate-sodium-calcium. Hydrocarbonates predominate in soil water in broad-leaved-pine type of forest, and potassium output decreases 10 times. Geochemical type of river water keeps features of chemical composition of soil drained by river section. Negligible output of sulfates, hydrocarbonates and calcium from ecosystem is established for the headwaters. Negative balance of hydrocarbonates and calcium is compensated by significant input of these components with throughfall at catchments with predominantly pine-broad-leaved forest types.

  3. The control of powerful neutral beams

    International Nuclear Information System (INIS)

    Theil, E.; Jacobson, V.

    1986-01-01

    While significant progress has been made in the development of neutral beams for the heating and sustaining of plasmas in large fusion experiments, the control of such devices has largely been a matter of hardware interlocks and operator experience. The need for computer-assisted control becomes more evident, however, with the initiation of multi-beamline experiments. This paper describes a software system that incorporates simple mathematical models coupled to Kalman filters for control of the high power (6 to 8 MW) beams currently under development at Lawrence Berkeley Laboratory's Neutral Beam Engineering Test Facility. Among the principal features of the system are: reduction of a large number of operator variables to just a few (usually one or two); the ability to describe most of the major neutral beams in use and under development; a foundation resting on statistical data analysis and control system principles rather than rules-of-thumb

  4. Neutralization kinetics of charged polymer surface

    Energy Technology Data Exchange (ETDEWEB)

    Mukherjee, S. [Surface Physics Division, Saha Institute of Nuclear Physics, 1/AF, Bidhannagar, Kolkata 700064 (India); Mukherjee, M. [Surface Physics Division, Saha Institute of Nuclear Physics, 1/AF, Bidhannagar, Kolkata 700064 (India)], E-mail: manabendra.mukherjee@saha.ac.in

    2008-04-15

    In case of photoemission spectroscopy of an insulating material the data obtained from the charged surface are normally distorted due to differential charging. Recently, we have developed a controlled surface neutralization technique to study the kinetics of the surface charging. Using this technique and the associated data analysis scheme with an effective charging model, quantitative information from the apparently distorted photoemission data from PTFE surfaces were extracted. The surface charging was controlled by tuning the electron flood current as well as the X-ray intensity. The effective model was found to describe the charging consistently for both the cases. It was shown that the non-linear neutralization response of differential charging around a critical neutralizing electron flux or a critical X-ray emission current was due to percolation of equipotential surface domains. The obtained value of the critical percolation exponent {gamma} close to unity indicates a percolation similar to that of avalanche breakdown or chain reaction.

  5. The Framing of Network Neutrality Governance

    DEFF Research Database (Denmark)

    Perry, James

    The neutrality of the internet with regard to applications (e.g. search, social networking, email, to mention only three) has been central to innovation and growth in the knowledge-economy over the past two decades. Until recently, neutrality was built into the internet's design via its core stan...... with a critical analysis of their respective operational paradigms, the paper seeks to understand who is framing the debate, how they are doing so, and to what (systemic) effect....... generative: Useful innovations in applications of the internet could take hold easily, and it was difficult – or indeed impossible - for incumbent business interests to disrupt or sabotage them. However, this neutrality is now under threat. New technologies have given incumbent businesses the ability...

  6. Current neutralization of converging ion beams

    International Nuclear Information System (INIS)

    Mosher, D.

    1978-01-01

    It is desired to consider the problem of current neutralization of heavy ion beams traversing gas backgrounds in which the conductivity changes due to beam heating and beam convergence. The procedure is to determine Green's-function solutions to the magnetic-diffusion equation derived from Maxwell's equations and an assumed scaler-plasma conductivity sigma for the background-electron current density j/sub e/. The present calculation is more general than some previously carried out in that arbitrary time variations for the beam current j/sub b/ and conductivity are allowed and the calculation is valid for both weak and strong neutralization. Results presented here must be combined with an appropriate energy-balance equation for the heated background in order to obtain the neutralization self-consistently

  7. Broad Spectrum Sanitizing Wipes with Food Additives, Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — Microcide proposes to develop novel multipurpose non-toxic sanitizing wipes that are aqueous based, have shelf life of 3-5 years, have broad spectrum microbicidal...

  8. Broadly Applicable Nanowafer Drug Delivery System for Treating Eye Injuries

    Science.gov (United States)

    2015-09-01

    Systems in Systemic , Dermal, Transdermal , and Ocular Drug Delivery . Crit. Rev. Ther. Drug 2008, 25, 545–584. 14. Choy, Y. B.; Park, J.-H.; McCarey, B...AWARD NUMBER: W81XWH-13-1-0146 TITLE: Broadly Applicable Nanowafer Drug Delivery System for Treating Eye Injuries PRINCIPAL INVESTIGATOR: Dr...Broadly Applicable Nanowafer Drug Delivery System for Treating Eye Injuries” 5b. GRANT NUMBER W81XWH-13-1-0146 5c. PROGRAM ELEMENT NUMBER 6

  9. The broad line region of AGN: Kinematics and physics

    Directory of Open Access Journals (Sweden)

    Popović L.Č.

    2006-01-01

    Full Text Available In this paper a discussion of kinematics and physics of the Broad Line Region (BLR is given. The possible physical conditions in the BLR and problems in determination of the physical parameters (electron temperature and density are considered. Moreover, one analyses the geometry of the BLR and the probability that (at least a fraction of the radiation in the Broad Emission Lines (BELs originates from a relativistic accretion disk.

  10. Optimal neutral beam heating scenario for FED

    International Nuclear Information System (INIS)

    Hively, L.M.; Houlberg, W.A.; Attenberger, S.E.

    1981-01-01

    Optimal neutral beam heating scenarios are determined for FED based on a 1/one-half/-D transport analysis. Tradeoffs are examined between neutral beam energy, power, and species mix for positive ion systems. A ramped density startup is found to provide the most economical heating. The resulting plasma power requirements are reduced by 10-30% from a constant density startup. For beam energies between 100 and 200 keV, the power needed to heat the plasma does not decrease significantly as beam energy is increased. This is due to reduced ion heating, more power in the fractional energy components, and rising power supply requirements as beam energy increases

  11. Inducing Risk Neutral Preferences with Binary Lotteries

    DEFF Research Database (Denmark)

    Harrison, Glenn W.; Martínez-Correa, Jimmy; Swarthout, J. Todd

    2013-01-01

    validity of any strategic equilibrium behavior, or even the customary independence axiom. We show that subjects sampled from our population are generally risk averse when lotteries are defined over monetary outcomes, and that the binary lottery procedure does indeed induce a statistically significant shift......We evaluate the binary lottery procedure for inducing risk neutral behavior. We strip the experimental implementation down to bare bones, taking care to avoid any potentially confounding assumptions about behavior having to be made. In particular, our evaluation does not rely on the assumed...... toward risk neutrality. This striking result generalizes to the case in which subjects make several lottery choices and one is selected for payment....

  12. Beam divergence scaling in neutral beam injectors

    International Nuclear Information System (INIS)

    Holmes, A.J.T.

    1976-01-01

    One of the main considerations in the design of neutral beam injectors is to monimize the divergence of the primary ion beam and hence maximize the beam transport and minimize the input of thermal gas. Experimental measurements of the divergence of a cylindrical ion beam are presented and these measurements are used to analyze the major components of ion beam divergence, namely: space charge expansion, gas-ion scattering, emittance and optical aberrations. The implication of these divergence components in the design of a neutral beam injector system is discussed and a method of maximizing the beam current is described for a given area of source plasma

  13. Simplified Stability Criteria for Delayed Neutral Systems

    Directory of Open Access Journals (Sweden)

    Xinghua Zhang

    2014-01-01

    Full Text Available For a class of linear time-invariant neutral systems with neutral and discrete constant delays, several existing asymptotic stability criteria in the form of linear matrix inequalities (LMIs are simplified by using matrix analysis techniques. Compared with the original stability criteria, the simplified ones include fewer LMI variables, which can obviously reduce computational complexity. Simultaneously, it is theoretically shown that the simplified stability criteria and original ones are equivalent; that is, they have the same conservativeness. Finally, a numerical example is employed to verify the theoretic results investigated in this paper.

  14. Neutral Naturalness from Orbifold Higgs Models

    Science.gov (United States)

    Craig, Nathaniel; Knapen, Simon; Longhi, Pietro

    2015-02-01

    We present a general class of natural theories in which the Higgs boson is a pseudo-Goldstone boson in an orbifolded gauge theory. The symmetry protecting the Higgs boson at low energies is an accidental global symmetry of the quadratic action, rather than a full continuous symmetry. The lightest degrees of freedom protecting the weak scale carry no standard model (SM) quantum numbers and interact with visible matter principally through the Higgs portal. This opens the door to the systematic study of "neutral naturalness": natural theories with SM-neutral states that are as yet untested by the LHC.

  15. Greenhouse gas neutral Germany in 2050

    International Nuclear Information System (INIS)

    Benndorf, Rosemarie; Bernicke, Maja; Bertram, Andreas

    2014-01-01

    In order to answer the question how a greenhouse gas neutral Germany would look like an interdisciplinary process was started by the Federal Environmental Agency. It was clear from the beginning of this work that a sustainable regenerative energy supply could not be sufficient. Therefore all relevant emission sources were included into the studies: traffic, industry, waste and waste water, agriculture, land usage, land usage changes and forestry. The necessary transformation paths to reach the aim of a greenhouse gas neutral Germany in 2050, economic considerations and political instruments were not part of this study.

  16. PDX neutral-beam reionization losses

    International Nuclear Information System (INIS)

    Kugel, H.W.; Dylla, H.F.; Eubank, H.P.; Kozub, T.A.; Moore, R.; Schilling, G.; Stewart, L.D.; von Halle, A.; Williams, M.D.

    1982-02-01

    Reionization losses for 1.5 MW H 0 and 2 MW D 0 neutral beams injected into the PDX tokamak were studied using pressure gauges, photo-transistors, thermocouples, surface shielding, and surface sample analysis. Considerable outgassing of conventionally prepared 304SS ducts occurred during initial injections and gradually decreased with the cumulative absorption of beam power. Reionization power losses are presently about 5% in the ducts and about 12% total for a beamline including the duct. Present duct pressures are attributed primarily to gas from the ion source and neutralizer with much smaller contributions from residual wall desorption. Physical mechanisms for the observed duct outgassing are discussed

  17. Water absorption in neutralized Nafion membranes

    International Nuclear Information System (INIS)

    Rodmacq, B.; Roche, E.; Pineri, M.; Escoubez, M.; Duplessix, R.; Eisenberg, A.

    1979-01-01

    In this paper some results are reported about the interactions between water and Nafion neutralized with different cations. The energy of water absorption have been measured in the whole range of relative humidity pressures. Moessbauer spectra permit to get information about the change of environment of the iron atoms during the hydration. Small angle neutron and X ray scattering experiments have then been performed to define a possible phase segregation. From these results a model of clustering in the Nafion membranes is proposed. The neutralized Nafion samples have been obtained by soaking the acid samples in solutions containing the different salts

  18. Neutral beam injection in 2XIIB

    International Nuclear Information System (INIS)

    Hibbs, S.M.

    1975-01-01

    Integrated into the operation of the 2XIIB controlled fusion experiment is a 600-A, 20-keV neutral injection system: the highest neutral-beam current capacity of any existing fusion machine. This paper outlines the requirements of the injection system and the design features to which they led. Both mechanical and electrical aspects are discussed. Also included is a brief description of some operational aspects of the system and some of the things we have learned along the way, as well as a short history of the most significant developments

  19. The net neutrality debate on Twitter

    Directory of Open Access Journals (Sweden)

    Wolf J. Schünemann

    2015-12-01

    Full Text Available The internet has been seen as a medium that empowers individual political actors in relation to established political elites and media gatekeepers. The present article discusses this “net empowerment hypothesis” and tests it empirically by analysing Twitter communication on the regulation of net neutrality. We extracted 503.839 tweets containing #NetNeutrality posted between January and March 2015 and analysed central developments and the network structure of the debate. The empirical results show that traditional actors from media and politics still maintain a central role.

  20. The Law of Neutrality in Outer Space

    National Research Council Canada - National Science Library

    Jarman, Robert W

    2008-01-01

    ...., Google Earth imagery, GPS receivers, and global voice and data transmissions). Consistent with broad historical trends, these technologies are inevitably influencing the way States think about, plan for, and conduct warfare...

  1. Ionized and Neutral Outflows in the QUEST QSOs

    Science.gov (United States)

    Veilleux, Sylvain

    2011-10-01

    The role of galactic winds in gas-rich mergers is of crucial importance to understand galaxy and SMBH evolution. In recent months, our group has had three major scientific breakthroughs in this area: {1} The discovery with Herschel of massive molecular {OH-absorbing} outflows in several ULIRGs, including the nearest quasar, Mrk 231. {2} The independent discovery from mm-wave interferometric observations in the same object of a spatially resolved molecular {CO-emitting} wind with estimated mass outflow rate 3x larger than the star formation rate and spatially coincident with blueshifted neutral {Na ID-absorbing} gas in optical long-slit spectra. {3} The unambiguous determination from recent Gemini/IFU observations that the Na ID outflow in this object is wide-angle, thus driven by a QSO wind rather than a jet. This powerful outflow may be the long-sought "smoking gun" of quasar mechanical feedback purported to transform gas-rich mergers. However, our Herschel survey excludes all FIR-faint {UV-bright} "classic" QSOs by necessity. So here we propose a complementary FUV absorption-line survey of all FIR-bright -and- FIR-faint QSOs from the same parent sample. New {19 targets} and archival {11} spectra will be used to study, for the first time, the gaseous environments of QSOs as a function of host properties and age across the merger sequence ULIRG -> QSO. These data will allow us to distinguish between ionized & neutral quasar-driven outflows, starburst-driven winds, and tidal debris around the mergers. They will also be uniquely suited for a shallow but broad study of the warm & warm-hot intergalactic media, complementary to on-going surveys that are deeper but narrower.

  2. Public support for neonatal screening for Pompe disease, a broad-phenotype condition

    Directory of Open Access Journals (Sweden)

    Weinreich Stephanie

    2012-03-01

    Full Text Available Abstract Background Neonatal screening for Pompe disease has been introduced in Taiwan and a few U.S. states, while other jurisdictions including some European countries are piloting or considering this screening. First-tier screening flags both classic infantile and late-onset Pompe disease, which challenges current screening criteria. Previously, advocacy groups have sometimes supported expanded neonatal screening more than professional experts, while neutral citizens' views were unknown. This study aimed to measure support for neonatal screening for Pompe disease in the general public and to compare it to support among (parents of patients with this condition. The study was done in the Netherlands, where newborns are not currently screened for Pompe disease. Newborn screening is not mandatory in the Netherlands but current uptake is almost universal. Methods A consumer panel (neutral group and (parents of patients with Pompe disease (Pompe group were sent information and a questionnaire. Responses were analyzed of 555 neutral and 58 Pompe-experienced informants who had demonstrated sufficient understanding. Results 87% of the neutral group and 88% of the Pompe group supported the introduction of screening (95% CI of difference -10 to 7%. The groups were similar in their moral reasoning about screening and acceptance of false positives, but the Pompe-experienced group expected greater benefit from neonatal detection of late-onset disease. Multivariate regression analysis controlling for demographics confirmed that approval of the introduction of screening was independent of having (a child with Pompe disease. Furthermore, respondents with university education, regardless of whether they have (a child with Pompe disease, were more likely to be reluctant about the introduction of screening than those with less education, OR for approval 0.29 (95% CI 0.18 to 0.49, p Conclusions This survey suggests a rather high level of support for newborn

  3. Structure-based, targeted deglycosylation of HIV-1 gp120 and effects on neutralization sensitivity and antibody recognition

    International Nuclear Information System (INIS)

    Koch, Markus; Pancera, Marie; Kwong, Peter D.; Kolchinsky, Peter; Grundner, Christoph; Wang Liping; Hendrickson, Wayne A.; Sodroski, Joseph; Wyatt, Richard

    2003-01-01

    The human immunodeficiency virus (HIV-1) exterior envelope glycoprotein, gp120, mediates receptor binding and is the major target for neutralizing antibodies. Primary HIV-1 isolates are characteristically more resistant to broadly neutralizing antibodies, although the structural basis for this resistance remains obscure. Most broadly neutralizing antibodies are directed against functionally conserved gp120 regions involved in binding to either the primary virus receptor, CD4, or the viral coreceptor molecules that normally function as chemokine receptors. These antibodies are known as CD4 binding site (CD4BS) and CD4-induced (CD4i) antibodies, respectively. Inspection of the gp120 crystal structure reveals that although the receptor-binding regions lack glycosylation, sugar moieties lie proximal to both receptor-binding sites on gp120 and thus in proximity to both the CD4BS and the CD4i epitopes. In this study, guided by the X-ray crystal structure of gp120, we deleted four N-linked glycosylation sites that flank the receptor-binding regions. We examined the effects of selected changes on the sensitivity of two prototypic HIV-1 primary isolates to neutralization by antibodies. Surprisingly, removal of a single N-linked glycosylation site at the base of the gp120 third variable region (V3 loop) increased the sensitivity of the primary viruses to neutralization by CD4BS antibodies. Envelope glycoprotein oligomers on the cell surface derived from the V3 glycan-deficient virus were better recognized by a CD4BS antibody and a V3 loop antibody than were the wild-type glycoproteins. Absence of all four glycosylation sites rendered a primary isolate sensitive to CD4i antibody-mediated neutralization. Thus, carbohydrates that flank receptor-binding regions on gp120 protect primary HIV-1 isolates from antibody-mediated neutralization

  4. First observations of partially neutralized and quasineutral plasmas in the Columbia Non-neutral Torus

    Science.gov (United States)

    Sarasola, Xabier; Brenner, Paul; Hahn, Michael; Pedersen, Thomas

    2009-11-01

    The Columbia Non-neutral Torus (CNT) is the first stellarator devoted to the study of pure electron, partially neutralized and positron-electron plasmas. To date, CNT usually operates with electron rich plasmas (with negligible ion density) [1], but a stellarator can also confine plasmas of arbitrary degree of neutralization. In CNT the accumulation of ions alters the equilibrium of electron plasmas and a global instability has been observed when the ion fraction exceeds 10 %. A characterization of this instability is presented in [2], analyzing its parameter dependence and spatial structure (non- resonant with rational surfaces). A new set of experiments is currently underway studying plasmas of arbitrary degree of neutralization, ranging from pure electron to quasineutral plasmas. Basic observations show that the plasma potential decouples from emitter bias when we increase the degree of the neutralization of our plasmas. Partially neutralized plasmas are also characterized by multiple mode behavior with dominant modes between 20 and 200 kHz. When the plasma becomes quasineutral, it reverts to single mode behavior. The first results on partially neutralized plasmas confined on magnetic surfaces will be presented. [1] J. Kremer, PRL 97, (2006) 095003 [2] Q. Marksteiner, PRL 100 (2008) 065002

  5. How Objective a Neutral Word Is? A Neutrosophic Approach for the Objectivity Degrees of Neutral Words

    Directory of Open Access Journals (Sweden)

    Mihaela Colhon

    2017-11-01

    Full Text Available In the latest studies concerning the sentiment polarity of words, the authors mostly consider the positive and negative constructions, without paying too much attention to the neutral words, which can have, in fact, significant sentiment degrees. More precisely, not all the neutral words have zero positivity or negativity scores, some of them having quite important nonzero scores for these polarities. At this moment, in the literature, a word is considered neutral if its positive and negative scores are equal, which implies two possibilities: (1 zero positive and negative scores; (2 nonzero, but equal positive and negative scores. It is obvious that these cases represent two different categories of neutral words that must be treated separately by a sentiment analysis task. In this paper, we present a comprehensive study about the neutral words applied to English as is developed with the aid of SentiWordNet 3.0: the publicly available lexical resource for opinion mining. We designed our study in order to provide an accurate classification of the so-called “neutral words” described in terms of sentiment scores and using measures from neutrosophy theory. The intended scope is to fill the gap concerning the neutrality aspect by giving precise measurements for the words’ objectivity.

  6. Neutralization escape mutants define a dominant immunogenic neutralization site on hepatitis A virus

    International Nuclear Information System (INIS)

    Stapleton, J.T.; Lemon, S.M.

    1987-01-01

    Hepatitis A virus is an hepatotrophic human picornavirus which demonstrates little antigenic variability. To topologically map immunogenic sites on hepatitis A virus which elicit neutralizing antibodies, eight neutralizing monoclonal antibodies were evaluated in competition immunoassays employing radiolabeled monoclonal antibodies and HM-175 virus. Whereas two antibodies (K3-4C8 and K3-2F2) bound to intimately overlapping epitopes, the epitope bound by a third antibody (B5-B3) was distinctly different as evidenced by a lack of competition between antibodies for binding to the virus. The other five antibodies variably blocked the binding of both K3-4C8-K3-2F2 and B5-B3, suggesting that these epitopes are closely spaced and perhaps part of a single neutralization immunogenic site. Several combinations of monoclonal antibodies blocked the binding of polyclonal human convalescent antibody by greater than 96%, indicating that the neutralization epitopes bound by these antibodies are immunodominant in humans. Spontaneously arising HM-175 mutants were selected for resistance to monoclonal antibody-mediated neutralization. Neutralization resistance was associated with reduced antibody binding. These results suggest that hepatitis A virus may differ from poliovirus in possessing a single, dominant neutralization immunogenic site and therefore may be a better candidate for synthetic peptide or antiidiotype vaccine development

  7. Is a neutral expression also a neutral stimulus? A study with functional magnetic resonance.

    Science.gov (United States)

    Carvajal, Fernando; Rubio, Sandra; Serrano, Juan M; Ríos-Lago, Marcos; Alvarez-Linera, Juan; Pacheco, Lara; Martín, Pilar

    2013-08-01

    Although neutral faces do not initially convey an explicit emotional message, it has been found that individuals tend to assign them an affective content. Moreover, previous research has shown that affective judgments are mediated by the task they have to perform. Using functional magnetic resonance imaging in 21 healthy participants, we focus this study on the cerebral activity patterns triggered by neutral and emotional faces in two different tasks (social or gender judgments). Results obtained, using conjunction analyses, indicated that viewing both emotional and neutral faces evokes activity in several similar brain areas indicating a common neural substrate. Moreover, neutral faces specifically elicit activation of cerebellum, frontal and temporal areas, while emotional faces involve the cuneus, anterior cingulated gyrus, medial orbitofrontal cortex, posterior superior temporal gyrus, precentral/postcentral gyrus and insula. The task selected was also found to influence brain activity, in that the social task recruited frontal areas while the gender task involved the posterior cingulated, inferior parietal lobule and middle temporal gyrus to a greater extent. Specifically, in the social task viewing neutral faces was associated with longer reaction times and increased activity of left dorsolateral frontal cortex compared with viewing facial expressions of emotions. In contrast, in the same task emotional expressions distinctively activated the left amygdale. The results are discussed taking into consideration the fact that, like other facial expressions, neutral expressions are usually assigned some emotional significance. However, neutral faces evoke a greater activation of circuits probably involved in more elaborate cognitive processing.

  8. Neutralization of tier-2 viruses and epitope profiling of plasma antibodies from human immunodeficiency virus type 1 infected donors from India.

    Directory of Open Access Journals (Sweden)

    Raiees Andrabi

    Full Text Available Broadly cross neutralizing antibodies (NAbs are generated in a group of HIV-1 infected individuals during the natural infection, but little is known about their prevalence in patients infected with viral subtypes from different geographical regions. We tested here the neutralizing efficiency of plasma antibodies from 80 HIV-1 infected antiretroviral drug naive patients against a panel of subtype-B and C tier 2 viruses. We detected cross-neutralizing antibodies in approximately 19-27% of the plasma, however the subtype-C specific neutralization efficiency predominated (p = 0.004. The neutralizing activity was shown to be exclusively mediated by the immunoglobulin G (IgG fraction in the representative plasma samples. Epitope mapping of three, the most cross-neutralizing plasma (CNP AIIMS206, AIIMS239 and AIIMS249 with consensus-C overlapping envelope peptides revealed ten different binding specificities with only V3 and IDR being common. The V3 and IDR were highly antigenic regions but no correlation between their reciprocal Max50 binding titers and neutralization was observed. In addition, the neutralizing activity of CNP was not substantially reduced by V3 and gp41 peptides except a modest contribution of MPER peptide. The MPER was rarely recognized by plasma antibodies though antibody depletion and competition experiments demonstrated MPER dependent neutralization in two out of three CNP. Interestingly, the binding specificity of one of the CNP (AIIMS206 overlapped with broadly neutralizing mAb 2F5 epitope. Overall, the data suggest that, despite the low immunogenicity of HIV-1 MPER, the antibodies directed to this region may serve as crucial reagents for HIV-1 vaccine design.

  9. Neutron production by neutral beam sources

    International Nuclear Information System (INIS)

    Berkner, K.H.; Massoletti, D.J.; McCaslin, J.B.; Pyle, R.V.; Ruby, L.

    1979-11-01

    Neutron yields, from interactions of multiampere 40- to 120-keV deuterium beams with deuterium atoms implanted in copper targets, have been measured in order to provide input data for shielding of neutral-deuterium beam facilities for magnetic fusion experiments

  10. Neutron production by neutral beam sources

    Energy Technology Data Exchange (ETDEWEB)

    Berkner, K.H.; Massoletti, D.J.; McCaslin, J.B.; Pyle, R.V.; Ruby, L.

    1979-11-01

    Neutron yields, from interactions of multiampere 40- to 120-keV deuterium beams with deuterium atoms implanted in copper targets, have been measured in order to provide input data for shielding of neutral-deuterium beam facilities for magnetic fusion experiments.

  11. The buffer effect in neutral electrolyte supercapacitors

    DEFF Research Database (Denmark)

    Thrane Vindt, Steffen; Skou, Eivind M.

    2016-01-01

    The observation that double-layer capacitors based on neutral aqueous electrolytes can have significantly wider usable potential windows than those based on acidic or alkaline electrolytes is studied. This effect is explained by a local pH change taking place at the electrode surfaces, leading...... potassium nitrate as the electrolyte and potassium phosphates as the buffer system....

  12. Special solutions of neutral functional differential equations

    Directory of Open Access Journals (Sweden)

    Győri István

    2001-01-01

    Full Text Available For a system of nonlinear neutral functional differential equations we prove the existence of an -parameter family of "special solutions" which characterize the asymptotic behavior of all solutions at infinity. For retarded functional differential equations the special solutions used in this paper were introduced by Ryabov.

  13. Engineering problems of future neutral beam injectors

    International Nuclear Information System (INIS)

    Fink, J.

    1977-01-01

    Because there is no limit to the energy or power that can be delivered by a neutral-beam injector, its use will be restricted by either its cost, size, or reliability. Studies show that these factors can be improved by the injector design, and several examples, taken from mirror reactor studies, are given

  14. Development of KSTAR Neutral Beam Heating System

    Energy Technology Data Exchange (ETDEWEB)

    Oh, B. H.; Song, W. S.; Yoon, B. J. (and others)

    2007-10-15

    The prototype components of a neutral beam injection (NBI) system have been developed for the KSTAR, and a capability of the manufactured components has been tested. High power ion source, acceleration power supply, other ion source power supplies, neutralizer, bending magnet for ion beam separation, calorimeter, and cryo-sorption pump have been developed by using the domestic technologies and tested for a neutral beam injection of 8 MW per beamline with a pulse duration of 300 seconds. The developed components have been continuously upgraded to achieve the design requirements. The development technology of high power and long pulse neutral beam injection system has been proved with the achievement of 5.2 MW output for a short pulse length and 1.6 MW output for a pulse length of 300 seconds. Using these development technologies, the domestic NB technology has been stabilized under the development of high power ion source, NB beamline components, high voltage and current power supplies, NB diagnostics, NB system operation and control.

  15. ICAN: High power neutral beam generation

    International Nuclear Information System (INIS)

    Moustaizis, S.D.; Lalousis, P.; Perrakis, K.; Auvray, P.; Larour, J.; Ducret, J.E.; Balcou, P.

    2015-01-01

    During the last few years there is an increasing interest on the development of alternative high power new negative ion source for Tokamak applications. The proposed new neutral beam device presents a number of advantages with respect to: the density current, the acceleration voltage, the relative compact dimension of the negative ion source, and the coupling of a high power laser beam for photo-neutralization of the negative ion beam. Here we numerically investigate, using a multi- fluid 1-D code, the acceleration and the extraction of high power ion beam from a Magnetically Insulated Diode (MID). The diode configuration will be coupled to a high power device capable of extracting a current up to a few kA with an accelerating voltage up to MeV. An efficiency of up to 92% of the coupling of the laser beam, is required in order to obtain a high power, up to GW, neutral beam. The new high energy, high average power, high efficiency (up to 30%) ICAN fiber laser is proposed for both the plasma generation and the photo-neutralizer configuration. (authors)

  16. elative controllability of nonlinear neutral Volterra Integrodiferential ...

    African Journals Online (AJOL)

    In this paper we established sufficient conditions for the relative controllability of the nonlinear neutral volterra integro-differential systems with distributed delays in the control. The results were established using the Schauder's fixed point theorem which is an extension of known results. Journal of the Nigerian Association of ...

  17. If It's Neutral, It's Not Technology

    Science.gov (United States)

    Strate, Lance

    2012-01-01

    Taking a media ecology perspective, this article argues that technology cannot be neutral, because it is a form of change, and it has an inherent bias based on the properties of its materials and methods. Additionally, the application of a technology is an intrinsic part of the technology itself, as is technique, instructions, software, or…

  18. Neutral beam data systems at ORNL

    International Nuclear Information System (INIS)

    Stewart, C.R.

    1982-01-01

    A control system for neutral injection beam lines has been designed, implemented, and used with much success. Despite the problems with very high power levels this system is very successful in relieving the operators burdens of slow conditioning, data recording, and mode switching. The use of computer control with multiple beam lines now appears very promising

  19. Risk neutral second best toll pricing.

    Science.gov (United States)

    2011-08-01

    We propose a risk-neutral second best toll pricing scheme to account for the possible no uniqueness : of user equilibrium solutions. The scheme is designed to optimize for the expected objective value : as the UE solution varies within the solution s...

  20. Neutral gas transport modeling with DEGAS 2

    International Nuclear Information System (INIS)

    Karney, C.; Stotler, D.

    1993-01-01

    The authors are currently re-writing the neutral gas transport code, DEGAS, with a view to making it both faster and easier to include new physics. They present model calculations including ionization and charge exchange illustrating the way that reactions are included into DEGAS 2 and its operation on a distributed network of workstations

  1. Niche versus neutrality: a dynamical analysis

    Science.gov (United States)

    Michael Kalyuzhny; Efrat Seri; Rachel Chocron; Curtis H. Flather; Ronen Kadmon; Nadav M. Shnerb

    2014-01-01

    Understanding the forces shaping ecological communities is of crucial importance for basic science and conservation. After 50 years in which ecological theory has focused on either stable communities driven by niche-based forces or nonstable “neutral” communities driven by demographic stochasticity, contemporary theories suggest that ecological communities are driven...

  2. Neutral anion receptors: design and application

    NARCIS (Netherlands)

    Antonisse, M.M.G.; Reinhoudt, David

    1998-01-01

    After the development of synthetic cation receptors in the late 1960s, only in the past decade has work started on the development of synthetic neutral anion receptors. Combination and preorganization of different anion binding groups, like amides, urea moieties, or Lewis acidic metal centers lead

  3. Laser cooling and trapping of neutral atoms

    International Nuclear Information System (INIS)

    Phillips, W.D.

    1998-01-01

    The article is a translation of the lecture given on the occasion of the 1997 Nobel Prize awarding ceremony. The history of the discovery of laser cooling and trapping of neutral atoms is described. An explanation of this phenomenon is presented and the author's personal contribution to the discovery is highlighted. The article is completed by Dr. Phillips' autobiography. (Z.J.)

  4. Possible neutral beam requirements for TFTR upgrades

    International Nuclear Information System (INIS)

    Prichard, B.A. Jr.; Little, R.; Post, D.E.; Schmidt, J.A.

    1977-01-01

    A discussion is provided of possible neutral beam requirements and constraints for a TFTR upgrade. The time scale is the early 80s and beams of 250 keV D 0 , probably using 65 ampere negative ion sources, existing power supplies and vacuum enclosures would be required

  5. Transition radiation of ultrarelativistic neutral particles

    International Nuclear Information System (INIS)

    Grimus, W.; Neufeld, H.

    1994-10-01

    We perform a quantum theoretical calculation of transition radiation by neutral particles with spin 1/2 equipped with magnetic moments and/or electric dipole moments. The limit of vanishing masses is treated exactly for arbitrary refraction index. Finally we apply our result to the solar neutrino flux. (author)

  6. A storage ring for neutral molecules

    NARCIS (Netherlands)

    Crompvoets, F.M.H.

    2005-01-01

    Time-varying inhomogeneous electric fields can be used to manipulate the motion of neutral molecules in phase-space, i.e., position-momentum space, via their electric dipole moment. A theoretical background is given on the motion of the molecules in phase-space. As the forces exerted on the

  7. Modeling of the lithium based neutralizer for ITER neutral beam injector

    Energy Technology Data Exchange (ETDEWEB)

    Dure, F., E-mail: franck.dure@u-psud.fr [LPGP, Laboratoire de Physique des Gaz et Plasmas, CNRS-Universite Paris Sud, Orsay (France); Lifschitz, A.; Bretagne, J.; Maynard, G. [LPGP, Laboratoire de Physique des Gaz et Plasmas, CNRS-Universite Paris Sud, Orsay (France); Simonin, A. [IRFM, Institut de Recherche sur la Fusion Magnetique, CEA Cadarache, 13108 Saint-Paul lez Durance (France); Minea, T. [LPGP, Laboratoire de Physique des Gaz et Plasmas, CNRS-Universite Paris Sud, Orsay (France)

    2012-04-04

    Highlights: Black-Right-Pointing-Pointer We compare different lithium based neutraliser configurations to the deuterium one. Black-Right-Pointing-Pointer We study characteristics of the secondary plasma and the propagation of the 1 MeV beam. Black-Right-Pointing-Pointer Using lithium increases the neutralisation effiency keeping correct beam focusing. Black-Right-Pointing-Pointer Using lithium also reduces the backstreaming effect in direction of the ion source. - Abstract: To achieve thermonuclear temperatures necessary to produce fusion reactions in the ITER Tokamak, additional heating systems are required. One of the main method to heat the plasma ions in ITER will be the injection of energetic neutrals (NBI). In the neutral beam injector, negative ions (D{sup -}) are electrostatically accelerated to 1 MeV, and then stripped of their extra electron via collisions with a target gas, in a structure known as neutralizer. In the current ITER specification, the target gas is deuterium. It has been recently proposed to use lithium vapor instead of deuterium as target gas in the neutralizer. This would allow to reduce the gas load in the NBI vessel and to improve the neutralization efficiency. A Particle-in-Cell Monte Carlo code has been developed to study the transport of the beams and the plasma formation in the neutralizer. A comparison between Li and D{sub 2} based neutralizers made with this code is presented here, as well as a parametric study on the geometry of the Li based neutralizer. Results demonstrate the feasibility of a Li based neutralizer, and its advantages with respect to the deuterium based one.

  8. Misconceptions and false expectations in neutral evolution

    Directory of Open Access Journals (Sweden)

    CARLOS Y. VALENZUELA

    2000-01-01

    Full Text Available Neutral evolution results from random recurrent mutation and genetic drift. A small part of random evolution, that which is related to protein or DNA polymorphisms, is the subject of the Neutral Theory of Evolution. One of the foundations of this theory is the demonstration that the mutation rate (m is equal to the substitution rate. Since both rates are independent of population size, they are independent of drift, which is dependent upon population size. Neutralists have erroneously equated the substitution rate with the fixation rate, despite the fact that they are antithetical conceptions. The neutralists then applied the random walk stochastic model to justify alleles or bases that were fixated or eliminated. In this model, once the allele or base frequencies reach the monomorphic states (values of 1.0 or 0.0, the absorbing barriers, they can no longer return to the polymorphic state. This operates in a pure mathematical model. If recurrent mutation occurs (as in biotic real systems fixation and elimination are impossible. A population of bacteria in which m=10-8 base mutation (or substitution/site/generation and the reproduction rate is 1000 cell cycle/year should replace all its genome bases in approximately 100,000 years. The expected situation for all sites is polymorphism for the four bases rather than monomorphism at 1.0 or 0.0 frequencies. If fixation and elimination of a base for more than 500,000 years are impossible, then most of the neutral theory is untenable. A new complete neutral model, which allows for recurrent substitutions, is proposed here based on recurrent mutation or substitution and drift alone. The model fits a binomial or Poisson distribution and not a geometric one, as does neutral theory.

  9. Broad-range PCR: past, present, or future of bacteriology?

    Science.gov (United States)

    Renvoisé, A; Brossier, F; Sougakoff, W; Jarlier, V; Aubry, A

    2013-08-01

    PCR targeting the gene encoding 16S ribosomal RNA (commonly named broad-range PCR or 16S PCR) has been used for 20 years as a polyvalent tool to study prokaryotes. Broad-range PCR was first used as a taxonomic tool, then in clinical microbiology. We will describe the use of broad-range PCR in clinical microbiology. The first application was identification of bacterial strains obtained by culture but whose phenotypic or proteomic identification remained difficult or impossible. This changed bacterial taxonomy and allowed discovering many new species. The second application of broad-range PCR in clinical microbiology is the detection of bacterial DNA from clinical samples; we will review the clinical settings in which the technique proved useful (such as endocarditis) and those in which it did not (such as characterization of bacteria in ascites, in cirrhotic patients). This technique allowed identifying the etiological agents for several diseases, such as Whipple disease. This review is a synthesis of data concerning the applications, assets, and drawbacks of broad-range PCR in clinical microbiology. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  10. Structures of phlebovirus glycoprotein Gn and identification of a neutralizing antibody epitope.

    Science.gov (United States)

    Wu, Yan; Zhu, Yaohua; Gao, Feng; Jiao, Yongjun; Oladejo, Babayemi O; Chai, Yan; Bi, Yuhai; Lu, Shan; Dong, Mengqiu; Zhang, Chang; Huang, Guangmei; Wong, Gary; Li, Na; Zhang, Yanfang; Li, Yan; Feng, Wen-Hai; Shi, Yi; Liang, Mifang; Zhang, Rongguang; Qi, Jianxun; Gao, George F

    2017-09-05

    Severe fever with thrombocytopenia syndrome virus (SFTSV) and Rift Valley fever virus (RVFV) are two arthropod-borne phleboviruses in the Bunyaviridae family, which cause severe illness in humans and animals. Glycoprotein N (Gn) is one of the envelope proteins on the virus surface and is a major antigenic component. Despite its importance for virus entry and fusion, the molecular features of the phleboviruse Gn were unknown. Here, we present the crystal structures of the Gn head domain from both SFTSV and RVFV, which display a similar compact triangular shape overall, while the three subdomains (domains I, II, and III) making up the Gn head display different arrangements. Ten cysteines in the Gn stem region are conserved among phleboviruses, four of which are responsible for Gn dimerization, as revealed in this study, and they are highly conserved for all members in Bunyaviridae Therefore, we propose an anchoring mode on the viral surface. The complex structure of the SFTSV Gn head and human neutralizing antibody MAb 4-5 reveals that helices α6 in subdomain III is the key component for neutralization. Importantly, the structure indicates that domain III is an ideal region recognized by specific neutralizing antibodies, while domain II is probably recognized by broadly neutralizing antibodies. Collectively, Gn is a desirable vaccine target, and our data provide a molecular basis for the rational design of vaccines against the diseases caused by phleboviruses and a model for bunyavirus Gn embedding on the viral surface.

  11. Predicting HIV-1 transmission and antibody neutralization efficacy in vivo from stoichiometric parameters.

    Directory of Open Access Journals (Sweden)

    Oliver F Brandenberg

    2017-05-01

    Full Text Available The potential of broadly neutralizing antibodies targeting the HIV-1 envelope trimer to prevent HIV-1 transmission has opened new avenues for therapies and vaccines. However, their implementation remains challenging and would profit from a deepened mechanistic understanding of HIV-antibody interactions and the mucosal transmission process. In this study we experimentally determined stoichiometric parameters of the HIV-1 trimer-antibody interaction, confirming that binding of one antibody is sufficient for trimer neutralization. This defines numerical requirements for HIV-1 virion neutralization and thereby enables mathematical modelling of in vitro and in vivo antibody neutralization efficacy. The model we developed accurately predicts antibody efficacy in animal passive immunization studies and provides estimates for protective mucosal antibody concentrations. Furthermore, we derive estimates of the probability for a single virion to start host infection and the risks of male-to-female HIV-1 transmission per sexual intercourse. Our work thereby delivers comprehensive quantitative insights into both the molecular principles governing HIV-antibody interactions and the initial steps of mucosal HIV-1 transmission. These insights, alongside the underlying, adaptable modelling framework presented here, will be valuable for supporting in silico pre-trial planning and post-hoc evaluation of HIV-1 vaccination or antibody treatment trials.

  12. One-electron capture and target ionization in He+-neutral-atom collisions

    International Nuclear Information System (INIS)

    Shevelko, V.P.; Tolstikhina, I.Yu.; Kato, D.; Tawara, H.; Song, M-.Y.; Yoon, J-.S.

    2009-12-01

    One-electron capture and target-ionization cross sections in collisions of He + ions with neutral atoms: He + + A → He + A + and He + + A → He + + A + + e, A = H, He(1s 2 , 1s2s), Ne, Ar, Kr, Xe, are calculated and compared with available experimental data over the broad energy range E = 0.1 keV/u - 10 MeV/u of He + ions. The role of the metastable states of neutral helium atoms in such collisions, which are of importance in plasma physics applications, is briefly discussed. The recommended cross section data for these processes are presented in a closed analytical form (nine-order polynomials) which can be used for a plasma modeling and diagnostics. (author)

  13. THE ROLL-OVER OF HELIOSPHERIC NEUTRAL HYDROGEN BELOW 100 eV: OBSERVATIONS AND IMPLICATIONS

    Energy Technology Data Exchange (ETDEWEB)

    Galli, A.; Wurz, P. [Physics Institute, University of Bern, Bern, 3012 (Switzerland); Schwadron, N. A.; Kucharek, H.; Möbius, E. [University of New Hampshire, Durham, NH 03824 (United States); Bzowski, M.; Sokół, J. M.; Kubiak, M. A. [Space Research Centre, Polish Academy of Sciences, Warsaw, 00-716 (Poland); Funsten, H. O. [Los Alamos National Laboratory, Intelligence and Space Research Division, Los Alamos, NM 87545 (United States); Fuselier, S. A.; McComas, D. J. [Southwest Research Institute, San Antonio, TX 78228 (United States)

    2016-04-20

    We present an improved analysis of the energy spectrum of energetic neutral hydrogen from the heliosheath observed with the IBEX -Lo sensor on the Interstellar Boundary EXplorer from the years 2009 to 2012. This analysis allows us to study the lowest energies between 10 and 100 eV although various background sources are more intense than the targeted signal over broad areas of the sky. The results improve our knowledge of the interaction region between our heliosphere and the interstellar plasma because these neutral atoms are direct messengers from the low-energy plasma in the heliosheath. We find a roll-over of the energy spectrum below 100 eV, which has major implications for the pressure balance of the plasma in the inner heliosheath. The results can also be compared directly with in situ observations of the Voyager 1 and 2 spacecraft.

  14. Phage Display-Derived Cross-Reactive Neutralizing Antibody against Enterovirus 71 and Coxsackievirus A16.

    Science.gov (United States)

    Zhang, Xiao; Sun, Chunyun; Xiao, Xiangqian; Pang, Lin; Shen, Sisi; Zhang, Jie; Cen, Shan; Yang, Burton B; Huang, Yuming; Sheng, Wang; Zeng, Yi

    2016-01-01

    Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are members of the Picornaviridae family and are considered the main causative agents of hand, foot and mouth disease (HFMD). In recent decades large HFMD outbreaks caused by EV71 and CVA16 have become significant public health concerns in the Asia-Pacific region. Vaccines and antiviral drugs are unavailable to prevent EV71 and CVA16 infection. In the current study, a chimeric antibody targeting a highly conserved peptide in the EV71 VP4 protein was isolated by using a phage display technique. The antibody showed cross-neutralizing capability against EV71 and CVA16 in vitro. The results suggest that this phage display-derived antibody will have great potential as a broad neutralizing antibody against EV71 and CVA16 after affinity maturation and humanization.

  15. Global panel of HIV-1 Env reference strains for standardized assessments of vaccine-elicited neutralizing antibodies.

    Science.gov (United States)

    deCamp, Allan; Hraber, Peter; Bailer, Robert T; Seaman, Michael S; Ochsenbauer, Christina; Kappes, John; Gottardo, Raphael; Edlefsen, Paul; Self, Steve; Tang, Haili; Greene, Kelli; Gao, Hongmei; Daniell, Xiaoju; Sarzotti-Kelsoe, Marcella; Gorny, Miroslaw K; Zolla-Pazner, Susan; LaBranche, Celia C; Mascola, John R; Korber, Bette T; Montefiori, David C

    2014-03-01

    Standardized assessments of HIV-1 vaccine-elicited neutralizing antibody responses are complicated by the genetic and antigenic variability of the viral envelope glycoproteins (Envs). To address these issues, suitable reference strains are needed that are representative of the global epidemic. Several panels have been recommended previously, but no clear answers have been available on how many and which strains are best suited for this purpose. We used a statistical model selection method to identify a global panel of reference Env clones from among 219 Env-pseudotyped viruses assayed in TZM-bl cells with sera from 205 HIV-1-infected individuals. The Envs and sera were sampled globally from diverse geographic locations and represented all major genetic subtypes and circulating recombinant forms of the virus. Assays with a panel size of only nine viruses adequately represented the spectrum of HIV-1 serum neutralizing activity seen with the larger panel of 219 viruses. An optimal panel of nine viruses was selected and augmented with three additional viruses for greater genetic and antigenic coverage. The spectrum of HIV-1 serum neutralizing activity seen with the final 12-virus panel closely approximated the activity seen with subtype-matched viruses. Moreover, the final panel was highly sensitive for detection of many of the known broadly neutralizing antibodies. For broader assay applications, all 12 Env clones were converted to infectious molecular clones using a proviral backbone carrying a Renilla luciferase reporter gene (Env.IMC.LucR viruses). This global panel should facilitate highly standardized assessments of vaccine-elicited neutralizing antibodies across multiple HIV-1 vaccine platforms in different parts of the world. An effective HIV-1 vaccine will need to overcome the extraordinary genetic variability of the virus, where most variation occurs in the viral envelope glycoproteins that are the sole targets for neutralizing antibodies. Efforts to elicit

  16. Social Pharmacy Research in Copenhagen—Maintaining a Broad Approach

    Directory of Open Access Journals (Sweden)

    Sofia Kälvemark Sporrong

    2016-02-01

    Full Text Available Social Pharmacy (SP is a multidisciplinary field to promote the adequate use of medicine. The field of SP is increasingly important due to a numbers of new trends all posing challenges to society. The SP group at the University of Copenhagen has for several years used a broad approach to SP teaching and research, often illustrated by the four levels: individual, group, organizational, and societal. In this paper the relevance of maintaining a broad approach to SP research is argued for and examples of the importance of such type of research is presented.

  17. Potent neutralization of influenza A virus by a single-domain antibody blocking M2 ion channel protein.

    Directory of Open Access Journals (Sweden)

    Guowei Wei

    Full Text Available Influenza A virus poses serious health threat to humans. Neutralizing antibodies against the highly conserved M2 ion channel is thought to offer broad protection against influenza A viruses. Here, we screened synthetic Camel single-domain antibody (VHH libraries against native M2 ion channel protein. One of the isolated VHHs, M2-7A, specifically bound to M2-expressed cell membrane as well as influenza A virion, inhibited replication of both amantadine-sensitive and resistant influenza A viruses in vitro, and protected mice from a lethal influenza virus challenge. Moreover, M2-7A showed blocking activity for proton influx through M2 ion channel. These pieces of evidence collectively demonstrate for the first time that a neutralizing antibody against M2 with broad specificity is achievable, and M2-7A may have potential for cross protection against a number of variants and subtypes of influenza A viruses.

  18. Research on Stress Neutral Layer Offset in the Straightening Process

    Directory of Open Access Journals (Sweden)

    Hailian Gui

    2015-01-01

    Full Text Available The stress neutral layer offset is analyzed by theoretical and numerical calculation methods. In traditional straightening theory, the stress neutral layer was consistent with the geometric central layer. However, there is a phenomenon that the stress neutral layer has some offset with the geometric neutral layer. This offset is a very important factor for improving the precision of the straightening force. The formula of the stress neutral layer offset is obtained by a theoretical method and the change law is given by numerical calculation method. The neutral layer offset theory provides the theoretical basis for establishing the model of straightening force precisely.

  19. (IAM Series No 005) Are “Market Neutral” Hedge Funds Really Market Neutral?

    OpenAIRE

    Andrew Patton

    2004-01-01

    One can consider the concept of market neutrality for hedge funds as having breadth and depth: breadth reflects the number of market risks to which a fund is neutral, while depth reflects the completeness of the neutrality of the fund to market risks. We focus on market neutrality depth, and propose five different neutrality concepts. Mean neutrality nests the standard correlation-based definition of neutrality. Variance neutrality, Value-at-Risk neutrality and tail neutrality all relate to t...

  20. Summary of fueling by neutral beams

    International Nuclear Information System (INIS)

    Jassby, D.L.

    1978-01-01

    Injected neutral beams supply energy, particles, and momentum to a plasma, while the thermalizing fast ions also increase the fusion reactivity by beam-target or hot-ion reactions. Magnetic mirror machines take advantage of all of these features, with the exception of the momentum input. Neutral-beam injection into toroidal plasmas has been proposed and has so far been utilized mainly as a source of heat, and secondarily as a source of increased neutron production. Nevertheless, fueling by injected beams can also play an important role in toroidal plasmas, especially in the start-up phase of ignited plasmas, or for the quasi-steady maintenance of low-Q plasmas where the average ion energy may exceed the electron energy by a large factor

  1. A new approach to entangling neutral atoms.

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jongmin [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Martin, Michael J. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Jau, Yuan-Yu [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Deutsch, Ivan H. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Biedermann, Grant W. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2016-11-01

    Our team has developed a new approach to entangling neutral atoms with a Rydberg-dressed interaction. Entangling neutral atoms is an essential key of quantum technologies such as quantum computation, many-body quantum simulation, and high-precision atomic sensors . The demonstrated Rydberg-dressed protocol involves adiabatically imposing a light shift on the ground state by coupling an excited Rydberg state with a tuned laser field. Using this technique, we have demonstrated a strong and tunable dipole - dipole interaction between two individually trapped atoms with energy shifts of order 1 MHz, which has been challenging to achieve in other protocols . During this program, we experimentally demonstrated Bell-state entanglement and the isomorphism to the Jaynes - Cumming model of a Rydberg-dressed two-atom system. Our theoretical calculations of a CPHASE quantum logic gate and arbitrary Dicke state quantum control in this system encourage further work.

  2. Particle reflection and TFTR neutral beam diagnostics

    International Nuclear Information System (INIS)

    Kamperschroer, J.H.; Grisham, L.R.; Kugel, H.W.; O'Connor, T.E.; Newman, R.A.; Stevenson, T.N.; von Halle, A.; Williams, M.D.

    1992-04-01

    Determination of two critical neutral beam parameters, power and divergence, are affected by the reflection of a fraction of the incident energy from the surface of the measuring calorimeter. On the TFTR Neutral Beam Test Stand, greater than 30% of the incident power directed at the target chamber calorimeter was unaccounted for. Most of this loss is believed due to reflection from the surface of the flat calorimeter, which was struck at a near grazing incidence (12 degrees). Beamline calorimeters, of a ''V''-shape design, while retaining the beam power, also suffer from reflection effects. Reflection, in this latter case, artificially peaks the power toward the apex of the ''V'', complicating the fitting technique, and increasing the power density on axis by 10 to 20%; an effect of import to future beamline designers. Agreement is found between measured and expected divergence values, even with 24% of the incident energy reflected

  3. Fast Neutral Pressure Gauges in NSTX

    International Nuclear Information System (INIS)

    Raman, R.; Kugel, H.W.; Gernhardt, R.; Provost, T.; Jarboe, T.R.; Soukhanovskii, V.

    2004-01-01

    Successful operation in NSTX of two prototype fast-response micro ionization gauges during plasma operations has motivated us to install five gauges at different toroidal and poloidal locations to measure the edge neutral pressure and its dependence on the type of discharge (L-mode, H-mode, CHI) and the fueling method and location. The edge neutral pressure is also used as an input to the transport analysis codes TRANSP and DEGAS-2. The modified PDX-type Penning gauges are well suited for pressure measurements in the NSTX divertor where the toroidal field is relatively high. Behind the NSTX outer divertor plates where the field is lower, an unshielded fast ion gauge of a new design has been installed. This gauge was developed after laboratory testing of several different designs in a vacuum chamber with applied magnetic fields

  4. Mass separated neutral particle energy analyser

    International Nuclear Information System (INIS)

    Takeuchi, Hiroshi; Matsuda, Toshiaki; Miura, Yukitoshi; Shiho, Makoto; Maeda, Hikosuke; Hashimoto, Kiyoshi; Hayashi, Kazuo.

    1983-09-01

    A mass separated neutral particle energy analyser which could simultaneously measure hydrogen and deuterium atoms emitted from tokamak plasma was constructed. The analyser was calibrated for the energy and mass separation in the energy range from 0.4 keV to 9 keV. In order to investigate the behavior of deuteron and proton in the JFT-2 tokamak plasma heated with ion cyclotron wave and neutral beam injection, this analyser was installed in JFT-2 tokamak. It was found that the energy spectrum could be determined with sufficient accuracy. The obtained ion temperature and ratio of deuteron and proton density from the energy spectrum were in good agreement with the value deduced from Doppler broadening of TiXIV line and the line intensities of H sub(α) and D sub(α) respectively. (author)

  5. Thermal Conductivity of the Multicomponent Neutral Atmosphere

    Science.gov (United States)

    Pavlov, A. V.

    2017-12-01

    Approximate expressions for the thermal conductivity coefficient of the multicomponent neutral atmosphere consisting of N2, O2, O, He, and H are analyzed and evaluated for the atmospheric conditions by comparing them with that given by the rigorous hydrodynamic theory. The new approximations of the thermal conductivity coefficients of simple gases N2, O2, O, He, and H are derived and used. It is proved that the modified Mason and Saxena approximation of the atmospheric thermal conductivity coefficient is more accurate in reproducing the atmospheric values of the rigorous hydrodynamic thermal conductivity coefficient in comparison with those that are generally accepted in atmospheric studies. This approximation of the thermal conductivity coefficient is recommended to use in calculations of the neutral temperature of the atmosphere.

  6. Biofilm community succession: a neutral perspective.

    Science.gov (United States)

    Woodcock, Stephen; Sloan, William T

    2017-05-22

    Although biofilms represent one of the dominant forms of life in aqueous environments, our understanding of the assembly and development of their microbial communities remains relatively poor. In recent years, several studies have addressed this and have extended the concepts of succession theory in classical ecology into microbial systems. From these datasets, niche-based conceptual models have been developed explaining observed biodiversity patterns and their dynamics. These models have not, however, been formulated mathematically and so remain untested. Here, we further develop spatially resolved neutral community models and demonstrate that these can also explain these patterns and offer alternative explanations of microbial succession. The success of neutral models suggests that stochastic effects alone may have a much greater influence on microbial community succession than previously acknowledged. Furthermore, such models are much more readily parameterised and can be used as the foundation of more complex and realistic models of microbial community succession.

  7. Neutralization method for a hydrofluoric acid release

    International Nuclear Information System (INIS)

    Williams, D.L.; Deacon, L.E.

    1976-01-01

    A laboratory investigation of methods for neutralizing a release at the hydrofluoric acid tank farm at the Portsmouth Gaseous Diffusion Plant has revealed that the best neutralization method incorporates the use of a lime/water slurry. In this method, settling of suspended solids in the liquid is enhanced by the application of sodium dodecyl sulfate, which causes immediate flocculation and settling. Dilution and expulsion of the supernatant liquid above the flocculated solids result in an effluent which meets the one part per million fluoride limit established by the U.S. Environmental Protection Agency. A fluoride specific ion electrode is used to determine fluoride concentration. This method presently is being adapted for use in the hydrofluoric acid tank farm and is being considered for use at the plant's fluorine generation facility. It could be adapted for use in any facility that contains fluoride in aqueous solution

  8. Capacitive Neutralization Dialysis for Direct Energy Generation.

    Science.gov (United States)

    Liu, Yue; Zhang, Yi; Ou-Yang, Wei; Bastos Sales, Bruno; Sun, Zhuo; Liu, Fei; Zhao, Ran

    2017-08-15

    Capacitive neutralization dialysis energy (CNDE) is proposed as a novel energy-harvesting technique that is able to utilize waste acid and alkaline solutions to produce electrical energy. CNDE is a modification based on neutralization dialysis. It was found that a higher NaCl concentration led to a higher open-circuit potential when the concentrations of acid and alkaline solutions were fixed. Upon closing of the circuit, the membrane potential was used as a driving force to move counter ions into the electrical double layers at the electrode-liquid interface, thereby creating an ionic current. Correspondingly, in the external circuit, electrons flow through an external resistor from one electrode to the other, thereby generating electrical energy directly. The influence of external resistances was studied to achieve greater energy extraction, with the maximum output of 110 mW/m 2 obtained by employing an external resistance of 5 Ω together with the AC-coated electrode.

  9. Trivalent combination vaccine induces broad heterologous immune responses to norovirus and rotavirus in mice.

    Directory of Open Access Journals (Sweden)

    Kirsi Tamminen

    Full Text Available Rotavirus (RV and norovirus (NoV are the two major causes of viral gastroenteritis (GE in children worldwide. We have developed an injectable vaccine design to prevent infection or GE induced with these enteric viruses. The trivalent combination vaccine consists of NoV capsid (VP1 derived virus-like particles (VLPs of GI-3 and GII-4 representing the two major NoV genogroups and tubular RV recombinant VP6 (rVP6, the most conserved and abundant RV protein. Each component was produced in insect cells by a recombinant baculovirus expression system and combined in vitro. The vaccine components were administered intramuscularly to BALB/c mice either separately or in the trivalent combination. High levels of NoV and RV type specific serum IgGs with high avidity (>50% as well as intestinal IgGs were detected in the immunized mice. Cross-reactive IgG antibodies were also elicited against heterologous NoV VLPs not used for immunization (GII-4 NO, GII-12 and GI-1 VLPs and to different RVs from cell cultures. NoV-specific serum antibodies blocked binding of homologous and heterologous VLPs to the putative receptors, histo-blood group antigens, suggesting broad NoV neutralizing activity of the sera. Mucosal antibodies of mice immunized with the trivalent combination vaccine inhibited RV infection in vitro. In addition, cross-reactive T cell immune responses to NoV and RV-specific antigens were detected. All the responses were sustained for up to six months. No mutual inhibition of the components in the trivalent vaccine combination was observed. In conclusion, the NoV GI and GII VLPs combination induced broader cross-reactive and potentially neutralizing immune responses than either of the VLPs alone. Therefore, trivalent vaccine might induce protective immune responses to the vast majority of circulating NoV and RV genotypes.

  10. Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Jinghe; Kang, Byong H.; Ishida, Elise; Zhou, Tongqing; Griesman, Trevor; Sheng, Zizhang; Wu, Fan; Doria-Rose, Nicole A.; Zhang, Baoshan; McKee, Krisha; O’Dell, Sijy; Chuang, Gwo-Yu; Druz, Aliaksandr; Georgiev, Ivelin S.; Schramm, Chaim A.; Zheng, Anqi; Joyce, M.  Gordon; Asokan, Mangaiarkarasi; Ransier, Amy; Darko, Sam; Migueles, Stephen A.; Bailer, Robert T.; Louder, Mark K.; Alam, S.  Munir; Parks, Robert; Kelsoe, Garnett; Von Holle, Tarra; Haynes, Barton F.; Douek, Daniel C.; Hirsch, Vanessa; Seaman, Michael S.; Shapiro, Lawrence; Mascola, John R.; Kwong, Peter D.; Connors, Mark

    2016-11-01

    Detailed studies of the broadly neutralizing antibodies (bNAbs) that underlie the best available examples of the humoral immune response to HIV are providing important information for the development of therapies and prophylaxis for HIV-1 infection. Here, we report a CD4-binding site (CD4bs) antibody, named N6, that potently neutralized 98% of HIV-1 isolates, including 16 of 20 that were resistant to other members of its class. N6 evolved a mode of recognition such that its binding was not impacted by the loss of individual contacts across the immunoglobulin heavy chain. In addition, structural analysis revealed that the orientation of N6 permitted it to avoid steric clashes with glycans, which is a common mechanism of resistance. Thus, an HIV-1-specific bNAb can achieve potent, near-pan neutralization of HIV-1, making it an attractive candidate for use in therapy and prophylaxis.

  11. Neutral Particle Analyzer Diagnostic on NSTX

    International Nuclear Information System (INIS)

    Medley, S.S.; Roquemore, A.L.

    2004-01-01

    The Neutral Particle Analyzer (NPA) diagnostic on the National Spherical Torus Experiment (NSTX) utilizes a PPPL-designed E||B spectrometer that measures the energy spectra of minority hydrogen and bulk deuterium species simultaneously with 39 energy channels per mass specie and a time resolution of 1 ms. The calibrated energy range is E = 0.5-150 keV and the energy resolution varies from AE/E = 3-7% over the surface of the microchannel plate detector

  12. PLT neutral injection ignitron accelerating supply

    International Nuclear Information System (INIS)

    Ashcroft, D.L.; Murray, J.G.; Newman, R.A.; Peterson, F.L.

    1975-11-01

    A phase-controlled rectifier was designed for the accelerating supply on the PLT Neutral Beam Injection system at PPPL. The rectifier must furnish 70 amperes at up to 50 KV for 300 milliseconds, with a duty cycle of up to 10 percent. Protection of the injectors requires the supply to withstand repeated crowbarring. The rectifying element selected to satisfy these requirements was a commercially-available ignitron, installed in a supporting frame and using firing circuits and controls designed by PPPL

  13. Neutral Particle Analyzer Diagnostic on NSTX

    Energy Technology Data Exchange (ETDEWEB)

    S.S. Medley; A.L. Roquemore

    2004-03-16

    The Neutral Particle Analyzer (NPA) diagnostic on the National Spherical Torus Experiment (NSTX) utilizes a PPPL-designed E||B spectrometer that measures the energy spectra of minority hydrogen and bulk deuterium species simultaneously with 39 energy channels per mass specie and a time resolution of 1 ms. The calibrated energy range is E = 0.5-150 keV and the energy resolution varies from AE/E = 3-7% over the surface of the microchannel plate detector.

  14. Neutral beam source commercialization study. Final report

    International Nuclear Information System (INIS)

    King, H.J.

    1980-06-01

    The basic tasks of this Phase II project were to: generate a set of design drawings suitable for quantity production of sources of this design; fabricate a functional neutral beam source incorporating as many of the proposed design changes as proved feasible; and document the procedures and findings developed during the contract. These tasks have been accomplished and represent a demonstrated milestone in the industrialization of this complete device

  15. What is a truly neutral particle?

    International Nuclear Information System (INIS)

    Tsan, Ung Chan

    2004-01-01

    An electrically charged particle is necessarily different from its antiparticle while an electrically neutral particle is either identical with or different from its antiparticle. A truly neutral particle is a particle identical to its antiparticle, which means that all its algebraic intrinsic properties are equal to zero since particle and antiparticle have all their algebraic intrinsic properties opposite. We propose two complementary methods to recognize the true nature of any electrically neutral particle. On the one hand, any non-null algebraic intrinsic property of a particle (properties such as Q, magnetic moment already known from classical physics, or quantum numbers such as baryonic number A, lepton number L or flavors, which are meaningful only in the quantum world) reveals that it is distinct from its antiparticle. On the other hand, any particle decaying through a self-conjugate channel or/and through both two conjugate channels is a truly neutral particle implying then that all algebraic intrinsic properties, known or yet unknown, of this particle are null. According to these methods, the neutrino, like any fermion, cannot be its own antiparticle, so neutrinoless double beta decay cannot take place in nature. We point out the internal contradiction required by the existence of hypothetical neutrinoless double beta decay. We suggest that persistent failure to find experimental evidence for this decay mechanism despite huge efforts dedicated to this aim is consistent with the physics of this process. The immediate consequence would be that limits of neutrino mass deduced from neutrinoless double beta decay cannot be used as constraints in contrast with mass limits deduced from the behavior of the end-point in simple beta spectra. (author)

  16. PLT neutral injection ignitron accelerating supply

    International Nuclear Information System (INIS)

    Ashcroft, D.L.; Murray, J.G.; Newman, R.A.; Peterson, F.L.

    1976-03-01

    A phase-controlled rectifier has been designed for the accelerating supply on the PLT Neutral Beam Injection system at PPPL. The rectifier must furnish 70 amperes at up to 50 KV for 300 milliseconds, with a duty cycle of up to 10 percent. Protection of the injectors requires the supply to withstand repeated crowbarring. The rectifying element selected to satisfy these requirements was a commercially-available ignitron, installed in a supporting frame and using firing circuits and controls designed by PPPL

  17. Oscillations of neutral B mesons systems

    CERN Document Server

    Boucrot, J.

    1999-01-01

    The oscillation phenomenon in the neutral B mesons systems is now well established. The motivations and principles of the measurements are given; then the most recent results from the LEP experiments, the CDF collaboration at Fermilab and the SLD collaboration at SLAC are reviewed. The present world average of the $\\bd$ meson oscillation frequency is $\\dmd = 0.471 \\pm 0.016 \\ps$ and the lower limit on the $\\bs$ oscillation frequency is

  18. Probing Supersymmetry with Neutral Current Scattering Experiments

    Science.gov (United States)

    Kurylov, A.; Ramsey-Musolf, M. J.; Su, S.

    2004-02-01

    We compute the supersymmetric contributions to the weak charges of the electron (QWe) and proton (QWp) in the framework of Minimal Supersymmetric Standard Model. We also consider the ratio of neutral current to charged current cross sections, R v and Rv¯ at v (v¯)-nucleus deep inelastic scattering, and compare the supersymmetric corrections with the deviations of these quantities from the Standard Model predictions implied by the recent NuTeV measurement.

  19. Molecular clock in neutral protein evolution

    Directory of Open Access Journals (Sweden)

    Wilke Claus O

    2004-08-01

    Full Text Available Abstract Background A frequent observation in molecular evolution is that amino-acid substitution rates show an index of dispersion (that is, ratio of variance to mean substantially larger than one. This observation has been termed the overdispersed molecular clock. On the basis of in silico protein-evolution experiments, Bastolla and coworkers recently proposed an explanation for this observation: Proteins drift in neutral space, and can temporarily get trapped in regions of substantially reduced neutrality. In these regions, substitution rates are suppressed, which results in an overall substitution process that is not Poissonian. However, the simulation method of Bastolla et al. is representative only for cases in which the product of mutation rate μ and population size Ne is small. How the substitution process behaves when μNe is large is not known. Results Here, I study the behavior of the molecular clock in in silico protein evolution as a function of mutation rate and population size. I find that the index of dispersion decays with increasing μNe, and approaches 1 for large μNe . This observation can be explained with the selective pressure for mutational robustness, which is effective when μNe is large. This pressure keeps the population out of low-neutrality traps, and thus steadies the ticking of the molecular clock. Conclusions The molecular clock in neutral protein evolution can fall into two distinct regimes, a strongly overdispersed one for small μNe, and a mostly Poissonian one for large μNe. The former is relevant for the majority of organisms in the plant and animal kingdom, and the latter may be relevant for RNA viruses.

  20. Hypernuclear physics with a neutral meson spectrometer

    International Nuclear Information System (INIS)

    Peng, J.C.

    1993-01-01

    The (K - , π degrees) reaction, which complements the (K - , π - ) and the (π + , K + ) reactions, offers another means to study hypernuclear physics. The physics motivation for measuring the (K - , π degrees) reaction is discussed. The feasibility for detecting π degrees using the LAMPF Neutral Meson Spectrometer is studied with Monte-Carlo simulations. We conclude that the (K - , π degrees) reaction can be well measured at existing kaon beam lines

  1. W+- pairs and neutral currents at ISABELLE

    International Nuclear Information System (INIS)

    Mikaelian, K.O.

    1975-01-01

    A report is presented on two different types of processes which may form part of the weak interactions program. The first is the production of pairs of charged weak bosons in the process pp → W + W - X; the second involves searching for neutral current effects in the rate for ordinary lepton production, without measuring any charge asymmetry or helicities using the reaction pp → l + l - X

  2. Neutral particle beam distributed data acquisition system

    International Nuclear Information System (INIS)

    Daly, R.T.; Kraimer, M.R.; Novick, A.H.

    1987-01-01

    A distributed data acquisition system has been designed to support experiments at the Argonne Neutral Particle Beam Accelerator. The system uses a host VAXstation II/GPX computer acting as an experimenter's station linked via Ethernet with multiple MicroVAX IIs and rtVAXs dedicated to acquiring data and controlling hardware at remote sites. This paper describes the hardware design of the system, the applications support software on the host and target computers, and the real-time performance

  3. Silver Nanoparticles with Broad Multiband Linear Optical Absorption

    KAUST Repository

    Bakr, Osman M.

    2009-07-06

    A simple one-pot method produces silver nanoparticles coated with aryl thiols that show intense, broad nonplasmonic optical properties. The synthesis works with many aryl-thiol capping ligands, including water-soluble 4-mercaptobenzoic acid. The nanoparticles produced show linear absorption that is broader, stronger, and more structured than most conventional organic and inorganic dyes.

  4. 78 FR 67084 - Drawbridge Operation Regulation; Broad Creek, Laurel, DE

    Science.gov (United States)

    2013-11-08

    ...-AA09 Drawbridge Operation Regulation; Broad Creek, Laurel, DE AGENCY: Coast Guard, DHS. ACTION: Notice....25, both at Laurel, DE. The proposed new rule would change the current regulation by requiring a..., mile 8.2, all at Laurel, shall open on signal if at least 48 hours notice is given. Previous regulation...

  5. Silver Nanoparticles with Broad Multiband Linear Optical Absorption

    KAUST Repository

    Bakr, Osman M.; Amendola, Vincenzo; Aikens, Christine M.; Wenseleers, Wim; Li, Rui; Dal Negro, Luca; Schatz, George C.; Stellacci, Francesco

    2009-01-01

    A simple one-pot method produces silver nanoparticles coated with aryl thiols that show intense, broad nonplasmonic optical properties. The synthesis works with many aryl-thiol capping ligands, including water-soluble 4-mercaptobenzoic acid. The nanoparticles produced show linear absorption that is broader, stronger, and more structured than most conventional organic and inorganic dyes.

  6. Extra Ovarian Serous Cystadenocarcinoma in the Broad Ligament ...

    African Journals Online (AJOL)

    The embryonic remnants of the gonadal ridge and the genital duct apparatus, the Mullerian apparatus, remain atretic throughout the life of a woman. The definitive organs arising from these, the Ovary, Fallopian tubes, Uterus, Cervix and the Broad ligaments share common coelomic origin. Epithelial metaplasia in any of ...

  7. Broad economic benefits of freight transportation infrastructure improvement.

    Science.gov (United States)

    2012-06-01

    This project strives to introduce a novel way to quantify the broad re-organization benefits associated with an : improvement in the freight infrastructure. Using the approach based on 1) the technique known as Field of Influence, and : 2) RAS adjust...

  8. Three Broad Parental Feeding Styles and Young Children's Snack Intake

    Science.gov (United States)

    Boots, Samantha B.; Tiggemann, Marika; Corsini, Nadia

    2017-01-01

    Objective: The aim of this study was to identify broad overarching feeding styles that parents may use and their effects on pre-school-aged children's healthy and unhealthy snack intake. Design: Cross sectional study Methods: Mothers (n = 611) of children aged 2-7 years (mean age 3.9 years) completed an online survey assessing parent-feeding…

  9. Children and trauma : a broad perspective on exposure and recovery

    NARCIS (Netherlands)

    Alisic, E.

    2011-01-01

    The purpose of this dissertation was to generate a broad overview of children’s exposure to and recovery from trauma in order to promote theory building and the design of prevention and intervention activities. First, a general population study was conducted in 1770 primary school children. They

  10. Argument for a non-standard broad-line region

    International Nuclear Information System (INIS)

    Collin, S.

    1987-01-01

    The region emitting the broad lines (BLR) in quasars and AGN has a ''Standard Status''. It is shown that this status raises strong problems concerning the energetic budget and the thermal state of the BLR. A possible solution is proposed [fr

  11. Socioeconomic evaluation of broad-scale land management strategies.

    Science.gov (United States)

    Lisa K. Crone; Richard W. Haynes

    2001-01-01

    This paper examines the socioeconomic effects of alternative management strategies for Forest Service and Bureau of Land Management lands in the interior Columbia basin. From a broad-scale perspective, there is little impact or variation between alternatives in terms of changes in total economic activity or social conditions in the region. However, adopting a finer...

  12. Broad-Band Spectroscopy of Hercules X-1 with Suzaku

    Science.gov (United States)

    Asami, Fumi; Enoto, Teruaki; Iwakiri, Wataru; Yamada, Shin'ya; Tamagawa, Toru; Mihara, Tatehiro; Nagase, Fumiaki

    2014-01-01

    Hercules X-1 was observed with Suzaku in the main-on state from 2005 to 2010. The 0.4- 100 keV wide-band spectra obtained in four observations showed a broad hump around 4-9 keV in addition to narrow Fe lines at 6.4 and 6.7 keV. The hump was seen in all the four observations regardless of the selection of the continuum models. Thus it is considered a stable and intrinsic spectral feature in Her X-1. The broad hump lacked a sharp structure like an absorption edge. Thus it was represented by two different spectral models: an ionized partial covering or an additional broad line at 6.5 keV. The former required a persistently existing ionized absorber, whose origin was unclear. In the latter case, the Gaussian fitting of the 6.5-keV line needs a large width of sigma = 1.0-1.5 keV and a large equivalent width of 400-900 eV. If the broad line originates from Fe fluorescence of accreting matter, its large width may be explained by the Doppler broadening in the accretion flow. However, the large equivalent width may be inconsistent with a simple accretion geometry.

  13. Document understanding for a broad class of documents

    NARCIS (Netherlands)

    Aiello, Marco; Monz, Christof; Todoran, Leon; Worring, Marcel

    2002-01-01

    We present a document analysis system able to assign logical labels and extract the reading order in a broad set of documents. All information sources, from geometric features and spatial relations to the textual features and content are employed in the analysis. To deal effectively with these

  14. Long-throated flumes and broad-crested weirs

    NARCIS (Netherlands)

    Bos, M.G.

    1985-01-01

    Vital for water management are structures that can measure the flow in a wide variety of channels. Chapter 1 introduces the long-throated flume and the broad-crested weir; it explains why this family of structures can meet the boundary conditions and hydraulic demands of most measuring

  15. African Journals Online: General Science (broad subject range)

    African Journals Online (AJOL)

    Items 51 - 86 of 86 ... The Journal of Science and Technology (JUST) aims principally at publishing articles ... basic sciences, public health, social medicine and medical politics. .... The SWJ is a peer review on-line international journal of broad ...

  16. Human monoclonal antibodies to a novel cluster of conformational epitopes on HCV E2 with resistance to neutralization escape in a genotype 2a isolate

    DEFF Research Database (Denmark)

    Keck, Zhen-yong; Xia, Jinming; Wang, Yong

    2012-01-01

    The majority of broadly neutralizing antibodies to hepatitis C virus (HCV) are against conformational epitopes on the E2 glycoprotein. Many of them recognize overlapping epitopes in a cluster, designated as antigenic domain B, that contains residues G530 and D535. To gain information on other reg...

  17. High-Latitude Neutral Mass Density Maxima

    Science.gov (United States)

    Huang, C. Y.; Huang, Y.; Su, Y.-J.; Huang, T.; Sutton, E. K.

    2017-10-01

    Recent studies have reported that thermospheric effects due to solar wind driving can be observed poleward of auroral latitudes. In these papers, the measured neutral mass density perturbations appear as narrow, localized maxima in the cusp and polar cap. They conclude that Joule heating below the spacecraft is the cause of the mass density increases, which are sometimes associated with local field-aligned current structures, but not always. In this paper we investigate neutral mass densities measured by accelerometers on the CHAllenging Minisatellite Payload (CHAMP) and Gravity Recovery and Climate Experiment (GRACE) spacecraft from launch until years 2010 (CHAMP) and 2012 (GRACE), approximately 10 years of observations from each satellite. We extract local maxima in neutral mass densities over the background using a smoothing window with size of one quarter of the orbit. The maxima have been analyzed for each year and also for the duration of each set of satellite observations. We show where they occur, under what solar wind conditions, and their relation to magnetic activity. The region with the highest frequency of occurrence coincides approximately with the cusp and mantle, with little direct evidence of an auroral zone source. Our conclusions agree with the "hot polar cap" observations that have been reported and studied in the past.

  18. Neutral Color Semitransparent Microstructured Perovskite Solar Cells

    KAUST Repository

    Eperon, Giles E.

    2014-01-28

    Neutral-colored semitransparent solar cells are commercially desired to integrate solar cells into the windows and cladding of buildings and automotive applications. Here, we report the use of morphological control of perovskite thin films to form semitransparent planar heterojunction solar cells with neutral color and comparatively high efficiencies. We take advantage of spontaneous dewetting to create microstructured arrays of perovskite "islands", on a length-scale small enough to appear continuous to the eye yet large enough to enable unattenuated transmission of light between the islands. The islands are thick enough to absorb most visible light, and the combination of completely absorbing and completely transparent regions results in neutral transmission of light. Using these films, we fabricate thin-film solar cells with respectable power conversion efficiencies. Remarkably, we find that such discontinuous films still have good rectification behavior and relatively high open-circuit voltages due to the inherent rectification between the n- and p-type charge collection layers. Furthermore, we demonstrate the ease of "color-tinting" such microstructured perovksite solar cells with no reduction in performance, by incorporation of a dye within the hole transport medium. © 2013 American Chemical Society.

  19. Intense diagnostic neutral beam development for ITER

    International Nuclear Information System (INIS)

    Rej, D.J.; Henins, I.; Fonck, R.J.; Kim, Y.J.

    1992-01-01

    For the next-generation, burning tokamak plasmas such as ITER, diagnostic neutral beams and beam spectroscopy will continue to be used to determine a variety of plasma parameters such as ion temperature, rotation, fluctuations, impurity content, current density profile, and confined alpha particle density and energy distribution. Present-day low-current, long-pulse beam technology will be unable to provide the required signal intensities because of higher beam attenuation and background bremsstrahlung radiation in these larger, higher-density plasmas. To address this problem, we are developing a short-pulse, intense diagnostic neutral beam. Protons or deuterons are accelerated using magnetic-insulated ion-diode technology, and neutralized in a transient gas cell. A prototype 25-kA, 100-kV, 1-μs accelerator is under construction at Los Alamos. Initial experiments will focus on ITER-related issues of beam energy distribution, current density, pulse length, divergence, propagation, impurity content, reproducibility, and maintenance

  20. Neutral beam current drive with balanced injection

    International Nuclear Information System (INIS)

    Eckhartt, D.

    1990-01-01

    Current drive with fast ions has proved its capability to sustain a tokamak plasma free of externally induced electric fields in a stationary state. The suprathermal ion population within the toroidal plasma was created by quasi-tangential and uni-directional injection of high-energy neutral atoms, their ionisation and subsequent deceleration by collisions with the background plasma particles. In future large tokamaks of the NET/INTER-type, with reactor-relevant values of plasma density and temperature, this current drive scheme is expected to maintain the toroidal current at the plasma centre, as current drive by lower hybrid waves will be restricted to the outer plasma regions owing to strong wave damping. Adequate penetration of the neutral atoms through the dense plasma requires particle energies of several hundred kilovolts per nucleon since beam absorption scales roughly with the ratio beam energy over density. The realisation of such high-energy high-power neutral beams, based on negative ion technology, is now under study. (author) 7 refs., 2 figs

  1. Antibody neutralization of retargeted measles viruses

    Science.gov (United States)

    Lech, Patrycja J.; Pappoe, Roland; Nakamura, Takafumi; Tobin, Gregory J.; Nara, Peter L.; Russell, Stephen J.

    2014-01-01

    The measles virus (MV) vaccine lineage is a promising oncolytic but prior exposure to the measles vaccine or wild-type MV strains limits treatment utility due to the presence of anti-measles antibodies. MV entry can be redirected by displaying a polypeptide ligand on the Hemagglutinin (H) C-terminus. We hypothesized that retargeted MV would escape neutralization by monoclonal antibodies (mAbs) recognizing the H receptor-binding surface and be less susceptible to neutralization by human antisera. Using chimeric H proteins, with and without mutations that ablate MV receptor binding, we show that retargeted MVs escape mAbs that target the H receptor-binding surface by virtue of mutations that ablate infection via SLAM and CD46. However, C-terminally displayed domains do not mediate virus entry in the presence of human antibodies that bind to the underlying H domain. In conclusion, utility of retargeted oncolytic measles viruses does not extend to evasion of human serum neutralization. PMID:24725950

  2. Dynamics of neutral and charged aerosol particles

    Energy Technology Data Exchange (ETDEWEB)

    Leppae, J.

    2012-07-01

    Atmospheric aerosol particles have various climate effects and adverse health effects, which both depend on the size and number concentration of the particles. Freshly-formed particles are not large enough to impact neither health nor climate and they are most susceptible to removal by collisions with larger pre-existing particles. Consequently, the knowledge of both the formation and the growth rate of particles are crucially important when assessing the health and climate effects of atmospheric new particle formation. The purpose of this thesis is to increase our knowledge of the dynamics of neutral and charged aerosol particles with a specific interest towards the particle growth rate and processes affecting the aerosol charging state. A new model, Ion-UHMA, which simulates the dynamics of neutral and charged particles, was developed for this purpose. Simple analytical formulae that can be used to estimate the growth rate due to various processes were derived and used to study the effects of charged particles on the growth rate. It was found that the growth rate of a freshly-formed particle population due to condensation and coagulation could be significantly increased when a considerable fraction of the particles are charged. Finally, recent data-analysis methods that have been applied to the aerosol charging states obtained from the measurements were modified for a charge asymmetric framework. The methods were then tested on data obtained from aerosol dynamics simulations. The methods were found to be able to provide reasonable estimates on the growth rate and proportion of particles formed via ion-induced nucleation, provided that the growth rate is high enough and that the charged particles do not grow much more rapidly than the neutral ones. A simple procedure for estimating whether the methods are suitable for analysing data obtained in specific conditions was provided. In this thesis, the dynamics of neutral and charged aerosol particles were studied in

  3. Disposal of leached residual in heap leaching by neutralization

    International Nuclear Information System (INIS)

    Wang Jingmin

    1993-01-01

    The disposal results of leached residual with lime are described. Using the ratio of residual to lime being 100 : 1 the ideal disposal results were obtained with the effluent of the neutralized residual close to neutral

  4. Stability of Neutral Fractional Neural Networks with Delay

    Institute of Scientific and Technical Information of China (English)

    LI Yan; JIANG Wei; HU Bei-bei

    2016-01-01

    This paper studies stability of neutral fractional neural networks with delay. By introducing the definition of norm and using the uniform stability, the sufficient condition for uniform stability of neutral fractional neural networks with delay is obtained.

  5. International Thermonuclear Experimental Reactor (ITER) neutral beam design

    International Nuclear Information System (INIS)

    Myers, T.J.; Brook, J.W.; Spampinato, P.T.; Mueller, J.P.; Luzzi, T.E.; Sedgley, D.W.

    1990-10-01

    This report discusses the following topics on ITER neutral beam design: ion dump; neutralizer and module gas flow analysis; vacuum system; cryogenic system; maintainability; power distribution; and system cost

  6. Neutral heavy lepton production in e+-e- collisions

    International Nuclear Information System (INIS)

    Ragiadakos, C.

    1977-01-01

    The cross-sections of the weak production of different kinds of neutral heavy leptons in e + -e - collisions are calculated and their signatures are studied. A possible electromagnetic production of neutral heavy leptons is also considered

  7. Status of HEP neutral net research in the USA

    International Nuclear Information System (INIS)

    Denby, B.; Linn, S.L.

    1989-01-01

    Progress on tracking with recurrent neutral networks is presented. Applications of feed-forward networks to high energy physics are discussed. The situation regarding hardware implementations of neutral networks is assessed. (orig.)

  8. Network Neutrality : A Survey of the Economic Literature

    NARCIS (Netherlands)

    Schuett, F.

    2010-01-01

    This paper reviews the small but growing economic literature on network neutrality. It considers a number of possible departures from network neutrality, in particular termination fees, second-degree price discrimination, and vertical foreclosure.

  9. THE ANXIETY SPECTRUM AND THE REFLEX PHYSIOLOGY OF DEFENSE: FROM CIRCUMSCRIBED FEAR TO BROAD DISTRESS

    Science.gov (United States)

    McTeague, Lisa M.; Lang, Peter J.

    2013-01-01

    Guided by the diagnostic nosology, anxiety patients are expected to show defensive hyperarousal during affective challenge, irrespective of the principal phenotype. In the current study, patients representing the whole spectrum of anxiety disorders (i.e., specific phobia, social phobia, panic disorder with or without agoraphobia, obsessive-compulsive disorder, generalized anxiety disorder (GAD), posttraumatic stress disorder(PTSD)), and healthy community control participants, completed an imagery-based fear elicitation paradigm paralleling conventional intervention techniques. Participants imagined threatening and neutral narratives as physiological responses were recorded. Clear evidence emerged for exaggerated reactivity to clinically relevant imagery—most pronounced in startle reflex responding. However, defensive propensity varied across principal anxiety disorders. Disorders characterized by focal fear and impairment (e.g., specific phobia) showed robust fear potentiation. Conversely, for disorders of long-enduring, pervasive apprehension and avoidance with broad anxiety and depression comorbidity (e.g., PTSD secondary to cumulative trauma, GAD), startle responses were paradoxically diminished to all aversive contents. Patients whose expressed symptom profiles were intermediate between focal fearfulness and broad anxious-misery in both severity and chronicity exhibited a still heightened but more generalized physiological propensity to respond defensively. Importantly, this defensive physiological gradient—the inverse of self-reported distress—was evident not only between but also within disorders. These results highlight that fear circuitry could be dysregulated in chronic, pervasive anxiety, and preliminary functional neuroimaging findings suggest that deficient amygdala recruitment could underlie attenuated reflex responding. In summary, adaptive defensive engagement during imagery may be compromised by long-term dysphoria and stress—a phenomenon

  10. 46 CFR 183.376 - Grounded distribution systems (neutral grounded).

    Science.gov (United States)

    2010-10-01

    ....376 Section 183.376 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SMALL PASSENGER... propulsion, power, lighting, or distribution system having a neutral bus or conductor must have the neutral... generator to ground before the generator is connected to the bus, except the neutral of an emergency power...

  11. 46 CFR 120.376 - Grounded distribution systems (Neutral grounded).

    Science.gov (United States)

    2010-10-01

    ....376 Section 120.376 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SMALL PASSENGER VESSELS CARRYING MORE THAN 150 PASSENGERS OR WITH OVERNIGHT ACCOMMODATIONS FOR MORE THAN 49 PASSENGERS... distribution system having a neutral bus or conductor must have the neutral grounded. (c) The neutral or each...

  12. COMPARISON THEOREMS AND APPLICATIONS OF OSCILLATION OF NEUTRAL DIFFERENTIAL EQUATIONS

    Institute of Scientific and Technical Information of China (English)

    燕居让

    1991-01-01

    We first establish comparison theorems of the oscillation for a higher-order neutral delaydifferential equation. By these comparison theorems, the criterion of oscillation propertiesof neutral delay differential equation is reduced to that of nonneutral delay differential equa-tion, from which we give a series of oscillation theorems for neutral delay differentialequation.

  13. Energy spectrum of neutrals formed in an ion accelerator

    International Nuclear Information System (INIS)

    Fink, J.H.

    1982-01-01

    This work presents an estimate of the energy distribution of the neutrals formed in the ion beam accelerator. However it does not determine the fraction of those neutrals which leave the neutral beam injector and go on into the reactor. To do that, more details of the beam line performance are needed

  14. Impact of neutral density fluctuations on gas puff imaging diagnostics

    Science.gov (United States)

    Wersal, C.; Ricci, P.

    2017-11-01

    A three-dimensional turbulence simulation of the SOL and edge regions of a toroidally limited tokamak is carried out. The simulation couples self-consistently the drift-reduced two-fluid Braginskii equations to a kinetic equation for neutral atoms. A diagnostic neutral gas puff on the low-field side midplane is included and the impact of neutral density fluctuations on D_α light emission investigated. We find that neutral density fluctuations affect the D_α emission. In particular, at a radial distance from the gas puff smaller than the neutral mean free path, neutral density fluctuations are anti-correlated with plasma density, electron temperature, and D_α fluctuations. It follows that the neutral fluctuations reduce the D_α emission in most of the observed region and, therefore, have to be taken into account when interpreting the amplitude of the D_α emission. On the other hand, higher order statistical moments (skewness, kurtosis) and turbulence characteristics (such as correlation length, or the autocorrelation time) are not significantly affected by the neutral fluctuations. At distances from the gas puff larger than the neutral mean free path, a non-local shadowing effect influences the neutral density fluctuations. There, the D_α fluctuations are correlated with the neutral density fluctuations, and the high-order statistical moments and measurements of other turbulence properties are strongly affected by the neutral density fluctuations.

  15. Report on neutral particle detectors and QED: PEP summer study

    International Nuclear Information System (INIS)

    Bloom, E.D.; Bulos, F.; Buschhorn, G.

    1974-08-01

    The exploration of the neutral particle final states in e + e/sup /minus// annihilation using a 4π neutral particle detector is discussed. Charge particle final state physics is also considered in the context of a neutral detector. Design criteria are discussed, and a possible detector design is presented. 15 refs., 13 figs., 2 tabs

  16. Energizing and depletion of neutrals by a collisional plasma

    International Nuclear Information System (INIS)

    Fruchtman, A

    2008-01-01

    Neutral depletion can significantly affect the steady state of low temperature plasmas. Recent theoretical analyses predicted previously unexpected effects of neutral depletion in both collisional and collisionless regimes. In this paper we address the effect of the energy deposited in the neutral gas by a collisional plasma. The fraction of power deposited in the neutrals is shown to be independent of the amount of power. The first case we address is of a thermalized neutral gas. It is shown that a low heat conductivity of the neutral gas is followed by a high neutral temperature that results in a high neutral depletion even if the plasma pressure is small. In the second case neutrals are accelerated through charge exchange with ions leading to what we call neutral pumping, which is equivalent to ion pumping in a collisionless plasma. Neutral depletion is found in the second case for both a closed system (no net mass flow) and an open system (a finite mass flow). A thruster that employs a collisional plasma and pumped neutrals is compared with the thruster analyzed before that employs collisionless plasma.

  17. Neutral-beam development plan, FY 1982-1987

    International Nuclear Information System (INIS)

    1981-09-01

    The following chapters are included: (1) status of BNL negative ion source development, (2) source development program plan, (3) status of beam transport and acceleration, (4) accelerator development program plan, (5) neutralizer concepts, (6) neutralization program plan, (7) neutral beam systems, (8) test facilities, (9) program milestones and time schedules, (10) organization and Grumman participation, and (11) funding tables

  18. Computational study of the first stage of hypersonic ion beam neutralization: The cross neutralization stage

    International Nuclear Information System (INIS)

    Pomot, C.; Dolique, J.M.

    1975-01-01

    A study is made of the first stage of evolution of a hypersonic ion beam in which thermoelectrons are emitted by a heated grid, known as the neutralizer. Downstream from the neutralizer there appears successively as a sheath a range of periodic and quasi-stationary electric field and a front where the electric field oscillates with the plasma frequency. The sheath is self-regulated. Some electrons are trapped in the periodic and stationary electric field. The characteristics of the periodic, quasi-stationary range correspond to those of both an experimental study and one-dimensional time-independent macroscopic theory. This quasi-stationary regime builds up in a time smaller than ω/subp/e -1 and is studied for a few periods ω/subP//sube/ -1 . The subsequent evolution of this state of nonequilibrium is not investigated. The experimental study has shown that, as for the neutralization of a subsonic ion beam, it leads to a field-free, homogeneous medium: a ''synthesized plasma.'' The importance of the first stage described herein, which may be called the gross neutralization stage, is due to the properties of mean neutrality in the current and in the charge insured by the regulating sheath, properties which will be preseved downstream

  19. Visual attention spreads broadly but selects information locally.

    Science.gov (United States)

    Shioiri, Satoshi; Honjyo, Hajime; Kashiwase, Yoshiyuki; Matsumiya, Kazumichi; Kuriki, Ichiro

    2016-10-19

    Visual attention spreads over a range around the focus as the spotlight metaphor describes. Spatial spread of attentional enhancement and local selection/inhibition are crucial factors determining the profile of the spatial attention. Enhancement and ignorance/suppression are opposite effects of attention, and appeared to be mutually exclusive. Yet, no unified view of the factors has been provided despite their necessity for understanding the functions of spatial attention. This report provides electroencephalographic and behavioral evidence for the attentional spread at an early stage and selection/inhibition at a later stage of visual processing. Steady state visual evoked potential showed broad spatial tuning whereas the P3 component of the event related potential showed local selection or inhibition of the adjacent areas. Based on these results, we propose a two-stage model of spatial attention with broad spread at an early stage and local selection at a later stage.

  20. Flow characteristics at trapezoidal broad-crested side weir

    Directory of Open Access Journals (Sweden)

    Říha Jaromír

    2015-06-01

    Full Text Available Broad-crested side weirs have been the subject of numerous hydraulic studies; however, the flow field at the weir crest and in front of the weir in the approach channel still has not been fully described. Also, the discharge coefficient of broad-crested side weirs, whether slightly inclined towards the stream or lateral, still has yet to be clearly determined. Experimental research was carried out to describe the flow characteristics at low Froude numbers in the approach flow channel for various combinations of in- and overflow discharges. Three side weir types with different oblique angles were studied. Their flow characteristics and discharge coefficients were analyzed and assessed based on the results obtained from extensive measurements performed on a hydraulic model. The empirical relation between the angle of side weir obliqueness, Froude numbers in the up- and downstream channels, and the coefficient of obliqueness was derived.

  1. The precipitation synthesis of broad-spectrum UV absorber nanoceria

    International Nuclear Information System (INIS)

    Nurhasanah, Iis; Sutanto, Heri; Puspaningrum, Nurul Wahyu

    2013-01-01

    In this paper the possibility of nanoceria as broad-spectrum UV absorber was evaluated. Nanoceria were synthesized by precipitation process from cerium nitrate solution and ammonium hydroxide as precipitant agent. Isopropanol was mixed with water as solvent to prevent hard agglomeration. The structure of resulting nanoceria was characterized by x-ray diffractometer (XRD). The transparency in the visible light and efficiency of protection in UV A region were studied using ultraviolet-visible (UV - Vis) spectrophotometer. The results show that nanoceria possess good tranparency in visible light and high UV light absorption. The critical absorption wavelenght of 368 nm was obtained which is desirable for excellent broad-spectrum protection absorbers. Moreover, analysis of photodegradation nanoceria to methylene blue solution shows poor photocatalytic activity. It indicates that nanoceria suitable for used as UV absorber in personal care products

  2. Shareholder, stakeholder-owner or broad stakeholder maximization

    DEFF Research Database (Denmark)

    Mygind, Niels

    2004-01-01

    With reference to the discussion about shareholder versus stakeholder maximization it is argued that the normal type of maximization is in fact stakeholder-owner maxi-mization. This means maximization of the sum of the value of the shares and stake-holder benefits belonging to the dominating...... including the shareholders of a company. Although it may be the ultimate goal for Corporate Social Responsibility to achieve this kind of maximization, broad stakeholder maximization is quite difficult to give a precise definition. There is no one-dimensional measure to add different stakeholder benefits...... not traded on the mar-ket, and therefore there is no possibility for practical application. Broad stakeholder maximization instead in practical applications becomes satisfying certain stakeholder demands, so that the practical application will be stakeholder-owner maximization un-der constraints defined...

  3. Clues to Quasar Broad Line Region Geometry and Kinematics

    DEFF Research Database (Denmark)

    Vestergaard, Marianne; Wilkes, B. J.; Barthel, P. D.

    2000-01-01

    width to show significant inverse correlations with the fractional radio core-flux density, R, the radio axis inclination indicator. Highly inclined systems have broader line wings, consistent with a high-velocity field perpendicular to the radio axis. By contrast, the narrow line-core shows...... no such relation with R, so the lowest velocity CIV-emitting gas has an inclination independent velocity field. We propose that this low-velocity gas is located at higher disk-altitudes than the high-velocity gas. A planar origin of the high-velocity CIV-emission is consistent with the current results...... and with an accretion disk-wind emitting the broad lines. A spherical distribution of randomly orbiting broad-line clouds and a polar high-ionization outflow are ruled out....

  4. Broad-band hard X-ray reflectors

    DEFF Research Database (Denmark)

    Joensen, K.D.; Gorenstein, P.; Hoghoj, P.

    1997-01-01

    Interest in optics for hard X-ray broad-band application is growing. In this paper, we compare the hard X-ray (20-100 keV) reflectivity obtained with an energy-dispersive reflectometer, of a standard commercial gold thin-film with that of a 600 bilayer W/Si X-ray supermirror. The reflectivity...... of the multilayer is found to agree extraordinarily well with theory (assuming an interface roughness of 4.5 Angstrom), while the agreement for the gold film is less, The overall performance of the supermirror is superior to that of gold, extending the band of reflection at least a factor of 2.8 beyond...... that of the gold, Various other design options are discussed, and we conclude that continued interest in the X-ray supermirror for broad-band hard X-ray applications is warranted....

  5. Identifying efficiency trends for Queensland broad-acre beef enterprises

    OpenAIRE

    Gregg, Daniel; Rolfe, John

    2010-01-01

    Productivity and efficiency improvements in agriculture have recently been targeted as Federal Government priorities in Australia. This research examined a dataset of 116 broad-acre beef enterprises from Queensland who participated in a program, Profit Probe, developed to improve management and profitability of enterprises. The aim of this research was to identify the sources, if any, of productivity growth for this sample of enterprises. Two potential sources of productivity growth were iden...

  6. Flow structure in front of the broad-crested weir

    Directory of Open Access Journals (Sweden)

    Zachoval Zbyněk

    2015-01-01

    Full Text Available The paper deals with research focused on description of flow structure in front of broad-crested weir. Based on experimental measurement, the flow structure in front of the weir (the recirculation zone of flow and tornado vortices and flow structure on the weir crest has been described. The determined flow character has been simulated using numerical model and based on comparing results the suitable model of turbulence has been recommended.

  7. Broad Absorption Line Quasar catalogues with Supervised Neural Networks

    International Nuclear Information System (INIS)

    Scaringi, Simone; Knigge, Christian; Cottis, Christopher E.; Goad, Michael R.

    2008-01-01

    We have applied a Learning Vector Quantization (LVQ) algorithm to SDSS DR5 quasar spectra in order to create a large catalogue of broad absorption line quasars (BALQSOs). We first discuss the problems with BALQSO catalogues constructed using the conventional balnicity and/or absorption indices (BI and AI), and then describe the supervised LVQ network we have trained to recognise BALQSOs. The resulting BALQSO catalogue should be substantially more robust and complete than BI-or AI-based ones.

  8. Broad spectrum antiangiogenic treatment for ocular neovascular diseases.

    Directory of Open Access Journals (Sweden)

    Ofra Benny

    2010-09-01

    Full Text Available Pathological neovascularization is a hallmark of late stage neovascular (wet age-related macular degeneration (AMD and the leading cause of blindness in people over the age of 50 in the western world. The treatments focus on suppression of choroidal neovascularization (CNV, while current approved therapies are limited to inhibiting vascular endothelial growth factor (VEGF exclusively. However, this treatment does not address the underlying cause of AMD, and the loss of VEGF's neuroprotective can be a potential side effect. Therapy which targets the key processes in AMD, the pathological neovascularization, vessel leakage and inflammation could bring a major shift in the approach to disease treatment and prevention. In this study we have demonstrated the efficacy of such broad spectrum antiangiogenic therapy on mouse model of AMD.Lodamin, a polymeric formulation of TNP-470, is a potent broad-spectrum antiangiogenic drug. Lodamin significantly reduced key processes involved in AMD progression as demonstrated in mice and rats. Its suppressive effects on angiogenesis, vascular leakage and inflammation were studied in a wide array of assays including; a Matrigel, delayed-type hypersensitivity (DTH, Miles assay, laser-induced CNV and corneal micropocket assay. Lodamin significantly suppressed the secretion of various pro-inflammatory cytokines in the CNV lesion including monocyte chemotactic protein-1 (MCP-1/Ccl2. Importantly, Lodamin was found to regress established CNV lesions, unlike soluble fms-like tyrosine kinase-1 (sFlk-1. The drug was found to be safe in mice and have little toxicity as demonstrated by electroretinography (ERG assessing retinal and by histology.Lodamin, a polymer formulation of TNP-470, was identified as a first in its class, broad-spectrum antiangiogenic drug that can be administered orally or locally to treat corneal and retinal neovascularization. Several unique properties make Lodamin especially beneficial for ophthalmic

  9. Broad beam X-rays attenuation in silicum glass

    International Nuclear Information System (INIS)

    Risticj, Dj.; Vukovicj, S.; Markovicj, P.

    1987-01-01

    Using broad beam geometry the attenuation for domestic silicum glass have been studied for constant X-ray potentials from 50 to 150 kV. The density of the silicium glass was 2,5x10 3 kg/m 3 . From the attenuation curves the half value layers were obtained. The use of this glass as the biological shield is pointed out. (author). 2 refs.; 2 tabs.; 2 figs

  10. Broad Halpha Wing Formation in the Planetary Nebula IC 4997.

    Science.gov (United States)

    Lee; Hyung

    2000-02-10

    The young and compact planetary nebula IC 4997 is known to exhibit very broad wings with a width exceeding 5000 km s-1 around Halpha. We propose that the broad wings are formed through Rayleigh-Raman scattering that involves atomic hydrogen, by which Lybeta photons with a velocity width of a few 102 km s-1 are converted to optical photons and fill the Halpha broad wing region. The conversion efficiency reaches 0.6 near the line center, where the scattering optical depth is much larger than 1, and rapidly decreases in the far wings. Assuming that close to the central star there exists an unresolved inner compact core of high density, nH approximately 109-1010 cm-3, we use the photoionization code "CLOUDY" to show that sufficient Lybeta photons for scattering are produced. Using a top-hat-incident profile for the Lybeta flux and a scattering region with a H i column density NHi=2x1020 cm-2 and a substantial covering factor, we perform a profile-fitting analysis in order to obtain a satisfactory fit to the observed flux. We briefly discuss the astrophysical implications of the Rayleigh-Raman processes in planetary nebulae and other emission objects.

  11. Extreme Variability in a Broad Absorption Line Quasar

    Energy Technology Data Exchange (ETDEWEB)

    Stern, Daniel; Jun, Hyunsung D. [Jet Propulsion Laboratory, California Institute of Technology, 4800 Oak Grove Drive, Mail Stop 169-221, Pasadena, CA 91109 (United States); Graham, Matthew J.; Djorgovski, S. G.; Donalek, Ciro; Drake, Andrew J.; Mahabal, Ashish A.; Steidel, Charles C. [California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125 (United States); Arav, Nahum; Chamberlain, Carter [Department of Physics, Virginia Tech, Blacksburg, VA 24061 (United States); Barth, Aaron J. [Department of Physics and Astronomy, 4129 Frederick Reines Hall, University of California, Irvine, CA 92697 (United States); Glikman, Eilat, E-mail: daniel.k.stern@jpl.nasa.gov [Department of Physics, Middlebury College, Middlebury, VT 05753 (United States)

    2017-04-20

    CRTS J084133.15+200525.8 is an optically bright quasar at z = 2.345 that has shown extreme spectral variability over the past decade. Photometrically, the source had a visual magnitude of V ∼ 17.3 between 2002 and 2008. Then, over the following five years, the source slowly brightened by approximately one magnitude, to V ∼ 16.2. Only ∼1 in 10,000 quasars show such extreme variability, as quantified by the extreme parameters derived for this quasar assuming a damped random walk model. A combination of archival and newly acquired spectra reveal the source to be an iron low-ionization broad absorption line quasar with extreme changes in its absorption spectrum. Some absorption features completely disappear over the 9 years of optical spectra, while other features remain essentially unchanged. We report the first definitive redshift for this source, based on the detection of broad H α in a Keck/MOSFIRE spectrum. Absorption systems separated by several 1000 km s{sup −1} in velocity show coordinated weakening in the depths of their troughs as the continuum flux increases. We interpret the broad absorption line variability to be due to changes in photoionization, rather than due to motion of material along our line of sight. This source highlights one sort of rare transition object that astronomy will now be finding through dedicated time-domain surveys.

  12. Broad beam ion sources and some surface processes

    International Nuclear Information System (INIS)

    Neumann, H.; Scholze, F.; Tarz, M.; Schindler, A.; Wiese, R.; Nestler, M.; Blum, T.

    2005-01-01

    Modern broad-beam multi-aperture ion sources are widely used in material and surface technology applications. Customizing the generated ion beam properties (i. e. the ion current density profile) for specific demands of the application is a main challenge in the improvement of the ion beam technologies. First we introduce ion sources based on different plasma excitation principles shortly. An overview of source plasma and ion beam measurement methods deliver input data for modelling methods. This beam profile modelling using numerical trajectory codes and the validation of the results by Faraday cup measurements as a basis for ion beam profile design are described. Furthermore possibilities for ex situ and in situ beam profile control are demonstrated, like a special method for in situ control of a linear ion source beam profile, a grid modification for circular beam profile design and a cluster principle for broad beam sources. By means of these methods, the beam shape may be adapted to specific technological demands. Examples of broad beam source application in ion beam figuring of optical surfaces, modification of stainless steel, photo voltaic processes and deposition of EUVL-multilayer stacks are finally presented. (Author)

  13. Broad-Band Analysis of Polar Motion Excitations

    Science.gov (United States)

    Chen, J.

    2016-12-01

    Earth rotational changes, i.e. polar motion and length-of-day (LOD), are driven by two types of geophysical excitations: 1) mass redistribution within the Earth system, and 2) angular momentum exchange between the solid Earth (more precisely the crust) and other components of the Earth system. Accurate quantification of Earth rotational excitations has been difficult, due to the lack of global-scale observations of mass redistribution and angular momentum exchange. The over 14-years time-variable gravity measurements from the Gravity Recovery and Climate Experiment (GRACE) have provided a unique means for quantifying Earth rotational excitations from mass redistribution in different components of the climate system. Comparisons between observed Earth rotational changes and geophysical excitations estimated from GRACE, satellite laser ranging (SLR) and climate models show that GRACE-derived excitations agree remarkably well with polar motion observations over a broad-band of frequencies. GRACE estimates also suggest that accelerated polar region ice melting in recent years and corresponding sea level rise have played an important role in driving long-term polar motion as well. With several estimates of polar motion excitations, it is possible to estimate broad-band noise variance and noise power spectra in each, given reasonable assumptions about noise independence. Results based on GRACE CSR RL05 solutions clearly outperform other estimates with the lowest noise levels over a broad band of frequencies.

  14. Hadronic structure of the weak neutral current

    International Nuclear Information System (INIS)

    Marriner, J.P.

    1977-01-01

    A comparison of neutral and charged current deep inelastic neutrino interactions is made in an experiment utilizing the Fermilab 15 ft. bubble chamber. The ratio of neutral current events (NC) to charged current events (CC) is 0.35 +- 0.06 when the visible hadronic energy is greater than 10 GeV. The distributions of NC and CC in a new variable called u/sub vis/, which depends only on the observed hadrons, are given. From these distributions and the assumption that the x distribution is the same for NC and CC, it is concluded that for a NC y distribution of the form (1 - eta) + 3 eta(1 - y) 2 , eta = .12 +- .32. The ratio rho/sub NC/(rho/sub CC/) of neutron to proton cross sections in NC(CC) is studied and the quotient rho/sub NC//rho/sub CC/ = 0.7 +- 0.2. The distribution of hadrons in z/sub vis/, the scaled hadronic momentum, is given. The CC hadrons fit the predictions of the quark fragmentation functions D/sub u//sup π + /(z) and D/sub u//sup π - /(z) as given by Field and Feynman. The neutral current events fit the form (1 - lambda)D/sub u//sup π + /(z) + lambda D/sub d//sup π + /(z) for positives and (1 - lambda)D/sub u//sup π - /(z) + lambda D/sub d//sup π - /(z) for negatives with lambda = 0.56 +- 0.10 and a fit confidence level of 4%

  15. A Neutral Beam Injector Upgrade for NSTX

    International Nuclear Information System (INIS)

    Stevenson, T.; McCormack, B.; Loesser, G.D.; Kalish, M.; Ramakrishnan, S.; Grisham, L.; Edwards, J.; Cropper, M.; Rossi, G.; Halle, A. von; Williams, M.

    2002-01-01

    The National Spherical Torus Experiment (NSTX) capability with a Neutral Beam Injector (NBI) capable of 80 kiloelectronvolt (keV), 5 Megawatt (MW), 5 second operation. This 5.95 million dollar upgrade reused a previous generation injector and equipment for technical, cost, and schedule reasons to obtain these specifications while retaining a legacy capability of 120 keV neutral particle beam delivery for shorter pulse lengths for possible future NSTX experiments. Concerns with NBI injection included power deposition in the plasma, aiming angles from the fixed NBI fan array, density profiles and beam shine through, orbit losses of beam particles, and protection of the vacuum vessel wall against beam impingement. The upgrade made use of the beamline and cryo panels from the Neutral Beam Test Stand facility, existing power supplies and controls, beamline components and equipment not contaminated by tritium during DT [deuterium-tritium] experiments, and a liquid Helium refrigerator plant to power and cryogenically pump a beamline and three ion sources. All of the Tokamak Fusion Test Reactor (TFTR) ion sources had been contaminated with tritium, so a refurbishment effort was undertaken on selected TFTR sources to rid the three sources destined for the NSTX NBI of as much tritium as possible. An interconnecting duct was fabricated using some spare and some new components to attach the beamline to the NSTX vacuum vessel. Internal vacuum vessel armor using carbon tiles was added to protect the stainless steel vacuum vessel from beam impingement in the absence of plasma and interlock failure. To date, the NBI has operated to 80 keV and 5 MW and has injected requested power levels into NSTX plasmas with good initial results, including high beta and strong heating characteristics at full rated plasma current

  16. Temporal behavior of neutral particle fluxes in TFTR [Tokamak Fusion Test Reactor] neutral beam injectors

    International Nuclear Information System (INIS)

    Kamperschroer, J.H.; Gammel, G.M.; Roquemore, A.L.

    1989-09-01

    Data from an E parallel B charge exchange neutral analyzer (CENA), which views down the axis of a neutral beamline through an aperture in the target chamber calorimeter of the TFTR neutral beam test facility, exhibit two curious effects. First, there is a turn-on transient lasting tens of milliseconds having a magnitude up to three times that of the steady-state level. Second, there is a 720 Hz, up to 20% peak-to-peak fluctuation persisting the entire pulse duration. The turn-on transient occurs as the neutralizer/ion source system reaches a new pressure equilibrium following the effective ion source gas throughput reduction by particle removal as ion beam. Widths of the transient are a function of the gas throughput into the ion source, decreasing as the gas supply rate is reduced. Heating of the neutalizer gas by the beam is assumed responsible, with gas temperature increasing as gas supply rate is decreased. At low gas supply rates, the transient is primarliy due to dynamic changes in the neutralizer line density and/or beam species composition. Light emission from the drift duct corroborate the CENA data. At high gas supply rates, dynamic changes in component divergence and/or spatial profiles of the source plasma are necessary to explain the observations. The 720 Hz fluctuation is attributed to a 3% peak-to-peak ripple of 720 Hz on the arc power supply amplified by the quadratic relationship between beam divergence and beam current. Tight collimation by CENA apertures cause it to accept a very small part of the ion source's velocity space, producing a signal linearly proportional to beam divergence. Estimated fluctuations in the peak power density delivered to the plasma under these conditions are a modest 3--8% peak to peak. The efffects of both phenomena on the injected neutral beam can be ameliorated by careful operion of the ion sources. 21 refs., 11 figs., 2 tabs

  17. Neutral beam injection on the PLT tokamak

    International Nuclear Information System (INIS)

    Schilling, G.; Ashcroft, D.L.; Eubank, H.P.; Grisham, L.R.; Knauer, R.C.; Stewart, L.D.; Stooksberry, R.W.; Ulrickson, M.; Williams, M.D.

    1981-01-01

    We describe the operation of the neutral beam injection system on the PLT tokamak. Improvements, retrofits, and conditioning have changed the injection system from an experiment in itself to a fairly reliable and useful plasma heating tool. We will present a brief overview of our physics achievements and then describe the system as it exists now. This will include injector performance, conditioning needs, maintenance needs, reliability, and daily operating sequences. We will also include hardware modifications and additions, electrical and mechanical, and point out remaining problem areas

  18. Large neutral amino acids in daily practice

    DEFF Research Database (Denmark)

    Ahring, Kirsten Kiær

    2010-01-01

    At the Kennedy Centre for Phenylketonuria, Denmark, large neutral amino acids (LNAAs) are being used to treat adult and adolescent patients who are nonadherent to dietary treatment for phenylketonuria (PKU). At the start of treatment, a patient must undergo dietary analysis and regular blood...... sampling to measure plasma amino acid (AA) concentrations. The aim of this analysis and treatment is that the patient receives 25-30% of the daily protein requirement from LNAA supplementation and the remaining 70-75% from natural, low-phenylalanine proteins (although some patients have difficulties...

  19. Supervisory control software for MFTF neutral beams

    International Nuclear Information System (INIS)

    Woodruff, J.P.

    1981-01-01

    We describe the software structures that control the operation of MFTF Sustaining Neutral Beam Power Supplies (SNBPS). These components of the Supervisory Control and Diagnostics System (SCDS) comprise ten distinct tasks that exist in the SCDS system environment. The codes total about 16,000 lines of commented Pascal code and occupy 240 kbytes of memory. The controls have been running since March 1981, and at this writing are being integrated to the Local Control System and to the power supply Pulse Power Module Controller

  20. TFTR neutral-beam power system

    International Nuclear Information System (INIS)

    Winje, R.A.

    1982-10-01

    The TFTR Neutral Beam Power System (NBPS) consists of the accelerator grid power supply and the auxiliary power supplies required to operate the TFTR 120-keV ion sources. The current configuration of the NBPS including the 11-MVA accelerator grid power supply and the Arc and Filament power supplies isolated for operation at accelerator grid voltages up to 120 kV, is described. The prototype NBPS has been assembled at the Princeton Plasma Physics Laboratory and has been operated. The results of the initial operation and the description and resolution of some of the technical problems encountered during the commissioning tests are presented

  1. TPX/TFTR Neutral Beam energy absorbers

    International Nuclear Information System (INIS)

    Dahlgren, F.; Wright, K.; Kamperschroer, J.; Grisham, L.; Lontai, L.; Peters, C.; VonHalle, A.

    1993-01-01

    The present beam energy absorbing surfaces on the TFTR Neutral Beams such as Ion Dumps, Calorimeters, beam defining apertures, and scrapers, are simple water cooled copper plates which wee designed to absorb (via their thermal inertia) the incident beam power for two seconds with a five minute coal down interval between pulses. These components are not capable of absorbing the anticipated beam power loading for 1000 second TPX pulses and will have to be replaced with an actively cooled design. While several actively cooled energy absorbing designs were considered,, the hypervapotron elements currently being used on the JET beamlines were chosen due to their lower cooling water demands and reliable performance on JET

  2. Neutral complexes of the indium dihalides

    Energy Technology Data Exchange (ETDEWEB)

    Sinclair, I.; Worrall, I.J. (Lancaster Univ. (UK))

    1982-03-15

    The neutral complexes In/sub 2/X/sub 4/.2L (X=Cl, Br, I; L 1,4-dioxan, tetrahydropyran, tetrahydrofuran, tetrahydrothiophene), In/sub 2/X/sub 4/.2L (X=Br, I; Ldimethylsulphide), In/sub 2/X/sub 4/.4L (X=Cl, Br, I; Lpiperidine, piperazine, morpholine), and In/sub 2/X/sub 4/.4L (X=Br, I; L=pyridine, dimethylsulphoxide) have been prepared. Solid state Raman spectra indicate that the compounds contain indium-indium bonds.

  3. Phenomenology of one extra neutral Z

    International Nuclear Information System (INIS)

    Verzegnassi, C.

    1990-12-01

    The main features and limits of present and future indirect searches of one extra neutral Z of general theoretical origin are overviewed. At the end of the LEP and of the pp collider runs, negative searches of a Z' will force this particle to be characterized in general by a high (more than ∼5-6 TeV) mass and by a very low mixing angle in orthodox cases. These negative features might lead to severe restrictions on the candidate models and, possibly, to a deeper theoretical understanding of their origin. (R.P.) 16 refs., 7 figs

  4. The Columbia Non-neutral Torus

    International Nuclear Information System (INIS)

    Pedersen, Thomas Sunn

    2009-01-01

    Final report for the Columbia Non-neutral Torus. This details the results from the design, construction and initial operation of the Columbia Non-neutral Torus. During the duration of this grant, I designed, built, and operated the Columbia Nonneutral Torus, the world's lowest aspect ratio stellarator, and arguably, the world's simplest stellarator. This demonstrates the ease and robustness of the chosen stellarator design and allowed us to commence the investigation of the physics of non-neutral plasmas confined on magnetic surfaces. These plasmas are unique in many ways and had not previously been studied in a stellarator. Our first results showed that it is possible to confine and study a relatively cold pure electron plasma in a stellarator. We confirmed that the plasma is stable, and that the plasma is reasonably well confined in a stellarator configuration. These results were published in Physics of Plasmas (2006) and Physical Review Letters (2006). They enabled the existing program which is resolving the underlying transport processes in a classical stellarator with intense self-electric fields and enable the next phase of operation, electron-positron plasma physics. During the period of this grant, two students were trained in experimental plasma physics and both received their PhD degrees shortly after the grant terminated. One student is now employed in the financial services industry, the other is a postdoctoral associate at Los Alamos National Laboratory. The chief goals were to build and begin operation of the Columbia Non-neutral Torus. These goals were achieved in the third year of funding. The development of diagnostic methods and the confirmation of stable equilibria were also achieved during the grant period. In summary, the main scientific goals were all met. The main educational goals were also met, as the experiment became the training ground not only for the two aforementioned graduate students but also for a number of undergraduate students

  5. Investigations of interactions mediated by neutral currents

    International Nuclear Information System (INIS)

    Witek, M.

    2007-03-01

    The report is devoted to four-fermion interactions mediated by the neutral currents. The results from the second phase of LEP are presented, when the production of two massive bosons was possible with the increased energy of the e + e - collisions. It enabled for a direct test of nonabelian structure of the electroweak theory. The results concern the four-fermion production of the pairs of the ZZ bosons, single Z and Zγ * production as well as search for anomalous gauge bosons couplings. The large part of the report is devoted to experimental techniques, physics analyses and discussion of results. (author)

  6. Search for fourth generation neutral heavy leptons

    International Nuclear Information System (INIS)

    Abachi, S.; Abbott, B.; Abolins, M.

    1995-07-01

    A search for fourth generation neutral heavy leptons (ν 4 ) in W decays was carried out the D0 detector at the Fermilab Tevatron at √ bar s = 1.8 TeV. The ν 4 is assumed to be produced via mixing with the first generation neutrino only. We looked for a three electron final state event topology. The data used in this analysis represent 12.2 pb -1 taken during the 1992--1993 run. No candidates were found. We set a preliminary limit beyond the LEP limit for the considered mixing case on the |U e4 | 2 - m ν4 plane

  7. Neutral beam system for an ignition tokamak

    International Nuclear Information System (INIS)

    Fasolo, J.; Fuja, R.; Jung, J.; Moenich, J.; Norem, J.; Praeg, W.; Stevens, H.

    1978-01-01

    We have attempted to make detailed designs of several neutral beam systems which would be applicable to a large machine, e.g. an ITR (Ignition Test Reactor), EPR (Experimental Power Reactor), or reactor. Detailed studies of beam transport to the reactor and neutron transport from the reactor have been made. We have also considered constraints imposed by the neutron radiation environment in the injectors, and the resulting shielding, radiation-damage, and maintenance problems. The effects of neutron heat loads on cryopanels and ZrAl getter panels have been considered. Design studies of power supplies, vacuum systems, bending magnets, and injector layouts are in progress and will be discussed

  8. Discovery of massive neutral vector mesons

    International Nuclear Information System (INIS)

    Anon.

    1976-01-01

    Personal accounts of the discovery of massive neutral vector mesons (psi particles) are given by researchers S. Ting, G. Goldhaber, and B. Richter. The double-arm spectrometer and the Cherenkov effect are explained in a technical note, and the solenoidal magnetic detector is discussed in an explanatory note for nonspecialists. Reprints of three papers in Physical Review Letters which announced the discovery of the particles are given: Experimental observation of a heavy particle J, Discovery of a narrow resonance in e + e - annihilation, and Discovery of a second narrow resonance in e + e - annihilation. A discussion of subsequent developments and scientific biographies of the three authors are also presented. 25 figures

  9. JET neutral beam duct Optical Interlock

    Energy Technology Data Exchange (ETDEWEB)

    Ash, A.D.; Jones, T.T.C.; Surrey, E.; Ćirić, D.; Hall, S.I.; Young, D.; Afzal, M.; Hackett, L.; Day, I.E.; King, R.

    2015-10-15

    Highlights: • Optical Interlocks were installed on the JET NBI system as part of the EP2 upgrade. • The system protects the JET tokamak and NBI systems from thermal load damage. • Balmer-α beam emission is used to monitor the neutral beam-line pressure. • We demonstrate an improved trip delay of 2 ms compared to 50 ms before EP2. - Abstract: The JET Neutral Beam Injection (NBI) system is the most powerful neutral beam plasma heating system currently operating. Optical Interlocks were installed on the beam lines in 2011 for the JET Enhancement Project 2 (EP2), when the heating power was increased from 23 MW to 34 MW. JET NBI has two beam lines. Each has eight positive ion injectors operating in deuterium at 80 kV–125 kV (accelerator voltage) and up to 65 A (beam current). Heating power is delivered through two ducts where the central power density can be more than 100 MW/m{sup 2}. In order to deliver this safely, the beam line pressure should be below 2 × 10{sup −5} mbar otherwise the power load on the duct from the re-ionised fraction of the beam is excessive. The new Optical Interlock monitors the duct pressure by measuring the Balmer-α beam emission (656 nm). This is proportional to the instantaneous beam flux and the duct pressure. Light is collected from a diagnostic window and focused into 1-mm diameter fibres. The Doppler shifted signal is selected using an angle-tuned interference filter. The light is measured by a photo-multiplier module with a logarithmic amplifier. The interlock activation time of 2 ms is sufficient to protect the system from a fully re-ionised beam—a significant improvement on the previous interlock. The dynamic range is sufficient to see bremsstrahlung emission from JET plasma and not saturate during plasma disruptions. For high neutron flux operations the optical fibres within the biological shield can be annealed to 350 °C. A self-test is possible by illuminating the diagnostic window with a test lamp and measuring

  10. Preparation of translationally cold neutral molecules.

    Science.gov (United States)

    Di Domenicantonio, Giulia; Bertsche, Benjamin; Osterwalder, Andreas

    2011-01-01

    Efforts at EPFL to obtain translationally cold neutral molecules are described. Active deceleration of polar molecules is performed by confining the molecules in moving three-dimensional electrostatic traps, and by appropriately choosing the velocity of those traps. Alternatively, cold molecules can be obtained by velocity filtering. Here, the velocity of the molecules is not changed, but instead the cold molecules are extracted from a thermal sample by using the competition between the electrostatic force and the centrifugal force inside a bent electrostatic guide for polar molecules.

  11. Monte Carlo neutral density calculations for ELMO Bumpy Torus

    International Nuclear Information System (INIS)

    Davis, W.A.; Colchin, R.J.

    1986-11-01

    The steady-state nature of the ELMO Bumpy Torus (EBT) plasma implies that the neutral density at any point inside the plasma volume will determine the local particle confinement time. This paper describes a Monte Carlo calculation of three-dimensional atomic and molecular neutral density profiles in EBT. The calculation has been done using various models for neutral source points, for launching schemes, for plasma profiles, and for plasma densities and temperatures. Calculated results are compared with experimental observations - principally spectroscopic measurements - both for guidance in normalization and for overall consistency checks. Implications of the predicted neutral profiles for the fast-ion-decay measurement of neutral densities are also addressed

  12. Controllability Problem of Fractional Neutral Systems: A Survey

    Directory of Open Access Journals (Sweden)

    Artur Babiarz

    2017-01-01

    Full Text Available The following article presents recent results of controllability problem of dynamical systems in infinite-dimensional space. Generally speaking, we describe selected controllability problems of fractional order systems, including approximate controllability of fractional impulsive partial neutral integrodifferential inclusions with infinite delay in Hilbert spaces, controllability of nonlinear neutral fractional impulsive differential inclusions in Banach space, controllability for a class of fractional neutral integrodifferential equations with unbounded delay, controllability of neutral fractional functional equations with impulses and infinite delay, and controllability for a class of fractional order neutral evolution control systems.

  13. Design of a negative ion neutral beam system for TNS

    International Nuclear Information System (INIS)

    Easoz, J.R.

    1978-05-01

    A conceptual design of a neutral beam line based on the neutralization of negative deuterium ions is presented. This work is a detailed design of a complete neutral beam line based on using negative ions from a direct extraction source. Anticipating major technological advancements, beam line components have been scaled including the negative ion sources and components for the direct energy recovery of charged beams and high speed cryogenic pumping. With application to the next step in experimental fusion reactors (TNS), the neutral beam injector system that has been designed provides 10 MW of 200 keV neutral deuterium atoms. Several arms are required for plasma ignition

  14. Impaired nutrient signaling and body weight control in a Na+ neutral amino acid cotransporter (Slc6a19)-deficient mouse.

    Science.gov (United States)

    Bröer, Angelika; Juelich, Torsten; Vanslambrouck, Jessica M; Tietze, Nadine; Solomon, Peter S; Holst, Jeff; Bailey, Charles G; Rasko, John E J; Bröer, Stefan

    2011-07-29

    Amino acid uptake in the intestine and kidney is mediated by a variety of amino acid transporters. To understand the role of epithelial neutral amino acid uptake in whole body homeostasis, we analyzed mice lacking the apical broad-spectrum neutral (0) amino acid transporter B(0)AT1 (Slc6a19). A general neutral aminoaciduria was observed similar to human Hartnup disorder which is caused by mutations in SLC6A19. Na(+)-dependent uptake of neutral amino acids into the intestine and renal brush-border membrane vesicles was abolished. No compensatory increase of peptide transport or other neutral amino acid transporters was detected. Mice lacking B(0)AT1 showed a reduced body weight. When adapted to a standard 20% protein diet, B(0)AT1-deficient mice lost body weight rapidly on diets containing 6 or 40% protein. Secretion of insulin in response to food ingestion after fasting was blunted. In the intestine, amino acid signaling to the mammalian target of rapamycin (mTOR) pathway was reduced, whereas the GCN2/ATF4 stress response pathway was activated, indicating amino acid deprivation in epithelial cells. The results demonstrate that epithelial amino acid uptake is essential for optimal growth and body weight regulation.

  15. HIV-Specific B Cell Frequency Correlates with Neutralization Breadth in Patients Naturally Controlling HIV-Infection

    Directory of Open Access Journals (Sweden)

    Angeline Rouers

    2017-07-01

    Full Text Available HIV-specific broadly neutralizing antibodies (bnAbs have been isolated from patients with high viremia but also from HIV controllers that repress HIV-1 replication. In these elite controllers (ECs, multiple parameters contribute to viral suppression, including genetic factors and immune responses. Defining the immune correlates associated with the generation of bnAbs may help in designing efficient immunotherapies. In this study, in ECs either positive or negative for the HLA-B*57 protective allele, in treated HIV-infected and HIV-negative individuals, we characterized memory B cell compartments and HIV-specific memory B cells responses using flow cytometry and ELISPOT. ECs preserved their memory B cell compartments and in contrast to treated patients, maintained detectable HIV-specific memory B cell responses. All ECs presented IgG1+ HIV-specific memory B cells but some individuals also preserved IgG2+ or IgG3+ responses. Importantly, we also analyzed the capacity of sera from ECs to neutralize a panel of HIV strains including transmitted/founder virus. 29% and 21% of HLA-B*57+ and HLA-B*57− ECs, respectively, neutralized at least 40% of the viral strains tested. Remarkably, in HLA-B*57+ ECs the frequency of HIV-Env-specific memory B cells correlated positively with the neutralization breadth suggesting that preservation of HIV-specific memory B cells might contribute to the neutralizing responses in these patients.

  16. Cleavage-Independent HIV-1 Trimers From CHO Cell Lines Elicit Robust Autologous Tier 2 Neutralizing Antibodies

    Directory of Open Access Journals (Sweden)

    Shridhar Bale

    2018-05-01

    Full Text Available Native flexibly linked (NFL HIV-1 envelope glycoprotein (Env trimers are cleavage-independent and display a native-like, well-folded conformation that preferentially displays broadly neutralizing determinants. The NFL platform simplifies large-scale production of Env by eliminating the need to co-transfect the precursor-cleaving protease, furin that is required by the cleavage-dependent SOSIP trimers. Here, we report the development of a CHO-M cell line that expressed BG505 NFL trimers at a high level of homogeneity and yields of ~1.8 g/l. BG505 NFL trimers purified by single-step lectin-affinity chromatography displayed a native-like closed structure, efficient recognition by trimer-preferring bNAbs, no recognition by non-neutralizing CD4 binding site-directed and V3-directed antibodies, long-term stability, and proper N-glycan processing. Following negative-selection, formulation in ISCOMATRIX adjuvant and inoculation into rabbits, the trimers rapidly elicited potent autologous tier 2 neutralizing antibodies. These antibodies targeted the N-glycan “hole” naturally present on the BG505 Env proximal to residues at positions 230, 241, and 289. The BG505 NFL trimers that did not expose V3 in vitro, elicited low-to-no tier 1 virus neutralization in vivo, indicating that they remained intact during the immunization process, not exposing V3. In addition, BG505 NFL and BG505 SOSIP trimers expressed from 293F cells, when formulated in Adjuplex adjuvant, elicited equivalent BG505 tier 2 autologous neutralizing titers. These titers were lower in potency when compared to the titers elicited by CHO-M cell derived trimers. In addition, increased neutralization of tier 1 viruses was detected. Taken together, these data indicate that both adjuvant and cell-type expression can affect the elicitation of tier 2 and tier 1 neutralizing responses in vivo.

  17. Role of neutral ceramidase in colon cancer.

    Science.gov (United States)

    García-Barros, Mónica; Coant, Nicolas; Kawamori, Toshihiko; Wada, Masayuki; Snider, Ashley J; Truman, Jean-Philip; Wu, Bill X; Furuya, Hideki; Clarke, Christopher J; Bialkowska, Agnieszka B; Ghaleb, Amr; Yang, Vincent W; Obeid, Lina M; Hannun, Yusuf A

    2016-12-01

    Alterations in sphingolipid metabolism, especially ceramide and sphingosine 1-phosphate, have been linked to colon cancer, suggesting that enzymes of sphingolipid metabolism may emerge as novel regulators and targets in colon cancer. Neutral ceramidase (nCDase), a key enzyme in sphingolipid metabolism that hydrolyzes ceramide into sphingosine, is highly expressed in the intestine; however, its role in colon cancer has not been defined. Here we show that molecular and pharmacological inhibition of nCDase in colon cancer cells increases ceramide, and this is accompanied by decreased cell survival and increased apoptosis and autophagy, with minimal effects on noncancerous cells. Inhibition of nCDase resulted in loss of β-catenin and inhibition of ERK, components of pathways relevant for colon cancer development. Furthermore, inhibition of nCDase in a xenograft model delayed tumor growth and increased ceramide while decreasing proliferation. It is noteworthy that mice lacking nCDase treated with azoxymethane were protected from tumor formation. Taken together, these studies show that nCDase is pivotal for regulating initiation and development of colon cancer, and these data suggest that this enzyme is a suitable and novel target for colon cancer therapy.-García-Barros, M., Coant, N., Kawamori, T., Wada, M., Snider, A. J., Truman, J.-P., Wu, B. X., Furuya, H., Clarke, C. J., Bialkowska, A. B., Ghaleb, A., Yang, V. W., Obeid, L. M., Hannun, Y. A. Role of neutral ceramidase in colon cancer. © FASEB.

  18. Transitions between neutral mesons in multiquark schemes

    International Nuclear Information System (INIS)

    Volkov, G.G.; Liparteliani, A.G.; Monich, V.A.; Nikitin, Y.P.

    1981-01-01

    A six-quark scheme based on the gauge group SU(2)/sub L/ x U(1) is used to obtain expressions for the amplitudes of the transitions K 0 bold-arrow-left-right K-bar 0 , D 0 bold-arrow-left-right D-bar 0 , B 0 bold-arrow-left-right B-bar 0 , B/sub S/ 0 bold-arrow-left-right B-bar/sub S/ 0 , T 0 bold-arrow-left-right T-bar 0 , and T/sub C/ 0 bold-arrow-left-right T-bar/sub C/ 0 for finite 4-momenta of the external lines of the Feynman box diagrams. An estimate is made of the degree of applicability of the approximation of vanishingly small 4-momenta of the valence quarks which form the neutral mesons such as the K 0 and K-bar 0 mesons. Constraints are found on the parameters of the unitary matrix of the weak charged currents for arbitrary values of the t-quark mass. Estimates are given of the numerical values of the mixing and CP-violation parameters for neutral systems such as the K 0 --K-bar 0 system

  19. Neutral Beam Power System for TPX

    International Nuclear Information System (INIS)

    Ramakrishnan, S.; Bowen, O.N.; O'Conner, T.; Edwards, J.; Fromm, N.; Hatcher, R.; Newman, R.; Rossi, G.; Stevenson, T.; von Halle, A.

    1993-01-01

    The Tokamak Physics Experiment (TPX) will utilize to the maximum extent the existing Tokamak Fusion Test Reactor (TFTR) equipment and facilities. This is particularly true for the TFTR Neutral Beam (NB) system. Most of the NB hardware, plant facilities, auxiliary sub-systems, power systems, service infrastructure, and control systems can be used as is. The major changes in the NB hardware are driven by the new operating duty cycle. The TFTR Neutral Beam was designed for operation of the Sources for 2 seconds every 150 seconds. The TPX requires operation for 1000 seconds every 4500 seconds. During the Conceptual Design Phase of TPX every component of the TFTR NB Electrical Power System was analyzed to verify whether the equipment can meet the new operational requirements with our without modifications. The Power System converts 13.8 kV prime power to controlled pulsed power required at the NB sources. The major equipment involved are circuit breakers, auto and rectifier transformers surge suppression components, power tetrodes, HV Decks, and HVDC power transmission to sources. Thermal models were developed for the power transformers to simulate the new operational requirements. Heat runs were conducted for the power tetrodes to verify capability. Other components were analyzed to verify their thermal limitations. This paper describes the details of the evaluation and redesign of the electrical power system components to meet the TPX operational requirements

  20. Quantum computing implementations with neutral particles

    DEFF Research Database (Denmark)

    Negretti, Antonio; Treutlein, Philipp; Calarco, Tommaso

    2011-01-01

    We review quantum information processing with cold neutral particles, that is, atoms or polar molecules. First, we analyze the best suited degrees of freedom of these particles for storing quantum information, and then we discuss both single- and two-qubit gate implementations. We focus our discu...... optimal control theory might be a powerful tool to enhance the speed up of the gate operations as well as to achieve high fidelities required for fault tolerant quantum computation.......We review quantum information processing with cold neutral particles, that is, atoms or polar molecules. First, we analyze the best suited degrees of freedom of these particles for storing quantum information, and then we discuss both single- and two-qubit gate implementations. We focus our...... discussion mainly on collisional quantum gates, which are best suited for atom-chip-like devices, as well as on gate proposals conceived for optical lattices. Additionally, we analyze schemes both for cold atoms confined in optical cavities and hybrid approaches to entanglement generation, and we show how...

  1. An efficiently cleaved HIV-1 clade C Env selectively binds to neutralizing antibodies.

    Directory of Open Access Journals (Sweden)

    Saikat Boliar

    Full Text Available An ideal HIV-1 Env immunogen is expected to mimic the native trimeric conformation for inducing broadly neutralizing antibody responses. The native conformation is dependent on efficient cleavage of HIV-1 Env. The clade B isolate, JRFL Env is efficiently cleaved when expressed on the cell surface. Here, for the first time, we report the identification of a native clade C Env, 4-2.J41 that is naturally and efficiently cleaved on the cell surface as confirmed by its biochemical and antigenic characteristics. In addition to binding to several conformation-dependent neutralizing antibodies, 4-2.J41 Env binds efficiently to the cleavage-dependent antibody PGT151; thus validating its native cleaved conformation. In contrast, 4-2.J41 Env occludes non-neutralizing epitopes. The cytoplasmic-tail of 4-2.J41 Env plays an important role in maintaining its conformation. Furthermore, codon optimization of 4-2.J41 Env sequence significantly increases its expression while retaining its native conformation. Since clade C of HIV-1 is the prevalent subtype, identification and characterization of this efficiently cleaved Env would provide a platform for rational immunogen design.

  2. Proceedings of the LAMPF workshop on photon and neutral meson physics at intermediate energies

    International Nuclear Information System (INIS)

    Baer, H.W.; Crannell, H.; Peterson, R.J.

    1987-12-01

    This volume contains the Proceedings of the Workshop on ''Photon and Neutral-Meson, Physics at Intermediate Energies,'' held at Los Alamos, New Mexico, January 7 to 9, 1987. The purpose of this workshop was to bring together scientists working in the areas of electromagnetic, heavy-ion, and light hadron physics to discuss both the physics that could be addressed and potential capabilities of new, large intermediate-energy photon detectors. Based on the papers contained in these proceedings, it appears clear that there are a number of important areas that could be addressed with a much higher resolution neutral meson detector. It is also clear that the technical capability for building a neutral meson detector for energies up to 4 GeV with solid angle of approximately 10 mrs and resolution of a few hundred keV now exists. It also appears entirely reasonable to construct such a detector to be easily transportable so that it would become a national facility, available for use at a number of different laboratories. From the many interesting papers presented and from the broad representation of physicists from laboratories in Asia, Canada, Europe, Japan, and the United States, there appears to be a strong case for proceeding with the construction of such a detector

  3. Attainment of high confinement in neutral beam heated divertor discharges in the PDX tokamak

    International Nuclear Information System (INIS)

    Kaye, S.M.; Bell, M.; Bol, K.

    1983-11-01

    The PDX divertor configuration has recently been converted from an open to a closed geometry to inhibit the return of neutral gas from the divertor region to the main chamber. Since then, operation in a regime with high energy confinement in neutral beam heated discharges (ASDEX H-mode) has been routine over a wide range of operating conditions. These H-mode discharges are characterized by a sudden drop in divertor density and H/sub α/ emission and a spontaneous rise in main chamber plasma density during neutral beam injection. The confinement time is found to scale nearly linearly with plasma current, but it can be degraded due to either the presence of edge instabilities or heavy gas puffing. Detailed Thomson scattering temperature profiles show high values of Te near the plasma edge (approx. 450 eV) with sharp radial gradients (approx. 400 eV/cm) near the separatrix. Density profiles are broad and also exhibit steep gradients close to the separatrix

  4. Observation of Beam Driven Modes during Neutral Beam Heating on the National Spherical Torus Experiment

    International Nuclear Information System (INIS)

    Fredrickson, E.D.; Gorelenkov, E.D.; Cheng, C.Z.; Bell, R.; Darrow, D.; Johnson, D.; Kaye, S.; LeBlanc, B.; Menard, J.; Kubota, S.; Peebles, W.

    2001-01-01

    With the first injection of neutral beams on the National Spherical Torus Experiment (NSTX), a broad and complicated spectrum of coherent modes was seen between approximately 0.4 MHz and 2.5 MHz [where f(subscript ''ci'')] for deuterium is approximately 2.2 MHz. The modes have been observed with high bandwidth magnetic pick-up coils and with a reflectometer. The parametric scaling of the mode frequency with density and magnetic field is consistent with Alfvenic modes (linear in B, inversely with the square root of density). These modes have been identified as magnetosonic waves or compressional Alfven eigenmodes (CAE) excited by a cyclotron resonance with the neutral-beam ions. Modes have also been observed in the frequency range 50-150 kHz with toroidal mode numbers n = 1-5. These lower frequency modes are thought to be related to the TAE [Toroidal Alfven Eigenmode] seen commonly in tokamaks and driven by energetic fast ion populations resulting from ICRF [ion cyclotron range of frequency] and NBI [neutral-beam injection] heating. There is no clear indication of enhanced fast ion losses associated with the modes

  5. Confinement and βsub(p)-studies in neutral injection heated ASDEX plasmas

    International Nuclear Information System (INIS)

    Wagner, F.; Becker, G.; Behringer, K.; Campbell, D.; Eberhagen, A.; Engelhardt, W.; Fussmann, G.; Gehre, O.; Gernhardt, J.; Gierke, G. von; Haas, G.; Huang, M.; Karger, F.; Keilhacker, M.; Klueber, O.; Kornherr, M.; Lackner, K.; Lisitano, G.; Lister, G.G.; Mayer, H.M.; Meisel, D.; Mueller, E.R.; Murmann, H.; Niedermeyer, H.; Poschenrieder, W.; Rapp, H.; Roehr, H; Schneider, F.; Siller, G.; Speth, E.; Staebler, A.; Steuer, K.H.; Succi, S.; Venus, G.; Vollmer, O.

    1983-03-01

    Neutral injection experiments into limiter and divertor discharges in ASDEX are described with hydrogen and deuterium as working gas. Two operational regimes have been observed in neutral injection heated divertor discharges. One regime is characterized by deteriorated energy and particle confinement. The global energy confinement times are comparable to those of neutral injection heated limited discharges. Tthe other regime has particle and energy confinement times comparable to those of ohmic discharges with tausub(E) = 40 - 60 msec at beam powers up to 3.1 MW. This regime is further characterized by high βsub(p)-values comparable to the aspect ratio A (βsub(p) proportional 0.65 A), by good electron heating (etasub(e) proportional 2.5 x 10 13 eV cm -3 kW -1 ) and ion heating (etasub(i) proportional 4.2 x 10 13 eV cm -3 kW -1 ). In both regimes, tausub(E) increases with plasma current but there is hardly any variation with density. The differences in confinement and scaling to ohmic discharges seem to be caused by modifications of the electron loss channel. The high βsub(p)-regime develops at an injection power >=1.8 MW, anti nsub(e) >= 3 x 10 13 cm -3 and q >= 2.45, and is so far only observed in divertor discharges. There are indications that this may be due to the broad profiles with high edge temperatures which can develop in divertor discharges. An indication of broad current density profiles is given by the lack of sawtooth activity in these discharges. (orig.)

  6. A safe and reliable neutralization assay based on pseudovirus to measure neutralizing antibody titer against poliovirus.

    Science.gov (United States)

    Liu, Shaohua; Song, Dongmei; Bai, Han; Lu, Weiwei; Dai, Xinxian; Hao, Chunsheng; Zhang, Zhongyang; Guo, Huijie; Zhang, Yue; Li, Xiuling

    2017-12-01

    With the promotion of inactivated poliomyelitis vaccine (IPV) and live attenuated oral poliomyelitis vaccine (OPV), the global reported cases of poliomyelitis have reduced sharply from 0.35 million in 1988 to 74 in 2015. The Polio Eradication & Endgame Strategic Plan published by WHO in 2013 included the strategy of implementation of poliovirus safe handling and containment measures to minimize the risks of facility-associated reintroduction of virus into the polio-free community to prevent the re-import of poliovirus. Toward this strategy, we produced replication-incompetent pseudovirus of poliovirus type 1, 2, 3 attenuated strains by constructing poliovirus capsid expression vectors and poliovirus replicon then transfecting HEK293T cells and developed a pseudovirus-based neutralization assay (pNA) to determine neutralizing antibody titer which is more secure, time-saving and reliable than conventional neutralization assay (cNA). By using anti-poliovirus rat serum, we demonstrated excellent correlation between neutralizing antibody titers measured by cNA and pNA. It was concluded that pNA can be a potential alternative to replace cNA as a safe and time-saving system for titer determination after live poliovirus's safekeeping. © 2017 Wiley Periodicals, Inc.

  7. Population growth enhances the mean fixation time of neutral mutations and the persistence of neutral variation.

    Science.gov (United States)

    Waxman, D

    2012-06-01

    A fundamental result of population genetics states that a new mutation, at an unlinked neutral locus in a randomly mating diploid population, has a mean time of fixation of ∼4N(e) generations, where N(e) is the effective population size. This result is based on an assumption of fixed population size, which does not universally hold in natural populations. Here, we analyze such neutral fixations in populations of changing size within the framework of the diffusion approximation. General expressions are derived for the mean and variance of the fixation time in changing populations. Some explicit results are given for two cases: (i) the effective population size undergoes a sudden change, representing a sudden population expansion or a sudden bottleneck; (ii) the effective population changes linearly for a limited period of time and then remains constant. Additionally, a lower bound for the mean time of fixation is obtained for an effective population size that increases with time, and this is applied to exponentially growing populations. The results obtained in this work show, among other things, that for populations that increase in size, the mean time of fixation can be enhanced, sometimes substantially so, over 4N(e,0) generations, where N(e,0) is the effective population size at the time the mutation arises. Such an enhancement is associated with (i) an increased probability of neutral polymorphism in a population and (ii) an enhanced persistence of high-frequency neutral variation, which is the variation most likely to be observed.

  8. The effect of quenched disorder in neutral theories

    International Nuclear Information System (INIS)

    Borile, Claudio; Maritan, Amos; Muñoz, Miguel A

    2013-01-01

    We study systems with two symmetric absorbing states, such as the voter model and its variations, which have been broadly used as minimal neutral models in genetics, population ecology, sociology, etc. We analyze the effects of a key ingredient inevitably present in most real applications: random-field-like quenched disorder. In accord with simulations and previous findings, coexistence between the two competing states/opinions turns out to be strongly favored by disorder in the standard voter model; actually, a disorder-induced phase transition is generated for any finite system size in the presence of an arbitrarily small spontaneous-inversion rate (preventing absorbing states from being stable). For nonlinear versions of the voter model a general theory (by Al Hammal et al) explains that the spontaneous breaking of the up/down symmetry and an absorbing state phase transition can occur either together or separately, giving rise to two different scenarios. Here, we show that the presence of quenched disorder in nonlinear voter models does not allow the separation of the up–down (Ising-like) symmetry breaking from the active-to-absorbing phase transition in low-dimensional systems: both phenomena can occur only simultaneously, as a consequence of the well-known Imry–Ma argument generalized to these non-equilibrium problems. When the two phenomena occur in unison, resulting in a genuinely non-equilibrium (‘generalized voter’) transition, the Imry–Ma argument is violated and the symmetry can be spontaneously broken even in low dimensions. (paper)

  9. First neutral beam injection experiments on KSTAR tokamak.

    Science.gov (United States)

    Jeong, S H; Chang, D H; Kim, T S; In, S R; Lee, K W; Jin, J T; Chang, D S; Oh, B H; Bae, Y S; Kim, J S; Park, H T; Watanabe, K; Inoue, T; Kashiwagi, M; Dairaku, M; Tobari, H; Hanada, M

    2012-02-01

    The first neutral beam (NB) injection system of the Korea Superconducting Tokamak Advanced Research (KSTAR) tokamak was partially completed in 2010 with only 1∕3 of its full design capability, and NB heating experiments were carried out during the 2010 KSTAR operation campaign. The ion source is composed of a JAEA bucket plasma generator and a KAERI large multi-aperture accelerator assembly, which is designed to deliver a 1.5 MW, NB power of deuterium at 95 keV. Before the beam injection experiments, discharge, and beam extraction characteristics of the ion source were investigated. The ion source has good beam optics in a broad range of beam perveance. The optimum perveance is 1.1-1.3 μP, and the minimum beam divergence angle measured by the Doppler shift spectroscopy is 0.8°. The ion species ratio is D(+):D(2)(+):D(3)(+) = 75:20:5 at beam current density of 85 mA/cm(2). The arc efficiency is more than 1.0 A∕kW. In the 2010 KSTAR campaign, a deuterium NB power of 0.7-1.5 MW was successfully injected into the KSTAR plasma with a beam energy of 70-90 keV. L-H transitions were observed within a wide range of beam powers relative to a threshold value. The edge pedestal formation in the T(i) and T(e) profiles was verified through CES and electron cyclotron emission diagnostics. In every deuterium NB injection, a burst of D-D neutrons was recorded, and increases in the ion temperature and plasma stored energy were found.

  10. First neutral beam injection experiments on KSTAR tokamaka)

    Science.gov (United States)

    Jeong, S. H.; Chang, D. H.; Kim, T. S.; In, S. R.; Lee, K. W.; Jin, J. T.; Chang, D. S.; Oh, B. H.; Bae, Y. S.; Kim, J. S.; Park, H. T.; Watanabe, K.; Inoue, T.; Kashiwagi, M.; Dairaku, M.; Tobari, H.; Hanada, M.

    2012-02-01

    The first neutral beam (NB) injection system of the Korea Superconducting Tokamak Advanced Research (KSTAR) tokamak was partially completed in 2010 with only 1/3 of its full design capability, and NB heating experiments were carried out during the 2010 KSTAR operation campaign. The ion source is composed of a JAEA bucket plasma generator and a KAERI large multi-aperture accelerator assembly, which is designed to deliver a 1.5 MW, NB power of deuterium at 95 keV. Before the beam injection experiments, discharge, and beam extraction characteristics of the ion source were investigated. The ion source has good beam optics in a broad range of beam perveance. The optimum perveance is 1.1-1.3 μP, and the minimum beam divergence angle measured by the Doppler shift spectroscopy is 0.8°. The ion species ratio is D+:D2+:D3+ = 75:20:5 at beam current density of 85 mA/cm2. The arc efficiency is more than 1.0 A/kW. In the 2010 KSTAR campaign, a deuterium NB power of 0.7-1.5 MW was successfully injected into the KSTAR plasma with a beam energy of 70-90 keV. L-H transitions were observed within a wide range of beam powers relative to a threshold value. The edge pedestal formation in the Ti and Te profiles was verified through CES and electron cyclotron emission diagnostics. In every deuterium NB injection, a burst of D-D neutrons was recorded, and increases in the ion temperature and plasma stored energy were found.

  11. New focal plane detector system for the broad range spectrometer

    International Nuclear Information System (INIS)

    Sjoreen, T.P.

    1984-01-01

    A focal plane detector system consisting of a vertical drift chamber, parallel plate avalanche counters, and an ionization chamber with segmented anodes has been installed in the Broad Range Spectrometer at the Holifield Facility at Oak Ridge. The system, which has been designed for use with light-heavy ions with energies ranging from 10 to 25 MeV/amu, has a position resolution of approx. 0.1 mm, a scattering angle resolution of approx. 3 mrad, and a mass resolution of approx. 1/60

  12. Essential tension: specialization with broad and general training in psychology.

    Science.gov (United States)

    Roberts, Michael C

    2006-11-01

    The practice fields of psychology develop through specialization in training and education. The recognized specialties play a major role in developing new opportunities for professional psychology and providing quality services for the public. The essential tension comes from the balance of innovation and tradition and, in professional psychology, from the balance of fragmentation and unification. As an example, specialization in clinical child psychology is integrated within the broad and general traditions. The greater degree of focused science and practice in a specialty is the logical consequence of advances of the discipline and profession of psychology. ((c) 2006 APA, all rights reserved).

  13. Broad-band spectrophotometry of HAT-P-32 b

    DEFF Research Database (Denmark)

    Mallonn, M.; Bernt, I.; Herrero, E.

    2016-01-01

    Multicolour broad-band transit observations offer the opportunity to characterize the atmosphere of an extrasolar planet with small- to medium-sized telescopes. One of the most favourable targets is the hot Jupiter HAT-P-32 b. We combined 21 new transit observations of this planet with 36 previou...... makes a recent tentative detection of a scattering feature less likely. Instead, the available spectral measurements of HAT-P-32 b favour a completely flat spectrum from the near-UV to the near-IR. A plausible interpretation is a thick cloud cover at high altitudes....

  14. Report on broad reconsiderations. Part 1. Energy and Climate

    International Nuclear Information System (INIS)

    2009-04-01

    In twenty policy areas various working groups have studied variants that can lead to a 20% budget cut in the government budgets of the Netherlands, which must be realized in 2015. The aim of the reconsiderations is to use less government means to realize the same results, or even better results if possible. The broad reconsideration in the field of energy and climate focuses on the expenditure for renewable energy and energy efficiency, mitigating (inter)national climate policy and fiscal benefits. This report addresses six policy variants. [nl

  15. 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

  16. Mapping Determinants of Virus Neutralization and Viral Escape for Rational Design of a Hepatitis C Virus Vaccine

    Directory of Open Access Journals (Sweden)

    Mei-Le Keck

    2018-05-01

    Full Text Available Hepatitis C virus (HCV continues to spread worldwide with an annual increase of 1.75 million new infections. The number of HCV cases in the U.S. is now greater than the number of HIV cases and is increasing in young adults because of the opioid epidemic sweeping the country. HCV-related liver disease is the leading indication of liver transplantation. An effective vaccine is of paramount importance to control and prevent HCV infection. While this vaccine will need to induce both cellular and humoral immunity, this review is focused on the required antibody responses. For highly variable viruses, such as HCV, isolation and characterization of monoclonal antibodies mediating broad virus neutralization are an important guide for vaccine design. The viral envelope glycoproteins, E1 and E2, are the main targets of these antibodies. Epitopes on the E2 protein have been studied more extensively than epitopes on E1, due to higher antibody targeting that reflects these epitopes having higher degrees of immunogenicity. E2 epitopes are overall organized in discrete clusters of overlapping epitopes that ranged from high conservation to high variability. Other epitopes on E1 and E1E2 also are targets of neutralizing antibodies. Taken together, these regions are important for vaccine design. Another element in vaccine design is based on information on how the virus escapes from broadly neutralizing antibodies. Escape mutations can occur within the epitopes that are involved in antibody binding and in regions that are not involved in their epitopes, but nonetheless reduce the efficiency of neutralizing antibodies. An understanding on the specificities of a protective B cell response, the molecular locations of these epitopes on E1, E2, and E1E2, and the mechanisms, which enable the virus to negatively modulate neutralizing antibody responses to these regions will provide the necessary guidance for vaccine design.

  17. Neutral Polymeric Micelles for RNA Delivery

    Science.gov (United States)

    Lundy, Brittany B.; Convertine, Anthony; Miteva, Martina; Stayton, Patrick S.

    2013-01-01

    RNA interference (RNAi) drugs have significant therapeutic potential but delivery systems with appropriate efficacy and toxicity profiles are still needed. Here, we describe a neutral, ampholytic polymeric delivery system based on conjugatable diblock polymer micelles. The diblock copolymer contains a hydrophilic poly[N-(2-hydroxypropyl) methacrylamide-co-N-(2-(pyridin-2- yldisulfanyl)ethyl)methacrylamide) (poly[HPMA-co-PDSMA]) segment to promote aqueous stability and facilitate thiol-disulfide exchange reactions, and a second ampholytic block composed of propyl acrylic acid (PAA), dimethylaminoethyl methacrylate (DMAEMA), and butyl methacrylate (BMA). The poly[(HPMA-co-PDSMA)-b-(PAA-co-DMAEMA-co-BMA)] was synthesized using Reversible Addition-Fragmentation chain Transfer (RAFT) polymerization with an overall molecular weight of 22,000 g/mol and a PDI of 1.88. Dynamic light scattering and fluorescence measurements indicated that the diblock copolymers self-assemble under aqueous conditions to form polymeric micelles with a hydrodynamic radius and critical micelle concentration of 25 nm and 25 μg/mL respectively. Red blood cell hemolysis experiments show that the neutral hydrophilic micelles have potent membrane destabilizing activity at endosomal pH values. Thiolated siRNA targeting glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was directly conjugated to the polymeric micelles via thiol exchange reactions with the pyridal disulfide groups present in the micelle corona. Maximum silencing activity in HeLa cells was observed at a 1:10 molar ratio of siRNA to polymer following a 48 h incubation period. Under these conditions 90 % mRNA knockdown and 65 % and protein knockdown of at 48 h was achieved with negligible toxicity. In contrast the polymeric micelles lacking a pH-responsive endosomalytic segment demonstrated negligible mRNA and protein knockdown under these conditions. The potent mRNA knockdown and excellent biocompatibility of the neutral siRNA conjugates

  18. Quasar outflow energetics from broad absorption line variability

    Science.gov (United States)

    McGraw, S. M.; Shields, J. C.; Hamann, F. W.; Capellupo, D. M.; Herbst, H.

    2018-03-01

    Quasar outflows have long been recognized as potential contributors to the co-evolution between supermassive black holes (SMBHs) and their host galaxies. The role of outflows in active galactic nucleus (AGN) feedback processes can be better understood by placing observational constraints on wind locations and kinetic energies. We utilize broad absorption line (BAL) variability to investigate the properties of a sample of 71 BAL quasars with P V broad absorption. The presence of P V BALs indicates that other BALs like C IV are saturated, such that variability in those lines favours clouds crossing the line of sight. We use these constraints with measurements of BAL variability to estimate outflow locations and energetics. Our data set consists of multiple-epoch spectra from the Sloan Digital Sky Survey and MDM Observatory. We detect significant (4σ) BAL variations from 10 quasars in our sample over rest-frame time-scales between ≤0.2-3.8 yr. Our derived distances for the 10 variable outflows are nominally ≲ 1-10 pc from the SMBH using the transverse-motion scenario, and ≲ 100-1000 pc from the central source using ionization-change considerations. These distances, in combination with the estimated high outflow column densities (i.e. NH ≳ 1022 cm-2), yield outflow kinetic luminosities between ˜ 0.001 and 1 times the bolometric luminosity of the quasar, indicating that many absorber energies within our sample are viable for AGN feedback.

  19. Broad spectrum microarray for fingerprint-based bacterial species identification

    Directory of Open Access Journals (Sweden)

    Frey Jürg E

    2010-02-01

    Full Text Available Abstract Background Microarrays are powerful tools for DNA-based molecular diagnostics and identification of pathogens. Most target a limited range of organisms and are based on only one or a very few genes for specific identification. Such microarrays are limited to organisms for which specific probes are available, and often have difficulty discriminating closely related taxa. We have developed an alternative broad-spectrum microarray that employs hybridisation fingerprints generated by high-density anonymous markers distributed over the entire genome for identification based on comparison to a reference database. Results A high-density microarray carrying 95,000 unique 13-mer probes was designed. Optimized methods were developed to deliver reproducible hybridisation patterns that enabled confident discrimination of bacteria at the species, subspecies, and strain levels. High correlation coefficients were achieved between replicates. A sub-selection of 12,071 probes, determined by ANOVA and class prediction analysis, enabled the discrimination of all samples in our panel. Mismatch probe hybridisation was observed but was found to have no effect on the discriminatory capacity of our system. Conclusions These results indicate the potential of our genome chip for reliable identification of a wide range of bacterial taxa at the subspecies level without laborious prior sequencing and probe design. With its high resolution capacity, our proof-of-principle chip demonstrates great potential as a tool for molecular diagnostics of broad taxonomic groups.

  20. Control of Neutralization Process Using Soft Computing

    Directory of Open Access Journals (Sweden)

    G. Balasubramanian

    2008-03-01

    Full Text Available A novel model-based nonlinear control strategy is proposed using an experimental pH neutralization process. The control strategy involves a non linear neural network (NN model, in the context of internal model control (IMC. When integrated into the internal model control scheme, the resulting controller is shown to have favorable practical implications as well as superior performance. The designed model based online IMC controller was implemented to a laboratory scaled pH process in real time using dSPACE 1104 interface card. The responses of pH and acid flow rate shows good tracking for both the set point and load chances over the entire nonlinear region.