Science.gov

Sample records for based gp collider

  1. A Photon Collider Experiment based on SLC

    SciTech Connect

    Gronberg, J

    2003-11-01

    Technology for a photon collider experiment at a future TeV-scale linear collider has been under development for many years. The laser and optics technology has reached the point where a GeV-scale photon collider experiment is now feasible. We report on the photon-photon luminosities that would be achievable at a photon collider experiment based on a refurbished Stanford Linear Collider.

  2. Musculoskeletal (MSK) and Sport and Exercise Medicine (SEM) in General Practice (GP): A Novel GP-based MSK and SEM Clinic for Managing Musculoskeletal symptoms in a GP

    PubMed Central

    Heron, Neil

    2015-01-01

    Musculoskeletal (MSK) complaints are common within primary care (1) (2) (3) but some General Practitioners (GPs)/family physicians do not feel comfortable managing these symptoms (3), preferring to refer onto hospital specialists or Integrated Clinical Assessment and Treatment Services (ICATs). Long waiting times for hospital outpatient reviews are a major cause of patient inconvenience and complaints (4). We therefore aimed to establish a GP-ran MSK and sport and exercise medicine (SEM) clinic based within a Belfast GP surgery that would contribute to a sustainable improvement in managing these common conditions within primary care as well as reducing waiting times for patients with these conditions to see a specialist. This shift from hospital-based to community-based management is in-keeping with recent policy changes within the UK health-system, including Transforming Your Care within Northern Ireland (NI) (5). The GP-ran MSK and SEM clinic was held monthly within a Belfast GP practice, staffed by one GP with a specialist interest in MSK and SEM conditions and its performance was reviewed over a three month period. Parameters audited included cases seen, orthopaedic and x-ray referral rates and secondary care referrals comparing the GP practice's performance to the same time period in the previous year as well as patient satisfaction questionnaires. PMID:26733320

  3. LASER-PLASMA-ACCELERATOR-BASED GAMMA GAMMA COLLIDERS

    SciTech Connect

    Schroeder, C. B.; Esarey, E.; Toth, Cs.; Geddes, C. G. R.; Leemans, W. P.

    2009-05-04

    Design considerations for a next-generation linear collider based on laser-plasma-accelerators are discussed, and a laser-plasma-accelerator-based gamma-gamma collider is considered. An example of the parameters for a 0.5 TeV laser-plasma-accelerator gamma gamma collider is presented.

  4. Eliciting neutralizing antibodies with gp120 outer domain constructs based on M-group consensus sequence.

    PubMed

    Qin, Yali; Banasik, Marisa; Kim, SoonJeung; Penn-Nicholson, Adam; Habte, Habtom H; LaBranche, Celia; Montefiori, David C; Wang, Chong; Cho, Michael W

    2014-08-01

    One strategy being evaluated for HIV-1 vaccine development is focusing immune responses towards neutralizing epitopes on the gp120 outer domain (OD) by removing the immunodominant, but non-neutralizing, inner domain. Previous OD constructs have not elicited strong neutralizing antibodies (nAbs). We constructed two immunogens, a monomeric gp120-OD and a trimeric gp120-OD×3, based on an M group consensus sequence (MCON6). Their biochemical and immunological properties were compared with intact gp120. Results indicated better preservation of critical neutralizing epitopes on gp120-OD×3. In contrast to previous studies, our immunogens induced potent, cross-reactive nAbs in rabbits. Although nAbs primarily targeted Tier 1 viruses, they exhibited significant breadth. Epitope mapping analyses indicated that nAbs primarily targeted conserved V3 loop elements. Although the potency and breadth of nAbs were similar for all three immunogens, nAb induction kinetics indicated that gp120-OD×3 was superior to gp120-OD, suggesting that gp120-OD×3 is a promising prototype for further gp120 OD-based immunogen development. PMID:25046154

  5. Eliciting Neutralizing Antibodies with gp120 Outer Domain Constructs Based on M-Group Consensus Sequence

    PubMed Central

    Qin, Yali; Banasik, Marisa; Kim, SoonJeung; Penn-Nicholson, Adam; Habte, Habtom H; Labranche, Celia; Montefiori, David C; Wang, Chong; Cho, Michael W

    2014-01-01

    One strategy being evaluated for HIV-1 vaccine development is focusing immune responses towards neutralizing epitopes on the gp120 outer domain (OD) by removing the immunodominant, but non-neutralizing, inner domain. Previous OD constructs have not elicited strong neutralizing antibodies (nAbs). We constructed two immunogens, a monomeric gp120-OD and a trimeric gp120-OD×3, based on an M group consensus sequence (MCON6). Their biochemical and immunological properties were compared with intact gp120. Results indicated better preservation of critical neutralizing epitopes on gp120-OD×3. In contrast to previous studies, our immunogens induced potent, cross-reactive nAbs in rabbits. Although nAbs primarily targeted Tier 1 viruses, they exhibited significant breadth. Epitope mapping analyses indicated that nAbs primarily targeted conserved V3 loop elements. Although the potency and breadth of nAbs were similar for all three immunogens, nAb induction kinetics indicated that gp120-OD×3 was superior to gp120-OD, suggesting that gp120-OD×3 is a promising prototype for further gp120 OD-based immunogen development. PMID:25046154

  6. Structural Analysis of a Highly Glycosylated and Unliganded gp120-Based Antigen Using Mass Spectrometry

    SciTech Connect

    L Wang; Y Qin; S Ilchenko; J Bohon; W Shi; M Cho; K Takamoto; M Chance

    2011-12-31

    Structural characterization of the HIV-1 envelope protein gp120 is very important for providing an understanding of the protein's immunogenicity and its binding to cell receptors. So far, the crystallographic structure of gp120 with an intact V3 loop (in the absence of a CD4 coreceptor or antibody) has not been determined. The third variable region (V3) of the gp120 is immunodominant and contains glycosylation signatures that are essential for coreceptor binding and entry of the virus into T-cells. In this study, we characterized the structure of the outer domain of gp120 with an intact V3 loop (gp120-OD8) purified from Drosophila S2 cells utilizing mass spectrometry-based approaches. We mapped the glycosylation sites and calculated the glycosylation occupancy of gp120-OD8; 11 sites from 15 glycosylation motifs were determined as having high-mannose or hybrid glycosylation structures. The specific glycan moieties of nine glycosylation sites from eight unique glycopeptides were determined by a combination of ECD and CID MS approaches. Hydroxyl radical-mediated protein footprinting coupled with mass spectrometry analysis was employed to provide detailed information about protein structure of gp120-OD8 by directly identifying accessible and hydroxyl radical-reactive side chain residues. Comparison of gp120-OD8 experimental footprinting data with a homology model derived from the ligated CD4-gp120-OD8 crystal structure revealed a flexible V3 loop structure in which the V3 tip may provide contacts with the rest of the protein while residues in the V3 base remain solvent accessible. In addition, the data illustrate interactions between specific sugar moieties and amino acid side chains potentially important to the gp120-OD8 structure.

  7. Laser-plasma-based linear collider using hollow plasma channels

    NASA Astrophysics Data System (ADS)

    Schroeder, C. B.; Benedetti, C.; Esarey, E.; Leemans, W. P.

    2016-09-01

    A linear electron-positron collider based on laser-plasma accelerators using hollow plasma channels is considered. Laser propagation and energy depletion in the hollow channel is discussed, as well as the overall efficiency of the laser-plasma accelerator. Example parameters are presented for a 1-TeV and 3-TeV center-of-mass collider based on laser-plasma accelerators.

  8. Development and Application of a gp60-Based Typing Assay for Cryptosporidium viatorum

    PubMed Central

    Elwin, K.; Winiecka-Krusnell, J.; Chalmers, R. M.; Xiao, L.; Lebbad, M.

    2015-01-01

    The apicomplexan intestinal parasites of the genus Cryptosporidium take a major toll on human and animal health and are frequent causes of waterborne outbreaks. Several species and genotypes can infect humans, including Cryptosporidium viatorum, which, to date, has only been found in humans. Molecular characterization of Cryptosporidium spp., critical to epidemiological analyses, is commonly based on gp60 gene analysis, which appears to require bespoke species- or group-specific PCR primers due to extensive genetic diversity across the genus. In this study, we amplified, sequenced, and characterized the gp60 gene of C. viatorum for the first time. Moreover, we developed and validated a gp60 typing assay for this species and applied it to 27 isolates originating from Asia, Africa, and Central America. A single subtype family, XVa, was identified containing multiple alleles. PMID:25832304

  9. Worrying about wasting GP time as a barrier to help-seeking: a community-based, qualitative study

    PubMed Central

    Cromme, Susanne K; Whitaker, Katriina L; Winstanley, Kelly; Renzi, Cristina; Smith, Claire Friedemann; Wardle, Jane

    2016-01-01

    Background Worrying about wasting GP time is frequently cited as a barrier to help-seeking for cancer symptoms. Aim To explore the circumstances under which individuals feel that they are wasting GP time. Design and setting Community-based, qualitative interview studies that took place in London, the South East and the North West of England. Method Interviewees (n = 62) were recruited from a sample (n = 2042) of adults aged ≥50 years, who completed a ‘health survey’ that included a list of cancer ‘alarm’ symptoms. Individuals who reported symptoms at baseline that were still present at the 3-month follow-up (n = 271), and who had also consented to be contacted (n = 215), constituted the pool of people invited for interview. Analyses focused on accounts of worrying about wasting GP time. Results Participants were worried about wasting GP time when time constraints were visible, while dismissive interactions with their GP induced a worry of unnecessary help-seeking. Many felt that symptoms that were not persistent, worsening, or life-threatening did not warrant GP attention. Additionally, patients considered it time-wasting when they perceived attention from nurses or pharmacists to be sufficient, or when appointment structures (for example, ‘one issue per visit’) were not adhered to. Close relationships with GPs eased worries about time-wasting, while some patients saw GPs as fulfilling a service financed by taxpayers. Conclusion Worrying about wasting GP time is a complex barrier to help-seeking. GP time and resource scarcity, symptom gravity, appointment etiquette, and previous GP interactions contribute to increasing worries. Friendly GP relationships, economic reasoning, and a focus on the GP’s responsibilities as a medical professional reduce this worry. PMID:27215569

  10. Human Antibody Titers to Epstein-Barr Virus (EBV) gp350 Correlate with Neutralization of Infectivity Better than Antibody Titers to EBV gp42 Using a Rapid Flow Cytometry-Based EBV Neutralization Assay

    PubMed Central

    Sashihara, Junji; Burbelo, Peter D.; Savoldo, Barbara; Pierson, Theodore C.; Cohen, Jeffrey I.

    2009-01-01

    Measurement of neutralizing antibodies to Epstein-Barr virus (EBV) is important for evaluation of candidate vaccines. The current neutralization assay is based on antibody inhibition of EBV transformation of B cells and requires 6 weeks to perform. We developed a rapid, quantitative flow cytometry assay and show that neutralizing antibody titers measured by the new assay strongly correlate with antibody titers in the standard transformation-based assay. Antibodies to EBV gp350 and gp42 have been shown to block infection of B cells by EBV. Using new assays to quantify antibodies to these glycoproteins, we show for the first time that that human plasma contains high titers of antibody to gp42; these titers correlate with neutralization of EBV infectivity or transformation. Furthermore, we show that antibody titers to EBV gp350 correlate more strongly with neutralization than antibody titers to gp42. These assays should be useful in accessing antibody responses to candidate EBV vaccines. PMID:19584018

  11. Accelerator physics in ERL based polarized electron ion collider

    SciTech Connect

    Hao, Yue

    2015-05-03

    This talk will present the current accelerator physics challenges and solutions in designing ERL-based polarized electron-hadron colliders, and illustrate them with examples from eRHIC and LHeC designs. These challenges include multi-pass ERL design, highly HOM-damped SRF linacs, cost effective FFAG arcs, suppression of kink instability due to beam-beam effect, and control of ion accumulation and fast ion instabilities.

  12. ALV-J GP37 Molecular Analysis Reveals Novel Virus-Adapted Sites and Three Tyrosine-Based Env Species

    PubMed Central

    Shang, Jianjun; Tian, Xiaoyan; Yang, Jialiang; Chen, Hongjun; Shao, Hongxia; Qin, Aijian

    2015-01-01

    Compared to other avian leukosis viruses (ALV), ALV-J primarily induces myeloid leukemia and hemangioma and causes significant economic loss for the poultry industry. The ALV-J Env protein is hypothesized to be related to its unique pathogenesis. However, the molecular determinants of Env for ALV-J pathogenesis are unclear. In this study, we compared and analyzed GP37 of ALV-J Env and the EAV-HP sequence, which has high homology to that of ALV-J Env. Phylogenetic analysis revealed five groups of ALV-J GP37 and two novel ALV-J Envs with endemic GP85 and EAV-HP-like GP37. Furthermore, at least 15 virus-adapted mutations were detected in GP37 compared to the EAV-HP sequence. Further analysis demonstrated that three tyrosine-based motifs (YxxM, ITIM (immune tyrosine-based inhibitory motif) and ITAM-like (immune tyrosine-based active motif like)) associated with immune disease and oncogenesis were found in the cytoplasmic tail of GP37. Based on the potential function and distribution of these motifs in GP37, ALV-J Env was grouped into three species, inhibitory Env, bifunctional Env and active Env. Accordingly, 36.91%, 61.74% and 1.34% of ALV-J Env sequences from GenBank are classified as inhibitory, bifunctional and active Env, respectively. Additionally, the Env of the ALV-J prototype strain, HPRS-103, and 17 of 18 EAV-HP sequences belong to the inhibitory Env. And models for signal transduction of the three ALV-J Env species were predicted. Our findings and models provide novel insights for identifying the roles and molecular mechanism of ALV-J Env in the unique pathogenesis of ALV-J. PMID:25849207

  13. Derivative Trade Optimizing Model Utilizing GP Based on Behavioral Finance Theory

    NASA Astrophysics Data System (ADS)

    Matsumura, Koki; Kawamoto, Masaru

    This paper proposed a new technique which makes the strategy trees for the derivative (option) trading investment decision based on the behavioral finance theory and optimizes it using evolutionary computation, in order to achieve high profitability. The strategy tree uses a technical analysis based on a statistical, experienced technique for the investment decision. The trading model is represented by various technical indexes, and the strategy tree is optimized by the genetic programming(GP) which is one of the evolutionary computations. Moreover, this paper proposed a method using the prospect theory based on the behavioral finance theory to set psychological bias for profit and deficit and attempted to select the appropriate strike price of option for the higher investment efficiency. As a result, this technique produced a good result and found the effectiveness of this trading model by the optimized dealings strategy.

  14. Immunogenicity of multi-epitope-based vaccine candidates administered with the adjuvant Gp96 against rabies.

    PubMed

    Niu, Yange; Liu, Ye; Yang, Limin; Qu, Hongren; Zhao, Jingyi; Hu, Rongliang; Li, Jing; Liu, Wenjun

    2016-04-01

    Rabies, a zoonotic disease, causes > 55,000 human deaths globally and results in at least 500 million dollars in losses every year. The currently available rabies vaccines are mainly inactivated and attenuated vaccines, which have been linked with clinical diseases in animals. Thus, a rabies vaccine with high safety and efficacy is urgently needed. Peptide vaccines are known for their low cost, simple production procedures and high safety. Therefore, in this study, we examined the efficacy of multi-epitope-based vaccine candidates against rabies virus. The ability of various peptides to induce epitope-specific responses was examined, and the two peptides that possessed the highest antigenicity and conservation, i.e., AR16 and hPAB, were coated with adjuvant canine-Gp96 and used to prepare vaccines. The peptides were prepared as an emulsion of oil in water (O/W) to create three batches of bivalent vaccine products. The vaccine candidates possessed high safety. Virus neutralizing antibodies were detected on the day 14 after the first immunization in mice and beagles, reaching 5-6 IU/mL in mice and 7-9 IU/mL in beagles by day 28. The protective efficacy of the vaccine candidates was about 70%-80% in mice challenged by a virulent strain of rabies virus. Thus, a novel multi-epitope-based rabies vaccine with Gp96 as an adjuvant was developed and validated in mice and dogs. Our results suggest that synthetic peptides hold promise for the development of novel vaccines against rabies. PMID:27068655

  15. Ingot Nb based SRF technology for the International Linear Collider

    NASA Astrophysics Data System (ADS)

    Yamamoto, Akira; Yamanaka, Masashi; Myneni, Ganapati

    2015-12-01

    The International Linear Collider (ILC) is anticipated to be built as the next energy-frontier electron-positron colliding accelerator with a global effort in particle physics. Niobium based Superconducting Radio-Frequency (SRF) technology is required to provide beam-accelerating structure with elliptical cavity strings to linearly accelerate the electron and positron beams up to 250 GeV and to realize a center-of-mass energy of 500 GeV in collisions. The accelerator design and R&D efforts progressed, and the ILC Technical Design Report (ILC-TDR) was published in 2013. Niobium will take a critical role to generate electric field gradient with a frequency of 1.3 GHz, for accelerating the beam with the best efficiency, in energy balance, using RF superconductivity. This paper discusses a technical approach to provide Nb material (ingot) and thin disks for producing the elliptical cavity structure, with direct slicing from Nb ingot having sufficiently optimized purity and residual resistance ration (RRR) necessary for the ILC SRF cavities.

  16. Ingot Nb based SRF technology for the International Linear Collider

    SciTech Connect

    Yamamoto, Akira; Yamanaka, Masashi; Myneni, Ganapati

    2015-12-04

    The International Linear Collider (ILC) is anticipated to be built as the next energy-frontier electron-positron colliding accelerator with a global effort in particle physics. Niobium based Superconducting Radio-Frequency (SRF) technology is required to provide beam-accelerating structure with elliptical cavity strings to linearly accelerate the electron and positron beams up to 250 GeV and to realize a center-of-mass energy of 500 GeV in collisions. The accelerator design and R&D efforts progressed, and the ILC Technical Design Report (ILC-TDR) was published in 2013. Niobium will take a critical role to generate electric field gradient with a frequency of 1.3 GHz, for accelerating the beam with the best efficiency, in energy balance, using RF superconductivity. This paper discusses a technical approach to provide Nb material (ingot) and thin disks for producing the elliptical cavity structure, with direct slicing from Nb ingot having sufficiently optimized purity and residual resistance ration (RRR) necessary for the ILC SRF cavities.

  17. Evaluation of a gp63–PCR Based Assay as a Molecular Diagnosis Tool in Canine Leishmaniasis in Tunisia

    PubMed Central

    Guerbouj, Souheila; Djilani, Fattouma; Bettaieb, Jihene; Lambson, Bronwen; Diouani, Mohamed Fethi; Ben Salah, Afif; Ben Ismail, Riadh; Guizani, Ikram

    2014-01-01

    A gp63PCR method was evaluated for the detection and characterization of Leishmania (Leishmania) (L.) parasites in canine lymph node aspirates. This tool was tested and compared to other PCRs based on the amplification of 18S ribosomal genes, a L. infantum specific repetitive sequence and kinetoplastic DNA minicircles, and to classical parasitological (smear examination and/or culture) or serological (IFAT) techniques on a sample of 40 dogs, originating from different L. infantum endemic regions in Tunisia. Sensitivity and specificity of all the PCR assays were evaluated on parasitologically confirmed dogs within this sample (N = 18) and control dogs (N = 45) originating from non–endemic countries in northern Europe and Australia. The gp63 PCR had 83.5% sensitivity and 100% specificity, a performance comparable to the kinetoplast PCR assay and better than the other assays. These assays had comparable results when the gels were southern transferred and hybridized with a radioactive probe. As different infection rates were found according to the technique, concordance of the results was estimated by (κ) test. Best concordance values were between the gp63PCR and parasitological methods (74.6%, 95% confidence intervals CI: 58.8–95.4%) or serology IFAT technique (47.4%, 95% CI: 23.5–71.3%). However, taken together Gp63 and Rib assays covered most of the samples found positive making of them a good alternative for determination of infection rates. Potential of the gp63PCR-RFLP assay for analysis of parasite genetic diversity within samples was also evaluated using 5 restriction enzymes. RFLP analysis confirmed assignment of the parasites infecting the dogs to L. infantum species and illustrated occurrence of multiple variants in the different endemic foci. Gp63 PCR assay thus constitutes a useful tool in molecular diagnosis of L. infantum infections in dogs in Tunisia. PMID:25153833

  18. LHC and VLHC Based ep Colliders: e-Linac versus e-Ring

    NASA Astrophysics Data System (ADS)

    Gladilin, L.; Karadeniz, H.; Recepoglu, E.; Sultansoy, S.

    2007-06-01

    Linac-ring analogues of the LHC and VLHC based standard type ep collider proposals are discussed. It is shown that sufficiently high luminosities can be obtained with TESLA like linacs, whereas essential modifications are required for CLIC technology. The physics search potential of proposed ep colliders is demonstrated using pair production of heavy quarks as an example.

  19. Intrinsic acid-base properties of a hexa-2'-deoxynucleoside pentaphosphate, d(ApGpGpCpCpT): neighboring effects and isomeric equilibria.

    PubMed

    Domínguez-Martín, Alicia; Johannsen, Silke; Sigel, Astrid; Operschall, Bert P; Song, Bin; Sigel, Helmut; Okruszek, Andrzej; González-Pérez, Josefa María; Niclós-Gutiérrez, Juan; Sigel, Roland K O

    2013-06-17

    The intrinsic acid-base properties of the hexa-2'-deoxynucleoside pentaphosphate, d(ApGpGpCpCpT) [=(A1∙G2∙G3∙C4∙C5∙T6)=(HNPP)⁵⁻] have been determined by ¹H NMR shift experiments. The pKa values of the individual sites of the adenosine (A), guanosine (G), cytidine (C), and thymidine (T) residues were measured in water under single-strand conditions (i.e., 10% D₂O, 47 °C, I=0.1 M, NaClO₄). These results quantify the release of H⁺ from the two (N7)H⁺ (G∙G), the two (N3)H⁺ (C∙C), and the (N1)H⁺ (A) units, as well as from the two (N1)H (G∙G) and the (N3)H (T) sites. Based on measurements with 2'-deoxynucleosides at 25 °C and 47 °C, they were transferred to pKa values valid in water at 25 °C and I=0.1 M. Intramolecular stacks between the nucleobases A1 and G2 as well as most likely also between G2 and G3 are formed. For HNPP three pKa clusters occur, that is those encompassing the pKa values of 2.44, 2.97, and 3.71 of G2(N7)H⁺, G3(N7)H⁺, and A1(N1)H⁺, respectively, with overlapping buffer regions. The tautomer populations were estimated, giving for the release of a single proton from five-fold protonated H₅(HNPP)(±) , the tautomers (G2)N7, (G3)N7, and (A1)N1 with formation degrees of about 74, 22, and 4%, respectively. Tautomer distributions reveal pathways for proton-donating as well as for proton-accepting reactions both being expected to be fast and to occur practically at no "cost". The eight pKa values for H₅(HNPP)(±) are compared with data for nucleosides and nucleotides, revealing that the nucleoside residues are in part affected very differently by their neighbors. In addition, the intrinsic acidity constants for the RNA derivative r(A1∙G2∙G3∙C4∙C5∙U6), where U=uridine, were calculated. Finally, the effect of metal ions on the pKa values of nucleobase sites is briefly discussed because in this way deprotonation reactions can easily be shifted to the physiological pH range. PMID:23595830

  20. Computational Design of Hypothetical New Peptides Based on a Cyclotide Scaffold as HIV gp120 Inhibitor

    PubMed Central

    Sangphukieo, Apiwat; Nawae, Wanapinun; Laomettachit, Teeraphan; Supasitthimethee, Umaporn; Ruengjitchatchawalya, Marasri

    2015-01-01

    Cyclotides are a family of triple disulfide cyclic peptides with exceptional resistance to thermal/chemical denaturation and enzymatic degradation. Several cyclotides have been shown to possess anti-HIV activity, including kalata B1 (KB1). However, the use of cyclotides as anti-HIV therapies remains limited due to the high toxicity in normal cells. Therefore, grafting anti-HIV epitopes onto a cyclotide might be a promising approach for reducing toxicity and simultaneously improving anti-HIV activity. Viral envelope glycoprotein gp120 is required for entry of HIV into CD4+ T cells. However, due to a high degree of variability and physical shielding, the design of drugs targeting gp120 remains challenging. We created a computational protocol in which molecular modeling techniques were combined with a genetic algorithm (GA) to automate the design of new cyclotides with improved binding to HIV gp120. We found that the group of modified cyclotides has better binding scores (23.1%) compared to the KB1. By using molecular dynamic (MD) simulation as a post filter for the final candidates, we identified two novel cyclotides, GA763 and GA190, which exhibited better interaction energies (36.6% and 22.8%, respectively) when binding to gp120 compared to KB1. This computational design represents an alternative tool for modifying peptides, including cyclotides and other stable peptides, as therapeutic agents before the synthesis process. PMID:26517259

  1. BEAM-BASED NON-LINEAR OPTICS CORRECTIONS IN COLLIDERS.

    SciTech Connect

    PILAT, R.; LUO, Y.; MALITSKY, N.; PTITSYN, V.

    2005-05-16

    A method has been developed to measure and correct operationally the non-linear effects of the final focusing magnets in colliders, that gives access to the effects of multi-pole errors by applying closed orbit bumps, and analyzing the resulting tune and orbit shifts. This technique has been tested and used during 4 years of RHIC (the Relativistic Heavy Ion Collider at BNL) operations. I will discuss here the theoretical basis of the method, the experimental set-up, the correction results, the present understanding of the machine model, the potential and limitations of the method itself as compared with other non-linear correction techniques.

  2. GP utilisation by education level among adults with COPD or asthma: a cross-sectional register-based study.

    PubMed

    Hetlevik, Øystein; Melbye, Hasse; Gjesdal, Sturla

    2016-01-01

    There is a marked socioeconomic gradient in the prevalence of chronic obstructive pulmonary disease (COPD) and asthma, but a large proportion of patients remain undiagnosed. It is a challenge for general practitioners (GPs) to both identify patients and contribute to equity and high quality in services delivered. The aim of this study was to identify patients with COPD and asthma diagnoses recorded by GPs and explore their utilisation of GP services by education level. This was a cross-sectional, national, register-based study from Norwegian general practice in the period 2009-2011. Based on claims from GPs, the number of patients aged ⩾40 years with a diagnosis of COPD or asthma and their GP services utilisation were estimated and linked to the national education database. Multivariate Poisson and logistic regression models were used to explore the variations in GP utilisation. In the population aged ⩾40 years, 2.8% had COPD and 3.8% had asthma according to GPs' diagnoses. COPD was four times more prevalent in patients with basic education than higher education; this increase was ⩽80% for asthma. Consultation rates were 12% higher (P<0.001) for COPD and 25% higher (P<0.001) for asthma in patients with low versus high education in the age group of 40-59 years after adjusting for comorbidity, and patient and GP characteristics. Approximately 25% of COPD patients and 20% of asthma patients had ⩾1 spirometry test in general practice in 2011, with no significant education differences in adjusted models. The higher consultation rate in lower-education groups indicates that GPs contribute to fair distribution of healthcare. PMID:27279354

  3. GP utilisation by education level among adults with COPD or asthma: a cross-sectional register-based study

    PubMed Central

    Hetlevik, Øystein; Melbye, Hasse; Gjesdal, Sturla

    2016-01-01

    There is a marked socioeconomic gradient in the prevalence of chronic obstructive pulmonary disease (COPD) and asthma, but a large proportion of patients remain undiagnosed. It is a challenge for general practitioners (GPs) to both identify patients and contribute to equity and high quality in services delivered. The aim of this study was to identify patients with COPD and asthma diagnoses recorded by GPs and explore their utilisation of GP services by education level. This was a cross-sectional, national, register-based study from Norwegian general practice in the period 2009–2011. Based on claims from GPs, the number of patients aged ⩾40 years with a diagnosis of COPD or asthma and their GP services utilisation were estimated and linked to the national education database. Multivariate Poisson and logistic regression models were used to explore the variations in GP utilisation. In the population aged ⩾40 years, 2.8% had COPD and 3.8% had asthma according to GPs’ diagnoses. COPD was four times more prevalent in patients with basic education than higher education; this increase was ⩽80% for asthma. Consultation rates were 12% higher (P<0.001) for COPD and 25% higher (P<0.001) for asthma in patients with low versus high education in the age group of 40–59 years after adjusting for comorbidity, and patient and GP characteristics. Approximately 25% of COPD patients and 20% of asthma patients had ⩾1 spirometry test in general practice in 2011, with no significant education differences in adjusted models. The higher consultation rate in lower-education groups indicates that GPs contribute to fair distribution of healthcare. PMID:27279354

  4. Structure-Based Design of a Protein Immunogen that Displays an HIV-1 gp41 Neutralizing Epitope

    SciTech Connect

    Stanfield, Robyn L.; Julien, Jean-Philippe; Pejchal, Robert; Gach, Johannes S.; Zwick, Michael B.; Wilson, Ian A.

    2012-06-27

    Antibody Z13e1 is a relatively broadly neutralizing anti-human immunodeficiency virus type 1 antibody that recognizes the membrane-proximal external region (MPER) of the human immunodeficiency virus type 1 envelope glycoprotein gp41. Based on the crystal structure of an MPER epitope peptide in complex with Z13e1 Fab, we identified an unrelated protein, interleukin (IL)-22, with a surface-exposed region that is structurally homologous in its backbone to the gp41 Z13e1 epitope. By grafting the gp41 Z13e1 epitope sequence onto the structurally homologous region in IL-22, we engineered a novel protein (Z13-IL22-2) that contains the MPER epitope sequence for use as a potential immunogen and as a reagent for the detection of Z13e1-like antibodies. The Z13-IL22-2 protein binds Fab Z13e1 with a K{sub d} of 73 nM. The crystal structure of Z13-IL22-2 in complex with Fab Z13e1 shows that the epitope region is faithfully replicated in the Fab-bound scaffold protein; however, isothermal calorimetry studies indicate that Fab binding to Z13-IL22-2 is not a lock-and-key event, leaving open the question of whether conformational changes upon binding occur in the Fab, in Z13-IL-22, or in both.

  5. A DSP based data acquisition module for colliding beam accelerators

    SciTech Connect

    Mead, J.A.; Shea, T.J.

    1995-10-01

    In 1999, the Relativistic Heavy Ion Collider (RHIC) at Brookhaven National Laboratory will accelerate and store two beams of gold ions. The ions will then collide head on at a total energy of nearly 40 trillion electron volts. Attaining these conditions necessitates real-time monitoring of beam parameters and for this purpose a flexible data acquisition platform has been developed. By incorporating a floating point digital signal processor (DSP) and standard input/output modules, this system can acquire and process data from a variety of beam diagnostic devices. The DSP performs real time corrections, filtering, and data buffering to greatly reduce control system computation and bandwidth requirements. We will describe the existing hardware and software while emphasizing the compromises required to achieve a flexible yet cost effective system. Applications in several instrumentation systems currently construction will also be presented.

  6. Mixed nanomicelles as potential carriers for systemic delivery of Z-GP-Dox, an FAPα-based doxorubicin prodrug: formulation and pharmacokinetic evaluation

    PubMed Central

    Zhang, Yuchen; Zhang, Xingwang; Liu, Hongming; Cai, Shaohui; Wu, Baojian

    2015-01-01

    Z-GP-Dox, the FAPα (fibroblast activation protein-α)-based doxorubicin prodrug, demonstrates excellent tumor targeting effects and a favorable toxicokinetic profile. However, the insoluble nature of Z-GP-Dox becomes a significant barrier to drug administration, particularly when it comes to the clinical stage. Here we developed a nanomicelle system to facilitate the systemic delivery of Z-GP-Dox, and evaluated its disposition in rats following administration of the micelles using a physiologically-based pharmacokinetic model. Z-GP-Dox-loaded mixed nanomicelles (ZGD-MNs) were prepared by dispersion of an ethanol solution of Z-GP-Dox, lecithin, and sodium oleate in water. The obtained ZGD-MNs were 86.6 nm in size with a drug loading of 14.03%. ZGD-MNs were fairly stable in phosphate-buffered saline and showed satisfactory physical and chemical stability over a 2-week observation period. Accumulative drug release was more than 56% within 24 hours. Further, the physiologically-based pharmacokinetic rat model consisting of various organs (ie, heart, liver, spleen, lung, kidney, and intestine) was fitted to the experimental data following administration of ZGD-loaded cosolvent (control) or micelles. Derived partition coefficient values revealed that the nanomicelles significantly altered the biodistribution of Z-GP-Dox. Of note, drug distribution to the lung, liver, and spleen was greatly enhanced and the fold change ranged from 2.4 to 33. In conclusion, this is the first report of a mixed micelle system being a viable carrier for delivery of Z-GP-Dox. Also, the pharmacokinetic behavior of Z-GP-Dox was satisfactorily described by the physiologically-based pharmacokinetic model. PMID:25759584

  7. Linac-ring type ep machines and γp colliders based on them

    NASA Astrophysics Data System (ADS)

    Aydin, Z. Z.; Çiftçi, A. K.; Sultansoy, S.

    1994-12-01

    Main parameters of new type of ep colliders and TeV energy γ p colliders on their bases are investigated. High energy γ beams are produced by the Compton backscattering of laser photons off electron beams from linear accelerators. We consider a number of possible proposals and show that sufficiently high ep and γp luminosities will be achievable due to reasonable improvements of proton beam parameters.

  8. A novel chimeric protein-based HIV-1 fusion inhibitor targeting gp41 glycoprotein with high potency and stability.

    PubMed

    Pan, Chungen; Cai, Lifeng; Lu, Hong; Lu, Lu; Jiang, Shibo

    2011-08-12

    T20 (enfuvirtide, Fuzeon) is the first generation HIV-1 fusion inhibitor approved for salvage therapy of HIV-1-infected patients refractory to current antiretroviral drugs. However, its application is limited by the high cost of peptide synthesis, rapid proteolysis, and poor efficacy against emerging drug-resistant strains. Here we reported the design of a novel chimera protein-based fusion inhibitor targeting gp41, TLT35, that uses a flexible 35-mer linker to couple T20 and T1144, the first and next generation HIV-1 fusion inhibitors, respectively. TLT35, which was expressed in Escherichia coli with good yield, showed low nm activity against HIV-1-mediated cell-cell fusion and infection by laboratory-adapted HIV-1 strains (X4 or R5), including T20-resistant variants and primary HIV-1 isolates of clades A to G and group O (R5 or X4R5). TLT35 was stable in human sera and in peripheral blood mononuclear cell culture and was more resistant to proteolysis than either T20 or T1144 alone. Circular dichroism spectra showed that TLT35 folded into a thermally stable conformation with high α-helical content and T(m) value in aqueous solution. It formed a highly stable complex with gp41 N-terminal heptad repeat peptide and blocked formation of the gp41 six-helix-bundle core. These merits combined with an anticipated low production cost for expression of TLT35 in E. coli make this novel protein-based fusion inhibitor a promising candidate for further development as an anti-HIV-1 microbicide or therapeutic for the prevention and treatment of HIV-1 infection. PMID:21690094

  9. Immunogenic properties of a trimeric gp41-based immunogen containing an exposed membrane-proximal external region.

    PubMed

    Habte, Habtom H; Banerjee, Saikat; Shi, Heliang; Qin, Yali; Cho, Michael W

    2015-12-01

    The membrane-proximal external region (MPER) of HIV-1 gp41 is an attractive target for vaccine development. Thus, better understanding of its immunogenic properties in various structural contexts is important. We previously described the crystal structure of a trimeric protein complex named gp41-HR1-54Q, which consists of the heptad repeat regions 1 and 2 and the MPER. The protein was efficiently recognized by broadly neutralizing antibodies. Here, we describe its immunogenic properties in rabbits. The protein was highly immunogenic, especially the C-terminal end of the MPER containing 4E10 and 10E8 epitopes ((671)NWFDITNWLWYIK(683)). Although antibodies exhibited strong competition activity against 4E10 and 10E8, neutralizing activity was not detected. Detailed mapping analyses indicated that amino acid residues critical for recognition resided on faces of the alpha helix that are either opposite of or perpendicular to the epitopes recognized by 4E10 and 10E8. These results provide critical information for designing the next generation of MPER-based immunogens. PMID:26454663

  10. [Calorimeter based detectors for high energy hadron colliders]. [Progress report

    SciTech Connect

    Not Available

    1992-08-04

    This document provides a progress report on research that has been conducted under DOE Grant DEFG0292ER40697 for the past year, and describes proposed work for the second year of this 8 year grant starting November 15, 1992. Personnel supported by the contract include 4 faculty, 1 research faculty, 4 postdocs, and 9 graduate students. The work under this grant has in the past been directed in two complementary directions -- DO at Fermilab, and the second SSC detector GEM. A major effort has been towards the construction and commissioning of the new Fermilab Collider detector DO, including design, construction, testing, the commissioning of the central tracking and the central calorimeters. The first DO run is now underway, with data taking and analysis of the first events. Trigger algorithms, data acquisition, calibration of tracking and calorimetry, data scanning and analysis, and planning for future upgrades of the DO detector with the advent of the FNAL Main Injector are all involved. The other effort supported by this grant has been towards the design of GEM, a large and general-purpose SSC detector with special emphasis on accurate muon measurement over a large solid angle. This effort will culminate this year in the presentation to the SSC laboratory of the GEM Technical Design Report. Contributions are being made to the detector design, coordination, and physics simulation studies with special emphasis on muon final states. Collaboration with the RD5 group at CERN to study muon punch through and to test cathode strip chamber prototypes was begun.

  11. NEUTRINO FACTORY BASED ON MUON-STORAGE-RINGS TO MUON COLLIDERS: PHYSICS AND FACILITIES.

    SciTech Connect

    PARSA,Z.

    2001-06-18

    Intense muon sources for the purpose of providing intense high energy neutrino beams ({nu} factory) represents very interesting possibilities. If successful, such efforts would significantly advance the state of muon technology and provides intermediate steps in technologies required for a future high energy muon collider complex. High intensity muon: production, capture, cooling, acceleration and multi-turn muon storage rings are some of the key technology issues that needs more studies and developments, and will briefly be discussed here. A muon collider requires basically the same number of muons as for the muon storage ring neutrino factory, but would require more cooling, and simultaneous capture of both {+-} {mu}. We present some physics possibilities, muon storage ring based neutrino facility concept, site specific examples including collaboration feasibility studies, and upgrades to a full collider.

  12. Interaction region design for a RHIC-based medium-energy electron-ion collider

    SciTech Connect

    Montag,C.; Beebe-Wang, J.

    2009-05-04

    As a first step in a staged approach towards a RHIC-based electron-ion collider, installation of a 4 GeV energy-recovery linac (ERL) in one of the RHIC interaction regions is currently under investigation. To minimize costs, the interaction region of this collider has to use the present RHIC magnets for focusing of the high-energy ion beam. Meanwhile, electron low-beta focusing needs to be added in the limited space available between the existing separator dipoles. We discuss the challenges and present the current design status of this e-A interaction region.

  13. International variation in GP treatment strategies for subclinical hypothyroidism in older adults: a case-based survey

    PubMed Central

    den Elzen, Wendy PJ; Lefèbre-van de Fliert, Anne A; Virgini, Vanessa; Mooijaart, Simon P; Frey, Peter; Kearney, Patricia M; Kerse, Ngaire; Mallen, Christian D; McCarthy, Vera JC; Muth, Christiane; Rosemann, Thomas; Russell, Audrey; Schers, Henk; Stott, David J; de Waal, Margot WM; Warner, Alex; Westendorp, Rudi GJ; Rodondi, Nicolas; Gussekloo, Jacobijn

    2015-01-01

    Background There is limited evidence about the impact of treatment for subclinical hypothyroidism, especially among older people. Aim To investigate the variation in GP treatment strategies for older patients with subclinical hypothyroidism depending on country and patient characteristics. Design and setting Case-based survey of GPs in the Netherlands, Germany, England, Ireland, Switzerland, and New Zealand. Method The treatment strategy of GPs (treatment yes/no, starting-dose thyroxine) was assessed for eight cases presenting a woman with subclinical hypothyroidism. The cases differed in the patient characteristics of age (70 versus 85 years), vitality status (vital versus vulnerable), and thyroid-stimulating hormone (TSH) concentration (6 versus 15 mU/L). Results A total of 526 GPs participated (the Netherlands n = 129, Germany n = 61, England n = 22, Ireland n = 21, Switzerland n = 262, New Zealand n = 31; overall response 19%). Across countries, differences in treatment strategy were observed. GPs from the Netherlands (mean treatment percentage 34%), England (40%), and New Zealand (39%) were less inclined to start treatment than GPs in Germany (73%), Ireland (62%), and Switzerland (52%) (P = 0.05). Overall, GPs were less inclined to start treatment in 85-year-old than in 70-year-old females (pooled odds ratio [OR] 0.74 [95% confidence interval [CI] = 0.63 to 0.87]). Females with a TSH of 15 mU/L were more likely to get treated than those with a TSH of 6 mU/L (pooled OR 9.49 [95% CI = 5.81 to 15.5]). Conclusion GP treatment strategies of older people with subclinical hypothyroidism vary largely by country and patient characteristics. This variation underlines the need for a new generation of international guidelines based on the outcomes of randomised clinical trials set within primary care. PMID:25624308

  14. Reply to ``Comment on `Beamstrahlung considerations in laser-plasma-accelerator-based linear colliders' ''

    NASA Astrophysics Data System (ADS)

    Schroeder, C. B.; Esarey, E.; Leemans, W. P.

    2013-10-01

    We reply to Lebedev and Nagaitsev’s foregoing Comment [Phys. Rev. ST Accel. Beams 16, 108001 (2013)PRABFM1098-4402]. We disagree with the conclusion of the Comment that scattering imposes a fundamental limitation on plasma-based accelerator technology. Laser-plasma accelerators are compatible with high-luminosity collider concepts.

  15. Performance-based seismic design of steel frames utilizing colliding bodies algorithm.

    PubMed

    Veladi, H

    2014-01-01

    A pushover analysis method based on semirigid connection concept is developed and the colliding bodies optimization algorithm is employed to find optimum seismic design of frame structures. Two numerical examples from the literature are studied. The results of the new algorithm are compared to the conventional design methods to show the power or weakness of the algorithm. PMID:25202717

  16. Performance-Based Seismic Design of Steel Frames Utilizing Colliding Bodies Algorithm

    PubMed Central

    Veladi, H.

    2014-01-01

    A pushover analysis method based on semirigid connection concept is developed and the colliding bodies optimization algorithm is employed to find optimum seismic design of frame structures. Two numerical examples from the literature are studied. The results of the new algorithm are compared to the conventional design methods to show the power or weakness of the algorithm. PMID:25202717

  17. Operational plasma density and laser parameters for future colliders based on laser-plasma accelerators

    SciTech Connect

    Schroeder, C. B.; Esarey, E.; Leemans, W. P.

    2012-12-21

    The operational plasma density and laser parameters for future colliders based on laser-plasma accelerators are discussed. Beamstrahlung limits the charge per bunch at low plasma densities. Reduced laser intensity is examined to improve accelerator efficiency in the beamstrahlung-limited regime.

  18. In silico Analysis of HIV-1 Env-gp120 Reveals Structural Bases for Viral Adaptation in Growth-Restrictive Cells

    PubMed Central

    Yokoyama, Masaru; Nomaguchi, Masako; Doi, Naoya; Kanda, Tadahito; Adachi, Akio; Sato, Hironori

    2016-01-01

    Variable V1/V2 and V3 loops on human immunodeficiency virus type 1 (HIV-1) envelope-gp120 core play key roles in modulating viral competence to recognize two infection receptors, CD4 and chemokine-receptors. However, molecular bases for the modulation largely remain unclear. To address these issues, we constructed structural models for a full-length gp120 in CD4-free and -bound states. The models showed topologies of gp120 surface loop that agree with those in reported structural data. Molecular dynamics simulation showed that in the unliganded state, V1/V2 loop settled into a thermodynamically stable arrangement near V3 loop for conformational masking of V3 tip, a potent neutralization epitope. In the CD4-bound state, however, V1/V2 loop was rearranged near the bound CD4 to support CD4 binding. In parallel, cell-based adaptation in the absence of anti-viral antibody pressures led to the identification of amino acid substitutions that individually enhance viral entry and growth efficiencies in association with reduced sensitivity to CCR5 antagonist TAK-779. Notably, all these substitutions were positioned on the receptors binding surfaces in V1/V2 or V3 loop. In silico structural studies predicted some physical changes of gp120 by substitutions with alterations in viral replication phenotypes. These data suggest that V1/V2 loop is critical for creating a gp120 structure that masks co-receptor binding site compatible with maintenance of viral infectivity, and for tuning a functional balance of gp120 between immune escape ability and infectivity to optimize HIV-1 replication fitness. PMID:26903989

  19. Photon collider Higgs factories

    NASA Astrophysics Data System (ADS)

    Telnov, V. I.

    2014-09-01

    The discovery of the Higgs boson (and still nothing else) have triggered appearance of many proposals of Higgs factories for precision measurement of the Higgs properties. Among them there are several projects of photon colliders (PC) without e+e- in addition to PLC based on e+e- linear colliders ILC and CLIC. In this paper, following a brief discussion of Higgs factories physics program I give an overview of photon colliders based on linear colliders ILC and CLIC, and of the recently proposed photon-collider Higgs factories with no e+e- collision option based on recirculation linacs in ring tunnels.

  20. Employees’ views on home-based, after-hours telephone triage by Dutch GP cooperatives

    PubMed Central

    2013-01-01

    Background Dutch out-of-hours (OOH) centers find it difficult to attract sufficient triage staff. They regard home-based triage as an option that might attract employees. Specially trained nurses are supposed to conduct triage by telephone from home for after-hours medical care. The central aim of this research is to investigate the views of employees of OOH centers in The Netherlands on home-based telephone triage in after-hours care. Methods The study is a Q methodology study. Triage nurses, general practitioners (GPs) and managers of OOH centers ranked 36 opinion statements on home-based triage. We interviewed 10 participants to help develop and validate the statements for the Q sort, and 77 participants did the Q sort. Results We identified four views on home-based telephone triage. Two generally favor home-based triage, one highlights some concerns and conditions, and one opposes it out of concern for quality. The four views perceive different sources of credibility for nurse triagists working from home. Conclusion Home-based telephone triage is a controversial issue among triage nurses, GPs and managers of OOH centers. By identifying consensus and dissension among GPs, triagists, managers and regulators, this study generates four perspectives on home-based triage. In addition, it reveals the conditions considered important for home-based triage. PMID:24188407

  1. SDA-based diagnostic and analysis tools for Collider Run II

    SciTech Connect

    Bolshakov, T.B.; Lebrun, P.; Panacek, S.; Papadimitriou, V.; Slaughter, J.; Xiao, A.; /Fermilab

    2005-05-01

    Operating and improving the understanding of the Fermilab Accelerator Complex for the colliding beam experiments requires advanced software methods and tools. The Shot Data Analysis (SDA) has been developed to fulfill this need. Data from the Fermilab Accelerator Complex is stored in a relational database, and is served to programs and users via Web-based tools. Summary tables are systematically generated during and after a store. These tables (the Supertable, the Recomputed Emittances, the Recomputed Intensities and other tables) are discussed here.

  2. Comparison of Two Widely Used Human Papillomavirus Detection and Genotyping Methods, GP5+/6+-Based PCR Followed by Reverse Line Blot Hybridization and Multiplex Type-Specific E7-Based PCR.

    PubMed

    Clifford, Gary M; Vaccarella, Salvatore; Franceschi, Silvia; Tenet, Vanessa; Umulisa, M Chantal; Tshomo, Ugyen; Dondog, Bolormaa; Vorsters, Alex; Tommasino, Massimo; Heideman, Daniëlle A M; Snijders, Peter J F; Gheit, Tarik

    2016-08-01

    GP5+/6+-based PCR followed by reverse line blot hybridization (GP5+/6+RLB) and multiplex type-specific PCR (E7-MPG) are two human papillomavirus (HPV) genotyping methodologies widely applied in epidemiological research. We investigated their relative analytical performance in 4,662 samples derived from five studies in Bhutan, Rwanda, and Mongolia coordinated by the International Agency for Research on Cancer (IARC). A total of 630 samples were positive by E7-MPG only (13.5%), 24 were positive by GP5+/6+RLB only (0.5%), and 1,014 were positive (21.8%) by both methods. Ratios of HPV type-specific positivity of the two tests (E7-MPG:GP5+/6+RLB ratio) were calculated among 1,668 samples that were HPV positive by one or both tests. E7-MPG:GP5+/6+RLB ratios were >1 for all types and highly reproducible across populations and sample types. E7-MPG:GP5+/6+RLB ratios were highest for HPV53 (7.5) and HPV68 (7.1). HPV16 (1.6) and HPV18 (1.7) had lower than average E7-MPG:GP5+/6+RLB ratios. Among E7-MPG positive infections, median mean fluorescence intensity (MFI; a semiquantitative measure of viral load) tended to be higher among samples positive for the same virus type by GP5+/6+RLB than for those negative for the same type by GP5+/6+RLB. Exceptions, however, included HPV53, -59, and -82, for which the chances of being undetected by GP5+/6+RLB appeared to be MFI independent. Furthermore, the probability of detecting an additional type by E7-MPG was higher when another type was already detected by GP5+/6+RLB, suggesting the existence of masking effects due to competition for GP5+/6+ PCR primers. In conclusion, this analysis is not an evaluation of clinical performance but may inform choices for HPV genotyping methods in epidemiological studies, when the relative merits and dangers of sensitivity versus specificity for individual types should be considered, as well as the potential to unmask nonvaccine types following HPV vaccination. PMID:27225411

  3. Comb-like amphiphilic polypeptide-based copolymer nanomicelles for co-delivery of doxorubicin and P-gp siRNA into MCF-7 cells.

    PubMed

    Suo, Aili; Qian, Junmin; Zhang, Yaping; Liu, Rongrong; Xu, Weijun; Wang, Hejing

    2016-05-01

    A comb-like amphiphilic copolymer methoxypolyethylene glycol-graft-poly(L-lysine)-block-poly(L-phenylalanine) (mPEG-g-PLL-b-Phe) was successfully synthesized. To synthesize mPEG-g-PLL-b-Phe, diblock copolymer PLL-b-Phe was first synthesized by successive ring-opening polymerization of α-amino acid N-carboxyanhydrides followed by the removal of benzyloxycarbonyl protecting groups, and then mPEG was grafted onto PLL-b-Phe by reductive amination via Schiff's base formation. The chemical structures of the copolymers were identified by (1)H NMR. mPEG-g-PLL-b-Phe copolymer had a critical micelle concentration of 6.0mg/L and could self-assemble in an aqueous solution into multicompartment nanomicelles with a mean diameter of approximately 78 nm. The nanomicelles could encapsulate doxorubicin (DOX) through hydrophobic and π-π stacking interactions between DOX molecules and Phe blocks and simultaneously complex P-gp siRNA with cationic PLL blocks via electrostatic interactions. The DOX/P-gp siRNA-loaded nanomicelles showed spherical morphology, possessed narrow particle size distribution and had a mean particle size of 120 nm. The DOX/P-gp siRNA-loaded nanomicelles exhibited pH-responsive release behaviors and displayed accelerated release under acidic conditions. The DOX/P-gp siRNA-loaded nanomicelles were efficiently internalized into MCF-7 cells, and DOX released could successfully reach nuclei. In vitro cytotoxicity assay demonstrated that the DOX/P-gp siRNA-loaded nanomicelles showed a much higher cytotoxicity in MCF-7 cells than DOX-loaded nanomicelles due to their synergistic killing effect and that the blank nanomicelles had good biocompatibility. Thus, the novel comb-like mPEG-g-PLL-b-Phe nanomicelles could be a promising vehicle for co-delivery of chemotherapeutic drug and genetic material. PMID:26952460

  4. Exploring GpG bases next to anticodon in tRNA subsets.

    PubMed

    Srinivasan, Thangavelu; Kumaran, Kubendiran; Selvakumar, Rajendran; Velmurugan, Devadasan; Sudarsanam, Dorairaj

    2013-01-01

    Transfer RNA (tRNA) structure, modifications and functions are evolutionary and established in bacteria, archaea and eukaryotes. Typically the tRNA modifications are indispensable for its stability and are required for decoding the mRNA into amino acids for protein synthesis. A conserved methylation has been located on the anticodon loop specifically at the 37(th) position and it is next to the anticodon bases. This modification is called as m1G37 and it is catalyzed by tRNA (m(1)G37) methyltransferase (TrmD). It is deciphered that G37 positions occur on few additional amino acids specific tRNA subsets in bacteria. Furthermore, Archaea and Eukaryotes have more number of tRNA subsets which contains G37 position next to the anticodon and the G residue are located at different positions such as G36, G37, G38, 39, and G40. In eight bacterial species, G (guanosine) residues are presents at the 37(th) and 38(th) position except three tRNA subsets having G residues at 36(th) and 39(th) positions. Therefore we propose that m1G37 modification may be feasible at 36(th), 37(th), 38(th), 39(th) and 40(th) positions next to the anticodon of tRNAs. Collectively, methylation at G residues close to the anticodon may be possible at different positions and without restriction of anticodon 3(rd) base A, C, U or G. PMID:23847401

  5. Paracoccidioides brasiliensis Vaccine Formulations Based on the gp43-Derived P10 Sequence and the Salmonella enterica FliC Flagellin▿

    PubMed Central

    Braga, Catarina J. M.; Rittner, Glauce M. G.; Muñoz Henao, Julian E.; Teixeira, Aline F.; Massis, Liliana M.; Sbrogio-Almeida, Maria E.; Taborda, Carlos P.; Travassos, Luiz R.; Ferreira, Luís C. S.

    2009-01-01

    Paracoccidioidomycosis (PCM) is a systemic granulomatous disease caused by the dimorphic fungus Paracoccidioides brasiliensis. Anti-PCM vaccine formulations based on the secreted fungal cell wall protein (gp43) or the derived P10 sequence containing a CD4+ T-cell-specific epitope have shown promising results. In the present study, we evaluated new anti-PCM vaccine formulations based on the intranasal administration of P. brasiliensis gp43 or the P10 peptide in combination with the Salmonella enterica FliC flagellin, an innate immunity agonist binding specifically to the Toll-like receptor 5, in a murine model. BALB/c mice immunized with gp43 developed high-specific-serum immunoglobulin G1 responses and enhanced interleukin-4 (IL-4) and IL-10 levels. On the other hand, mice immunized with recombinant purified flagellins genetically fused with P10 at the central hypervariable domain, either flanked or not by two lysine residues, or the synthetic P10 peptide admixed with purified FliC elicited a prevailing Th1-type immune response based on lung cell-secreted type 1 cytokines. Mice immunized with gp43 and FliC and intratracheally challenged with P. brasiliensis yeast cells had increased fungal proliferation and lung tissue damage. In contrast, mice immunized with the chimeric flagellins and particularly those immunized with P10 admixed with FliC reduced P. brasiliensis growth and lung damage. Altogether, these results indicate that S. enterica FliC flagellin modulates the immune response to P. brasiliensis P10 antigen and represents a promising alternative for the generation of anti-PCM vaccines. PMID:19204092

  6. Broadly Neutralizing Antibody PGT121 Allosterically Modulates CD4 Binding via Recognition of the HIV-1 gp120 V3 Base and Multiple Surrounding Glycans

    PubMed Central

    Julien, Jean-Philippe; Sok, Devin; Khayat, Reza; Lee, Jeong Hyun; Doores, Katie J.; Walker, Laura M.; Ramos, Alejandra; Diwanji, Devan C.; Pejchal, Robert; Cupo, Albert; Katpally, Umesh; Depetris, Rafael S.; Stanfield, Robyn L.; McBride, Ryan; Marozsan, Andre J.; Paulson, James C.; Sanders, Rogier W.; Moore, John P.; Burton, Dennis R.; Poignard, Pascal; Ward, Andrew B.; Wilson, Ian A.

    2013-01-01

    New broad and potent neutralizing HIV-1 antibodies have recently been described that are largely dependent on the gp120 N332 glycan for Env recognition. Members of the PGT121 family of antibodies, isolated from an African donor, neutralize ∼70% of circulating isolates with a median IC50 less than 0.05 µg ml−1. Here, we show that three family members, PGT121, PGT122 and PGT123, have very similar crystal structures. A long 24-residue HCDR3 divides the antibody binding site into two functional surfaces, consisting of an open face, formed by the heavy chain CDRs, and an elongated face, formed by LCDR1, LCDR3 and the tip of the HCDR3. Alanine scanning mutagenesis of the antibody paratope reveals a crucial role in neutralization for residues on the elongated face, whereas the open face, which accommodates a complex biantennary glycan in the PGT121 structure, appears to play a more secondary role. Negative-stain EM reconstructions of an engineered recombinant Env gp140 trimer (SOSIP.664) reveal that PGT122 interacts with the gp120 outer domain at a more vertical angle with respect to the top surface of the spike than the previously characterized antibody PGT128, which is also dependent on the N332 glycan. We then used ITC and FACS to demonstrate that the PGT121 antibodies inhibit CD4 binding to gp120 despite the epitope being distal from the CD4 binding site. Together, these structural, functional and biophysical results suggest that the PGT121 antibodies may interfere with Env receptor engagement by an allosteric mechanism in which key structural elements, such as the V3 base, the N332 oligomannose glycan and surrounding glycans, including a putative V1/V2 complex biantennary glycan, are conformationally constrained. PMID:23658524

  7. Broadly neutralizing antibody PGT121 allosterically modulates CD4 binding via recognition of the HIV-1 gp120 V3 base and multiple surrounding glycans.

    PubMed

    Julien, Jean-Philippe; Sok, Devin; Khayat, Reza; Lee, Jeong Hyun; Doores, Katie J; Walker, Laura M; Ramos, Alejandra; Diwanji, Devan C; Pejchal, Robert; Cupo, Albert; Katpally, Umesh; Depetris, Rafael S; Stanfield, Robyn L; McBride, Ryan; Marozsan, Andre J; Paulson, James C; Sanders, Rogier W; Moore, John P; Burton, Dennis R; Poignard, Pascal; Ward, Andrew B; Wilson, Ian A

    2013-01-01

    New broad and potent neutralizing HIV-1 antibodies have recently been described that are largely dependent on the gp120 N332 glycan for Env recognition. Members of the PGT121 family of antibodies, isolated from an African donor, neutralize ∼70% of circulating isolates with a median IC50 less than 0.05 µg ml(-1). Here, we show that three family members, PGT121, PGT122 and PGT123, have very similar crystal structures. A long 24-residue HCDR3 divides the antibody binding site into two functional surfaces, consisting of an open face, formed by the heavy chain CDRs, and an elongated face, formed by LCDR1, LCDR3 and the tip of the HCDR3. Alanine scanning mutagenesis of the antibody paratope reveals a crucial role in neutralization for residues on the elongated face, whereas the open face, which accommodates a complex biantennary glycan in the PGT121 structure, appears to play a more secondary role. Negative-stain EM reconstructions of an engineered recombinant Env gp140 trimer (SOSIP.664) reveal that PGT122 interacts with the gp120 outer domain at a more vertical angle with respect to the top surface of the spike than the previously characterized antibody PGT128, which is also dependent on the N332 glycan. We then used ITC and FACS to demonstrate that the PGT121 antibodies inhibit CD4 binding to gp120 despite the epitope being distal from the CD4 binding site. Together, these structural, functional and biophysical results suggest that the PGT121 antibodies may interfere with Env receptor engagement by an allosteric mechanism in which key structural elements, such as the V3 base, the N332 oligomannose glycan and surrounding glycans, including a putative V1/V2 complex biantennary glycan, are conformationally constrained. PMID:23658524

  8. Simulation Studies of Beam-Beam Effects of a Ring-Ring Electron-Ion Collider Based on CEBAF

    SciTech Connect

    Yuhong Zhang,Ji Qiang

    2009-05-01

    The collective beam-beam effect can potentially cause a rapid growth of beam sizes and reduce the luminosity of a collider to an unacceptably low level. The ELIC, a proposed ultra high luminosity electron-ion collider based on CEBAF, employs high repetition rate crab crossing colliding beams with very small bunch transverse sizes and very short bunch lengths, and collides them at up to 4 interaction points with strong final focusing. All of these features can make the beam-beam effect challenging. In this paper, we present simulation studies of the beam-beam effect in ELIC using a self-consistent strong-strong beam-beam simulation code developed at Lawrence Berkeley National Laboratory. This simulation study is used for validating the ELIC design and for searching for an optimal parameter set.

  9. Half-day release in vocational GP training: a case study of redesign based on qualitative evaluation.

    PubMed

    Rigby, Carolyn

    2010-11-01

    Mindful of the changes to general practice (GP) and GP training over recent years, one vocational training scheme (VTS) decided to thoroughly evaluate its long-running half-day release scheme to decide if it remained fit for purpose, and to plan and implement changes in the light of findings. A literature review was first carried out to ascertain what is known about the contribution that day release and half-day release (HDR) programmes make to GP training. Little has been published on content or evaluation but there is varied experience of incorporating release training into hospital training. This case study reports the views of trainers and trainees on the HDR at Tees Valley Vocational Training Scheme, and the resultant changes made to this HDR programme by the participants. Trainers mostly valued their commitment to HDR small group teaching for their personal development as teachers and for the opportunity to 'keep in touch' with trainees during their hospital posts. Trainees were positive about the HDR programme, but requested more continuity. The plan that evolved is to continue weekly HDR throughout the training programme, keeping trainees in the same small group for three years. In ST1 and ST3 years one programme director per group facilitates each session, maintaining consistency over the year, and liaising with specialists around content. Trainers each teach two sessions in ST2 year. Elective sessions are planned for extended training. PMID:21144173

  10. Exotic colliders

    SciTech Connect

    Chattopadhyay, S.

    1994-11-01

    The motivation, feasibility and potential for two unconventional collider concepts - the Gamma-Gamma Collider and the Muon Collider - are described. The importance of the development of associated technologies such as high average power, high repetition rate lasers and ultrafast phase-space techniques are outlined.

  11. Photon Colliders

    SciTech Connect

    Gronberg, J

    2002-10-07

    A photon collider interaction region has the possibility of expanding the physics reach of a future TeV scale electron-positron collider. A survey of ongoing efforts to design the required lasers and optics to create a photon collider is presented in this paper.

  12. Clinical Evaluation of a GP5+/6+-Based Luminex Assay Having Full High-Risk Human Papillomavirus Genotyping Capability and an Internal Control

    PubMed Central

    Cuschieri, K.; de Koning, M. N. C.; van Doorn, L. J.; Snijders, P. J. F.; Meijer, C. J. L. M.; Quint, W. G. V.; Arbyn, M.

    2014-01-01

    The LMNX genotyping kit HPV GP (LMNX) is based on the clinically validated GP5+/6+ PCR, with a genotyping readout as an alternative for the more established enzyme immunoassay (EIA) detection of 14 targeted high-risk human papillomavirus (HPV) types. LMNX is additionally provided with an internal control probe. Here, we present an analysis of the clinical performance of the LMNX using a sample panel and infrastructure provided by the international VALGENT (Validation of Genotyping Tests) project. This panel consisted of cervical specimens from approximately 1,000 women attending routine screening, “enriched” with 300 women with abnormal cytology. Cases were defined as women classified with cervical intraepithelial neoplasia (CIN) grade 2+ (CIN2+) (n = 102) or CIN3+ (n = 55) within the previous 18 months. Controls were women who had normal cytology results over two subsequent screening rounds at a 3-year interval (n = 746). The GP5+/6+-PCR EIA (EIA) was used as a comparator assay and showed sensitivities of 94.1% and 98.2% for CIN2+ and CIN3+, respectively, with a clinical specificity of 92.4% among women aged ≥30 years. The LMNX demonstrated clinical sensitivities of 96.1% for CIN2+ and of 98.2% for CIN3+ and a clinical specificity of 92.6% for women aged ≥30 years. The LMNX and EIA were in high agreement (Cohen's kappa = 0.969) for the detection of 14 hrHPVs in aggregate, and no significant difference was observed (McNemar's P = 0.629). The LMNX internal control detected 0.6% inadequate specimens. Based on our study results, we consider the LMNX, similarly to the EIA, useful for HPV-based cervical cancer screening. PMID:25210073

  13. Conceptual design of International Linear Collider damping ring wiggler based on a hybrid technology.

    PubMed

    Smirnov, Alexei V

    2009-01-01

    A magnetic design of a failure-free damping ring wiggler with 100% duty factor, 55.6 mm gap, and field exceeding 1.6 T is proposed. The insertion device is based on permanent magnets and specially shimmed poles that capable to meet the requirements of the International Linear Collider (ILC) damping rings (including positron one), with field quality and gap comparable to that projected for ILC using superconducting wiggler. Performance improvement of the modified hybrid design is attained due to yoke reduction down to six separated strips and maximized packaging of the midgrade (or high-grade) parallelepiped magnet blocks surrounding the Permendur poles. Economical efficiency is demonstrated on the base of calculated amount of magnetic material. A cryogenic variant of the hybrid design may certainly provide good sustainability to harsh radiation environment and further enhancement of the design efficiency within the state of the art. PMID:19191428

  14. Conceptual design of International Linear Collider damping ring wiggler based on a hybrid technology

    NASA Astrophysics Data System (ADS)

    Smirnov, Alexei V.

    2009-01-01

    A magnetic design of a failure-free damping ring wiggler with 100% duty factor, 55.6 mm gap, and field exceeding 1.6 T is proposed. The insertion device is based on permanent magnets and specially shimmed poles that capable to meet the requirements of the International Linear Collider (ILC) damping rings (including positron one), with field quality and gap comparable to that projected for ILC using superconducting wiggler. Performance improvement of the modified hybrid design is attained due to yoke reduction down to six separated strips and maximized packaging of the midgrade (or high-grade) parallelepiped magnet blocks surrounding the Permendur poles. Economical efficiency is demonstrated on the base of calculated amount of magnetic material. A cryogenic variant of the hybrid design may certainly provide good sustainability to harsh radiation environment and further enhancement of the design efficiency within the state of the art.

  15. Conceptual design of International Linear Collider damping ring wiggler based on a hybrid technology

    SciTech Connect

    Smirnov, Alexei V.

    2009-01-15

    A magnetic design of a failure-free damping ring wiggler with 100% duty factor, 55.6 mm gap, and field exceeding 1.6 T is proposed. The insertion device is based on permanent magnets and specially shimmed poles that capable to meet the requirements of the International Linear Collider (ILC) damping rings (including positron one), with field quality and gap comparable to that projected for ILC using superconducting wiggler. Performance improvement of the modified hybrid design is attained due to yoke reduction down to six separated strips and maximized packaging of the midgrade (or high-grade) parallelepiped magnet blocks surrounding the Permendur poles. Economical efficiency is demonstrated on the base of calculated amount of magnetic material. A cryogenic variant of the hybrid design may certainly provide good sustainability to harsh radiation environment and further enhancement of the design efficiency within the state of the art.

  16. Positron source investigation by using CLIC drive beam for Linac-LHC based e+p collider

    NASA Astrophysics Data System (ADS)

    Arιkan, Ertan; Aksakal, Hüsnü

    2012-08-01

    Three different methods which are alternately conventional, Compton backscattering and Undulator based methods employed for the production of positrons. The positrons to be used for e+p collisions in a Linac-LHC (Large Hadron Collider) based collider have been studied. The number of produced positrons as a function of drive beam energy and optimum target thickness has been determined. Three different targets have been used as a source investigation which are W75-Ir25, W75-Ta25, and W75-Re25 for three methods. Estimated number of the positrons has been performed with FLUKA simulation code. Then, these produced positrons are used for following Adiabatic matching device (AMD) and capture efficiency is determined. Then e+p collider luminosity corresponding to the methods mentioned above have been calculated by CAIN code.

  17. Results from a Prototype Chicane-Based Energy Spectrometer for a Linear Collider

    SciTech Connect

    Lyapin, A.; Schreiber, H.J.; Viti, M.; Adolphsen, C.; Arnold, R.; Boogert, S.; Boorman, G.; Chistiakova, M.V.; Gournaris, F.; Duginov, V.; Hast, C.; Hildreth, M.; Hlaing, C.; Jackson, F.; Khainovsky, O.; Kolomensky, Yu.G.; Kostromin, S.; Kumar, K.; Maiheu, B.; McCormick, D.; Miller, D.J.; /University Coll. London /Dubna, JINR /UC, Berkeley /LBL, Berkeley /Caltech /UC, Berkeley /LBL, Berkeley /Cambridge U. /SLAC /Cambridge U. /Fermilab /University Coll. London /SLAC

    2011-02-28

    The International Linear Collider (ILC) and other proposed high energy e{sup +}e{sup -} machines aim to measure with unprecedented precision Standard Model quantities and new, not yet discovered phenomena. One of the main requirements for achieving this goal is a measurement of the incident beam energy with an uncertainty close to 10{sup -4}. This article presents the analysis of data from a prototype energy spectrometer commissioned in 2006-2007 in SLAC's End Station A beamline. The prototype was a 4-magnet chicane equipped with beam position monitors measuring small changes of the beam orbit through the chicane at different beam energies. A single bunch energy resolution close to 5 {center_dot} 10{sup -4} was measured, which is satisfactory for most scenarios. We also report on the operational experience with the chicane-based spectrometer and suggest ways of improving its performance.

  18. An FEL design for gamma-gamma colliders based on chirped pulse amplification techniques

    SciTech Connect

    Kim, K.J.; Xie, M.; Sessler, A.M.

    1995-12-31

    A next generation e{sup +}-e{sup -} linear collider in the TeV range can be converted into a {gamma}-{gamma} collider by converting it to e{sup -}-e{sup -} operation and then generating {gamma}-rays via Compton backscattering with optical beams. This provides unique access to some areas of fundamental physics as well as highly desirable redundancy to the collisions. The required optical beam (with a wavelength of about 1 micron) must have very high peak power, (about 1 TW) as well as average power (about 10 kW). To achieve a 1 : 1 conversion from an electron to {gamma}-quantum, each micropulse must contain about one Joule and must be about one picosecond long, the micropulse peak power being about one Terawatt. To match the electron beam pulse structure, a macropulse consists of a sequence of about one hundred micropulses separated by about one nanosecond, and the macropulses am repeated at a rate of about 100 Hz. Thus, the time average power is about 10 kW propose and analyze a promising scheme to produce the required optical beam based on the chirped pulse amplification technique. In this scheme, a low power optical beam of the same time structure required for the {gamma}-{gamma} collider is passed through a grating pair to stretch and chirp the picosecond micropulses to about one nanosecond, so that each macropulse will be an almost continuous, 100 nanosecond long pulse, but with chirps (from red to blue) within each nanosecond. The optical beam is then amplified in an FEL, driven by an intense electron beam from an induction linac. The amplified beam is then passed through another grating pair to compress the micropulses, thus recovering the original time structure, but containing about one Joule per micropulse. The requirements for electron beams, about 100 MeV energy, 1 kA current, 50 mm-mrad rms emittance, 10{sup -3} energy spread, are consistent with the state-of-the-art induction linac technology.

  19. Bylaws for GP Section

    NASA Astrophysics Data System (ADS)

    Individual sections of AGU are governed by collections of bylaws adopted by each membership. The GP Section, at the present time, has no bylaws. Such a document would include articles defining the name, objectives, and membership of the section. Also present would be a description of officers (president, president-elect, and secretary), their duties, nomination and election procedures, and information on committees, meetings, and publications. The GP Section now functions by following some standard, although unwritten, procedures. The usual bylaws used by AGU sections would not change any of the functions or procedures used by our section but would put in writing the structure that we follow. It is possible, in the membership clause, to allow members to be affiliated with more than one section and to no longer claim only a “primary” section. The GP Executive Committee intends to discuss the possibility of adopting our own bylaws at the spring business meeting. We would appreciate any input from GP membership on this topic prior to May. Please direct your comments to Laurie Brown or Subir Banerjee (addresses above).

  20. Muon colliders

    SciTech Connect

    Palmer, R.B. |; Sessler, A.; Skrinsky, A.

    1996-01-01

    Muon Colliders have unique technical and physics advantages and disadvantages when compared with both hadron and electron machines. They should thus be regarded as complementary. Parameters are given of 4 TeV and 0.5 TeV high luminosity {micro}{sup +}{micro}{sup {minus}}colliders, and of a 0.5 TeV lower luminosity demonstration machine. We discuss the various systems in such muon colliders, starting from the proton accelerator needed to generate the muons and proceeding through muon cooling, acceleration and storage in a collider ring. Problems of detector background are also discussed.

  1. The Photon Collider at Tesla

    NASA Astrophysics Data System (ADS)

    Badelek, B.; Blöchinger, C.; Blümlein, J.; Boos, E.; Brinkmann, R.; Burkhardt, H.; Bussey, P.; Carimalo, C.; Chyla, J.; Çiftçi, A. K.; Decking, W.; de Roeck, A.; Fadin, V.; Ferrario, M.; Finch, A.; Fraas, H.; Franke, F.; Galynskii, M.; Gamp, A.; Ginzburg, I.; Godbole, R.; Gorbunov, D. S.; Gounaris, G.; Hagiwara, K.; Han, L.; Heuer, R.-D.; Heusch, C.; Illana, J.; Ilyin, V.; Jankowski, P.; Jiang, Y.; Jikia, G.; Jönsson, L.; Kalachnikow, M.; Kapusta, F.; Klanner, R.; Klassen, M.; Kobayashi, K.; Kon, T.; Kotkin, G.; Krämer, M.; Krawczyk, M.; Kuang, Y. P.; Kuraev, E.; Kwiecinski, J.; Leenen, M.; Levchuk, M.; Ma, W. F.; Martyn, H.; Mayer, T.; Melles, M.; Miller, D. J.; Mtingwa, S.; Mühlleitner, M.; Muryn, B.; Nickles, P. V.; Orava, R.; Pancheri, G.; Penin, A.; Potylitsyn, A.; Poulose, P.; Quast, T.; Raimondi, P.; Redlin, H.; Richard, F.; Rindani, S. D.; Rizzo, T.; Saldin, E.; Sandner, W.; Schönnagel, H.; Schneidmiller, E.; Schreiber, H. J.; Schreiber, S.; Schüler, K. P.; Serbo, V.; Seryi, A.; Shanidze, R.; da Silva, W.; Söldner-Rembold, S.; Spira, M.; Stasto, A. M.; Sultansoy, S.; Takahashi, T.; Telnov, V.; Tkabladze, A.; Trines, D.; Undrus, A.; Wagner, A.; Walker, N.; Watanabe, I.; Wengler, T.; Will, I.; Wipf, S.; Yavaş, Ö.; Yokoya, K.; Yurkov, M.; Zarnecki, A. F.; Zerwas, P.; Zomer, F.

    High energy photon colliders (γγ,γe) are based on e-e- linear colliders where high energy photons are produced using Compton scattering of laser light on high energy electrons just before the interaction point. This paper is a part of the Technical Design Report of the linear collider TESLA.1 Physics program, possible parameters and some technical aspects of the photon collider at TESLA are discussed.

  2. Novel peptide inhibitors of Leishmania gp63 based on the cleavage site of MARCKS (myristoylated alanine-rich C kinase substrate)-related protein.

    PubMed Central

    Corradin, Sally; Ransijn, Adriana; Corradin, Giampietro; Bouvier, Jacques; Delgado, Maria Belen; Fernandez-Carneado, Jimena; Mottram, Jeremy C; Vergères, Guy; Mauël, Jacques

    2002-01-01

    The zinc metalloprotease gp63 (leishmanolysin; promastigote surface protease) is expressed at high density at the surface of Leishmania promastigotes. Efficient non-toxic inhibitors of gp63 do not exist, and its precise role in parasite physiology remains unknown. MARCKS (myristoylated alanine-rich C kinase substrate) and MARCKS-related protein (MRP; MacMARCKS) are protein kinase C substrates in various cells, including macrophages. We reported previously that MRP is an excellent substrate for gp63. A major cleavage site was identified within the MRP effector domain (ED), a highly basic 24-amino-acid sequence, and the synthetic ED peptide (MRP(ED)) was shown to inhibit MRP hydrolysis. In the present study, MRP cleavage was used as an assay to measure the capacity of various MRP or MARCKS ED peptides to block gp63 activity. On a molar basis, MRP(ED) inhibited gp63 to a greater extent than two previously described gp63 inhibitors, o -phenanthroline and benzyloxycarbonyl-Tyr-Leu-NHOH. MARCKS(ED) analogues containing modifications in the gp63 consensus cleavage site showed significant differences in inhibitory capacity. As phosphorylation of ED serine residues prevented gp63-mediated MRP degradation, we synthesized a pseudophosphorylated peptide in which serine residues were substituted by aspartate (3DMRP(ED)). 3DMRP(ED) was a highly effective inhibitor of both soluble and parasite-associated gp63. Finally, MRP ED peptides were synthesized together with an N-terminal HIV-1 Tat transduction domain (TD) to obtain cell-permeant peptide constructs. Such peptides retained gp63 inhibitory activity and efficiently entered both macrophages and parasites in a Tat TD-dependent manner. These studies may provide the basis for developing potent cell-permeant inhibitors of gp63. PMID:12137567

  3. Integrated musculoskeletal service design by GP consortia

    PubMed Central

    2011-01-01

    Background Musculoskeletal conditions are common in primary care and are associated with significant co-morbidity and impairment of quality of life. Traditional care pathways combined community-based physiotherapy with GP referral to hospital for a consultant opinion. Locally, this model led to only 30% of hospital consultant orthopaedic referrals being listed for surgery, with the majority being referred for physiotherapy. The NHS musculoskeletal framework proposed the use of interface services to provide expertise in diagnosis, triage and management of musculoskeletal problems not requiring surgery. The White Paper Equity and Excellence: Liberating the NHS has replaced PCT commissioning with GP consortia, who will lead future service development. Setting Primary and community care, integrated with secondary care, in the NHS in England. Question How can GP consortia lead the development of integrated musculoskeletal services? Review: The Ealing experience We explore here how Ealing implemented a ‘See and Treat’ interface clinic model to improve surgical conversion rates, reduce unnecessary hospital referrals and provide community treatment more efficiently than a triage model. A high-profile GP education programme enabled GPs to triage in their practices and manage patients without referral. Conclusion In Ealing, we demonstrated that most patients with musculoskeletal conditions can be managed in primary care and community settings. The integrated musculoskeletal service provides clear and fast routes to secondary care. This is both clinically effective and cost-effective, reserving hospital referral for patients most likely to need surgery. GP consortia, in conjunction with strong clinical leadership, inbuilt organisational and professional learning, and a GP champion, are well placed to deliver service redesign by co-ordinating primary care development, local commissioning of community services and the acute commissioning vehicles responsible for secondary

  4. HIGGS PHYSICS WITH A GAMMA GAMMA COLLIDER BASED ON CLIC 1*.

    SciTech Connect

    ASNER,D.; BURKHARDT,H.; DE ROECK,A.; ELLIS,J.; GRONBERG,J.; HEINEMEYER,S.; SCHMITT,M.; SCHULTE,D.; VELASCO,M.; ZIMMERMAN,F.

    2001-11-01

    We present the machine parameters and physics capabilities of the CLIC Higgs Experiment (CLICHE), a low-energy {gamma}{gamma} collider based on CLIC 1, the demonstration project for the higher-energy two-beam accelerator CLIC. CLICHE is conceived as a factory capable of producing around 20,000 light Higgs bosons per year. We discuss the requirements for the CLIC 1 beams and a laser backscattering system capable of producing a {gamma}{gamma} total (peak) luminosity of 2.0 (0.36) x 10{sup 34} cm{sup -2} s{sup -1} with E{sub CM}({gamma}{gamma}) 115 GeV. We show how CLICHE could be used to measure accurately the mass, {bar b}b, WW and {gamma}{gamma} decays of a light Higgs boson. We illustrate how these measurements may distinguish between the Standard Model Higgs boson and those in supersymmetric and more general two-Higgs-doublet models, complementing the measurements to be made with other accelerators. We also comment on other prospects in {gamma}{gamma} and e{sup -}{gamma} physics with CLICHE.

  5. Nonuniversal scalar masses: A signal-based analysis for the CERN Large Hadron Collider

    SciTech Connect

    Bhattacharya, Subhaditya; Datta, AseshKrishna; Mukhopadhyaya, Biswarup

    2008-08-01

    We study the possible signatures of nonuniversal scalar masses in supersymmetry at the Large Hadron Collider (LHC). This is done, following our recent study on gaugino nonuniversality, via a multichannel analysis, based largely on the ratios of event rates for different final states, aimed at minimizing irregularity in the pattern due to extraneous effects and errors. We have studied (a) squark-slepton nonuniversality, (b) nonuniversality in sfermion masses of the third family, (c) the effects of SO(10) D-terms in supersymmetric grand unified theories. After presenting an elaborate numerical analysis of like- and opposite-sign dileptons, inclusive and hadronically quiet trileptons, as well as inclusive jet final states, we point out specific features of the spectrum in each case, which can be differentiated in the above channels from the spectrum for a minimal supergravity scenario with a universal scalar mass at high scale. The event selection criteria and the situations where the signals are sizable enough for a comparative study, are also delineated. It is found that, with some exceptions, the trilepton channels are likely to be especially useful for this purpose.

  6. FEL-based coherent electron cooling for high-energy hadron colliders

    SciTech Connect

    Litvinenko,V.N.; Derbenev, Y.S.

    2008-06-23

    Cooling intense high-energy hadron beams is a major challenge in modern accelerator physics. Synchrotron radiation is too feeble and two common methods--stochastic and electron cooling--are not efficient in providing significant cooling for high energy, high intensity proton colliders. In this paper they discuss a practical scheme of Coherent Electron Cooling (CeC), which promises short cooling times (below one hour) for intense proton beams in RHIC at 250 GeV or in LHC at 7 TeV. A possibility of CeC using various microwave instabilities was discussed since 1980s. In this paper, they present first evaluation of specific CeC scheme based on capabilities of present-day accelerator technology, ERLs, and high-gain Free-Electron lasers (FELs). They discuss the principles, the main limitations of this scheme and present some predictions for Coherent Electron Cooling in RHIC and the LHC operating with ions or protons, summarized in Table 1.

  7. Proposing a Laser Based Beam Size Monitor for the Future Linear Collider

    SciTech Connect

    Ross, Marc C

    2001-12-10

    Compton scattering techniques for the measurement of the transverse beam size of particle beams at future linear colliders (FLC) are proposed. At several locations of the beam delivery system (BDS) of the FLC, beam spot sizes ranging from several hundreds to a few micrometers have to be measured. This is necessary to verify beam optics, to obtain the transverse beam emittance, and to achieve the highest possible luminosity. The large demagnification of the beam in the BDS and the high beam power puts extreme conditions on any measuring device. With conventional techniques at their operational limit in FLC scenarios, new methods for the detection of the transverse beam size have to be developed. For this laser based techniques are proposed capable of measuring high power beams with sizes in the micrometer range. In this paper general aspects and critical issues of a generic device are outlined and specific solutions proposed. Plans to install a laser wire experiment at an accelerator test facility are presented.

  8. Ion colliders

    SciTech Connect

    Fischer, W.

    2011-12-01

    Ion colliders are research tools for high-energy nuclear physics, and are used to test the theory of Quantum Chromo Dynamics (QCD). The collisions of fully stripped high-energy ions create matter of a temperature and density that existed only microseconds after the Big Bang. Ion colliders can reach higher densities and temperatures than fixed target experiments although at a much lower luminosity. The first ion collider was the CERN Intersecting Storage Ring (ISR), which collided light ions [77Asb1, 81Bou1]. The BNL Relativistic Heavy Ion Collider (RHIC) is in operation since 2000 and has collided a number of species at numerous energies. The CERN Large Hadron Collider (LHC) started the heavy ion program in 2010. Table 1 shows all previous and the currently planned running modes for ISR, RHIC, and LHC. All three machines also collide protons, which are spin-polarized in RHIC. Ion colliders differ from proton or antiproton colliders in a number of ways: the preparation of the ions in the source and the pre-injector chain is limited by other effects than for protons; frequent changes in the collision energy and particle species, including asymmetric species, are typical; and the interaction of ions with each other and accelerator components is different from protons, which has implications for collision products, collimation, the beam dump, and intercepting instrumentation devices such a profile monitors. In the preparation for the collider use the charge state Z of the ions is successively increased to minimize the effects of space charge, intrabeam scattering (IBS), charge change effects (electron capture and stripping), and ion-impact desorption after beam loss. Low charge states reduce space charge, intrabeam scattering, and electron capture effects. High charge states reduce electron stripping, and make bending and acceleration more effective. Electron stripping at higher energies is generally more efficient. Table 2 shows the charge states and energies in the

  9. Photon collider at TESLA

    NASA Astrophysics Data System (ADS)

    Telnov, Valery

    2001-10-01

    High energy photon colliders ( γγ, γe) based on backward Compton scattering of laser light is a very natural addition to e +e - linear colliders. In this report, we consider this option for the TESLA project. Recent study has shown that the horizontal emittance in the TESLA damping ring can be further decreased by a factor of four. In this case, the γγ luminosity in the high energy part of spectrum can reach about (1/3) Le +e -. Typical cross-sections of interesting processes in γγ collisions are higher than those in e +e - collisions by about one order of magnitude, so the number of events in γγ collisions will be more than that in e +e - collisions. Photon colliders can, certainly, give additional information and they are the best for the study of many phenomena. The main question is now the technical feasibility. The key new element in photon colliders is a very powerful laser system. An external optical cavity is a promising approach for the TESLA project. A free electron laser is another option. However, a more straightforward solution is "an optical storage ring (optical trap)" with a diode pumped solid state laser injector which is today technically feasible. This paper briefly reviews the status of a photon collider based on the linear collider TESLA, its possible parameters and existing problems.

  10. Muon Collider

    SciTech Connect

    Palmer, R.

    2009-10-19

    Parameters are given of muon colliders with center of mass energies of 1.5 and 3 TeV. Pion production is from protons on a mercury target. Capture, decay, and phase rotation yields bunch trains of both muon signs. Six dimensional cooling reduces the emittances until the trains are merged into single bunches, one of each sign. Further cooling in 6 dimensions is then applied, followed by final transverse cooling in 50 T solenoids. After acceleration the muons enter the collider ring. Ongoing R&D is discussed.

  11. Final Report for the UNIVERSITY-BASED DETECTOR RESEARCH AND DEVELOPMENT FOR THE INTERNATIONAL LINEAR COLLIDER

    SciTech Connect

    Brau, James E

    2013-04-22

    The U.S Linear Collider Detector R&D program, supported by the DOE and NSF umbrella grants to the University of Oregon, made significant advances on many critical aspects of the ILC detector program. Progress advanced on vertex detector sensor development, silicon and TPC tracking, calorimetry on candidate technologies, and muon detection, as well as on beamline measurements of luminosity, energy, and polarization.

  12. Muon collider design

    SciTech Connect

    Palmer, R. |; Sessler, A.; Skrinsky, A.

    1996-03-01

    The possibility of muon colliders was introduced by Skrinsky et al., Neuffer, and others. More recently, several workshops and collaboration meetings have greatly increased the level of discussion. In this paper we present scenarios for 4 TeV and 0.5 TeV colliders based on an optimally designed proton source, and for a lower luminosity 0.5 TeV demonstration based on an upgraded version of the AGS. It is assumed that a demonstration version based on upgrades of the FERMILAB machines would also be possible. 53 refs., 25 figs., 8 tabs.

  13. Linear collider development at SLAC

    SciTech Connect

    Irwin, J.

    1993-08-01

    Linear collider R&D at SLAC comprises work on the present Stanford Linear Collider (SLC) and work toward the next linear collider (NLC). Recent SLC developments are summarized. NLC studies are divided into hardware-based and theoretical. We report on the status of the NLC Test Accelerator (NLCTA) and the final focus test beam (FFTB), describe plans for ASSET, an installation to measure accelerator structure wakefields, and mention IR design developments. Finally we review recent NLC theoretical studies, ending with the author`s view of next linear collider parameter sets.

  14. Beam-based alignment technique for the SLC (Stanford Linear Collider) linac

    SciTech Connect

    Adolphsen, C.E.; Lavine, T.L.; Atwood, W.B.; Himel, T.M.; Lee, M.J.; Mattison, T.S.; Pitthan, R.; Seeman, J.T.; Williams, S.H.; Trilling, G.H.

    1989-03-01

    Misalignment of quadrupole magnets and beam position monitors (BPMs) in the linac of the SLAC Linear Collider (SLC) cause the electron and positron beams to be steered off-center in the disk-loaded waveguide accelerator structures. Off-center beams produce wakefields which limit the SLC performance at high beam intensities by causing emittance growth. Here, we present a general method for simultaneously determining quadrupole magnet and BPM offsets using beam trajectory measurements. Results from the application of the method to the SLC linac are described. The alignment precision achieved is approximately 100 ..mu..m, which is significantly better than that obtained using optical surveying techniques. 2 refs., 4 figs.

  15. Preservation of Ultra Low Emittances Using Adiabatic Matching in Future Plasma Wakefield-based Colliders

    SciTech Connect

    Gholizadeh, Reza; Muggli, Patric; Katsouleas, Tom; Mori, Warren

    2009-01-22

    The Plasma Wakefield Accelerator is a promising technique to lower the cost of the future high energy colliders by offering orders of magnitude higher gradients than the conventional accelerators. It has been shown that ion motion is an important issue to account for in the extreme regime of ultra high energies and ultra low emittances, characteristics of future high energy collider beams. In this regime, the transverse electric field of the beam is so high that in simulations, the plasma ions cannot be considered immobile at the time scale of electron plasma oscillation, thereby leading to a nonlinear focusing force. Therefore, the transverse emittance of a beam will not be preserved under these circumstances. However, we show that matched profile in case of a nonlinear focusing force still exists and can be derived from Vlasov equation. Furthermore, we introduce a plasma section that can reduce the emittance growth by adiabatically reducing the ion mass and hence increasing the nonlinear term in the focusing force. Simulation results are presented.

  16. Discovery of novel anti-HIV-1 agents based on a broadly neutralizing antibody against the envelope gp120 V3 loop: a computational study.

    PubMed

    Andrianov, Alexander M; Kashyn, Ivan A; Tuzikov, Alexander V

    2014-12-01

    A computer-aided search for novel anti-HIV-1 agents able to mimic the pharmacophore properties of broadly neutralizing antibody (bNAb) 3074 was carried out based on the analysis of X-ray complexes of this antibody Fab with the MN, UR29, and VI191 peptides from the V3 loop of the HIV envelope protein gp120. Using these empirical data, peptidomimetic candidates of bNAb 3074 were identified by a public, web-oriented virtual screening platform (pepMMsMIMIC) and models of these candidates bound to the above V3 peptides were generated by molecular docking. The docking calculations identified four molecules exhibiting a high affinity to all of the V3 peptides. These molecules were selected as the most probable peptidomimetics of bNAb 3074. Finally, the stability of the complexes of these molecules with the MN, UR29, and VI191 V3 peptides was estimated by molecular dynamics and free energy simulations. Specific binding to the V3 loop was accomplished primarily by π-π interactions between the aromatic rings of the peptidomimetics and the conserved Phe-20 and/or Tyr-21 of the V3 immunogenic crown. In a mechanism similar to that of bNAb 3074, these compounds were found to block the tip of the V3 loop forming its invariant structural motif that contains residues critical for cell tropism. Based on these findings, the compounds selected are considered as promising basic structures for the rational design of novel, potent, and broad-spectrum anti-HIV-1 therapeutics. PMID:24251545

  17. Yellow fever 17D-vectored vaccines expressing Lassa virus GP1 and GP2 glycoproteins provide protection against fatal disease in guinea pigs.

    PubMed

    Jiang, Xiaohong; Dalebout, Tim J; Bredenbeek, Peter J; Carrion, Ricardo; Brasky, Kathleen; Patterson, Jean; Goicochea, Marco; Bryant, Joseph; Salvato, Maria S; Lukashevich, Igor S

    2011-02-01

    Yellow Fever (YF) and Lassa Fever (LF) are two prevalent hemorrhagic fevers co-circulating in West Africa and responsible for thousands of deaths annually. The YF vaccine 17D has been used as a vector for the Lassa virus glycoprotein precursor (LASV-GPC) or their subunits, GP1 (attachment glycoprotein) and GP2 (fusion glycoprotein). Cloning shorter inserts, LASV-GP1 and -GP2, between YF17D E and NS1 genes enhanced genetic stability of recombinant viruses, YF17D/LASV-GP1 and -GP2, in comparison with YF17D/LASV-GPC recombinant. The recombinant viruses were replication competent and properly processed YF proteins and LASV GP antigens in infected cells. YF17D/LASV-GP1 and -GP2 induced specific CD8+ T cell responses in mice and protected strain 13 guinea pigs against fatal LF. Unlike immunization with live attenuated reassortant vaccine ML29, immunization with YF17D/LASV-GP1 and -GP2 did not provide sterilizing immunity. This study demonstrates the feasibility of YF17D-based vaccine to control LF in West Africa. PMID:21145373

  18. Yellow fever 17D-vectored vaccines expressing Lassa virus GP1 and GP2 glycoproteins provide protection against fatal disease in guinea pigs

    PubMed Central

    Jiang, Xiaohong; Dalebout, Tim J.; Bredenbeek, Peter J.; Carrion, Ricardo; Brasky, Kathleen; Patterson, Jean; Goicochea, Marco; Bryant, Joseph; Salvato, Maria S.; Lukashevich, Igor S.

    2010-01-01

    Yellow Fever (YF) and Lassa Fever (LF) are two prevalent hemorrhagic fevers co-circulating in West Africa and responsible for thousands of deaths annually. The YF vaccine 17D has been used as a vector for the Lassa virus glycoprotein precursor (LASV-GPC) or their subunits, GP1 (attachment glycoprotein) and GP2 (fusion glycoprotein). Cloning shorter inserts, LASV GP1 and GP2, between YF17D E and NS1 genes enhanced genetic stability of recombinant viruses, YF17D/LASV-GP1 and –GP2, in comparison with YF17D/LASV-GPC recombinant. The recombinant viruses were replication competent and properly processed YF and LASV GP proteins in infected cells. YF17D/LASV-GP1&GP2 induced specific CD8+ T cell responses in mice and protected strain 13 guinea pigs against fatal LF. Unlike immunization with live attenuated reassortant vaccine ML29, immunization with YF17D/LASV-GP1&GP2 did not provide sterilizing immunity. This study demonstrates the feasibility of YF17D-based vaccine to control LF in West Africa. PMID:21145373

  19. A comparative immunogenicity study in rabbits of disulfide-stabilized, proteolytically cleaved, soluble trimeric human immunodeficiency virus type 1 gp140, trimeric cleavage-defective gp140 and monomeric gp120

    SciTech Connect

    Beddows, Simon; Franti, Michael; Dey, Antu K.; Kirschner, Marc; Iyer, Sai Prasad N.; Fisch, Danielle C.; Ketas, Thomas; Yuste, Eloisa; Desrosiers, Ronald C.; Klasse, Per Johan; Maddon, Paul J.; Olson, William C.; Moore, John P. . E-mail: jpm2003@med.cornell.edu

    2007-04-10

    The human immunodeficiency virus type 1 (HIV-1) surface envelope glycoprotein (Env) complex, a homotrimer containing gp120 surface glycoprotein and gp41 transmembrane glycoprotein subunits, mediates the binding and fusion of the virus with susceptible target cells. The Env complex is the target for neutralizing antibodies (NAbs) and is the basis for vaccines intended to induce NAbs. Early generation vaccines based on monomeric gp120 subunits did not confer protection from infection; one alternative approach is therefore to make and evaluate soluble forms of the trimeric Env complex. We have directly compared the immunogenicity in rabbits of two forms of soluble trimeric Env and monomeric gp120 based on the sequence of HIV-1{sub JR-FL}. Both protein-only and DNA-prime, protein-boost immunization formats were evaluated, DNA-priming having little or no influence on the outcome. One form of trimeric Env was made by disrupting the gp120-gp41 cleavage site by mutagenesis (gp140{sub UNC}), the other contains an intramolecular disulfide bond to stabilize the cleaved gp120 and gp41 moieties (SOSIP.R6 gp140). Among the three immunogens, SOSIP.R6 gp140 most frequently elicited neutralizing antibodies against the homologous, neutralization-resistant strain, HIV-1{sub JR-FL}. All three proteins induced NAbs against more sensitive strains, but the breadth of activity against heterologous primary isolates was limited. When antibodies able to neutralize HIV-1{sub JR-FL} were detected, antigen depletion studies showed they were not directed at the V3 region but were targeted at other, undefined gp120 and also non-gp120 epitopes.

  20. A high-efficiency recombineering system with PCR-based ssDNA in Bacillus subtilis mediated by the native phage recombinase GP35.

    PubMed

    Sun, Zhaopeng; Deng, Aihua; Hu, Ting; Wu, Jie; Sun, Qinyun; Bai, Hua; Zhang, Guoqiang; Wen, Tingyi

    2015-06-01

    Bacillus subtilis and its closely related species are important strains for industry, agriculture, and medicine. However, it is difficult to perform genetic manipulations using the endogenous recombination machinery. In many bacteria, phage recombineering systems have been employed to improve recombineering frequencies. To date, an efficient phage recombineering system for B. subtilis has not been reported. Here, we, for the first time, identified that GP35 from the native phage SPP1 exhibited a high recombination activity in B. subtilis. On this basis, we developed a high-efficiency GP35-meditated recombineering system. Taking single-stranded DNA (ssDNA) as a recombineering substrate, ten recombinases from diverse sources were investigated in B. subtilis W168. GP35 showed the highest recombineering frequency (1.71 ± 0.15 × 10(-1)). Besides targeting the purine nucleoside phosphorylase gene (deoD), we also demonstrated the utility of GP35 and Beta from Escherichia coli lambda phage by deleting the alpha-amylase gene (amyE) and uracil phosphoribosyltransferase gene (upp). In all three genetic loci, GP35 exhibited a higher frequency than Beta. Moreover, a phylogenetic tree comparing the kinship of different recombinase hosts with B. subtilis was constructed, and the relationship between the recombineering frequency and the kinship of the host was further analyzed. The results suggested that closer kinship to B. subtilis resulted in higher frequency in B. subtilis. In conclusion, the recombinase from native phage or prophage can significantly promote the genetic recombineering frequency in its host, providing an effective genetic tool for constructing genetically engineered strains and investigating bacterial physiology. PMID:25750031

  1. Identification and Characterization of a Broadly Cross-Reactive HIV-1 Human Monoclonal Antibody That Binds to Both gp120 and gp41

    PubMed Central

    Zhang, Mei-Yun; Yuan, Tingting; Li, Jingjing; Rosa Borges, Andrew; Watkins, Jennifer D.; Guenaga, Javier; Yang, Zheng; Wang, Yanping; Wilson, Richard; Li, Yuxing; Polonis, Victoria R.; Pincus, Seth H.; Ruprecht, Ruth M.; Dimitrov, Dimiter S.

    2012-01-01

    Identification of broadly cross-reactive HIV-1-neutralizing antibodies (bnAbs) may assist vaccine immunogen design. Here we report a novel human monoclonal antibody (mAb), designated m43, which co-targets the gp120 and gp41 subunits of the HIV-1 envelope glycoprotein (Env). M43 bound to recombinant gp140 s from various primary isolates, to membrane-associated Envs on transfected cells and HIV-1 infected cells, as well as to recombinant gp120 s and gp41 fusion intermediate structures containing N-trimer structure, but did not bind to denatured recombinant gp140 s and the CD4 binding site (CD4bs) mutant, gp120 D368R, suggesting that the m43 epitope is conformational and overlaps the CD4bs on gp120 and the N-trimer structure on gp41. M43 neutralized 34% of the HIV-1 primary isolates from different clades and all the SHIVs tested in assays based on infection of peripheral blood mononuclear cells (PBMCs) by replication-competent virus, but was less potent in cell line-based pseudovirus assays. In contrast to CD4, m43 did not induce Env conformational changes upon binding leading to exposure of the coreceptor binding site, enhanced binding of mAbs 2F5 and 4E10 specific for the membrane proximal external region (MPER) of gp41 Envs, or increased gp120 shedding. The overall modest neutralization activity of m43 is likely due to the limited binding of m43 to functional Envs which could be increased by antibody engineering if needed. M43 may represent a new class of bnAbs targeting conformational epitopes overlapping structures on both gp120 and gp41. Its novel epitope and possibly new mechanism(s) of neutralization could helpdesign improved vaccine immunogens and candidate therapeutics. PMID:22970187

  2. Alternation of adriamycin penetration kinetics in MCF-7 cells from 2D to 3D culture based on P-gp expression through the Chk2/p53/NF-κB pathway.

    PubMed

    Lu, Meng; Zhou, Fang; Hao, Kun; Liu, Jiali; Chen, Qianying; Ni, Ping; Zhou, Honghao; Wang, Guangji; Zhang, Jingwei

    2015-01-15

    Monolayer cells are largely different from tumor masses, and might misguide drug screenings. 3D in vitro cell culture models simulate the characteristics of tumor masses in vivo and have recently been used in many studies of anti-cancer drugs. Among various 3D cell culture models, multi-cellular layer (MCL) models allow for the direct quantitative assessment of the penetration of chemotherapeutic agents through solid tissue environments without requiring the use of fluorescently labeled drugs or imaging molecules. Therefore, in our present study, a 3D-no base and embedded MCF-7 MCL model was successfully developed for a 14-day culture. Over time, its thickness and cell layers increased and exhibited highly proliferative properties and drug resistance to adriamycin (ADR) with markedly elevated IC50 values. Meanwhile, G2/M stage cycle arrest was also observed, which likely up-regulated P-gp expression through the Chk2/p53/NF-κB pathway. The elevated P-gp expression altered the ADR penetration kinetics in MCF-7 MCLs in vitro by accelerating the apparent penetration of ADR through the intercellular spaces of the MCLs. Additionally, a decreased ADR retention within tumor cells was observed, but could be significantly reversed by a P-gp inhibitor. The attenuated ADR retention in the deeper cells of tumor masses was confirmed in xenografted mice in vivo. This phenomenon could be elucidated by the mathematical modeling of penetration kinetics parameters. Our study provided a new model that evaluated and improved the quantification of the drug penetration kinetics, revealed the relationship between P-gp and drug penetration through tumor masses, and suggested the potential molecular mechanisms. PMID:25478729

  3. (Calorimeter based detectors for high energy hadron colliders). [State Univ. of New York

    SciTech Connect

    Not Available

    1992-08-04

    This document provides a progress report on research that has been conducted under DOE Grant DEFG0292ER40697 for the past year, and describes proposed work for the second year of this 8 year grant starting November 15, 1992. Personnel supported by the contract include 4 faculty, 1 research faculty, 4 postdocs, and 9 graduate students. The work under this grant has in the past been directed in two complementary directions -- DO at Fermilab, and the second SSC detector GEM. A major effort has been towards the construction and commissioning of the new Fermilab Collider detector DO, including design, construction, testing, the commissioning of the central tracking and the central calorimeters. The first DO run is now underway, with data taking and analysis of the first events. Trigger algorithms, data acquisition, calibration of tracking and calorimetry, data scanning and analysis, and planning for future upgrades of the DO detector with the advent of the FNAL Main Injector are all involved. The other effort supported by this grant has been towards the design of GEM, a large and general-purpose SSC detector with special emphasis on accurate muon measurement over a large solid angle. This effort will culminate this year in the presentation to the SSC laboratory of the GEM Technical Design Report. Contributions are being made to the detector design, coordination, and physics simulation studies with special emphasis on muon final states. Collaboration with the RD5 group at CERN to study muon punch through and to test cathode strip chamber prototypes was begun.

  4. Peptides presenting the binding site of human CD4 for the HIV-1 envelope glycoprotein gp120

    PubMed Central

    Meier, Julia; Kassler, Kristin; Sticht, Heinrich

    2012-01-01

    Summary Based on the structure of the HIV-1 glycoprotein gp120 in complex with its cellular receptor CD4, we have designed and synthesized peptides that mimic the binding site of CD4 for gp120. The ability of these peptides to bind to gp120 can be strongly enhanced by increasing their conformational stability through cyclization, as evidenced by binding assays, as well as through molecular-dynamics simulations of peptide–gp120 complexes. The specificity of the peptide–gp120 interaction was demonstrated by using peptide variants, in which key residues for the interaction with gp120 were replaced by alanine or D-amino acids. PMID:23209523

  5. Beam-based measurements of long-range transverse wakefields in the Compact Linear Collider main-linac accelerating structure

    NASA Astrophysics Data System (ADS)

    Zha, Hao; Latina, Andrea; Grudiev, Alexej; De Michele, Giovanni; Solodko, Anastasiya; Wuensch, Walter; Schulte, Daniel; Adli, Erik; Lipkowitz, Nate; Yocky, Gerald S.

    2016-01-01

    The baseline design of CLIC (Compact Linear Collider) uses X-band accelerating structures for its main linacs. In order to maintain beam stability in multibunch operation, long-range transverse wakefields must be suppressed by 2 orders of magnitude between successive bunches, which are separated in time by 0.5 ns. Such strong wakefield suppression is achieved by equipping every accelerating structure cell with four damping waveguides terminated with individual rf loads. A beam-based experiment to directly measure the effectiveness of this long-range transverse wakefield and benchmark simulations was made in the FACET test facility at SLAC using a prototype CLIC accelerating structure. The experiment showed good agreement with the simulations and a strong suppression of the wakefields with an unprecedented minimum resolution of 0.1 V /(pC mm m ) .

  6. Covalent Conjugation of a Peptide Triazole to HIV-1 gp120 Enables Intramolecular Binding Site Occupancy

    PubMed Central

    2015-01-01

    the PT–gp120 conjugate to the noncovalent PT–gp120 complex support the orientation of binding of PT to gp120 predicted in the molecular dynamics simulation model of the PT–gp120 noncovalent complex. The conformationally stabilized covalent conjugate can be used to expand the structural definition of the PT-induced “off” state of gp120, for example, by high-resolution structural analysis. Such structures could provide a guide for improving the subsequent structure-based design of inhibitors with the peptide triazole mode of action. PMID:24801282

  7. Structures of Ebola virus GP and sGP in complex with therapeutic antibodies.

    PubMed

    Pallesen, Jesper; Murin, Charles D; de Val, Natalia; Cottrell, Christopher A; Hastie, Kathryn M; Turner, Hannah L; Fusco, Marnie L; Flyak, Andrew I; Zeitlin, Larry; Crowe, James E; Andersen, Kristian G; Saphire, Erica Ollmann; Ward, Andrew B

    2016-01-01

    The Ebola virus (EBOV) GP gene encodes two glycoproteins. The major product is a soluble, dimeric glycoprotein (sGP) that is secreted abundantly. Despite the abundance of sGP during infection, little is known regarding its structure or functional role. A minor product, resulting from transcriptional editing, is the transmembrane-anchored, trimeric viral surface glycoprotein (GP). GP mediates attachment to and entry into host cells, and is the intended target of antibody therapeutics. Because large portions of sequence are shared between GP and sGP, it has been hypothesized that sGP may potentially subvert the immune response or may contribute to pathogenicity. In this study, we present cryo-electron microscopy structures of GP and sGP in complex with GP-specific and GP/sGP cross-reactive antibodies undergoing human clinical trials. The structure of the sGP dimer presented here, in complex with both an sGP-specific antibody and a GP/sGP cross-reactive antibody, permits us to unambiguously assign the oligomeric arrangement of sGP and compare its structure and epitope presentation to those of GP. We also provide biophysical evaluation of naturally occurring GP/sGP mutations that fall within the footprints identified by our high-resolution structures. Taken together, our data provide a detailed and more complete picture of the accessible Ebolavirus glycoprotein landscape and a structural basis to evaluate patient and vaccine antibody responses towards differently structured products of the GP gene. PMID:27562261

  8. Roles of conserved and allelic regions of the major merozoite surface protein (gp195) in immunity against Plasmodium falciparum.

    PubMed Central

    Hui, G S; Hashimoto, A; Chang, S P

    1992-01-01

    The Plasmodium falciparum major merozoite surface protein gp195 is a candidate antigen for a vaccine against human malaria. The significance of allelism and polymorphism in vaccine-induced immunity to gp195 was investigated in this study. Rabbits were immunized with each of two allelic forms of gp195 that were affinity purified from the FUP and FVO parasite isolates. gp195-specific antibodies raised against one allelic form of gp195 cross-reacted extensively with the gp195 of the heterologous allele in enzyme-linked immunosorbent assays (ELISAs) and immunofluorescence assays. Competitive binding ELISAs with homologous and heterologous gp195s confirmed that a majority of the anti-gp195 antibodies produced against either allelic protein were cross-reactive. Moreover, the biological activities of the gp195 antibody responses were also highly cross-reactive, since anti-gp195 sera inhibited the in vitro growth of the homologous and heterologous parasites with equal efficiency. The degree of cross-reactivity with strain-specific and allele-specific determinants of gp195 in the ELISA was low. These results suggest that the immunological cross-reactivity between the two gp195 proteins is due to recognition of conserved determinants. They also suggest that a gp195-based vaccine may be effective against blood-stage infection with a diverse array of parasite isolates. Images PMID:1548068

  9. Infiltration of Neutrophils and Eosinophils during Allergic Inflammation is Regulated by the Inhibitory Receptor gp-49B

    Technology Transfer Automated Retrieval System (TEKTRAN)

    gp49B, an Ig-like receptor, negatively regulates the activity of mast cells and neutrophils through cytoplasmic immuno-receptor tyrosine-based inhibition motifs (ITIM). To further characterize the role of gp49B in vivo, gp49B-deficient mice were tested in two allergic models. Responses to ragweed (R...

  10. The International Linear Collider

    NASA Astrophysics Data System (ADS)

    List, Benno

    2014-04-01

    The International Linear Collider (ILC) is a proposed e+e- linear collider with a centre-of-mass energy of 200-500 GeV, based on superconducting RF cavities. The ILC would be an ideal machine for precision studies of a light Higgs boson and the top quark, and would have a discovery potential for new particles that is complementary to that of LHC. The clean experimental conditions would allow the operation of detectors with extremely good performance; two such detectors, ILD and SiD, are currently being designed. Both make use of novel concepts for tracking and calorimetry. The Japanese High Energy Physics community has recently recommended to build the ILC in Japan.

  11. High Energy Colliders

    NASA Astrophysics Data System (ADS)

    Palmer, R. B.; Gallardo, J. C.

    INTRODUCTION PHYSICS CONSIDERATIONS GENERAL REQUIRED LUMINOSITY FOR LEPTON COLLIDERS THE EFFECTIVE PHYSICS ENERGIES OF HADRON COLLIDERS HADRON-HADRON MACHINES LUMINOSITY SIZE AND COST CIRCULAR e^{+}e^- MACHINES LUMINOSITY SIZE AND COST e^{+}e^- LINEAR COLLIDERS LUMINOSITY CONVENTIONAL RF SUPERCONDUCTING RF AT HIGHER ENERGIES γ - γ COLLIDERS μ ^{+} μ^- COLLIDERS ADVANTAGES AND DISADVANTAGES DESIGN STUDIES STATUS AND REQUIRED R AND D COMPARISION OF MACHINES CONCLUSIONS DISCUSSION

  12. The SPL7013 dendrimer destabilizes the HIV-1 gp120-CD4 complex

    NASA Astrophysics Data System (ADS)

    Nandy, Bidisha; Saurabh, Suman; Sahoo, Anil Kumar; Dixit, Narendra M.; Maiti, Prabal K.

    2015-11-01

    The poly (l-lysine)-based SPL7013 dendrimer with naphthalene disulphonate surface groups blocks the entry of HIV-1 into target cells and is in clinical trials for development as a topical microbicide. Its mechanism of action against R5 HIV-1, the HIV-1 variant implicated in transmission across individuals, remains poorly understood. Using docking and fully atomistic MD simulations, we find that SPL7013 binds tightly to R5 gp120 in the gp120-CD4 complex but weakly to gp120 alone. Further, the binding, although to multiple regions of gp120, does not occlude the CD4 binding site on gp120, suggesting that SPL7013 does not prevent the binding of R5 gp120 to CD4. Using MD simulations to compute binding energies of several docked structures, we find that SPL7013 binding to gp120 significantly weakens the gp120-CD4 complex. Finally, we use steered molecular dynamics (SMD) to study the kinetics of the dissociation of the gp120-CD4 complex in the absence of the dendrimer and with the dendrimer bound in each of the several stable configurations to gp120. We find that SPL7013 significantly lowers the force required to rupture the gp120-CD4 complex and accelerates its dissociation. Taken together, our findings suggest that SPL7013 compromises the stability of the R5 gp120-CD4 complex, potentially preventing the accrual of the requisite number of gp120-CD4 complexes across the virus-cell interface, thereby blocking virus entry.The poly (l-lysine)-based SPL7013 dendrimer with naphthalene disulphonate surface groups blocks the entry of HIV-1 into target cells and is in clinical trials for development as a topical microbicide. Its mechanism of action against R5 HIV-1, the HIV-1 variant implicated in transmission across individuals, remains poorly understood. Using docking and fully atomistic MD simulations, we find that SPL7013 binds tightly to R5 gp120 in the gp120-CD4 complex but weakly to gp120 alone. Further, the binding, although to multiple regions of gp120, does not occlude

  13. Beam Collimation at Hadron Colliders

    NASA Astrophysics Data System (ADS)

    Mokhov, N. V.

    2003-12-01

    Operational and accidental beam losses in hadron colliders can have a serious impact on machine and detector performance, resulting in effects ranging from minor to catastrophic. Principles and realization are described for a reliable beam collimation system required to sustain favorable background conditions in the collider detectors, provide quench stability of superconducting magnets, minimize irradiation of accelerator equipment, maintain operational reliability over the life of the machine, and reduce the impact of radiation on personnel and the environment. Based on detailed Monte-Carlo simulations, such a system has been designed and incorporated in the Tevatron collider. Its performance, comparison to measurements and possible ways to further improve the collimation efficiency are described in detail. Specifics of the collimation systems designed for the SSC, LHC, VLHC, and HERA colliders are discussed.

  14. Period change in GP And

    NASA Astrophysics Data System (ADS)

    Rodriguez, E.; Rolland, A.; Lopez de Coca, P.

    1993-05-01

    GP And is a high amplitude d Scuti type star with V~10.m75, DV~0.m55, P=0.d0787 and spectral type A3 (Lopez de Coca et al. 1990, A & A 83, 51). To study the stability of its fundamental pulsation we have carried out simultaneous uvby photometry of this star in the years 1987 and 1992 at Sierra Nevada and Caltar Alto observatories, both in Spain. Ten new times of light maxima were obtained. In total, forty-one time s of light maxima (from 1973 to 1992, collected from Splittgerber 1976, Mitt. Veraend. Sterne 7, 137; Eggen 1978, IBVS 1517; Gieseking et al. 1979, A & AS 36, 457; Burchi et al. 1992, Mem. Soc. Astron. Ital. 63, 87 and us) were used to determinate the ephemeris of the light curve of GP And by means of the classical O-C method.

  15. Construction of a GP integration model.

    PubMed

    Batterham, R; Southern, D; Appleby, N; Elsworth, G; Fabris, S; Dunt, D; Young, D

    2002-04-01

    There are frequent calls to improve integration of health services, within and between primary and secondary care sectors. In Australia, general medical practitioners (GPs) are central to these endeavours. This paper aims to better conceptualise GP integration and to develop a model and index based on this. A conceptualisation of integration is proposed based on integration fundamentally as an activity or process not structure. Integration process is the frequency and quality of episodes of information exchange involving the GP and another practitioner or patient and aimed at fulfilling the objectives of the health care system with regard to patient care. These are both direct responses to structural forces and emergent GP capacities and dispositions. The content of this typology was studied using Concept Mapping in 11 groups of GPs, consumers and other practitioners. Clusters of related statements within thematic domains were used as the basis for a provisional model. This was tested using confirmatory factor analysis in a data set derived from a national probability sample of 501 GPs. Some re-specification of the model was necessary, with three integration process factors needing to be subdivided. One factor congeneric model assumptions were used to identify the constituent items for these factors. The result was a model in which 50 items measured nine integration process factors and 20 items measured five enabling factors. Two distinct but correlated higher order factors, relating to individual patient care and public (or community) health--in contrast to a single higher order factor for integration--were identified. The re-specified model was tested with a new sample of 151 GPs and exhibited strong psychometric properties. Reliability and validity were acceptable to this stage of the indices' development. Further testing of the index is necessary to demonstrate factor invariance of the indices in other contexts as well as their utility in cross

  16. The SPL7013 dendrimer destabilizes the HIV-1 gp120-CD4 complex.

    PubMed

    Nandy, Bidisha; Saurabh, Suman; Sahoo, Anil Kumar; Dixit, Narendra M; Maiti, Prabal K

    2015-11-28

    The poly (l-lysine)-based SPL7013 dendrimer with naphthalene disulphonate surface groups blocks the entry of HIV-1 into target cells and is in clinical trials for development as a topical microbicide. Its mechanism of action against R5 HIV-1, the HIV-1 variant implicated in transmission across individuals, remains poorly understood. Using docking and fully atomistic MD simulations, we find that SPL7013 binds tightly to R5 gp120 in the gp120-CD4 complex but weakly to gp120 alone. Further, the binding, although to multiple regions of gp120, does not occlude the CD4 binding site on gp120, suggesting that SPL7013 does not prevent the binding of R5 gp120 to CD4. Using MD simulations to compute binding energies of several docked structures, we find that SPL7013 binding to gp120 significantly weakens the gp120-CD4 complex. Finally, we use steered molecular dynamics (SMD) to study the kinetics of the dissociation of the gp120-CD4 complex in the absence of the dendrimer and with the dendrimer bound in each of the several stable configurations to gp120. We find that SPL7013 significantly lowers the force required to rupture the gp120-CD4 complex and accelerates its dissociation. Taken together, our findings suggest that SPL7013 compromises the stability of the R5 gp120-CD4 complex, potentially preventing the accrual of the requisite number of gp120-CD4 complexes across the virus-cell interface, thereby blocking virus entry. PMID:26495445

  17. A plausible explanation for enhanced bioavailability of P-gp substrates in presence of piperine: simulation for next generation of P-gp inhibitors.

    PubMed

    Singh, Durg Vijay; Godbole, Madan M; Misra, Krishna

    2013-01-01

    P-glycoprotein (P-gp) has a major role to play in drug pharmacokinetics and pharmacodynamics, since it effluxes many cytotoxic hydrophobic anticancer drugs from gastrointestinal tract, brain, liver and kidney. Piperine is known to enhance the bioavailability of curcumin, as a substrate of P-gp by at least 2000%. Besides these at least 50 other substrates and inhibitors of P-gp have been reported so far. All P-gp inhibitors have diverse structures. Although little is known about binding of some flavonoids and steroids at the NBD (nucleotide binding domain) of P-gp in the vicinity of ATP binding site inhibiting its hydrolysis, a valid explanation of how P-gp accommodates such a diverse set of inhibitors is still awaited. In the present study, piperine up to 100 μM has not shown observable cytotoxic effect on MDCK cell line, and it has been shown to accumulate rhodamine by fluorescence microscopy and fluorescent activated cell sorter in MDCK cells. Computational simulation for piperine and some first and second generation P-gp inhibitors has shown that these dock at the NBD site of P-gp. A comparative simulation study has been carried out regarding their docking and binding energies. Binding conformation of P-gp co-crystallized complexes with ADP, AMP-PNP (Adenylyl-imidodiphosphate), and ATP were compared with piperine. The receptor based E-pharmacophore of docked piperine has been simulated to find common features amongst P-gp inhibitors. Finally it has been concluded that piperine could be utilized as base molecule for design and development of safe non-toxic inhibitor of P-gp in order to enhance the bioavailability of most of its substrates. PMID:22864626

  18. On-orbit GP-B Operations

    NASA Astrophysics Data System (ADS)

    Muhlfelder, B.; Green, G.; Keiser, G. M.; Smith, M.

    Gravity Probe B (GP-B) is a space-based experiment designed to measure two non-Newtonian precessions of precision gyroscopes in orbit about the Earth. The on-orbit mission is divided into three phases: initialization, science, and post-science calibration. The initialization phase configures the space vehicle for science and spans the first two months of the 18 month on-orbit dewar lifetime. Initialization consists of adjusting the vehicle's 640 km orbit to within 0.003 degrees of a nearly polar orbit, use of an on-board tracking telescope to point the vehicle to a distant fixed reference star, and spinning each of the science gyroscopes to approximately 100 Hz. After initialization, science data are collected for each gyroscope. A London Moment based gyroscope readout system provides a measurement of the precession of the gyroscope spin axis orientation. Following the collection of the science data, the Newtonian drift rates of the gyroscopes are intentionally enhanced. This calibration provides a bound of the amount of Newtonian gyroscope precession present in the science phase, gyroscope data. All vehicle commanding and data collection will be performed using the GP-B ground station. The team is now readying for the planned April 2004 launch.

  19. HIV Subtypes B and C gp120 and Methamphetamine Interaction: Dopaminergic System Implicates Differential Neuronal Toxicity.

    PubMed

    Samikkannu, Thangavel; Rao, Kurapati V K; Salam, Abdul Ajees Abdul; Atluri, Venkata S R; Kaftanovskaya, Elena M; Agudelo, Marisela; Perez, Suray; Yoo, Changwon; Raymond, Andrea D; Ding, Hong; Nair, Madhavan P N

    2015-01-01

    HIV subtypes or clades differentially induce HIV-associated neurocognitive disorders (HAND) and substance abuse is known to accelerate HIV disease progression. The HIV-1 envelope protein gp120 plays a major role in binding and budding in the central nervous system (CNS) and impacts dopaminergic functions. However, the mechanisms utilized by HIV-1 clades to exert differential effects and the methamphetamine (METH)-associated dopaminergic dysfunction are poorly understood. We hypothesized that clade B and C gp120 structural sequences, modeling based analysis, dopaminergic effect, and METH potentiate neuronal toxicity in astrocytes. We evaluated the effect of clade B and C gp120 and/or METH on the DRD-2, DAT, CaMKs and CREBP transcription. Both the structural sequence and modeling studies demonstrated that clade B gp120 in V1-V4, α -2 and N-glycosylated sites are distinct from clade C gp120. The distinct structure and sequence variation of clade B gp120 differentially impact DRD-2, DAT, CaMK II and CaMK IV mRNA, protein and intracellular expression compared to clade C gp120. However, CREB transcription is upregulated by both clade B and C gp120, and METH co-treatment potentiated these effects. In conclusion, distinct structural sequences of HIV-1 clade B and C gp120 differentially regulate the dopaminergic pathway and METH potentiates neurotoxicity. PMID:26057350

  20. HIV Subtypes B and C gp120 and Methamphetamine Interaction: Dopaminergic System Implicates Differential Neuronal Toxicity

    PubMed Central

    Samikkannu, Thangavel; Rao, Kurapati V. K.; Salam, Abdul Ajees Abdul; Atluri, Venkata S. R.; Kaftanovskaya, Elena M.; Agudelo, Marisela; Perez, Suray; Yoo, Changwon; Raymond, Andrea D.; Ding, Hong; Nair, Madhavan P. N.

    2015-01-01

    HIV subtypes or clades differentially induce HIV-associated neurocognitive disorders (HAND) and substance abuse is known to accelerate HIV disease progression. The HIV-1 envelope protein gp120 plays a major role in binding and budding in the central nervous system (CNS) and impacts dopaminergic functions. However, the mechanisms utilized by HIV-1 clades to exert differential effects and the methamphetamine (METH)-associated dopaminergic dysfunction are poorly understood. We hypothesized that clade B and C gp120 structural sequences, modeling based analysis, dopaminergic effect, and METH potentiate neuronal toxicity in astrocytes. We evaluated the effect of clade B and C gp120 and/or METH on the DRD-2, DAT, CaMKs and CREBP transcription. Both the structural sequence and modeling studies demonstrated that clade B gp120 in V1-V4, α -2 and N-glycosylated sites are distinct from clade C gp120. The distinct structure and sequence variation of clade B gp120 differentially impact DRD-2, DAT, CaMK II and CaMK IV mRNA, protein and intracellular expression compared to clade C gp120. However, CREB transcription is upregulated by both clade B and C gp120, and METH co-treatment potentiated these effects. In conclusion, distinct structural sequences of HIV-1 clade B and C gp120 differentially regulate the dopaminergic pathway and METH potentiates neurotoxicity. PMID:26057350

  1. Search for top quark at Fermilab Collider

    SciTech Connect

    Sliwa, K.; The CDF Collaboration

    1991-10-01

    The status of a search for the top quark with Collider Detector at Fermilab (CDF), based on a data sample recorded during the 1988--1989 run is presented. The plans for the next Fermilab Collider run in 1992--1993 and the prospects of discovering the top quark are discussed. 19 refs., 4 figs., 2 tabs.

  2. Results from hadron colliders

    SciTech Connect

    Pondrom, L.G. )

    1990-12-14

    The present status of hadron collider physics is reviewed. The total cross section for {bar p} + p has been measured at 1.8 TeV: {sigma}{sub tot} = 72.1 {plus minus} 3.3 mb. New data confirm the UA2 observation of W/Z {yields} {bar q}q. Precision measurements of M{sub W} by UA2 and CDF give an average value M{sub W} = 80.13 {plus minus} 0.30 GeV/c{sup 2}. When combined with measurements of M{sub Z} from LEP and SLC this number gives sin{sup 2}{theta}{sub W} = 0.227 {plus minus} 0.006, or m{sub top} = 130{sub {minus}60}{sup +40} GeV/c{sup 2} from the EWK radiative correction term {Delta}r. Evidence for hadron colliders as practical sources of b quarks has been strengthened, while searches for t quarks have pushed the mass above M{sub W}: m{sub top} > 89 GeV/c{sup 2} 95% cl (CDF Preliminary). Searches beyond the standard model based on the missing E{sub T} signature have not yet produced any positive results. Future prospects for the discovery of the top quark in the range m{sub top} < 200 GeV/c{sup 2} look promising. 80 refs., 35 figs., 7 tabs.

  3. A novel tetrameric gp350 1-470 as a potential Epstein-Barr virus vaccine.

    PubMed

    Cui, Xinle; Cao, Zhouhong; Sen, Goutam; Chattopadhyay, Gouri; Fuller, Deborah H; Fuller, James T; Snapper, Dustin M; Snow, Andrew L; Mond, James J; Snapper, Clifford M

    2013-06-26

    Infectious mononucleosis and B-cell transformation in response to infection with Epstein-Barr virus (EBV) is dependent upon binding of the EBV envelope glycoprotein gp350 to CD21 on B-cells. Gp350-specific antibody comprises most of the EBV neutralizing activity in the serum of infected patients, making this protein a promising target antigen for a prophylactic EBV vaccine. We describe a novel, tetrameric gp350-based vaccine that exhibits markedly enhanced immunogenicity relative to its monomeric counterpart. Plasmid DNA was constructed for synthesis, within transfected CHO cells, of a tetrameric, truncated (a.a. 1-470) gp350 protein (gp350(1-470)). Tetrameric gp350(1-470) induced ≈ 20-fold higher serum titers of gp350(1-470)-specific IgG and >19-fold enhancements in neutralizing titers at the highest dose, and was >25-fold more immunogenic on a per-weight basis than monomeric gp350(1-470). Further, epidermal immunization with plasmid DNA encoding gp350(1-470) tetramer induced 8-fold higher serum titers of gp350(1-470)-specific IgG relative to monomer. Tetrameric gp350(1-470) binding to human CD21 was >24-fold more efficient on a per-weight basis than monomer, but neither tetramer nor monomer mediated polyclonal human B-cell activation. Finally, the introduction of strong, universal tetanus toxoid (TT)-specific CD4+ T-cell epitopes into the tetrameric gp350(1-470) had no effect on the gp350(1-470)-specific IgG response in naïve mice, and resulted in suppressed gp350(1-470)-specific IgG responses in TT-primed mice. Collectively, these data suggest that tetrameric gp350(1-470) is a potentially promising candidate for testing as a prophylactic EBV vaccine, and that protein multimerization, using the approach described herein, is likely to be clinically relevant for enhancing the immunogenicity of other proteins of vaccine interest. PMID:23665339

  4. A novel tetrameric gp3501-470 as a potential Epstein-Barr virus vaccine

    PubMed Central

    Cui, Xinle; Cao, Zhouhong; Sen, Goutam; Chattopadhyay, Gouri; Fuller, Deborah H.; Fuller, James T.; Snapper, Dustin M.; Snow, Andrew; Mond, James J.; Snapper, Clifford M.

    2013-01-01

    Infectious mononucleosis and B-cell transformation in response to infection with Epstein-Barr virus (EBV) is dependent upon binding of the EBV envelope glycoprotein gp350 to CD21 on B-cells. Gp350-specific antibody comprises most of the EBV neutralizing activity in the serum of infected patients, making this protein a promising target antigen for a prophylactic EBV vaccine. We describe a novel, tetrameric gp350-based vaccine that exhibits markedly enhanced immunogenicity relative to its monomeric counterpart. Plasmid DNA was constructed for synthesis, within transfected CHO cells, of a tetrameric, truncated (a.a. 1-470) gp350 protein (gp3501-470). Tetrameric gp3501-470 induced ~20-fold higher serum titers of gp3501-470-specific IgG and >19-fold enhancements in neutralizing titers at the highest dose, and was >25-fold more immunogenic on a per-weight basis than monomeric gp3501-470. Further, epidermal immunization with plasmid DNA encoding gp3501-470 tetramer induced 8-fold higher serum titers of gp3501-470-specific IgG relative to monomer. Tetrameric gp3501-470 binding to human CD21 was >24-fold more efficient on a per-weight basis than monomer, but neither tetramer nor monomer mediated polyclonal human B-cell activation. Finally, the introduction of strong, universal tetanus toxoid (TT)-specific CD4+ T-cell epitopes into the tetrameric gp3501-470 had no effect on the gp3501-470-specific IgG response in naïve mice, and resulted in suppressed gp3501-470-specific IgG responses in TT-primed mice. Collectively, these data suggest that tetrameric gp3501-470 is a potentially promising candidate for testing as a prophylactic EBV vaccine, and that protein multimerization, using the approach described herein, is likely to be clinically relevant for enhancing the immunogenicity of other proteins of vaccine interest. PMID:23665339

  5. Beam-based alignment and tuning procedures for e sup + e sup minus collider final focus systems

    SciTech Connect

    Bulos, F.; Burke, D.; Helm, R.; Irwin, J.; Odian, A.; Roy, G.; Ruth, R.; Yamamoto, N.

    1991-05-01

    For future linear colliders, with very small emittances and beam sizes and demanding tolerances on final focus system alignment and magnet errors, it becomes increasingly important to use the beam as a diagnostic tool. We report here procedures we have identified and will be implemented in the Final Focus Test Beam at SLAC incorporating (1) quadrupole strength changes, (2) central orbit modifications, (3) spot size measurements, and (4) beam stability monitoring. 3 refs., 4 figs., 3 tabs.

  6. Screening and Identification of ssDNA Aptamer for Human GP73

    PubMed Central

    Du, Jingchun; Hong, Jianming; Xu, Chun; Cai, Yuanyuan; Xiang, Bo; Zhou, Chengbo; Xu, Xia

    2015-01-01

    As one tumor marker of HCC, Golgi Protein 73 (GP73) is given more promise in the early diagnosis of HCC, and aptamers have been developed to compete with antibodies as biorecognition probes in different detection system. In this study, we utilized GP73 to screen specific ssDNA aptamers by SELEX technique. First, GP73 proteins were expressed and purified by prokaryotic expression system and Nickle ion affinity chromatography, respectively. At the same time, the immunogenicity of purified GP73 was confirmed by Western blotting. The enriched ssDNA library with high binding capacity for GP73 was obtained after ten rounds of SELEX. Then, thirty ssDNA aptamers were sequenced, in which two ssDNA aptamers with identical DNA sequence were confirmed, based on the alignment results, and designated as A10-2. Furthermore, the specific antibody could block the binding of A10-2 to GP73, and the specific binding of A10-2 to GP73 was also supported by the observation that several tumor cell lines exhibited variable expression level of GP73. Significantly, the identified aptamer A10-2 could distinguish normal and cancerous liver tissues. So, our results indicate that the aptamer A10-2 might be developed into one molecular probe to detect HCC from normal liver specimens. PMID:26583119

  7. A single amino acid substitution modulates low-pH-triggered membrane fusion of GP64 protein in Autographa californica and Bombyx mori nucleopolyhedroviruses

    SciTech Connect

    Katou, Yasuhiro; Yamada, Hayato; Ikeda, Motoko; Kobayashi, Michihiro

    2010-09-01

    We have previously shown that budded viruses of Bombyx mori nucleopolyhedrovirus (BmNPV) enter the cell cytoplasm but do not migrate into the nuclei of non-permissive Sf9 cells that support a high titer of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) multiplication. Here we show, using the syncytium formation assay, that low-pH-triggered membrane fusion of BmNPV GP64 protein (Bm-GP64) is significantly lower than that of AcMNPV GP64 protein (Ac-GP64). Mutational analyses of GP64 proteins revealed that a single amino acid substitution between Ac-GP64 H155 and Bm-GP64 Y153 can have significant positive or negative effects on membrane fusion activity. Studies using bacmid-based GP64 recombinant AcMNPV harboring point-mutated ac-gp64 and bm-gp64 genes showed that Ac-GP64 H155Y and Bm-GP64 Y153H substitutions decreased and increased, respectively, the multiplication and cell-to-cell spread of progeny viruses. These results indicate that Ac-GP64 H155 facilitates the low-pH-triggered membrane fusion reaction between virus envelopes and endosomal membranes.

  8. An Afterburner at the ILC: The Collider Viewpoint

    SciTech Connect

    Raubenheimer, Tor O.

    2004-12-07

    The concept of a high-gradient plasma wakefield accelerator is considered as an upgrade path for the International Linear Collider, a future linear collider. Basic parameters are presented based on those developed for the SLC 'Afterburner'. Basic layout considerations are described and the primary concerns related to the collider operation are discussed.

  9. An Afterburner at the ILC: The Collider Viewpoint

    SciTech Connect

    Raubenheimer, T

    2004-09-01

    The concept of a high-gradient plasma wakefield accelerator is considered as an upgrade path for the International Linear Collider, a future linear collider. Basic parameters are presented based on those developed for the SLC ''Afterburner.'' Basic layout considerations are described and the primary concerns related to the collider operation are discussed.

  10. Higgs boson and Z physics at the first muon collider

    SciTech Connect

    Demarteau, M.; Han, T.

    1998-01-01

    The potential for the Higgs boson and Z-pole physics at the first muon collider is summarized, based on the discussions at the ``Workshop on the Physics at the First Muon Collider and at the Front End of a Muon Collider``.

  11. Preliminary design report of a relativistic-Klystron two-beam-accelerator based power source for a 1 TeV center-of-mass next linear collider

    SciTech Connect

    Yu, S.; Goffeney, N.; Henestroza, E.

    1995-02-22

    A preliminary point design for an 11.4 GHz power source for a 1 TeV center-of-mass Next Linear Collider (NLC) based on the Relativistic-Klystron Two-Beam-Accelerator (RK-TBA) concept is presented. The present report is the result of a joint LBL-LLNL systems study. consisting of three major thrust areas: physics, engineering, and costing. The new RK-TBA point design, together with our findings in each of these areas, are reported.

  12. SLAC Linear Collider

    SciTech Connect

    Richter, B.

    1985-12-01

    A report is given on the goals and progress of the SLAC Linear Collider. The status of the machine and the detectors are discussed and an overview is given of the physics which can be done at this new facility. Some ideas on how (and why) large linear colliders of the future should be built are given.

  13. Topcolor and the First Muon Collider

    SciTech Connect

    Hill, C.T.

    1998-04-01

    We describe a class of models of electroweak symmetry breaking that involve strong dynamics and top quark condensation. A new scheme based upon a seesaw mechanism appears particularly promising. Various implications for the first-stage muon collider are discussed.

  14. Application of independent component analysis to ac dipole based optics measurement and correction at the Relativistic Heavy Ion Collider

    NASA Astrophysics Data System (ADS)

    Shen, X.; Lee, S. Y.; Bai, M.; White, S.; Robert-Demolaize, G.; Luo, Y.; Marusic, A.; Tomás, R.

    2013-11-01

    Correction of beta-beat is of great importance for performance improvement of high energy accelerators, like the Relativistic Hadron Ion Collider (RHIC). At RHIC, using the independent component analysis method, linear optical functions are extracted from the turn by turn beam position data of the ac dipole driven betatron oscillation. Despite the constraint of a limited number of available quadrupole correctors at RHIC, a global beta-beat correction scheme using a beta-beat response matrix method was developed and experimentally demonstrated. In both rings, a factor of 2 or better reduction of beta-beat was achieved within available beam time. At the same time, a new scheme of using horizontal closed orbit bump at sextupoles to correct beta-beat in the arcs was demonstrated in the Yellow ring of RHIC at beam energy of 255 GeV, and a peak beta-beat of approximately 7% was achieved.

  15. The VCSEL-based array optical transmitter (ATx) development towards 120-Gbps link for collider detector: development update

    NASA Astrophysics Data System (ADS)

    Guo, D.; Liu, C.; Chen, J.; Chramowicz, J.; Gong, D.; Hou, S.; Huang, D.; Jin, G.; Li, X.; Liu, T.; Prosser, A.; Teng, P. K.; Ye, J.; Zhou, Y.; You, Y.; Xiang, A. C.; Liang, H.

    2015-01-01

    A compact radiation-tolerant array optical transmitter module (ATx) is developed to provide data transmission up to 10Gbps per channel with 12 parallel channels for collider detector applications. The ATx integrates a Vertical Cavity Surface-Emitting Laser (VCSEL) array and driver circuitry for electrical to optical conversion, an edge warp substrate for the electrical interface and a micro-lens array for the optical interface. This paper reports the continuing development of the ATx custom package. A simple, high-accuracy and reliable active-alignment method for the optical coupling is introduced. The radiation-resistance of the optoelectronic components is evaluated and the inclusion of a custom-designed array driver is discussed.

  16. SLAC linear collider

    SciTech Connect

    Richter, B.; Bell, R.A.; Brown, K.L.

    1980-06-01

    The SLAC LINEAR COLLIDER is designed to achieve an energy of 100 GeV in the electron-positron center-of-mass system by accelerating intense bunches of particles in the SLAC linac and transporting the electron and positron bunches in a special magnet system to a point where they are focused to a radius of about 2 microns and made to collide head on. The rationale for this new type of colliding beam system is discussed, the project is described, some of the novel accelerator physics issues involved are discussed, and some of the critical technical components are described.

  17. Electron-ion collider eRHIC

    NASA Astrophysics Data System (ADS)

    Litvinenko, Vladimir N.

    In this article, we describe our planned future electron-ion collider (EIC), based on the existing Relativistic Heavy Ion Collider (RHIC) hadron facility, with two intersecting superconducting rings, each 3.8 km in circumference [1]. We plan to add a polarized electron beam with energy tunable within the 5-30-GeV range to collide with variety of species in the existing RHIC accelerator complex, from polarized protons with a maximum energy of 250 GeV, to heavy, fully striped ions with energies up to 100 GeV/u.

  18. Accurate models for P-gp drug recognition induced from a cancer cell line cytotoxicity screen.

    PubMed

    Levatić, Jurica; Ćurak, Jasna; Kralj, Marijeta; Šmuc, Tomislav; Osmak, Maja; Supek, Fran

    2013-07-25

    P-glycoprotein (P-gp, MDR1) is a promiscuous drug efflux pump of substantial pharmacological importance. Taking advantage of large-scale cytotoxicity screening data involving 60 cancer cell lines, we correlated the differential biological activities of ∼13,000 compounds against cellular P-gp levels. We created a large set of 934 high-confidence P-gp substrates or nonsubstrates by enforcing agreement with an orthogonal criterion involving P-gp overexpressing ADR-RES cells. A support vector machine (SVM) was 86.7% accurate in discriminating P-gp substrates on independent test data, exceeding previous models. Two molecular features had an overarching influence: nearly all P-gp substrates were large (>35 atoms including H) and dense (specific volume of <7.3 Å(3)/atom) molecules. Seven other descriptors and 24 molecular fragments ("effluxophores") were found enriched in the (non)substrates and incorporated into interpretable rule-based models. Biological experiments on an independent P-gp overexpressing cell line, the vincristine-resistant VK2, allowed us to reclassify six compounds previously annotated as substrates, validating our method's predictive ability. Models are freely available at http://pgp.biozyne.com . PMID:23772653

  19. Muon collider progress

    SciTech Connect

    Noble, Robert J. FNAL

    1998-08-01

    Recent progress in the study of muon colliders is presented. An international collaboration consisting of over 100 individuals is involved in calculations and experiments to demonstrate the feasibility of this new type of lepton collider. Theoretical efforts are now concentrated on low-energy colliders in the 100 to 500 GeV center-of-mass energy range. Credible machine designs are emerging for much of a hypothetical complex from proton source to the final collider. Ionization cooling has been the most difficult part of the concept, and more powerful simulation tools are now in place to develop workable schemes. A collaboration proposal for a muon cooling experiment has been presented to the Fermilab Physics Advisory Committee, and a proposal for a targetry and pion collection channel experiment at Brookhaven National Laboratory is in preparation. Initial proton bunching and space-charge compensation experiments at existing hadron facilities have occurred to demonstrate proton driver feasibility.

  20. Linear collider: a preview

    SciTech Connect

    Wiedemann, H.

    1981-11-01

    Since no linear colliders have been built yet it is difficult to know at what energy the linear cost scaling of linear colliders drops below the quadratic scaling of storage rings. There is, however, no doubt that a linear collider facility for a center of mass energy above say 500 GeV is significantly cheaper than an equivalent storage ring. In order to make the linear collider principle feasible at very high energies a number of problems have to be solved. There are two kinds of problems: one which is related to the feasibility of the principle and the other kind of problems is associated with minimizing the cost of constructing and operating such a facility. This lecture series describes the problems and possible solutions. Since the real test of a principle requires the construction of a prototype I will in the last chapter describe the SLC project at the Stanford Linear Accelerator Center.

  1. Relativistic Heavy Ion Collider

    SciTech Connect

    Willen, E.H.

    1986-01-01

    The Relativistic Heavy Ion Collider (RHIC) is a proposed research facility at Brookhaven National Laboratory to study the collision of beams of heavy ions, up to gold in mass and at beam energies up to 100 GeV/nucleon. The physics to be explored by this collider is an overlap between the traditional disciplines of nuclear physics and high energy physics and is a continuation of the planned program of light and heavy ion physics at BNL. The machine is to be constructed in the now-empty tunnel built for the former CBA project. Various other facilities to support the collider are either in place or under construction at BNL. The collider itself, including the magnets, is in an advanced state of design, and a construction start is anticipated in the next several years.

  2. Gp96 enhances the immunogenicity of subunit vaccine of porcine reproductive and respiratory syndrome virus.

    PubMed

    Chen, Caiwei; Li, Jing; Bi, Yuhai; Jia, Xiaojuan; Meng, Songdong; Sun, Lei; Liu, Wenjun

    2012-08-01

    Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic losses in the pig industry worldwide. Currently available commercial vaccines provide limited protection due to delayed and weak cell-mediated immunity and neutralizing antibody production, thus the immunomodulators should be considered in order to improve the efficacy of PRRSV vaccines. Heat shock protein gp96 may be used as a modulator to enhance both innate and adaptive immune responses. In the present study, two multi-epitope subunit vaccines, named as Cp1 and Cp2, were designed based on the conserved B cell epitopes of viral proteins with the N-terminal 22-370 amino acids (aa) of porcine gp96 (Gp96N) chosen as the adjuvant. Immune responses elicited by the different combinations of Cp1/Cp2 and Gp96N were examined in mice and piglets. The results indicated that the group of Cp1/Cp2-Gp96N (CG) combination induced 3-4-fold higher titers of Cp1/Cp2-ELISA antibodies and neutralizing antibodies (NAs) in mice than the groups which received Cp1/Cp2 immunization alone or with Freund's adjuvant. Additionally, Gp96N significantly enhanced the levels of lymphocyte proliferative responses of splenocytes or peripheral blood mononuclear cells from vaccinated mice or piglets. The production of IFN-γ in mice splenocytes, TNF-α, IFN-γ, and IL-12 in sera of piglets were also remarkably increased with the treatment of Gp96N, while IL-4 was reduced by half and IL-10 was decreased to an undetectable level. These results suggest that the porcine Gp96N could effectively enhance the innate and adaptive immune responses of Cp1/Cp2 with a Th1-type bias. Therefore, the multi-epitope subunit vaccine Cp1/Cp2 co-administered with porcine Gp96N might potentially be a promising candidate vaccine for the prevention and control of PRRSV in pigs. PMID:22561908

  3. Transverse emittance-preserving arc compressor for high-brightness electron beam-based light sources and colliders

    NASA Astrophysics Data System (ADS)

    Di Mitri, S.; Cornacchia, M.

    2015-03-01

    Bunch length magnetic compression is used in high-brightness linacs driving free-electron lasers (FELs) and particle colliders to increase the peak current of the injected beam. To date, it is performed in dedicated insertions made of few degrees bending magnets and the compression factor is limited by the degradation of the beam transverse emittance owing to emission of coherent synchrotron radiation (CSR). We reformulate the known concept of CSR-driven optics balance for the general case of varying bunch length and demonstrate, through analytical and numerical results, that a 500 pC charge beam can be time-compressed in a periodic 180 deg arc at 2.4 GeV beam energy and lower, by a factor of up to 45, reaching peak currents of up to 2 kA and with a normalized emittance growth at the 0.1 μ \\text{m} rad level. The proposed solution offers new schemes of beam longitudinal gymnastics; an application to an energy recovery linac driving FEL is discussed.

  4. Screening HIV-1 fusion inhibitors based on capillary electrophoresis head-end microreactor targeting to the core structure of gp41.

    PubMed

    Liu, Lihong; Xu, Xiaoying; Liu, Yanhui; Zhang, Xuanxuan; Li, Lin; Jia, Zhimin

    2016-02-20

    In this paper, we design a microreactor based on electrophoretically mediated microanalysis (EMMA) with capillary electrophoresis (CE) for screening HIV-1 inhibitors that bind to the N-terminal heptad repeat (NHR, N36) region. Initially, a test sample plug is loaded into a capillary filled with buffer solution followed by N36 peptide solution, and the two solutions simultaneously mix by diffusion. Then, voltage is applied, and the sample molecules pass through the N36 peptide zone. The active compounds combine with N36, leading to a loss in the peak height of the active compound. More than 100 traditional Chinese medicine extracts (TCME) were screened, and an extract of Pheretima aspergillum (E. Perrier) (L5) was identified as having potent inhibitory activity. The results showed that L5 could significantly inhibit the HIV-1JR-FL pseudotyped virus infection; the 50% effective concentration (EC50) of L5 was approximately 32.1±1.2μg/mL, and the 50% cytotoxicity concentration (CC50) value of L5 was 146.9±4.4μg/mL, suggesting that L5 had low in vitro cytotoxicity on U87-CD4-CCR5 cells. The new method is simple and rapid, is free of antibodies, and does not require tedious processes. PMID:26730512

  5. Mapping the interactions of the single-stranded DNA binding protein of bacteriophage T4 (gp32) with DNA lattices at single nucleotide resolution: gp32 monomer binding.

    PubMed

    Jose, Davis; Weitzel, Steven E; Baase, Walter A; von Hippel, Peter H

    2015-10-30

    Combining biophysical measurements on T4 bacteriophage replication complexes with detailed structural information can illuminate the molecular mechanisms of these 'macromolecular machines'. Here we use the low energy circular dichroism (CD) and fluorescent properties of site-specifically introduced base analogues to map and quantify the equilibrium binding interactions of short (8 nts) ssDNA oligomers with gp32 monomers at single nucleotide resolution. We show that single gp32 molecules interact most directly and specifically near the 3'-end of these ssDNA oligomers, thus defining the polarity of gp32 binding with respect to the ssDNA lattice, and that only 2-3 nts are directly involved in this tight binding interaction. The loss of exciton coupling in the CD spectra of dimer 2-AP (2-aminopurine) probes at various positions in the ssDNA constructs, together with increases in fluorescence intensity, suggest that gp32 binding directly extends the sugar-phosphate backbone of this ssDNA oligomer, particularly at the 3'-end and facilitates base unstacking along the entire 8-mer lattice. These results provide a model (and 'DNA map') for the isolated gp32 binding to ssDNA targets, which serves as the nucleation step for the cooperative binding that occurs at transiently exposed ssDNA sequences within the functioning T4 DNA replication complex. PMID:26275775

  6. Design considerations for a laser-plasma linear collider

    SciTech Connect

    Schroeder, C. B.; Esarey, E.; Geddes, C. G. R.; Toth, Cs.; Leemans, W. P.

    2009-01-22

    Design considerations for a next-generation electron-positron linear collider based on laser-plasma-accelerators are discussed. Several of the advantages and challenges of laser-plasma-based accelerator technology are addressed. An example of the parameters for a 1 TeV laser-plasma-based collider is presented.

  7. Design considerations for a laser-plasma linear collider

    SciTech Connect

    Schroeder, C. B.; Esarey, E.; Geddes, C. G. R.; Toth, Cs.; Leemans, W. P.

    2008-08-01

    Design considerations for a next-generation electron-positron linear collider based on laser-plasma-accelerators are discussed. Several of the advantages and challenges of laser-plasma based accelerator technology are addressed. An example of the parameters for a 1 TeV laser-plasma based collider is presented.

  8. Messenger RNAs encoding the beta subunits of guinea pig (Cavia porcellus) luteinizing hormone (gpLH) and putative chorionic gonadotropin (gpCG) are transcribed from a single-copy gpLH/CGbeta gene.

    PubMed

    Sherman, G B; Heilman, D F; Hoss, A J; Bunick, D; Lund, L A

    2001-06-01

    mammalian pituitary LHbeta mRNAs ( approximately 750 nucleotides). Despite amplifying gpCGbeta from placental RNA, positive signal was not detected in Northern blot lanes containing guinea pig total RNA prepared from placentae collected at three gestational ages (17.3 days, 24.3 days and 68 days (term)). Other data suggest that inability to detect Northern blot signal could have been due to low relative tissue concentrations of gpCGbeta transcript and/or sampling at gestational time-points that missed peak periods of mRNA expression. We conclude that, with respect to gene copy number, coding sequence and pituitary mRNA size, the gpLH/CGbeta gene locus reflects the CTP-less consensus mammalian LHbeta condition. However, based on the capacity of this single-copy gene to express in both pituitary and placental tissues, gpLH/CGbeta also exhibits functional similarities with the single-copy equine LH/CGbeta locus. PMID:11357063

  9. The Muon Collider

    SciTech Connect

    Zisman, Michael S.

    2011-01-05

    We describe the scientific motivation for a new type of accelerator, the muon collider. This accelerator would permit an energy-frontier scientific program and yet would fit on the site of an existing laboratory. Such a device is quite challenging, and requires a substantial R&D program. After describing the ingredients of the facility, the ongoing R&D activities of the Muon Accelerator Program are discussed. A possible U.S. scenario that could lead to a muon collider at Fermilab is briefly mentioned.

  10. Stabilization of HIV-1 gp120-CD4 receptor complex through targeted interchain disulfide exchange.

    PubMed

    Cerutti, Nichole; Mendelow, Barry V; Napier, Grant B; Papathanasopoulos, Maria A; Killick, Mark; Khati, Makobetsa; Stevens, Wendy; Capovilla, Alexio

    2010-08-13

    HIV-1 enters cells via interaction between the trimeric envelope (Env) glycoprotein gp120/gp41 and the host cell surface receptor molecule CD4. The requirement of CD4 for viral entry has rationalized the development of recombinant CD4-based proteins as competitive viral attachment inhibitors and immunotherapeutic agents. In this study, we describe a novel recombinant CD4 protein designed to bind gp120 through a targeted disulfide-exchange mechanism. According to structural models of the gp120-CD4 receptor complex, substitution of Ser(60) on the CD4 domain 1 alpha-helix with Cys positions a thiol in proximity of the gp120 V1/V2 loop disulfide (Cys(126)-Cys(196)), satisfying the stereochemical and geometric conditions for redox exchange between CD4 Cys(60) and gp120 Cys(126), and the consequent formation of an interchain disulfide bond. In this study, we provide experimental evidence for this effect by describing the expression, purification, refolding, receptor binding and antiviral activity analysis of a recombinant two-domain CD4 variant containing the S60C mutation (2dCD4-S60C). We show that 2dCD4-S60C binds HIV-1 gp120 with a significantly higher affinity than wild-type protein under conditions that facilitate disulfide exchange and that this translates into a corresponding increase in the efficacy of CD4-mediated viral entry inhibition. We propose that targeted redox exchange between conserved gp120 disulfides and nucleophilic moieties positioned strategically on CD4 (or CD4-like scaffolds) conceptualizes a new strategy in the development of high affinity HIV-1 Env ligands, with important implications for therapy and vaccine development. More generally, this chalcogen substitution approach provides a general means of stabilizing receptor-ligand complexes where the structural and biophysical conditions for disulfide exchange are satisfied. PMID:20538591

  11. Stabilization of HIV-1 gp120-CD4 Receptor Complex through Targeted Interchain Disulfide Exchange*

    PubMed Central

    Cerutti, Nichole; Mendelow, Barry V.; Napier, Grant B.; Papathanasopoulos, Maria A.; Killick, Mark; Khati, Makobetsa; Stevens, Wendy; Capovilla, Alexio

    2010-01-01

    HIV-1 enters cells via interaction between the trimeric envelope (Env) glycoprotein gp120/gp41 and the host cell surface receptor molecule CD4. The requirement of CD4 for viral entry has rationalized the development of recombinant CD4-based proteins as competitive viral attachment inhibitors and immunotherapeutic agents. In this study, we describe a novel recombinant CD4 protein designed to bind gp120 through a targeted disulfide-exchange mechanism. According to structural models of the gp120-CD4 receptor complex, substitution of Ser60 on the CD4 domain 1 α-helix with Cys positions a thiol in proximity of the gp120 V1/V2 loop disulfide (Cys126–Cys196), satisfying the stereochemical and geometric conditions for redox exchange between CD4 Cys60 and gp120 Cys126, and the consequent formation of an interchain disulfide bond. In this study, we provide experimental evidence for this effect by describing the expression, purification, refolding, receptor binding and antiviral activity analysis of a recombinant two-domain CD4 variant containing the S60C mutation (2dCD4-S60C). We show that 2dCD4-S60C binds HIV-1 gp120 with a significantly higher affinity than wild-type protein under conditions that facilitate disulfide exchange and that this translates into a corresponding increase in the efficacy of CD4-mediated viral entry inhibition. We propose that targeted redox exchange between conserved gp120 disulfides and nucleophilic moieties positioned strategically on CD4 (or CD4-like scaffolds) conceptualizes a new strategy in the development of high affinity HIV-1 Env ligands, with important implications for therapy and vaccine development. More generally, this chalcogen substitution approach provides a general means of stabilizing receptor-ligand complexes where the structural and biophysical conditions for disulfide exchange are satisfied. PMID:20538591

  12. Immune Focusing and Enhanced Neutralization Induced by HIV-1 gp140 Chemical Cross-Linking

    PubMed Central

    Schiffner, T.; Kong, L.; Duncan, C. J. A.; Back, J. W.; Benschop, J. J.; Shen, X.; Huang, P. S.; Stewart-Jones, G. B.; DeStefano, J.; Seaman, M. S.; Tomaras, G. D.; Montefiori, D. C.; Schief, W. R.

    2013-01-01

    Experimental vaccine antigens based upon the HIV-1 envelope glycoproteins (Env) have failed to induce neutralizing antibodies (NAbs) against the majority of circulating viral strains as a result of antibody evasion mechanisms, including amino acid variability and conformational instability. A potential vaccine design strategy is to stabilize Env, thereby focusing antibody responses on constitutively exposed, conserved surfaces, such as the CD4 binding site (CD4bs). Here, we show that a largely trimeric form of soluble Env can be stably cross-linked with glutaraldehyde (GLA) without global modification of antigenicity. Cross-linking largely conserved binding of all potent broadly neutralizing antibodies (bNAbs) tested, including CD4bs-specific VRC01 and HJ16, but reduced binding of several non- or weakly neutralizing antibodies and soluble CD4 (sCD4). Adjuvanted administration of cross-linked or unmodified gp140 to rabbits generated indistinguishable total gp140-specific serum IgG binding titers. However, sera from animals receiving cross-linked gp140 showed significantly increased CD4bs-specific antibody binding compared to animals receiving unmodified gp140. Moreover, peptide mapping of sera from animals receiving cross-linked gp140 revealed increased binding to gp120 C1 and V1V2 regions. Finally, neutralization titers were significantly elevated in sera from animals receiving cross-linked gp140 rather than unmodified gp140. We conclude that cross-linking favors antigen stability, imparts antigenic modifications that selectively refocus antibody specificity and improves induction of NAbs, and might be a useful strategy for future vaccine design. PMID:23843636

  13. Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41

    PubMed Central

    Lu, Lu; Yu, Fei; Cai, Lifeng; Debnath, Asim K.; Jiang, Shibo

    2015-01-01

    Human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein surface subunit gp120 and transmembrane subunit gp41 play important roles in HIV-1 entry, thus serving as key targets for the development of HIV-1 entry inhibitors. T20 peptide (enfuvirtide) is the first U.S. FDA-approved HIV entry inhibitor; however, its clinical application is limited by the lack of oral availability. Here, we have described the structure and function of the HIV-1 gp120 and gp41 subunits and reviewed advancements in the development of small-molecule HIV entry inhibitors specifically targeting these two Env glycoproteins. We then compared the advantages and disadvantages of different categories of HIV entry inhibitor candidates and further predicted the future trend of HIV entry inhibitor development. PMID:26324044

  14. Gp15 and gp16 cooperate in translocating bacteriophage T7 DNA into the infected cell

    PubMed Central

    Chang, Chung-Yu; Kemp, Priscilla; Molineux, Ian J.

    2010-01-01

    Loss of up to four amino acids from the C terminus of the 1318 residue bacteriophage T7 gp16 allows plaque formation at normal efficiencies. Loss of five residues results in non-infective virions, and loss of twelve prevents assembly of stable particles. However, replacing the C-terminal seven with nineteen non-native residues allows assembly of non-infective virions. The latter adsorb and eject internal core proteins into the cell envelope but no phage DNA enters the cytoplasm. Extragenic suppressors of the defective gene 16 lie in gene 15; the mutant gp15 proteins not only re-establish infectivity, they fully restore the kinetics of genome internalization to those exhibited by wild-type phage. After ejection from the infecting particle, gp15 and gp16 thus function together in ratcheting the leading end of the T7 genome into the cytoplasm of the infected cell. PMID:20036409

  15. Tau anomalous magnetic moment in γγ colliders

    NASA Astrophysics Data System (ADS)

    Peressutti, Javier; Sampayo, Oscar A.

    2012-08-01

    We investigate the possibility of setting model independent limits for a nonstandard anomalous magnetic moment aτNP of the tau lepton, in future γγ colliders based on Compton backscattering. For a hypothetical collider we find that, at various levels of confidence, the limits for aτNP could be improved, compared to previous studies based on LEP1, LEP2 and SLD data. We show the results for a realistic range of the center of mass energy of the e+e- collider. As a more direct application, we also present the results of the simulation for the photon collider at the TESLA project.

  16. Structural and functional characterization of EIAV gp45 fusion peptide proximal region and asparagine-rich layer.

    PubMed

    Duan, Liangwei; Du, Jiansen; Wang, Xuefeng; Zhou, Jianhua; Wang, Xiaojun; Liu, Xinqi

    2016-04-01

    Equine infectious anaemia virus (EIAV) and human immunodeficiency virus (HIV) are members of the lentiviral genus. Similar to HIV gp41, EIAV gp45 is a fusogenic protein that mediates fusion between the viral particle and the host cell membrane. The crystal structure of gp45 reported reveals a different conformation in the here that includes the fusion peptide proximal region (FPPR) and neighboring asparagine-rich layer compared with previous HIV-1 gp41 structures. A complicated hydrogen-bond network containing a cluster of solvent molecules appears to be critical for the stability of the gp45 helical bundle. Interestingly, viral replication was relatively unaffected by site-directed mutagenesis of EIAV, in striking contrast to that of HIV-1. Based on these observations, we speculate that EIAV is more adaptable to emergent mutations, which might be important for the evolution of EIAV as a quasi-species, and could potentially contribute to the success of the EIAV vaccine. PMID:26874586

  17. GP trainers and trainees - trait and gender differences in personality: implications for GP training.

    PubMed

    Joffe, Megan; MacLeod, Sheona; Kedziora, Marta; Main, Paul

    2016-05-01

    This study looked at differences between established GP trainers and current GP trainees in relation to personality traits. Personality differences are particularly important for training in the UK context where the attributes of successful GPs may be evolving as the context changes, and where there is a unique one-to-one relationship between trainer and trainee. GP trainers and trainees attending educational events were invited to participate in this study by completing the NEO-PI-R, a personality measure. Correlation and multiple regression analysis demonstrated differences between these groups; some in line with expected differences relating to age and gender. Others, such as lower reported levels of emotional resilience, may be particular to this trainee population. Overall the gender differences are significant given the trend towards the feminisation of the medical profession. Generational differences may also explain some behaviour and attitudinal differences which can aid trainers' understanding of training issues. The findings have important implications for training, particularly in relation to the development of emotional resilience for GP trainees, and for recruitment. Further research correlating educational outcomes and perceived satisfaction with a GP career and GP training would indicate if trainer/trainee personality differences have a direct bearing on educational outcomes and future practice. PMID:27059247

  18. Hadron collider physics

    SciTech Connect

    Pondrom, L.

    1991-10-03

    An introduction to the techniques of analysis of hadron collider events is presented in the context of the quark-parton model. Production and decay of W and Z intermediate vector bosons are used as examples. The structure of the Electroweak theory is outlined. Three simple FORTRAN programs are introduced, to illustrate Monte Carlo calculation techniques. 25 refs.

  19. Introductory Lectures on Collider Physics

    NASA Astrophysics Data System (ADS)

    Tait, Tim M. P.; Wang, Lian-Tao

    2013-12-01

    These are elementary lectures about collider physics. They are aimed at graduate students who have some background in computing Feynman diagrams and the Standard Model, but assume no particular sophistication with the physics of high energy colliders.

  20. Fast feedback for linear colliders

    SciTech Connect

    Hendrickson, L.; Adolphsen, C.; Allison, S.; Gromme, T.; Grossberg, P.; Himel, T.; Krauter, K.; MacKenzie, R.; Minty, M.; Sass, R.

    1995-05-01

    A fast feedback system provides beam stabilization for the SLC. As the SLC is in some sense a prototype for future linear colliders, this system may be a prototype for future feedbacks. The SLC provides a good base of experience for feedback requirements and capabilities as well as a testing ground for performance characteristics. The feedback system controls a wide variety of machine parameters throughout the SLC and associated experiments, including regulation of beam position, angle, energy, intensity and timing parameters. The design and applications of the system are described, in addition to results of recent performance studies.

  1. High luminosity muon collider design

    SciTech Connect

    Palmer, R.; Gallardo, J.

    1996-10-01

    Muon Colliders have unique technical and physics advantages and disadvantages when compared with both hadron and electron machines. They should be regarded as complementary. Parameters are given of 4 TeV high luminosity {mu}{sup +}{mu}{sup {minus}} collider, and of a 0.5 TeV lower luminosity demonstration machine. We discuss the various systems in such muon colliders.

  2. Identification and Characterization of an Immunogenic Hybrid Epitope Formed by both HIV gp120 and Human CD4 Proteins ▿

    PubMed Central

    Lewis, George K.; Fouts, Timothy R.; Ibrahim, Sani; Taylor, Brian M.; Salkar, Rachita; Guan, Yongjun; Kamin-Lewis, Roberta; DeVico, Anthony L.

    2011-01-01

    Certain antibodies from HIV-infected humans bind conserved transition state (CD4 induced [CD4i]) domains on the HIV envelope glycoprotein, gp120, and demonstrate extreme dependence on the formation of a gp120-human CD4 receptor complex. The epitopes recognized by these antibodies remain undefined although recent crystallographic studies of the anti-CD4i monoclonal antibody (MAb) 21c suggest that contacts with CD4 as well as gp120 might occur. Here, we explore the possibility of hybrid epitopes that demand the collaboration of both gp120 and CD4 residues to enable antibody reactivity. Analyses with a panel of human anti-CD4i MAbs and gp120-CD4 antigens with specific mutations in predicted binding domains revealed one putative hybrid epitope, defined by the human anti-CD4i MAb 19e. In virological and immunological tests, MAb 19e did not bind native or constrained gp120 except in the presence of CD4. This contrasted with other anti-CD4i MAbs, including MAb 21c, which bound unliganded, full-length gp120 held in a constrained conformation. Conversely, MAb 19e exhibited no specific reactivity with free human CD4. Computational modeling of MAb 19e interactions with gp120-CD4 complexes suggested a distinct binding profile involving antibody heavy chain interactions with CD4 and light chain interactions with gp120. In accordance, targeted mutations in CD4 based on this model specifically reduced MAb 19e interactions with stable gp120-CD4 complexes that retained reactivity with other anti-CD4i MAbs. These data represent a rare instance of an antibody response that is specific to a pathogen-host cell protein interaction and underscore the diversity of immunogenic CD4i epitope structures that exist during natural infection. PMID:21994452

  3. Fast cooling, muon acceleration and the prospect of muon colliders

    NASA Astrophysics Data System (ADS)

    Palmer, Mark

    Facilities based on stored muons offer unique potential for future high-energy physics capabilities. Three key characteristics of the muon make this possible: * The muon is a lepton; * The muon is roughly 200 times as massive as the electron; * The muon decays to an electron and two neutrinos. As the next heavier members of the lepton family with respect to the electron and positron, μ+ and μ-. beams can be collided to provide a precision lepton probe of the electroweak couplings. This makes a muon collider a suitable option for a lepton collider companion to a hadron collider discovery machine...

  4. The Very Large Hadron Collider: The farthest energy frontier

    SciTech Connect

    Barletta, William A.

    2001-06-21

    The Very Large Hadron Collider (or Eloisatron) represents what may well be the final step on the energy frontier of accelerator-based high energy physics. While an extremely high luminosity proton collider at 100-200 TeV center of mass energy can probably be built in one step with LHC technology, that machine would cost more than what is presently politically acceptable. This talk summarizes the strategies of collider design including staged deployment, comparison with electron-positron colliders, opportunities for major innovation, and the technical challenges of reducing costs to manageable proportions. It also presents the priorities for relevant R and D for the next few years.

  5. The impact of a GP clinical audit on the provision of smoking cessation advice

    PubMed Central

    McKay-Brown, Lisa; Bishop, Nicole; Balmford, James; Borland, Ron; Kirby, Catherine; Piterman, Leon

    2008-01-01

    Aim To investigate whether participation in a clinical audit and education session would improve GP management of patients who smoke. Methods GPs who participated in an associated smoking cessation research program were invited to complete a three-stage clinical audit. This process included a retrospective self-audit of smoking cessation management practices over the 6 months prior to commencing the study, attending a 2.5 hour education session about GP management of smoking cessation, and completion of a second retrospective self-audit 6 months later. Twenty-eight GPs completed the full audit and education process, providing information about their smoking cessation management with 1114 patients. The main outcome measure was changes in GP management of smoking cessation with patients across the audit period, as measured by the clinical audit tool. Results The majority of GPs (57%) indicated that as a result of the audit process they had altered their approach to the management of patients who smoke. Quantitative analyses confirmed significant increases in various forms of evidence-based smoking cessation management practices to assist patients to quit, or maintain quitting across the audit period. However comparative analyses of patient data challenged these findings, suggesting that the clinical audit process had less impact on GP practice than suggested in GP's self-reported audit data. Conclusion This study provides some support for the combined use of self-auditing, feedback and education to improve GP management of smoking cessation. However further research is warranted to examine GP- and patient-based reports of outcomes from clinical audit and other educational interventions. PMID:18973708

  6. Hyperion 5113/GP Infrasound Sensor Evaluation.

    SciTech Connect

    Merchant, Bion J.

    2015-08-01

    Sandia National Laboratories has tested and evaluated an infrasound sensor, the 5113/GP manufactured by Hyperion. These infrasound sensors measure pressure output by a methodology developed by the University of Mississippi. The purpose of the infrasound sensor evaluation was to determine a measured sensitivity, transfer function, power, self-noise, dynamic range, and seismic sensitivity. These sensors are being evaluated prior to deployment by the U.S. Air Force.

  7. GpIIb/IIIa+ subpopulation of rat megakaryocyte progenitor cells exhibits high responsiveness to human thrombopoietin.

    PubMed

    Kato, T; Horie, K; Hagiwara, T; Maeda, E; Tsumura, H; Ohashi, H; Miyazaki, H

    1996-08-01

    The recently cloned factor thrombopoietin (TPO) has been shown to exhibit megakaryocyte colony-stimulating activity in vitro. In this investigation, to further evaluate the action of TPO on megakaryocyte progenitor cells (colony-forming units-megakaryocyte [CFU-MK]), GpIIb/IIIa+ and GpIIb/IIIa- populations of CFU-MK were prepared from rat bone marrow cells based on their reactivity with P55 antibody, a monoclonal antibody against rat GpIIb/IIIa, and their responsiveness to recombinant human TPO (rhTPO) and recombinant rat interleukin-3 (rrIL-3) was examined using a megakaryocyte colony-forming assay (Meg-CSA). rhTPO supported only megakaryocyte colony growth from both fractions in a dose-dependent fashion. The mean colony size observed with the GpIIb/IIIa+ population was smaller than that seen with the GpIIb/IIIa- population. With the optimal concentration of either rhTPO or rrIL-3, similar numbers of megakaryocyte colonies were formed from the GpIIb/IIIa+ population previously shown to be highly enriched for CFU-MK. In contrast, the maximum number of megakaryocyte colonies from the GpIIb/IIIa- population stimulated by rhTPO was only 24.2% of that achieved with rrIL-3. Morphologic analysis of rhTPO-promoted megakaryocyte colonies from the GpIIb/IIIa+ population showed that the average colony size was smaller but that the mean diameter of individual megakaryocytes was larger than in megakaryocyte colonies promoted with rrIL-3. rhTPO plus rrIL-3, each at suboptimal concentrations, had an additive effect on proliferation of CFU-MK in the GpIIb/IIIa+ fraction, whereas rhTPO plus murine IL-6 or murine granulocyte-macrophage colony-stimulating factor (mG-M-CSF) modestly but significantly reduced megakaryocyte colony growth. These results indicate that TPO preferentially acts on GpIIb/IIIa+ late CFU-MK with lower proliferative capacity and interacts with some other cytokines in CFU-MK development. PMID:8765496

  8. N-terminal substitutions in HIV-1 gp41 reduce the expression of non-trimeric envelope glycoproteins on the virus

    SciTech Connect

    Dey, Antu K.; David, Kathryn B.; Ray, Neelanjana; Ketas, Thomas J.; Klasse, Per J.; Doms, Robert W.; Moore, John P.

    2008-03-01

    The native, functional HIV-1 envelope glycoprotein (Env) complex is a trimer of two non-covalently associated subunits: the gp120 surface glycoprotein and the gp41 transmembrane glycoprotein. However, various non-functional forms of Env are present on virus particles and HIV-1-infected cells, some of which probably arise as the native complex decays. The aberrant forms include gp120-gp41 monomers and oligomers, as well as gp41 subunits from which gp120 has dissociated. The presence of non-functional Env creates binding sites for antibodies that do not recognize native Env complexes and that are, therefore, non-neutralizing. Non-native Env forms (monomers, dimers, tetramers and aggregates) can also arise when soluble gp140 proteins, lacking the cytoplasmic and transmembrane domains of gp41, are expressed for vaccine studies. We recently identified five amino acids in the gp41 N-terminal region (I535, Q543, S553, K567 and R588) that promote gp140 trimerization. We have now studied their influence on the function and antigenic properties of JR-FL Env expressed on the surfaces of pseudoviruses and Env-transfected cells. The 5 substitutions in gp41 reduce the expression of non-trimeric gp160s, without affecting trimer levels. Pseudovirions bearing the mutant Env are fully infectious with similar kinetics of Env-mediated fusion. Various non-neutralizing antibodies bind less strongly to the Env mutant, but neutralizing antibody binding is unaffected. Hence the gp41 substitutions do not adversely affect Env structure, supporting their use for making new Env-based vaccines. The mutant Env might also help in studies intended to correlate antibody binding to virus neutralization. Of note is that the 5 residues are much more frequent, individually or collectively, in viruses from subtypes other than B.

  9. GP Workbench Manual: Technical Manual, User's Guide, and Software Guide

    USGS Publications Warehouse

    Oden, Charles P.; Moulton, Craig W.

    2006-01-01

    GP Workbench is an open-source general-purpose geophysical data processing software package written primarily for ground penetrating radar (GPR) data. It also includes support for several USGS prototype electromagnetic instruments such as the VETEM and ALLTEM. The two main programs in the package are GP Workbench and GP Wave Utilities. GP Workbench has routines for filtering, gridding, and migrating GPR data; as well as an inversion routine for characterizing UXO (unexploded ordinance) using ALLTEM data. GP Workbench provides two-dimensional (section view) and three-dimensional (plan view or time slice view) processing for GPR data. GP Workbench can produce high-quality graphics for reports when Surfer 8 or higher (Golden Software) is installed. GP Wave Utilities provides a wide range of processing algorithms for single waveforms, such as filtering, correlation, deconvolution, and calculating GPR waveforms. GP Wave Utilities is used primarily for calibrating radar systems and processing individual traces. Both programs also contain research features related to the calibration of GPR systems and calculating subsurface waveforms. The software is written to run on the Windows operating systems. GP Workbench can import GPR data file formats used by major commercial instrument manufacturers including Sensors and Software, GSSI, and Mala. The GP Workbench native file format is SU (Seismic Unix), and subsequently, files generated by GP Workbench can be read by Seismic Unix as well as many other data processing packages.

  10. Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility

    SciTech Connect

    Pancera, Marie; Majeed, Shahzad; Ban, Yih-En Andrew; Chen, Lei; Huang, Chih-chin; Kong, Leopold; Kwon, Young Do; Stuckey, Jonathan; Zhou, Tongqing; Robinson, James E.; Schief, William R.; Sodroski, Joseph; Wyatt, Richard; Kwong, Peter D.

    2010-04-15

    The viral spike of HIV-1 is composed of three gp120 envelope glycoproteins attached noncovalently to three gp41 transmembrane molecules. Viral entry is initiated by binding to the CD4 receptor on the cell surface, which induces large conformational changes in gp120. These changes not only provide a model for receptor-triggered entry, but affect spike sensitivity to drug- and antibody-mediated neutralization. Although some of the details of the CD4-induced conformational change have been visualized by crystal structures and cryoelectron tomograms, the critical gp41-interactive region of gp120 was missing from previous atomic-level characterizations. Here we determine the crystal structure of an HIV-1 gp120 core with intact gp41-interactive region in its CD4-bound state, compare this structure to unliganded and antibody-bound forms to identify structurally invariant and plastic components, and use ligand-oriented cryoelectron tomograms to define component mobility in the viral spike context. Newly defined gp120 elements proximal to the gp41 interface complete a 7-stranded {beta}-sandwich, which appeared invariant in conformation. Loop excursions emanating from the sandwich form three topologically separate - and structurally plastic - layers, topped off by the highly glycosylated gp120 outer domain. Crystal structures, cryoelectron tomograms, and interlayer chemistry were consistent with a mechanism in which the layers act as a shape-changing spacer, facilitating movement between outer domain and gp41-associated {beta}-sandwich and providing for conformational diversity used in immune evasion. A 'layered' gp120 architecture thus allows movement among alternative glycoprotein conformations required for virus entry and immune evasion, whereas a {beta}-sandwich clamp maintains gp120-gp41 interaction and regulates gp41 transitions.

  11. Bouncing and Colliding Branes

    SciTech Connect

    Lehners, Jean-Luc

    2007-11-20

    In a braneworld description of our universe, we must allow for the possibility of having dynamical branes around the time of the big bang. Some properties of such domain walls in motion are discussed here, for example the ability of negative-tension domain walls to bounce off spacetime singularities and the consequences for cosmological perturbations. In this context, we will also review a colliding branes solution of heterotic M-theory that has been proposed as a model for early universe cosmology.

  12. Muon Collider Progress: Accelerators

    SciTech Connect

    Zisman, Michael S.

    2011-09-10

    A muon collider would be a powerful tool for exploring the energy-frontier with leptons, and would complement the studies now under way at the LHC. Such a device would offer several important benefits. Muons, like electrons, are point particles so the full center-of-mass energy is available for particle production. Moreover, on account of their higher mass, muons give rise to very little synchrotron radiation and produce very little beamstrahlung. The first feature permits the use of a circular collider that can make efficient use of the expensive rf system and whose footprint is compatible with an existing laboratory site. The second feature leads to a relatively narrow energy spread at the collision point. Designing an accelerator complex for a muon collider is a challenging task. Firstly, the muons are produced as a tertiary beam, so a high-power proton beam and a target that can withstand it are needed to provide the required luminosity of ~1 × 10{sup 34} cm{sup –2}s{sup –1}. Secondly, the beam is initially produced with a large 6D phase space, which necessitates a scheme for reducing the muon beam emittance (“cooling”). Finally, the muon has a short lifetime so all beam manipulations must be done very rapidly. The Muon Accelerator Program, led by Fermilab and including a number of U.S. national laboratories and universities, has undertaken design and R&D activities aimed toward the eventual construction of a muon collider. Design features of such a facility and the supporting R&D program are described.

  13. Binary Encoded-Prototype Tree for Probabilistic Model Building GP

    NASA Astrophysics Data System (ADS)

    Yanase, Toshihiko; Hasegawa, Yoshihiko; Iba, Hitoshi

    In recent years, program evolution algorithms based on the estimation of distribution algorithm (EDA) have been proposed to improve search ability of genetic programming (GP) and to overcome GP-hard problems. One such method is the probabilistic prototype tree (PPT) based algorithm. The PPT based method explores the optimal tree structure by using the full tree whose number of child nodes is maximum among possible trees. This algorithm, however, suffers from problems arising from function nodes having different number of child nodes. These function nodes cause intron nodes, which do not affect the fitness function. Moreover, the function nodes having many child nodes increase the search space and the number of samples necessary for properly constructing the probabilistic model. In order to solve this problem, we propose binary encoding for PPT. In this article, we convert each function node to a subtree of binary nodes where the converted tree is correct in grammar. Our method reduces ineffectual search space, and the binary encoded tree is able to express the same tree structures as the original method. The effectiveness of the proposed method is demonstrated through the use of two computational experiments.

  14. COLLIDING CRYSTALLINE BEAMS.

    SciTech Connect

    WEI, J.

    1998-06-26

    The understanding of crystalline beams has advanced to the point where one can now, with reasonable confidence, undertake an analysis of the luminosity of colliding crystalline beams. Such a study is reported here. It is necessary to observe the criteria, previously stated, for the creation and stability of crystalline beams. This requires, firstly, the proper design of a lattice. Secondly, a crystal must be formed, and this can usually be done at various densities. Thirdly, the crystals in a colliding-beam machine are brought into collision. We study all of these processes using the molecular dynamics (MD) method. The work parallels what was done previously, but the new part is to study the crystal-crystal interaction in collision. We initially study the zero-temperature situation. If the beam-beam force (or equivalent tune shift) is too large then overlapping crystals can not be created (rather two spatially separated crystals are formed). However, if the beam-beam force is less than but comparable to that of the space-charge forces between the particles, we find that overlapping crystals can be formed and the beam-beam tune shift can be of the order of unity. Operating at low but non-zero temperature can increase the luminosity by several orders of magnitude over that of a usual collider. The construction of an appropriate lattice, and the development of adequately strong cooling, although theoretically achievable, is a challenge in practice.

  15. Colliding Crystalline Beams

    SciTech Connect

    Wei, Jie; Sessler, A.M.

    1998-06-01

    The understanding of crystalline beams has advanced to the point where one can now, with reasonable confidence, undertake an analysis of the luminosity of colliding crystalline beams. Such a study is reported here. It is necessary to observe the criteria, previously stated, for the creation and stability of crystalline beams. This requires, firstly, the proper design of a lattice. Secondly, a crystal must be formed, and this can usually be done at various densities. Thirdly, the crystals in a colliding-beam machine are brought into collision. We study all of these processes using the molecular dynamics (MD) method. The work parallels what was done previously, but the new part is to study the crystal-crystal interaction in collision. We initially study the zero-temperature situation. If the beam-beam force (or equivalent tune shift) is too large then over-lapping crystals can not be created (rather two spatially separated crystals are formed). However, if the beam-beam force is less than but comparable to that of the space-charge forces between the particles, we find that overlapping crystals can be formed and the beam-beam tune shift can be of the order of unity. Operating at low but non-zero temperature can increase the luminosity by several orders of magnitude over that of a usual collider. The construction of an appropriate lattice, and the development of adequately strong coding, although theoretically achievable, is a challenge in practice.

  16. Connecting, Supporting, Colliding: The Work-Based Interactions of Young LGBQ-Identifying Workers and Older Queer Colleagues

    ERIC Educational Resources Information Center

    Willis, Paul

    2010-01-01

    While attention has been given to older employees' experiences of sexuality-based discrimination and harassment, this paper explores young lesbian, gay, bisexual, and queer identifying employees' (18-26 years old) accounts of working with queer coworkers and managers in Australian workplaces. Two sets of relationships are evidenced and discussed:…

  17. Human cytomegalovirus Fcγ binding proteins gp34 and gp68 antagonize Fcγ receptors I, II and III.

    PubMed

    Corrales-Aguilar, Eugenia; Trilling, Mirko; Hunold, Katja; Fiedler, Manuela; Le, Vu Thuy Khanh; Reinhard, Henrike; Ehrhardt, Katrin; Mercé-Maldonado, Eva; Aliyev, Enver; Zimmermann, Albert; Johnson, David C; Hengel, Hartmut

    2014-05-01

    Human cytomegalovirus (HCMV) establishes lifelong infection with recurrent episodes of virus production and shedding despite the presence of adaptive immunological memory responses including HCMV immune immunoglobulin G (IgG). Very little is known how HCMV evades from humoral and cellular IgG-dependent immune responses, the latter being executed by cells expressing surface receptors for the Fc domain of IgG (FcγRs). Remarkably, HCMV expresses the RL11-encoded gp34 and UL119-118-encoded gp68 type I transmembrane glycoproteins which bind Fcγ with nanomolar affinity. Using a newly developed FcγR activation assay, we tested if the HCMV-encoded Fcγ binding proteins (HCMV FcγRs) interfere with individual host FcγRs. In absence of gp34 or/and gp68, HCMV elicited a much stronger activation of FcγRIIIA/CD16, FcγRIIA/CD32A and FcγRI/CD64 by polyclonal HCMV-immune IgG as compared to wildtype HCMV. gp34 and gp68 co-expression culminates in the late phase of HCMV replication coinciding with the emergence of surface HCMV antigens triggering FcγRIII/CD16 responses by polyclonal HCMV-immune IgG. The gp34- and gp68-dependent inhibition of HCMV immune IgG was fully reproduced when testing the activation of primary human NK cells. Their broad antagonistic function towards FcγRIIIA, FcγRIIA and FcγRI activation was also recapitulated in a gain-of-function approach based on humanized monoclonal antibodies (trastuzumab, rituximab) and isotypes of different IgG subclasses. Surface immune-precipitation showed that both HCMV-encoded Fcγ binding proteins have the capacity to bind trastuzumab antibody-HER2 antigen complexes demonstrating simultaneous linkage of immune IgG with antigen and the HCMV inhibitors on the plasma membrane. Our studies reveal a novel strategy by which viral FcγRs can compete for immune complexes against various Fc receptors on immune cells, dampening their activation and antiviral immunity. PMID:24830376

  18. Lattice of the NICA Collider Rings

    SciTech Connect

    Sidorin, Anatoly; Kozlov, Oleg; Meshkov, Igor; Mikhaylov, Vladimir; Trubnikov, Grigoriy; Lebedev, Valeri Nagaitsev, Sergei; Senichev, Yurij; /Julich, Forschungszentrum

    2010-05-01

    The Nuclotron-based Ion Collider fAcility (NICA) is a new accelerator complex being constructed at JINR. It is designed for collider experiments with ions and protons and has to provide ion-ion (Au{sup 79+}) and ion-proton collisions in the energy range 1 {divided_by} 4.5 GeV/n and collisions of polarized proton-proton and deuteron-deuteron beams. Collider conceptions with constant {gamma}{sub tr} and with possibility of its variation are considered. The ring has the racetrack shape with two arcs and two long straight sections. Its circumference is about 450m. The straight sections are optimized to have {beta}* {approx} 35cm in two IPs and a possibility of final betatron tune adjustment.

  19. An essential role for the baseplate protein Gp45 in phage adsorption to Staphylococcus aureus

    PubMed Central

    Li, Xuehua; Koç, Cengiz; Kühner, Petra; Stierhof, York-Dieter; Krismer, Bernhard; Enright, Mark C.; Penadés, José R.; Wolz, Christiane; Stehle, Thilo; Cambillau, Christian; Peschel, Andreas; Xia, Guoqing

    2016-01-01

    Despite the importance of phages in driving horizontal gene transfer (HGT) among pathogenic bacteria, the underlying molecular mechanisms mediating phage adsorption to S. aureus are still unclear. Phage ϕ11 is a siphovirus with a high transducing efficiency. Here, we show that the tail protein Gp45 localized within the ϕ11 baseplate. Phage ϕ11 was efficiently neutralized by anti-Gp45 serum, and its adsorption to host cells was inhibited by recombinant Gp45 in a dose-dependent manner. Flow cytometry analysis demonstrated that biotin-labelled Gp45 efficiently stained the wild-type S. aureus cell but not the double knockout mutant ΔtarM/S, which lacks both α- and β-O-GlcNAc residues on its wall teichoic acids (WTAs). Additionally, adsorption assays indicate that GlcNAc residues on WTAs and O-acetyl groups at the 6-position of muramic acid residues in peptidoglycan are essential components of the ϕ11 receptor. The elucidation of Gp45-involved molecular interactions not only broadens our understanding of siphovirus-mediated HGT, but also lays the groundwork for the development of sensitive affinity-based diagnostics and therapeutics for S. aureus infection. PMID:27212064

  20. An essential role for the baseplate protein Gp45 in phage adsorption to Staphylococcus aureus.

    PubMed

    Li, Xuehua; Koç, Cengiz; Kühner, Petra; Stierhof, York-Dieter; Krismer, Bernhard; Enright, Mark C; Penadés, José R; Wolz, Christiane; Stehle, Thilo; Cambillau, Christian; Peschel, Andreas; Xia, Guoqing

    2016-01-01

    Despite the importance of phages in driving horizontal gene transfer (HGT) among pathogenic bacteria, the underlying molecular mechanisms mediating phage adsorption to S. aureus are still unclear. Phage ϕ11 is a siphovirus with a high transducing efficiency. Here, we show that the tail protein Gp45 localized within the ϕ11 baseplate. Phage ϕ11 was efficiently neutralized by anti-Gp45 serum, and its adsorption to host cells was inhibited by recombinant Gp45 in a dose-dependent manner. Flow cytometry analysis demonstrated that biotin-labelled Gp45 efficiently stained the wild-type S. aureus cell but not the double knockout mutant ΔtarM/S, which lacks both α- and β-O-GlcNAc residues on its wall teichoic acids (WTAs). Additionally, adsorption assays indicate that GlcNAc residues on WTAs and O-acetyl groups at the 6-position of muramic acid residues in peptidoglycan are essential components of the ϕ11 receptor. The elucidation of Gp45-involved molecular interactions not only broadens our understanding of siphovirus-mediated HGT, but also lays the groundwork for the development of sensitive affinity-based diagnostics and therapeutics for S. aureus infection. PMID:27212064

  1. Nonuniversal scalar mass scenario with Higgs funnel region of supersymmetric dark matter: A signal-based analysis for the Large Hadron Collider

    SciTech Connect

    Bhattacharya, Subhaditya; Mukhopadhyaya, Biswarup; Chattopadhyay, Utpal; Das, Debottam; Choudhury, Debajyoti

    2010-04-01

    We perform a multilepton channel analysis in the context of the Large Hadron Collider (LHC) for Wilkinson Microwave Anisotropy Probe compatible points in a model with nonuniversal scalar masses, which admits a Higgs funnel region of supersymmetry dark matter even for a small tan{beta}. In addition to two- and three-lepton final states, four-lepton events, too, are shown to be useful for this purpose. We also compare the collider signatures in similar channels for Wilkinson Microwave Anisotropy Probe compatible points in the minimal supergravity (mSUGRA) framework with similar gluino masses. Some definite features of such nonuniversal scenario emerge from the analysis.

  2. Distinct effects of Broncho-Vaxom (OM-85 BV) on gp130 binding cytokines

    PubMed Central

    Roth, M; Block, L

    2000-01-01

    BACKGROUND—Broncho-Vaxom (OM-85 BV) is known to support respiratory tract resistance to bacterial infections. In vivo and in vitro studies in animals and humans have shown that the action of the drug is based on the modulation of the host immune response, and it has been found to upregulate interferon γ (IFN-γ) and interleukin (IL)-2, IL-6, and IL-8. These immunomodulatory effects of the compound may explain its stimulation on T helper cells and natural killer cells. Following earlier findings that OM-85 BV induces the synthesis of IL-6, a study was undertaken to investigate its possible effect on other gp130 binding cytokines including IL-11, IL-12, leukaemia inhibitory factor (LIF), oncostatin M (OSM), and ciliary neutrophil factor (CNTF). Its modulation of the corresponding receptors of the above mentioned cytokines and of the signal transducer gp130 in human pulmonary fibroblasts and peripheral blood lymphocytes was also studied.
METHODS—Transcription of cytokines was assessed by Northern blot analysis. Secretion of cytokines was analysed using commercially available enzyme linked immunosorbent assay kits. Cytokine receptors and gp130 proteins were determined by Western blot analysis.
RESULTS—OM-85 BV increased the expression of IL-11 in human lung fibroblasts, but not in lymphocytes, in a dose and time dependent manner by maximal fivefold within 20 hours. The compound inhibited serum induced IL-12 expression in peripheral blood lymphocytes but did not induce OSM, LIF, or CNTF at any concentration. In lung fibroblasts the expression of the IL-6 receptor was enhanced fourfold at a concentration of 10 µg/ml OM-85 BV while that of the IL-11 receptor was not altered. In peripheral blood lymphocytes LIF receptor α expression was downregulated in the presence of 10 µg/ml OM-85 BV. At a concentration of 10 µg/ml OM-85 BV enhanced gp130 gene transcription fivefold and increased gp130 protein accumulation in cell membranes by 2.5times

  3. Hadron-hadron colliders

    SciTech Connect

    Month, M.; Weng, W.T.

    1983-06-21

    The objective is to investigate whether existing technology might be extrapolated to provide the conceptual framework for a major hadron-hadron collider facility for high energy physics experimentation for the remainder of this century. One contribution to this large effort is to formalize the methods and mathematical tools necessary. In this report, the main purpose is to introduce the student to basic design procedures. From these follow the fundamental characteristics of the facility: its performance capability, its size, and the nature and operating requirements on the accelerator components, and with this knowledge, we can determine the technology and resources needed to build the new facility.

  4. The super collider revisited

    SciTech Connect

    Hussein, M.S.; Pato, M.P. )

    1992-05-20

    In this paper, the authors suggest a revised version of the Superconducting Super Collider (SSC) that employs the planned SSC first stage machine as an injector of 0.5 TeV protons into a power laser accelerator. The recently developed Non-linear Amplification of Inverse Bremsstrahlung Acceleration (NAIBA) concept dictates the scenario of the next stage of acceleration. Post Star Wars lasers, available at several laboratories, can be used for the purpose. The 40 TeV CM energy, a target of the SSC, can be obtained with a new machine which can be 20 times smaller than the planned SSC.

  5. Muon Colliders and Neutrino Factories

    SciTech Connect

    Geer, Steve; /Fermilab

    2009-11-01

    Over the past decade, there has been significant progress in developing the concepts and technologies needed to produce, capture, and accelerate {Omicron}(10{sup 21}) muons per year. These developments have paved the way for a new type of neutrino source (neutrino factory) and a new type of very high energy lepton-antilepton collider (muon collider). This article reviews the motivation, design, and research and development for future neutrino factories and muon colliders.

  6. Muon colliders and neutrino factories

    SciTech Connect

    Geer, S.; /Fermilab

    2010-09-01

    Over the last decade there has been significant progress in developing the concepts and technologies needed to produce, capture and accelerate {Omicron}(10{sup 21}) muons/year. This development prepares the way for a new type of neutrino source (Neutrino Factory) and a new type of very high energy lepton-antilepton collider (Muon Collider). This article reviews the motivation, design and R&D for Neutrino Factories and Muon Colliders.

  7. Muon Colliders and Neutrino Factories *

    NASA Astrophysics Data System (ADS)

    Geer, Steve

    2009-11-01

    Over the past decade, there has been significant progress in developing the concepts and technologies needed to produce, capture, and accelerate O(1021) muons per year. These developments have paved the way for a new type of neutrino source (neutrino factory) and a new type of very high energy lepton-antilepton collider (muon collider). This article reviews the motivation, design, and research and development for future neutrino factories and muon colliders.

  8. The Next Linear Collider: NLC2001

    SciTech Connect

    D. Burke et al.

    2002-01-14

    Recent studies in elementary particle physics have made the need for an e{sup +}e{sup -} linear collider able to reach energies of 500 GeV and above with high luminosity more compelling than ever [1]. Observations and measurements completed in the last five years at the SLC (SLAC), LEP (CERN), and the Tevatron (FNAL) can be explained only by the existence of at least one particle or interaction that has not yet been directly observed in experiment. The Higgs boson of the Standard Model could be that particle. The data point strongly to a mass for the Higgs boson that is just beyond the reach of existing colliders. This brings great urgency and excitement to the potential for discovery at the upgraded Tevatron early in this decade, and almost assures that later experiments at the LHC will find new physics. But the next generation of experiments to be mounted by the world-wide particle physics community must not only find this new physics, they must find out what it is. These experiments must also define the next important threshold in energy. The need is to understand physics at the TeV energy scale as well as the physics at the 100-GeV energy scale is now understood. This will require both the LHC and a companion linear electron-positron collider. A first Zeroth-Order Design Report (ZDR) [2] for a second-generation electron-positron linear collider, the Next Linear Collider (NLC), was published five years ago. The NLC design is based on a high-frequency room-temperature rf accelerator. Its goal is exploration of elementary particle physics at the TeV center-of-mass energy, while learning how to design and build colliders at still higher energies. Many advances in accelerator technologies and improvements in the design of the NLC have been made since 1996. This Report is a brief update of the ZDR.

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

    SciTech Connect

    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

    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.

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

    PubMed

    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

    2014-11-01

    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. PMID:25186731

  11. GP130 activation induces myeloma and collaborates with MYC

    PubMed Central

    Dechow, Tobias; Steidle, Sabine; Götze, Katharina S.; Rudelius, Martina; Behnke, Kerstin; Pechloff, Konstanze; Kratzat, Susanne; Bullinger, Lars; Fend, Falko; Soberon, Valeria; Mitova, Nadya; Li, Zhoulei; Thaler, Markus; Bauer, Jan; Pietschmann, Elke; Albers, Corinna; Grundler, Rebekka; Schmidt-Supprian, Marc; Ruland, Jürgen; Peschel, Christian; Duyster, Justus; Rose-John, Stefan; Bassermann, Florian; Keller, Ulrich

    2014-01-01

    Multiple myeloma (MM) is a plasma cell neoplasm that results from clonal expansion of an Ig-secreting terminally differentiated B cell. Advanced MM is characterized by tissue damage that involves bone, kidney, and other organs and is typically associated with recurrent genetic abnormalities. IL-6 signaling via the IL-6 signal transducer GP130 has been implicated as an important driver of MM pathogenesis. Here, we demonstrated that ectopic expression of constitutively active GP130 (L-GP130) in a murine retroviral transduction-transplantation model induces rapid MM development of high penetrance. L-GP130–expressing mice recapitulated all of the characteristics of human disease, including monoclonal gammopathy, BM infiltration with lytic bone lesions, and protein deposition in the kidney. Moreover, the disease was easily transplantable and allowed different therapeutic options to be evaluated in vitro and in vivo. Using this model, we determined that GP130 signaling collaborated with MYC to induce MM and was responsible and sufficient for directing the plasma cell phenotype. Accordingly, we identified Myc aberrations in the L-GP130 MM model. Evaluation of human MM samples revealed recurrent activation of STAT3, a downstream target of GP130 signaling. Together, our results indicate that deregulated GP130 activity contributes to MM pathogenesis and that pathways downstream of GP130 activity have potential as therapeutic targets in MM. PMID:25384216

  12. Cost optimization of a hadron collider

    SciTech Connect

    Vadim V. Kashikhin and Peter J. Limon

    2001-11-30

    This paper discusses cost scaling laws and optimization of hadron colliders based on high field magnets. Using a few simplifying assumptions that should give a reasonable approximation, cost of the magnet is divided among several major components. Scaling law for every component is determined along with the weight factors that allow cost comparison between different magnet designs. Cost of hadron collider as a function of field, aperture size and critical current density in superconductor is described analytically that allows cost optimization by changing magnet parameters. The optimum magnetic field is determined for machines based on NbTi superconductor, operating at 4.2 K or 1.9 K and NB{sub 3}Sn superconductor operating at 4.2 K. Analyzed influence of main magnet design parameters on a machine cost provided information on ways leading to the magnet cost reduction. Economical justification of a NB{sub 3}Sn collider is performed, which lets to determine the maximum price ratio between NB{sub 3}Sn and NbTi superconductors that makes NB{sub 3}Sn collider economically effective.

  13. How Do Gut Feelings Feature in Tutorial Dialogues on Diagnostic Reasoning in GP Traineeship?

    ERIC Educational Resources Information Center

    Stolper, C. F.; Van de Wiel, M. W. J.; Hendriks, R. H. M.; Van Royen, P.; Van Bokhoven, M. A.; Van der Weijden, T.; Dinant, G. J.

    2015-01-01

    Diagnostic reasoning is considered to be based on the interaction between analytical and non-analytical cognitive processes. Gut feelings, a specific form of non-analytical reasoning, play a substantial role in diagnostic reasoning by general practitioners (GPs) and may activate analytical reasoning. In GP traineeships in the Netherlands, trainees…

  14. Development and validation of the GP frequency of interprofessional collaboration instrument (FICI-GP) in primary care.

    PubMed

    Van, Connie; Costa, Daniel; Mitchell, Bernadette; Abbott, Penny; Krass, Ines

    2012-07-01

    Existing validated measures of pharmacist-physician collaboration focus on measuring attitudes toward collaboration and do not measure frequency of interactions that comprise actual collaborative behavior. Therefore, the aim of this study was to develop and validate an instrument to measure the frequency of collaboration between general practitioners (GPs) and pharmacists from the GP's perspective. An 11-item Frequency of Interprofessional Collaboration Instrument for GPs (FICI-GP) was developed and administered to 1118 GPs in eight divisions of general practice in New South Wales, Australia. Two hundred and fifty-eight (23%) GP surveys were completed and returned. Principal component analysis suggested removal of one item for a final one-factor solution. The refined 10-item FICI-GP had a Cronbach's alpha of 0.87. After collapsing the original five-point response scale to a three-point response scale, the refined FICI-GP demonstrated fit to the Rasch model. Criterion validity of the FICI-GP was supported by the correlation of FICI-GP scores with scores on a previously validated physician-pharmacist collaboration instrument as well as by predicted differences in FICI-GP scores between subgroups of respondents stratified on age, co-location with pharmacists and interactions during residency. The refined 10-item FICI-GP was shown to have good internal consistency, criterion validity and fit to the Rasch model. PMID:22563657

  15. Structural Characterization of HIV gp41 with the Membrane-proximal External Region

    SciTech Connect

    Shi, W.; Bohon, J; Han, D; Habte, H; Qin, Y; Cho, M; Chance, M

    2010-01-01

    Human immunodeficiency virus, type 1 (HIV-1) envelope glycoprotein (gp120/gp41) plays a critical role in virus infection and pathogenesis. Three of the six monoclonal antibodies considered to have broadly neutralizing activities (2F5, 4E10, and Z13e1) bind to the membrane-proximal external region (MPER) of gp41. This makes the MPER a desirable template for developing immunogens that can elicit antibodies with properties similar to these monoclonal antibodies, with a long term goal of developing antigens that could serve as novel HIV vaccines. In order to provide a structural basis for rational antigen design, an MPER construct, HR1-54Q, was generated for x-ray crystallographic and x-ray footprinting studies to provide both high resolution atomic coordinates and verification of the solution state of the antigen, respectively. The crystal structure of HR1-54Q reveals a trimeric, coiled-coil six-helical bundle, which probably represents a postfusion form of gp41. The MPER portion extends from HR2 in continuation of a slightly bent long helix and is relatively flexible. The structures observed for the 2F5 and 4E10 epitopes agree well with existing structural data, and enzyme-linked immunosorbent assays indicate that the antigen binds well to antibodies that recognize the above epitopes. Hydroxyl radical-mediated protein footprinting of the antigen in solution reveals specifically protected and accessible regions consistent with the predictions based on the trimeric structure from the crystallographic data. Overall, the HR1-54Q antigen, as characterized by crystallography and footprinting, represents a postfusion, trimeric form of HIV gp41, and its structure provides a rational basis for gp41 antigen design suitable for HIV vaccine development.

  16. Structural characterization of HIV gp41 with the membrane-proximal external region.

    PubMed

    Shi, Wuxian; Bohon, Jen; Han, Dong P; Habte, Habtom; Qin, Yali; Cho, Michael W; Chance, Mark R

    2010-07-30

    Human immunodeficiency virus, type 1 (HIV-1) envelope glycoprotein (gp120/gp41) plays a critical role in virus infection and pathogenesis. Three of the six monoclonal antibodies considered to have broadly neutralizing activities (2F5, 4E10, and Z13e1) bind to the membrane-proximal external region (MPER) of gp41. This makes the MPER a desirable template for developing immunogens that can elicit antibodies with properties similar to these monoclonal antibodies, with a long term goal of developing antigens that could serve as novel HIV vaccines. In order to provide a structural basis for rational antigen design, an MPER construct, HR1-54Q, was generated for x-ray crystallographic and x-ray footprinting studies to provide both high resolution atomic coordinates and verification of the solution state of the antigen, respectively. The crystal structure of HR1-54Q reveals a trimeric, coiled-coil six-helical bundle, which probably represents a postfusion form of gp41. The MPER portion extends from HR2 in continuation of a slightly bent long helix and is relatively flexible. The structures observed for the 2F5 and 4E10 epitopes agree well with existing structural data, and enzyme-linked immunosorbent assays indicate that the antigen binds well to antibodies that recognize the above epitopes. Hydroxyl radical-mediated protein footprinting of the antigen in solution reveals specifically protected and accessible regions consistent with the predictions based on the trimeric structure from the crystallographic data. Overall, the HR1-54Q antigen, as characterized by crystallography and footprinting, represents a postfusion, trimeric form of HIV gp41, and its structure provides a rational basis for gp41 antigen design suitable for HIV vaccine development. PMID:20525690

  17. Structural Characterization of HIV gp41 with the Membrane-proximal External Region*

    PubMed Central

    Shi, Wuxian; Bohon, Jen; Han, Dong P.; Habte, Habtom; Qin, Yali; Cho, Michael W.; Chance, Mark R.

    2010-01-01

    Human immunodeficiency virus, type 1 (HIV-1) envelope glycoprotein (gp120/gp41) plays a critical role in virus infection and pathogenesis. Three of the six monoclonal antibodies considered to have broadly neutralizing activities (2F5, 4E10, and Z13e1) bind to the membrane-proximal external region (MPER) of gp41. This makes the MPER a desirable template for developing immunogens that can elicit antibodies with properties similar to these monoclonal antibodies, with a long term goal of developing antigens that could serve as novel HIV vaccines. In order to provide a structural basis for rational antigen design, an MPER construct, HR1-54Q, was generated for x-ray crystallographic and x-ray footprinting studies to provide both high resolution atomic coordinates and verification of the solution state of the antigen, respectively. The crystal structure of HR1-54Q reveals a trimeric, coiled-coil six-helical bundle, which probably represents a postfusion form of gp41. The MPER portion extends from HR2 in continuation of a slightly bent long helix and is relatively flexible. The structures observed for the 2F5 and 4E10 epitopes agree well with existing structural data, and enzyme-linked immunosorbent assays indicate that the antigen binds well to antibodies that recognize the above epitopes. Hydroxyl radical-mediated protein footprinting of the antigen in solution reveals specifically protected and accessible regions consistent with the predictions based on the trimeric structure from the crystallographic data. Overall, the HR1-54Q antigen, as characterized by crystallography and footprinting, represents a postfusion, trimeric form of HIV gp41, and its structure provides a rational basis for gp41 antigen design suitable for HIV vaccine development. PMID:20525690

  18. Composite leptoquarks in hadronic colliders

    SciTech Connect

    Eboli, O.J.P.; Olinto, A.V.

    1988-12-01

    We study the production of composite scalar leptoquarks in hadronic colliders (CERN p-barp, Fermilab Tevatron p-barp, and the Superconducting Super Collider pp). We examine its direct single production via qg..-->..l+leptoquark, and its effect on the production of lepton pairs (p/sup (-)/p..-->..l/sup +/l/sup -/).

  19. ALPs at colliders

    NASA Astrophysics Data System (ADS)

    Mimasu, Ken; Sanz, Verónica

    2015-06-01

    New pseudo-scalars, often called axion-like particles (ALPs), abound in model-building and are often associated with the breaking of a new symmetry. Traditional searches and indirect bounds are limited to light axions, typically in or below the KeV range for ALPs coupled to photons. We present collider bounds on ALPs from mono-γ, tri-γ and mono-jet searches in a model independent fashion, as well as the prospects for the LHC and future machines. We find that they are complementary to existing searches, as they are sensitive to heavier ALPs and have the capability to cover an otherwise inaccessible region of parameter space. We also show that, assuming certain model dependent correlations between the ALP coupling to photons and gluons as well as considering the validity of the effective description of ALP interactions, mono-jet searches are in fact more suitable and effective in indirectly constraining ALP scenarios.

  20. Collider Signal I :. Resonance

    NASA Astrophysics Data System (ADS)

    Tait, Tim M. P.

    2010-08-01

    These TASI lectures were part of the summer school in 2008 and cover the collider signal associated with resonances in models of physics beyond the Standard Model. I begin with a review of the Z boson, one of the best-studied resonances in particle physics, and review how the Breit-Wigner form of the propagator emerges in perturbation theory and discuss the narrow width approximation. I review how the LEP and SLAC experiments could use the kinematics of Z events to learn about fermion couplings to the Z. I then make a brief survey of models of physics beyond the Standard Model which predict resonances, and discuss some of the LHC observables which we can use to discover and identify the nature of the BSM physics. I finish up with a discussion of the linear moose that one can use for an effective theory description of a massive color octet vector particle.

  1. Positrons for linear colliders

    SciTech Connect

    Ecklund, S.

    1987-11-01

    The requirements of a positron source for a linear collider are briefly reviewed, followed by methods of positron production and production of photons by electromagnetic cascade showers. Cross sections for the electromagnetic cascade shower processes of positron-electron pair production and Compton scattering are compared. A program used for Monte Carlo analysis of electromagnetic cascades is briefly discussed, and positron distributions obtained from several runs of the program are discussed. Photons from synchrotron radiation and from channeling are also mentioned briefly, as well as positron collection, transverse focusing techniques, and longitudinal capture. Computer ray tracing is then briefly discussed, followed by space-charge effects and thermal heating and stress due to showers. (LEW)

  2. Colliding Beam Fusion Reactors

    NASA Astrophysics Data System (ADS)

    Rostoker, Norman; Qerushi, Artan; Binderbauer, Michl

    2003-06-01

    The recirculating power for virtually all types of fusion reactors has previously been calculated [1] with the Fokker-Planck equation. The reactors involve non-Maxwellian plasmas. The calculations are generic in that they do not relate to specific confinement devices. In all cases except for a Tokamak with D-T fuel the recirculating power was found to exceed the fusion power by a large factor. In this paper we criticize the generality claimed for this calculation. The ratio of circulating power to fusion power is calculated for the Colliding Beam Reactor with fuels D-T, D-He3 and p-B11. The results are respectively, 0.070, 0.141 and 0.493.

  3. When Worlds Collide

    SciTech Connect

    Chang, Spencer; Kleban, Matthew; Levi, Thomas S E-mail: mk161@nyu.edu

    2008-04-15

    We analyze the cosmological signatures visible to an observer in a Coleman-de Luccia bubble when another such bubble collides with it. We use a gluing procedure to generalize the results of Freivogel, Horowitz and Shenker to the case of a general cosmological constant in each bubble and study the resulting spacetimes. The collision breaks the isotropy and homogeneity of the bubble universe and provides a cosmological 'axis of evil' which can affect the cosmic microwave background in several unique and potentially detectable ways. Unlike more conventional perturbations to the inflationary initial state, these signatures can survive even relatively long periods of inflation. In addition, we find that for a given collision the observers in the bubble with smaller cosmological constant are safest from collisions with domain walls, possibly providing another anthropic selection principle for small positive vacuum energy.

  4. The Gp78 ubiquitin ligase: probing endoplasmic reticulum complexity.

    PubMed

    St Pierre, Pascal; Nabi, Ivan R

    2012-02-01

    The endoplasmic reticulum (ER) has been classically divided, based on electron microscopy analysis, into parallel ribosome-studded rough ER sheets and a tubular smooth ER network. Recent studies have identified molecular constituents of the ER, the reticulons and DP1, that drive ER tubule formation and whose expression determines expression of ER sheets and tubules and thereby rough and smooth ER. However, segregation of the ER into only two domains remains simplistic and multiple functionally distinct ER domains necessarily exist. In this review, we will discuss the sub-organization of the ER in different domains focusing on the localization and role of the gp78 ubiquitin ligase in the mitochondria-associated smooth ER and on the evidence for a quality control ERAD domain. PMID:22045301

  5. 77 FR 73635 - Northwest Storage GP, LLC; Notice of Application

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-11

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Northwest Storage GP, LLC; Notice of Application Take notice that on November 21, 2012, Northwest Storage GP, LLC. (Northwest) filed with the Federal Energy...

  6. 78 FR 42513 - Northwest Pipeline GP; Notice of Application

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-16

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Northwest Pipeline GP; Notice of Application Take notice that on June 25, 2013, Northwest Pipeline GP (Northwest), 295 Chipeta Way, Salt Lake City, Utah 84108, filed in Docket No. CP13-507-000 an abbreviated...

  7. 76 FR 4890 - Northwest Pipeline GP; Notice of Application

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-27

    ... Energy Regulatory Commission Northwest Pipeline GP; Notice of Application January 20, 2011. Take notice that on January 11, 2011, Northwest Pipeline GP (Northwest), 295 Chipeta Way, Salt Lake City, Utah... Project consists of: Abandonment in place of approximately 15 miles of 16-inch diameter pipeline...

  8. Design study of beam dynamics issues for 1 TeV next linear collider based upon the relativistic-klystron two-beam accelerator

    SciTech Connect

    Li, H.; Goffeney, N.; Henestroza, E.; Sessler, A.; Yu, S.; Houck, T.; Westenskow, G.

    1994-11-01

    A design study has recently been conducted for exploring the feasibility of a relativistic-klystron two-beam accelerator (RK-TBA) system as a rf power source for a 1 TeV linear collider. The author present, in this paper, the beam dynamics part of this study. They have achieved in their design study acceptable transverse and longitudinal beam stability properties for the resulting high efficiency and low cost RK-TBA.

  9. A system of beam energy measurement based on the Compton backscattered laser photons for the VEPP-2000 electron-positron collider

    NASA Astrophysics Data System (ADS)

    Abakumova, E. V.; Achasov, M. N.; Berkaev, D. E.; Kaminsky, V. V.; Koop, I. A.; Korol, A. A.; Koshuba, S. V.; Krasnov, A. A.; Muchnoi, N. Yu.; Perevedentsev, E. A.; Pyata, E. E.; Shatunov, P. Yu.; Shatunov, Yu. M.; Shwartz, D. B.

    2014-04-01

    The beam energy measurement system for the VEPP-2000 electron-positron collider is described. The method of Compton backscattering of CO laser photons on the electron beam is used. The relative systematic uncertainty of the beam energy determination is estimated as 6×10-5. It was obtained through comparison of the results of the beam energy measurements using the Compton backscattering and resonance depolarization methods.

  10. Quantum-beamsstrahlung laser collider

    SciTech Connect

    Tajima, T.; Chattopadyay, S.; Xie, M.

    1997-11-01

    An e{sup +}e{sup {minus}} linear collider at energies beyond a TeV runs into a problem of severe beamsstrahlung, characterized by {Upsilon} on the order of unity (and beyond). In the regime of extremely high {Upsilon} the beamsstrahlung may be largely suppressed due to the quantum effect. In the design of an e{sup +}e{sup {minus}} collider there are two ways to satisfy the collider physics constraints. One is to decrease the number of particles per bunch (and thus to increase the repetition rate) and the other is to decrease the longitudinal bunch length. The former approach can limit {Upsilon}, while the latter boosts it. (It may be useful to reevaluate the future collider parameters in view of this.) The laser wakefield driver for a collider in comparison with the microwave driver naturally offers a very short bunch length, which is appropriate for the latter collider option. The authors show that this choice of collider design with a short bunch length and high {Upsilon} has advantages and provide sample design parameters at 5 TeV. Such sample design parameters challenge them in a number of fronts, such as the preservation of high quality bunches, efficient high repetition rate lasers, etc. The collision point physics simulated by the CAIN code shows a surprisingly well preserved luminosity spectrum.

  11. The standard model and colliders

    SciTech Connect

    Hinchliffe, I.

    1987-03-01

    Some topics in the standard model of strong and electroweak interactions are discussed, as well as how these topics are relevant for the high energy colliders which will become operational in the next few years. The radiative corrections in the Glashow-Weinberg-Salam model are discussed, stressing how these corrections may be measured at LEP and the SLC. CP violation is discussed briefly, followed by a discussion of the Higgs boson and the searches which are relevant to hadron colliders are then discussed. Some of the problems which the standard model does not solve are discussed, and the energy ranges accessible to the new colliders are indicated. (LEW)

  12. Hadron collider physics at UCR

    SciTech Connect

    Kernan, A.; Shen, B.C.

    1997-07-01

    This paper describes the research work in high energy physics by the group at the University of California, Riverside. Work has been divided between hadron collider physics and e{sup +}-e{sup {minus}} collider physics, and theoretical work. The hadron effort has been heavily involved in the startup activities of the D-Zero detector, commissioning and ongoing redesign. The lepton collider work has included work on TPC/2{gamma} at PEP and the OPAL detector at LEP, as well as efforts on hadron machines.

  13. Vanilla technicolor at linear colliders

    NASA Astrophysics Data System (ADS)

    Frandsen, Mads T.; Järvinen, Matti; Sannino, Francesco

    2011-08-01

    We analyze the reach of linear colliders for models of dynamical electroweak symmetry breaking. We show that linear colliders can efficiently test the compositeness scale, identified with the mass of the new spin-one resonances, until the maximum energy in the center of mass of the colliding leptons. In particular we analyze the Drell-Yan processes involving spin-one intermediate heavy bosons decaying either leptonically or into two standard model gauge bosons. We also analyze the light Higgs production in association with a standard model gauge boson stemming also from an intermediate spin-one heavy vector.

  14. Laser cooling of electron beams for linear colliders

    SciTech Connect

    Telnov, V.

    1996-10-01

    A novel method of electron beam cooling is considered which can be used for linear colliders. The electron beam is cooled during collision with focused powerful laser pulse. With reasonable laser parameters (laser flash energy about 10 J) one can decrease transverse beam emittances by a factor about 10 per one stage. The ultimate transverse emittances are much below that given by other methods. Depolarization of a beam during the cooling is about 5--15% for one stage. This method is especially useful for photon colliders and open new possibilities for e{sup +}e{sup {minus}} colliders and x-ray FEL based on high energy linacs.

  15. GP2-expressing cells in the conjunctiva and tear ducts of mice: identification of a novel type of cells in the squamous stratified epithelium.

    PubMed

    Kimura, Shunsuke; Kishimoto, Ayuko; Mutoh, Mami; Takahashi-Iwanaga, Hiromi; Iwanaga, Toshihiko

    2015-01-01

    GP2 is a membrane-associated secretory protein originally identified in zymogen granules of pancreatic acinar cells. Recently, this glycoprotein has attracted attention as a marker substance of M cells of Peyer's patches and for its involvement in the selective uptake of pathological bacteria via M cells. When we stained the conjunctiva and tear ducts of mice using a GP2 antibody, all goblet cells in the squamous stratified epithelium of the conjunctiva were intensely immunolabeled, while goblet cells in the intestine and airway were devoid of the immunoreactivity, indicating that the conjunctiva contains a special type of goblet cell. Further immunostaining for GP-2 labeled dispersed cells of peculiar shapes within the stratified squamous epithelium in the lacrimal canaliculi, lacrimal sac, and nasolacrimal duct. The GP2-immunoreactive cells in the tear duct projected arched or branched processes toward the basement membrane. Electron-microscopically, immunogold particles for GP2 outlined the basolateral plasma membrane of both the conjuntival goblet cells and the peculiarly shaped cells in the tear duct. Intracellularly, GP2 products of the goblet cells were localized around secretory granules in the apical cytoplasm and those of the tear duct cells inside the vesicles. The luminal contents close to apical plasma membrane were heavily labeled with immunogold particles, suggesting an exocytosis-based targeting of GP2 to the plasma membrane and its release into the lumen. The possible function of GP2 in tear ducts is discussed in relation to a defense system against invasive microoranisms and antigens. PMID:26299485

  16. Mapping the interactions of the single-stranded DNA binding protein of bacteriophage T4 (gp32) with DNA lattices at single nucleotide resolution: polynucleotide binding and cooperativity

    PubMed Central

    Jose, Davis; Weitzel, Steven E.; Baase, Walter A.; Michael, Miya M.; von Hippel, Peter H.

    2015-01-01

    We here use our site-specific base analog mapping approach to study the interactions and binding equilibria of cooperatively-bound clusters of the single-stranded DNA binding protein (gp32) of the T4 DNA replication complex with longer ssDNA (and dsDNA) lattices. We show that in cooperatively bound clusters the binding free energy appears to be equi-partitioned between the gp32 monomers of the cluster, so that all bind to the ssDNA lattice with comparable affinity, but also that the outer domains of the gp32 monomers at the ends of the cluster can fluctuate on and off the lattice and that the clusters of gp32 monomers can slide along the ssDNA. We also show that at very low binding densities gp32 monomers bind to the ssDNA lattice at random, but that cooperatively bound gp32 clusters bind preferentially at the 5′-end of the ssDNA lattice. We use these results and the gp32 monomer-binding results of the companion paper to propose a detailed model for how gp32 might bind to and interact with ssDNA lattices in its various binding modes, and also consider how these clusters might interact with other components of the T4 DNA replication complex. PMID:26275774

  17. Mapping the interactions of the single-stranded DNA binding protein of bacteriophage T4 (gp32) with DNA lattices at single nucleotide resolution: polynucleotide binding and cooperativity.

    PubMed

    Jose, Davis; Weitzel, Steven E; Baase, Walter A; Michael, Miya M; von Hippel, Peter H

    2015-10-30

    We here use our site-specific base analog mapping approach to study the interactions and binding equilibria of cooperatively-bound clusters of the single-stranded DNA binding protein (gp32) of the T4 DNA replication complex with longer ssDNA (and dsDNA) lattices. We show that in cooperatively bound clusters the binding free energy appears to be equi-partitioned between the gp32 monomers of the cluster, so that all bind to the ssDNA lattice with comparable affinity, but also that the outer domains of the gp32 monomers at the ends of the cluster can fluctuate on and off the lattice and that the clusters of gp32 monomers can slide along the ssDNA. We also show that at very low binding densities gp32 monomers bind to the ssDNA lattice at random, but that cooperatively bound gp32 clusters bind preferentially at the 5'-end of the ssDNA lattice. We use these results and the gp32 monomer-binding results of the companion paper to propose a detailed model for how gp32 might bind to and interact with ssDNA lattices in its various binding modes, and also consider how these clusters might interact with other components of the T4 DNA replication complex. PMID:26275774

  18. Critical review and hydrologic application of threshold detection methods for the generalized Pareto (GP) distribution

    NASA Astrophysics Data System (ADS)

    Mamalakis, Antonios; Langousis, Andreas; Deidda, Roberto

    2016-04-01

    Estimation of extreme rainfall from data constitutes one of the most important issues in statistical hydrology, as it is associated with the design of hydraulic structures and flood water management. To that extent, based on asymptotic arguments from Extreme Excess (EE) theory, several studies have focused on developing new, or improving existing methods to fit a generalized Pareto (GP) distribution model to rainfall excesses above a properly selected threshold u. The latter is generally determined using various approaches, such as non-parametric methods that are intended to locate the changing point between extreme and non-extreme regions of the data, graphical methods where one studies the dependence of GP distribution parameters (or related metrics) on the threshold level u, and Goodness of Fit (GoF) metrics that, for a certain level of significance, locate the lowest threshold u that a GP distribution model is applicable. In this work, we review representative methods for GP threshold detection, discuss fundamental differences in their theoretical bases, and apply them to 1714 daily rainfall records from the NOAA-NCDC open-access database, with more than 110 years of data. We find that non-parametric methods that are intended to locate the changing point between extreme and non-extreme regions of the data are generally not reliable, while methods that are based on asymptotic properties of the upper distribution tail lead to unrealistically high threshold and shape parameter estimates. The latter is justified by theoretical arguments, and it is especially the case in rainfall applications, where the shape parameter of the GP distribution is low; i.e. on the order of 0.1 ÷ 0.2. Better performance is demonstrated by graphical methods and GoF metrics that rely on pre-asymptotic properties of the GP distribution. For daily rainfall, we find that GP threshold estimates range between 2÷12 mm/d with a mean value of 6.5 mm/d, while the existence of quantization in the

  19. When Black Holes Collide

    NASA Technical Reports Server (NTRS)

    Baker, John

    2010-01-01

    Among the fascinating phenomena predicted by General Relativity, Einstein's theory of gravity, black holes and gravitational waves, are particularly important in astronomy. Though once viewed as a mathematical oddity, black holes are now recognized as the central engines of many of astronomy's most energetic cataclysms. Gravitational waves, though weakly interacting with ordinary matter, may be observed with new gravitational wave telescopes, opening a new window to the universe. These observations promise a direct view of the strong gravitational dynamics involving dense, often dark objects, such as black holes. The most powerful of these events may be merger of two colliding black holes. Though dark, these mergers may briefly release more energy that all the stars in the visible universe, in gravitational waves. General relativity makes precise predictions for the gravitational-wave signatures of these events, predictions which we can now calculate with the aid of supercomputer simulations. These results provide a foundation for interpreting expect observations in the emerging field of gravitational wave astronomy.

  20. Polarized muon beams for muon collider

    NASA Astrophysics Data System (ADS)

    Skrinsky, A. N.

    1996-11-01

    An option for the production of intense and highly polarized muon beams, suitable for a high-luminosity muon collider, is described briefly. It is based on a multi-channel pion-collection system, narrow-band pion-to-muon decay channels, proper muon spin gymnastics, and ionization cooling to combine all of the muon beams into a single bunch of ultimately low emittance.

  1. A human monoclonal antibody neutralizes diverse HIV-1 isolates by binding a critical gp41 epitope

    PubMed Central

    Miller, Michael D.; Geleziunas, Romas; Bianchi, Elisabetta; Lennard, Simon; Hrin, Renee; Zhang, Hangchun; Lu, Meiqing; An, Zhiqiang; Ingallinella, Paolo; Finotto, Marco; Mattu, Marco; Finnefrock, Adam C.; Bramhill, David; Cook, James; Eckert, Debra M.; Hampton, Richard; Patel, Mayuri; Jarantow, Stephen; Joyce, Joseph; Ciliberto, Gennaro; Cortese, Riccardo; Lu, Ping; Strohl, William; Schleif, William; McElhaugh, Michael; Lane, Steven; Lloyd, Christopher; Lowe, David; Osbourn, Jane; Vaughan, Tristan; Emini, Emilio; Barbato, Gaetano; Kim, Peter S.; Hazuda, Daria J.; Shiver, John W.; Pessi, Antonello

    2005-01-01

    HIV-1 entry into cells is mediated by the envelope glycoprotein receptor-binding (gp120) and membrane fusion-promoting (gp41) subunits. The gp41 heptad repeat 1 (HR1) domain is the molecular target of the fusion-inhibitor drug enfuvirtide (T20). The HR1 sequence is highly conserved and therefore considered an attractive target for vaccine development, but it is unknown whether antibodies can access HR1. Herein, we use gp41-based peptides to select a human antibody, 5H/I1-BMV-D5 (D5), that binds to HR1 and inhibits the assembly of fusion intermediates in vitro. D5 inhibits the replication of diverse HIV-1 clinical isolates and therefore represents a previously unknown example of a crossneutralizing IgG selected by binding to designed antigens. NMR studies and functional analyses map the D5-binding site to a previously identified hydrophobic pocket situated in the HR1 groove. This hydrophobic pocket was proposed as a drug target and subsequently identified as a common binding site for peptide and peptidomimetic fusion inhibitors. The finding that the D5 fusion-inhibitory antibody shares the same binding site suggests that the hydrophobic pocket is a “hot spot” for fusion inhibition and an ideal target on which to focus a vaccine-elicited antibody response. Our data provide a structural framework for the design of new immunogens and therapeutic antibodies with crossneutralizing potential. PMID:16203977

  2. Determining the Structure of an Unliganded and Fully Glycosylated SIV gp120 Envelope Glycoprotein

    SciTech Connect

    Chen, Bing; Vogan, Erik M.; Gong, Haiyun; Skehel, John J.; Wiley, Don C.; Harrison, Stephen C.

    2010-07-13

    HIV/SIV envelope glycoproteins mediate the first steps in viral infection. They are trimers of a membrane-anchored polypeptide chain, cleaved into two fragments known as gp120 and gp41. The structure of HIV gp120 bound with receptor (CD4) has been known for some time. We have now determined the structure of a fully glycosylated SIV gp120 envelope glycoprotein in an unliganded conformation by X-ray crystallography at 4.0 {angstrom} resolution. We describe here our experimental and computational approaches, which may be relevant to other resolution-limited crystallographic problems. Key issues were attention to details of beam geometry mandated by small, weakly diffracting crystals, and choice of strategies for phase improvement, starting with two isomorphous derivatives and including multicrystal averaging. We validated the structure by analyzing composite omit maps, averaged among three distinct crystal lattices, and by calculating model-based, SeMet anomalous difference maps. There are at least four ordered sugars on many of the thirteen oligosaccharides.

  3. Stable massive particles at colliders

    SciTech Connect

    Fairbairn, M.; Kraan, A.C.; Milstead, D.A.; Sjostrand, T.; Skands, P.; Sloan, T.; /Lancaster U.

    2006-11-01

    We review the theoretical motivations and experimental status of searches for stable massive particles (SMPs) which could be sufficiently long-lived as to be directly detected at collider experiments. The discovery of such particles would address a number of important questions in modern physics including the origin and composition of dark matter in the universe and the unification of the fundamental forces. This review describes the techniques used in SMP-searches at collider experiments and the limits so far obtained on the production of SMPs which possess various colour, electric and magnetic charge quantum numbers. We also describe theoretical scenarios which predict SMPs, the phenomenology needed to model their production at colliders and interactions with matter. In addition, the interplay between collider searches and open questions in cosmology such as dark matter composition are addressed.

  4. Beam Rounders for Circular Colliders

    SciTech Connect

    A. Burov; S. Nagaitsev; Ya. Derbenev

    2001-07-01

    By means of linear optics, an arbitrary uncoupled beam can be locally transformed into a round (rotation-invariant) state and then back. This provides an efficient way to round beams in the interaction region of circular colliders.

  5. [New technology for linear colliders

    SciTech Connect

    McIntyre, P.M.

    1992-08-12

    This report discusses the following topics on research of microwave amplifiers for linear colliders: Context in current microwave technology development; gated field emission for microwave cathodes; cathode fabrication and tests; microwave cathode design using field emitters; and microwave localization.

  6. Physicists dream of supersized collider

    NASA Astrophysics Data System (ADS)

    Hao, Cindy

    2015-12-01

    Particle physicists in China are hopeful that the Chinese government will allocate 1 billion yuan (about £104m) to design what would be the world's largest particle accelerator - the Circular Electron Positron Collider (CEPC).

  7. COLLIDE-2: Collisions Into Dust Experiment-2

    NASA Technical Reports Server (NTRS)

    Colwell, Joshua E.

    2002-01-01

    The Collisions Into Dust Experimental (COLLIDE-2) was the second flight of the COLLIDE payload. The payload performs six low-velocity impact experiments to study the collisions that are prevalent in planetary ring systems and in the early stages of planet formation. Each impact experiment is into a target of granular material, and the impacts occur at speeds between 1 and 100 cm/s in microgravity and in a vacuum. The experiments are recorded on digital videotape which is later analyzed. During the period of performance a plan was developed to address some of the technical issues that prevented the first flight of COLLIDE from being a complete success, and also to maximize the scientific return based on the science results from the first flight. The experiment was modified following a series of reviews of the design plan, and underwent extensive testing. The data from the experiment show that the primary goal of identifying transition regimes for low-velocity impacts based on cratering versus accretion was achieved. Following a brief period of storage, the experiment flew regimes for low-velocity impacts based on cratering versus accretion was achieved. as a Hitchhiker payload on the MACH-1 Hitchhiker bridge on STS-108 in December 2001. These data have been analyzed and submitted for publication. That manuscript is attached to this report. The experiment was retrieved in January 2002, and all six impact experiments functioned nominally. Preliminary results were reported at the Lunar and Planetary Science Conference.

  8. Neutrino physics at muon colliders

    SciTech Connect

    King, B.J.

    1998-03-01

    An overview is given of the neutrino physics potential of future muon storage rings that use muon collider technology to produce, accelerate and store large currents of muons. After a general characterization of the neutrino beam and its interactions, some crude quantitative estimates are given for the physics performance of a muon ring neutrino experiment (MURINE) consisting of a high rate, high performance neutrino detector at a 250 GeV muon collider storage ring.

  9. Crystal Ball: On the Future High Energy Colliders

    SciTech Connect

    Shiltsev, Vladimir

    2015-09-20

    High energy particle colliders have been in the forefront of particle physics for more than three decades. At present the near term US, European and international strategies of the particle physics community are centered on full exploitation of the physics potential of the Large Hadron Collider (LHC) through its high-luminosity upgrade (HL-LHC). A number of next generation collider facilities have been proposed and are currently under consideration for the medium- and far-future of the accelerator-based high energy physics. In this paper we offer a uniform approach to evaluation of various accelerators based on the feasibility of their energy reach, performance reach and cost range. We briefly review such post-LHC options as linear e+e- colliders in Japan (ILC) or at CERN (CLIC), muon collider, and circular lepton or hadron colliders in China (CepC/SppC) and Europe (FCC). We conclude with a look into ultimate energy reach accelerators based on plasmas and crystals, and some perspectives for the far future of accelerator-based particle physics.

  10. Muon muon collider: Feasibility study

    SciTech Connect

    1996-06-18

    A feasibility study is presented of a 2 + 2 TeV muon collider with a luminosity of L = 10{sup 35} cm{sup {minus}2} s{sup {minus}1}. The resulting design is not optimized for performance, and certainly not for cost; however, it does suffice--the authors believe--to allow them to make a credible case, that a muon collider is a serious possibility for particle physics and, therefore, worthy of R and D support so that the reality of, and interest in, a muon collider can be better assayed. The goal of this support would be to completely assess the physics potential and to evaluate the cost and development of the necessary technology. The muon collider complex consists of components which first produce copious pions, then capture the pions and the resulting muons from their decay; this is followed by an ionization cooling channel to reduce the longitudinal and transverse emittance of the muon beam. The next stage is to accelerate the muons and, finally, inject them into a collider ring which has a small beta function at the colliding point. This is the first attempt at a point design and it will require further study and optimization. Experimental work will be needed to verify the validity of diverse crucial elements in the design.

  11. Physics at Future Circular Colliders

    NASA Astrophysics Data System (ADS)

    Kotwal, Ashutosh

    2016-03-01

    The Large Hadron Collider has been a grand success with the discovery of the Higgs boson, with bright prospects for additional discoveries since the recent increase in collider energy and the anticipated large datasets. Big open questions such as the nature of dark matter, the origin of the matter-antimatter asymmetry in the Universe, and the theoretical puzzle of the finely-tuned parameters in the Higgs sector, demand new physics principles that extend the established Standard Model paradigm. Future circular colliders in a substantially larger tunnel can house both a high luminosity electron-positron collider for precision measurements of Higgs and electroweak parameters, as well as a very high energy proton-proton collider which can directly manifest particles associated with these new physics principles. We discuss the physics goals of these future circular colliders, and the prospects for elucidating fundamental new laws of nature that will significantly extend our understanding of the Universe. Detailed studies of the discovery potential in specific benchmark models will be presented, with implications for detector design.

  12. GP IIb/IIIa Blockade During Peripheral Artery Interventions

    SciTech Connect

    Tepe, Gunnar Wiskirchen, Jakub; Pereira, Philippe; Claussen, Claus D.; Miller, Stephen; Duda, Stephan H.

    2008-01-15

    The activation of the platelet GP IIb/IIIa receptor is the final and common pathway in platelet aggregation. By blocking this receptor, platelet aggregation can be inhibited independently of the stimulus prompted the targeting of this receptor. Several years ago, three drugs have been approved for coronary artery indications. Since that time, there is increasing evidence that GP IIb/IIIa receptor blockade might have also an important role in peripheral arterial intervention. This article summarizes the action and differences of GP Ilb/IIIa receptor inhibitors and its possible indication in peripheral arteries.

  13. PAH determination based on a rapid and novel gas purge-microsyringe extraction (GP-MSE) technique in road dust of Shanghai, China: Characterization, source apportionment, and health risk assessment.

    PubMed

    Zheng, Xin; Yang, Yi; Liu, Min; Yu, Yingpeng; Zhou, John L; Li, Donghao

    2016-07-01

    A novel cleanup technique termed as gas purge-microsyringe extraction (GP-MSE) was evaluated and applied for polycyclic aromatic hydrocarbon (PAH) determination in road dust samples. A total of 68 road dust samples covering almost the entire Shanghai area were analyzed for 16 priority PAHs using gas chromatography-mass spectrometry. The results indicate that the total PAH concentrations over the investigated sites ranged from 1.04μg/g to 134.02μg/g dw with an average of 13.84μg/g. High-molecular-weight compounds (4-6 rings PAHs) were significantly dominant in the total mass of PAHs, and accounted for 77.85% to 93.62%. Diagnostic ratio analysis showed that the road dust PAHs were mainly from the mixture of petroleum and biomass/coal combustions. Principal component analysis in conjunction with multiple linear regression indicated that the two major origins of road dust PAHs were vehicular emissions and biomass/fossil fuel combustions, which contributed 66.7% and 18.8% to the total road dust PAH burden, respectively. The concentration of benzo[a]pyrene equivalent (BaPeq) varied from 0.16μg/g to 24.47μg/g. The six highly carcinogenic PAH species (benz(a)anthracene, benzo(a)pyrene, benzo(b)fluoranthene, benzo(k)fluoranthene, dibenz(a,h)anthracene, and indeno(1,2,3-cd)pyrene) accounted for 98.57% of the total BaPeq concentration. Thus, the toxicity of PAHs in road dust was highly associated with high-molecular-weight compounds. PMID:27037890

  14. Striking HIV-1 Entry by Targeting HIV-1 gp41. But, Where Should We Target?

    PubMed Central

    Teixeira, Cátia; Barbault, Florent; Couesnon, Thierry; Gomes, José R. B.; Gomes, Paula; Maurel, François

    2016-01-01

    HIV-1 gp41 facilitates the viral fusion through a conformational switch involving the association of three C-terminal helices along the conserved hydrophobic grooves of three N-terminal helices coiled-coil. The control of these structural rearrangements is thought to be central to HIV-1 entry and, therefore, different strategies of intervention are being developed. Herewith, we describe a procedure to simulate the folding of an HIV-1 gp41 simplified model. This procedure is based on the construction of plausible conformational pathways, which describe protein transition between non-fusogenic and fusogenic conformations. The calculation of the paths started with 100 molecular dynamics simulations of the non-fusogenic conformation, which were found to converge to different intermediate states. Those presenting defined criteria were selected for separate targeted molecular dynamics simulations, subjected to a force constant imposing a movement towards the gp41 fusogenic conformation. Despite significant diversity, a preferred sequence of events emerged when the simulations were analyzed in terms of the formation, breakage and evolution of the contacts. We pointed out 29 residues as the most relevant for the movement of gp41; also, 2696 possible interactions were reduced to only 48 major interactions, which reveals the efficiency of the method. The analysis of the evolution of the main interactions lead to the detection of four main behaviors for those contacts: stable, increasing, decreasing and repulsive interactions. Altogether, these results suggest a specific small cavity of the HIV-1 gp41 hydrophobic groove as the preferred target to small molecules. PMID:26785380

  15. Reversal of P-gp and BCRP-mediated MDR by tariquidar derivatives.

    PubMed

    Li, Xu-Qin; Wang, Lin; Lei, Yan; Hu, Tao; Zhang, Fei-Long; Cho, Chi-Hin; To, Kenneth K W

    2015-08-28

    With an aim to generate non-toxic, specific and highly potent multidrug resistance (MDR) modulators, a novel series of anthranilic acid amide-substituted tariquidar derivatives were synthesized. The new compounds were evaluated for their cytotoxicity toward normal human colon fibroblasts (CCD18-Co), human gastric epithelial cell line (HFE) and primary rat liver cells, and for their ability to inhibit P-gp/BCRP-mediated drug efflux and reversal of P-gp and BCRP-mediated MDR in parental and drug-resistant cancer cell lines (LCC6 MDR1, MCF-7 FLV1000, R-HepG2, SW620-Ad300). While tariquidar is highly toxic to normal cells, the new derivatives exhibited much lower or negligible cytotoxicity. Some of the new tariquidar derivatives inhibited both P-gp and BCRP-mediated drug efflux whereas a few of them bearing a sulfonamide functional group (1, 5, and 16) are specific to P-gp. The new compounds were also found to potentiate the anticancer activity of the transporter substrate anticancer drugs in the corresponding transporter-overexpressing cell lines. The extent of resistance reversal was found to be consistent with the transporter inhibitory effect of the new derivatives. To further understand the mechanism of P-gp and BCRP inhibition, the tariquidar derivatives were found to interact with the transporters using an antibody-based UIC2 or 5D3 shift assay. Moreover, the transporters-inhibiting derivatives were found to modulate the ATPase activities of the two MDR transporters. Our data thus advocate further development of the new compounds for the circumvention of MDR. PMID:26197160

  16. Nonglobal correlations in collider physics

    DOE PAGESBeta

    Moult, Ian; Larkoski, Andrew J.

    2016-01-13

    Despite their importance for precision QCD calculations, correlations between in- and out-of-jet regions of phase space have never directly been observed. These so-called non-global effects are present generically whenever a collider physics measurement is not explicitly dependent on radiation throughout the entire phase space. In this paper, we introduce a novel procedure based on mutual information, which allows us to isolate these non-global correlations between measurements made in different regions of phase space. We study this procedure both analytically and in Monte Carlo simulations in the context of observables measured on hadronic final states produced in e+e- collisions, though itmore » is more widely applicable.The procedure exploits the sensitivity of soft radiation at large angles to non-global correlations, and we calculate these correlations through next-to-leading logarithmic accuracy. The bulk of these non-global correlations are found to be described in Monte Carlo simulation. They increase by the inclusion of non-perturbative effects, which we show can be incorporated in our calculation through the use of a model shape function. As a result, this procedure illuminates the source of non-global correlations and has connections more broadly to fundamental quantities in quantum field theory.« less

  17. Nonglobal correlations in collider physics

    NASA Astrophysics Data System (ADS)

    Larkoski, Andrew J.; Moult, Ian

    2016-01-01

    Despite their importance for precision QCD calculations, correlations between in- and out-of-jet regions of phase space have never directly been observed. These so-called nonglobal effects are present generically whenever a collider physics measurement is not explicitly dependent on radiation throughout the entire phase space. In this paper, we introduce a novel procedure based on mutual information, which allows us to isolate these nonglobal correlations between measurements made in different regions of phase space. We study this procedure both analytically and in Monte Carlo simulations in the context of observables measured on hadronic final states produced in e+e- collisions, though it is more widely applicable. The procedure exploits the sensitivity of soft radiation at large angles to nonglobal correlations, and we calculate these correlations through next-to-leading logarithmic accuracy. The bulk of these nonglobal correlations are found to be described in Monte Carlo simulation. They increase by the inclusion of nonperturbative effects, which we show can be incorporated in our calculation through the use of a model shape function. This procedure illuminates the source of nonglobal correlations and has connections more broadly to fundamental quantities in quantum field theory.

  18. Binding of Full-Length HIV-1 gp120 to CD4 Induces Structural Reorientation around the gp120 Core

    SciTech Connect

    Ashish,F.; Garg, R.; Anguita, J.; Krueger, J.

    2006-01-01

    Small-angle x-ray scattering data on the unliganded full-length fully glycosylated HIV-1 gp120, the soluble CD4 (domains 1-2) receptor and their complex in solution are presented. Ab initio structure restorations using these data provides the first look at the envelope shape for the unliganded and the complexed gp120 molecule. Fitting known crystal structures of the unliganded SIV and the complexed HIV gp120 core regions within our resultant shape constraints reveals movement of the V3 loop upon binding.

  19. An intervention modelling experiment to change GPs' intentions to implement evidence-based practice: using theory-based interventions to promote GP management of upper respiratory tract infection without prescribing antibiotics #2

    PubMed Central

    Hrisos, Susan; Eccles, Martin; Johnston, Marie; Francis, Jill; Kaner, Eileen FS; Steen, Nick; Grimshaw, Jeremy

    2008-01-01

    Background Psychological theories of behaviour may provide a framework to guide the design of interventions to change professional behaviour. Behaviour change interventions, designed using psychological theory and targeting important motivational beliefs, were experimentally evaluated for effects on the behavioural intention and simulated behaviour of GPs in the management of uncomplicated upper respiratory tract infection (URTI). Methods The design was a 2 × 2 factorial randomised controlled trial. A postal questionnaire was developed based on three theories of human behaviour: Theory of Planned Behaviour; Social Cognitive Theory and Operant Learning Theory. The beliefs and attitudes of GPs regarding the management of URTI without antibiotics and rates of prescribing on eight patient scenarios were measured at baseline and post-intervention. Two theory-based interventions, a "graded task" with "action planning" and a "persuasive communication", were incorporated into the post-intervention questionnaire. Trial groups were compared using co-variate analyses. Results Post-intervention questionnaires were returned for 340/397 (86%) GPs who responded to the baseline survey. Each intervention had a significant effect on its targeted behavioural belief: compared to those not receiving the intervention GPs completing Intervention 1 reported stronger self-efficacy scores (Beta = 1.41, 95% CI: 0.64 to 2.25) and GPs completing Intervention 2 had more positive anticipated consequences scores (Beta = 0.98, 95% CI = 0.46 to 1.98). Intervention 2 had a significant effect on intention (Beta = 0.90, 95% CI = 0.41 to 1.38) and simulated behaviour (Beta = 0.47, 95% CI = 0.19 to 0.74). Conclusion GPs' intended management of URTI was significantly influenced by their confidence in their ability to manage URTI without antibiotics and the consequences they anticipated as a result of doing so. Two targeted behaviour change interventions differentially affected these beliefs. One

  20. Status of the MEIC ion collider ring design

    SciTech Connect

    None, None

    2015-07-14

    We present an update on the design of the ion collider ring of the Medium-energy Electron-Ion Collider (MEIC) proposed by Jefferson Lab. The design is based on the use of super-ferric magnets. It provides the necessary momentum range of 8 to 100 GeV/c for protons and ions, matches the electron collider ring design using PEP-II components, fits readily on the JLab site, offers a straightforward path for a future full-energy upgrade by replacing the magnets with higher-field ones in the same tunnel, and is more cost effective than using presently available current-dominated super-conducting magnets. We describe complete ion collider optics including an independently-designed modular detector region.

  1. Status of the MEIC ion collider ring design

    SciTech Connect

    Morozov, Vasiliy; Derbenev, Yaroslav; Harwood, Leigh; Hutton, Andrew; Lin, Fanglei; Pilat, Fulvia; Zhang, Yuhong; Cai, Yunhai; Nosochkov, Y. M.; Sullivan, Michael; Wang, M.-H.; Wienands, Uli; Gerity, James; Mann, Thomas; McIntyre, Peter; Pogue, Nathaniel; Sattarov, Akhdiyor

    2015-09-01

    We present an update on the design of the ion collider ring of the Medium-energy Electron-Ion Collider (MEIC) proposed by Jefferson Lab. The design is based on the use of super-ferric magnets. It provides the necessary momentum range of 8 to 100 GeV/c for protons and ions, matches the electron collider ring design using PEP-II components, fits readily on the JLab site, offers a straightforward path for a future full-energy upgrade by replacing the magnets with higher-field ones in the same tunnel, and is more cost effective than using presently available current-dominated super-conducting magnets. We describe complete ion collider optics including an independently-designed modular detector region.

  2. A GP's duty to follow up test results.

    PubMed

    Bird, Sara

    2003-01-01

    Medical negligence claims alleging 'failure to diagnose' are a common cause of claims against general practitioners. In these claims there is often an underlying weakness in the GP's test result and patient tracking systems. This article discusses the duty of care of a GP to follow up patients and their test results. Guidance is provided on how to establish an effective test result tracking system in order to minimise the possibility of a claim arising from 'failure to diagnose'. PMID:12647659

  3. Recombinant expression, purification, and biophysical characterization of the transmembrane and membrane proximal domains of HIV-1 gp41

    PubMed Central

    Gong, Zhen; Kessans, Sarah A; Song, Lusheng; Dörner, Katerina; Lee, Ho-Hsien; Meador, Lydia R; LaBaer, Joshua; Hogue, Brenda G; Mor, Tsafrir S; Fromme, Petra

    2014-01-01

    The transmembrane subunit (gp41) of the envelope glycoprotein of HIV-1 associates noncovalently with the surface subunit (gp120) and together they play essential roles in viral mucosal transmission and infection of target cells. The membrane proximal region (MPR) of gp41 is highly conserved and contains epitopes of broadly neutralizing antibodies. The transmembrane (TM) domain of gp41 not only anchors the envelope glycoprotein complex in the viral membrane but also dynamically affects the interactions of the MPR with the membrane. While high-resolution X-ray structures of some segments of the MPR were solved in the past, they represent the post-fusion forms. Structural information on the TM domain of gp41 is scant and at low resolution. Here we describe the design, expression and purification of a protein construct that includes MPR and the transmembrane domain of gp41 (MPR-TMTEV-6His), which reacts with the broadly neutralizing antibodies 2F5 and 4E10 and thereby may represent an immunologically relevant conformation mimicking a prehairpin intermediate of gp41. The expression level of MPR-TMTEV-6His was improved by fusion to the C-terminus of Mistic protein, yielding ∼1 mg of pure protein per liter. The isolated MPR-TMTEV-6His protein was biophysically characterized and is a monodisperse candidate for crystallization. This work will enable further investigation into the structure of MPR-TMTEV-6His, which will be important for the structure-based design of a mucosal vaccine against HIV-1. PMID:25155369

  4. Muon Collider Machine-Detector Interface

    SciTech Connect

    Mokhov, Nikolai V.; /Fermilab

    2011-08-01

    In order to realize the high physics potential of a Muon Collider (MC) a high luminosity of {mu}{sup +}{mu}{sup -}-collisions at the Interaction Point (IP) in the TeV range must be achieved ({approx}10{sup 34} cm{sup -2}s{sup -1}). To reach this goal, a number of demanding requirements on the collider optics and the IR hardware - arising from the short muon lifetime and from relatively large values of the transverse emittance and momentum spread in muon beams that can realistically be obtained with ionization cooling should be satisfied. These requirements are aggravated by limitations on the quadrupole gradients as well as by the necessity to protect superconducting magnets and collider detectors from muon decay products. The overall detector performance in this domain is strongly dependent on the background particle rates in various sub-detectors. The deleterious effects of the background and radiation environment produced by the beam in the ring are very important issues in the Interaction Region (IR), detector and Machine-Detector Interface (MDI) designs. This report is based on studies presented very recently.

  5. Neutrino Factory and Muon Collider Fellow

    SciTech Connect

    Hanson, Gail G.; Snopak, Pavel; Bao, Yu

    2015-03-20

    Muons are fundamental particles like electrons but much more massive. Muon accelerators can provide physics opportunities similar to those of electron accelerators, but because of the larger mass muons lose less energy to radiation, allowing more compact facilities with lower operating costs. The way muon beams are produced makes them too large to fit into the vacuum chamber of a cost-effective accelerator, and the short muon lifetime means that the beams must be reduced in size rather quickly, without losing too many of the muons. This reduction in size is called "cooling." Ionization cooling is a new technique that can accomplish such cooling. Intense muon beams can then be accelerated and injected into a storage ring, where they can be used to produce neutrino beams through their decays or collided with muons of the opposite charge to produce a muon collider, similar to an electron-positron collider. We report on the research carried out at the University of California, Riverside, towards producing such muon accelerators, as part of the Muon Accelerator Program based at Fermilab. Since this research was carried out in a university environment, we were able to involve both undergraduate and graduate students.

  6. Development of the gas puff charge exchange recombination spectroscopy (GP-CXRS) technique for ion measurements in the plasma edge

    SciTech Connect

    Churchill, R. M.; Theiler, C.; Lipschultz, B.; Dux, R.; Pütterich, T.; Viezzer, E.; Collaboration: Alcator C-Mod Team; ASDEX Upgrade Team

    2013-09-15

    A novel charge-exchange recombination spectroscopy (CXRS) diagnostic method is presented, which uses a simple thermal gas puff for its donor neutral source, instead of the typical high-energy neutral beam. This diagnostic, named gas puff CXRS (GP-CXRS), is used to measure ion density, velocity, and temperature in the tokamak edge/pedestal region with excellent signal-background ratios, and has a number of advantages to conventional beam-based CXRS systems. Here we develop the physics basis for GP-CXRS, including the neutral transport, the charge-exchange process at low energies, and effects of energy-dependent rate coefficients on the measurements. The GP-CXRS hardware setup is described on two separate tokamaks, Alcator C-Mod and ASDEX Upgrade. Measured spectra and profiles are also presented. Profile comparisons of GP-CXRS and a beam based CXRS system show good agreement. Emphasis is given throughout to describing guiding principles for users interested in applying the GP-CXRS diagnostic technique.

  7. The Role of NKG2D Signaling in Inhibition of Cytotoxic T-Lymphocyte Lysis by the Murine Cytomegalovirus Immunoevasin m152/gp40▿

    PubMed Central

    Pinto, Amelia K.; Jamieson, Amanda M.; Raulet, David H.; Hill, Ann B.

    2007-01-01

    Three proteins encoded by murine cytomegalovirus (MCMV)— gp34, encoded by m04 (m04/gp34), gp48, encoded by m06 (m06/gp48), and gp40, encoded by m152 (m152/gp40)—act together to powerfully impact the ability of primed cytotoxic CD8 T lymphocytes (CTL) to kill virus-infected cells. Of these three, the impact of m152/gp40 on CTL lysis appears greater than would be expected based on its impact on cell surface major histocompatibility complex (MHC) class I. In addition to MHC class I, m152/gp40 also downregulates the RAE-1 family of NKG2D ligands, which can provide costimulation for CD8 T cells. We hypothesized that m152/gp40 may impact CTL lysis so profoundly because it inhibits both antigen presentation and NKG2D-mediated costimulation. We therefore tested the extent to which m152/gp40's ability to inhibit CTL lysis of MCMV-infected cells could be accounted for by its inhibition of NKG2D signaling. As was predictable from the results reported in the literature, NKG2D ligands were not detected by NKG2D tetramer staining of cells infected with wild-type MCMV, whereas those infected with MCMV lacking m152/gp40 displayed measurable levels of the NKG2D ligand. To determine whether NKG2D signaling contributed to the ability of CTL to lyse these cells, we used a blocking anti-NKG2D antibody. Blocking NKG2D signaling did affect the killing of MCMV-infected cells for some epitopes. However, for all epitopes, the impact of m152/gp40 on CTL lysis was much greater than the impact of inhibition of NKG2D signaling. We conclude that the downregulation of NKG2D ligands by MCMV makes only a small contribution to the impact of m152/gp40 on CTL lysis and only for a small subset of CTL. PMID:17855532

  8. Oligoribonuclease is the primary degradative enzyme for pGpG in Pseudomonas aeruginosa that is required for cyclic-di-GMP turnover

    PubMed Central

    Orr, Mona W.; Donaldson, Gregory P.; Severin, Geoffrey B.; Wang, Jingxin; Sintim, Herman O.; Waters, Christopher M.; Lee, Vincent T.

    2015-01-01

    The bacterial second messenger cyclic di-GMP (c-di-GMP) controls biofilm formation and other phenotypes relevant to pathogenesis. Cyclic-di-GMP is synthesized by diguanylate cyclases (DGCs). Phosphodiesterases (PDE-As) end signaling by linearizing c-di-GMP to 5ʹ-phosphoguanylyl-(3ʹ,5ʹ)-guanosine (pGpG), which is then hydrolyzed to two GMP molecules by yet unidentified enzymes termed PDE-Bs. We show that pGpG inhibits a PDE-A from Pseudomonas aeruginosa. In a dual DGC and PDE-A reaction, excess pGpG extends the half-life of c-di-GMP, indicating that removal of pGpG is critical for c-di-GMP homeostasis. Thus, we sought to identify the PDE-B enzyme(s) responsible for pGpG degradation. A differential radial capillary action of ligand assay-based screen for pGpG binding proteins identified oligoribonuclease (Orn), an exoribonuclease that hydrolyzes two- to five-nucleotide-long RNAs. Purified Orn rapidly converts pGpG into GMP. To determine whether Orn is the primary enzyme responsible for degrading pGpG, we assayed cell lysates of WT and ∆orn strains of P. aeruginosa PA14 for pGpG stability. The lysates from ∆orn showed 25-fold decrease in pGpG hydrolysis. Complementation with WT, but not active site mutants, restored hydrolysis. Accumulation of pGpG in the ∆orn strain could inhibit PDE-As, increasing c-di-GMP concentration. In support, we observed increased transcription from the c-di-GMP–regulated pel promoter. Additionally, the c-di-GMP–governed auto-aggregation and biofilm phenotypes were elevated in the ∆orn strain in a pel-dependent manner. Finally, we directly detect elevated pGpG and c-di-GMP in the ∆orn strain. Thus, we identified that Orn serves as the primary PDE-B enzyme that removes pGpG, which is necessary to complete the final step in the c-di-GMP degradation pathway. PMID:26305945

  9. Oligoribonuclease is the primary degradative enzyme for pGpG in Pseudomonas aeruginosa that is required for cyclic-di-GMP turnover.

    PubMed

    Orr, Mona W; Donaldson, Gregory P; Severin, Geoffrey B; Wang, Jingxin; Sintim, Herman O; Waters, Christopher M; Lee, Vincent T

    2015-09-01

    The bacterial second messenger cyclic di-GMP (c-di-GMP) controls biofilm formation and other phenotypes relevant to pathogenesis. Cyclic-di-GMP is synthesized by diguanylate cyclases (DGCs). Phosphodiesterases (PDE-As) end signaling by linearizing c-di-GMP to 5'-phosphoguanylyl-(3',5')-guanosine (pGpG), which is then hydrolyzed to two GMP molecules by yet unidentified enzymes termed PDE-Bs. We show that pGpG inhibits a PDE-A from Pseudomonas aeruginosa. In a dual DGC and PDE-A reaction, excess pGpG extends the half-life of c-di-GMP, indicating that removal of pGpG is critical for c-di-GMP homeostasis. Thus, we sought to identify the PDE-B enzyme(s) responsible for pGpG degradation. A differential radial capillary action of ligand assay-based screen for pGpG binding proteins identified oligoribonuclease (Orn), an exoribonuclease that hydrolyzes two- to five-nucleotide-long RNAs. Purified Orn rapidly converts pGpG into GMP. To determine whether Orn is the primary enzyme responsible for degrading pGpG, we assayed cell lysates of WT and ∆orn strains of P. aeruginosa PA14 for pGpG stability. The lysates from ∆orn showed 25-fold decrease in pGpG hydrolysis. Complementation with WT, but not active site mutants, restored hydrolysis. Accumulation of pGpG in the ∆orn strain could inhibit PDE-As, increasing c-di-GMP concentration. In support, we observed increased transcription from the c-di-GMP-regulated pel promoter. Additionally, the c-di-GMP-governed auto-aggregation and biofilm phenotypes were elevated in the ∆orn strain in a pel-dependent manner. Finally, we directly detect elevated pGpG and c-di-GMP in the ∆orn strain. Thus, we identified that Orn serves as the primary PDE-B enzyme that removes pGpG, which is necessary to complete the final step in the c-di-GMP degradation pathway. PMID:26305945

  10. Muon collider interaction region design

    SciTech Connect

    Alexahin, Y.I.; Gianfelice-Wendt, E.; Kashikhin, V.V.; Mokhov, N.V.; Zlobin, A.V.; Alexakhin, V.Y.; /Dubna, JINR

    2010-05-01

    Design of a muon collider interaction region (IR) presents a number of challenges arising from low {beta}* < 1 cm, correspondingly large beta-function values and beam sizes at IR magnets, as well as the necessity to protect superconducting magnets and collider detectors from muon decay products. As a consequence, the designs of the IR optics, magnets and machine-detector interface are strongly interlaced and iterative. A consistent solution for the 1.5 TeV c.o.m. muon collider IR is presented. It can provide an average luminosity of 10{sup 34} cm{sup -2}s{sup -1} with an adequate protection of magnet and detector components.

  11. Luminosity determination at proton colliders

    NASA Astrophysics Data System (ADS)

    Grafström, P.; Kozanecki, W.

    2015-03-01

    Luminosity is a key parameter in any particle collider, and its precise determination has proven particularly challenging at hadron colliders. After introducing the concept of luminosity in its multiple incarnations and offering a brief survey of the pp and p p bar colliders built to date, this article outlines the various methods that have been developed for relative-luminosity monitoring, as well as the complementary approaches considered for establishing an absolute luminosity scale. This is followed by a survey, from both a historical and a technical perspective, of luminosity determination at the ISR, the S p p ¯ S, the Tevatron, RHIC and the LHC. For each of these, we first delineate the interplay between the experimental context, the specificities of the accelerator, and the precision targets suggested by the physics program. We then detail how the different methods were applied to specific experimental environments and how successfully they meet the precision goals.

  12. Synthetic B- and T-cell epitope peptides of porcine reproductive and respiratory syndrome virus with Gp96 as adjuvant induced humoral and cell-mediated immunity.

    PubMed

    Chen, Caiwei; Li, Jing; Bi, Yuhai; Yang, Limin; Meng, Shanshan; Zhou, Yuancheng; Jia, Xiaojuan; Meng, Songdong; Sun, Lei; Liu, Wenjun

    2013-04-01

    Highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) has recently caused huge economic losses in the pig industry worldwide. Commercial vaccines, including inactivated vaccines and attenuated live vaccines, are available but fail to provide sustainable protection, especially against genetically heterologous strains. Thus several approaches have been used to develop more effective PRRSV vaccines and/or immune modulators to accelerate and magnify immune responses to PRRSV vaccines. Heat shock protein Gp96 is one such modulator that enhances both the innate and adaptive immune responses. In the present study, two B-cell epitopes and seven T-cell epitopes from PRRSV and a Pan DR T-helper cell epitope were synthesized and mixed with the N-terminal 22-355 aa of Gp96 (Gp96N) as an adjuvant, and immune responses were evaluated. Our results show that Gp96N activated PRRSV-specific humoral immune responses elicited by BCE-peptides and promoted the PRRSV-specific cellular immunity induced by TCE-peptides. Moreover, higher levels of IL-12 and TNF-α and lower levels of IL-4 and IL-10 were observed in the serum of Gp96N-vaccinated piglets compared to piglets immunized with no Gp96N, displaying a predominant Th1 type of immune response induced by Gp96N. Following challenge with the virulent HP-PRRSV isolate JXwn06, piglets vaccinated with the mixture of peptides and Gp96N presented with milder clinical symptoms, lower viremia, and less pathological lesions in their lungs, however, this vaccine could not provide lasting and effective protection against HP-PRRSV infection. These data provide important bases for the development of PRRSV epitope-based synthetic peptide vaccines combined with Gp96N as attractive immunomodulators in swine. PMID:23395588

  13. A recombinant mimetics of the HIV-1 gp41 prehairpin fusion intermediate fused with human IgG Fc fragment elicits neutralizing antibody response in the vaccinated mice

    SciTech Connect

    Qi, Zhi; Pan, Chungen; Lu, Hong; Shui, Yuan; Li, Lin; Li, Xiaojuan; Xu, Xueqing; Liu, Shuwen; Jiang, Shibo

    2010-07-30

    Research highlights: {yields} One recombinant mimetics of gp41 prehairpin fusion intermediate (PFI) consisting of gp41 N46 sequence, foldon and IgG Fc, designated N46FdFc, was expressed. {yields} N46FdFc-induced antibodies in mice that neutralized HIV-1 infection, inhibited PIE7 binding to PFI, blocked gp41 six-helix bundle formation, and suppressed HIV-1 mediated cell-cell fusion. {yields} These findings provide an important clue for developing recombinant gp41 PFI mimetics-based HIV vaccines. -- Abstract: HIV-1 gp41 prehairpin fusion intermediate (PFI) composed of three N-terminal heptad repeats (NHR) plays a crucial role in viral fusion and entry and represents an attractive target for anti-HIV therapeutics (e.g., enfuvirtide) and vaccines. In present study, we constructed and expressed two recombinant gp41 PFI mimetics, designated N46Fd and N46FdFc. N46Fd consists of N46 (residues 536-581) in gp41 NHR and foldon (Fd), a trimerization motif. N46FdFc is composed of N46Fd fused with human IgG Fc fragment as an immunoenhancer. We immunized mice with N46 peptide, N46Fd and N46FdFc, respectively, and found that only N46FdFc elicited neutralizing antibody response in mice against infection by HIV-1 strains IIIB (clade B, X4), 92US657 (clade B, R5), and 94UG103 (clade A, X4R5). Anti-N46FdFc antibodies inhibited PIE7 binding to PFI, blocked gp41 six-helix bundle formation, and suppressed HIV-1 mediated cell-cell fusion. These findings provide an important clue for developing recombinant gp41 PFI mimetics-based HIV vaccines.

  14. Muon Collider Task Force Report

    SciTech Connect

    Ankenbrandt, C.; Alexahin, Y.; Balbekov, V.; Barzi, E.; Bhat, C.; Broemmelsiek, D.; Bross, A.; Burov, A.; Drozhdin, A.; Finley, D.; Geer, S.; /Fermilab /Argonne /Brookhaven /Jefferson Lab /LBL, Berkeley /MUONS Inc., Batavia /UCLA /UC, Riverside /Mississippi U.

    2007-12-01

    Muon Colliders offer a possible long term path to lepton-lepton collisions at center-of-mass energies {radical}s {ge} 1 TeV. In October 2006 the Muon Collider Task Force (MCTF) proposed a program of advanced accelerator R&D aimed at developing the Muon Collider concept. The proposed R&D program was motivated by progress on Muon Collider design in general, and in particular, by new ideas that have emerged on muon cooling channel design. The scope of the proposed MCTF R&D program includes muon collider design studies, helical cooling channel design and simulation, high temperature superconducting solenoid studies, an experimental program using beams to test cooling channel RF cavities and a 6D cooling demonstration channel. The first year of MCTF activities are summarized in this report together with a brief description of the anticipated FY08 R&D activities. In its first year the MCTF has made progress on (1) Muon Collider ring studies, (2) 6D cooling channel design and simulation studies with an emphasis on the HCC scheme, (3) beam preparations for the first HPRF cavity beam test, (4) preparations for an HCC four-coil test, (5) further development of the MANX experiment ideas and studies of the muon beam possibilities at Fermilab, (6) studies of how to integrate RF into an HCC in preparation for a component development program, and (7) HTS conductor and magnet studies to prepare for an evaluation of the prospects for of an HTS high-field solenoid build for a muon cooling channel.

  15. Cbl-b inhibits P-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers

    PubMed Central

    Zhang, Ye; Qu, Xiujuan; Teng, Yuee; Li, Zhi; Xu, Ling; Liu, Jing; Ma, Yanju; Fan, Yibo; Li, Ce; Liu, Shizhou; Wang, Zhenning; Hu, Xuejun; Zhang, Jingdong; Liu, Yunpeng

    2015-01-01

    The transport function of P-glycoprotein (P-gp) requires its efficient localization to caveolae, a subset of lipid rafts, and disruption of caveolae suppresses P-gp transport function. However, the regulatory molecules involved in the translocation of P-gp into caveolae remain unknown. In the present study, we showed that c-Src dependent Caveolin-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in multidrug resistance in adriamycin resistant gastric cancer SGC7901/Adr and breast cancer MCF-7/Adr cells. In a negative feedback loop, the translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae resulting in the reversal of MDR through the ubiquitination and degradation of c-Src. Clinical data showed a significant positive relationship between Cbl-b expression and survival in P-gp positive breast cancer patients who received anthracycline-based chemotherapy. Our findings identified a new regulatory mechanism of P-gp transport function in multiple drug-resistant gastric and breast cancers. PMID:25788263

  16. A cross-sectional study describing factors associated with utilisation of GP services by a cohort of people who inject drugs

    PubMed Central

    2014-01-01

    Background People who inject drugs (PWID) use healthcare services, including primary care, at a disproportionately high rate. We investigated key correlates of general practitioner (GP) related service utilisation within a cohort of PWID. Methods Using baseline data from a cohort of 645 community-recruited PWID based in Melbourne, Victoria, we conducted a secondary analysis of associations between past month use of GP services unrelated to opioid substitution therapy (OST) and socio-demographic and drug use characteristics and self-reported health using multivariate logistic regression. Results Just under one-third (29%) of PWID had accessed GP services in the month prior to being surveyed. Participants who reported living with children (adjusted odds ratio, AOR 1.97, 95% CI 1.04 - 3.73) or having had contact with a social worker in the past month (AOR 1.92, 95% CI 1.24 - 2.98) were more likely to have seen a GP in the past month. Participants who were injecting daily or more frequently (AOR 0.50, 95% CI 0.30 - 0.83) or had a weekly income of less than $400 (AOR 0.59, 95% CI 0.38 - 0.91) were less likely to report having seen a GP in the past month. Conclusions Our sample frequently attended GP services for health needs unrelated to OST. Findings highlight both the characteristics of PWID accessing GP services and also those potentially missing out on primary care and preventive services. PMID:25030526

  17. The Cytoplasmic Domain of the HIV-1 Glycoprotein gp41 Induces NF-κB Activation Through TGF-β-Activated Kinase 1

    PubMed Central

    Postler, Thomas S.; Desrosiers, Ronald C.

    2012-01-01

    SUMMARY The human and simian immunodeficiency viruses (HIV and SIV) primarily infect lymphocytes, which must be activated for efficient viral replication. We show that the cytoplasmic domain of the transmembrane glycoprotein gp41 (gp41CD) of both HIV-1 and SIV induces activation of NF-κB, a cellular factor important for proviral genome transcription and lymphocyte activation. This NF-κB activating property localized to a region 12–25 (SIV) or 59–70 (HIV-1) residues from the gp41 membrane-spanning domain. An siRNA-based screen of 42 key NF-κB regulators revealed that gp41CD-mediated activation occurs through the canonical NF-κB pathway via TGF-β-activated kinase 1 (TAK1). TAK1 activity was required for gp41CD-mediated NF-κB activation, and HIV-1-derived gp41CD physically interacted with TAK1 through the same region required for NF-κB activation. Importantly, an NF-κB activation-deficient HIV-1 mutant exhibited increased dependence on cellular activation for replication. These findings demonstrate an evolutionarily conserved role for gp41CD in activating NF-κB to promote infection. PMID:22341466

  18. gp78 functions downstream of Hrd1 to promote degradation of misfolded proteins of the endoplasmic reticulum

    PubMed Central

    Zhang, Ting; Xu, Yue; Liu, Yanfen; Ye, Yihong

    2015-01-01

    Eukaryotic cells eliminate misfolded proteins from the endoplasmic reticulum (ER) via a conserved process termed ER-associated degradation (ERAD). Central regulators of the ERAD system are membrane-bound ubiquitin ligases, which are thought to channel misfolded proteins through the ER membrane during retrotranslocation. Hrd1 and gp78 are mammalian ubiquitin ligases homologous to Hrd1p, an ubiquitin ligase essential for ERAD in Saccharomyces cerevisiae. However, the functional relevance of these proteins to Hrd1p is unclear. In this paper, we characterize the gp78-containing ubiquitin ligase complex and define its functional interplay with Hrd1 using biochemical and recently developed CRISPR-based genetic tools. Our data show that transient inactivation of the gp78 complex by short hairpin RNA–mediated gene silencing causes significant stabilization of both luminal and membrane ERAD substrates, but unlike Hrd1, which plays an essential role in retrotranslocation and ubiquitination of these ERAD substrates, knockdown of gp78 does not affect either of these processes. Instead, gp78 appears to act downstream of Hrd1 to promote ERAD via cooperation with the BAG6 chaperone complex. We conclude that the Hrd1 complex forms an essential retrotranslocation module that is evolutionarily conserved, but the mammalian ERAD system uses additional ubiquitin ligases to assist Hrd1 during retrotranslocation. PMID:26424800

  19. Muon Muon Collider: Feasibility Study

    SciTech Connect

    Gallardo, J.C.; Palmer, R.B.; Tollestrup, A.V.; Sessler, A.M.; Skrinsky, A.N.; Ankenbrandt, C.; Geer, S.; Griffin, J.; Johnstone, C.; Lebrun, P.; McInturff, A.; Mills, Frederick E.; Mokhov, N.; Moretti, A.; Neuffer, D.; Ng, K.Y.; Noble, R.; Novitski, I.; Popovic, M.; Qian, C.; Van Ginneken, A. /Fermilab /Brookhaven /Wisconsin U., Madison /Tel Aviv U. /Indiana U. /UCLA /LBL, Berkeley /SLAC /Argonne /Sobolev IM, Novosibirsk /UC, Davis /Munich, Tech. U. /Virginia U. /KEK, Tsukuba /DESY /Novosibirsk, IYF /Jefferson Lab /Mississippi U. /SUNY, Stony Brook /MIT /Columbia U. /Fairfield U. /UC, Berkeley

    2012-04-05

    A feasibility study is presented of a 2 + 2 TeV muon collider with a luminosity of L = 10{sup 35} cm{sup -2}s{sup -1}. The resulting design is not optimized for performance, and certainly not for cost; however, it does suffice - we believe - to allow us to make a credible case, that a muon collider is a serious possibility for particle physics and, therefore, worthy of R and D support so that the reality of, and interest in, a muon collider can be better assayed. The goal of this support would be to completely assess the physics potential and to evaluate the cost and development of the necessary technology. The muon collider complex consists of components which first produce copious pions, then capture the pions and the resulting muons from their decay; this is followed by an ionization cooling channel to reduce the longitudinal and transverse emittance of the muon beam. The next stage is to accelerate the muons and, finally, inject them into a collider ring wich has a small beta function at the colliding point. This is the first attempt at a point design and it will require further study and optimization. Experimental work will be needed to verify the validity of diverse crucial elements in the design. Muons because of their large mass compared to an electron, do not produce significant synchrotron radiation. As a result there is negligible beamstrahlung and high energy collisions are not limited by this phenomena. In addition, muons can be accelerated in circular devices which will be considerably smaller than two full-energy linacs as required in an e{sup +} - e{sup -} collider. A hadron collider would require a CM energy 5 to 10 times higher than 4 TeV to have an equivalent energy reach. Since the accelerator size is limited by the strength of bending magnets, the hadron collider for the same physics reach would have to be much larger than the muon collider. In addition, muon collisions should be cleaner than hadron collisions. There are many detailed particle

  20. Fixing the conformations of diamineplatinum(II)-GpG chelates: NMR and CD signatures of individual rotamers.

    PubMed

    Over, Diana; Bertho, Gildas; Elizondo-Riojas, Miguel-Angel; Kozelka, Jirí

    2006-03-01

    The bulky, asymmetric analog of the antitumor drug cisplatin, [PtCl(2)(tmen)] (tmen = N,N,N'-trimethylethylenediamine), was used to produce crosslinks with the dinucleotide d(GpG), modeling the most frequent lesions that cisplatin and its analogs cause to DNA. The ligand tmen was chosen because it is expected to constrain the guanine cis to the NMe(2) group in the adduct [Pt(tmen){d(GpG)}](+) to an orientation perpendicular to the coordination plane and to stabilize the other guanine in an oblique orientation, thus maintaining a head-to-head geometry typical of cisplatin-d(GpG) crosslinks within single- and double-stranded DNA. Of the four possible combinations of tmen chirality (R or S symmetry of the coordinated NHMe group) and crosslink direction (5'-G bound cis to the secondary or the tertiary amino group of tmen), two isomers were preponderantly formed, [Pt(R-tmen){d(GpG)}](+) with 5'-G bound cis to NMe(2) and [Pt(S-tmen){d(GpG)}](+) with 5'-G bound cis to NHMe. The former was shown to have a right-handed R2 orientation of guanines similar to that found in duplex DNA, whereas the latter had a left-handed L1 orientation that modeled cisplatin-d(GpG) adducts within single-stranded DNA. The R2 rotamer was found to be in an equilibrium (as observed using EXSY spectroscopy) with a minor fraction (< or =4%) of a Delta-HT rotamer related to R2 by rotation of the 3'-G about the Pt-N7 bond. The major rotamers R2 and L1 were isolated using reverse-phase HPLC, and their NMR and CD signatures were compared to those of the corresponding rotamers of the less hindered adduct [Pt(dmen)(GpG)](+) (dmen = N,N-dimethylethylenediamine). From this and other comparisons with previously reported platinum dinucleotide complexes, and from molecular modeling, it could be concluded that both steric repulsion between guanine and substituents of the cis amino group and N-H...O6 hydrogen bonding are significant effects favoring the oblique orientation of one guanine base typical of the HH

  1. Enhanced Immune Responses to HIV-1 Envelope Elicited by a Vaccine Regimen Consisting of Priming with Newcastle Disease Virus Expressing HIV gp160 and Boosting with gp120 and SOSIP gp140 Proteins.

    PubMed

    Khattar, Sunil K; DeVico, Anthony L; LaBranche, Celia C; Panda, Aruna; Montefiori, David C; Samal, Siba K

    2016-02-01

    Newcastle disease virus (NDV) expressing HIV-1 BaL gp160 was evaluated either alone or with monomeric BaL gp120 and BaL SOSIP gp140 protein in a prime-boost combination in guinea pigs to enhance envelope (Env)-specific humoral and mucosal immune responses. We showed that a regimen consisting of an NDV prime followed by a protein boost elicited stronger serum and mucosal Th-1-biased IgG responses and neutralizing antibody responses than NDV-only immunizations. Additionally, these responses were higher after the gp120 than after the SOSIP gp140 protein boost. PMID:26581986

  2. ‘I need her to be a doctor’: patients’ experiences of presenting health information from the internet in GP consultations

    PubMed Central

    Bowes, Parvathy; Stevenson, Fiona; Ahluwalia, Sanjiv; Murray, Elizabeth

    2012-01-01

    Background Patients are increasingly using the internet for health-related information and may bring this to a GP consultation. There is scant information about why patients do this and what they expect from their GP. Aim The aim was to explore patients’ motivation in presenting information, their perception of the GP’s response and what they wanted from their doctor. Design and setting Qualitative study based in North London involving patients with experience of bringing health information from the internet to their GP. Method Semi-structured face-to-face and telephone interviews using a critical incident technique, recorded, transcribed verbatim, and subjected to thematic analysis by a multidisciplinary team of researchers. Results Twenty-six interviews were completed. Participants reported using the internet to become better informed about their health and hence make best use of the limited time available with the GP and to enable the GP to take their problem more seriously. Patients expected their GP to acknowledge the information; discuss, explain, or contextualise it; and offer a professional opinion. Patients tended to prioritise the GP opinion over the internet information. However, if the GP appeared disinterested, dismissive or patronising patients reported damage to the doctor–patient relationship, occasionally to the extent of seeking a second opinion or changing their doctor. Conclusion This is the first in-depth qualitative study to explore why patients present internet information to their GP within the consultation and what they want when they do this. This information should help GPs respond appropriately in such circumstances. PMID:23211176

  3. An HIV gp120-CD4 Immunogen Does Not Elicit Autoimmune Antibody Responses in Cynomolgus Macaques.

    PubMed

    Schwartz, Jennifer A; Prado, Ilia; Misamore, Johnathan; Weiss, Deborah; Francis, Jesse; Pal, Ranajit; Huaman, Maria; Cristillo, Anthony; Lewis, George K; Gallo, Robert C; DeVico, Anthony L; Fouts, Timothy R

    2016-07-01

    are unlikely to elicit autoimmune antibody responses, supporting the advancement of gp120-CD4 complex-based antigens, such as FLSC, into clinical testing. PMID:27193040

  4. Recombinant gp19 as a potential antigen for detecting anti-Ehrlichia canis antibodies in dog sera.

    PubMed

    Oliveira, Rômulo Silva de; Cunha, Rodrigo Casquero; Moraes-Filho, Jonas; Gonçales, Relber Aguiar; Lara, Ana Paula de Souza Stori de; Avila, Luciana Farias da Costa de; Labruna, Marcelo Bahia; Leite, Fábio Pereira Leivas

    2015-01-01

    The canine monocytic ehrlichiosis, caused by Ehrlichia canis, is endemic in several regions of Brazil. Some serological diagnostic techniques using immunodominant proteins of E. canis as antigens are available, but their specificities and sensitivities are questionable. Based on this, the objective of this study was to test the antigenic potential of the recombinant gp19 protein (rGP19) for subsequent use in diagnostic tests. The rGP19 expressed in the Escherichia coli strain BL21 (DE3) C41 was recognized in the sera from experimentally infected dogs using ELISA and Western blotting. Thus, it was possible to obtain a promising antigen with the ability to differentiate between E. canis-positive and -negative animals, even 1 week after infection. PMID:26291145

  5. B physics at hadron colliders

    SciTech Connect

    Butler, J.N.; /Fermilab

    2005-09-01

    This paper discusses the physics opportunity and challenges for doing high precision B physics experiments at hadron colliders. It describes how these challenges have been addressed by the two currently operating experiments, CDF and D0, and how they are addressed by three experiments, ATLAS, CMS, and LHCb, at the LHC.

  6. Muon Colliders: The Next Frontier

    ScienceCinema

    Tourun, Yagmur [Illinois Institute of Technology, Chicago, Illinois, United States

    2010-01-08

    Muon Colliders provide a path to the energy frontier in particle physics but have been regarded to be "at least 20 years away" for 20 years. I will review recent progress in design studies and hardware R&D and show that a Muon Collider can be established as a real option for the post-LHC era if the current vigorous R&D effort revitalized by the Muon Collider Task Force at Fermilab can be supported to its conclusion. All critical technologies are being addressed and no show-stoppers have emerged. Detector backgrounds have been studied in detail and appear to be manageable and the physics can be done with existing detector technology. A muon facility can be built through a staged scenario starting from a low-energy muon source with unprecedented intensity for exquisite reach for rare processes, followed by a Neutrino Factory with ultrapure neutrino beams with unparalleled sensitivity for disentangling neutrino mixing, leading to an energy frontier Muon Collider with excellent energy resolution.

  7. Muon Colliders: The Next Frontier

    SciTech Connect

    Tourun, Yagmur

    2009-07-29

    Muon Colliders provide a path to the energy frontier in particle physics but have been regarded to be 'at least 20 years away' for 20 years. I will review recent progress in design studies and hardware R&D and show that a Muon Collider can be established as a real option for the post-LHC era if the current vigorous R&D effort revitalized by the Muon Collider Task Force at Fermilab can be supported to its conclusion. All critical technologies are being addressed and no show-stoppers have emerged. Detector backgrounds have been studied in detail and appear to be manageable and the physics can be done with existing detector technology. A muon facility can be built through a staged scenario starting from a low-energy muon source with unprecedented intensity for exquisite reach for rare processes, followed by a Neutrino Factory with ultrapure neutrino beams with unparalleled sensitivity for disentangling neutrino mixing, leading to an energy frontier Muon Collider with excellent energy resolution.

  8. Muon Colliders: The Next Frontier

    SciTech Connect

    Tourun, Yagmur

    2009-07-29

    Muon Colliders provide a path to the energy frontier in particle physics but have been regarded to be "at least 20 years away" for 20 years. I will review recent progress in design studies and hardware R&D and show that a Muon Collider can be established as a real option for the post-LHC era if the current vigorous R&D effort revitalized by the Muon Collider Task Force at Fermilab can be supported to its conclusion. All critical technologies are being addressed and no show-stoppers have emerged. Detector backgrounds have been studied in detail and appear to be manageable and the physics can be done with existing detector technology. A muon facility can be built through a staged scenario starting from a low-energy muon source with unprecedented intensity for exquisite reach for rare processes, followed by a Neutrino Factory with ultrapure neutrino beams with unparalleled sensitivity for disentangling neutrino mixing, leading to an energy frontier Muon Collider with excellent energy resolution.

  9. The very large hadron collider

    SciTech Connect

    1998-09-01

    This paper reviews the purposes to be served by a very large hadron collider and the organization and coordination of efforts to bring it about. There is some discussion of magnet requirements and R&D and the suitability of the Fermilab site.

  10. CERN's Large Hadron Collider project

    NASA Astrophysics Data System (ADS)

    Fearnley, Tom A.

    1997-03-01

    The paper gives a brief overview of CERN's Large Hadron Collider (LHC) project. After an outline of the physics motivation, we describe the LHC machine, interaction rates, experimental challenges, and some important physics channels to be studied. Finally we discuss the four experiments planned at the LHC: ATLAS, CMS, ALICE and LHC-B.

  11. Japanese lab spells out collider needs

    NASA Astrophysics Data System (ADS)

    Banks, Michael

    2016-02-01

    Japan's High Energy Accelerator Research Organization (KEK) last month issued a plan for the International Linear Collider (ILC) that calls on Japan to ramp up its expertise as it prepares to host the world's next-generation particle collider.

  12. Physics at hadron colliders: Experimental view

    SciTech Connect

    Siegrist, J.L.

    1987-08-01

    The physics of the hadron-hadron collider experiment is considered from an experimental point of view. The problems encountered in determination of how well the standard model describes collider results are discussed. 53 refs., 58 figs.

  13. Physics at high energy photon photon colliders

    SciTech Connect

    Chanowitz, M.S.

    1994-06-01

    I review the physic prospects for high energy photon photon colliders, emphasizing results presented at the LBL Gamma Gamma Collider Workshop. Advantages and difficulties are reported for studies of QCD, the electroweak gauge sector, supersymmetry, and electroweak symmetry breaking.

  14. Characteristics of Epstein-Barr Virus Envelope Protein gp42

    PubMed Central

    Shaw, Pamela L.; Kirschner, Austin N.; Jardetzky, Theodore S.; Longnecker, Richard

    2010-01-01

    Epstein-Barr virus (EBV) glycoprotein 42 (gp42) is a membrane protein essential for fusion and entry of EBV into host B-lymphocytes. Gp42 is a member of the protein fold family C-type lectin or lectin-like domains (CLECT or CTLD) and specifically is classified as a natural-killer receptor (NKR)- like CLECT. Literature review and phylogenetic comparison show that EBV gp42 shares a common structure with other NKR-like CLECTs and possibly with many viral CTLDs, but does not appear to exhibit some common binding characteristics of many CTLDs, such as features required for calcium binding. The flexible N-terminal region adjacent to the CTLD fold is important for binding to other EBV glycoproteins and for a cleavage site that is necessary for infection of host cells. From structural studies of gp42 unbound and bound to receptor and extensive mutational analysis, a general model of how gp42 triggers membrane fusion utilizing both the flexible N-terminal region and the CTLD domain has emerged. PMID:20162447

  15. Liposome-Mediated Cellular Delivery of Active gp91phox

    PubMed Central

    Marques, Bruno; Liguori, Lavinia; Paclet, Marie-Hélène; Villegas-Mendéz, Ana; Rothe, Romy; Morel, Françoise; Lenormand, Jean-Luc

    2007-01-01

    Background Gp91phox is a transmembrane protein and the catalytic core of the NADPH oxidase complex of neutrophils. Lack of this protein causes chronic granulomatous disease (CGD), a rare genetic disorder characterized by severe and recurrent infections due to the incapacity of phagocytes to kill microorganisms. Methodology Here we optimize a prokaryotic cell-free expression system to produce integral mammalian membrane proteins. Conclusions Using this system, we over-express truncated forms of the gp91phox protein under soluble form in the presence of detergents or lipids resulting in active proteins with a “native-like” conformation. All the proteins exhibit diaphorase activity in the presence of cytosolic factors (p67phox, p47phox, p40phox and Rac) and arachidonic acid. We also produce proteoliposomes containing gp91phox protein and demonstrate that these proteins exhibit activities similar to their cellular counterpart. The proteoliposomes induce rapid cellular delivery and relocation of recombinant gp91phox proteins to the plasma membrane. Our data support the concept of cell-free expression technology for producing recombinant proteoliposomes and their use for functional and structural studies or protein therapy by complementing deficient cells in gp91phox protein. PMID:17848987

  16. From Neutrino Factory to Muon Collider

    SciTech Connect

    Geer, S.; /Fermilab

    2010-01-01

    Both Muon Colliders and Neutrino Factories require a muon source capable of producing and capturing {Omicron}(10{sup 21}) muons/year. This paper reviews the similarities and differences between Neutrino Factory and Muon Collider accelerator complexes, the ongoing R&D needed for a Muon Collider that goes beyond Neutrino Factory R&D, and some thoughts about how a Neutrino Factory on the CERN site might eventually be upgraded to a Muon Collider.

  17. Magnetic merging in colliding flux tubes

    NASA Technical Reports Server (NTRS)

    Zweibel, Ellen G.; Rhoads, James E.

    1995-01-01

    We develop an analytical theory of reconnection between colliding, twisted magnetic flux tubes. Our analysis is restricted to direct collisions between parallel tubes and is based on the collision dynamics worked out by Bogdan (1984). We show that there is a range of collision velocities for which neutral point reconnection of the Parker-Sweet type can occur, and a smaller range for which reconnection leads to coalescence. Mean velocities within the solar convection zone are probably significantly greater than the upper limit for coalescence. This suggests that the majority of flux tube collisions do not result in merging, unless the frictional coupling of the tubes to the background flow is extremely strong.

  18. The next linear collider damping ring lattices

    SciTech Connect

    Wolski, Andrzej; Corlett, John N.

    2001-06-20

    We report on the lattice design of the Next Linear Collider (NLC) damping rings. The damping rings are required to provide low emittance electron and positron bunch trains to the NLC linacs, at a rate of 120 Hz. We present an optical design, based on a theoretical minimum emittance (TME) lattice, to produce the required normalized extracted beam emittances gex = 3 mm-mrad and gey = 0.02 mm mrad. An assessment of dynamic aperture and non-linear effects is given. The positron pre-damping ring, required to reduce the emittance of the positron beam such that it may be accepted by a main damping ring, is also described.

  19. String resonances at the Large Hadron Collider

    SciTech Connect

    Roy, Arunava; Cavaglia, Marco

    2009-07-01

    The Large Hadron Collider promises to discover new physics beyond the standard model. An exciting possibility is the formation of string resonances at the TeV scale. In this article, we show how string resonances may be detected at the LHC in the pp{yields}{gamma}+jet channel. Our study is based on event-shape variables, missing energy and momentum, maximum transverse momentum of photons and dijet invariant mass. These observables provide interesting signatures which enable us to discriminate string events from the standard model background.

  20. HIGH ENERGY PHYSICS POTENTIAL AT MUON COLLIDERS

    SciTech Connect

    PARSA,Z.

    2000-04-07

    In this paper, high energy physics possibilities and future colliders are discussed. The {mu}{sup +} {mu}{sup {minus}} collider and experiments with high intensity muon beams as the stepping phase towards building Higher Energy Muon Colliders (HEMC) are briefly reviewed and encouraged.

  1. Linear Collider Flavour Identification status report: Sensors for the International Linear Collider

    NASA Astrophysics Data System (ADS)

    Stefanov, K. D.

    2007-12-01

    The Linear Collider Flavour Identification (LCFI) collaboration is continuing the work to develop column-parallel CCDs (CPCCD) and CMOS readout chips to be used in the vertex detector at the international linear collider (ILC). The CPCCD achieves several orders of magnitude faster readout than conventional CCDs because every column is equipped with amplifier and ADC, enabling efficient data taking with low occupancy. Already two generations of CPCCDs and readout chips have been manufactured and the first chips have been fully tested. The second generation devices are now being evaluated. A new CCD-based device, the in-situ storage image sensor (ISIS) has also been developed. The ISIS offers numerous advantages in terms of relaxed readout, increased radiation hardness and great immunity to EMI. In this paper we present the results from the tests of the CPCCDs, readout chips and ISIS, as well as the plans for future developments.

  2. EpCAM and gpA33 are markers of Barrett's metaplasia

    PubMed Central

    Wong, N A C S; Warren, B F; Piris, J; Maynard, N; Marshall, R; Bodmer, W F

    2006-01-01

    Aims To characterise a specific and sensitive marker of Barrett's metaplasia (BM). Methods Cases of normal oesophageal squamous mucosa (11 fresh endoscopic biopsies and 10 formalin fixed, paraffin embedded tissue blocks), BM (11 biopsies and 11 tissue blocks), and normal gastric body mucosa (five biopsies and five tissue blocks) were analysed using reverse transcriptase PCR, Western blotting, and immunohistochemistry for EpCAM, and reverse transcriptase PCR for gpA33. Results Strong EpCAM mRNA expression was detected in all the BM cases, in contrast to weak expression in all the normal gastric mucosal samples and no expression in any of the normal oesophageal mucosal samples tested. Strong gpA33 mRNA expression was detected in all the BM cases, in contrast to weak expression in a quarter of the normal gastric mucosal samples and no expression in any of the normal oesophageal mucosal samples tested. Western blotting showed EpCAM protein expression in all the BM cases and in none of the normal gastric or oesophageal mucosal samples tested. Immunohistochemistry showed strong EpCAM protein expression in BM and complete absence of expression in normal oesophageal squamous epithelium. Scattered EpCAM expressing cells were found in the gland bases of normal gastric body mucosa. Conclusions EpCAM protein and gpA33 mRNA expressions are specific and sensitive markers of BM. PMID:16473928

  3. Future Electron-Hadron Colliders

    SciTech Connect

    Litvinenko, V.

    2010-05-23

    Outstanding research potential of electron-hadron colliders (EHC) was clearly demonstrated by first - and the only - electron-proton collider HERA (DESY, Germany). Physics data from HERA revealed new previously unknown facets of Quantum Chromo-Dynamics (QCD). EHC is an ultimate microscope probing QCD in its natural environment, i.e. inside the hadrons. In contrast with hadrons, electrons are elementary particles with known initial state. Hence, scattering electrons from hadrons provides a clearest pass to their secrets. It turns EHC into an ultimate machine for high precision QCD studies and opens access to rich physics with a great discovery potential: solving proton spin puzzle, observing gluon saturation or physics beyond standard model. Access to this physics requires high-energy high-luminosity EHCs and a wide reach in the center-of-mass (CM) energies. This paper gives a brief overview of four proposed electron-hadron colliders: ENC at GSI (Darmstadt, Germany), ELIC/MEIC at TJNAF (Newport News, VA, USA), eRHIC at BNL (Upton, NY, USA) and LHeC at CERN (Geneva, Switzerland). Future electron-hadron colliders promise to deliver very rich physics not only in the quantity but also in the precision. They are aiming at very high luminosity two-to-four orders of magnitude beyond the luminosity demonstrated by the very successful HERA. While ENC and LHeC are on opposite side of the energy spectrum, eRHIC and ELIC are competing for becoming an electron-ion collider (EIC) in the U.S. Administrations of BNL and Jlab, in concert with US DoE office of Nuclear Physics, work on the strategy for down-selecting between eRHIC and ELIC. The ENC, EIC and LHeC QCD physics programs to a large degree are complimentary to each other and to the LHC physics. In last decade, an Electron Ion Collider (EIC) collaboration held about 25 collaboration meetings to develop physics program for EIC with CM energy {approx}100 GeV. One of these meetings was held at GSI, where ENC topic was in the

  4. Antibodies with specificity to native gp120 and neutralization activity against primary human immunodeficiency virus type 1 isolates elicited by immunization with oligomeric gp160.

    PubMed Central

    VanCott, T C; Mascola, J R; Kaminski, R W; Kalyanaraman, V; Hallberg, P L; Burnett, P R; Ulrich, J T; Rechtman, D J; Birx, D L

    1997-01-01

    Current human immunodeficiency virus type 1 (HIV-1) envelope vaccine candidates elicit high antibody binding titers with neutralizing activity against T-cell line-adapted but not primary HIV-1 isolates. Serum antibodies from these human vaccine recipients were also found to be preferentially directed to linear epitopes within gp120 that are poorly exposed on native gp120. Systemic immunization of rabbits with an affinity-purified oligomeric gp160 protein formulated with either Alhydrogel or monophosphoryl lipid A-containing adjuvants resulted in the induction of high-titered serum antibodies that preferentially bound epitopes exposed on native forms of gp120 and gp160, recognized a restricted number of linear epitopes, efficiently bound heterologous strains of monomeric gp120 and cell surface-expressed oligomeric gp120/gp41, and neutralized several strains of T-cell line-adapted HIV-1. Additionally, those immune sera with the highest oligomeric gp160 antibody binding titers had neutralizing activity against some primary HIV-1 isolates, using phytohemagglutinin-stimulated peripheral blood mononuclear cell targets. Induction of an antibody response preferentially reactive with natively folded gp120/gp160 was dependent on the tertiary structure of the HIV-1 envelope immunogen as well as its adjuvant formulation, route of administration, and number of immunizations administered. These studies demonstrate the capacity of a soluble HIV-1 envelope glycoprotein vaccine to elicit an antibody response capable of neutralizing primary HIV-1 isolates. PMID:9151820

  5. COLLIDE: Collisions into Dust Experiment

    NASA Technical Reports Server (NTRS)

    Colwell, Joshua E.

    1999-01-01

    The Collisions Into Dust Experiment (COLLIDE) was completed and flew on STS-90 in April and May of 1998. After the experiment was returned to Earth, the data and experiment were analyzed. Some anomalies occurred during the flight which prevented a complete set of data from being obtained. However, the experiment did meet its criteria for scientific success and returned surprising results on the outcomes of very low energy collisions into powder. The attached publication, "Low Velocity Microgravity Impact Experiments into Simulated Regolith," describes in detail the scientific background, engineering, and scientific results of COLLIDE. Our scientific conclusions, along with a summary of the anomalies which occurred during flight, are contained in that publication. We offer it as our final report on this grant.

  6. Overview of linear collider designs

    SciTech Connect

    Siemann, R.H.

    1993-04-01

    Linear collider design and development have become focused on a center-of-mass energy E{sub CM} = 0.5 TeV and a luminosity L {approximately} 5 {times} 10{sup 33} cm{sup {minus}2}sec{sup {minus}1}. There are diverse approaches to meeting these general objectives. The diversity arises from different judgements about the ease of developing new and improving existing technology, costs, extension to higher energies, experimental backgrounds and center-of-mass energy spectrum, and tolerances and beam power. The parameters of possible colliders are given in this paper. This report will focus on some of the common themes of these designs and the different between them.

  7. Crab Cavities for Linear Colliders

    SciTech Connect

    Burt, G.; Ambattu, P.; Carter, R.; Dexter, A.; Tahir, I.; Beard, C.; Dykes, M.; Goudket, P.; Kalinin, A.; Ma, L.; McIntosh, P.; Shulte, D.; Jones, Roger M.; Bellantoni, L.; Chase, B.; Church, M.; Khabouline, T.; Latina, A.; Adolphsen, C.; Li, Z.; Seryi, Andrei; /SLAC

    2011-11-08

    Crab cavities have been proposed for a wide number of accelerators and interest in crab cavities has recently increased after the successful operation of a pair of crab cavities in KEK-B. In particular crab cavities are required for both the ILC and CLIC linear colliders for bunch alignment. Consideration of bunch structure and size constraints favour a 3.9 GHz superconducting, multi-cell cavity as the solution for ILC, whilst bunch structure and beam-loading considerations suggest an X-band copper travelling wave structure for CLIC. These two cavity solutions are very different in design but share complex design issues. Phase stabilisation, beam loading, wakefields and mode damping are fundamental issues for these crab cavities. Requirements and potential design solutions will be discussed for both colliders.

  8. Solid State Technology Meets Collider Challenge

    SciTech Connect

    Hazi, A

    2005-09-20

    Probing the frontiers of particle physics and delving into the mysteries of the universe and its beginnings require machines that can accelerate beams of fundamental particles to very high energies and then collide those beams together, producing a multitude of exotic subatomic particles. The proposed Next Linear Collider (NLC), being developed by Stanford Linear Accelerator Center (SLAC), Lawrence Livermore and Lawrence Berkeley national laboratories, and Fermi National Accelerator Laboratory (Fermilab), is such a machine. The NLC is expected to produce a variety of subatomic particles by smashing together electrons and their antimatter counterparts (positrons) at nearly the speed of light with energies in the teraelectronvolt (TeV) range. Plans are that the NLC will initially operate at 0.5 TeV and ultimately be scaled up to 1.5 TeV. (See S&TR, April 2000, pp. 12-16.) Work at the facility will complement the research to be conducted at another high-energy particle accelerator, the 14-TeV Large Hadron Collider at the European Laboratory for Particle Physics (commonly known by the acronym CERN from its former name) in Geneva, which is scheduled for completion in 2007. Achieving beam energy levels in the TeV range requires modulator systems that can convert ac line power--the same type of power one gets from the wall plug--into dc pulses. Ultimately, these pulses are transformed into radiofrequency (rf) pulses that ''kick'' the particles up to the required energy levels. Livermore scientists and engineers have designed a solid-state modulator to replace oldstyle modulators based on vacuum-tube technology. These new modulators promise to be far more efficient, reliable, and serviceable than the previous components. Livermore's Laboratory Directed Research and Development Program supported the basic research and development on the solid-state modulator technology, and SLAC supported the systems integration.

  9. Chromaticity correction for a muon collider optics

    SciTech Connect

    Alexahin, Y.; Gianfelice-Wendt, E.; Kapin, V.; /Fermilab

    2011-03-01

    Muon Collider (MC) is a promising candidate for the next energy frontier machine. However, in order to obtain peak luminosity in the 10{sup 34} cm{sup 2}s{sup -1} range the collider lattice designmust satisfy a number of stringent requirements. In particular the expected large momentum spread of the muon beam and the very small {beta}* call for a careful correction of the chromatic effects. Here we present a particular solution for the interaction region (IR) optics whose distinctive feature is a three-sextupole local chromatic correction scheme. The scheme may be applied to other future machines where chromatic effects are expected to be large. The expected large muon energy spread requires the optics to be stable over a wide range of momenta whereas the required luminosity calls for {beta}* in the mm range. To avoid luminosity degradation due to hour-glass effect, the bunch length must be comparatively small. To keep the needed RF voltage within feasible limits the momentum compaction factor must be small over the wide range of momenta. A low {beta}* means high sensitivity to alignment and field errors of the Interaction Region (IR) quadrupoles and large chromatic effects which limit the momentum range of optics stability and require strong correction sextupoles, which eventually limit the Dynamic Aperture (DA). Finally, the ring circumference should be as small as possible, luminosity being inversely proportional to the collider length. A promising solution for a 1.5 TeV center of mass energy MC with {beta}* = 1 m in both planes has been proposed. This {beta}* value has been chosen as a compromise between luminosity and feasibility based on the magnet design and energy deposition considerations. The proposed solution for the IR optics together with a new flexible momentum compaction arc cell design allows to satisfy all requirements and is relatively insensitive to the beam-beam effect.

  10. Supergravity at colliders

    NASA Astrophysics Data System (ADS)

    Buchmüller, Wilfried; Hamaguchi, Koichi; Ratz, Michael; Yanagida, Tsutomu

    2004-05-01

    We consider supersymmetric theories where the gravitino is the lightest superparticle (LSP). Assuming that the long-lived next-to-lightest superparticle (NSP) is a charged slepton, we investigate two complementary ways to prove the existence of supergravity in nature. The first is based on the NSP lifetime which in supergravity depends only on the Planck scale and the NSP and gravitino masses. With the gravitino mass inferred from kinematics, the measurement of the NSP lifetime will test an unequivocal prediction of supergravity. The second way makes use of the 3-body NSP decay. The angular and energy distributions and the polarizations of the final state photon and lepton carry the information on the spin of the gravitino and on its couplings to matter and radiation.

  11. In vivo alteration of humoral responses to HIV-1 envelope glycoprotein gp120 by antibodies to the CD4-binding site of gp120

    PubMed Central

    Visciano, Maria Luisa; Tuen, Michael; Gorny, Miroslaw K.; Hioe, Catarina E.

    2008-01-01

    The binding of antibodies to the CD4-binding site (CD4bs) of the HIV-1 envelope glycoprotein gp120 has been shown to induce gp120 to undergo conformational changes that can expose and/or shield specific epitopes on gp120. Here, we study alterations in the antigenicity and immunogenicity of gp120 when complexed with human monoclonal antibodies (mAbs) specific for the CD4bs of gp120. The data showed that gp120 bound by anti-CD4bs mAbs had enhanced reactivity with mAbs to the V3 and N-terminal regions, but not with mAb to the C terminus. Moreover, mice immunized with the gp120/anti-CD4bs mAb complexes produced higher titers of gp120-specific serum IgG and IgA than mice immunized with uncomplexed gp120 or other gp120/mAb complexes. Notably, the enhanced antibody production was directed against V3 and correlated with better exposure of V3 on the gp120/anti-CD4bs mAb complexes. The higher antibody reactivity was evident against the homologous V3LAI peptide, but not against heterologous V3 peptides. Potent neutralization activity against HIV-1LAI was also observed in the sera from mice immunized with gp120/anti-CD4bs mAb complexes, although the sera exhibited poor neutralizing activities against other viruses tested. These results indicate that the anti-CD4bs antibodies alter the antigenicity and immunogenicity of gp120, leading to enhanced production of anti-gp120 antibodies directed particularly against the V3 region. PMID:18054978

  12. String resonances at hadron colliders

    NASA Astrophysics Data System (ADS)

    Anchordoqui, Luis A.; Antoniadis, Ignatios; Dai, De-Chang; Feng, Wan-Zhe; Goldberg, Haim; Huang, Xing; Lüst, Dieter; Stojkovic, Dejan; Taylor, Tomasz R.

    2014-09-01

    We consider extensions of the standard model based on open strings ending on D-branes, with gauge bosons due to strings attached to stacks of D-branes and chiral matter due to strings stretching between intersecting D-branes. Assuming that the fundamental string mass scale Ms is in the TeV range and that the theory is weakly coupled, we discuss possible signals of string physics at the upcoming HL-LHC run (integrated luminosity =3000 fb-1) with a center-of-mass energy of √s =14 TeV and at potential future pp colliders, HE-LHC and VLHC, operating at √s =33 and 100 TeV, respectively (with the same integrated luminosity). In such D-brane constructions, the dominant contributions to full-fledged string amplitudes for all the common QCD parton subprocesses leading to dijets and γ +jet are completely independent of the details of compactification and can be evaluated in a parameter-free manner. We make use of these amplitudes evaluated near the first (n=1) and second (n=2) resonant poles to determine the discovery potential for Regge excitations of the quark, the gluon, and the color singlet living on the QCD stack. We show that for string scales as large as 7.1 TeV (6.1 TeV) lowest massive Regge excitations are open to discovery at the ≥5σ in dijet (γ +jet) HL-LHC data. We also show that for n=1 the dijet discovery potential at HE-LHC and VLHC exceedingly improves: up to 15 TeV and 41 TeV, respectively. To compute the signal-to-noise ratio for n=2 resonances, we first carry out a complete calculation of all relevant decay widths of the second massive level string states (including decays into massless particles and a massive n=1 and a massless particle), where we rely on factorization and conformal field theory techniques. Helicity wave functions of arbitrary higher spin massive bosons are also constructed. We demonstrate that for string scales Ms≲10.5 TeV (Ms≲28 TeV) detection of n =2 Regge recurrences at HE-LHC (VLHC) would become the smoking gun for D

  13. The construction of a decision tool to analyse local demand and local supply for GP care using a synthetic estimation model

    PubMed Central

    2013-01-01

    Background This study addresses the growing academic and policy interest in the appropriate provision of local healthcare services to the healthcare needs of local populations to increase health status and decrease healthcare costs. However, for most local areas information on the demand for primary care and supply is missing. The research goal is to examine the construction of a decision tool which enables healthcare planners to analyse local supply and demand in order to arrive at a better match. Methods National sample-based medical record data of general practitioners (GPs) were used to predict the local demand for GP care based on local populations using a synthetic estimation technique. Next, the surplus or deficit in local GP supply were calculated using the national GP registry. Subsequently, a dynamic internet tool was built to present demand, supply and the confrontation between supply and demand regarding GP care for local areas and their surroundings in the Netherlands. Results Regression analysis showed a significant relationship between sociodemographic predictors of postcode areas and GP consultation time (F [14, 269,467] = 2,852.24; P <0.001). The statistical model could estimate GP consultation time for every postcode area with >1,000 inhabitants in the Netherlands covering 97% of the total population. Confronting these estimated demand figures with the actual GP supply resulted in the average GP workload and the number of full-time equivalent (FTE) GP too much/too few for local areas to cover the demand for GP care. An estimated shortage of one FTE GP or more was prevalent in about 19% of the postcode areas with >1,000 inhabitants if the surrounding postcode areas were taken into consideration. Underserved areas were mainly found in rural regions. Conclusions The constructed decision tool is freely accessible on the Internet and can be used as a starting point in the discussion on primary care service provision in local communities and it can

  14. Advances in Beam Cooling for Muon Colliders

    SciTech Connect

    R.P. Johnson, Y.S. Derbenev

    2006-09-01

    A six-dimensional (6D) ionization cooling channel based on helical magnets surrounding RF cavities filled with dense hydrogen gas is the basis for the latest plans for muon colliders. This helical cooling channel (HCC) has solenoidal, helical dipole, and helical quadrupole magnetic fields, where emittance exchange is achieved by using a continuous homogeneous absorber. Momentum-dependent path length differences in the dense hydrogen energy absorber provide the required correlation between momentum and ionization loss to accomplish longitudinal cooling. Recent studies of an 800 MHz RF cavity pressurized with hydrogen, as would be used in this application, show that the maximum gradient is not limited by a large external magnetic field, unlike vacuum cavities. Two new cooling ideas, Parametric-resonance Ionization Cooling and Reverse Emittance Exchange, will be employed to further reduce transverse emittances to a few mm-mr, which allows high luminosity with fewer muons than previously imagined. We describe these new ideas as well as a new precooling idea based on a HCC with z dependent fields that is being developed for an exceptional 6D cooling demonstration experiment. The status of the designs, simulations, and tests of the cooling components for a high luminosity, low emittance muon collider will be reviewed.

  15. State of hadron collider physics

    SciTech Connect

    Grannis, P.D. |

    1993-12-01

    The 9th Topical Workshop on Proton-Antiproton Collider Physics in Tsukuba Japan demonstrated clearly the enormous breadth of physics accessible in hadron cowders. Although no significant chinks were reported in the armor of the Standard Model, new results presented in this meeting have expanded our knowledge of the electroweak and strong interactions and have extended the searches for non-standard phenomena significantly. Much of the new data reported came from the CDF and D0 experiments at the Fermilab cowder. Superb operation of the Tevatron during the 1992-1993 Run and significant advances on the detector fronts -- in particular, the emergence of the new D0 detector as a productive physics instrument in its first outing and the addition of the CDF silicon vertex detector -- enabled much of this advance. It is noteworthy however that physics from the CERN collider experiments UA1 and UA4 continued to make a large impact at this meeting. In addition, very interesting summary talks were given on new results from HERA, cosmic ray experiments, on super-hadron collider physics, and on e{sup +}e{sup {minus}} experiments at LEP and TRISTAN. These summaries are reported in elsewhere in this volume.

  16. Immunization with Hexon Modified Adenoviral Vectors Integrated with gp83 Epitope Provides Protection against Trypanosoma cruzi Infection

    PubMed Central

    Gu, Linlin; Krendelchtchikova, Valentina; Nde, Pius N.; Pratap, Siddharth; Lima, Maria F.; Villalta, Fernando; Matthews, Qiana L.

    2014-01-01

    Background Trypanosoma cruzi is the causative agent of Chagas disease. Chagas disease is an endemic infection that affects over 8 million people throughout Latin America and now has become a global challenge. The current pharmacological treatment of patients is unsuccessful in most cases, highly toxic, and no vaccines are available. The results of inadequate treatment could lead to heart failure resulting in death. Therefore, a vaccine that elicits neutralizing antibodies mediated by cell-mediated immune responses and protection against Chagas disease is necessary. Methodology/Principal Findings The “antigen capsid-incorporation” strategy is based upon the display of the T. cruzi epitope as an integral component of the adenovirus' capsid rather than an encoded transgene. This strategy is predicted to induce a robust humoral immune response to the presented antigen, similar to the response provoked by native Ad capsid proteins. The antigen chosen was T. cruzi gp83, a ligand that is used by T. cruzi to attach to host cells to initiate infection. The gp83 epitope, recognized by the neutralizing MAb 4A4, along with His6 were incorporated into the Ad serotype 5 (Ad5) vector to generate the vector Ad5-HVR1-gp83-18 (Ad5-gp83). This vector was evaluated by molecular and immunological analyses. Vectors were injected to elicit immune responses against gp83 in mouse models. Our findings indicate that mice immunized with the vector Ad5-gp83 and challenged with a lethal dose of T. cruzi trypomastigotes confer strong immunoprotection with significant reduction in parasitemia levels, increased survival rate and induction of neutralizing antibodies. Conclusions/Significance This data demonstrates that immunization with adenovirus containing capsid-incorporated T. cruzi antigen elicits a significant anti-gp83-specific response in two different mouse models, and protection against T. cruzi infection by eliciting neutralizing antibodies mediated by cell-mediated immune responses

  17. The HIV Protein gp120 Alters Mitochondrial Dynamics in Neurons.

    PubMed

    Avdoshina, Valeria; Fields, Jerel Adam; Castellano, Paul; Dedoni, Simona; Palchik, Guillermo; Trejo, Margarita; Adame, Anthony; Rockenstein, Edward; Eugenin, Eliseo; Masliah, Eliezer; Mocchetti, Italo

    2016-05-01

    Neurotoxicity of human immunodeficiency virus-1 (HIV) includes synaptic simplification and neuronal apoptosis. However, the mechanisms of HIV-associated neurotoxicity remain unclear, thus precluding an effective treatment of the neurological complications. The present study was undertaken to characterize novel mechanisms of HIV neurotoxicity that may explain how HIV subjects develop neuronal degeneration. Several neurodegenerative disorders are characterized by mitochondrial dysfunction; therefore, we hypothesized that HIV promotes mitochondrial damage. We first analyzed brains from HIV encephalitis (HIVE) by electron microscopy. Several sections of HIVE subjects contained enlarged and damaged mitochondria compared to brains from HIV subjects with no neurological complications. Similar pathologies were observed in mice overexpressing the HIV protein gp120, suggesting that this viral protein may be responsible for mitochondrial pathology found in HIVE. To gain more information about the cellular mechanisms of gp120 neurotoxicity, we exposed rat cortical neurons to gp120 and we determined cellular oxygen consumption rate, mitochondrial distribution, and trafficking. Our data show that gp120 evokes impairment in mitochondrial function and distribution. These data suggest that one of the mechanisms of HIV neurotoxicity includes altered mitochondrial dynamics in neurons. PMID:26936603

  18. Update on the MEIC electron collider ring design

    SciTech Connect

    Lin, Fangei; Derbenev, Yaroslav S.; Harwood, Leigh; Hutton, Andrew; Morozov, Vasiliy; Pilat, Fulvia; Zhang, Yuhong; Cai, Y.; Nosochkov, Y. M.; Sullivan, Michael; Wang, M.-H; Wienands, Uli

    2015-09-01

    The electron collider ring of the Medium-energy Electron-Ion Collider (MEIC) at Jefferson Lab is designed to accumulate and store a high-current polarized electron beam for collisions with an ion beam. We consider a design of the electron collider ring based on reusing PEP-II components, such as magnets, power supplies, vacuum system, etc. This has the potential to significantly reduce the cost and engineering effort needed to bring the project to fruition. This paper reports on an electron ring optics design considering the balance of PEP-II hardware parameters (such as dipole sagitta, magnet field strengths and acceptable synchrotron radiation power) and electron beam quality in terms of equilibrium emittances.

  19. Symmetric Achromatic Low-Beta Collider Interaction Region Design Concept

    SciTech Connect

    Morozov, Vasiliy S.; Derbenev, Yaroslav S.; Lin, Fanglei; Johnson, Rolland P.

    2013-01-01

    We present a new symmetry-based concept for an achromatic low-beta collider interaction region design. A specially-designed symmetric Chromaticity Compensation Block (CCB) induces an angle spread in the passing beam such that it cancels the chromatic kick of the final focusing quadrupoles. Two such CCB?s placed symmetrically around an interaction point allow simultaneous compensation of the 1st-order chromaticities and chromatic beam smear at the IP without inducing significant 2nd-order aberrations. We first develop an analytic description of this approach and explicitly formulate 2nd-order aberration compensation conditions at the interaction point. The concept is next applied to develop an interaction region design for the ion collider ring of an electron-ion collider. We numerically evaluate performance of the design in terms of momentum acceptance and dynamic aperture. The advantages of the new concept are illustrated by comparing it to the conventional distributed-sextupole chromaticity compensation scheme.

  20. Update on the MEIC electron collider ring design

    SciTech Connect

    Lin, F.; Derbenev, Ya. S.; Harwood, L.; Hutton, A.; Morozov, V. S.; Pilat, F.; Zhang, Y.; Cai, Y.; Nosochkov, Y. M.; Sullivan, M.; Wang, M-H; Wienands, U.

    2015-07-14

    The electron collider ring of the Medium-energy Electron-Ion Collider (MEIC) at Jefferson Lab is designed to accumulate and store a high-current polarized electron beam for collisions with an ion beam. We consider a design of the electron collider ring based on reusing PEPII components, such as magnets, power supplies, vacuum system, etc. This has the potential to significantly reduce the cost and engineering effort needed to bring the project to fruition. This paper reports on an electron ring optics design considering the balance of PEP-II hardware parameters (such as dipole sagitta, magnet field strengths and acceptable synchrotron radiation power) and electron beam quality in terms of equilibrium emittances.

  1. Massive Stars in Colliding Wind Systems: the GLAST Perspective

    SciTech Connect

    Reimer, Anita; Reimer, Olaf; /Stanford U., HEPL /KIPAC, Menlo Park

    2011-11-29

    Colliding winds of massive stars in binary systems are considered as candidate sites of high-energy non-thermal photon emission. They are already among the suggested counterparts for a few individual unidentified EGRET sources, but may constitute a detectable source population for the GLAST observatory. The present work investigates such population study of massive colliding wind systems at high-energy gamma-rays. Based on the recent detailed model (Reimer et al. 2006) for non-thermal photon production in prime candidate systems, we unveil the expected characteristics of this source class in the observables accessible at LAT energies. Combining the broadband emission model with the presently cataloged distribution of such systems and their individual parameters allows us to conclude on the expected maximum number of LAT-detections among massive stars in colliding wind binary systems.

  2. The Multi-Purpose Detector (MPD) of the collider experiment

    NASA Astrophysics Data System (ADS)

    Golovatyuk, V.; Kekelidze, V.; Kolesnikov, V.; Rogachevsky, O.; Sorin, A.

    2016-08-01

    The project NICA (Nuclotron-based Ion Collider fAcility) is aimed to study dense baryonic matter in heavy-ion collisions in the energy range up to √{s_{NN}} = 11 GeV with average luminosity of L = 1027 cm-2s-1 (for 197Au79). The experimental program at the NICA collider will be performed with the Multi-Purpose Detector (MPD). We report on the main physics objectives of the NICA heavy-ion program and present the main detector components.

  3. The crystal structure of HIV CRF07 B′/C gp41 reveals a hyper-mutant site in the middle of HR2 heptad repeat

    SciTech Connect

    Du, Jiansen; Xue, Hailing; Ma, Jing; Liu, Fang; Zhou, Jianhua; Shao, Yiming; Liu, Xinqi

    2013-11-15

    HIV CRF07 B′/C is a strain circulating mainly in northwest region of China. The gp41 region of CRF07 is derived from a clade C virus. In order to compare the difference of CRF07 gp41 with that of typical clade B virus, we solved the crystal structure of the core region of CRF07 gp41. Compared with clade B gp41, CRF07 gp41 evolved more basic and hydrophilic residues on its helix bundle surface. Based on sequence alignment, a hyper-mutant cluster located in the middle of HR2 heptads repeat was identified. The mutational study of these residues revealed that this site is important in HIV mediated cell–cell fusion and plays critical roles in conformational changes during viral invasion. - Highlights: • We solved the crystal structure of HIV CRF07 gp41 core region. • A hyper-mutant cluster in the middle of HR2 heptads repeat was identified. • The hyper-mutant site is important in HIV-cell fusion. • The model will help to understand the HIV fusion process.

  4. Relationship of the human immunodeficiency virus type 1 gp120 third variable loop to a component of the CD4 binding site in the fourth conserved region.

    PubMed Central

    Wyatt, R; Thali, M; Tilley, S; Pinter, A; Posner, M; Ho, D; Robinson, J; Sodroski, J

    1992-01-01

    Neutralizing antibodies that recognize the human immunodeficiency virus gp120 exterior envelope glycoprotein and are directed against either the third variable (V3) loop or conserved, discontinuous epitopes overlapping the CD4 binding region have been described. Here we report several observations that suggest a structural relationship between the V3 loop and amino acids in the fourth conserved (C4) gp120 region that constitute part of the CD4 binding site and the conserved neutralization epitopes. Treatment of the gp120 glycoprotein with ionic detergents resulted in a V3 loop-dependent masking of both linear C4 epitopes and discontinuous neutralization epitopes overlapping the CD4 binding site. Increased recognition of the native gp120 glycoprotein by an anti-V3 loop monoclonal antibody, 9284, resulted from from single amino acid changes either in the base of the V3 loop or in the gp120 C4 region. These amino acid changes also resulted in increased exposure of conserved epitopes overlapping the CD4 binding region. The replication-competent subset of these mutants exhibited increased sensitivity to neutralization by antibody 9284 and anti-CD4 binding site antibodies. The implied relationship of the V3 loop, which mediates post-receptor binding steps in virus entry, and components of the CD4 binding region may be important for the interaction of these functional gp120 domains and for the observed cooperativity of neutralizing antibodies directed against these regions. Images PMID:1279195

  5. Cooling of electronics in collider experiments

    SciTech Connect

    Richard P. Stanek et al.

    2003-11-07

    Proper cooling of detector electronics is critical to the successful operation of high-energy physics experiments. Collider experiments offer unique challenges based on their physical layouts and hermetic design. Cooling systems can be categorized by the type of detector with which they are associated, their primary mode of heat transfer, the choice of active cooling fluid, their heat removal capacity and the minimum temperature required. One of the more critical detector subsystems to require cooling is the silicon vertex detector, either pixel or strip sensors. A general design philosophy is presented along with a review of the important steps to include in the design process. Factors affecting the detector and cooling system design are categorized. A brief review of some existing and proposed cooling systems for silicon detectors is presented to help set the scale for the range of system designs. Fermilab operates two collider experiments, CDF & D0, both of which have silicon systems embedded in their detectors. A review of the existing silicon cooling system designs and operating experience is presented along with a list of lessons learned.

  6. Effect of the delegation of GP-home visits on the development of the number of patients in an ambulatory healthcare centre in Germany

    PubMed Central

    2012-01-01

    Background The AGnES-concept (AGnES: GP-supporting, community-based, e-health-assisted, systemic intervention) was developed to support general practitioners (GPs) in undersupplied regions. The project aims to delegate GP-home visits to qualified AGnES-practice assistants, to increase the number of patients for whom medical care can be provided. This paper focuses on the effect of delegating GP-home visits on the total number of patients treated. First, the theoretical number of additional patients treated by delegating home visits to AGnES-practice assistants was calculated. Second, actual changes in the number of patients in participating GP-practices were analyzed. Methods The calculation of the theoretical increase in the number of patients was based on project data, data which were provided by the Association of Statutory Health Insurance Physicians, or which came from the literature. Setting of the project was an ambulatory healthcare centre in the rural county Oberspreewald-Lausitz in the Federal State of Brandenburg, which employed six GPs, four of which participated in the AGnES project. The analysis of changes in the number of patients in the participating GP-practices was based on the practices’ reimbursement data. Results The calculated mean capacity of AGnES-practice assistants was 1376.5 home visits/year. GPs perform on average 1200 home visits/year. Since home visits with an urgent medical reason cannot be delegated, we included only half the capacity of the AGnES-practice assistants in the analysis (corresponding to a 20 hour-work week). Considering all parameters in the calculation model, 360.1 GP-working hours/year can be saved. These GP-hours could be used to treat 170 additional patients/quarter year. In the four participating GP-practices the number of patients increased on average by 133 patients/quarter year during the project period, which corresponds to 78% of the theoretically possible number of patients. Conclusions The empirical

  7. Managerialism and the British GP: the GP as manager and as managed.

    PubMed

    Warwicker, T

    1998-01-01

    The focus of the paper is on the relationship between General Practitioners (GPs) and central government. This relationship dates from the introduction of national health insurance in the UK. From the outset it had an impact on GPs' medical role, their professional status and income. The structure created in 1911 meant that GPs operated as franchisees and, notwithstanding Labour's policy objective of creating a salaried service, this role continued, effectively unchanged, after the creation of the National Health Service (NHS) in 1948. General practice was also the poor relation in contrast to hospital medicine, a feature intensified by the priorities of the NHS. These forces meant that GPs had a dual role: that of clinician and gatekeeper to specialist hospital services, a role in which they exercised substantial clinical freedom: and running a small business, a feature which was exaggerated by the absence of grant aid to improve premises prior to the Family Doctor Charter of 1965. This structural relationship has been progressively transformed by changes in the 1980s and 1990s. On the one hand the emphasis on cost control has seen central government attempting to combine a financial with a clinical gate-keeping keeping role. The crucial change in this respect is the creation of GP fundholding which, in turn, could be seen to have implications for the subordinate status of GPs within the medical profession. However, this has been combined with trends to greater measures of control over GPs. Of central importance in this respect were the changes introduced by the 1990 GP contract. The contract involved an attempt to substantially reduce clinical autonomy by building in much more detailed contractual duties with respect, for example, to health promotion activities. This was combined with the use of financial incentives to reach, for example, immunization targets. Control over clinical autonomy has also involved constraints over prescribing and the shift from Family

  8. Binding-induced Stabilization and Assembly of the Phage P22 Tail Accessory Factor gp4

    SciTech Connect

    Olia,A.; Al-Bassam, J.; Winn-Stapley, D.; Joss, L.; Casjens, S.; Cingolani, G.

    2006-01-01

    To infect and replicate, bacteriophage P22 injects its 43 kbp genome across the cell wall of Salmonella enterica serovar Typhimurium. The attachment of phage P22 to the host cell as well as the injection of the viral DNA into the host is mediated by the virion's tail complex. This 2.8 MDa molecular machine is formed by five proteins, which include the portal protein gp1, the adhesion tailspike protein gp9, and three tail accessory factors: gp4, gp10, gp26. We have isolated the tail accessory factor gp4 and characterized its structure and binding interactions with portal protein. Interestingly, gp4 exists in solution as a monomer, which displays an exceedingly low structural stability (T{sub m} 34 {sup o}C). Unfolded gp4 is prone to aggregation within a narrow range of temperatures both in vitro and in Salmonella extracts. In the virion the thermal unfolding of gp4 is prevented by the interaction with the dodecameric portal protein, which stabilizes the structure of gp4 and suppresses unfolded gp4 from irreversibly aggregating in the Salmonella milieu. The structural stabilization of gp4 is accompanied by the concomitant oligomerization of the protein to form a ring of 12 subunits bound to the lower end of the portal ring. The interaction of gp4 with portal protein is complex and likely involves the distinct binding of two non-equivalent sets of six gp4 proteins. Binding of the first set of six gp4 equivalents to dodecameric portal protein yields a gp(1){sub 12}:gp(4){sub 6} assembly intermediate, which is stably populated at 30 {sup o}C and can be resolved by native gel electrophoresis. The final product of the assembly reaction is a bi-dodecameric gp(1){sub 12}:gp(4){sub 12} complex, which appears hollow by electron microscopy, suggesting that gp4 does not physically plug the DNA entry/exit channel, but acts as a structural adaptor for the other tail accessory factors: gp10 and gp26.

  9. A model for computing at the SSC (Superconducting Super Collider)

    SciTech Connect

    Baden, D. . Dept. of Physics); Grossman, R. . Lab. for Advanced Computing)

    1990-06-01

    High energy physics experiments at the Superconducting Super Collider (SSC) will show a substantial increase in complexity and cost over existing forefront experiments, and computing needs may no longer be met via simple extrapolations from the previous experiments. We propose a model for computing at the SSC based on technologies common in private industry involving both hardware and software. 11 refs., 1 fig.

  10. Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model

    PubMed Central

    Hatting, M; Spannbauer, M; Peng, J; Al Masaoudi, M; Sellge, G; Nevzorova, Y A; Gassler, N; Liedtke, C; Cubero, F J; Trautwein, C

    2015-01-01

    Chronic liver inflammation is a crucial event in the development and growth of hepatocellular carcinoma (HCC). Compelling evidence has shown that interleukin-6 (IL-6)/gp130-dependent signaling has a fundamental role in liver carcinogenesis. Thus, in the present study we aimed to investigate the role of gp130 in hepatocytes for the initiation and progression of HCC. Hepatocyte-specific gp130 knockout mice (gp130Δhepa) and control animals (gp130f/f) were treated with diethylnitrosamine (DEN). The role of gp130 for acute injury (0–144 h post treatment), tumor initiation (24 weeks) and progression (40 weeks) was analyzed. After acute DEN-induced liver injury we observed a reduction in the inflammatory response in gp130Δhepa animals as reflected by decreased levels of IL-6 and oncostatin M. The loss of gp130 slightly attenuated the initiation of HCC 24 weeks after DEN treatment. In contrast, 40 weeks after DEN treatment, male and female gp130Δhepa mice showed smaller tumors and reduced tumor burden, indicating a role for hepatocyte-specific gp130 expression during HCC progression. Oxidative stress and DNA damage were substantially and similarly increased by DEN in both gp130f/f and gp130Δhepa animals. However, gp130Δhepa livers revealed aberrant STAT5 activation and decreased levels of transforming growth factor-β (TGFβ), pSMAD2/3 and SMAD2, whereas phosphorylation of STAT3 at Tyr705 and Ser727 was absent. Our results indicate that gp130 deletion in hepatocytes reduces progression, but not HCC initiation in the DEN model. Gp130 deletion resulted in STAT3 inhibition but increased STAT5 activation and diminished TGF-dependent signaling. Hence, blocking gp130 in hepatocytes might be an interesting therapeutic target to inhibit the growth of HCC. PMID:25741592

  11. CGP lil-gp 2.1;1.02 User's Manual

    NASA Technical Reports Server (NTRS)

    Janikow, Cezary Z.; DeWeese, Scott W.

    1997-01-01

    This document describes extensions provided to lil-gp facilitating dealing with constraints. This document deals specifically with lil-gp 1.02, and the resulting extension is referred to as CGP lil-gp 2.1; 1.02 (the first version is for the extension, the second for the utilized lil-gp version). Unless explicitly needed to avoid confusion, version numbers are omitted.

  12. Platelet GP IIb-IIIa Receptor Antagonists in Primary Angioplasty: Back to the Future.

    PubMed

    De Luca, Giuseppe; Savonitto, Stefano; van't Hof, Arnoud W J; Suryapranata, Harry

    2015-07-01

    Coronary artery disease and acute myocardial infarction still represent the leading cause of mortality in developed countries. Therefore, great efforts have been made in the last decades to improve reperfusion strategies and adjunctive antithrombotic therapies. In fact, despite optimal epicardial recanalisation, a large proportion of patients still experience impaired reperfusion and in-stent thrombosis. The adjunctive use of glycoprotein (GP) IIb-IIIa inhibitors may certainly contribute in the reduction of such complications, especially when administered in the early phase of infarction. In fact, in this phase a larger platelet composition of the thrombus and the presence of a larger amount of viable myocardium, as compared to a delayed phase, may increase the benefits from this therapy and counterbalance the potential higher risk of bleeding. A large body of evidence has been accumulated on the benefits from GP IIb-IIIa inhibitors in terms of prevention of stent thrombosis, and benefits in mortality, especially among high-risk patients and as upstream strategy. Therefore, based on current available data, GP IIb-IIIa inhibitors can be recommended as early as possible (upstream strategy) among high-risk patients, such as those with advanced Killip class or anterior myocardial infarction (MI), and those presenting within the first three hours. Even though it is not universally accepted, in our opinion this strategy should be implemented in a pre-hospital setting (in ambulance) or at first hospital admission (Emergency Room or Coronary Care Unit, irrespective of whether they are in the spoke or hub hospitals). Peri-procedural intracoronary administration of GP IIb-IIIa inhibitors has not provided additional benefits as compared to intravenous administration and therefore cannot be recommended. Even though the vast majority of trials have been conducted with abciximab, several meta-analyses comparing small molecules (mainly high-dose tirofiban rather than eptifibatide

  13. A Molecular Switch Abrogates Glycoprotein 100 (gp100) T-cell Receptor (TCR) Targeting of a Human Melanoma Antigen*

    PubMed Central

    Bianchi, Valentina; Bulek, Anna; Fuller, Anna; Lloyd, Angharad; Attaf, Meriem; Rizkallah, Pierre J.; Dolton, Garry; Sewell, Andrew K.; Cole, David K.

    2016-01-01

    Human CD8+ cytotoxic T lymphocytes can mediate tumor regression in melanoma through the specific recognition of HLA-restricted peptides. Because of the relatively weak affinity of most anti-cancer T-cell receptors (TCRs), there is growing emphasis on immunizing melanoma patients with altered peptide ligands in order to induce strong anti-tumor immunity capable of breaking tolerance toward these self-antigens. However, previous studies have shown that these immunogenic designer peptides are not always effective. The melanocyte differentiation protein, glycoprotein 100 (gp100), encodes a naturally processed epitope that is an attractive target for melanoma immunotherapies, in particular peptide-based vaccines. Previous studies have shown that substitutions at peptide residue Glu3 have a broad negative impact on polyclonal T-cell responses. Here, we describe the first atomic structure of a natural cognate TCR in complex with this gp100 epitope and highlight the relatively high affinity of the interaction. Alanine scan mutagenesis performed across the gp100280–288 peptide showed that Glu3 was critically important for TCR binding. Unexpectedly, structural analysis demonstrated that the Glu3 → Ala substitution resulted in a molecular switch that was transmitted to adjacent residues, abrogating TCR binding and T-cell recognition. These findings help to clarify the mechanism of T-cell recognition of gp100 during melanoma responses and could direct the development of altered peptides for vaccination. PMID:26917722

  14. Hierarchical kernel mixture models for the prediction of AIDS disease progression using HIV structural gp120 profiles

    PubMed Central

    2010-01-01

    Changes to the glycosylation profile on HIV gp120 can influence viral pathogenesis and alter AIDS disease progression. The characterization of glycosylation differences at the sequence level is inadequate as the placement of carbohydrates is structurally complex. However, no structural framework is available to date for the study of HIV disease progression. In this study, we propose a novel machine-learning based framework for the prediction of AIDS disease progression in three stages (RP, SP, and LTNP) using the HIV structural gp120 profile. This new intelligent framework proves to be accurate and provides an important benchmark for predicting AIDS disease progression computationally. The model is trained using a novel HIV gp120 glycosylation structural profile to detect possible stages of AIDS disease progression for the target sequences of HIV+ individuals. The performance of the proposed model was compared to seven existing different machine-learning models on newly proposed gp120-Benchmark_1 dataset in terms of error-rate (MSE), accuracy (CCI), stability (STD), and complexity (TBM). The novel framework showed better predictive performance with 67.82% CCI, 30.21 MSE, 0.8 STD, and 2.62 TBM on the three stages of AIDS disease progression of 50 HIV+ individuals. This framework is an invaluable bioinformatics tool that will be useful to the clinical assessment of viral pathogenesis. PMID:21143806

  15. Bone age assessment in Hispanic children: digital hand atlas compared with the Greulich and Pyle (G&P) atlas

    NASA Astrophysics Data System (ADS)

    Fernandez, James Reza; Zhang, Aifeng; Vachon, Linda; Tsao, Sinchai

    2008-03-01

    Bone age assessment is most commonly performed with the use of the Greulich and Pyle (G&P) book atlas, which was developed in the 1950s. The population of theUnited States is not as homogenous as the Caucasian population in the Greulich and Pyle in the 1950s, especially in the Los Angeles, California area. A digital hand atlas (DHA) based on 1,390 hand images of children of different racial backgrounds (Caucasian, African American, Hispanic, and Asian) aged 0-18 years was collected from Children's Hospital Los Angeles. Statistical analysis discovered significant discrepancies exist between Hispanic and the G&P atlas standard. To validate the usage of DHA as a clinical standard, diagnostic radiologists performed reads on Hispanic pediatric hand and wrist computed radiography images using either the G&P pediatric radiographic atlas or the Children's Hospital Los Angeles Digital Hand Atlas (DHA) as reference. The order in which the atlas is used (G&P followed by DHA or vice versa) for each image was prepared before actual reading begins. Statistical analysis of the results was then performed to determine if a discrepancy exists between the two readings.

  16. Functional characterization of Autographa californica multiple nucleopolyhedrovirus gp16 (ac130)

    SciTech Connect

    Yang, Ming; Huang, Cui; Qian, Duo-Duo; Li, Lu-Lin

    2014-09-15

    To investigate the function of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) gp16, multiple gp16-knockout and repair mutants were constructed and characterized. No obvious difference in productivity of budded virus, DNA synthesis, late gene expression and morphogenesis was observed between gp16-knockout and repair viruses, but gp16 deletion resulted in six hours of lengthening in ST{sub 50} to the third instar Spodoptera exigua larvae in bioassays. GP16 was fractionated mainly in the light membrane fraction, by subcellular fractionation. A GP16-EGFP fusion protein was predominantly localized close around the nuclear membrane in infected cells, being coincident with formation of the vesicles associated with the nuclear membrane, which hosted nucleocapsids released from the nucleus. These data suggest that gp16 is not required for viral replication, but may be involved in membrane trafficking associated with the envelopment/de-envelopment of budded viruses when they cross over the nuclear membrane and pass through cytoplasm. - Highlights: • gp16 knockout and repair mutants of AcMNPV were constructed and characterized. • AcMNPV gp16 is not essential to virus replication. • Deletion of gp16 resulted in time lengthening to kill S. exigua larvae. • GP16 was localized close around the nuclear membrane of infected cells. • GP16 was fractionated in the light membrane fraction in subcellular fractionation.

  17. LHC: The Large Hadron Collider

    SciTech Connect

    Lincoln, Don

    2015-03-04

    The Large Hadron Collider (or LHC) is the world’s most powerful particle accelerator. In 2012, scientists used data taken by it to discover the Higgs boson, before pausing operations for upgrades and improvements. In the spring of 2015, the LHC will return to operations with 163% the energy it had before and with three times as many collisions per second. It’s essentially a new and improved version of itself. In this video, Fermilab’s Dr. Don Lincoln explains both some of the absolutely amazing scientific and engineering properties of this modern scientific wonder.

  18. Colliding-beam-accelerator lattice

    SciTech Connect

    Claus, J.; Cornacchia, M.; Courant, E.D.; Parzen, G.

    1983-01-01

    We describe the lattice of the Colliding Beam Accelerator, a 400 x 400 GeV pp facility proposed for construction at Brookhaven National Laboratory. The structure adopted is very versatile, in part in consequence of its desirable behavior as function of momentum deviation and as function of the betatron tunes. Each of the six insertions can be arranged to meet specific requirements at the crossing points as illustrated by a discussion of the tuneable low-beta insertions. The luminosity in these low-beta insertions (2 x 10/sup 33/ cm/sup -2/ sec/sup -1/) would be an order of magnitude larger than the standard insertions.

  19. Physics at the linear collider

    NASA Astrophysics Data System (ADS)

    Moortgat-Pick, G.; Baer, H.; Battaglia, M.; Belanger, G.; Fujii, K.; Kalinowski, J.; Heinemeyer, S.; Kiyo, Y.; Olive, K.; Simon, F.; Uwer, P.; Wackeroth, D.; Zerwas, P. M.; Arbey, A.; Asano, M.; Bagger, J.; Bechtle, P.; Bharucha, A.; Brau, J.; Brümmer, F.; Choi, S. Y.; Denner, A.; Desch, K.; Dittmaier, S.; Ellwanger, U.; Englert, C.; Freitas, A.; Ginzburg, I.; Godfrey, S.; Greiner, N.; Grojean, C.; Grünewald, M.; Heisig, J.; Höcker, A.; Kanemura, S.; Kawagoe, K.; Kogler, R.; Krawczyk, M.; Kronfeld, A. S.; Kroseberg, J.; Liebler, S.; List, J.; Mahmoudi, F.; Mambrini, Y.; Matsumoto, S.; Mnich, J.; Mönig, K.; Mühlleitner, M. M.; Pöschl, R.; Porod, W.; Porto, S.; Rolbiecki, K.; Schmitt, M.; Serpico, P.; Stanitzki, M.; Stål, O.; Stefaniak, T.; Stöckinger, D.; Weiglein, G.; Wilson, G. W.; Zeune, L.; Moortgat, F.; Xella, S.; Bagger, J.; Brau, J.; Ellis, J.; Kawagoe, K.; Komamiya, S.; Kronfeld, A. S.; Mnich, J.; Peskin, M.; Schlatter, D.; Wagner, A.; Yamamoto, H.

    2015-08-01

    A comprehensive review of physics at an linear collider in the energy range of GeV-3 TeV is presented in view of recent and expected LHC results, experiments from low-energy as well as astroparticle physics. The report focusses in particular on Higgs-boson, top-quark and electroweak precision physics, but also discusses several models of beyond the standard model physics such as supersymmetry, little Higgs models and extra gauge bosons. The connection to cosmology has been analysed as well.

  20. Tevatron instrumentation: boosting collider performance

    SciTech Connect

    Shiltsev, Vladimir; Jansson, Andreas; Moore, Ronald; /Fermilab

    2006-05-01

    The Tevatron in Collider Run II (2001-present) is operating with six times more bunches, many times higher beam intensities and luminosities than in Run I (1992-1995). Beam diagnostics were crucial for the machine start-up and the never-ending luminosity upgrade campaign. We present the overall picture of the Tevatron diagnostics development for Run II, outline machine needs for new instrumentation, present several notable examples that led to Tevatron performance improvements, and discuss the lessons for the next big machines--LHC and ILC.

  1. Detector Background at Muon Colliders

    SciTech Connect

    Mokhov, N.V.; Striganov, S.I.; /Fermilab

    2011-09-01

    Physics goals of a Muon Collider (MC) can only be reached with appropriate design of the ring, interaction region (IR), high-field superconducting magnets, machine-detector interface (MDI) and detector. Results of the most recent realistic simulation studies are presented for a 1.5-TeV MC. It is shown that appropriately designed IR and MDI with sophisticated shielding in the detector have a potential to substantially suppress the background rates in the MC detector. The main characteristics of backgrounds are studied.

  2. Colliding with a crunching bubble

    SciTech Connect

    Freivogel, Ben; Freivogel, Ben; Horowitz, Gary T.; Shenker, Stephen

    2007-03-26

    In the context of eternal inflation we discuss the fate of Lambda = 0 bubbles when they collide with Lambda< 0 crunching bubbles. When the Lambda = 0 bubble is supersymmetric, it is not completely destroyed by collisions. If the domain wall separating the bubbles has higher tension than the BPS bound, it is expelled from the Lambda = 0 bubble and does not alter its long time behavior. If the domain wall saturates the BPS bound, then it stays inside the Lambda = 0 bubble and removes a finite fraction of future infinity. In this case, the crunch singularity is hidden behind the horizon of a stable hyperbolic black hole.

  3. Tevatron collider operations and plans

    SciTech Connect

    Peter H. Garbincius

    2004-06-17

    Fermilab's Tevatron is a proton-antiproton collider with center of mass energy of 1.96 TeV. The antiprotons are produced by 125 GeV protons from the Main Injector striking a stainless steel target. The 8 GeV antiprotons are collected and cooled in the Debuncher and Accumulator rings of the Antiproton Source and, just recently, in the Recycler ring before acceleration by the Main Injector and the Tevatron. In addition to energy, a vital parameter for generating physics data is the Luminosity delivered to the experiments given by a formula that is listed in detail in the paper.

  4. Dynamic collimation for linear colliders

    SciTech Connect

    Merminga, N.; Ruth, R.D.

    1990-06-01

    Experience with the SLC has indicated that backgrounds caused by the tails of the transverse beam distribution will be a serious problem for a next generation linear collider. Mechanical scrapers may not provide the best solution, because they may be damaged by the tiny, intense beams, and also because they may induce wakefield kicks large enough to cause emittance dilution. In this paper, we present a possible solution, which uses several nonlinear lenses to drive the tails of the beam to large amplitudes where they can by more easily scraped mechanically. Simulations of several different schemes are presented and evaluated with respect to effectiveness, tolerances and wakefield effects. 4 refs., 6 figs.

  5. Estimates of Fermilab Tevatron collider performance

    SciTech Connect

    Dugan, G.

    1991-09-01

    This paper describes a model which has been used to estimate the average luminosity performance of the Tevatron collider. In the model, the average luminosity is related quantitatively to various performance parameters of the Fermilab Tevatron collider complex. The model is useful in allowing estimates to be developed for the improvements in average collider luminosity to be expected from changes in the fundamental performance parameters as a result of upgrades to various parts of the accelerator complex.

  6. International Workshop on Linear Colliders 2010

    ScienceCinema

    None

    2011-10-06

    IWLC2010 International Workshop on Linear Colliders 2010ECFA-CLIC-ILC joint meeting: Monday 18 October - Friday 22 October 2010Venue: CERN and CICG (International Conference Centre Geneva, Switzerland) This year, the International Workshop on Linear Colliders organized by the European Committee for Future Accelerators (ECFA) will study the physics, detectors and accelerator complex of a linear collider covering both CLIC and ILC options.Contact Workshop Secretariat  IWLC2010 is hosted by CERN

  7. Physics considerations for laser-plasma linear colliders

    SciTech Connect

    Schroeder, Carl; Esarey, Eric; Geddes, Cameron; Benedetti, Carlo; Leemans, Wim

    2010-06-11

    Physics considerations for a next-generation linear collider based on laser-plasma accelerators are discussed. The ultra-high accelerating gradient of a laser-plasma accelerator and short laser coupling distance between accelerator stages allows for a compact linac. Two regimes of laser-plasma acceleration are discussed. The highly nonlinear regime has the advantages of higher accelerating fields and uniform focusing forces, whereas the quasi-linear regime has the advantage of symmetric accelerating properties for electrons and positrons. Scaling of various accelerator and collider parameters with respect to plasma density and laser wavelength are derived. Reduction of beamstrahlung effects implies the use of ultra-short bunches of moderate charge. The total linac length scales inversely with the square root of the plasma density, whereas the total power scales proportional to the square root of the density. A 1 TeV center-of-mass collider based on stages using a plasma density of 10{sup 17} cm{sup -3} requires tens of J of laser energy per stage (using 1 {micro}m wavelength lasers) with tens of kHz repetition rate. Coulomb scattering and synchrotron radiation are examined and found not to significantly degrade beam quality. A photon collider based on laser-plasma accelerated beams is also considered. The requirements for the scattering laser energy are comparable to those of a single laser-plasma accelerator stage.

  8. FUTURE LEPTON COLLIDERS AND LASER ACCELERATION

    SciTech Connect

    PARSA,Z.

    2000-05-30

    Future high energy colliders along with their physics potential, and relationship to new laser technology are discussed. Experimental approaches and requirements for New Physics exploration are also described.

  9. Expression and immunological characterization of cardamom mosaic virus coat protein displaying HIV gp41 epitopes.

    PubMed

    Damodharan, Subha; Gujar, Ravindra; Pattabiraman, Sathyamurthy; Nesakumar, Manohar; Hanna, Luke Elizabeth; Vadakkuppattu, Ramanathan D; Usha, Ramakrishnan

    2013-05-01

    The coat protein of cardamom mosaic virus (CdMV), a member of the genus Macluravirus, assembles into virus-like particles when expressed in an Escherichia coli expression system. The N and C-termini of the coat protein were engineered with the Kennedy peptide and the 2F5 and 4E10 epitopes of gp41 of HIV. The chimeric proteins reacted with sera from HIV positive persons and also stimulated secretion of cytokines by peripheral blood mononuclear cells from these persons. Thus, a system based on the coat protein of CdMV can be used to display HIV-1 antigens. PMID:23668610

  10. New technology for linear colliders

    SciTech Connect

    McIntyre, P.M.

    1991-08-01

    The purpose of this contract is to develop and evaluate new technology for future e{sup +}e{sup {minus}} linac colliders. TeV linac colliders will require major improvements in the performance of microwave power tubes: >100 mW/m peak power, {approximately}20 GHz frequency, and high frequency. For the past three years we have been developing gigatron, a new design concept for microwave power tubes. It incorporates three key innovations: a gated field-emitter cathode which produces a fully modulated electron beam directly into the vacuum; a ribbon beam geometry which eliminates space charge and phase dispersion, and a traveling wave coupler which provides optimum output coupling even over a wide ribbon beam. During the past year we have built prototypes of two cathode designs: a stripline edge-emitter array and a porous silicon dioxide cathode. A highlight of our results is the development and testing of the porous SiO{sub 2} cathode. It delivers exceptional performance as a modulated electron source in general and for gigatron in particular. Its high emitter density and low work function accommodate higher tube gain, simpler cathode coupling, and higher peak power than any other technology. The protection of the active emitting surface by {approximately}2 {mu}m of porous SiO{sub 2} should provide for rugged operation in a tube environment.

  11. Hadron colliders (SSC/LHC)

    SciTech Connect

    Chao, A.W.; Palmer, R.B.; Evans, L.; Gareyte, J.; Siemann, R.H.

    1992-12-31

    The nominal SSC and LHC designs should operate conservatively at luminosities up to 10{sup 33} cm{sup {minus}2} s{sup {minus}1}. This luminosity is dictated by the event rates that can be handled by the detectors. However, this limit is event dependent (e.g. it does not take much of a detector to detect the event pp {yields} elephant; all one needs is extremely high luminosity). As such, it is useful to explore the possibility of going beyond the 10{sup 33} cm{sup {minus}2} s{sup {minus}1} level. Such exploration will also improve the accelerator physics understanding of pp collider designs. If the detector limitations are removed, the first accelerator limits occur when the luminosity is at the level of 10{sup 34} cm{sup {minus}2}s{sup {minus}1}. These accelerator limits will first be reviewed. The authors will then continue on to explore even higher luminosity as the ultimate limit of pp colliders. Accelerator technologies needed to achieve this ultimate luminosity as well as the R and D needed to reach it are discussed.

  12. Very large hadron collider (VLHC)

    SciTech Connect

    1998-09-01

    A VLHC informal study group started to come together at Fermilab in the fall of 1995 and at the 1996 Snowmass Study the parameters of this machine took form. The VLHC as now conceived would be a 100 TeV hadron collider. It would use the Fermilab Main Injector (now nearing completion) to inject protons at 150 GeV into a new 3 TeV Booster and then into a superconducting pp collider ring producing 100 TeV c.m. interactions. A luminosity of {approximately}10{sup 34} cm{sup -2}s{sup -1} is planned. Our plans were presented to the Subpanel on the Planning for the Future of US High- Energy Physics (the successor to the Drell committee) and in February 1998 their report stated ``The Subpanel recommends an expanded program of R&D on cost reduction strategies, enabling technologies, and accelerator physics issues for a VLHC. These efforts should be coordinated across laboratory and university groups with the aim of identifying design concepts for an economically and technically viable facility`` The coordination has been started with the inclusion of physicists from Brookhaven National Laboratory (BNL), Lawrence Berkeley National Laboratory (LBNL), and Cornell University. Clearly, this collaboration must expanded internationally as well as nationally. The phrase ``economically and technically viable facility`` presents the real challenge.

  13. The muon collider (Sandro's snake)

    SciTech Connect

    Ruggiero, A.G.

    1992-01-01

    This paper describes a feasibility study for the design of a muon collider. Recognized the fact that the particle lifetime increases linearly with the energy, we have adopted a scheme where steps of cooling and acceleration are entwined. We have indeed found convenient to accelerate the beam as fast as possible to increase its chances of survival, and necessary to dilute the action of cooling throughout the entire accelerating process to make it more effective and affordable. All acceleration and cooling steps are executed in a single pass essentially along a curvilinear and open path. We do not believe it is possible to handle the beam otherwise in circular and closed rings, as it has been proposed in the past. The example shown in this paper describes a muon collider at the energy of 250 GeV per beam and a luminosity of 4 [times] 10[sup 28] cm[sup [minus]2]s[sup [minus]1]. We have adopted an extrapolation of the stochastic cooling method for the reduction of the beam emittance.

  14. Shed GP of Ebola Virus Triggers Immune Activation and Increased Vascular Permeability

    PubMed Central

    Escudero-Pérez, Beatriz; Volchkova, Valentina A.; Dolnik, Olga; Lawrence, Philip; Volchkov, Viktor E.

    2014-01-01

    During Ebola virus (EBOV) infection a significant amount of surface glycoprotein GP is shed from infected cells in a soluble form due to cleavage by cellular metalloprotease TACE. Shed GP and non-structural secreted glycoprotein sGP, both expressed from the same GP gene, have been detected in the blood of human patients and experimentally infected animals. In this study we demonstrate that shed GP could play a particular role during EBOV infection. In effect it binds and activates non-infected dendritic cells and macrophages inducing the secretion of pro- and anti-inflammatory cytokines (TNFα, IL1β, IL6, IL8, IL12p40, and IL1-RA, IL10). Activation of these cells by shed GP correlates with the increase in surface expression of co-stimulatory molecules CD40, CD80, CD83 and CD86. Contrary to shed GP, secreted sGP activates neither DC nor macrophages while it could bind DCs. In this study, we show that shed GP activity is likely mediated through cellular toll-like receptor 4 (TLR4) and is dependent on GP glycosylation. Treatment of cells with anti-TLR4 antibody completely abolishes shed GP-induced activation of cells. We also demonstrate that shed GP activity is negated upon addition of mannose-binding sera lectin MBL, a molecule known to interact with sugar arrays present on the surface of different microorganisms. Furthermore, we highlight the ability of shed GP to affect endothelial cell function both directly and indirectly, demonstrating the interplay between shed GP, systemic cytokine release and increased vascular permeability. In conclusion, shed GP released from virus-infected cells could activate non-infected DCs and macrophages causing the massive release of pro- and anti-inflammatory cytokines and effect vascular permeability. These activities could be at the heart of the excessive and dysregulated inflammatory host reactions to infection and thus contribute to high virus pathogenicity. PMID:25412102

  15. Development work for a superconducting linear collider

    NASA Technical Reports Server (NTRS)

    Matheisen, Axel

    1995-01-01

    For future linear e(+)e(-) colliders in the TeV range several alternatives are under discussion. The TESLA approach is based on the advantages of superconductivity. High Q values of the accelerator structures give high efficiency for converting RF power into beam power. A low resonance frequency for the RF structures can be chosen to obtain a large number of electrons (positrons) per bunch. For a given luminosity the beam dimensions can be chosen conservatively which leads to relaxed beam emittance and tolerances at the final focus. Each individual superconducting accelerator component (resonator cavity) of this linear collider has to deliver an energy gain of 25 MeV/m to the beam. Today s.c. resonators are in use at CEBAF/USA, at DESY/Germany, Darmstadt/Germany KEK/Japan and CERN/Geneva. They show acceleration gradients between 5 MV/m and 10 MV/m. Encouraging experiments at CEA Saclay and Cornell University showed acceleration gradients of 20 MV/m and 25 MV/m in single and multicell structures. In an activity centered at DESY in Hamburg/Germany the TESLA collaboration is constructing a 500 MeV superconducting accelerator test facility (TTF) to demonstrate that a linear collider based on this technique can be built in a cost effective manner and that the necessary acceleration gradients of more than 15 MeV/m can be reached reproducibly. The test facility built at DESY covers an area of 3.000 m2 and is divided into 3 major activity areas: (1) The testlinac, where the performance ofthe modular components with an electron beam passing the 40 m long acceleration section can be demonstrated. (2) The test area, where all individual resonators are tested before installation into a module. (3) The preparation and assembly area, where assembly of cavities and modules take place. We report here on the design work to reach a reduction of costs compared to actual existing superconducting accelerator structures and on the facility set up to reach high acceleration gradients in

  16. gp130 receptor ligands as potential therapeutic targets for obesity

    PubMed Central

    Febbraio, Mark A.

    2007-01-01

    Obesity and its related cluster of pathophysiologic conditions including insulin resistance, glucose intolerance, dyslipidemia, and hypertension are recognized as growing threats to world health. It is now estimated that 10% of the world’s population is overweight or obese. As a result, new therapeutic options for the treatment of obesity are clearly warranted. Recent research has focused on the role that gp130 receptor ligands may play as potential therapeutic targets in obesity. One cytokine in particular, ciliary neurotrophic factor (CNTF), acts both centrally and peripherally and mimics the biologic actions of the appetite control hormone leptin, but unlike leptin, CNTF appears to be effective in obesity and as such may have therapeutic potential. In addition, CNTF suppresses inflammatory signaling cascades associated with lipid accumulation in liver and skeletal muscle. This review examines the potential role of gp130 receptor ligands as part of a therapeutic strategy to treat obesity. PMID:17404609

  17. Current and Future Scientific Investigations at GP-SANS

    NASA Astrophysics Data System (ADS)

    Debeer-Schmitt, Lisa; Bailey, Katherine; Melnichenko, Yuri; He, Lilin; Littrell, Ken

    The general-purpose small-angle neutron scattering beam line, GP-SANS, in operation since 2007, is optimized for investigation of structures with dimensions from 0.5 to 200 nm. Along with high neutron flux, sample environments can easily be integrated into the beam line providing the user a versatile temperature range from 30 mK to 1600 K. In addition, there are two cryomagnets (horizontal 4.5 T and vertical 8 T), pressure cells, stop flow cell, electrochemical cell, load frames and custom-build equipment available to users allowing for significant flexibility in experimental setup. GP-SANS has supported investigation of a diverse array of intriguing scientific topics, including polymer solutions, gel and blends, colloids, micelles, , molecular self-assembly and interactions in complex fluids, microemulsions, spin textures and magnetic domains in novel materials, porosity in geological materials and phase separation, grain growth, and orientation in metallurgical alloys.

  18. Lessons learned from an Internet GP information system.

    PubMed

    Briggs, J S; Bradley, M P

    1998-01-01

    We describe the prototype of an application that in actual use would allow GPs to find out more information about consultants at hospitals. This would aid the GP in making the decision about which consultant a patient should be referred to. The requirements of the application from the GP's perspective are described, together with some of the issues that have to be resolved before hospitals can provide the necessary information in a standard format. The application is implemented as a client--server system using standard Internet technologies such as Java and HTML. This architecture has a number of advantages but also revealed some issues concerning security and the format of data, among other things. The project showed that there is a desire for such a system and that that desire can be fulfilled at a relatively low cost. PMID:9785327

  19. In vitro culture and structural differences in the major immunoreactive protein gp36 of geographically distant Ehrlichia canis isolates.

    PubMed

    Zweygarth, Erich; Cabezas-Cruz, Alejandro; Josemans, Antoinette I; Oosthuizen, Marinda C; Matjila, Paul T; Lis, Katarzyna; Broniszewska, Marzena; Schöl, Heidrun; Ferrolho, Joana; Grubhoffer, Libor; Passos, Lygia M F

    2014-06-01

    Ehrlichia canis, the etiologic agent of canine ehrlichiosis, is an obligate intracytoplasmic Gram-negative tick-borne bacterium belonging to the Anaplasmataceae family. E. canis is distributed worldwide and can cause serious and fatal infections in dogs. Among strains of E. canis, the 16S rRNA gene DNA sequences are highly conserved. Using this gene to genetically differentiate isolates is therefore difficult. As an alternative, the gene gp36, which encodes for a major immunoreactive protein in E. canis, has been successfully used to characterize the genetic diversity of this pathogen. The present study describes the isolation and continuous propagation of a Spanish and 2 South African isolates of E. canis in IDE8 tick cells. Subsequently, canine DH82 cell cultures were infected using initial bodies obtained from infected IDE8 cultures. It was possible to mimic the life cycle of E. canis in vitro by transferring infection from tick cells to canine cells and back again. To characterize these E. canis strains at the molecular level, the 16S rRNA and gp36 genes were amplified by PCR, sequenced, and aligned with corresponding sequences available in GenBank. All 16S rRNA sequences amplified in this study were identical to previously reported E. canis strains. Maximum likelihood analysis based on the gp36 amino acid sequences showed that the South African and Spanish strains fall into 2 well-defined phylogenetic clusters amongst other E. canis strains. The members of these 2 phylogenetic clusters shared 2 unique molecular properties in the gp36 amino acid sequences: (i) deletion of glycine 117 and (ii) the presence of an additional putative N-linked glycosylation site. We further show correlation between the putative secondary structure and the theoretical isoelectric point (pI) of the gp36 amino acid sequences. A putative role of gp36 as an adhesin in E. canis is discussed. Overall, we report the successful in vitro culture of 3 new E. canis strains which present

  20. Helicase assembly protein Gp59 of bacteriophage T4: fluorescence anisotropy and sedimentation studies of complexes formed with derivatives of Gp32, the phage ssDNA binding protein.

    PubMed

    Xu, H; Wang, Y; Bleuit, J S; Morrical, S W

    2001-06-26

    The gene 59 protein (gp59) of bacteriophage T4 performs a vital function in phage DNA replication by directing the assembly of gp41, the DNA helicase component of the T4 primosome, onto lagging strand ssDNA at nascent replication forks. The helicase assembly activity of gp59 is required for optimum efficiency of helicase acquisition by the replication fork during strand displacement DNA synthesis and is essential for helicase and primosome assembly during T4 recombination-dependent DNA replication transactions. Of central importance is the ability of gp59 to load the gp41 helicase onto ssDNA previously coated with cooperatively bound molecules of gp32, the T4 ssDNA binding protein. Gp59 heteroassociations with ssDNA, gp32, and gp41 all appear to be essential for this loading reaction. Previous studies demonstrated that a tripartite complex containing gp59 and gp32 simultaneously cooccupying ssDNA is an essential intermediate in gp59-dependent helicase loading; however, the biochemical and structural parameters of gp59-gp32 complexes with or without ssDNA are currently unknown. To better understand gp59-gp32 interactions, we performed fluorescence anisotropy and analytical ultracentrifugation experiments employing native or rhodamine-labeled gp59 species in combination with altered forms of gp32, allowing us to determine their binding parameters, shape parameters, and other hydrodynamic properties. Two truncated forms of gp32 were used: gp32-B, which lacks the N-terminal B-domain required for cooperative binding to ssDNA and for stable self-association, and A-domain fragment, which is the C-terminal peptide of gp32 lacking ssDNA binding ability. Results indicate that gp59 binds with high affinity to either gp32 derivative to form a 1:1 heterodimer. In both cases, heterodimer formation is accompanied by a conformational change in gp59 which correlates with decreased gp59-DNA binding affinity. Hydrodynamic modeling suggests an asymmetric prolate ellipsoid shape for gp

  1. Oligomerization of the hydrophobic heptad repeat of gp41.

    PubMed Central

    Bernstein, H B; Tucker, S P; Kar, S R; McPherson, S A; McPherson, D T; Dubay, J W; Lebowitz, J; Compans, R W; Hunter, E

    1995-01-01

    The transmembrane protein of human immunodeficiency virus type 1 (HIV-1) contains a leucine zipper-like (hydrophobic heptad) repeat which has been predicted to form an amphipathic alpha helix. To evaluate the potential of the hydrophobic heptad repeat to induce protein oligomerization, this region of gp41 has been cloned into the bacterial expression vector pRIT2T. The resulting plasmid, pRIT3, expresses a fusion protein consisting of the Fc binding domain of monomeric protein A, a bacterial protein, and amino acids 538 to 593 of HIV-1 gp41. Gel filtration chromatography demonstrated the presence of oligomeric forms of the fusion protein, and analytical centrifugation studies confirmed that the chimeric protein formed a higher-order multimer that was greater than a dimer. Thus, we have identified a region of HIV-1 gp41 which is capable of directing the oligomerization of a fusion protein containing monomeric protein A. Point mutations, previously shown to inhibit the biological activity of the HIV-1 envelope glycoprotein, have been engineered into the segment of gp41 contained in the fusion protein, and expressed mutant proteins were purified and analyzed via fast protein liquid chromatography. A point mutation in the heptad repeat, which changed the central isoleucine to an alanine, caused a significant (> 60%) decrease in oligomerization, whereas changing the central isoleucine to aspartate or proline resulted in almost a complete loss of oligomerization. Deletions of one, two, or three amino acids following the first isoleucine also resulted in a profound decrease in oligomerization. The inhibitory effects of the mutations on oligomer formation correlated with the effects of the same mutations on envelope glycoprotein-mediated fusion. A possible role of the leucine zipper-like region in the fusion process and in an oligomerization event distinct from assembly of the envelope glycoprotein complex is discussed. PMID:7707497

  2. Australian GP registrars' use of e-resources.

    PubMed

    Denny, Bianca; Chester, Andrea; Butler, Mexie; Brown, James

    2015-03-01

    Traditional face-to-face learning opportunities for Australian GP registrars are complemented by the use of e-resources. The current study aimed to investigate GP trainees' use of e-resources and their preferences for sourcing clinical information to inform the prospective direction and design of e-resources for the GP education and training sector. One-hundred and nineteen registrars completed a custom online survey measuring the type and frequency of use of e-resources, and preferences for their design and content. Results indicated that for the majority of registrars e-resources were the first preference for obtaining clinical information (77.3%). The most frequently used e-resources included non-medical search engines, medical journals and prescribing software. Factors relevant to registrars' selection and use of e-resources included the accuracy and comprehensiveness of the information. It is concluded that the use of e-resources provides a valuable supplement to registrars' learning and teaching. However, issues of quality and consistency raise some concerns regarding the use of e-resources for obtaining clinical information. PMID:25898296

  3. HIV-1 gp120 as a therapeutic target: Navigating a moving labyrinth

    PubMed Central

    Acharya, Priyamvada; Lusvarghi, Sabrina; Bewley, Carole A.; Kwong, Peter D.

    2015-01-01

    Introduction The HIV-1 gp120 envelope (Env) glycoprotein mediates attachment of virus to human target cells that display requisite receptors, CD4 and co-receptor, generally CCR5. Despite high affinity interactions with host receptors and proof-of-principle by the drug maraviroc that interference with CCR5 provides therapeutic benefit, no licensed drug currently targets gp120. Areas covered An overview of the role of gp120 in HIV-1 entry and of sites of potential gp120 vulnerability to therapeutic inhibition is presented. Viral defenses that protect these sites and turn gp120 into a moving labyrinth are discussed together with strategies for circumventing these defenses to allow therapeutic targeting of gp120 sites of vulnerability. Expert opinion The gp120 envelope glycoprotein interacts with host proteins through multiple interfaces and has conserved structural features at these interaction sites. In spite of this, targeting gp120 for therapeutic purposes is challenging. Env mechanisms evolved to evade the humoral immune response also shield it from potential therapeutics. Nevertheless, substantial progress has been made in understanding HIV-1 gp120 structure and its interactions with host receptors, and in developing therapeutic leads that potently neutralize diverse HIV-1 strains. Synergies between advances in understanding, needs for therapeutics against novel viral targets, and characteristics of breadth and potency for a number of gp120-targetting lead molecules bodes well for gp120 as a HIV-1 therapeutic target. PMID:25724219

  4. Experimental examination of strain field within GP zone in an Al-Zn-Mg-Cu alloy

    NASA Astrophysics Data System (ADS)

    Bai, P. C.; Liu, F.; Hou, X. H.; Zhao, C. W.; Xing, Y. M.

    2012-11-01

    The strain field of GP zone plays a very important role in strengthening of the precipitation-hardened aluminum alloys by prohibiting movement of dislocations; however, quantitative analysis about the strain field of the GP zone in the aluminum alloys has been seldom reported elsewhere. In this paper, the microstructure of GP zone in an Al-Zn-Mg-Cu alloy was explored by using high-resolution transmission electron microscopy (HRTEM), and the displacement field of lattice planes within the GP zone was experimentally measured by geometric phase analysis (GPA) technique; then, the quantitative results about strains of the distorted lattice planes within the GP zone were also obtained. It is found that the GP zone core is convergence region of the strains, and the maximum value of the compressive strains within the GP zone is about 7.6%.

  5. Characterization of a trimeric MPER containing HIV-1 gp41 antigen

    SciTech Connect

    Hinz, Andreas; Schoehn, Guy; Quendler, Heribert; Hulsik, David Lutje; Stiegler, Gabi; Katinger, Hermann; Seaman, Michael S.; Montefiori, David; Weissenhorn, Winfried

    2009-08-01

    The membrane-proximal external region (MPER) of gp41 is considered as a prime target for the induction of neutralizing antibodies, since it contains the epitopes for three broadly neutralizing antibodies (2F5, 4E10 and Z13). Here we present a novel gp41 construct (HA-gp41) comprising gp41 HR2 and MPER fused to two triple-stranded coiled-coil domains at both ends. HA-gp41 is trimeric, has a high helical content in solution and forms rod-like structures as revealed by negative staining electron microscopy. Immunization of rabbits with HA-gp41 induced antibodies directed against MPER, which failed to exert significant neutralization capacity against envelopes from primary isolates. Thus trimerisation of MPER regions does not suffice to induce a potent neutralizing antibody response specific for conserved regions within gp41.

  6. Research and Development of Future Muon Collider

    SciTech Connect

    Yonehara, K.; /Fermilab

    2012-05-01

    Muon collider is a considerable candidate of the next generation high-energy lepton collider machine. A novel accelerator technology must be developed to overcome several intrinsic issues of muon acceleration. Recent research and development of critical beam elements for a muon accelerator, especially muon beam phase space ionization cooling channel, are reviewed in this paper.

  7. ACCELERATION FOR A HIGH ENERGY MUON COLLIDER

    SciTech Connect

    BERG,J.S

    2000-04-07

    The authors describe a method for designing the acceleration systems for a muon collider, with particular application and examples for a high energy muon collider. This paper primarily concentrates on design considerations coming from longitudinal motion, but some transverse issues are briefly discussed.

  8. Polarization Effects at a Muon Collider

    SciTech Connect

    Parsa, Z.

    1998-11-01

    For Muon Colliders, Polarization will be a useful tool if high polarization is achievable with little luminosity loss. Formulation and effects of beam polarization and luminosity including polarization effects in Higgs resonance studies are discussed for improving precision measurements and Higgs resonance ''discovery'' capability e.g. at the First Muon Collider (FMC).

  9. Regulation of the expression of chaperone gp96 in macrophages and dendritic cells.

    PubMed

    Wolfram, Lutz; Fischbeck, Anne; Frey-Wagner, Isabelle; Wojtal, Kacper A; Lang, Silvia; Fried, Michael; Vavricka, Stephan R; Hausmann, Martin; Rogler, Gerhard

    2013-01-01

    The chaperone function of the ER-residing heat shock protein gp96 plays an important role in protein physiology and has additionally important immunological functions due to its peptide-binding capacity. Low amounts of gp96 stimulate immunity; high quantities induce tolerance by mechanisms not fully understood. A lack of gp96 protein in intestinal macrophages (IMACs) from Crohn`s disease (CD) patients correlates with loss of tolerance against the host gut flora, leading to chronic inflammation. Since gp96 shows dose-dependent direction of immunological reactions, we studied primary IMACs and developed cell models to understand the regulation of gp96 expression. Induction of gp96-expression was higher in in vitro differentiated dendritic cells (i.v.DCs) than in in vitro differentiated macrophages (i.v.MACs), whereas monocytes (MOs) expressed only low gp96 levels. The highest levels of expression were found in IMACs. Lipopolysaccharide (LPS), muramyl dipeptide (MDP), tumour necrosis factor (TNF), and Interleukin (IL)-4 induced gp96-expression, while IL12, IL-17, IL-23 and interferon (IFN)-γ were not effective indicating that Th1 and Th17 cells are probably not involved in the induction of gp96. Furthermore, gp96 was able to induce its own expression. The ER-stress inducer tunicamycin increased gp96-expression in a concentration- and time-dependent manner. Both ulcerative colitis (UC) and CD patients showed significantly elevated gp96 mRNA levels in intestinal biopsies which correlated positively with the degree of inflammation of the tissue. Since gp96 is highly expressed on the one hand upon stress induction as during inflammation and on the other hand possibly mediating tolerance, these results will help to understand the whether gp96 plays a role in the pathophysiology of inflammatory bowel disease (IBD). PMID:24146856

  10. A new member of the GP138 multigene family implicated in cell interactions in Dictyostelium discoideum.

    PubMed

    Hata, T; Yamaguchi, N; Tanaka, Y; Urushihara, H

    1999-06-01

    The cellular slime mold Dictyostelium discoideum reproduces sexually under submerged and dark conditions. Its mating system is polymorphic and particularly interesting with respect to mechanisms of cell recognition. The cell-surface glycoprotein gp138 has been implicated in sexual cell interactions, as it was identified as a target molecule for the antibodies that block sexual cell fusion in D. discoideum. Two mutually homologous genes, GP138A and GP138B, have been cloned, but gene disruption experiments to clarify their functional relationships suggested that there is at least one more gene for gp138. Further protein analysis including peptide mapping also revealed that gp138 exists as three isoforms, DdFRP1, DdFRP2, and DdFRP3. GP138A encodes DdFRP2 and GP138B, DdFRP3, and the presence of a third gp138 gene encoding DdFRP1 was suggested. Here, we isolated and characterized a third GP138 gene, GP138C. Although the deduced amino acid sequences of GP138C matched completely with those of peptide fragments of DdFRP1 in the N-terminal half, the rest did not give complete matches. Overexpression of GP138C caused an increase in the intensity of DdFRP1, but disruption of this gene did not diminish DdFRP1. Our results indicate that GP138C encodes a protein very similar to but distinct from DdFRP1. The GP138 multigene family is thus composed of more members than previously expected, and their functional relationships are of special interest. PMID:10462174

  11. GP3 is a structural component of the PRRSV type II (US) virion

    SciTech Connect

    Lima, M. de; Ansari, I.H.; Das, P.B.; Ku, B.J.; Martinez-Lobo, F.J.; Pattnaik, A.K.; Osorio, F.A.

    2009-07-20

    Glycoprotein 3 (GP3) is a highly glycosylated PRRSV envelope protein which has been reported as being present in the virions of PRRSV type I, while missing in the type II PRRSV (US) virions. We herein present evidence that GP3 is indeed incorporated in the virus particles of a North American strain of PRRSV (FL12), at a density that is consistent with the minor structural role assigned to GP3 in members of the Arterivirus genus. Two 15aa peptides corresponding to two different immunodominant linear epitopes of GP3 derived from the North American strain of PRRSV (FL12) were used as antigen to generate a rabbit monospecific antiserum to this protein. The specificity of this anti-GP3 antiserum was confirmed by radioimmunoprecipitation (RIP) assay using BHK-21 cells transfected with GP3 expressing plasmid, MARC-145 cells infected with FL12 PRRSV, as well as by confocal microscopy on PRRSV-infected MARC-145 cells. To test if GP3 is a structural component of the virion, {sup 35}S-labelled PRRSV virions were pelleted through a 30% sucrose cushion, followed by a second round of purification on a sucrose gradient (20-60%). Virions were detected in specific gradient fractions by radioactive counts and further confirmed by viral infectivity assay in MARC 145 cells. The GP3 was detected in gradient fractions containing purified virions by RIP using anti-GP3 antiserum. Predictably, the GP3 was less abundant in purified virions than other major structural envelope proteins such as GP5 and M. Further evidence of the presence of GP3 at the level of PRRSV FL12 envelope was obtained by immunogold staining of purified virions from the supernatant of infected cells with anti-GP3 antiserum. Taken together, these results indicate that GP3 is a minor structural component of the PRRSV type II (FL12 strain) virion, as had been previously described for PRRSV type I.

  12. Antibody to gp41 MPER Alters Functional Properties of HIV-1 Env without Complete Neutralization

    PubMed Central

    Kim, Arthur S.; Leaman, Daniel P.; Zwick, Michael B.

    2014-01-01

    Human antibody 10E8 targets the conserved membrane proximal external region (MPER) of envelope glycoprotein (Env) subunit gp41 and neutralizes HIV-1 with exceptional potency. Remarkably, HIV-1 containing mutations that reportedly knockout 10E8 binding to linear MPER peptides are partially neutralized by 10E8, producing a local plateau in the dose response curve. Here, we found that virus partially neutralized by 10E8 becomes significantly less neutralization sensitive to various MPER antibodies and to soluble CD4 while becoming significantly more sensitive to antibodies and fusion inhibitors against the heptad repeats of gp41. Thus, 10E8 modulates sensitivity of Env to ligands both pre- and post-receptor engagement without complete neutralization. Partial neutralization by 10E8 was influenced at least in part by perturbing Env glycosylation. With unliganded Env, 10E8 bound with lower apparent affinity and lower subunit occupancy to MPER mutant compared to wild type trimers. However, 10E8 decreased functional stability of wild type Env while it had an opposite, stabilizing effect on MPER mutant Envs. Clade C isolates with natural MPER polymorphisms also showed partial neutralization by 10E8 with altered sensitivity to various gp41-targeted ligands. Our findings suggest a novel mechanism of virus neutralization by demonstrating how antibody binding to the base of a trimeric spike cross talks with adjacent subunits to modulate Env structure and function. The ability of an antibody to stabilize, destabilize, partially neutralize as well as alter neutralization sensitivity of a virion spike pre- and post-receptor engagement may have implications for immunotherapy and vaccine design. PMID:25058619

  13. Neonatal intrahippocampal injection of the HIV-1 proteins gp120 and Tat: Differential effects on behavior and the relationship to stereological hippocampal measures

    PubMed Central

    Fitting, Sylvia; Booze, Rosemarie M.; Mactutus, Charles F.

    2008-01-01

    HIV-1 proteins, such as Tat and gp120 are believed to play a crucial role in the central nervous system (CNS) pathology of acquired immune deficiency syndrome (AIDS). The present study sought to determine the potential role of Tat and/or gp120 on behavioral development and the relationship with the assessed long-term effects of the HIV-1 proteins on the rat hippocampus. Male pups of 13 Sprague-Dawley litters were bilaterally injected on postnatal day (P)1. Every litter contributed an animal to each of four treatment condition: VEH (0.5µl sterile buffer), gp120 (100ng), Tat (25µg) or combined gp120+Tat (100ng+25µg). Body weight was not affected by either protein group. Tat revealed a transient effect on many of the behavioral assessments early in development as well as on preattentive processes and spatial memory in adulthood. Gp120 had more selective effects on negative geotaxis (P8–10) and on locomotor activity (P94–96). Combined gp120+Tat effects were noted for eye opening with potential interactive effects of gp120 and Tat on negative geotaxis. Anatomical assessment at ~7½ month of age was conducted by using design-based stereology to quantify the total cell number in five hippocampal subregions [granule layer (GL), hilus of the dentate gyrus (DGH), cornu ammonis fields (CA)2/3, CA1, and subiculum (SUB)] (Fitting et al., 2007a). A relationship between early reflex development and estimated cell number in the adult hippocampus was indicated by simple regression analyses. In addition, estimated number of neurons and astrocytes in the DGH explained 81% of the variance of the distribution of searching behavior in the probe test. Collectively, these data indicate that the DGH may participate in the spatial memory alterations observed in adulthood consequent to neonatal exposure to HIV-1 proteins. (Supported by DA013137, DA014401, HD043680). PMID:18674522

  14. XXth Hadron Collider Physics Symposium

    NASA Astrophysics Data System (ADS)

    In 2009, the Hadron Collider Physics Symposium took place in Evian (France), on the shore of the Geneva Lake, from 16-20 November. It was jointly organised by CERN and the French HEP community (CNRS-IN2P3 and CEA-IRFU). This year's symposium come at an important time for both the Tevatron and LHC communities. It stimulated the completion of analyses for a significant Tevatron data sample, and it allowed an in-depth review of the readiness of the LHC and its detectors just before first collisions. The programme includes sessions on top-quark and electro-weak physics, QCD, B physics, new phenomena, electro-weak symmetry breaking, heavy ions, and the status and commissioning of the LHC machine and its experiments. Conference website : http://hcp2009.in2p3.fr/

  15. Collider searches for extra dimensions

    SciTech Connect

    Landsberg, Greg; /Brown U.

    2004-12-01

    Searches for extra spatial dimensions remain among the most popular new directions in our quest for physics beyond the Standard Model. High-energy collider experiments of the current decade should be able to find an ultimate answer to the question of their existence in a variety of models. Until the start of the LHC in a few years, the Tevatron will remain the key player in this quest. In this paper, we review the most recent results from the Tevatron on searches for large, TeV{sup -1}-size, and Randall-Sundrum extra spatial dimensions, which have reached a new level of sensitivity and currently probe the parameter space beyond the existing constraints. While no evidence for the existence of extra dimensions has been found so far, an exciting discovery might be just steps away.

  16. Mutual colliding impact fast ignition

    NASA Astrophysics Data System (ADS)

    Winterberg, Friedwardt

    2014-09-01

    It is proposed to apply the well established colliding beam technology of high energy physics to the fast hot spot ignition of a highly compressed DT (deuterium-tritium) target igniting a larger D (deuterium) burn, by accelerating a small amount of solid deuterium, and likewise a small amount of tritium, making a head-on collision in the center of the target, projecting them through conical ducts situated at the opposite side of the target and converging in its center. In their head-on collision, the relative collision velocity is 5/3 times larger compared to the collision velocity of a stationary target. The two pieces have for this reason to be accelerated to a smaller velocity than would otherwise be needed to reach upon impact the same temperature. Since the velocity distribution of the two head-on colliding projectiles is with its two velocity peaks non-Maxwellian, the maximum cross section velocity product turns out to be substantially larger than the maximum if averaged over a Maxwellian. The D and T projectiles would have to be accelerated with two sabots driven by powerful particle or laser beams, permitting a rather large acceleration length. With the substantially larger cross section-velocity product by virtue of the non-Maxwellian velocity distribution, a further advantage is that the head-on collision produces a large magnetic field by the thermomagnetic Nernst effect, enhancing propagating burn. With this concept, the ignition of the neutron-less hydrogen-boron (HB11) reaction might even be possible in a heterogeneous assembly of the hydrogen and the boron to reduce the bremsstrahlung-losses, resembling the heterogeneous assembly in a graphite-natural uranium reactor, there to reduce the neutron losses.

  17. Mutual colliding impact fast ignition

    SciTech Connect

    Winterberg, Friedwardt

    2014-09-15

    It is proposed to apply the well established colliding beam technology of high energy physics to the fast hot spot ignition of a highly compressed DT (deuterium-tritium) target igniting a larger D (deuterium) burn, by accelerating a small amount of solid deuterium, and likewise a small amount of tritium, making a head-on collision in the center of the target, projecting them through conical ducts situated at the opposite side of the target and converging in its center. In their head-on collision, the relative collision velocity is 5/3 times larger compared to the collision velocity of a stationary target. The two pieces have for this reason to be accelerated to a smaller velocity than would otherwise be needed to reach upon impact the same temperature. Since the velocity distribution of the two head-on colliding projectiles is with its two velocity peaks non-Maxwellian, the maximum cross section velocity product turns out to be substantially larger than the maximum if averaged over a Maxwellian. The D and T projectiles would have to be accelerated with two sabots driven by powerful particle or laser beams, permitting a rather large acceleration length. With the substantially larger cross section-velocity product by virtue of the non-Maxwellian velocity distribution, a further advantage is that the head-on collision produces a large magnetic field by the thermomagnetic Nernst effect, enhancing propagating burn. With this concept, the ignition of the neutron-less hydrogen-boron (HB{sup 11}) reaction might even be possible in a heterogeneous assembly of the hydrogen and the boron to reduce the bremsstrahlung-losses, resembling the heterogeneous assembly in a graphite-natural uranium reactor, there to reduce the neutron losses.

  18. Critical transitions in colliding cascades

    PubMed

    Gabrielov; Keilis-Borok; Zaliapin; Newman

    2000-07-01

    We consider here the interaction of direct and inverse cascades in a hierarchical nonlinear system that is continuously loaded by external forces. The load is applied to the largest element and is transferred down the hierarchy to consecutively smaller elements, thereby forming a direct cascade. The elements of the system fail (i. e., break down) under the load. The smallest elements fail first. The failures gradually expand up the hierarchy to the larger elements, thus forming an inverse cascade. Eventually the failures heal, ensuring that the system will function indefinitely. The direct and inverse cascades collide and interact. Loading triggers the failures, while failures release and redistribute the load. Notwithstanding its relative simplicity, this model reproduces the major dynamical features observed in seismicity, including the seismic cycle, intermittence of seismic regime, power-law energy distribution, clustering in space and time, long-range correlations, and a set of seismicity patterns premonitory to a strong earthquake. In this context, the hierarchical structure of the model crudely imitates a system of tectonic blocks spread by a network of faults (note that the behavior of such a network is different from that of a single fault). Loading mimics the impact of tectonic forces, and failures simulate earthquakes. The model exhibits three basic types of premonitory pattern reflecting seismic activity, clustering of earthquakes in space and time, and the range of correlation between the earthquakes. The colliding-cascade model seemingly exhibits regularities that are common in a wide class of complex hierarchical systems, not necessarily Earth specific. PMID:11088457

  19. Design and performance of the Stanford Linear Collider Control System

    SciTech Connect

    Melen, R.E.

    1984-10-01

    The success of the Stanford Linear Collider (SLC) will be dependent upon the implementation of a very large advanced computer-based instrumentation and control system. This paper describes the architectural design of this system as well as a critique of its performance. This critique is based on experience obtained from its use in the control and monitoring of 1/3 of the SLAC linac and in support of an expensive experimental machine physics experimental program. 11 references, 3 figures.

  20. The Relativistic Heavy Ion Collider control system

    SciTech Connect

    Clifford, T.S.; Barton, D.S.; Oerter, B.R.

    1997-12-01

    The Relativistic Heavy Ion Collider control system has been used in the commissioning of the AGS to RHIC transfer line and in the first RHIC sextant test. Much of the controls infrastructure for networks and links has been installed throughout the collider. All of the controls hardware modules needed to be built for early RHIC operations have been designed and tested. Many of these VME modules are already being used in normal AGS operations. Over 150 VME based front end computers and device controllers will be installed by the Summer of 1998 in order to be ready for Fall of 1998. A few features are being added to the front end computer core software. The bulk of the Accelerator Device Objects (ADOs) which are instantiated in the FECs, have been written and tested in the early commissioning. A configuration database has been designed. Generic control and display of ADO parameters via a spreadsheet like program on the console level computers was provided early on in the control system development. User interface tools that were developed for the AGS control system have been used in RHIC applications. Some of the basic operations programs, like alarm display and save/restore, that are used in the AGS operations have been or will be expanded to support RHIC operations. A model for application programs which involves a console level manager servicing ADOs have been verified with a few RHIC applications. More applications need to be written for the Fall of 1998 commissioning effort. A sequencer for automatic control of the fill is being written with the expectation that it will be useful in early commissioning.

  1. Structural Basis for Species Selectivity in the HIV-1 gp120-CD4 Interaction: Restoring Affinity to gp120 in Murine CD4 Mimetic Peptides

    PubMed Central

    Kassler, Kristin; Meier, Julia; Eichler, Jutta; Sticht, Heinrich

    2011-01-01

    The first step of HIV-1 infection involves interaction between the viral glycoprotein gp120 and the human cellular receptor CD4. Inhibition of the gp120-CD4 interaction represents an attractive strategy to block HIV-1 infection. In an attempt to explore the known lack of affinity of murine CD4 to gp120, we have investigated peptides presenting the putative gp120-binding site of murine CD4 (mCD4). Molecular modeling indicates that mCD4 protein cannot bind gp120 due to steric clashes, while the larger conformational flexibility of mCD4 peptides allows an interaction. This finding is confirmed by experimental binding assays, which also evidenced specificity of the peptide-gp120 interaction. Molecular dynamics simulations indicate that the mCD4-peptide stably interacts with gp120 via an intermolecular β-sheet, while an important salt-bridge formed by a C-terminal lysine is lost. Fixation of the C-terminus by introducing a disulfide bridge between the N- and C-termini of the peptide significantly enhanced the affinity to gp120. PMID:22312332

  2. Mini-P-gp and P-gp Co-Expression in Brown Trout Erythrocytes: A Prospective Blood Biomarker of Aquatic Pollution

    PubMed Central

    Valton, Emeline; Amblard, Christian; Desmolles, François; Combourieu, Bruno; Penault-Llorca, Frédérique; Bamdad, Mahchid

    2015-01-01

    In aquatic organisms, such as fish, blood is continually exposed to aquatic contaminants. Multidrug Resistance (MDR) proteins are ubiquitous detoxification membrane pumps, which recognize various xenobiotics. Moreover, their expression is induced by a large class of drugs and pollutants. We have highlighted the co-expression of a mini P-gp of 75 kDa and a P-gp of 140 kDa in the primary culture of brown trout erythrocytes and in the erythrocytes of wild brown trout collected from three rivers in the Auvergne region of France. In vitro experiments showed that benzo[a]pyrene, a highly toxic pollutant model, induced the co-expression of mini-P-gp and P-gp in trout erythrocytes in a dose-dependent manner and relay type response. Similarly, in the erythrocytes of wild brown trout collected from rivers contaminated by a mixture of PAH and other multi-residues of pesticides, mini-P-gp and P-gp were able to modulate their expression, according to the nature of the pollutants. The differential and complementary responses of mini-P-gp and P-gp in trout erythrocytes suggest the existence in blood cells of a real protective network against xenobiotics/drugs. This property could be exploited to develop a blood biomarker of river pollution. PMID:26854141

  3. One-Loop Helicity Amplitudes for tt Production at Hadron Colliders

    SciTech Connect

    Badger, Simon; Sattler, Ralf; Yundin, Valery

    2011-04-01

    We present compact analytic expressions for all one-loop helicity amplitudes contributing to tt production at hadron colliders. Using recently developed generalized unitarity methods and a traditional Feynman based approach we produce a fast and flexible implementation.

  4. Colliding nuclei to colliding galaxies: Illustrations using a simple colliding liquid-drop apparatus

    NASA Astrophysics Data System (ADS)

    Becchetti, F. D.; Mack, S. L.; Robinson, W. R.; Ojaruega, M.

    2015-10-01

    A simple apparatus suitable for observing the collisions between drops of fluids of various properties is described. Typical results are shown for experiments performed by undergraduate students using various types of fluids. The collisions take place under free-fall (zero-g) conditions, with analysis employing digital video. Two specific types of collisions are examined in detail, head-on collisions and peripheral, grazing collisions. The collisions for certain fluids illustrate many types of nuclear collisions and provide useful insight into these processes, including both fusion and non-fusion outcomes, often with the formation of exotic shapes or emission of secondary fragments. Collisions of other liquids show a more chaotic behavior, often resembling galactic collisions. As expected, the Weber number associated with a specific collision impact parameter is found to be the important quantity in determining the initial outcome of these colliding systems. The features observed resemble those reported by others using more elaborate experimental techniques.

  5. Models for the Binary Complex of Bacteriophage T4 Gp59 Helicase Loading Protein. GP32 Single-Stranded DNA-Binding Protein and Ternary Complex with Pseudo-Y Junction DNA

    SciTech Connect

    Hinerman, Jennifer M.; Dignam, J. David; Mueser, Timothy C.

    2012-04-05

    The bacteriophage T4 gp59 helicase assembly protein (gp59) is required for loading of gp41 replicative helicase onto DNA protected by gp32 single-stranded DNA-binding protein. The gp59 protein recognizes branched DNA structures found at replication and recombination sites. Binding of gp32 protein (full-length and deletion constructs) to gp59 protein measured by isothermal titration calorimetry demonstrates that the gp32 protein C-terminal A-domain is essential for protein-protein interaction in the absence of DNA. Sedimentation velocity experiments with gp59 protein and gp32ΔB protein (an N-terminal B-domain deletion) show that these proteins are monomers but form a 1:1 complex with a dissociation constant comparable with that determined by isothermal titration calorimetry. Small angle x-ray scattering (SAXS) studies indicate that the gp59 protein is a prolate monomer, consistent with the crystal structure and hydrodynamic properties determined from sedimentation velocity experiments. SAXS experiments also demonstrate that gp32ΔB protein is a prolate monomer with an elongated A-domain protruding from the core. Moreover, fitting structures of gp59 protein and the gp32 core into the SAXS-derived molecular envelope supports a model for the gp59 protein-gp32ΔB protein complex. Our earlier work demonstrated that gp59 protein attracts full-length gp32 protein to pseudo-Y junctions. A model of the gp59 protein-DNA complex, modified to accommodate new SAXS data for the binary complex together with mutational analysis of gp59 protein, is presented in the accompanying article (Dolezal, D., Jones, C. E., Lai, X., Brister, J. R., Mueser, T. C., Nossal, N. G., and Hinton, D. M. (2012) J. Biol. Chem. 287, 18596–18607).

  6. Molecular and Physicochemical Factors Governing Solubility of the HIV gp41 Ectodomain.

    PubMed

    Manssour-Triedo, Fadia; Crespillo, Sara; Morel, Bertrand; Casares, Salvador; Mateo, Pedro L; Notka, Frank; Roger, Marie G; Mouz, Nicolas; El-Habib, Raphaelle; Conejero-Lara, Francisco

    2016-08-23

    The HIV gp41 ectodomain (e-gp41) is an attractive target for the development of vaccines and drugs against HIV because of its crucial role in viral fusion to the host cell. However, because of the high insolubility of e-gp41, most biophysical and structural analyses have relied on the production of truncated versions removing the loop region of gp41 or the utilization of nonphysiological solubilizing conditions. The loop region of gp41 is also known as principal immunodominant domain (PID) because of its high immunogenicity, and it is essential for gp41-mediated HIV fusion. In this study we identify the aggregation-prone regions of the amino acid sequence of the PID and engineer a highly soluble mutant that preserves the trimeric structure of the wild-type e-gp41 under physiological pH. Furthermore, using a reverse mutagenesis approach, we analyze the role of mutated amino acids upon the physicochemical factors that govern solubility of e-gp41. On this basis, we propose a molecular model for e-gp41 self-association, which can guide the production of soluble e-gp41 mutants for future biophysical analyses and biotechnological applications. PMID:27558714

  7. A Mutation in the Human Immunodeficiency Virus Type 1 Gag Protein Destabilizes the Interaction of the Envelope Protein Subunits gp120 and gp41

    PubMed Central

    Davis, Melody R.; Jiang, Jiyang; Zhou, Jing; Freed, Eric O.; Aiken, Christopher

    2006-01-01

    The Gag protein of human immunodeficiency virus type 1 (HIV-1) associates with the envelope protein complex during virus assembly. The available evidence indicates that this interaction involves recognition of the gp41 cytoplasmic tail (CT) by the matrix protein (MA) region of Pr55Gag. Here we show that substitution of Asp for Leu at position 49 (L49D) in MA results in a specific reduction in particle-associated gp120 without affecting the levels of gp41. Mutant virions were markedly reduced in single-cycle infectivity despite a relatively modest defect in fusion with target cells. Studies with HIV-1 particles containing decreased levels of envelope proteins suggested that the L49D mutation also inhibits a postentry step in infection. Truncation of the gp41 tail, or pseudotyping by vesicular stomatitis virus glycoprotein, restored both the fusion and infectivity of L49D mutant virions to wild-type levels. Truncation of gp41 also resulted in equivalent levels of gp120 on particles with and without the MA mutation and enhanced the replication of the L49D mutant virus in T cells. The impaired fusion and infectivity of L49D mutant particles were also complemented by a single point mutation in the gp41 CT that disrupted the tyrosine-containing endocytic motif. Our results suggest that an altered interaction between the MA domain of Gag and the gp41 cytoplasmic tail leads to dissociation of gp120 from gp41 during HIV-1 particle assembly, thus resulting in impaired fusion and infectivity. PMID:16474147

  8. Guinea pig cytomegalovirus GP84 is a functional homolog of the human cytomegalovirus (HCMV) UL84 gene that can complement for the loss of UL84 in a chimeric HCMV.

    PubMed

    McGregor, A; Choi, K Y; Schleiss, M R

    2011-02-01

    The guinea pig cytomegalovirus (GPCMV) co-linear gene and potential functional homolog of HCMV UL84 (GP84) was investigated. The GP84 gene had delayed early transcription kinetics and transient expression studies of GP84 protein (pGP84) demonstrated that it targeted the nucleus and co-localized with the viral DNA polymerase accessory protein as described for HCMV pUL84. Additionally, pGP84 exhibited a transdominant inhibitory effect on viral growth as described for HCMV. The inhibitory domain could be localized to a minimal peptide sequence of 99 aa. Knockout of GP84 generated virus with greatly impaired growth kinetics. Lastly, the GP84 ORF was capable of complementing for the loss of the UL84 coding sequence in a chimeric HCMV. Based on this research and previous studies we conclude that GPCMV is similar to HCMV by encoding single copy co-linear functional homologs of HCMV UL82 (pp71), UL83 (pp65) and UL84 genes. PMID:21094510

  9. Induction of Strong HIV-1-specific CD4+ T Cell Responses using an HIV-1 gp120/NefTat Vaccine adjuvanted with AS02A in ARV Treated HIV-1-Infected Individuals

    PubMed Central

    Lichterfeld, Mathias; Gandhi, Rajesh T.; Simmons, Rachel P.; Flynn, Teresa; Sbrolla, Amy; Yu, Xu G.; Basgoz, Nesli; Mui, Stanley; Williams, Katie; Streeck, Hendrik; Burgett-Yandow, Nicole; Roy, Gilbert; Janssens, Michel; Pedneault, Louise; Vandepapelière, Pierre; Koutsoukos, Marguerite; Demoitié, Marie-Ange; Bourguignon, Patricia; McNally, Lisa; Voss, Gerald; Altfeld, Marcus

    2011-01-01

    Background Induction of HIV-1-specific CD4+ T cell responses by therapeutic vaccination represents an attractive intervention to potentially increase immune control of HIV-1. Methods We performed a double-blinded, randomized, placebo-controlled clinical trial to determine the safety and immunogenicity of GSK Biologicals' HIV-1 gp120/NefTat subunit protein vaccine formulated with the AS02A adjuvant in subjects with well controlled chronic HIV-1 infection on HAART. Ten individuals received the vaccine; while adjuvant alone or placebo was given to five subjects each. Immunogenicity was monitored by intracellular cytokine flow cytometry and CFSE-based proliferation assays. Results The vaccine was well tolerated with no related SAEs. Vaccine recipients had significantly stronger gp120-specific CD4+ T cell responses which persisted until week 48 and greater gp120-specific CD4+ T cell proliferation activity as compared to controls. In the vaccine group, the number of participants that demonstrated positive responses for both gp120-specific CD4+ T cell IL-2 production and gp120-specific CD8+ T cell proliferation was significantly higher at week 6. Conclusions The gp120/NefTat/AS02A vaccine induced strong gp120-specific CD4+ T cell responses, and a higher number of vaccinees developed both HIV-1-specific CD4+ T cell responses and CD8+ T cell proliferation. The induction of these responses may be important in enhancing immune-mediated viral control. PMID:21963936

  10. Feasibility of Production of Moly-99 via 1-neutron Exchange Reaction 98 Mo +100 Mo -->299Mo in Strong-Focusing Auto Collider (``EXYDER'') of natural Molybdenum nuclei based on T and He-3 production data from d +d weak focusing Auto-Collider MIGMA IV

    NASA Astrophysics Data System (ADS)

    Hester, Tim; Maglich, Bogdan; Calsec Collaboration

    2015-10-01

    Copious T and 3He production from D(d, p) T and D(d, n) 3He reactions in 725 KeV colliding beams was observed in weak-focusing Self-Collider1-4 radius 15 cm, in B = 3.12 T, stabilized5 non-linearly by electron cloud oscillations with confinement time ~ 23 s. BARC's simulations7 predict that by switching to Strong Focusing Self Collider proposed by Blewett6, 10 deuterons 0.75 MeV each, will generate 1 3He + 1T +1p + 1n at a total input energy cost of 10.72 MeV. Economic value of T and 3He is 65 and 120 MeV/atom respectively. While energy balance is negative, we project economic gain 205 MeV/10.72 MeV ~ 20 i.e. 3He production/sale will fund cost of T. Assuming the luminosity achieved in MIGMA IV, we replace D beam injection with a high energy beam of 14 times ionized natural Mo ions and look for the 1-neutron reactions of the type 98Mo+100Mo -->299Mo, where 99Mo14+ will be EM channeled into a mass spectrometer and collected at one loci/ radius, while all other masses/radii rejected. Physics and engineering parameters required to produce at least 1 g of 99Mo per day, at an electricity cost of 100K, will be presented. 2- and 3-neutron exchange reactions will be considered, too.

  11. High frequency planar accelerating structures for future linear colliders

    SciTech Connect

    Yu, D.; Ben-Menahem, S.; Wilson, P.; Miller, R.; Ruth, R.; Nassiri, A.

    1994-12-31

    Modern microfabrication techniques based on deep etch x-ray lithography, e.g., LIGA, can be used to produce large-aspect-ratio, metallic or dielectric, planar structures suitable for high-frequency RF acceleration of charged particle beams. Specifically, these techniques offer significant advantages over conventional manufacturing methods for future linear colliders (beyond NLC, the Next Linear Collider) because of several unique systems requirements. First, to have the required ac wall plug power within reasonable limits, such future linear colliders (5 TeV) must operate at high frequency (30 GHz). Secondly, luminosity requirements suggest the use of multi-bunch acceleration of electrons and positrons in the linear collider. Thirdly, in order to clearly discriminate physics events in the final interaction point at which electrons and positrons collide, it is required that secondary particle production from beamstrahlung be minimized. Flat electron and positron beams with a large aspect ratio will be beneficial in reducing beamstrahlung in the final focus region, but cause the beam to be more sensitive to wakefields in the vertical dimension. In principle, a flat beam can be accelerated in a planar structure with reduced wakefield in the vertical direction for the entire length of the accelerator. The LIGA process is particularly suitable for manufacturing miniaturized, planar, asymmetric cavities at high frequency. The main advantages of the LIGA process are fabrication of structures with high aspect ratio, small dimensional tolerances, and arbitrary mask shape (cross-section). Other advantages include mass-production with excellent repeatability and precision of up to an entire section of an accelerating structure consisting of a number of cells. It eliminates the need of tedious machining and brazing, for example, of individual disks and cups in conventional disk-loaded structures. Also, planar input/output couplers for the accelerating structure can be easily

  12. Changes in health care utilisation following a reform involving choice and privatisation in Swedish primary care: a five-year follow-up of GP-visits

    PubMed Central

    2013-01-01

    Background The organisation of Swedish primary health care has changed following introduction of free choice of provider for the population in combination with freedom of establishment for private primary care providers. Our aim was to investigate changes in individual health care utilisation following choice and privatisation in Swedish primary care from an equity perspective, in subgroups defined by age, gender and family income. Methods The study is based on register data years 2007 – 2011 from the Skåne Regional Council (population 1.2 million) regarding individual health care utilisation in the form of visits to general practitioner (GP). Health utilisation data was matched with data about individual’s age, gender and family income provided by Statistics Sweden. Multilevel, logistic regression models were constructed to analyse changes in health utilisation in different subgroups and the probability of a GP-visit before and after reform. Results Health care utilisation in terms of both number of individuals that had visited a GP and number of GP-visits per capita increased in all defined subgroups, but to a varying degree. Multilevel logistic regression showed that individuals of both genders aged above 64 and belonging to a family with an income above median had more advantage of the reform, OR 1.25-1.29. Conclusions Reforms involving choice and privatisation in Swedish primary health care improved access to GP-visits generally, but more so for individuals belonging to a family with income above the median. PMID:24171894

  13. Addition of a Single gp120 Glycan Confers Increased Binding to Dendritic Cell-Specific ICAM-3-Grabbing Nonintegrin and Neutralization Escape to Human Immunodeficiency Virus Type 1

    PubMed Central

    Lue, James; Hsu, Mayla; Yang, David; Marx, Preston; Chen, Zhiwei; Cheng-Mayer, Cecilia

    2002-01-01

    The potential role of dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) binding in human immunodeficiency virus transmission across the mucosal barrier was investigated by assessing the ability of simian-human immunodeficiency chimeric viruses (SHIVs) showing varying degrees of mucosal transmissibility to bind the DC-SIGN expressed on the surface of transfected cells. We found that gp120 of the highly transmissible, pathogenic CCR5-tropic SHIVSF162P3 bound human and rhesus DC-SIGN with an efficiency threefold or greater than that of gp120 of the nonpathogenic, poorly transmissible parental SHIVSF162, and this increase in binding to the DC-SIGN of the SHIVSF162P3 envelope gp120 translated into an enhancement of T-cell infection in trans. The presence of an additional glycan at the N-terminal base of the V2 loop of SHIVSF162P3 gp120 compared to that of the parental virus was shown to be responsible for the increase in binding to DC-SIGN. Interestingly, this glycan also conferred escape from autologous neutralization, raising the possibility that the modification occurred as a result of immune selection. Our data suggest that more-efficient binding of envelope gp120 to DC-SIGN could be relevant to the enhanced mucosal transmissibility of SHIVSF162P3 compared to that of parental SHIVSF162. PMID:12239306

  14. Optimizing integrated luminosity of future hadron colliders

    NASA Astrophysics Data System (ADS)

    Benedikt, Michael; Schulte, Daniel; Zimmermann, Frank

    2015-10-01

    The integrated luminosity, a key figure of merit for any particle-physics collider, is closely linked to the peak luminosity and to the beam lifetime. The instantaneous peak luminosity of a collider is constrained by a number of boundary conditions, such as the available beam current, the maximum beam-beam tune shift with acceptable beam stability and reasonable luminosity lifetime (i.e., the empirical "beam-beam limit"), or the event pileup in the physics detectors. The beam lifetime at high-luminosity hadron colliders is largely determined by particle burn off in the collisions. In future highest-energy circular colliders synchrotron radiation provides a natural damping mechanism, which can be exploited for maximizing the integrated luminosity. In this article, we derive analytical expressions describing the optimized integrated luminosity, the corresponding optimum store length, and the time evolution of relevant beam parameters, without or with radiation damping, while respecting a fixed maximum value for the total beam-beam tune shift or for the event pileup in the detector. Our results are illustrated by examples for the proton-proton luminosity of the existing Large Hadron Collider (LHC) at its design parameters, of the High-Luminosity Large Hadron Collider (HL-LHC), and of the Future Circular Collider (FCC-hh).

  15. Minor interspecies variations in the sequence of the gp53 TSL-1 antigen of Trichinella define species-specific immunodominant epitopes.

    PubMed

    Perteguer, M J; Rodríguez, E; Romarís, F; Escalante, M; Bonay, P; Ubeira, F M; Gárate, M T

    2004-06-01

    Among the Trichinella TSL-1 antigens, whose antigenicity is generally due mainly to tyvelose-containing epitopes, gp53 is unusual in that its antigenicity is due mainly to protein epitopes. In the present study we mapped two of these epitopes, recognized by monoclonal antibodies (mAbs) that specifically recognize gp53 from all encysting Trichinella species (mAb US9), or gp53 from Trichinella spiralis alone (mAb US5). Based on previously published sequences of this glycoprotein [Mol. Biochem. Parasitol. 72 (1995) 253], in this study, we cloned the full gp53 cDNA from a new strain, Trichinella britovi (ISS 11; AN: ), and from another T. spiralis isolate (ISS 115; AN: ). The gp53 sequence comprised an ORF of 1239bp, coding for 412 amino acids, with 61 nucleotide differences (resulting in 38 residue changes) between the two species. Mapping of US5- and US9-recognized epitopes was undertaken through the construction and expression in the pGEX4T vector of truncated gp53 peptides, and by the construction of peptides derived from the antigenic regions. The epitope recognized by mAb US9 was a linear peptide of 8 residues, 33Met- 40Ser, located in the amino-terminal region, while the corresponding epitope recognized by mAb US5 was a 47-amino acid sequence containing two alpha-helix regions flanked by random coils, 290Thr- 336Lys. Molecular modeling of these peptides seems to indicate that recognition of the US9 epitope depends on the presence of two available hydroxyl groups provided by one methionine and one serine on T. spiralis gp53 (not present on Trichinella pseudospiralis gp53). Additionally, the stability of the US5 epitope seems to depend on correct folding of the 47-amino acid sequence (only present in T. spiralis). The relevance of these findings for understanding the antigenic recognition of Trichinella TSL-1 antigens, and for further studies to investigate possible function(s) of gp53 in Trichinella, is discussed. PMID:15163539

  16. Compensatable muon collider calorimeter with manageable backgrounds

    SciTech Connect

    Raja, Rajendran

    2015-02-17

    A method and system for reducing background noise in a particle collider, comprises identifying an interaction point among a plurality of particles within a particle collider associated with a detector element, defining a trigger start time for each of the pixels as the time taken for light to travel from the interaction point to the pixel and a trigger stop time as a selected time after the trigger start time, and collecting only detections that occur between the start trigger time and the stop trigger time in order to thereafter compensate the result from the particle collider to reduce unwanted background detection.

  17. Beamstrahlung spectra in next generation linear colliders

    SciTech Connect

    Barklow, T.; Chen, P. ); Kozanecki, W. )

    1992-04-01

    For the next generation of linear colliders, the energy loss due to beamstrahlung during the collision of the e{sup +}e{sup {minus}} beams is expected to substantially influence the effective center-of-mass energy distribution of the colliding particles. In this paper, we first derive analytical formulae for the electron and photon energy spectra under multiple beamstrahlung processes, and for the e{sup +}e{sup {minus}} and {gamma}{gamma} differential luminosities. We then apply our formulation to various classes of 500 GeV e{sup +}e{sup {minus}} linear collider designs currently under study.

  18. SLAC linear collider conceptual design report

    SciTech Connect

    Not Available

    1980-06-01

    The linear collider system is described in detail, including the transport system, the collider lattice, final focusing system, positron production, beam damping and compression, high current electron source, instrumentation and control, and the beam luminosity. The experimental facilities and the experimental uses are discussed along with the construction schedule and estimated costs. Appendices include a discussion of space charge effects in the linear accelerator, emittance growth in the collider, the final focus system, beam-beam instabilities and pinch effects, and detector backgrounds. (GHT)

  19. The principles and construction of linear colliders

    SciTech Connect

    Rees, J.

    1986-09-01

    The problems posed to the designers and builders of high-energy linear colliders are discussed. Scaling laws of linear colliders are considered. The problem of attainment of small interaction areas is addressed. The physics of damping rings, which are designed to condense beam bunches in phase space, is discussed. The effect of wake fields on a particle bunch in a linac, particularly the conventional disk-loaded microwave linac structures, are discussed, as well as ways of dealing with those effects. Finally, the SLAC Linear Collider is described. 18 refs., 17 figs. (LEW)

  20. CP violation and flavor-changing-currents at {mu}{sup +}{mu}{sup minus} colliders

    SciTech Connect

    Soni, A.

    1996-04-02

    Production and decay (CP) asymmetries at {mu}{sup +}{mu}{sup {minus}} collider, in extensions of the Standard Model (SM) are reported. Production asymmetries appear to be very promising for a large range of parameters, decays are less effective. Importance of flavor- changing scalar currents involving the top are emphasized. At lepton colliders, the top-anticharm final state is uniquely suited for such searches. At a muon collider there is the novel possibility of tree level {mu}{sup +}{mu}{sup {minus}} {r_arrow} t{ovr c}. This talk is based on works done in collaboration with David Atwood and Laura Reina. 10 refs., 8 figs.

  1. High pulse power rf sources for linear colliders

    SciTech Connect

    Wilson, P.B.

    1983-09-01

    RF sources with high peak power output and relatively short pulse lengths will be required for future high gradient e/sup +/e/sup -/ linear colliders. The required peak power and pulse length depend on the operating frequency, energy gradient and geometry of the collider linac structure. The frequency and gradient are in turn constrained by various parameters which depend on the beam-beam collision dynamics, and on the total ac wall-plug power that has been committed to the linac rf system. Various rf sources which might meet these requirements are reviewed. Existing source types (e.g., klystrons, gyrotrons) and sources which show future promise based on experimental prototypes are first considered. Finally, several proposals for high peak power rf sources based on unconventional concepts are discussed. These are an FEL source (two beam accelerator), rf energy storage cavities with switching, and a photocathode device which produces an rf current by direct emission modulation of the cathode.

  2. Genetic analysis of the Rous sarcoma virus subgroup D env gene: mammal tropism correlates with temperature sensitivity of gp85.

    PubMed Central

    Bova-Hill, C; Olsen, J C; Swanstrom, R

    1991-01-01

    Subgroup D avian sarcoma and leukosis viruses can penetrate a variety of mammalian cells in addition to cells from their natural host, chickens. Sequences derived from the gp85-coding domain within the env gene of a mammal-tropic subgroup D virus (Schmidt-Ruppin D strain of Rous sarcoma virus [SR-D RSV]) and a non-mammal-tropic subgroup B virus (Rous-associated virus type 2) were recombined to map genetic determinants that allow penetration of mammalian cells. The following conclusions were based on host range analysis of the recombinant viruses. (i) The determinants of gp85 that result in the mammal tropism phenotype of SR-D RSV are encoded within the 160 codons that lie 3' of codon 121 from the corresponding amino terminus of the gp85 protein. (ii) Small linear domains of the SR-D RSV gp85-coding domain placed in the subgroup B background did not yield viruses with titers equal to that of the subgroup D virus in a human cell line. (iii) Recombinant viruses that contained subgroup D sequences within the hr1 variable domain of gp85 showed modest-to-significant increases in infectivity on human cells relative to chicken cells. A recombinant virus that contained three fortuitous amino acid substitutions in the gp85-coding domain was found to penetrate the human cell line and give a titer similar to that of the subgroup D virus. In addition, we found that the subgroup D virus, the mutant virus, and recombinant viruses with an increased mammal tropism phenotype were unstable at 42 degrees C. These results suggest that the mammal tropism of the SR-D strain is not related to altered receptor specificity but rather to an unstable and fusogenic viral glycoprotein. A temperature sensitivity phenotype for infectivity of mammalian cells was also observed for another mammal-tropic avian retrovirus, the Bratislava 77 strain of RSV, a subgroup C virus, but was not seen for any other avian retrovirus tested, strengthening the correlation between mammal tropism and temperature

  3. The gp130 Receptor Cytokine Family: Regulators of Adipocyte Development and Function

    PubMed Central

    White, Ursula A.; Stephens, Jacqueline M.

    2011-01-01

    Gp130 cytokines are involved in the regulation of numerous biological processes, including hematopoiesis, immune response, inflammation, cardiovascular action, and neuronal survival. These cytokines share glycoprotein 130 as a common signal transducer in their receptor complex and typically activate STAT3. Most gp130 cytokines have paracrine or endocrine actions, and their levels can be measured in circulation in rodents and humans. In recent years, various laboratories have conducted studies to demonstrate that gp130 cytokines can modulate adipocyte development and function. Therefore, these studies suggest that some gp130 cytokines may be viable anti-obesity therapeutics. In this review, we will summarize the reported effects of gp130 cytokines on adipocyte differentiation and adipocyte function. In addition, the modulation of gp130 cytokines in conditions of obesity, insulin resistance, and Type 2 diabetes will be presented. PMID:21375496

  4. The Relativistic Heavy Ion Collider

    NASA Astrophysics Data System (ADS)

    Fischer, Wolfram

    The Relativistic Heavy Ion Collider (RHIC), shown in Fig. 1, was build to study the interactions of quarks and gluons at high energies [Harrison, Ludlam and Ozaki (2003)]. The theory of Quantum Chromodynamics (QCD) describes these interactions. One of the main goals for the RHIC experiments was the creation and study of the Quark-Gluon Plasma (QGP), which was expected to be formed after the collision of heavy ions at a temperature of approximately 2 trillion kelvin (or equivalently an energy of 150 MeV). The QGP is the substance which existed only a few microseconds after the Big Bang. The QGP was anticipated to be weakly interacting like a gas but turned out to be strongly interacting and more like a liquid. Among its unusual properties is its extremely low viscosity [Auerbach and Schlomo (2009)], which makes the QGP the substance closest to a perfect liquid known to date. The QGP is opaque to moderate energy quarks and gluons leading to a phenomenon called jet quenching, where of a jet and its recoil jet only one is observable and the other suppressed after traversing and interacting with the QGP [Jacak and Müller (2012)]...

  5. Proton-antiproton collider physics

    SciTech Connect

    Shochet, M.J.

    1995-07-01

    The 9th {anti p}p Workshop was held in Tsukuba, Japan in October, 1993. A number of important issues remained after that meeting: Does QCD adequately describe the large cross section observed by CDF for {gamma} production below 30 GeV? Do the CDF and D0 b-production cross sections agree? Will the Tevatron live up to its billing as a world-class b-physics facility? How small will the uncertainty in the W mass be? Is there anything beyond the Minimal Standard Model? And finally, where is the top quark? Presentations at this workshop addressed all of these issues. Most of them are now resolved, but new questions have arisen. This summary focuses on the experimental results presented at the meeting by CDF and D0 physicists. Reviews of LEP and HERA results, future plans for hadron colliders and their experiments, as well as important theoretical presentations are summarized elsewhere in this volume. Section 1 reviews physics beyond the Minimal Standard Model. Issues in b and c physics are addressed in section 3. Section 4 focuses on the top quark. Electroweak physics is reviewed in section 5, followed by QCD studies in section 6. Conclusions are drawn in section 7.

  6. Time evolution of the luminosity of colliding heavy-ion beams in BNL Relativistic Heavy Ion Collider and CERN Large Hadron Collider

    NASA Astrophysics Data System (ADS)

    Bruce, R.; Jowett, J. M.; Blaskiewicz, M.; Fischer, W.

    2010-09-01

    We have studied the time evolution of the heavy-ion luminosity and bunch intensities in the Relativistic Heavy Ion Collider (RHIC) at BNL, and in the Large Hadron Collider (LHC) at CERN. First, we present measurements from a large number of RHIC stores (from run-7), colliding 100GeV/nucleon Au79+197 beams without stochastic cooling. These are compared with two different calculation methods. The first is a simulation based on multiparticle tracking taking into account collisions, intrabeam scattering, radiation damping, and synchrotron and betatron motion. In the second, faster, method, a system of ordinary differential equations with terms describing the corresponding effects on emittances and bunch populations is solved numerically. Results of the tracking method agree very well with the RHIC data. With the faster method, significant discrepancies are found since the losses of particles diffusing out of the rf bucket due to intrabeam scattering are not modeled accurately enough. Finally, we use both methods to make predictions of the time evolution of the future Pb82+208 beams in the LHC at injection and collision energy. For this machine, the two methods agree well.

  7. Time evolution of the luminosity of colliding heavy-ion beams in BNL Relativistic Heavy Ion Collider and CERN Large Hadron Collider

    SciTech Connect

    Bruce, R.; Blaskiewicz, M.; Jowett, J.M.; Fischer, W.

    2010-09-07

    We have studied the time evolution of the heavy ion luminosity and bunch intensities in the Relativistic Heavy Ion Collider (RHIC), at BNL, and in the Large Hadron Collider (LHC), at CERN. First, we present measurements from a large number of RHIC stores (from Run 7), colliding 100 GeV/nucleon {sup 197}Au{sup 79}+ beams without stochastic cooling. These are compared with two different calculation methods. The first is a simulation based on multi-particle tracking taking into account collisions, intrabeam scattering, radiation damping, and synchrotron and betatron motion. In the second, faster, method, a system of ordinary differential equations with terms describing the corresponding effects on emittances and bunch populations is solved numerically. Results of the tracking method agree very well with the RHIC data. With the faster method, significant discrepancies are found since the losses of particles diffusing out of the RF bucket due to intrabeam scattering are not modeled accurately enough. Finally, we use both methods to make predictions of the time evolution of the future {sup 208}Pb+{sup 82+} beams in the LHC at injection and collision energy. For this machine, the two methods agree well.

  8. Discriminating Supersymmetry and Black Holes at the Large Hadron Collider

    NASA Astrophysics Data System (ADS)

    Roy, Arunava; Cavaglia, Marco

    2008-04-01

    We assess the distinguishability between supersymmetry and black hole events at the Large Hadron Collider. Black hole events are simulated with the CATFISH black hole generator. Supersymmetry simulations use a combination of PYTHIA and ISAJET. Our study, based on event shape variables, visible and missing momenta, and analysis of dilepton events, shows that supersymmetry and black hole events at the LHC can be easily discriminated.

  9. INTRA-BEAM SCATTERING SCALING FOR VERY LARGE HADRON COLLIDERS.

    SciTech Connect

    WEI,J.; PARZEN,G.

    2001-06-18

    For Very Large Hadron Colliders (VLHC), flat hadron beams [2] with their vertical emittance much smaller than their horizontal emittance are proposed to maximize the design luminosity. Emittance growth caused by intra-beam scattering (IBS) is a concern on the realization of such flat-beam conditions. Based on existing IBS formalism on beams of Gaussian distribution, we analytically derive [6] the IBS growth rate and determine the IBS limit on the aspect ratio for a flat beam.

  10. Signaling Pathway of GP88 (Progranulin) in Breast Cancer Cells: Upregulation and Phosphorylation of c-myc by GP88/Progranulin in Her2-Overexpressing Breast Cancer Cells

    PubMed Central

    Kim, Wes E.; Yue, Binbin; Serrero, Ginette

    2015-01-01

    Her2 is a receptor tyrosine kinase overexpressed in 25% of breast tumors. We have shown that the 88 kDa autocrine growth and survival factor GP88 (progranulin) stimulated Her2 phosphorylation and proliferation and conferred Herceptin resistance in Her2-overexpressing cells. Herein, we report that GP88 stimulates c-myc phosphorylation and upregulates c-myc levels in Her2-overexpressing cells. c-myc phosphorylation and upregulation by GP88 were not observed in non-Her2-overexpressing breast cancer cells. c-myc activation was inhibited upon treatment with ERK, PI3 kinase, and c-src pathway inhibitors, U0126, LY294002, and PP2. GP88 also stimulated c-src phosphorylation, a known upstream regulator of c-myc. Thus, we describe here a signaling pathway for GP88 in Her2-overexpressing cells, with GP88 stimulating Src phosphorylation, followed by phosphorylation and upregulation of c-myc. These data would suggest that targeting GP88 could provide a novel treatment approach in breast cancer. PMID:27168723

  11. Healthcare use among preschool children attending GP-led urgent care centres: a descriptive, observational study

    PubMed Central

    Gnani, S; Ramzan, F; Davison, M; Ladbrooke, T; Saxena, S

    2016-01-01

    Objective Urgent care centres’ (UCCs) hours were developed with the aim of reducing inappropriate emergency department (ED) attendances in England. We aimed to examine the presenting complaint and outcomes of care in 2 general practitioner (GP)-led UCCs with extended opening times. Design Retrospective observational epidemiological study using routinely collected data. Setting 2 GP-led UCCs in London, colocated with a hospital ED. Participants All children aged under 5 years, attending 2 GP-led UCCs over a 3-year period. Outcomes Outcomes of care for the children including: primary diagnosis; registration status with a GP; destination following review within the UCC; and any medication prescribed. Comparison between GP-led UCC visit rates and routine general practices was also made. Results 3% (n=7747/282 947) of all attenders at the GP-led UCCs were children aged under 5 years. The most common reason for attendance was a respiratory illness (27%), followed by infectious illness (17%). 18% (n=1428) were either upper respiratory tract infections or viral infections. The majority (91%) of children attending were registered with a GP, and over two-thirds of attendances were ‘out of hours’. Overall 79% were seen and discharged home. Preschool children were more likely to attend their GP (47.0 per 100) than a GP-led UCC (9.4 per 100; 95% CI 8.9 to 10.0). Conclusions Two-thirds of preschool children attending GP-led UCCs do so out of hours, despite the majority being registered with a GP. The case mix is comparable with those presenting to an ED setting, with the majority managed exclusively by the GPs in the UCC before discharge home. Further work is required to understand the benefits of a GP-led urgent system in influencing future use of services especially emergency care. PMID:27288373

  12. Exacerbated inflammatory arthritis in response to hyperactive gp130 signalling is independent of IL-17A

    PubMed Central

    Jones, G W; Greenhill, C J; Williams, J O; Nowell, M A; Williams, A S; Jenkins, B J; Jones, S A

    2013-01-01

    Objective Interleukin (IL)-17A producing CD4 T-cells (TH-17 cells) are implicated in rheumatoid arthritis (RA). IL-6/STAT3 signalling drives TH-17 cell differentiation, and hyperactive gp130/STAT3 signalling in the gp130F/F mouse promotes exacerbated pathology. Conversely, STAT1-activating cytokines (eg, IL-27, IFN-γ) inhibit TH-17 commitment. Here, we evaluate the impact of STAT1 ablation on TH-17 cells during experimental arthritis and relate this to IL-17A-associated pathology. Methods Antigen-induced arthritis (AIA) was established in wild type (WT), gp130F/F mice displaying hyperactive gp130-mediated STAT signalling and the compound mutants gp130F/F:Stat1−/− and gp130F/F:Il17a−/− mice. Joint pathology and associated peripheral TH-17 responses were compared. Results Augmented gp130/STAT3 signalling enhanced TH-17 commitment in vitro and exacerbated joint pathology. Ablation of STAT1 in gp130F/F mice (gp130F/F:Stat1−/−) promoted the hyperexpansion of TH-17 cells in vitro and in vivo during AIA. Despite this heightened peripheral TH-17 cell response, disease severity and the number of joint-infiltrating T-cells were comparable with that of WT mice. Thus, gp130-mediated STAT1 activity within the inflamed synovium controls T-cell trafficking and retention. To determine the contribution of IL-17A, we generated gp130F/F:IL-17a−/− mice. Here, loss of IL-17A had no impact on arthritis severity. Conclusions Exacerbated gp130/STAT-driven disease in AIA is associated with an increase in joint infiltrating T-cells but synovial pathology is IL-17A independent. PMID:23894061

  13. Protection of podocytes from hyperhomocysteinemia-induced injury by deletion of gp91phox gene

    PubMed Central

    Zhang, Chun; Hu, Jun-Jun; Xia, Min; Boini, Krishna M.; Brimson, Christopher A.; Laperle, Laura A.; Li, Pin-Lan

    2010-01-01

    In the present study, mice lacking gp91phox gene were used to address the role of NADPH oxidase in hyperhomocysteinemia-induced podocyte injury. It was found that the folate-free diet increased plasma homocysteine levels, but failed to increase O2.− production in the glomeruli from gp91phox gene knockout (gp91−/−) mice, compared with wild-type (gp91+/+) mice. Proteinuria and glomerular damage index (GDI) were significantly lower, while the glomerular filtration rate (GFR) was higher in gp91−/− than gp91+/+ mice when they were on the folate-free diet (Urine albumin excretion: 21.23±1.88 vs. 32.86±4.03 μg/24 h; GDI: 1.17±0.18 vs. 2.59 ±0.49; and GFR: 53.01±4.69 vs. 40.98±1.44 μL/min). Hyperhomocysteinemia-induced decrease in nephrin expression and increase in desmin expression in gp91+/+ mice were not observed in gp91−/− mice. Morphologically, foot process effacement and podocyte loss due to hyperhomocysteinemia were significantly attenuated in gp91−/− mice. In in vitro studies of podocytes, homocysteine was found to increase gp91phox expression and O2.− generation, which was substantially inhibited by gp91phox siRNA. Functionally, homocysteine-induced decrease in vascular endothelial growth factor-A (VEGF-A) production was abolished by gp91phox siRNA or diphenyleneiodonium, a NADPH oxidase inhibitor. These results suggest that the functional integrity of NADPH oxidase is essential for hyperhomocysteinemia-induced podocyte injury and glomerulosclerosis. PMID:20116427

  14. Linear accelerators for TeV colliders

    SciTech Connect

    Wilson, P.B.

    1985-05-01

    This paper summarizes four tutorial lectures on linear electron accelerators: Electron Linacs for TeV Colliders, Emittance and Damping Rings, Wake Fields: Basic Concepts, and Wake Field Effects in Linacs.

  15. Photon Collider Physics with Real Photon Beams

    SciTech Connect

    Gronberg, J; Asztalos, S

    2005-11-03

    Photon-photon interactions have been an important probe into fundamental particle physics. Until recently, the only way to produce photon-photon collisions was parasitically in the collision of charged particles. Recent advances in short-pulse laser technology have made it possible to consider producing high intensity, tightly focused beams of real photons through Compton scattering. A linear e{sup +}e{sup -} collider could thus be transformed into a photon-photon collider with the addition of high power lasers. In this paper they show that it is possible to make a competitive photon-photon collider experiment using the currently mothballed Stanford Linear Collider. This would produce photon-photon collisions in the GeV energy range which would allow the discovery and study of exotic heavy mesons with spin states of zero and two.

  16. The Status of the International Linear Collider

    NASA Astrophysics Data System (ADS)

    Harrison, Michael

    2016-03-01

    The International Linear Collider is under consideration in Japan as the next major global high energy physics facility. In this talk we shall describe the site and accelerator footprint together with the latest technical information on the superconducting RF technology.

  17. A study into the effectiveness of unqualified GP assistants.

    PubMed

    Philip, Marilyn; Turnbull, Betty

    This article aims to address the potential shortfall in care provision offered by general practitioners (GPs) resulting from pending retirement and the retention and recruitment crisis. An educational module was developed that offered both theory and practise to unqualified general practice assistants. The module content was determined following discussion with local GPs. A small qualitative study of six students was carried out to review efficacy of participants in their new role. Using a grounded theory approach, participant and supervisor views of course content and delivery, role preparation diversity were analysed and compared. Tape-recorded interviews were conducted and analysis carried out employing the constant comparative method. Data were coded and emergent themes categorized. Overall, participants agreed that the module had strengthened their knowledge, added new skills, heightened their job satisfaction, added significant diversity to their role and enhanced their employability potential. Five participants communicated that they were more confident in performing clinical skills and advising health improvement techniques. Supervisors also reported that participants displayed a more competent and professional approach to health care, which was complementary to the role of the GP and practice nurse. Ultimately this allowed both GP and practice nurse to focus on dealing with chronic illness targets, as required in the new directive (Scottish Executive, 2004). PMID:16936620

  18. Intracellular mannose binding lectin mediates subcellular trafficking of HIV-1 gp120 in neurons.

    PubMed

    Teodorof, C; Divakar, S; Soontornniyomkij, B; Achim, C L; Kaul, M; Singh, K K

    2014-09-01

    Human immunodeficiency virus-1 (HIV-1) enters the brain early during infection and leads to severe neuronal damage and central nervous system impairment. HIV-1 envelope glycoprotein 120 (gp120), a neurotoxin, undergoes intracellular trafficking and transport across neurons; however mechanisms of gp120 trafficking in neurons are unclear. Our results show that mannose binding lectin (MBL) that binds to the N-linked mannose residues on gp120, participates in intravesicular packaging of gp120 in neuronal subcellular organelles and also in subcellular trafficking of these vesicles in neuronal cells. Perinuclear MBL:gp120 vesicular complexes were observed and MBL facilitated the subcellular trafficking of gp120 via the endoplasmic reticulum (ER) and Golgi vesicles. The functional carbohydrate recognition domain of MBL was required for perinuclear organization, distribution and subcellular trafficking of MBL:gp120 vesicular complexes. Nocodazole, an agent that depolymerizes the microtubule network, abolished the trafficking of MBL:gp120 vesicles, suggesting that these vesicular complexes were transported along the microtubule network. Live cell imaging confirmed the association of the MBL:gp120 complexes with dynamic subcellular vesicles that underwent trafficking in neuronal soma and along the neurites. Thus, our findings suggest that intracellular MBL mediates subcellular trafficking and transport of viral glycoproteins in a microtubule-dependent mechanism in the neurons. PMID:24825317

  19. Intracellular Mannose Binding Lectin Mediates Subcellular Trafficking of HIV-1 gp120 in Neurons

    PubMed Central

    Teodorof, C; Divakar, S; Soontornniyomkij, B; Achim, CL; Kaul, M; Singh, KK

    2014-01-01

    Human immunodeficiency virus -1 (HIV-1) enters the brain early during infection and leads to severe neuronal damage and central nervous system impairment. HIV-1 envelope glycoprotein 120 (gp120), a neurotoxin, undergoes intracellular trafficking and transport across neurons; however mechanisms of gp120 trafficking in neurons are unclear. Our results show that mannose binding lectin (MBL) that binds to the N-linked mannose residues on gp120, participates in intravesicular packaging of gp120 in neuronal subcellular organelles and also in subcellular trafficking of these vesicles in neuronal cells. Perinuclear MBL:gp120 vesicular complexes were observed and MBL facilitated the subcellular trafficking of gp120 via the endoplasmic reticulum (ER) and Golgi vesicles. The functional carbohydrate recognition domain of MBL was required for perinuclear organization, distribution and subcellular trafficking of MBL:gp120 vesicular complexes. Nocodazole, an agent that depolymerizes the microtubule network, abolished the trafficking of MBL:gp120 vesicles, suggesting that these vesicular complexes were transported along the microtubule network. Live cell imaging confirmed the association of the MBL:gp120 complexes with dynamic subcellular vesicles that underwent trafficking in neuronal soma and along the neurites. Thus, our findings suggest that intracellular MBL mediates subcellular trafficking and transport of viral glycoproteins in a microtubule-dependent mechanism in the neurons. PMID:24825317

  20. Reduction of cerebral glucose utilization by the HIV envelope glycoprotein Gp-120

    SciTech Connect

    Kimes, A.S.; London, E.D.; Szabo, G.; Raymon, L.; Tabakoff, B. )

    1991-05-01

    Gp-120 is a glycoprotein constituent of the human immunodeficiency virus (HIV) envelope. The effects of gp-120 on cerebral glucose utilization in rats were studied by the quantitative 2-deoxy-D-(1-14C) glucose method. Intracerebroventricular injection of gp-120 significantly reduced glucose utilization in the lateral habenula and the suprachiasmatic nucleus and decreased the global cerebral metabolic rate for glucose. The findings suggest that gp-120 and closely related peptides can alter neuronal function, thereby contributing to the sequelae of HIV infection.

  1. A Betabaculovirus-Encoded gp64 Homolog Codes for a Functional Envelope Fusion Protein

    PubMed Central

    Ardisson-Araújo, Daniel M. P.; Melo, Fernando L.; Clem, Rollie J.; Wolff, José L. C.

    2015-01-01

    The GP64 envelope fusion protein is a hallmark of group I alphabaculoviruses. However, the Diatraea saccharalis granulovirus genome sequence revealed the first betabaculovirus species harboring a gp64 homolog (disa118). In this work, we have shown that this homolog encodes a functional envelope fusion protein and could enable the infection and fusogenic abilities of a gp64-null prototype baculovirus. Therefore, GP64 may complement or may be in the process of replacing F protein activity in this virus lineage. PMID:26537678

  2. A Betabaculovirus-Encoded gp64 Homolog Codes for a Functional Envelope Fusion Protein.

    PubMed

    Ardisson-Araújo, Daniel M P; Melo, Fernando L; Clem, Rollie J; Wolff, José L C; Ribeiro, Bergmann M

    2016-02-01

    The GP64 envelope fusion protein is a hallmark of group I alphabaculoviruses. However, the Diatraea saccharalis granulovirus genome sequence revealed the first betabaculovirus species harboring a gp64 homolog (disa118). In this work, we have shown that this homolog encodes a functional envelope fusion protein and could enable the infection and fusogenic abilities of a gp64-null prototype baculovirus. Therefore, GP64 may complement or may be in the process of replacing F protein activity in this virus lineage. PMID:26537678

  3. Heavy flavor physics at hadron colliders

    SciTech Connect

    Barbaro-Galtieri, A.

    1991-12-01

    The search for the top quark has dominated heavy flavor physics at hadron colliders. For Standard model decay of top the present mass limit in m{sub t} > 89 GeV (95% C.L.). Bottom production cross sections are quite large at hadron colliders, thus providing enough statistics for extensive studies. Results on cross sections, B{sup 0} {minus} {bar B}{sup 0} mixing, exclusive channels and rare B decays will be summarized.

  4. RF pulse compression for future linear colliders

    SciTech Connect

    Wilson, P.B.

    1995-05-01

    Future (nonsuperconducting) linear colliders will require very high values of peak rf power per meter of accelerating structure. The role of rf pulse compression in producing this power is examined within the context of overall rf system design for three future colliders at energies of 1.0--1.5 TeV, 5 TeV and 25 TeV. In order keep the average AC input power and the length of the accelerator within reasonable limits, a collider in the 1.0--1.5 TeV energy range will probably be built at an x-band rf frequency, and will require a peak power on the order of 150--200 MW per meter of accelerating structure. A 5 TeV collider at 34 GHz with a reasonable length (35 km) and AC input power (225 MW) would require about 550 MW per meter of structure. Two-beam accelerators can achieve peak powers of this order by applying dc pulse compression techniques (induction linac modules) to produce the drive beam. Klystron-driven colliders achieve high peak power by a combination of dc pulse compression (modulators) and rf pulse compression, with about the same overall rf system efficiency (30--40%) as a two-beam collider. A high gain (6.8) three-stage binary pulse compression system with high efficiency (80%) is described, which (compared to a SLED-11 system) can be used to reduce the klystron peak power by about a factor of two, or alternately, to cut the number of klystrons in half for a 1.0--1.5 TeV x-band collider. For a 5 TeV klystron-driven collider, a high gain, high efficiency rf pulse compression system is essential.

  5. Accelerator considerations of large circular colliders

    NASA Astrophysics Data System (ADS)

    Chao, Alex

    2016-07-01

    As we consider the tremendous physics reaches of the big future circular electron-positron and proton-proton colliders, it might be advisable to keep a close track of what accelerator challenges they face. Good progresses are being made, and yet it is reported here that substantial investments in funding, manpower, as well as a long sustained time to the R&D efforts will be required in preparation to realize these dream colliders.

  6. Photon Linear Collider Gamma-Gamma Summary

    SciTech Connect

    Gronberg, J

    2012-02-27

    High energy photon - photon collisions can be achieved by adding high average power short-pulse lasers to the Linear Collider, enabling an expanded physics program for the facility. The technology required to realize a photon linear collider continues to mature. Compton back-scattering technology is being developed around the world for low energy light source applications and high average power lasers are being developed for Inertial Confinement Fusion.

  7. World lays groundwork for future linear collider

    SciTech Connect

    Feder, Toni

    2010-07-15

    With the Large Hadron Collider at CERN finally working, the particle-physics community can now afford to divide its attention between achieving LHC results and preparing for the next machine on its wish list, an electron-positron linear collider. The preparations involve developing and deciding on the technology for such a machine, the mode of its governance, and how to balance regional and global particle- and accelerator-physics programs.

  8. Physics goals of the next linear collider

    SciTech Connect

    Kuhlman, S.; Marciano, W.J.; Gunion, J. F.; NLC ZDR Design Group; NLC Physics Working Group

    1996-05-01

    We present the prospects for the next generation of high-energy physics experiments with electron-positron colliding beams. This report summarizes the current status of the design and technological basis of a linear collider of center of mass energy 500 GeV-1.5 TeV, and the opportunities for high-energy physics experiments that this machine is expected to open. 132 refs., 54 figs., 14 tabs.

  9. Colliding beam fusion reactor space propulsion system

    NASA Astrophysics Data System (ADS)

    Wessel, Frank J.; Binderbauer, Michl W.; Rostoker, Norman; Rahman, Hafiz Ur; O'Toole, Joseph

    2000-01-01

    We describe a space propulsion system based on the Colliding Beam Fusion Reactor (CBFR). The CBFR is a high-beta, field-reversed, magnetic configuration with ion energies in the range of hundreds of keV. Repetitively-pulsed ion beams sustain the plasma distribution and provide current drive. The confinement physics is based on the Vlasov-Maxwell equation, including a Fokker Planck collision operator and all sources and sinks for energy and particle flow. The mean azimuthal velocities and temperatures of the fuel ion species are equal and the plasma current is unneutralized by the electrons. The resulting distribution functions are thermal in a moving frame of reference. The ion gyro-orbit radius is comparable to the dimensions of the confinement system, hence classical transport of the particles and energy is expected and the device is scaleable. We have analyzed the design over a range of 106-109 Watts of output power (0.15-150 Newtons thrust) with a specific impulse of, Isp~106 sec. A 50 MW propulsion system might involve the following parameters: 4-meters diameter×10-meters length, magnetic field ~7 Tesla, ion beam current ~10 A, and fuels of either D-He3,P-B11,P-Li6,D-Li6, etc. .

  10. New Methods of Particle Collimation in Colliders

    SciTech Connect

    Stancari, Giulio; /Fermilab

    2011-10-01

    The collimation system is an essential part of the design of any high-power accelerator. Its functions include protection of components from accidental and intentional energy deposition, reduction of backgrounds, and beam diagnostics. Conventional multi-stage systems based on scatterers and absorbers offer robust shielding and efficient collection of losses. Two complementary concepts have been proposed to address some of the limitations of conventional systems: channeling and volume reflection in bent crystals and collimation with hollow electron beams. The main focus of this paper is the hollow electron beam collimator, a novel concept based on the interaction of the circulating beam with a 5-keV, magnetically confined, pulsed hollow electron beam in a 2-m-long section of the ring. The electrons enclose the circulating beam, kicking halo particles transversely and leaving the beam core unperturbed. By acting as a tunable diffusion enhancer and not as a hard aperture limitation, the hollow electron beam collimator extends conventional collimation systems beyond the intensity limits imposed by tolerable losses. The concept was tested experimentally at the Fermilab Tevatron proton-antiproton collider. Results on the collimation of 980-GeV antiprotons are presented, together with prospects for the future.

  11. Quantum Suppression of beamstrahlung for future e+e- linear collider: an evaluation of QED backgrounds

    SciTech Connect

    Xie, Ming

    1998-10-13

    Beamstrahlung at interaction point may present severe limitations on linear collider performance. The approach to reduce this effect adopted for all current designs at 0.5 TeV range in center-of-mass energy will become more difficult and less effective at higher energy. We discuss the feasibility of an alternative approach, based on an effect known as quantum suppression of beamstrahlung, for future linear colliders at multi-TeV energy.

  12. Method study of parameter choice for a circular proton-proton collider

    NASA Astrophysics Data System (ADS)

    Su, Feng; Gao, Jie; Xiao, Ming; Wang, Dou; Wang, Yi-Wei; Bai, Sha; Bian, Tian-Jian

    2016-01-01

    In this paper we show a systematic method of appropriate parameter choice for a circular proton-proton collider by using an analytical expression for the beam-beam tune shift limit, starting from a given design goal and technical limitations. A suitable parameter space has been explored. Based on the parameter scan, sets of appropriate parameters designed for a 50 km and 100 km circular proton-proton collider are proposed. Supported by National Natural Science Foundation of China (11175192)

  13. A Laser-Driven Linear Collider: Sample Machine Parameters and Configuration

    SciTech Connect

    Colby, E.R.; England, R.J.; Noble, R.J.; /SLAC

    2011-05-20

    We present a design concept for an e{sup +}e{sup -} linear collider based on laser-driven dielectric accelerator structures, and discuss technical issues that must be addressed to realize such a concept. With a pulse structure that is quasi-CW, dielectric laser accelerators potentially offer reduced beamstrahlung and pair production, reduced event pileup, and much cleaner environment for high energy physics and. For multi-TeV colliders, these advantages become significant.

  14. Vibration Stabilization of a Mechanical Model of a X-Band Linear Collider Final Focus Magnet

    SciTech Connect

    Frisch, Josef; Chang, Allison; Decker, Valentin; Doyle, Eric; Eriksson, Leif; Hendrickson, Linda; Himel, Thomas; Markiewicz, Thomas; Partridge, Richard; Seryi, Andrei; /SLAC

    2006-09-28

    The small beam sizes at the interaction point of a X-band linear collider require mechanical stabilization of the final focus magnets at the nanometer level. While passive systems provide adequate performance at many potential sites, active mechanical stabilization is useful if the natural or cultural ground vibration is higher than expected. A mechanical model of a room temperature linear collider final focus magnet has been constructed and actively stabilized with an accelerometer based system.

  15. Cost optimization of induction linac drivers for linear colliders

    SciTech Connect

    Barletta, W.A.

    1986-12-29

    Recent developments in high reliability components for linear induction accelerators (LIA) make possible the use of these devices as economical power drives for very high gradient linear colliders. A particularly attractive realization of this ''two-beam accelerator'' approach is to configure the LIA as a monolithic relativistic klystron operating at 10 to 12 GHz with induction cells providing periodic reacceleration of the high current beam. Based upon a recent engineering design of a state-of-the-art, 10- to 20-MeV LIA at Lawrence Livermore National Laboratory, this paper presents an algorithm for scaling the cost of the relativistic klystron to the parameter regime of interest for the next generation high energy physics machines. The algorithm allows optimization of the collider luminosity with respect to cost by varying the characteristics (pulse length, drive current, repetition rate, etc.) of the klystron. It also allows us to explore cost sensitivities as a guide to research strategies for developing advanced accelerator technologies.

  16. Generation of ultrashort electron bunches by colliding laser pulses

    SciTech Connect

    Schroeder, C. B.; Lee, P. B.; Wurtele, J. S.; Esarey, E.; Leemans, W. P.

    1999-07-12

    A proposed laser-plasma based relativistic electron source [E. Esarey et al., Phys. Rev. Lett. 79, 2682 (1997)] using laser triggered injection of electrons is investigated. The source generates ultrashort electron bunches by dephasing and trapping background plasma electrons undergoing fluid oscillations in an excited plasma wake. The plasma electrons are dephased by colliding two counter-propagating laser pulses which generate a slow phase velocity beat wave. Laser pulse intensity thresholds for trapping and the optimal wake phase for injection are calculated. Numerical simulations of test particles, with prescribed plasma and laser fields, are used to verify analytic predictions and to study the longitudinal and transverse dynamics of the trapped plasma electrons. Simulations indicate that the colliding laser pulse injection scheme has the capability to produce relativistic femtosecond electron bunches with fractional energy spread of order a few percent and normalized transverse emittance less than 1 mm mrad using 1 TW injection laser pulses.

  17. Generation of ultrashort electron bunches by colliding laser pulses.

    PubMed

    Schroeder, C B; Lee, P B; Wurtele, J S; Esarey, E; Leemans, W P

    1999-05-01

    A proposed laser-plasma-based relativistic electron source [E. Esarey et al., Phys. Rev. Lett. 79, 2682 (1997)] using laser-triggered injection of electrons is investigated. The source generates ultrashort electron bunches by dephasing and trapping background plasma electrons undergoing fluid oscillations in an excited plasma wake. The plasma electrons are dephased by colliding two counterpropagating laser pulses which generate a slow phase velocity beat wave. Laser pulse intensity thresholds for trapping and the optimal wake phase for injection are calculated. Numerical simulations of test particles, with prescribed plasma and laser fields, are used to verify analytic predictions and to study the longitudinal and transverse dynamics of the trapped plasma electrons. Simulations indicate that the colliding laser pulse injection scheme has the capability to produce relativistic femtosecond electron bunches with fractional energy spread of order a few percent and normalized transverse emittance less than 1 mm mrad using 1 TW injection laser pulses. PMID:11969588

  18. Non-collider searches for stable massive particles

    NASA Astrophysics Data System (ADS)

    Burdin, S.; Fairbairn, M.; Mermod, P.; Milstead, D.; Pinfold, J.; Sloan, T.; Taylor, W.

    2015-06-01

    The theoretical motivation for exotic stable massive particles (SMPs) and the results of SMP searches at non-collider facilities are reviewed. SMPs are defined such that they would be sufficiently long-lived so as to still exist in the cosmos either as Big Bang relics or secondary collision products, and sufficiently massive such that they are typically beyond the reach of any conceivable accelerator-based experiment. The discovery of SMPs would address a number of important questions in modern physics, such as the origin and composition of dark matter and the unification of the fundamental forces. This review outlines the scenarios predicting SMPs and the techniques used at non-collider experiments to look for SMPs in cosmic rays and bound in matter. The limits so far obtained on the fluxes and matter densities of SMPs which possess various detection-relevant properties such as electric and magnetic charge are given.

  19. Qualitative study of depression management in primary care: GP and patient goals, and the value of listening

    PubMed Central

    Johnston, Olwyn; Kumar, Satinder; Kendall, Kathleen; Peveler, Robert; Gabbay, John; Kendrick, Tony

    2007-01-01

    Background Guidelines for depression management have been developed but little is known about GP and patient goals, which are likely to influence treatment offers, uptake, and adherence. Aim To identify issues of importance to GPs, patients, and patients' supporters regarding depression management. GP and patient goals for depression management became a focus of the study. Design of study Grounded theory-based qualitative study. Setting GPs were drawn from 28 practices. The majority of patients and supporters were recruited from 10 of these practices. Method Sixty-one patients (28 depressed, 18 previously depressed, 15 never depressed), 18 supporters, and 32 GPs were interviewed. Results GPs described encouraging patients to view depression as separate from the self and ‘normal’ sadness. Patients and supporters often questioned such boundaries, rejecting the notion of a medical cure and emphasising self-management. The majority of participants who were considering depression-management strategies wanted to ‘get out’ of their depression. However, a quarter did not see this as immediately relevant or achievable. They focused on getting by from day to day, which had the potential to clash with GP priorities. GP frustration and uncertainty could occur when depression was resistant to cure. Participants identified the importance of GPs listening to patients, but often felt that this did not happen. Conclusion Physicians need greater awareness of the extent to which their goals for the management of depression are perceived as relevant or achievable by patients. Future research should explore methods of negotiating agreed strategies for management. PMID:17976282

  20. HIV-1 gp41 Core with Exposed Membrane-Proximal External Region Inducing Broad HIV-1 Neutralizing Antibodies

    PubMed Central

    Zhou, Leilei; Xu, Liling; Jiang, Shibo; Chen, Ying-hua

    2011-01-01

    The membrane-proximal external region (MPER) of the HIV-1 gp41 consists of epitopes for the broadly cross-neutralizing monoclonal antibodies 2F5 and 4E10. However, antigens containing the linear sequence of these epitopes are unable to elicit potent and broad neutralizing antibody responses in vaccinated hosts, possibly because of inappropriate conformation of these epitopes. Here we designed a recombinant antigen, designated NCM, which comprises the N- and C-terminal heptad repeats that can form a six-helix bundle (6HB) core and the MPER domain of gp41. Two mutations (T569A and I675V) previously reported to expose the neutralization epitopes were introduced into NCM to generate mutants named NCM(TA), NCM(IV), and NCM(TAIV). Our results showed that NCM and its mutants could react with antibodies specific for 6HB and MPER of gp41, suggesting that these antigens are in the form of a trimer of heterodimer (i.e., 6HB) with three exposed MPER tails. Antigen with double mutations, NCM(TAIV), elicited much stronger antibody response in rabbits than immunogens with single mutation, NCM(TA) and NCM(IV), or no mutation, NCM. The purified MPER-specific antibodies induced by NCM(TAIV) exhibited broad neutralizing activity, while the purified 6HB-specific antibodies showed no detectable neutralizing activity. Our recombinant antigen design supported by an investigation of its underlying molecular mechanisms provides a strong scientific platform for the discovery of a gp41 MPER-based AIDS vaccine. PMID:21483871

  1. Characterization of a phenazine-producing strain Pseudomonas chlororaphis GP72 with broad-spectrum antifungal activity from green pepper rhizosphere

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A new Pseudomonas strain, designated GP72, was isolated from green pepper rhizosphere and identified as a member of species Pseudomonas chlororaphis based on morphology; conventional biochemical and physiologic tests; Biolog GN system (Biolog Inc., Hayward, CA); and 16S rDNA sequence analysis. The s...

  2. Registration of Peanut Germplasm Line TifGP-1 with Resistance to the Root-knot Nematode and Tomato Spotted Wilt Virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    TifGP-1 (Reg. No. , PI ) is a runner-type peanut (Arachis hypogaea L. subsp. hypogaea var. hypogaea) germplasm line that was released by the USDA-ARS and the Georgia Agricultural Experiment Stations in 2006. This material was released based on resistance to both tomato spotted wilt (caused b...

  3. Characterization of two novel porcine reproductive and respiratory syndrome virus isolates with deletions in the GP2 gene.

    PubMed

    Chen, Jia-zeng; Peng, Jin-mei; Bai, Yun; Wang, Qian; Liu, Yi-min; Zhang, Qiu-yue; Chang, Dan; Zhang, Wu-chao; Zhao, Hong-yuan; Ye, Chao; An, Tong-qing; Cai, Xue-hui; Tian, Zhi-jun; Tong, Guang-zhi

    2015-04-17

    Two newly emerged, porcine reproductive and respiratory syndrome virus (PRRSV) strains (Henan-A10 and A11) were isolated from the sera of aborting sows. Interestingly, both of the isolates could replicate in primary porcine alveolar macrophage (PAM) cells but not in MARC-145 cells. A phylogenetic tree based on the complete genome was constructed and the results showed that Henan-A10 and A11 were most closely related to other highly pathogenic PRRSV (HP-PRRSV) strains. However, genomic sequence analysis showed that Henan-A10 and A11 shared only 96.8-97.8% nucleotide identity with the representative HP-PRRSV strain JXA1. Notably, a 10 amino acids deletion in the GP2 endodomain was identified for the first time. A full-length, infectious cDNA clone of HuN4-F112 (attenuated strain from a HP-PRRSV) was used to construct a chimeric clone with the corresponding deletion in GP2. We found that the deletion did not affect viral growth in MARC-145 cells, indicating that the endodomain of PRRSV GP2 may be variable. PMID:25669596

  4. Comparison of Predicted Scaffold-Compatible Sequence Variation in the Triple-Hairpin Structure of Human Immunodeficiency Virus Type 1 gp41 with Patient Data

    PubMed Central

    Boutonnet, Nathalie; Janssens, Wouter; Boutton, Carlo; Verschelde, Jean-Luc; Heyndrickx, Leo; Beirnaert, Els; van der Groen, Guido; Lasters, Ignace

    2002-01-01

    It has been proposed that the ectodomain of human immunodeficiency virus type 1 (HIV-1) gp41 (e-gp41), involved in HIV entry into the target cell, exists in at least two conformations, a pre-hairpin intermediate and a fusion-active hairpin structure. To obtain more information on the structure-sequence relationship in e-gp41, we performed in silico a full single-amino-acid substitution analysis, resulting in a Fold Compatible Database (FCD) for each conformation. The FCD contains for each residue position in a given protein a list of values assessing the energetic compatibility (ECO) of each of the 20 natural amino acids at that position. Our results suggest that FCD predictions are in good agreement with the sequence variation observed for well-validated e-gp41 sequences. The data show that at a minECO threshold value of 5 kcal/mol, about 90% of the observed patient sequence variation is encompassed by the FCD predictions. Some inconsistent FCD predictions at N-helix positions packing against residues of the C helix suggest that packing of both peptides may involve some flexibility and may be attributed to an altered orientation of the C-helical domain versus the N-helical region. The permissiveness of sequence variation in the C helices is in agreement with FCD predictions. Comparison of N-core and triple-hairpin FCDs suggests that the N helices may impose more constraints on sequence variation than the C helices. Although the observed sequences of e-gp41 contain many multiple mutations, our method, which is based on single-point mutations, can predict the natural sequence variability of e-gp41 very well. PMID:12097573

  5. A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies

    PubMed Central

    Sanders, Rogier W.; Derking, Ronald; Cupo, Albert; Julien, Jean-Philippe; Yasmeen, Anila; de Val, Natalia; Kim, Helen J.; Blattner, Claudia; de la Peña, Alba Torrents; Korzun, Jacob; Golabek, Michael; de los Reyes, Kevin; Ketas, Thomas J.; van Gils, Marit J.; King, C. Richter; Wilson, Ian A.; Ward, Andrew B.; Klasse, P. J.; Moore, John P.

    2013-01-01

    A desirable but as yet unachieved property of a human immunodeficiency virus type 1 (HIV-1) vaccine candidate is the ability to induce broadly neutralizing antibodies (bNAbs). One approach to the problem is to create trimeric mimics of the native envelope glycoprotein (Env) spike that expose as many bNAb epitopes as possible, while occluding those for non-neutralizing antibodies (non-NAbs). Here, we describe the design and properties of soluble, cleaved SOSIP.664 gp140 trimers based on the subtype A transmitted/founder strain, BG505. These trimers are highly stable, more so even than the corresponding gp120 monomer, as judged by differential scanning calorimetry. They are also homogenous and closely resemble native virus spikes when visualized by negative stain electron microscopy (EM). We used several techniques, including ELISA and surface plasmon resonance (SPR), to determine the relationship between the ability of monoclonal antibodies (MAbs) to bind the soluble trimers and neutralize the corresponding virus. In general, the concordance was excellent, in that virtually all bNAbs against multiple neutralizing epitopes on HIV-1 Env were highly reactive with the BG505 SOSIP.664 gp140 trimers, including quaternary epitopes (CH01, PG9, PG16 and PGT145). Conversely, non-NAbs to the CD4-binding site, CD4-induced epitopes or gp41ECTO did not react with the trimers, even when their epitopes were present on simpler forms of Env (e.g. gp120 monomers or dissociated gp41 subunits). Three non-neutralizing MAbs to V3 epitopes did, however, react strongly with the trimers but only by ELISA, and not at all by SPR and to only a limited extent by EM. These new soluble trimers are useful for structural studies and are being assessed for their performance as immunogens. PMID:24068931

  6. Governance of the International Linear Collider Project

    SciTech Connect

    Foster, B.; Barish, B.; Delahaye, J.P.; Dosselli, U.; Elsen, E.; Harrison, M.; Mnich, J.; Paterson, J.M.; Richard, F.; Stapnes, S.; Suzuki, A.; Wormser, G.; Yamada, S.; /KEK, Tsukuba

    2012-05-31

    Governance models for the International Linear Collider Project are examined in the light of experience from similar international projects around the world. Recommendations for one path which could be followed to realize the ILC successfully are outlined. The International Linear Collider (ILC) is a unique endeavour in particle physics; fully international from the outset, it has no 'host laboratory' to provide infrastructure and support. The realization of this project therefore presents unique challenges, in scientific, technical and political arenas. This document outlines the main questions that need to be answered if the ILC is to become a reality. It describes the methodology used to harness the wisdom displayed and lessons learned from current and previous large international projects. From this basis, it suggests both general principles and outlines a specific model to realize the ILC. It recognizes that there is no unique model for such a laboratory and that there are often several solutions to a particular problem. Nevertheless it proposes concrete solutions that the authors believe are currently the best choices in order to stimulate discussion and catalyze proposals as to how to bring the ILC project to fruition. The ILC Laboratory would be set up by international treaty and be governed by a strong Council to whom a Director General and an associated Directorate would report. Council would empower the Director General to give strong management to the project. It would take its decisions in a timely manner, giving appropriate weight to the financial contributions of the member states. The ILC Laboratory would be set up for a fixed term, capable of extension by agreement of all the partners. The construction of the machine would be based on a Work Breakdown Structure and value engineering and would have a common cash fund sufficiently large to allow the management flexibility to optimize the project's construction. Appropriate contingency, clearly

  7. Dissection of Genetic Mechanisms Governing the Expression of Serum Retroviral gp70 Implicated in Murine Lupus Nephritis1

    PubMed Central

    Baudino, Lucie; Yoshinobu, Kumiko; Morito, Naoki; Kikuchi, Shuichi; Fossati-Jimack, Liliane; Morley, Bernard J.; Vyse, Timothy J.; Hirose, Sachiko; Jørgensen, Trine N.; Tucker, Rebecca M.; Roark, Christina L.; Kotzin, Brian L.; Evans, Leonard H.; Izui, Shozo

    2008-01-01

    The endogenous retroviral envelope glycoprotein, gp70, implicated in murine lupus nephritis is secreted by hepatocytes as an acute phase protein, and has been believed to be a product of an endogenous xenotropic virus, NZB-X1. However, since endogenous polytropic (PT) and modified polytropic (mPT) viruses encode gp70s that are closely related to xenotropic gp70, these viruses can be additional sources of serum gp70. To better understand the genetic basis of the expression of serum gp70, we analyzed the abundance of xenotropic, PT or mPT gp70 RNAs in livers and the genomic composition of corresponding proviruses in various strains of mice, including two different Sgp (serum gp70 production) congenic mice. Our results demonstrated that the expression of different viral gp70 RNAs was remarkable heterogeneous among various mouse strains and that the level of serum gp70 production was regulated by multiple structural and regulatory genes. In addition, a significant contribution of PT and mPT gp70s to serum gp70 was revealed by the detection of PT and mPT, but not xenotropic transcripts in 129 mice and by a closer correlation of serum levels of gp70 with the abundance of PT and mPT gp70 RNAs than with that of xenotropic gp70 RNA in Sgp3 congenic mice. Furthermore, the injection of lipopolysaccharides selectively up-regulated the expression of xenotropic and mPT gp70 RNAs, but not PT gp70 RNA. Our data indicate that the genetic origin of serum gp70 is more heterogeneous than previously believed, and that distinct retroviral gp70s are differentially regulated in physiological vs. inflammatory conditions. PMID:18684976

  8. Vertex detectors and the linear collider

    NASA Astrophysics Data System (ADS)

    Damerell, C. J. S.

    2006-11-01

    We review the physics requirements for the ILC vertex detectors, which lead to the specification of silicon pixel sensors arranged as nested barrels, possibly augmented by endcap detectors for enhanced coverage of small polar angles. We describe how the detector requirements are a natural outgrowth of 25 years development of CCD-based vertex detectors in fixed-target and colliding beam experiments, culminating in the 307 Mpixel SLD vertex detector. We discuss how the technology has recently branched out into about a dozen architectures which might be made to work at the ILC, where the main challenge is to increase the effective readout rate by about a factor 1000 compared to conventional CCDs, while preserving the small pixels (˜20 μm) and low-power dissipation. Preserving gaseous cooling as at SLD opens the door to layer thicknesses as low as 0.1% X0. Finally, we consider how best to manage electromagnetic interference associated with the beam wakefields and other RF sources during the bunch train. In conclusion, we suggest a strategy for moving on from the present rich R&D programmes to optimal detectors for the startup of the ILC physics programme.

  9. Multimerized HIV-gp41-derived peptides as fusion inhibitors and vaccines.

    PubMed

    Nomura, Wataru; Mizuguchi, Takaaki; Tamamura, Hirokazu

    2016-11-01

    To date, several antigens based on the amino-terminal leucine/isoleucine heptad repeat (NHR) region of an HIV-1 envelope protein gp41 and fusion inhibitors based on the carboxy-terminal leucine/isoleucine heptad repeat (CHR) region of gp41 have been reported. We have developed a synthetic antigen targeting the membrane-fusion mechanism of HIV-1. This uses a template designed with C3-symmetric linkers and mimics the trimeric form of the NHR-derived peptide N36. The antiserum obtained by immunization of the N36 trimeric antigen binds preferentially to the N36 trimer and blocks HIV-1 infection effectively, compared with the antiserum obtained by immunization of the N36 monomer. Using another template designed with different C3-symmetric linkers, we have also developed a synthetic peptide mimicking the trimeric form of the CHR-derived peptide C34, with ∼100 times the inhibitory activity against the HIV-1 fusion mechanism than that of the monomer C34 peptide. A dimeric derivative of C34 has potent inhibitory activity at almost the same levels as this C34 trimer mimic, suggesting that presence of a dimeric form of C34 is structurally critical for fusion inhibitors. As examples of rising mid-size drugs, this review describes an effective strategy for the design of HIV vaccines and fusion inhibitors based on a relationship with the native structure of proteins involved in HIV fusion mechanisms. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 622-628, 2016. PMID:26583370

  10. Status of the Future Circular Collider Study

    NASA Astrophysics Data System (ADS)

    Benedikt, Michael

    2016-03-01

    Following the 2013 update of the European Strategy for Particle Physics, the international Future Circular Collider (FCC) Study has been launched by CERN as host institute, to design an energy frontier hadron collider (FCC-hh) in a new 80-100 km tunnel with a centre-of-mass energy of about 100 TeV, an order of magnitude beyond the LHC's, as a long-term goal. The FCC study also includes the design of a 90-350 GeV high-luminosity lepton collider (FCC-ee) installed in the same tunnel, serving as Higgs, top and Z factory, as a potential intermediate step, as well as an electron-proton collider option (FCC-he). The physics cases for such machines will be assessed and concepts for experiments will be developed in time for the next update of the European Strategy for Particle Physics by the end of 2018. The presentation will summarize the status of machine designs and parameters and discuss the essential technical components to be developed in the frame of the FCC study. Key elements are superconducting accelerator-dipole magnets with a field of 16 T for the hadron collider and high-power, high-efficiency RF systems for the lepton collider. In addition the unprecedented beam power presents special challenges for the hadron collider for all aspects of beam handling and machine protection. First conclusions of geological investigations and implementation studies will be presented. The status of the FCC collaboration and the further planning for the study will be outlined.

  11. A High Field Magnet Design for A Future Hadron Collider

    SciTech Connect

    Gupta, R.; Chow, K.; Dietderich, D.; Gourlay, S.; Millos, G.; McInturff, A.; Scanlan, R.

    1998-09-01

    US high energy physics community is exploring the possibilities of building a Very Large Hadron Collider (VLHC) after the completion of LHC. This paper presents a high field magnet design option based on Nb{sub 3}Sn technology. A preliminary magnetic and mechanical design of a 14-16 T, 2-in-1 dipole based on the 'common coil design' approach is presented. The computer code ROXIE has been upgraded to perform the field quality optimization of magnets based on the racetrack coil geometry. A magnet R&D program to investigate the issues related to high field magnet designs is also outlined.

  12. PROSPECTS FOR COLLIDERS AND COLLIDER PHYSICS TO THE 1 PEV ENERGY SCALE

    SciTech Connect

    KING,B.J.

    2000-05-05

    A review is given of the prospects for future colliders and collider physics at the energy frontier. A proof-of-plausibility scenario is presented for maximizing the authors progress in elementary particle physics by extending the energy reach of hadron and lepton colliders as quickly and economically as might be technically and financially feasible. The scenario comprises 5 colliders beyond the LHC--one each of e{sup +}e{sup {minus}} and hadron colliders and three {mu}{sup +}{mu}{sup {minus}} colliders--and is able to hold to the historical rate of progress in the log-energy reach of hadron and lepton colliders, reaching the 1 PeV constituent mass scale by the early 2040's. The technical and fiscal requirements for the feasibility of the scenario are assessed and relevant long-term R and D projects are identified. Considerations of both cost and logistics seem to strongly favor housing most or all of the colliders in the scenario in a new world high energy physics laboratory.

  13. Spectroscopic Classification of ASASSN-16gp as a Type Ia SN

    NASA Astrophysics Data System (ADS)

    Strader, Jay; Chomiuk, Laura; Prieto, Jose L.

    2016-07-01

    We obtained an optical spectrum of ASASSN-16gp (ATel #9199) on UT July 6.96 with the Goodman Spectrograph on the SOAR telescope. Classification with SNID (Blondin and Tonry 2007, ApJ, 666, 1024) indicates ASASSN-16gp is a normal Type Ia SN observed at 20-30 days after peak.

  14. Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130.

    PubMed Central

    Narazaki, M; Witthuhn, B A; Yoshida, K; Silvennoinen, O; Yasukawa, K; Ihle, J N; Kishimoto, T; Taga, T

    1994-01-01

    The interleukin 6 receptor-associated signal transducer, gp130, is shared by receptor complexes for leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and interleukin 11. We show here that JAK2 kinase is rapidly tyrosine phosphorylated in mouse embryonic stem cells whose pluripotentiality is maintained only by gp130-sharing cytokines after stimulation that is known to induce gp130 homodimerization. JAK1 is also tyrosine phosphorylated, but to a lesser extent, under the same conditions. Comparable results are obtained with hemopoietic lineage cells such as myeloid leukemic M1 cells and pro-B-cell line-derived transfectants expressing gp130, the former of which differentiate into macrophages after stimulation of gp130 and the latter of which initiate DNA synthesis. gp130-dimerizing stimulus upregulates kinase activity of JAK2 as revealed by immunocomplex kinase assay. Deletion or point mutation in the membrane-proximal cytoplasmic motifs in gp130 that are conserved in the hemopoietic cytokine receptor family results in the loss of tyrosine phosphorylation of JAK2, which coincides with the lack of signal transducing capability of gp130 mutants. Images PMID:8134389

  15. Generalized immunological recognition of the major merozoite surface antigen (gp195) of Plasmodium falciparum

    SciTech Connect

    Chang, S.P.; Hui, G.S.N.; Kato, A.; Siddiqui, W.A. )

    1989-08-01

    The antibody response to the Plasmodium falciparum major merozoite surface antigen (gp195) of congenic mouse strains differing in H-2 haplotype has been examined. All seven strains of mice were capable of producing gp195-specific antibodies. Generalized immune recognition of gp195 by mice of diverse H-2 haplotypes distinguished gp195 from the P. falciparum circumsporozoite protein and the 230-kDa and 48/45-kDa gamete surface antigens. However, the H-2 genetic locus appeared to influence the specificity of gp105-specific antibodies. Immunoblot patterns of mouse sera with parasite antigens revealed a complex pattern of reactivity with terminal and intermediate processing fragments of gp195. The majority of immunoblot bands observed were similar for all of the mouse strains; however, there were several strains that additionally recognized a few unique fragments or displayed more intense reactivities with specific processing fragments. These results suggest that while individuals of diverse major histocompatibility complex makeup are capable of recognizing the gp195 antigen, the recognition of specific gp195 B-cell and T-cell epitopes may be under control of the major histocompatibility complex.

  16. Immunogenicity and Protective Efficacy of Oligomeric Human Immunodeficiency Virus Type 1 gp140

    PubMed Central

    Earl, Patricia L.; Sugiura, Wataru; Montefiori, David C.; Broder, Christopher C.; Lee, Susan A.; Wild, Carl; Lifson, Jeffrey; Moss, Bernard

    2001-01-01

    The biologically active form of the human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein is oligomeric. We previously described a soluble HIV-1 IIIB Env protein, gp140, with a stable oligomeric structure composed of uncleaved gp120 linked to the ectodomain of gp41 (P. L. Earl, C. C. Broder, D. Long, S. A. Lee, J. Peterson, S. Chakrabarti, R. W. Doms, and B. Moss, J. Virol. 68:3015–3026, 1994). Here we compared the antibody responses of rabbits to gp120 and gp140 that had been produced and purified in an identical manner. The gp140 antisera exhibited enhanced cross-reactivity with heterologous Env proteins as well as greater neutralization of HIV-1 compared to the gp120 antisera. To examine both immunogenicity and protective efficacy, we immunized rhesus macaques with oligomeric gp140. Strong neutralizing antibodies against a homologous virus and modest neutralization of heterologous laboratory-adapted isolates were elicited. No neutralization of primary isolates was observed. However, a substantial fraction of the neutralizing activity could not be blocked by a V3 loop peptide. After intravenous challenge with simian-HIV virus SHIV-HXB2, three of the four vaccinated macaques exhibited no evidence of virus replication. PMID:11134278

  17. The neurotrophin receptor p75 mediates gp120-induced loss of synaptic spines in aging mice.

    PubMed

    Bachis, Alessia; Wenzel, Erin; Boelk, Allyssia; Becker, Jodi; Mocchetti, Italo

    2016-10-01

    Human immunodeficiency virus 1 and its envelope protein gp120 reduce synaptodendritic complexity. However, the mechanisms contributing to this pathological feature are still not understood. The proneurotrophin brain-derived neurotrophic factor promotes synaptic simplification through the activation of the p75 neurotrophin receptor (p75NTR). Here, we have used gp120 transgenic (gp120tg) mice to investigate whether p75NTR has a role in gp120-mediated neurotoxicity. Old (∼10 months) gp120tg mice exhibited an increase in proneurotrophin brain-derived neurotrophic factor levels in the hippocampus as well as a decrease in the number of dendritic spines when compared to age-matched wild type. These effects were not observed in 3- or 6-month-old mice. To test if the reduction in spine density and morphology is caused by the activation of p75NTR, we crossed gp120tg mice with p75NTR null mice. We found that deletion of only 1 copy of the p75NTR gene in gp120tg mice is sufficient to normalize the number of hippocampal spines, strongly suggesting that the neurotoxic effect of gp120 is mediated by p75NTR. These data indicate that p75NTR antagonists could provide an adjunct therapy against synaptic simplification caused by human immunodeficiency virus 1. PMID:27498053

  18. Physics of leptoquarks in precision experiments and at particle colliders

    NASA Astrophysics Data System (ADS)

    Doršner, I.; Fajfer, S.; Greljo, A.; Kamenik, J. F.; Košnik, N.

    2016-06-01

    We present a comprehensive review of physics effects generated by leptoquarks (LQs), i.e., hypothetical particles that can turn quarks into leptons and vice versa, of either scalar or vector nature. These considerations include discussion of possible completions of the Standard Model that contain LQ fields. The main focus of the review is on those LQ scenarios that are not problematic with regard to proton stability. We accordingly concentrate on the phenomenology of light leptoquarks that is relevant for precision experiments and particle colliders. Important constraints on LQ interactions with matter are derived from precision low-energy observables such as electric dipole moments, (g - 2) of charged leptons, atomic parity violation, neutral meson mixing, Kaon, B, and D meson decays, etc. We provide a general analysis of indirect constraints on the strength of LQ interactions with the quarks and leptons to make statements that are as model independent as possible. We address complementary constraints that originate from electroweak precision measurements, top, and Higgs physics. The Higgs physics analysis we present covers not only the most recent but also expected results from the Large Hadron Collider (LHC). We finally discuss direct LQ searches. Current experimental situation is summarized and self-consistency of assumptions that go into existing accelerator-based searches is discussed. A progress in making next-to-leading order predictions for both pair and single LQ productions at colliders is also outlined.

  19. Vector resonances from a strong electroweak sector at linear colliders

    NASA Astrophysics Data System (ADS)

    Casalbuoni, R.; Chiappetta, P.; Deandrea, A.; de Curtis, S.; Dominici, D.; Gatto, R.

    1993-06-01

    We explore the usefulness of very energetic linear e + e - colliders in the TeV range in studying an alternative scheme of electroweak symmetry breaking based on a strong interacting sector. The calculations are performed within the BESS model which contains new vector resonances. If the mass M V of the new boson multiplet lies not far from the maximum machine energy, or if it is lower, such a resonant contribution would be quite manifest. A result of our analysis is that also virtual effects are important. It appears that annihilation into a fermion pair in such machines, at the considered luminosities, would improve only marginally on existing limits if polarized beams are available and left-right asymmetries are measured. On the other hand, the process of W-pair production by e + e - annihilation would allow for sensitive tests of the hypothesized strong sector, especially if the W polarizations are reconstructed from their decay distributions, and the more so the higher the energy of the machine. An e + e - collider with c.m. energysqrt s = 500 GeV could improve the limits on the model for the range 500< M V (GeV)<1000 when W polarization is not reconstructed. If W polarizations are reconstructed, then the bounds improve for the entire expected range of M V . These bounds become more stringent for larger energy of the collider. We have also studied the detectability of the new resonances through the fusion subprocesses, but this channel does not seem to be interesting even for a collider with a c.m. energysqrt s = 2 TeV.

  20. Future proton and electron colliders: Dreams for the 1990's

    SciTech Connect

    Richter, B.

    1988-10-01

    In this paper I have reviewed the possibilities for new colliders that might be available in the 1990's. One or more new proton should be available in the late-90s based on plans of Europe, the US and the USSR. The two very high energy machines, LHC and SSC, are quite expensive, and their construction will be more decided by the politicians' view on the availability of resources than by the physicists' view of the need for new machines. Certainly something will be built, but the question is when. New electron colliders beyond LEP II could be available in the late 1990's as well. Most of the people who have looked at this problem believe that at a minimum three years of RandD are required before a proposal can be made, two years will be required to convince the authorities to go ahead, and five years will be required to build such a machine. Thus the earliest time a new electron collider at high energy could be available is around 1988. A strong international RandD program will be required to meet that schedule. In the field of B factories, PSI's proposal is the first serious step beyond the capabilities of CESR. There are other promising techniques but these need more RandD. The least RandD would be required for the asymmetric storage ring systems, while the most would be required for high luminosity linear colliders. For the next decade, high energy physics will be doing its work at the high energy frontier with Tevatron I and II, UNK, SLC, LEP I and II, and HERA. The opportunities for science presented by experiments at these facilities are very great, and it is to be hoped that the pressure for funding to construct the next generation facilities will not badly affect the operating budgets of the ones we now have or which will soon be turning on. 9 refs., 12 figs., 6 tabs.

  1. Status of the SLAC Linear Collider Project

    SciTech Connect

    Stiening, R.

    1983-01-01

    The SLAC Linear Collider Project has two principal goals. The first is to serve as a prototype for a future very high energy linear electron-positron collider. The second is to quickly, at low cost, achieve sufficient luminosity at 100 GeV center-of-mass energy to explore the physics of the Z/sup 0/. The first goal is important to the future of electron-positron physics because the rapid increase of synchrotron radiation with energy causes the cost of circular storage ring colliders to whereas the cost of linear colliders increases only in proportion to the center-of-mass energy. The second is important because the existance at SLAC of a linear accelerator which can be converted at low cost to collider operation makes possible a unique opportunity to quickly achieve 100 GeV center-of-mass collisions. At the design luminosity of 6.0 x 10/sup 30/ many thousands of Z/sup 0/ decays should be observed in each day of operation.

  2. Antiviral activity of glycoprotein GP-1 isolated from Streptomyces kanasensis ZX01.

    PubMed

    Zhang, Guoqiang; Feng, Juntao; Han, Lirong; Zhang, Xing

    2016-07-01

    Plant virus diseases have seriously damaged global food security. However, current antiviral agents are not efficient enough for the requirement of agriculture production. So, developing new efficient and nontoxic antiviral agents is imperative. GP-1, from Streptomyces kanasensis ZX01, is a new antiviral glycoprotein, of which the antiviral activity and the mode of action against Tobacco mosaic virus (TMV) were investigated in this study. The results showed that GP-1 could fracture TMV particles, and the infection and accumulation of TMV in host plants were inhibited. Moreover, GP-1 could induce systematic resistance against TMV in the host, according to the results of activities of defensive enzymes increasing, MDA decreasing and overexpression of pathogenesis-related proteins. Furthermore, GP-1 could promote growth of the host plant. In conclusion, GP-1 showed the ability to be developed as an efficient antiviral agent and a fertilizer for agriculture. PMID:27091231

  3. Isolation and identification of renal cell carcinoma-derived peptides associated with GP96.

    PubMed

    Li, H-Z; Li, C-W; Li, C-Y; Zhang, B-F; Li, L-T; Li, J-M; Zheng, J-N; Chang, J-W

    2013-08-01

    We determined the possible associated determinants and analyzed whether gp96-_associated antigenic peptides can be found in renal cell carcinoma (RCC). The gp96-peptide complexes were chromatographically purified from resected tumor tissue of RCC patients. SDS-PAGE and Western blot analysis confirmed gp96 using the gp96 monoclonal antibody, and its concentration was measured using BCA. Approximately 20 to 50 μg gp96-peptide complexes was obtained from 1 g RCC tissue. The mass spectrometry (MS) analysis of the eluted peptides included the initial profiling using matrix-assisted laser desorption/ionization time-of-flight MS. Quadrupole time-of-flight MS combined with the Mascot search engine was used to identify the peptides and find proteins from primary sequence databases. MS analysis results demonstrated that the mass range of peptide associated with gp96 was from 1046.48 to 3501.56 Da. Further research confirmed the sequences of two gp96-associated peptides, namely, LVPLEGWGGNVM and PPVYYVPYVVL. However, the original protein of the two peptides could not be found. The results demonstrated that the gp96-associated peptides are small molecular peptides, and the two peptides are deduced to be RCC-associated peptides. The identified peptides were confirmed to be associated with gp96 using the protocols described above. However, the specificity and relevance of the association to the immunogenicity of gp96 remains to be examined. Further analysis must be accomplished before the findings can be applied in peptide vaccine. PMID:23448575

  4. Expression of HIV gp120 protein increases sensitivity to the rewarding properties of methamphetamine in mice.

    PubMed

    Kesby, James P; Hubbard, David T; Markou, Athina; Semenova, Svetlana

    2014-07-01

    Methamphetamine abuse and human immunodeficiency virus (HIV) infection induce neuropathological changes in corticolimbic brain areas involved in reward and cognitive function. Little is known about the combined effects of methamphetamine and HIV infection on cognitive and reward processes. The HIV/gp120 protein induces neurodegeneration in mice, similar to HIV-induced pathology in humans. We investigated the effects of gp120 expression on associative learning, preference for methamphetamine and non-drug reinforcers, and sensitivity to the conditioned rewarding properties of methamphetamine in transgenic (tg) mice expressing HIV/gp120 protein (gp120-tg). gp120-tg mice learned the operant response for food at the same rate as non-tg mice. In the two-bottle choice procedure with restricted access to drugs, gp120-tg mice exhibited greater preference for methamphetamine and saccharin than non-tg mice, whereas preference for quinine was similar between genotypes. Under conditions of unrestricted access to methamphetamine, the mice exhibited a decreased preference for increasing methamphetamine concentrations. However, male gp120-tg mice showed a decreased preference for methamphetamine at lower concentrations than non-tg male mice. gp120-tg mice developed methamphetamine-induced conditioned place preference at lower methamphetamine doses compared with non-tg mice. No differences in methamphetamine pharmacokinetics were found between genotypes. These results indicate that gp120-tg mice exhibit no deficits in associative learning or reward/motivational function for a natural reinforcer. Interestingly, gp120 expression resulted in increased preference for methamphetamine and a highly palatable non-drug reinforcer (saccharin) and increased sensitivity to methamphetamine-induced conditioned reward. These data suggest that HIV-positive individuals may have increased sensitivity to methamphetamine, leading to high methamphetamine abuse potential in this population. PMID

  5. Expression of HIV gp120 protein increases sensitivity to the rewarding properties of methamphetamine in mice

    PubMed Central

    Kesby, James P.; Hubbard, David T.; Markou, Athina; Semenova, Svetlana

    2012-01-01

    Methamphetamine abuse and human immunodeficiency virus (HIV) infection induce neuropathological changes in corticolimbic brain areas involved in reward and cognitive function. Little is known about the combined effects of methamphetamine and HIV infection on cognitive and reward processes. The HIV/gp120 protein induces neurodegeneration in mice, similar to HIV-induced pathology in humans. We investigated the effects of gp120 expression on associative learning, preference for methamphetamine and non-drug reinforcers, and sensitivity to the conditioned rewarding properties of methamphetamine in transgenic (tg) mice expressing HIV/gp120 protein (gp120-tg). gp120-tg mice learned the operant response for food at the same rate as non-tg mice. In the two-bottle choice procedure with restricted access to drugs, gp120-tg mice exhibited greater preference for methamphetamine and saccharin than non-tg mice, whereas preference for quinine was similar between genotypes. Under conditions of unrestricted access to methamphetamine, the mice exhibited a decreased preference for increasing methamphetamine concentrations. However, male gp120-tg mice showed a decreased preference for methamphetamine at lower concentrations than non-tg male mice. gp120-tg mice developed methamphetamine-induced conditioned place preference at lower methamphetamine doses compared with non-tg mice. No differences in methamphetamine pharmacokinetics were found between genotypes. These results indicate that gp120-tg mice exhibit no deficits in associative learning or reward/motivational function for a natural reinforcer. Interestingly, gp120 expression resulted in increased preference for methamphetamine and a highly palatable non-drug reinforcer (saccharin) and increased sensitivity to methamphetamine-induced conditioned reward. These data suggest that HIV-positive individuals may have increased sensitivity to methamphetamine, leading to high methamphetamine abuse potential in this population. PMID

  6. Asymmetric Deactivation of HIV-1 gp41 following Fusion Inhibitor Binding

    PubMed Central

    Kahle, Kristen M.; Steger, H. Kirby; Root, Michael J.

    2009-01-01

    Both equilibrium and nonequilibrium factors influence the efficacy of pharmaceutical agents that target intermediate states of biochemical reactions. We explored the intermediate state inhibition of gp41, part of the HIV-1 envelope glycoprotein complex (Env) that promotes viral entry through membrane fusion. This process involves a series of gp41 conformational changes coordinated by Env interactions with cellular CD4 and a chemokine receptor. In a kinetic window between CD4 binding and membrane fusion, the N- and C-terminal regions of the gp41 ectodomain become transiently susceptible to inhibitors that disrupt Env structural transitions. In this study, we sought to identify kinetic parameters that influence the antiviral potency of two such gp41 inhibitors, C37 and 5-Helix. Employing a series of C37 and 5-Helix variants, we investigated the physical properties of gp41 inhibition, including the ability of inhibitor-bound gp41 to recover its fusion activity once inhibitor was removed from solution. Our results indicated that antiviral activity critically depended upon irreversible deactivation of inhibitor-bound gp41. For C37, which targets the N-terminal region of the gp41 ectodomain, deactivation was a slow process that depended on chemokine receptor binding to Env. For 5-Helix, which targets the C-terminal region of the gp41 ectodomain, deactivation occurred rapidly following inhibitor binding and was independent of chemokine receptor levels. Due to this kinetic disparity, C37 inhibition was largely reversible, while 5-Helix inhibition was functionally irreversible. The fundamental difference in deactivation mechanism points to an unappreciated asymmetry in gp41 following inhibitor binding and impacts the development of improved fusion inhibitors and HIV-1 vaccines. The results also demonstrate how the activities of intermediate state inhibitors critically depend upon the final disposition of inhibitor-bound states. PMID:19956769

  7. The Large Hadron Collider: Redefining High Energy

    SciTech Connect

    Demers, Sarah

    2007-06-19

    Particle physicists have a description of the forces of nature known as the Standard Model that has successfully withstood decades of testing at laboratories around the world. Though the Standard Model is powerful, it is not complete. Important details like the masses of particles are not explained well, and realities as fundamental as gravity, dark matter, and dark energy are left out altogether. I will discuss gaps in the model and why there is hope that some puzzles will be solved by probing high energies with the Large Hadron Collider. Beginning next year, this machine will accelerate protons to record energies, hurling them around a 27 kilometer ring before colliding them 40 million times per second. Detectors the size of five-story buildings will record the debris of these collisions. The new energy frontier made accessible by the Large Hadron Collider will allow thousands of physicists to explore nature's fundamental forces and particles from a fantastic vantage point.

  8. The Relativistic Heavy Ion Collider at Brookhaven

    SciTech Connect

    Hahn, H.

    1989-01-01

    The conceptual design of a collider capable of accelerating and colliding heavy ions and to be constructed in the existing 3.8 km tunnel at Brookhaven has been developed. The collider has been designed to provide collisions of gold ions at six intersection points with a luminosity of about 2 /times/ 10/sup 26/ cm/sup /minus/2/sec/sup /minus/1/ at an energy per nucleon of 100 GeV in each beam. Collisions with different ion species, including protons, will be possible. The salient design features and the reasons for major design choices of the proposed machine are discussed in this paper. 28 refs., 2 figs., 1 tab.

  9. Seismic studies for Fermilab future collider projects

    SciTech Connect

    Lauh, J.; Shiltsev, V.

    1997-11-01

    Ground motion can cause significant beam emittance growth and orbit oscillations in large hadron colliders due to a vibration of numerous focusing magnets. Larger accelerator ring circumference leads to smaller revolution frequency and, e.g. for the Fermilab Very Large Hadron Collider(VLHC) 50-150 Hz vibrations are of particular interest as they are resonant with the beam betatron frequency. Seismic measurements at an existing large accelerator under operation can help to estimate the vibrations generated by the technical systems in future machines. Comparison of noisy and quiet microseismic conditions might be useful for proper choice of technical solutions for future colliders. This article presents results of wide-band seismic measurements at the Fermilab site, namely, in the tunnel of the Tevatron and on the surface nearby, and in two deep tunnels in the Illinois dolomite which is though to be a possible geological environment of the future accelerators.

  10. Dynamics of laser ablated colliding plumes

    SciTech Connect

    Gupta, Shyam L.; Pandey, Pramod K.; Thareja, Raj K.

    2013-01-15

    We report the dynamics of single and two collinearly colliding laser ablated plumes of ZnO studied using fast imaging and the spectroscopic measurements. Two dimensional imaging of expanding plume and temporal evolution of various species in interacting zones of plumes are used to calculate plume front velocity, electron temperature, and density of plasma. The two expanding plumes interact with each other at early stage of expansion ({approx}20 ns) resulting in an interaction zone that propagates further leading to the formation of stagnation layer at later times (>150 ns) at the lateral collision front of two plumes. Colliding plumes have larger concentration of higher ionic species, higher temperature, and increased electron density in the stagnation region. A one-to-one correlation between the imaging and optical emission spectroscopic observations in interaction zone of the colliding plumes is reported.

  11. Collider and detector protection at beam accidents

    SciTech Connect

    I. L. Rakhno; N. V. Mokhov; A. I. Drozhdin

    2003-12-10

    Dealing with beam loss due to abort kicker prefire is considered for hadron colliders. The prefires occurred at Tevatron (Fermilab) during Run I and Run II are analyzed and a protection system implemented is described. The effect of accidental beam loss in the Large Hadron Collider (LHC) at CERN on machine and detector components is studied via realistic Monte Carlo calculations. The simulations show that beam loss at an unsynchronized beam abort would result in severe heating of conventional and superconducting magnets and possible damage to the collider detector elements. A proposed set of collimators would reduce energy deposition effects to acceptable levels. Special attention is paid to reducing peak temperature rise within the septum magnet and minimizing quench region length downstream of the LHC beam abort straight section.

  12. Quirky collider signals of folded supersymmetry

    NASA Astrophysics Data System (ADS)

    Burdman, Gustavo; Chacko, Z.; Goh, Hock-Seng; Harnik, Roni; Krenke, Christopher A.

    2008-10-01

    We investigate the collider signals associated with scalar quirks (squirks) in folded supersymmetric models. As opposed to regular superpartners in supersymmetric models these particles are uncolored, but are instead charged under a new confining group, leading to radically different collider signals. Because of the new strong dynamics, squirks that are pair produced do not hadronize separately, but rather form a highly excited bound state. The excited squirkonium loses energy to radiation before annihilating back into standard model particles. We calculate the branching fractions into various channels for this process, which is prompt on collider time scales. The most promising annihilation channel for discovery is W+photon which dominates for squirkonium near its ground state. We demonstrate the feasibility of the LHC search, showing that the mass peak is visible above the SM continuum background and estimate the discovery reach.

  13. 2009 Linear Collider Workshop of the Americas

    SciTech Connect

    Seidel, Sally

    2009-09-29

    The 2009 Linear Collider Workshop of the Americas was held on the campus of the University of New Mexico from 29 September to 3 October, 2009. This was a joint meeting of the American Linear Collider Physics Group and the ILC Global Design Effort. Two hundred fifty people attended. The number of scientific contributions was 333. The complete agenda, with links to all of the presentations, is available at physics.unm.edu/LCWA09/. The meeting brought together international experts as well as junior scientists, to discuss the physics potential of the linear collider and advances in detector technology. The validation of detector designs was announced, and the detector design groups planned the next phase of the effort. Detector R&D teams reported on progress on many topics including calorimetry and tracking. Recent accelerator design considerations were discussed in a special session for experimentalists and theorists.

  14. Antiproton - Ion Collider for FAIR Project

    SciTech Connect

    Beller, P.; Franzke, B.; Kienle, P.; Kruecken, R.; Koop, I.; Parkhomchuk, V.; Shatunov, Y.; Skrinsky, A.; Vostrikov, V.; Widmann, E.

    2006-03-20

    An antiproton-ion collider (AIC), with extensive using of electron cooling, is proposed to determine rms radii for protons and neutrons in unstable and short lived nuclei by means of antiproton absorption at medium energies. The experiment makes use of the electron-ion collider complex with appropriate modifications of the electron ring to store, cool and collide antiprotons of 30 MeV energy with 740 MeV/unit ions in the NESR. Antiprotons are collected, cooled, decelerated up to 30 MeV and transferred to the electron storage ring. The radioactive nuclei beams are transferred to the CR and cooled at 740A MeV and transported via the RESR to NESR, in which especially short lived nuclei are accumulated continuously to increase the luminosity. Luminosities of about 1023 cm-2s-1 may be reached with 106 ions accumulated in the NESR in coasting mode of operation, used for Schottky spectroscopy of the fragments.

  15. The Tevatron Hadron Collider: A short history

    SciTech Connect

    Tollestrup, A.V.

    1994-11-01

    The subject of this presentation was intended to cover the history of hadron colliders. However this broad topic is probably better left to historians. I will cover a much smaller portion of this subject and specialize my subject to the history of the Tevatron. As we will see, the Tevatron project is tightly entwined with the progress in collider technology. It occupies a unique place among accelerators in that it was the first to make use of superconducting magnets and indeed the basic design now forms a template for all machines using this technology. It was spawned in an incredibly productive era when new ideas were being generated almost monthly and it has matured into our highest energy collider complete with two large detectors that provide the major facility in the US for probing high Pt physics for the coming decade.

  16. Calorimetry At Very High Energy Colliders

    SciTech Connect

    Chiu, Mickey

    2011-06-01

    The capability of hadron colliders has increased to where it will soon be possible to collide protons at center of mass energies of 14 TeV with the advent of the LHC. With increasing collision energy, calorimeters become ever more essential components of a detector, and collaborations often choose very different technologies to meet their goals. From the perspective of a high energy particle and nuclear physicist, a survey is presented of the differences in design considerations and actual performance of the wide variety of calorimeters used in modern hadron colliders such as the Tevatron, RHIC, and LHC. The lessons learned and some ideas for future development of calorimetry will also be discussed.

  17. International linear collider reference design report

    SciTech Connect

    Aarons, G.

    2007-06-22

    The International Linear Collider will give physicists a new cosmic doorway to explore energy regimes beyond the reach of today's accelerators. A proposed electron-positron collider, the ILC will complement the Large Hadron Collider, a proton-proton collider at the European Center for Nuclear Research (CERN) in Geneva, Switzerland, together unlocking some of the deepest mysteries in the universe. With LHC discoveries pointing the way, the ILC -- a true precision machine -- will provide the missing pieces of the puzzle. Consisting of two linear accelerators that face each other, the ILC will hurl some 10 billion electrons and their anti-particles, positrons, toward each other at nearly the speed of light. Superconducting accelerator cavities operating at temperatures near absolute zero give the particles more and more energy until they smash in a blazing crossfire at the centre of the machine. Stretching approximately 35 kilometres in length, the beams collide 14,000 times every second at extremely high energies -- 500 billion-electron-volts (GeV). Each spectacular collision creates an array of new particles that could answer some of the most fundamental questions of all time. The current baseline design allows for an upgrade to a 50-kilometre, 1 trillion-electron-volt (TeV) machine during the second stage of the project. This reference design provides the first detailed technical snapshot of the proposed future electron-positron collider, defining in detail the technical parameters and components that make up each section of the 31-kilometer long accelerator. The report will guide the development of the worldwide R&D program, motivate international industrial studies and serve as the basis for the final engineering design needed to make an official project proposal later this decade.

  18. Recent SuperB Design Choices Improve Next-Generation e e___ B-Factory Collider

    SciTech Connect

    Wittmer, W.; Bertsche, K.; Chao, A.; Novokhatski, A.; Nosochkov, Y.; Seeman, J.; Sullivan, M.K.; Wienands, U.; Bogomyagkov, A.V.; Levichev, E.; Nikitin, S.; Piminov, P.; Shatilov, D.; Sinyatkin, S.; Vobly, P.; Okunev, I.N.; Bolzon, B.; Brunetti, L.; Jeremie, A.; Biagini, M.E.; Boni, R.; /Frascati /INFN, Pisa /Pisa U. /INFN, Genoa /Genoa U. /CERN /Orsay, LAL /Saclay

    2011-08-19

    The SuperB international team continues to optimize the design of an electron-positron collider, which will allow the enhanced study of the origins of flavor physics. The project combines the best features of a linear collider (high single-collision luminosity) and a storage-ring collider (high repetition rate), bringing together all accelerator physics aspects to make a very high luminosity of 10{sup 36} cm{sup -2} sec{sup -1}. This asymmetric-energy collider with a polarized electron beam will produce hundreds of millions of B-mesons at the {Upsilon}(4S) resonance. The present design is based on extremely low emittance beams colliding at a large Piwinski angle to allow very low {beta}*{sub y} without the need for ultra short bunches. Use of crab-waist sextupoles will enhance the luminosity, suppressing dangerous resonances and allowing for a higher beam-beam parameter. The project has flexible beam parameters, improved dynamic aperture, and spin-rotators in the Low Energy Ring for longitudinal polarization of the electron beam at the Interaction Point. Optimized for best colliding-beam performance, the facility may also provide high-brightness photon beams for synchrotron radiation applications.

  19. Collider physics for the late 1980's

    SciTech Connect

    Hinchliffe, I.

    1987-02-27

    Topics in the Standard Model of strong and electroweak interactions and how these topics are relevant for the high energy colliders are discussed. Radiative corrections in the Glashow-Weinberg-Salam model are discussed, stressing how these corrections may be measured at LEP and the SLC. CP violation is discussed, followed by a discussion of the Higgs boson and the searches which can be carried out for it. Some features of quantum chromodynamics are discussed which are relevant to hadron colliders. Some of the problems which the Standard Model does not solve are discussed. 115 refs., 53 figs. (LEW)

  20. Top quark studies at hadron colliders

    SciTech Connect

    Sinervo, P.K.; CDF Collaboration

    1996-08-01

    The techniques used to study top quarks at hadron colliders are presented. The analyses that discovered the top quark are described, with emphasis on the techniques used to tag {ital b} quark jets in candidate events. The most recent measurements of top quark properties by the CDF and D{null} collaborations are reviewed, including the top quark cross section, mass, branching fractions and production properties. Future top quark studies at hadron colliders are discussed, and predictions for event yields and uncertainties in the measurements of top quark properties are presented.

  1. Top quark studies at hadron colliders

    SciTech Connect

    Sinervo, P.K.

    1997-01-01

    The techniques used to study top quarks at hadron colliders are presented. The analyses that discovered the top quark are described, with emphasis on the techniques used to tag b quark jets in candidate events. The most recent measurements of top quark properties by the CDF and DO Collaborations are reviewed, including the top quark cross section, mass, branching fractions, and production properties. Future top quark studies at hadron colliders are discussed, and predictions for event yields and uncertainties in the measurements of top quark properties are presented.

  2. Beam instrumentation for the Tevatron Collider

    SciTech Connect

    Moore, Ronald S.; Jansson, Andreas; Shiltsev, Vladimir; /Fermilab

    2009-10-01

    The Tevatron in Collider Run II (2001-present) is operating with six times more bunches and many times higher beam intensities and luminosities than in Run I (1992-1995). Beam diagnostics were crucial for the machine start-up and the never-ending luminosity upgrade campaign. We present the overall picture of the Tevatron diagnostics development for Run II, outline machine needs for new instrumentation, present several notable examples that led to Tevatron performance improvements, and discuss the lessons for future colliders.

  3. Suppressing Electron Cloud in Future Linear Colliders

    SciTech Connect

    Pivi, M; Kirby, R.E.; Raubenheimer, T.O.; Le Pimpec, F.; /PSI, Villigen

    2005-05-27

    Any accelerator circulating positively charged beams can suffer from a build-up of an electron cloud (EC) in the beam pipe. The cloud develops through ionization of residual gases, synchrotron radiation and secondary electron emission and, when severe, can cause instability, emittance blow-up or loss of the circulating beam. The electron cloud is potentially a luminosity limiting effect for both the Large Hadron Collider (LHC) and the International Linear Collider (ILC). For the ILC positron damping ring, the development of the electron cloud must be suppressed. This paper discusses the state-of-the-art of the ongoing SLAC and international R&D program to study potential remedies.

  4. Physics Beyond the Standard Model at Colliders

    NASA Astrophysics Data System (ADS)

    Matchev, Konstantin

    These lectures introduce the modern machinery used in searches and studies of new physics Beyond the Standard Model (BSM) at colliders. The first lecture provides an overview of the main simulation tools used in high energy physics, including automated parton-level calculators, general purpose event generators, detector simulators, etc. The second lecture is a brief introduction to low energy supersymmetry (SUSY) as a representative BSM paradigm. The third lecture discusses the main collider signatures of SUSY and methods for measuring the masses of new particles in events with missing energy.

  5. FFAG Designs for Muon Collider Acceleration

    SciTech Connect

    Berg, J. Scott

    2014-01-13

    I estimate FFAG parameters for a muon collider with a 70mm longitudinal emittance. I do not discuss the lower emittance beam for a Higgs factory. I produce some example designs, giving only parameters relevant to estimating cost and performance. The designs would not track well, but the parameters of a good design will be close to those described. I compare these cost estimates to those for a fast-ramping synchrotron and a recirculating linear accelerator. I conclude that FFAGs do not appear to be cost-effective for the large longitudinal emittance in a high-energy muon collider.

  6. Fangchinoline Inhibits Human Immunodeficiency Virus Type 1 Replication by Interfering with gp160 Proteolytic Processing

    PubMed Central

    Wan, Zhitao; Lu, Yimei; Liao, Qingjiao; Wu, Yang; Chen, Xulin

    2012-01-01

    The introduction of highly active antiretroviral therapy has led to a significant reduction in the morbidity and mortality of acquired immunodeficiency syndrome patients. However, the emergence of drug resistance has resulted in the failure of treatments in large numbers of patients and thus necessitates the development of new classes of anti-HIV drugs. In this study, more than 200 plant-derived small-molecule compounds were evaluated in a cell-based HIV-1 antiviral screen, resulting in the identification of a novel HIV-1 inhibitor (fangchinoline). Fangchinoline, a bisbenzylisoquinoline alkaloid isolated from Radix Stephaniae tetrandrae, exhibited antiviral activity against HIV-1 laboratory strains NL4-3, LAI and BaL in MT-4 and PM1 cells with a 50% effective concentration ranging from 0.8 to 1.7 µM. Mechanism-of-action studies showed that fangchinoline did not exhibit measurable antiviral activity in TZM-b1 cells but did inhibit the production of infectious virions in HIV-1 cDNA transfected 293T cells, which suggests that the compound targets a late event in infection cycle. Furthermore, the antiviral effect of fangchinoline seems to be HIV-1 enve1ope-dependent, as the production of infectious HIV-1 particles packaged with a heterologous envelope, the vesicular stomatitis virus G glycoprotein, was unaffected by fangchinoline. Western blot analysis of HIV envelope proteins expressed in transfected 293T cells and in isolated virions showed that fangchinoline inhibited HIV-1 gp160 processing, resulting in reduced envelope glycoprotein incorporation into nascent virions. Collectively, our results demonstrate that fangchinoline inhibits HIV-1 replication by interfering with gp160 proteolytic processing. Fangchinoline may serve as a starting point for developing a new HIV-1 therapeutic approach. PMID:22720080

  7. Fangchinoline inhibits human immunodeficiency virus type 1 replication by interfering with gp160 proteolytic processing.

    PubMed

    Wan, Zhitao; Lu, Yimei; Liao, Qingjiao; Wu, Yang; Chen, Xulin

    2012-01-01

    The introduction of highly active antiretroviral therapy has led to a significant reduction in the morbidity and mortality of acquired immunodeficiency syndrome patients. However, the emergence of drug resistance has resulted in the failure of treatments in large numbers of patients and thus necessitates the development of new classes of anti-HIV drugs. In this study, more than 200 plant-derived small-molecule compounds were evaluated in a cell-based HIV-1 antiviral screen, resulting in the identification of a novel HIV-1 inhibitor (fangchinoline). Fangchinoline, a bisbenzylisoquinoline alkaloid isolated from Radix Stephaniae tetrandrae, exhibited antiviral activity against HIV-1 laboratory strains NL4-3, LAI and BaL in MT-4 and PM1 cells with a 50% effective concentration ranging from 0.8 to 1.7 µM. Mechanism-of-action studies showed that fangchinoline did not exhibit measurable antiviral activity in TZM-b1 cells but did inhibit the production of infectious virions in HIV-1 cDNA transfected 293T cells, which suggests that the compound targets a late event in infection cycle. Furthermore, the antiviral effect of fangchinoline seems to be HIV-1 envelope-dependent, as the production of infectious HIV-1 particles packaged with a heterologous envelope, the vesicular stomatitis virus G glycoprotein, was unaffected by fangchinoline. Western blot analysis of HIV envelope proteins expressed in transfected 293T cells and in isolated virions showed that fangchinoline inhibited HIV-1 gp160 processing, resulting in reduced envelope glycoprotein incorporation into nascent virions. Collectively, our results demonstrate that fangchinoline inhibits HIV-1 replication by interfering with gp160 proteolytic processing. Fangchinoline may serve as a starting point for developing a new HIV-1 therapeutic approach. PMID:22720080

  8. The C-terminal tail of the gp41 transmembrane envelope glycoprotein of HIV-1 clades A, B, C, and D may exist in two conformations: an analysis of sequence, structure, and function

    SciTech Connect

    Hollier, Mark J.; Dimmock, Nigel J. . E-mail: n.j.dimmock@warwick.ac.uk

    2005-07-05

    In addition to the major ectodomain, the gp41 transmembrane glycoprotein of HIV-1 is now known to have a minor ectodomain that is part of the long C-terminal tail. Both ectodomains are highly antigenic, carry neutralizing and non-neutralizing epitopes, and are involved in virus-mediated fusion activity. However, data have so far been biologically based, and derived solely from T cell line-adapted (TCLA), B clade viruses. Here we have carried out sequence and theoretically based structural analyses of 357 gp41 C-terminal sequences of mainly primary isolates of HIV-1 clades A, B, C, and D. Data show that all these viruses have the potential to form a tail loop structure (the minor ectodomain) supported by three, {beta}-sheet, membrane-spanning domains (MSDs). This means that the first (N-terminal) tyrosine-based sorting signal of the gp41 tail is situated outside the cell membrane and is non-functional, and that gp41 that reaches the cell surface may be recycled back into the cytoplasm through the activity of the second tyrosine-sorting signal. However, we suggest that only a minority of cell-associated gp41 molecules - those destined for incorporation into virions - has 3 MSDs and the minor ectodomain. Most intracellular gp41 has the conventional single MSD, no minor ectodomain, a functional first tyrosine-based sorting signal, and in line with current thinking is degraded intracellularly. The gp41 structural diversity suggested here can be viewed as an evolutionary strategy to minimize HIV-1 envelope glycoprotein expression on the cell surface, and hence possible cytotoxicity and immune attack on the infected cell.

  9. Pharmacokinetics, tissue distribution and excretion of 40kDa PEG and PEGylated rFVIII (N8-GP) in rats.

    PubMed

    Bjørnsdottir, Inga; Sternebring, Ola; Kappers, Wendela A; Selvig, Helle; Kornø, Hanne T; Kristensen, Jesper B; Bagger, Morten A

    2016-05-25

    The biologic fate of the [(3)H]PEG-moiety incorporated into N8-GP was evaluated based on single i.v. bolus doses to rats. Furthermore, the 40kDa [(3)H]PEG-moiety was given separately to rats by single i.v. bolus doses, to investigate if the pharmacokinetics were dose-dependent. For both compounds, plasma pharmacokinetics, distribution and excretion pathways were investigated, based on total radioactivity measurements ([(3)H]N8-GP: 0.17-4.1mg/kg;~1300-30,000U/kg, PEG load of ~0.03-0.7mg/kg); ([(3)H]PEG: 0.6, 1, 12, 100 and 200mg/kg). The plasma concentration of the intact N8-GP conjugate was also measured by ELISA. After single i.v. administration to rats, both [(3)H]N8-GP and [(3)H]PEG were shown to be widely distributed, mainly in highly vascularized tissues, with the lowest levels of radioactivity found in the CNS. Though a slow elimination of radioactivity was observed over the 12-week study period, approximately half of the radioactive dose of either compound was removed from the body 1week post-dose. The radioactivity was eliminated mainly via the kidney into urine but also via the liver into feces, with a larger fraction found in the feces for [(3)H]N8-GP. Elimination of the 40kDa PEG-moiety was shown to be dose-dependent with faster elimination at lower dose levels. The clinical dose of N8-GP provides a substantially lower PEG exposure (50-75U/kg; PEG load of <0.002mg/kg) when compared to the PEG doses investigated in this paper (0.03-200mg/kg). This may imply an even faster clearance of the PEG-moiety after N8-GP administration of clinically relevant doses. PMID:26517963

  10. Molecular Features of the Broadly Neutralizing Immunoglobulin G1 b12 Required for Recognition of Human Immunodeficiency Virus Type 1 gp120

    PubMed Central

    Zwick, Michael B.; Parren, Paul W. H. I.; Saphire, Erica O.; Church, Sarah; Wang, Meng; Scott, Jamie K.; Dawson, Philip E.; Wilson, Ian A.; Burton, Dennis R.

    2003-01-01

    IgG1 b12 is a broadly neutralizing antibody against human immunodeficiency virus type 1 (HIV-1). The epitope recognized by b12 overlaps the CD4 receptor-binding site (CD4bs) on gp120 and has been a target for vaccine design. Determination of the three-dimensional structure of immunoglobulin G1 (IgG1) b12 allowed modeling of the b12-gp120 interaction in which the protruding third complementarity-determining region (CDR) of the heavy chain (H3) was crucial for antibody binding. In the present study, extensive mutational analysis of the antigen-binding site of Fab b12 was carried out to investigate the validity of the model and to identify residues important for gp120 recognition and, by inference, key to the anti-HIV-1 activity of IgG1 b12. In all, 50 mutations were tested: 40 in H3, 4 each in H2 and L1, and 2 in L3. The results suggest that the interaction of gp120 with H3 of b12 is crucially dependent not only on a Trp residue at the apex of the H3 loop but also on a number of residues at the base of the loop. The arrangement of these residues, including aromatic side chains and side chains that hydrogen bond across the base of the loop, may rigidify H3 for penetration of the recessed CD4-binding cavity. The results further emphasize the importance to gp120 binding of a Tyr residue at the apex of the H2 loop that forms a second finger-like structure and a number of Arg residues in L1 that form a positively charged, shelf-like structure. In general, the data are consistent with the b12-gp120 interaction model previously proposed. At the gene level, somatic mutation is seen to be crucial for the generation of many of the structural features described. The Fab b12 mutants were also tested against the b12 epitope-mimic peptide B2.1, and the reactivity profile had many similarities but also significant differences from that observed for gp120. The paratope map of b12 may facilitate the design of molecules that are able to elicit b12-like activities. PMID:12719580

  11. Esters of the Marine-Derived Triterpene Sipholenol A Reverse P-GP-Mediated Drug Resistance

    PubMed Central

    Zhang, Yongchao; Zhang, Yun-Kai; Wang, Yi-Jun; Vispute, Saurabh G.; Jain, Sandeep; Chen, Yangmin; Li, Jessalyn; Youssef, Diaa T. A.; El Sayed, Khalid A.; Chen, Zhe-Sheng

    2015-01-01

    Our previous studies showed that several sipholane triterpenes, sipholenol A, sipholenone E, sipholenol L and siphonellinol D, have potent reversal effect for multidrug resistance (MDR) in cancer cells that overexpressed P-glycoprotein (P-gp/ABCB1). Through comparison of cytotoxicity towards sensitive and multi-drug resistant cell lines, we identified that the semisynthetic esters sipholenol A-4-O-acetate and sipholenol A-4-O-isonicotinate potently reversed P-gp-mediated MDR but had no effect on MRP1/ABCC1 and BCRP/ABCG2-mediated MDR. The results from [3H]-paclitaxel accumulation and efflux studies suggested that these two triterpenoids were able to increase the intracellular accumulation of paclitaxel by inhibiting its active efflux. In addition, western blot analysis revealed that these two compounds did not alter the expression levels of P-gp when treated up to 72 h. These sipholenol derivatives also stimulated the ATPase activity of P-gp membranes, which suggested that they might be substrates of P-gp. Moreover, in silico molecular docking studies revealed the virtual binding modes of these two compounds into human homology model of P-gp. In conclusion, sipholenol A-4-O-acetate and sipholenol A-4-O-isonicotinate efficiently inhibit the P-gp and may represent potential reversal agents for the treatment of multidrug resistant cancers. PMID:25874923

  12. Gp63-like molecules in Phytomonas serpens: possible role in the insect interaction.

    PubMed

    d'Avila-Levy, Claudia M; Santos, Lívia O; Marinho, Fernanda A; Dias, Felipe A; Lopes, Angela H; Santos, André L S; Branquinha, Marta H

    2006-06-01

    In this study, we demonstrated that metallopeptidase inhibitors (EDTA, EGTA, and 1,10-phenanthroline) were able to arrest Phytomonas serpens growth in distinct patterns. This parasite released exclusively metallopeptidases to the extracellular environment, whereas in cellular extracts only cysteine peptidases were detected. In addition, an extracellular polypeptide of 60 kDa reacted in Western blotting probed with polyclonal antibody raised against gp63 of Leishmania amazonensis. In the cellular parasite extract, this antibody recognized bands migrating at 63 and 52 kDa, which partitioned on both aqueous and membrane-rich fractions. Flow cytometry and fluorescence microscopy analyses showed that the gp63-like molecules have a surface location. Moreover, phospholipase C (PLC)-treated parasites reduced the number of gp63-positive cells. The anti-cross-reacting determinant (CRD) and anti-gp63 antibodies recognized the 60-kDa band in the supernatant from PLC-treated cells, suggesting that this protein is glycosylphosphatidylinositol-anchored to the plasma membrane. This is the first report on the presence of gp63-like molecules in members of the Phytomonas genus. The pretreatment of the parasites with anti-gp63 antibody significantly diminished their adhesion index to explanted salivary glands of the phytophagous insect Oncopeltus fasciatus, suggesting a potential involvement of the gp63-like molecules in the adhesive process of this plant trypanosomatid. PMID:16732452

  13. TssA forms a gp6-like ring attached to the type VI secretion sheath.

    PubMed

    Planamente, Sara; Salih, Osman; Manoli, Eleni; Albesa-Jové, David; Freemont, Paul S; Filloux, Alain

    2016-08-01

    The type VI secretion system (T6SS) is a supra-molecular bacterial complex that resembles phage tails. It is a killing machine which fires toxins into target cells upon contraction of its TssBC sheath. Here, we show that TssA1 is a T6SS component forming dodecameric ring structures whose dimensions match those of the TssBC sheath and which can accommodate the inner Hcp tube. The TssA1 ring complex binds the T6SS sheath and impacts its behaviour in vivo In the phage, the first disc of the gp18 sheath sits on a baseplate wherein gp6 is a dodecameric ring. We found remarkable sequence and structural similarities between TssA1 and gp6 C-termini, and propose that TssA1 could be a baseplate component of the T6SS Furthermore, we identified similarities between TssK1 and gp8, the former interacting with TssA1 while the latter is found in the outer radius of the gp6 ring. These observations, combined with similarities between TssF and gp6N-terminus or TssG and gp53, lead us to propose a comparative model between the phage baseplate and the T6SS. PMID:27288401

  14. Human immunodeficiency virus glycoprotein (gp120) induction of monocyte arachidonic acid metabolites and interleukin 1.

    PubMed Central

    Wahl, L M; Corcoran, M L; Pyle, S W; Arthur, L O; Harel-Bellan, A; Farrar, W L

    1989-01-01

    This study reports on the direct effect of the envelope glycoprotein (gp120) of the human immunodeficiency virus type 1 (HIV-1) on human monocyte function. Addition of preparations of purified gp120 from the HIV-1 to human monocytes resulted in the production of interleukin 1 (IL-1) and arachidonic acid metabolites from the cyclooxygenase and lipoxygenase pathways. Quantification of prostaglandin E2 (PGE2) and IL-1 revealed an increase in both mediators with 50 ng of gp120 per ml and an increase of 12- and 30- to 40-fold with 200-400 ng of gp120 per ml, respectively. Unlike native gp120, the recombinant nonglycosylated gp120 fragments PB1-RF and PB1-IIIB, as well as one of the core structural proteins of HIV-1, p24, did not increase arachidonic acid metabolism or IL-1 activity. Cytofluorometric analysis revealed that gp120 blocked the binding of OKT4A to the CD4 on monocytes, whereas OKT4 binding was unaffected. Involvement of the CD4 in signal transduction was further demonstrated by the ability of OKT4 and OKT4A monoclonal antibodies to increase monocyte PGE2, IL-1 activity, and nanogram amounts of IL-1 beta. PMID:2536171

  15. Structural delineation of a quaternary, cleavage-dependent epitope at the gp41-gp120 interface on intact HIV-1 Env trimers

    PubMed Central

    Blattner, Claudia; Lee, Jeong Hyun; Sliepen, Kwinten; Derking, Ronald; Falkowska, Emilia; de la Peña, Alba Torrents; Cupo, Albert; Julien, Jean-Philippe; van Gils, Marit; Lee, Peter S.; Peng, Wenjie; Paulson, James C.; Poignard, Pascal; Burton, Dennis R.; Moore, John P.; Sanders, Rogier W.

    2014-01-01

    Summary All previously characterized broadly neutralizing antibodies to the HIV-1 envelope glycoprotein (Env) target one of four major sites of vulnerability. Here, we define and structurally characterize a unique epitope on Env that is recognized by a recently discovered family of human monoclonal antibodies (PGT151-158). The PGT151 epitope is comprised of residues and glycans at the interface of gp41 and gp120 within a single protomer and glycans from both subunits of a second protomer and represents a neutralizing epitope that is dependent on both gp120 and gp41. As PGT151 binds only to properly formed, cleaved trimers, this distinctive property, and its ability to stabilize Env trimers, has enabled the successful purification of mature, cleaved Env trimers from the cell surface as a complex with PGT151. Here we compare the structural and functional properties of membrane-extracted Env trimers from several clades with those of the soluble, cleaved SOSIP gp140 trimer. PMID:24768348

  16. HIV-1 viral envelope protein gp41: An NMR investigation of dodecyl phosphocholine embedded gp41 reveals a dynamic pre-fusion intermediate conformation

    PubMed Central

    Lakomek, Nils-Alexander; Kaufman, Joshua D.; Stahl, Stephen J.; Wingfield, Paul T.

    2014-01-01

    Summary Human immunodeficiency viral (HIV-1) fusion is mediated by the viral envelope gp120/gp41 complex (ENVelope glycoprotein). After gp120 shedding, gp41 is exposed and elicits membrane fusion via a cascade of conformational changes. In contrast to pre-fusion and post-fusion conformation, little is known about any intermediate conformation. We report on a solution NMR investigation of homotrimeric HIV-1 gp4127–194, comprising the transmembrane region and reconstituted in dodecyl phosphocholine (DPC) micelles. The protein is mainly α-helical but experiences internal dynamics on the nanosecond and micro-to millisecond time scale and transient α-helical behavior for certain residues in the N-terminal heptad repeat (NHR). Strong lipid interactions are observed, in particular for C-terminal residues of the NHR and imunodominant loop region connecting NHR and C-terminal heptad repeat (CHR). Our data indicate an extended conformation with features anticipated for a pre-fusion intermediate, presumably in exchange with a lowly populated post-fusion six-helical bundle conformation. PMID:25132083

  17. The Genotype of Early-Transmitting HIV gp120s Promotes α4β7 –Reactivity, Revealing α4β7+/CD4+ T cells As Key Targets in Mucosal Transmission

    PubMed Central

    Van Ryk, Donald; Block, Katharine E.; Jelicic, Katija; McNally, Jonathan P.; Ogundare, Olajumoke; Pascuccio, Massimiliano; Patel, Nikita; Wei, Danlan; Fauci, Anthony S.; Arthos, James

    2011-01-01

    Mucosal transmission of HIV is inefficient. The virus must breach physical barriers before it infects mucosal CD4+ T cells. Low-level viral replication occurs initially in mucosal CD4+ T cells, but within days high-level replication occurs in Peyer's patches, the gut lamina propria and mesenteric lymph nodes. Understanding the early events in HIV transmission may provide valuable information relevant to the development of an HIV vaccine. The viral quasispecies in a donor contracts through a genetic bottleneck in the recipient, such that, in low-risk settings, infection is frequently established by a single founder virus. Early-transmitting viruses in subtypes A and C mucosal transmission tend to encode gp120s with reduced numbers of N-linked glycosylation sites at specific positions throughout the V1-V4 domains, relative to typical chronically replicating isolates in the donor quasispecies. The transmission advantage gained by the absence of these N-linked glycosylation sites is unknown. Using primary α4β7+/CD4+ T cells and a flow-cytometry based steady-state binding assay we show that the removal of transmission-associated N-linked glycosylation sites results in large increases in the specific reactivity of gp120 for integrin- α4β7. High-affinity for integrin α4β7, although not found in many gp120s, was observed in early-transmitting gp120s that we analyzed. Increased α4β7 affinity is mediated by sequences encoded in gp120 V1/V2. α4β7-reactivity was also influenced by N-linked glycosylation sites located in C3/V4. These results suggest that the genetic bottleneck that occurs after transmission may frequently involve a relative requirement for the productive infection of α4β7+/CD4+ T cells. Early-transmitting gp120s were further distinguished by their dependence on avidity-effects to interact with CD4, suggesting that these gp120s bear unusual structural features not present in many well-characterized gp120s derived from chronically replicating viruses

  18. Beam dynamics issues for linear colliders

    SciTech Connect

    Ruth, R.D.

    1987-09-01

    In this paper we discuss various beam dynamics issues for linear colliders. The emphasis is to explore beam dynamics effects which lead to an effective dilution of the emittance of the beam and thus to a loss of luminosity. These considerations lead to various tolerances which are evaluated for a particular parameter set.

  19. Proton-proton colliding beam facility ISABELLE

    SciTech Connect

    Hahn, H

    1980-01-01

    This paper attempts to present the status of the ISABELLE construction project, which has the objective of building a 400 + 400 GeV proton colliding beam facility. The major technical features of the superconducting accelerators with their projected performance are described. Progress made so far, difficulties encountered, and the program until completion in 1986 is briefly reviewed.

  20. Precision electroweak physics at future collider experiments

    SciTech Connect

    Baur, U.; Demarteau, M.

    1996-11-01

    We present an overview of the present status and prospects for progress in electroweak measurements at future collider experiments leading to precision tests of the Standard Model of Electroweak Interactions. Special attention is paid to the measurement of the {ital W} mass, the effective weak mixing angle, and the determination of the top quark mass. Their constraints on the Higgs boson mass are discussed.

  1. Search for new physics at colliders

    SciTech Connect

    Chiarelli, Giorgio; /INFN, Pisa

    2005-09-01

    In this paper I present the most recent results of the ongoing searches, mainly from Tevatron Collider experiments, for new physics beyond the Standard Model. While no signal has been seen so far, many analyses are reaching the point in which either a discovery will take place or strong limit on currently popular theories will be set.

  2. Difficult Decisions: The Superconducting Super Collider.

    ERIC Educational Resources Information Center

    Newton, David E.; Slesnick, Irwin L.

    1990-01-01

    The fundamental principles of the superconducting super collider are presented. Arguments for the construction of this apparatus and policy issues surrounding its construction are discussed. Charts of the fundamental atomic particles and forces and the history of particle accelerators are provided. An activity for discussing this controversial…

  3. From the LHC to Future Colliders

    SciTech Connect

    De Roeck, A.; Ellis, J.; Grojean, C.; Heinemeyer, S.; Jakobs, K.; Weiglein, G.; Azuelos, G.; Dawson, S.; Gripaios, B.; Han, T.; Hewett, J.; Lancaster, M.; Mariotti, C.; Moortgat, F.; Moortgat-Pick, G.; Polesello, G.; Riemann, S.; Assamagan, K.; Bechtle, P.; Carena, M.; Chachamis, G.; /more authors..

    2010-06-11

    Discoveries at the LHC will soon set the physics agenda for future colliders. This report of a CERN Theory Institute includes the summaries of Working Groups that reviewed the physics goals and prospects of LHC running with 10 to 300 fb{sup -1} of integrated luminosity, of the proposed sLHC luminosity upgrade, of the ILC, of CLIC, of the LHeC and of a muon collider. The four Working Groups considered possible scenarios for the first 10 fb{sup -1} of data at the LHC in which (i) a state with properties that are compatible with a Higgs boson is discovered, (ii) no such state is discovered either because the Higgs properties are such that it is difficult to detect or because no Higgs boson exists, (iii) a missing-energy signal beyond the Standard Model is discovered as in some supersymmetric models, and (iv) some other exotic signature of new physics is discovered. In the contexts of these scenarios, theWorking Groups reviewed the capabilities of the future colliders to study in more detail whatever new physics may be discovered by the LHC. Their reports provide the particle physics community with some tools for reviewing the scientific priorities for future colliders after the LHC produces its first harvest of new physics from multi-TeV collisions.

  4. Physics Case for the International Linear Collider

    SciTech Connect

    Fujii, Keisuke; Grojean, Christophe; Peskin, Michael E.; Barklow, Tim; Gao, Yuanning; Kanemura, Shinya; Kim, Hyungdo; List, Jenny; Nojiri, Mihoko; Perelstein, Maxim; Poeschl, Roman; Reuter, Juergen; Simon, Frank; Tanabe, Tomohiko; Yu, Jaehoon; Wells, James D.; Murayama, Hitoshi; Yamamoto, Hitoshi; /Tohoku U.

    2015-06-23

    We summarize the physics case for the International Linear Collider (ILC). We review the key motivations for the ILC presented in the literature, updating the projected measurement uncertainties for the ILC experiments in accord with the expected schedule of operation of the accelerator and the results of the most recent simulation studies.

  5. Beam-beam issues in asymmetric colliders

    SciTech Connect

    Furman, M.A.

    1992-07-01

    We discuss generic beam-beam issues for proposed asymmetric e{sup +}- e{sup -} colliders. We illustrate the issues by choosing, as examples, the proposals by Cornell University (CESR-B), KEK, and SLAC/LBL/LLNL (PEP-II).

  6. Collider Tests of the Little Higgs Model

    SciTech Connect

    Burdman, Gustavo; Perelstein, Maxim; Pierce, Aaron

    2002-12-16

    The little Higgs model provides an alternative to traditional candidates for new physics at the TeV scale. The new heavy gauge bosons predicted by this model should be observable at the Large Hadron Collider (LHC). We discuss how the LHC experiments could test the little Higgs model by studying the production and decay of these particles.

  7. Future Accelerators, Muon Colliders, and Neutrino Factories

    SciTech Connect

    Richard A Carrigan, Jr.

    2001-12-19

    Particle physics is driven by five great topics. Neutrino oscillations and masses are now at the fore. The standard model with extensions to supersymmetry and a Higgs to generate mass explains much of the field. The origins of CP violation are not understood. The possibility of extra dimensions has raised tantalizing new questions. A fifth topic lurking in the background is the possibility of something totally different. Many of the questions raised by these topics require powerful new accelerators. It is not an overstatement to say that for some of the issues, the accelerator is almost the experiment. Indeed some of the questions require machines beyond our present capability. As this volume attests, there are parts of the particle physics program that have been significantly advanced without the use of accelerators such as the subject of neutrino oscillations and many aspects of the particle-cosmology interface. At this stage in the development of physics, both approaches are needed and important. This chapter first reviews the status of the great accelerator facilities now in operation or coming on within the decade. Next, midrange possibilities are discussed including linear colliders with the adjunct possibility of gamma-gamma colliders, muon colliders, with precursor neutrino factories, and very large hadron colliders. Finally visionary possibilities are considered including plasma and laser accelerators.

  8. Black Holes and the Large Hadron Collider

    ERIC Educational Resources Information Center

    Roy, Arunava

    2011-01-01

    The European Center for Nuclear Research or CERN's Large Hadron Collider (LHC) has caught our attention partly due to the film "Angels and Demons." In the movie, an antimatter bomb attack on the Vatican is foiled by the protagonist. Perhaps just as controversial is the formation of mini black holes (BHs). Recently, the American Physical Society…

  9. Tau physics at p[bar p] colliders

    SciTech Connect

    Konigsberg, J. . High Energy Physics Lab.)

    1993-01-01

    Tau detection techniques in hadron colliders are discussed together with the measurements and searches performed so far. We also underline the importance tau physics has in present and future collider experiments.

  10. Tau physics at p{bar p} colliders

    SciTech Connect

    Konigsberg, J.

    1993-01-01

    Tau detection techniques in hadron colliders are discussed together with the measurements and searches performed so far. We also underline the importance tau physics has in present and future collider experiments.

  11. Linear Collider Physics Resource Book Snowmass 2001

    SciTech Connect

    Ronan , M.T.

    2001-06-01

    The American particle physics community can look forward to a well-conceived and vital program of experimentation for the next ten years, using both colliders and fixed target beams to study a wide variety of pressing questions. Beyond 2010, these programs will be reaching the end of their expected lives. The CERN LHC will provide an experimental program of the first importance. But beyond the LHC, the American community needs a coherent plan. The Snowmass 2001 Workshop and the deliberations of the HEPAP subpanel offer a rare opportunity to engage the full community in planning our future for the next decade or more. A major accelerator project requires a decade from the beginning of an engineering design to the receipt of the first data. So it is now time to decide whether to begin a new accelerator project that will operate in the years soon after 2010. We believe that the world high-energy physics community needs such a project. With the great promise of discovery in physics at the next energy scale, and with the opportunity for the uncovering of profound insights, we cannot allow our field to contract to a single experimental program at a single laboratory in the world. We believe that an e{sup +}e{sup -} linear collider is an excellent choice for the next major project in high-energy physics. Applying experimental techniques very different from those used at hadron colliders, an e{sup +}e{sup -} linear collider will allow us to build on the discoveries made at the Tevatron and the LHC, and to add a level of precision and clarity that will be necessary to understand the physics of the next energy scale. It is not necessary to anticipate specific results from the hadron collider programs to argue for constructing an e{sup +}e{sup -} linear collider; in any scenario that is now discussed, physics will benefit from the new information that e{sup +}e{sup -} experiments can provide. This last point merits further emphasis. If a new accelerator could be designed and

  12. Mechanisms and structural determinants of HIV-1 coat protein, gp41-induced neurotoxicity.

    PubMed

    Adamson, D C; Kopnisky, K L; Dawson, T M; Dawson, V L

    1999-01-01

    Of the individuals with human immunodeficiency virus type 1 (HIV-1) infection, 20-30% will develop the neurological complication of HIV-associated dementia (HAD). The mechanisms underlying HAD are unknown; however, indirect immunologically mediated mechanisms are theorized to play a role. Recently, the HIV-1 coat protein gp41 has been implicated as a major mediator of HAD through induction of neurocytokines and subsequent neuronal cell death. Using primary mixed cortical cultures from neuronal nitric oxide synthase (NOS) null (nNOS-/-) mice and immunological NOS null (iNOS-/-) mice, we establish iNOS-derived NO as a major mediator of gp41 neurotoxicity. Neurotoxicity elicited by gp41 is markedly attenuated in iNOS-/- cultures compared with wild-type and nNOS-/- cultures. The NOS inhibitor L-nitroarginine methyl ester is neuroprotective in wild-type and nNOS-/- cultures, confirming the role of iNOS-derived NO in gp41 neurotoxicity. Confirming that iNOS-/- cultures lack iNOS, gp41 did not induce iNOS in iNOS-/- cultures, but it markedly induced iNOS in wild-type and nNOS-/- cultures. We elucidate the region of gp41 that is critical for iNOS induction and neuronal cell death by monitoring iNOS induction with overlapping peptides spanning gp41. We show that the N-terminal region of gp41, which we designate as the neurotoxic domain, induces iNOS protein activity and iNOS-dependent neurotoxicity at picomolar concentrations in a manner similar to recombinant gp41 protein. Our experiments suggest that gp41 is eliciting the induction of iNOS through potential cell surface receptors or binding sites because the induction of iNOS is dose dependent and saturable and occurs at physiologically relevant concentrations. These data confirm that the induction of iNOS by gp41 and the production of NO are primary mediators of neuronal damage and identify a neurotoxic domain of gp41 that may play an important role in HAD. PMID:9870939

  13. Towards a Future Linear Collider and The Linear Collider Studies at CERN

    ScienceCinema

    None

    2011-10-06

    During the week 18-22 October, more than 400 physicists will meet at CERN and in the CICG (International Conference Centre Geneva) to review the global progress towards a future linear collider. The 2010 International Workshop on Linear Colliders will study the physics, detectors and accelerator complex of a linear collider covering both the CLIC and ILC options. Among the topics presented and discussed will be the progress towards the CLIC Conceptual Design Report in 2011, the ILC Technical Design Report in 2012, physics and detector studies linked to these reports, and an increasing numbers of common working group activities. The seminar will give an overview of these topics and also CERN?s linear collider studies, focusing on current activities and initial plans for the period 2011-16. n.b: The Council Chamber is also reserved for this colloquium with a live transmission from the Main Auditorium.

  14. Membrane insertion and assembly of epitope-tagged gp9 at the tip of the M13 phage

    PubMed Central

    2011-01-01

    Background Filamentous M13 phage extrude from infected Escherichia coli with a tip structure composed of gp7 and gp9. This tip structure is extended by the assembly of the filament composed of the major coat protein gp8. Finally, gp3 and gp6 terminate the phage structure at the proximal end. Up to now, gp3 has been the primary tool for phage display technology. However, gp7, gp8 and gp9 could also be used for phage display and these phage particles should bind to two different or more surfaces when the modified coat proteins are combined. Therefore, we tested here if the amino-terminal end of gp9 can be modified and whether the modified portion is exposed and detectable on the M13 phage particles. Results The amino-terminal region of gp9 was modified by inserting short sequences that encode antigenic epitopes. We show here that the modified gp9 proteins correctly integrate into the membrane using the membrane insertase YidC exposing the modified epitope into the periplasm. The proteins are then efficiently assembled onto the phage particles. Also extensions up to 36 amino acid residues at the amino-terminal end of gp9 did not interfere with membrane integration and phage assembly. The exposure of the antigenic tags on the phage was visualised with immunogold labelling by electron microscopy and verified by dot blotting with antibodies to the tags. Conclusions Our results suggest that gp9 at the phage tip is suitable for the phage display technology. The modified gp9 can be supplied in trans from a plasmid and fully complements M13 phage with an amber mutation in gene 9. The modified phage tip is very well accessible to antibodies. PMID:21943062

  15. High-brightness injectors for hadron colliders

    SciTech Connect

    Wangler, T.P.

    1990-01-01

    The counterrotating beams in collider rings consist of trains of beam bunches with N{sub B} particles per bunch, spaced a distance S{sub B} apart. When the bunches collide, the interaction rate is determined by the luminosity, which is defined as the interaction rate per unit cross section. For head-on collisions between cylindrical Gaussian beams moving at speed {beta}c, the luminosity is given by L = N{sub B}{sup 2}{beta}c/4{pi}{sigma}{sup 2}S{sub B}, where {sigma} is the rms beam size projected onto a transverse plane (the two transverse planes are assumed identical) at the interaction point. This beam size depends on the rms emittance of the beam and the focusing strength, which is a measure of the 2-D phase-space area in each transverse plane, and is defined in terms of the second moments of the beam distribution. Our convention is to use the rms normalized emittance, without factors of 4 or 6 that are sometimes used. The quantity {tilde {beta}} is the Courant-Synder betatron amplitude function at the interaction point, a characteristic of the focusing lattice and {gamma} is the relativistic Lorentz factor. Achieving high luminosity at a given energy, and at practical values of {tilde {beta}} and S{sub B}, requires a large value for the ratio N{sub B}{sup 2}/{var epsilon}{sub n}, which implies high intensity and small emittance. Thus, specification of the luminosity sets the requirements for beam intensity and emittance, and establishes the requirements on the performance of the injector to the collider ring. In general, for fixed N{sub B}, the luminosity can be increased if {var epsilon}{sub n} can be reduced. The minimum emittance of the collider is limited by the performance of the injector; consequently the design of the injector is of great importance for the ultimate performance of the collider.

  16. Muon capture for the front end of a muon collider

    SciTech Connect

    Neuffer, D.; Yoshikawa, C.; /MUONS Inc., Batavia

    2011-03-01

    We discuss the design of the muon capture front end for a {mu}{sup +}-{mu}{sup -} Collider. In the front end, a proton bunch on a target creates secondary pions that drift into a capture transport channel, decaying into muons. A sequence of rf cavities forms the resulting muon beams into strings of bunches of differing energies, aligns the bunches to (nearly) equal central energies, and initiates ionization cooling. The muons are then cooled and accelerated to high energy into a storage ring for high-energy high luminosity collisions. Our initial design is based on the somewhat similar front end of the International Design Study (IDS) neutrino factory.

  17. Neutrino Factory and Muon Collider Collaboration R and D Program

    SciTech Connect

    Zisman, M.S.

    2000-07-01

    The Neutrino Factory and Muon Collider Collaboration (MC) comprises some 140 scientists and engineers located at U.S. National Laboratories and Universities, and at a number of non-U.S. research institutions. In the past year, the MC R and D program has shifted its focus mainly toward the design issues related to the development of a Neutrino Factory based on a muon storage ring. In this paper the status of the various R and D activities is described, and future plans are outlined.

  18. Design of a 6 TeV Muon Collider

    SciTech Connect

    Wang, M-H.; Nosochkov, Y.; Cai, Y.; Palmer, M.

    2015-06-01

    A design of a muon collider ring with the center of mass energy of 6 TeV is presented. The ring circumference is about 6.3 km, and the $\\beta$ functions at collision point are 1 cm in both planes. The ring linear optics, the non-linear chromaticity correction scheme in the Interaction Region (IR), and the additional non-linear field orthogonal knobs are described. The IR magnet specifications are based on the maximum pole tip field of 20 T in dipoles and 15 T in quadrupoles. The results of the beam dynamics optimization for maximum dynamic aperture are presented.

  19. Double diffraction dissociation at the Fermilab Tevatron collider.

    PubMed

    Affolder, T; Akimoto, H; Akopian, A; Albrow, M G; Amaral, P; Amidei, D; Anikeev, K; Antos, J; Apollinari, G; Arisawa, T; Asakawa, T; Ashmanskas, W; Azfar, F; Azzi-Bacchetta, P; Bacchetta, N; Bailey, M W; Bailey, S; de Barbaro, P; Barbaro-Galtieri, A; Barnes, V E; Barnett, B A; Baroiant, S; Barone, M; Bauer, G; Bedeschi, F; Belforte, S; Bell, W H; Bellettini, G; Bellinger, J; Benjamin, D; Bensinger, J; Beretvas, A; Berge, J P; Berryhill, J; Bhatti, A; Binkley, M; Bisello, D; Bishai, M; Blair, R E; Blocker, C; Bloom, K; Blumenfeld, B; Blusk, S R; Bocci, A; Bodek, A; Bokhari, W; Bolla, G; Bonushkin, Y; Borras, K; Bortoletto, D; Boudreau, J; Brandl, A; van Den Brink, S; Bromberg, C; Brozovic, M; Bruner, N; Buckley-Geer, E; Budagov, J; Budd, H S; Burkett, K; Busetto, G; Byon-Wagner, A; Byrum, K L; Cabrera, S; Calafiura, P; Campbell, M; Carithers, W; Carlson, J; Carlsmith, D; Caskey, W; Castro, A; Cauz, D; Cerri, A; Chan, A W; Chang, P S; Chang, P T; Chapman, J; Chen, C; Chen, Y C; Cheng, M T; Chertok, M; Chiarelli, G; Chirikov-Zorin, I; Chlachidze, G; Chlebana, F; Christofek, L; Chu, M L; Chung, Y S; Ciobanu, C I; Clark, A G; Connolly, A; Convery, M; Conway, J; Cordelli, M; Cranshaw, J; Cropp, R; Culbertson, R; Dagenhart, D; D'Auria, S; DeJongh, F; Dell'Agnello, S; Dell'Orso, M; Demortier, L; Deninno, M; Derwent, P F; Devlin, T; Dittmann, J R; Dominguez, A; Donati, S; Done, J; D'Onofrio, M; Dorigo, T; Eddy, N; Einsweiler, K; Elias, J E; Engels, E; Erbacher, R; Errede, D; Errede, S; Fan, Q; Feild, R G; Fernandez, J P; Ferretti, C; Field, R D; Fiori, I; Flaugher, B; Foster, G W; Franklin, M; Freeman, J; Friedman, J; Fukui, Y; Furic, I; Galeotti, S; Gallas, A; Gallinaro, M; Gao, T; Garcia-Sciveres, M; Garfinkel, A F; Gatti, P; Gay, C; Gerdes, D W; Giannetti, P; Glagolev, V; Glenzinski, D; Gold, M; Goldstein, J; Gorelov, I; Goshaw, A T; Gotra, Y; Goulianos, K; Green, C; Grim, G; Gris, P; Groer, L; Grosso-Pilcher, C; Guenther, M; Guillian, G; Guimaraes Da Costa, J; Haas, R M; Haber, C; Hahn, S R; Hall, C; Handa, T; Handler, R; Hao, W; Happacher, F; Hara, K; Hardman, A D; Harris, R M; Hartmann, F; Hatakeyama, K; Hauser, J; Heinrich, J; Heiss, A; Herndon, M; Hill, C; Hoffman, K D; Holck, C; Hollebeek, R; Holloway, L; Hughes, R; Huston, J; Huth, J; Ikeda, H; Incandela, J; Introzzi, G; Iwai, J; Iwata, Y; James, E; Jones, M; Joshi, U; Kambara, H; Kamon, T; Kaneko, T; Karr, K; Kasha, H; Kato, Y; Keaffaber, T A; Kelley, K; Kelly, M; Kennedy, R D; Kephart, R; Khazins, D; Kikuchi, T; Kilminster, B; Kim, B J; Kim, D H; Kim, H S; Kim, M J; Kim, S B; Kim, S H; Kim, Y K; Kirby, M; Kirk, M; Kirsch, L; Klimenko, S; Koehn, P; Kondo, K; Konigsberg, J; Korn, A; Korytov, A; Kovacs, E; Kroll, J; Kruse, M; Kuhlmann, S E; Kurino, K; Kuwabara, T; Laasanen, A T; Lai, N; Lami, S; Lammel, S; Lancaster, J; Lancaster, M; Lander, R; Latino, G; LeCompte, T; Lee, A M; Lee, K; Leone, S; Lewis, J D; Lindgren, M; Liss, T M; Liu, J B; Liu, Y C; Litvintsev, D O; Lobban, O; Lockyer, N; Loken, J; Loreti, M; Lucchesi, D; Lukens, P; Lusin, S; Lyons, L; Lys, J; Madrak, R; Maeshima, K; Maksimovic, P; Malferrari, L; Mangano, M; Mariotti, M; Martignon, G; Martin, A; Matthews, J A; Mayer, J; Mazzanti, P; McFarland, K S; McIntyre, P; McKigney, E; Menguzzato, M; Menzione, A; Mesropian, C; Meyer, A; Miao, T; Miller, R; Miller, J S; Minato, H; Miscetti, S; Mishina, M; Mitselmakher, G; Moggi, N; Moore, E; Moore, R; Morita, Y; Moulik, T; Mulhearn, M; Mukherjee, A; Muller, T; Munar, A; Murat, P; Murgia, S; Nachtman, J; Nagaslaev, V; Nahn, S; Nakada, H; Nakano, I; Nelson, C; Nelson, T; Neu, C; Neuberger, D; Newman-Holmes, C; Ngan, C Y; Niu, H; Nodulman, L; Nomerotski, A; Oh, S H; Oh, Y D; Ohmoto, T; Ohsugi, T; Oishi, R; Okusawa, T; Olsen, J; Orejudos, W; Pagliarone, C; Palmonari, F; Paoletti, R; Papadimitriou, V; Partos, D; Patrick, J; Pauletta, G; Paulini, M; Paus, C; Pescara, L; Phillips, T J; Piacentino, G; Pitts, K T; Pompos, A; Pondrom, L; Pope, G; Popovic, M; Prokoshin, F; Proudfoot, J; Ptohos, F; Pukhov, O; Punzi, G; Rakitine, A; Reher, D; Reichold, A; Ribon, A; Riegler, W; Rimondi, F; Ristori, L; Riveline, M; Robertson, W J; Robinson, A; Rodrigo, T; Rolli, S; Rosenson, L; Roser, R; Rossin, R; Roy, A; Ruiz, A; Safonov, A; St Denis, R; Sakumoto, W K; Saltzberg, D; Sanchez, C; Sansoni, A; Santi, L; Sato, H; Savard, P; Schlabach, P; Schmidt, E E; Schmidt, M P; Schmitt, M; Scodellaro, L; Scott, A; Scribano, A; Segler, S; Seidel, S; Seiya, Y; Semenov, A; Semeria, F; Shah, T; Shapiro, M D; Shepard, P F; Shibayama, T; Shimojima, M; Shochet, M; Sidoti, A; Siegrist, J; Sill, A; Sinervo, P; Singh, P; Slaughter, A J; Sliwa, K; Smith, C; Snider, F D; Solodsky, A; Spalding, J; Speer, T; Sphicas, P; Spinella, F; Spiropulu, M; Spiegel, L; Steele, J; Stefanini, A; Strologas, J; Strumia, F; Stuart, D; Sumorok, K; Suzuki, T; Takano, T; Takashima, R; Takikawa, K; Tamburello, P; Tanaka, M

    2001-10-01

    We present results from a measurement of double diffraction dissociation in pp collisions at the Fermilab Tevatron collider. The production cross section for events with a central pseudorapidity gap of width Deltaeta(0)>3 (overlapping eta = 0) is found to be 4.43+/-0.02(stat)+/-1.18(syst) mb [ 3.42+/-0.01(stat)+/-1.09(syst) mb] at square root of (s) = 1800[630] GeV. Our results are compared with previous measurements and with predictions based on Regge theory and factorization. PMID:11580642

  20. Murine leukemia virus envelope gp70 is a shared biomarker for the high-sensitivity quantification of murine tumor burden

    PubMed Central

    Scrimieri, Francesca; Askew, David; Corn, David J; Eid, Saada; Bobanga, Iuliana D; Bjelac, Jaclyn A; Tsao, Matthew L; Allen, Frederick; Othman, Youmna S; Wang, Shih-Chung G; Huang, Alex Y

    2013-01-01

    The preclinical development of anticancer drugs including immunotherapeutics and targeted agents relies on the ability to detect minimal residual tumor burden as a measure of therapeutic efficacy. Real-time quantitative (qPCR) represents an exquisitely sensitive method to perform such an assessment. However, qPCR-based applications are limited by the availability of a genetic defect associated with each tumor model under investigation. Here, we describe an off-the-shelf qPCR-based approach to detect a broad array of commonly used preclinical murine tumor models. In particular, we report that the mRNA coding for the envelope glycoprotein 70 (gp70) encoded by the endogenous murine leukemia virus (MuLV) is universally expressed in 22 murine cancer cell lines of disparate histological origin but is silent in 20 out of 22 normal mouse tissues. Further, we detected the presence of as few as 100 tumor cells in whole lung extracts using qPCR specific for gp70, supporting the notion that this detection approach has a higher sensitivity as compared with traditional tissue histology methods. Although gp70 is expressed in a wide variety of tumor cell lines, it was absent in inflamed tissues, non-transformed cell lines, or pre-cancerous lesions. Having a high-sensitivity biomarker for the detection of a wide range of murine tumor cells that does not require additional genetic manipulations or the knowledge of specific genetic alterations present in a given neoplasm represents a unique experimental tool for investigating metastasis, assessing antitumor therapeutic interventions, and further determining tumor recurrence or minimal residual disease. PMID:24482753

  1. The use of aqueous two-phase systems to concentrate and purify bovine leukemia virus outer envelope protein gp51.

    PubMed

    Hammar, L; Merza, M; Malm, K; Eriksson, S; Morein, B

    1989-06-01

    Enzootic bovine leucosis is a chronic lymphoproliferative disease of cattle. The causative agent, bovine leukemia virus (BLV), is related to the human retroviruses HTLV-I and -II. The external env-protein of BLV, a glycoprotein of 51 kDa, carries neutralizing epitopes and should be an essential component in a vaccine against the virus. Problems have been encountered with the concentration and purification of intact virions of BLV and other retroviruses. During centrifugation procedures the external env-proteins are to a great extent detached and consequently poorly recovered with the virion particles. Therefore, other methods are sought to obtain a high yield of the external glycoproteins. The use of two-phase systems based on water soluble polymers is described for the extraction of BLV-gp51 from culture medium. Several polymer systems were tested and the results showed that some were attractive for large scale application. The classical combination dextran-polyethylene glycol gave promising results; a partition coefficient of about 0.02 was obtained for the distribution of the gp51 between the top and combined inter- and bottom phases. In a single extraction step it was possible to obtain 45% of the glycoprotein in a small volume bottom phase and at the same time about 15-fold purified. That should be compared with a recovery of less than 20% with the conventional centrifugation procedures. It is concluded that extraction in phase systems based on water soluble polymers is a methodology well suited for the concentration and purification of BLV-gp51. PMID:2474306

  2. First Results from the Phobos Experiment at the RHIC Collider

    NASA Astrophysics Data System (ADS)

    Katzy, Judith; Back, B. B.; Baker, M. D.; Barton, D. S.; Betts, R. R.; Bindel, R.; Budzanowski, A.; Busza, W.; Carroll, A.; Decowski, M. P.; Garcia, E.; George, N.; Gulbrandsen, K.; Gushue, S.; Halliwell, C.; Heintzelman, G. A.; Henderson, C.; Holyński, R.; Hofman, D.; Holzman, B.; Johnson, E.; Kane, J.; Katzy, J.; Kulinich, P.; Kucewicz, W.; Lin, W. T.; McLeod, D.; Manly, S.; Michalowski, J.; Mignerey, A.; Muelmenstaedt, J.; Nouicer, R.; Olszewski, A.; Pak, R.; Park, I. C.; Pernegger, H.; Reed, C.; Remsberg, L. P.; Reuter, M.; Roland, C.; Roland, G.; Rosenberg, L.; Sarin, P.; Sawicki, P.; Skulski, W.; Steadman, S. G.; Stephans, G. S. F.; Steinberg, P.; Stodulski, M.; Sukhanov, A.; Tang, J.-L.; Teng, R.; Trzupek, A.; Vale, C.; van Nieuwenhuizen, G. J.; Verdier, R.; Wadsworth, B.; Wolfs, F. L. H.; Wosiek, B.; Woźniak, K.; Wuosmaa, A. H.; Wysłouch, B.

    PHOBOS is one of the four experiments at the Relativistic Heavy Ion Collider that started colliding gold nuclei at a center of mass energy of √sNN = 56 and 130 GeV per pair of colliding nucleons in June 2000. The pseudorapidity density of primary charged particles in central collisions has been measured near mid-rapidity.

  3. Role for the disulfide-bonded region of human immunodeficiency virus type 1 gp41 in receptor-triggered activation of membrane fusion function

    SciTech Connect

    Bellamy-McIntyre, Anna K.; Baer, Severine; Ludlow, Louise; Drummer, Heidi E.; Poumbourios, Pantelis

    2010-04-16

    The conserved disulfide-bonded region (DSR) of the human immunodeficiency virus type 1 (HIV-1) fusion glycoprotein, gp41, mediates association with the receptor-binding glycoprotein, gp120. Interactions between gp120, CD4 and chemokine receptors activate the fusion activity of gp41. The introduction of W596L and W610F mutations to the DSR of HIV-1{sub QH1549.13} blocked viral entry and hemifusion without affecting gp120-gp41 association. The fusion defect correlated with inhibition of CD4-triggered gp41 pre-hairpin formation, consistent with the DSR mutations having decoupled receptor-induced conformational changes in gp120 from gp41 activation. Our data implicate the DSR in sensing conformational changes in the gp120-gp41 complex that lead to fusion activation.

  4. Increased Generation of HIV-1 gp120-Reactive CD8+ T Cells by a DNA Vaccine Construct Encoding the Chemokine CCL3

    PubMed Central

    Øynebråten, Inger; Hinkula, Jorma; Fredriksen, Agnete B.; Bogen, Bjarne

    2014-01-01

    DNA vaccines based on subunits from pathogens have several advantages over other vaccine strategies. DNA vaccines can easily be modified, they show good safety profiles, are stable and inexpensive to produce, and the immune response can be focused to the antigen of interest. However, the immunogenicity of DNA vaccines which is generally quite low needs to be improved. Electroporation and co-delivery of genetically encoded immune adjuvants are two strategies aiming at increasing the efficacy of DNA vaccines. Here, we have examined whether targeting to antigen-presenting cells (APC) could increase the immune response to surface envelope glycoprotein (Env) gp120 from Human Immunodeficiency Virus type 1 (HIV-1). To target APC, we utilized a homodimeric vaccine format denoted vaccibody, which enables covalent fusion of gp120 to molecules that can target APC. Two molecules were tested for their efficiency as targeting units: the antibody-derived single chain Fragment variable (scFv) specific for the major histocompatilibility complex (MHC) class II I-E molecules, and the CC chemokine ligand 3 (CCL3). The vaccines were delivered as DNA into muscle of mice with or without electroporation. Targeting of gp120 to MHC class II molecules induced antibodies that neutralized HIV-1 and that persisted for more than a year after one single immunization with electroporation. Targeting by CCL3 significantly increased the number of HIV-1 gp120-reactive CD8+ T cells compared to non-targeted vaccines and gp120 delivered alone in the absence of electroporation. The data suggest that chemokines are promising molecular adjuvants because small amounts can attract immune cells and promote immune responses without advanced equipment such as electroporation. PMID:25122197

  5. The Cholera Toxin B Subunit (CTB) Fused to the Porcine Arterivirus Matrix M and GP5 Envelope Proteins Fails to Enhance the GP5-Specific Antibody Response in Pigs Immunized with Adenovectors.

    PubMed

    Roques, Elodie; Lessard, Martin; Archambault, Denis

    2015-08-01

    The porcine reproductive and respiratory syndrome virus (PRRSV) is an arterivirus of the Arteriviridae family. As the current commercial vaccines are incompletely protective effective against PRRSV infection, we developed a vaccine strategy using replicating but non-disseminating adenovectors (rAdVs) expressing the PRRSV M matrix protein in fusion with the neutralizing major epitope-carrying GP5 envelope protein (Roques et al. in Vet Res 44:17, 2013). Although production of GP5-specific antibodies (Abs) was observed, no PRRSV-specific neutralizing Abs (NAbs) were induced in pigs given the rAdVs expressing M-GP5 or M-GP5m (GP5m being a mutant form of GP5). Nevertheless, partial protection was observed in the M-GP5m-rAdV-inoculated pigs experimentally infected with PRRSV. Here, we determined the impact of the cholera toxin B subunit (CTB, known for its adjuvant effect) in fusion with the C-terminus of M-GP5m on the Ab response to PRRSV. Three-week-old pigs were immunized twice both intramuscularly and intranasally at 3-week intervals with rAdV-expressing the green fluorescent protein (rAdV-GFP), rAdV-M-GP5m, or rAdV-M-GP5m-CTB. Pigs immunized with rAdV-M-GP5m showed a high level of serum GP5-specific Abs (as determined by an indirect ELISA). In contrast, CTB in fusion with M-GP5m had an unexpected severe negative impact on GP5-specific Ab production. PRRSV-specific NAbs could not be detected in any pigs of all groups. PMID:25801418

  6. An energy recovery electron linac-on-ring collider

    SciTech Connect

    Merminga, L.; Krafft, G.A.; Lebedev, V.A.; Ben-Zvi, I.

    2000-09-14

    We present the design of high-luminosity electron-proton/ion colliders in which the electrons are produced by an Energy Recovering Linac (ERL). Electron-proton/ion colliders with center of mass energies between 14 GeV and 100 GeV (protons) or 63 GeV/A (ions) and luminosities at the 10{sup 33}(per nucleon) level have been proposed recently as a means for studying hadronic structure. The linac-on-ring option presents significant advantages with respect to: (1) spin manipulations (2) reduction of the synchrotron radiation load in the detectors (3) a wide range of continuous energy variability. Rf power and beam dump considerations require that the electron linac recover the beam energy. Based on extrapolations from actual measurements and calculations, energy recovery is expected to be feasible at currents of a few hundred mA and multi-GeV energies. Luminosity projections for the linac-ring scenario based on fundamental limitations are presented. The feasibility of an energy recovery electron linac-on-proton ring collider is investigated and four conceptual point designs are shown corresponding to electron to proton energies of: 3 GeV on 15 GeV, 5 GeV on 50 GeV and 10 GeV on 250 GeV, and for gold ions with 100 GeV/A. The last two designs assume that the protons or ions are stored in the existing RHIC accelerator. Accelerator physics issues relevant to proton rings and energy recovery linacs are discussed and a list of required R and D for the realization of such a design is presented.

  7. Department of Energy assessment of the Large Hadron Collider

    SciTech Connect

    1996-06-01

    This report summarizes the conclusions of the committee that assessed the cost estimate for the Large Hadron Collider (LHC). This proton-proton collider will be built at CERN, the European Laboratory for Particle Physics near Geneva, Switzerland. The committee found the accelerator-project cost estimate of 2.3 billion in 1995 Swiss francs, or about $2 billion US, to be adequate and reasonable. The planned project completion date of 2005 also appears achievable, assuming the resources are available when needed. The cost estimate was made using established European accounting procedures. In particular, the cost estimate does not include R and D, prototyping and testing, spare parts, and most of the engineering labor. Also excluded are costs for decommissioning the Large Electron-Positron collider (LEP) that now occupies the tunnel, modifications to the injector system, the experimental areas, preoperations costs, and CERN manpower. All these items are assumed by CERN to be included in the normal annual operations budget rather than the construction budget. Finally, contingency is built into the base estimate, in contrast to Department of Energy (DOE) estimates that explicitly identify contingency. The committee`s charge, given by Dr. James F. Decker, Deputy Directory of the DOE Office of Energy Research, was to understand the basis for the LHC cost estimate, identify uncertainties, and judge the overall validity of the estimate, proposed schedule, and related issues. The committee met at CERN April 22--26, 1996. The assessment was based on the October 1995 LHC Conceptual Design Report or ``Yellow Book,`` cost estimates and formal presentations made by the CERN staff, site inspection, detailed discussions with LHC technical experts, and the committee members` considerable experience.

  8. Engineering and exploitation of a fluorescent HIV-1 gp120 for live cell CD4 binding assays

    SciTech Connect

    Costantini, Lindsey M.; Irvin, Susan C.; Kennedy, Steven C.; Guo, Feng; Goldstein, Harris; Herold, Betsy C.; Snapp, Erik L.

    2015-02-15

    The HIV-1 envelope glycoprotein, gp120, binds the host cell receptor, CD4, in the initial step of HIV viral entry and infection. This process is an appealing target for the development of inhibitory drugs and neutralizing antibodies. To study gp120 binding and intracellular trafficking, we engineered a fluorescent fusion of the humanized gp120 JRFL HIV-1 variant and GFP. Gp120-sfGFP is glycosylated with human sugars, robustly expressed, and secreted from cultured human cells. Protein dynamics, quality control, and trafficking can be visualized in live cells. The fusion protein can be readily modified with different gp120 variants or fluorescent proteins. Finally, secreted gp120-sfGFP enables a sensitive and easy binding assay that can quantitatively screen potential inhibitors of gp120-CD4 binding on live cells via fluorescence imaging or laser scanning cytometry. This adaptable research tool should aid in studies of gp120 cell biology and the development of novel anti-HIV drugs. - Highlights: • Development of fluorescent protein labeled HIV-1 envelope gp120. • Imaging of gp120 dynamics and trafficking in live cells. • Quantitative visual assay of antibody-mediated inhibition of gp120 binding to CD4 on live cells.

  9. A gp130-Src-YAP Module Links Inflammation to Epithelial Regeneration

    PubMed Central

    Taniguchi, Koji; Wu, Li-Wha; Grivennikov, Sergei I.; de Jong, Petrus R.; Lian, Ian; Yu, Fa-Xing; Wang, Kepeng; Ho, Samuel B.; Boland, Brigid S.; Chang, John T.; Sandborn, William J.; Hardiman, Gary; Raz, Eyal; Maehara, Yoshihiko; Yoshimura, Akihiko; Zucman-Rossi, Jessica; Guan, Kun-Liang; Karin, Michael

    2015-01-01

    Summary Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members whose expression is elevated in many diseases, including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). We show that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the classic gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signaling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated upon receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signaling module is strongly activated upon mucosal injury to promote healing and maintain barrier function. PMID:25731159

  10. The human fibroblast receptor for gp86 of human cytomegalovirus is a phosphorylated glycoprotein.

    PubMed Central

    Keay, S; Baldwin, B

    1992-01-01

    A human embryonic lung (HEL) cell receptor for gp86 of human cytomegalovirus that functions in virus-cell fusion was further characterized. Anti-idiotype antibodies that mimic gp86 were used to immunoprecipitate the 92.5-kDa fibroblast membrane receptor for gp86, which was preincubated with various endoglycosidases. The receptor, which has a pI ranging from 5.3 to 5.6, appears to be a glycoprotein with primarily N-linked sugar residues, some of which have high concentrations of mannose and some of which are complex oligosaccharides. Western blots (immunoblots) of electrophoretically transferred receptor incubated with various biotinylated lectins confirmed the presence of sugar moieties, including N-acetylglucosamine, glucose or mannose, and galactose, but not fucose or N-acetylgalactosamine. This gp86 receptor from uninfected HEL cells also incorporated radiolabeled phosphate from orthophosphoric acid, indicating that it is a constitutively phosphorylated receptor. Images PMID:1321272

  11. 76 FR 28764 - Northwest Pipeline, GP; Notice of Availability of the Environmental Assessment for the Proposed...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-18

    ... Energy Regulatory Commission Northwest Pipeline, GP; Notice of Availability of the Environmental Assessment for the Proposed Molalla Capacity Replacement Project The staff of the Federal Energy Regulatory Commission (FERC or Commission) has prepared an environmental assessment (EA) for the Molalla...

  12. Effects of heat shock protein gp96 on human dendritic cell maturation and CTL expansion.

    PubMed

    Zhang, Yuxia; Zan, Yanlu; Shan, Ming; Liu, Changmei; Shi, Ming; Li, Wei; Zhang, Zhixin; Liu, Na; Wang, Fusheng; Zhong, Weidong; Liao, Fulian; Gao, George F; Tien, Po

    2006-06-01

    We reported previously that heat shock protein gp96 and its N-terminal fragment were able to stimulate CTL expansion specific for a HBV peptide (SYVNTNMGL) in BALB/c mice. Here we characterized the adjuvant effects of gp96 on human HLA-A2 restricted T cells. Full-length gp96 isolated from healthy human liver and recombinant fragments both from prokaryotic cells and eukaryotic cells were analyzed for their ability to stimulate maturation of human dendritic cells. It was found that in vitro these proteins were capable of maturating human monocyte-derived dendritic cells (MDDC) isolated from healthy donors as well as from HBV-positive, hepatocellular carcinoma (HCC) patients. In HLA-A2.1/Kb transgenic mice, gp96 and the recombinant fragments were found to augment CTL response specific for the HBcAg(18-27) FLPSDFFPSV peptide of hepatitis B virus. PMID:16630554

  13. Lessons from the GP-B Experience for Future Fundamental Physics Missions in Space

    NASA Technical Reports Server (NTRS)

    Kolodziejczak, Jeffery

    2006-01-01

    Gravity Probe B launched in April 2004 and completed its science data collection in September 2005, with the objective of sub-milliarcsec measurement of two General Relativistic effects on the spin axis orientation of orbiting gyroscopes. Much of the technology required by GP-B has potential application in future missions intended to make precision measurements. The philosophical approach and experiment design principles developed for GP-B are equally adaptable to these mission concepts. This talk will discuss GP-B's experimental approach and the technological and philosophical lessons learned that apply to future experiments in fundamental physics. Measurement of fundamental constants to high precision, probes of short-range forces, searches for equivalence principle violations, and detection of gravitational waves are examples of concepts and missions that will benefit kern GP-B's experience.

  14. N-alkylated isatins evade P-gp mediated efflux and retain potency in MDR cancer cell lines.

    PubMed

    Vine, Kara L; Belfiore, Lisa; Jones, Luke; Locke, Julie M; Wade, Samantha; Minaei, Elahe; Ranson, Marie

    2016-01-01

    The search for novel anticancer therapeutics with the ability to overcome multi-drug resistance (MDR) mechanisms is of high priority. A class of molecules that show potential in overcoming MDR are the N-alkylated isatins. In particular 5,7-dibromo-N-alkylisatins are potent microtubule destabilizing agents that act to depolymerize microtubules, induce apoptosis and inhibit primary tumor growth in vivo. In this study we evaluated the ability of four dibrominated N-alkylisatin derivatives and the parent compound, 5,7-dibromoisatin, to circumvent MDR. All of the isatin-based compounds examined retained potency against the MDR cell lines; U937VbR and MES-SA/Dx5 and displayed bioequivalent dose-dependent cytotoxicity to that of the parental control cell lines. We show that one mechanism by which the isatin-based compounds overcome MDR is by circumventing P-glycoprotein (P-gp) mediated drug efflux. Thus, as the isatin-based compounds are not susceptible to extrusion from P-gp overexpressing tumor cells, they represent a promising alternative strategy as a stand-alone or combination therapy for treating MDR cancer. PMID:27441242

  15. 9-D polarized proton transport in the MEIC figure-8 collider ring: first steps

    SciTech Connect

    Meot, F.; Morozov, V. S.

    2014-10-24

    Spin tracking studies in the MEIC figure-8 collider ion ring are presented, based on a very preliminary design of the lattice. They provide numerical illustrations of some of the aspects of the figure-8 concept, including spin-rotator based spin control, and lay out the path towards a complete spin tracking simulation of a figure-8 ring.

  16. 9-D polarized proton transport in the MEIC figure 8 collider ring - first steps

    SciTech Connect

    Meot, F.; Morozov, V. S.

    2015-05-03

    Spin tracking studies in the MEIC figure-8 collider ion ring are presented, based on a very preliminary design of the lattice. They provide numerical illustrations of some of the aspects of the figure-8 concept, including spin-rotator based spin control, and lay out the path towards a complete spin tracking simulation of a figure-8 ring.

  17. A review of further training for GP appraisers in Scotland.

    PubMed

    Staples, Ian; Wakeling, Judy; Cameron, Niall

    2010-01-01

    A one-day further intensive skills (FIS) course has been developed to provide additional training for existing general practitioner (GP) appraisers in Scotland. The course focuses on skills in developing the appraisee's personal development portfolio (PDP) and skills in responding to significant issues (with emotional content) presented by appraisees - both key areas for effective appraisals. The course is briefly described. An initial pilot of the course led to some changes being made to the content, as it was discovered that the inclusion of training on Summary Form completion in the pilot made the course too dense and distracted from the experiential elements of the training. Two subsequent course deliveries were evaluated by conducting semi-structured interviews with over 40% of the participants from these two courses. The main purpose of the evaluation was to discover to what extent the participants felt they had benefited from the training and whether they felt the training had led to any changes in their practice as appraisers. Secondary aims were to discover the acceptability of the use of video recording as a training technique and views regarding a reaccreditation process for appraisers. Key findings were that almost all participants found this training beneficial and judged it to have led to positive changes in their practice, as well as reassuring them that their skills were up to scratch. Some appraisers felt that it had encouraged a slightly more challenging approach. The acceptability of the use of video recording during the training, as a means of allowing participants to gain further benefit from the work undertaken after the course was finished, was tested. This technique received a mixed response, with opinion divided as to whether it added value. Opinion amongst the participants was also mixed regarding whether this training should contribute towards their reaccreditation as appraisers. However, a number of participants felt this could be a

  18. A Wnt5a signaling pathway in the pathogenesis of HIV-1 gp120-induced pain

    PubMed Central

    Yuan, Su-Bo; Ji, Guangchen; Li, Bei; Andersson, Tommy; Neugebauer, Volker; Tang, Shao-Jun

    2015-01-01

    Pathological pain is one of the most common neurological complications in HIV-1/AIDS patients. However, the pathogenic process is unclear. Our recent studies show that Wnt5a is up-regulated in the spinal cord dorsal horn of the HIV patients who develop pain and that HIV-1 gp120, a potential causal factor of the HIV-associated pain, rapidly up-regulates Wnt5a in the mouse SDH. Using a mouse model, we show here that a specific Wnt5a antagonist, Box-5, attenuated gp120-induced mechanical allodynia. Conversely, a Wnt5a agonist, Foxy5, facilitated the allodynia. To elucidate the molecular mechanism by which Wnt5a regulates gp120-induced allodynia, we tested the role of the JNK/TNF-α pathway. We observed that the JNK-specific inhibitor SP600125 blocked either gp120- or Foxy5-induced allodynia. Similarly, the TNF-α-specific antagonist Enbrel also reversed either gp120- or Foxy5-induced allodynia. These data suggest that JNK and TNF-α mediate the biological effects of Wnt5a in regulating gp120-induced allodynia. To investigate the cellular mechanism, we performed extracellular single-unit recording from SDH neurons in anesthetized mice. Both Box5 and SP600125 negated gp120-induced potentiation of SDH neuron spiking evoked by mechanical stimulation of the hindpaw. Furthermore, while Foxy5 potentiated spike frequency of SDH neurons, either SP600125 or Enbrel blocked the potentiation. The data indicate that Wnt5a potentiates the activity of SDH neurons via the JNK-TNF-α pathway. Collectively, our findings suggest that Wnt5a regulates the pathogenesis of gp120-induced pain, likely by sensitizing pain-processing SDH neurons via JNK/TNF-α signaling. PMID:25840108

  19. Targeting HIV-1 Env gp140 to LOX-1 Elicits Immune Responses in Rhesus Macaques.

    PubMed

    Zurawski, Gerard; Zurawski, Sandra; Flamar, Anne-Laure; Richert, Laura; Wagner, Ralf; Tomaras, Georgia D; Montefiori, David C; Roederer, Mario; Ferrari, Guido; Lacabaratz, Christine; Bonnabau, Henri; Klucar, Peter; Wang, Zhiqing; Foulds, Kathryn E; Kao, Shing-Fen; Yates, Nicole L; LaBranche, Celia; Jacobs, Bertram L; Kibler, Karen; Asbach, Benedikt; Kliche, Alexander; Salazar, Andres; Reed, Steve; Self, Steve; Gottardo, Raphael; Galmin, Lindsey; Weiss, Deborah; Cristillo, Anthony; Thiebaut, Rodolphe; Pantaleo, Giuseppe; Levy, Yves

    2016-01-01

    Improved antigenicity against HIV-1 envelope (Env) protein is needed to elicit vaccine-induced protective immunity in humans. Here we describe the first tests in non-human primates (NHPs) of Env gp140 protein fused to a humanized anti-LOX-1 recombinant antibody for delivering Env directly to LOX-1-bearing antigen presenting cells, especially dendritic cells (DC). LOX-1, or 1ectin-like oxidized low-density lipoprotein (LDL) receptor-1, is expressed on various antigen presenting cells and endothelial cells, and is involved in promoting humoral immune responses. The anti-LOX-1 Env gp140 fusion protein was tested for priming immune responses and boosting responses in animals primed with replication competent NYVAC-KC Env gp140 vaccinia virus. Anti-LOX-1 Env gp140 vaccination elicited robust cellular and humoral responses when used for either priming or boosting immunity. Co-administration with Poly ICLC, a TLR3 agonist, was superior to GLA, a TLR4 agonist. Both CD4+ and CD8+ Env-specific T cell responses were elicited by anti-LOX-1 Env gp140, but in particular the CD4+ T cells were multifunctional and directed to multiple epitopes. Serum IgG and IgA antibody responses induced by anti-LOX-1 Env gp140 against various gp140 domains were cross-reactive across HIV-1 clades; however, the sera neutralized only HIV-1 bearing sequences most similar to the clade C 96ZM651 Env gp140 carried by the anti-LOX-1 vehicle. These data, as well as the safety of this protein vaccine, justify further exploration of this DC-targeting vaccine approach for protective immunity against HIV-1. PMID:27077384

  20. Targeting HIV-1 Env gp140 to LOX-1 Elicits Immune Responses in Rhesus Macaques

    PubMed Central

    Zurawski, Sandra; Flamar, Anne-Laure; Richert, Laura; Wagner, Ralf; Tomaras, Georgia D.; Montefiori, David C.; Roederer, Mario; Ferrari, Guido; Lacabaratz, Christine; Bonnabau, Henri; Klucar, Peter; Wang, Zhiqing; Foulds, Kathryn E.; Kao, Shing-Fen; Yates, Nicole L.; LaBranche, Celia; Jacobs, Bertram L.; Kibler, Karen; Asbach, Benedikt; Kliche, Alexander; Salazar, Andres; Reed, Steve; Self, Steve; Gottardo, Raphael; Galmin, Lindsey; Weiss, Deborah; Cristillo, Anthony; Thiebaut, Rodolphe; Pantaleo, Giuseppe; Levy, Yves

    2016-01-01

    Improved antigenicity against HIV-1 envelope (Env) protein is needed to elicit vaccine-induced protective immunity in humans. Here we describe the first tests in non-human primates (NHPs) of Env gp140 protein fused to a humanized anti-LOX-1 recombinant antibody for delivering Env directly to LOX-1-bearing antigen presenting cells, especially dendritic cells (DC). LOX-1, or 1ectin-like oxidized low-density lipoprotein (LDL) receptor-1, is expressed on various antigen presenting cells and endothelial cells, and is involved in promoting humoral immune responses. The anti-LOX-1 Env gp140 fusion protein was tested for priming immune responses and boosting responses in animals primed with replication competent NYVAC-KC Env gp140 vaccinia virus. Anti-LOX-1 Env gp140 vaccination elicited robust cellular and humoral responses when used for either priming or boosting immunity. Co-administration with Poly ICLC, a TLR3 agonist, was superior to GLA, a TLR4 agonist. Both CD4+ and CD8+ Env-specific T cell responses were elicited by anti-LOX-1 Env gp140, but in particular the CD4+ T cells were multifunctional and directed to multiple epitopes. Serum IgG and IgA antibody responses induced by anti-LOX-1 Env gp140 against various gp140 domains were cross-reactive across HIV-1 clades; however, the sera neutralized only HIV-1 bearing sequences most similar to the clade C 96ZM651 Env gp140 carried by the anti-LOX-1 vehicle. These data, as well as the safety of this protein vaccine, justify further exploration of this DC-targeting vaccine approach for protective immunity against HIV-1. PMID:27077384