Science.gov

Sample records for fusion inhibitor escape

  1. Inhibition of HIV-1 by fusion inhibitors.

    PubMed

    Eggink, Dirk; Berkhout, Ben; Sanders, Rogier W

    2010-01-01

    The envelope glycoprotein complex (Env) is responsible for entry of the human immunodeficiency virus type 1 (HIV-1) into cells by mediating attachment to target cells and subsequent membrane fusion. Env consists of three gp120 subunits that mediate receptor and co-receptor attachment and three gp41 subunits responsible for membrane fusion. Several steps of the entry process can serve as drug targets. Receptor antagonists prevent attachment of gp120 to the receptor or co-receptor and conformational changes within gp41 required for membrane fusion can be inhibited by fusion inhibitors. Enfuvirtide (T20, Fuzeon) is a peptide based on the gp41 sequence and is the only approved fusion inhibitor. It prevents membrane fusion by competitively binding to gp41 and blocking the formation of the post-fusion structure. New generations of T20-like peptides have been developed with improved potency and stability. Besides T20 and derivatives, other fusion inhibitors have been developed that target different domains of gp41. Here we discuss the development of fusion inhibitors, their mode of action and their potential for incorporation in future drug regimens.

  2. Sifuvirtide, a potent HIV fusion inhibitor peptide

    SciTech Connect

    Wang, Rui-Rui; Yang, Liu-Meng; Wang, Yun-Hua; Pang, Wei; Tam, Siu-Cheung; Tien, Po; Zheng, Yong-Tang

    2009-05-08

    Enfuvirtide (ENF) is currently the only FDA approved HIV fusion inhibitor in clinical use. Searching for more drugs in this category with higher efficacy and lower toxicity seems to be a logical next step. In line with this objective, a synthetic peptide with 36 amino acid residues, called Sifuvirtide (SFT), was designed based on the crystal structure of gp41. In this study, we show that SFT is a potent anti-HIV agent with relatively low cytotoxicity. SFT was found to inhibit replication of all tested HIV strains. The effective concentrations that inhibited 50% viral replication (EC{sub 50}), as determined in all tested strains, were either comparable or lower than benchmark values derived from well-known anti-HIV drugs like ENF or AZT, while the cytotoxic concentrations causing 50% cell death (CC{sub 50}) were relatively high, rendering it an ideal anti-HIV agent. A GST-pull down assay was performed to confirm that SFT is a fusion inhibitor. Furthermore, the activity of SFT on other targets in the HIV life cycle was also investigated, and all assays showed negative results. To further understand the mechanism of action of HIV peptide inhibitors, resistant variants of HIV-1{sub IIIB} were derived by serial virus passage in the presence of increasing doses of SFT or ENF. The results showed that there was cross-resistance between SFT and ENF. In conclusion, SFT is an ideal anti-HIV agent with high potency and low cytotoxicity, but may exhibit a certain extent of cross-resistance with ENF.

  3. Development of HIV-1 fusion inhibitors targeting gp41.

    PubMed

    Lu, K; Asyifah, M R; Shao, F; Zhang, D

    2014-06-01

    The HIV-1 envelope protein glycoprotein 41 (gp41) is crucial in the HIV-1 infection process, therefore gp41 has emerged as an attractive target for drug design against AIDS. During the past few decades, tremendous efforts have been made on developing inhibitors that can prevent the HIV-1 entry process via suppressing functional gp41. In this review, the development of HIV-1 fusion inhibitors targeting gp41 including peptide inhibitors, small molecule inhibitors, vaccines and neutralized antibodies will be discussed.

  4. A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways.

    PubMed

    Spring, Bryan Q; Bryan Sears, R; Zheng, Lei Zak; Mai, Zhiming; Watanabe, Reika; Sherwood, Margaret E; Schoenfeld, David A; Pogue, Brian W; Pereira, Stephen P; Villa, Elizabeth; Hasan, Tayyaba

    2016-04-01

    Nanoscale drug delivery vehicles can facilitate multimodal therapies of cancer by promoting tumour-selective drug release. However, few are effective because cancer cells develop ways to resist and evade treatment. Here, we introduce a photoactivable multi-inhibitor nanoliposome (PMIL) that imparts light-induced cytotoxicity in synchrony with a photoinitiated and sustained release of inhibitors that suppress tumour regrowth and treatment escape signalling pathways. The PMIL consists of a nanoliposome doped with a photoactivable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing cabozantinib (XL184)--a multikinase inhibitor--encapsulated inside. Near-infrared tumour irradiation, following intravenous PMIL administration, triggers photodynamic damage of tumour cells and microvessels, and simultaneously initiates release of XL184 inside the tumour. A single PMIL treatment achieves prolonged tumour reduction in two mouse models and suppresses metastatic escape in an orthotopic pancreatic tumour model. The PMIL offers new prospects for cancer therapy by enabling spatiotemporal control of drug release while reducing systemic drug exposure and associated toxicities.

  5. Characterization of Potent Fusion Inhibitors of Influenza Virus

    PubMed Central

    Rowse, Michael; Qiu, Shihong; Tsao, Jun; Xian, Tongmei; Khawaja, Sarah; Yamauchi, Yohei; Yang, Zhen; Wang, Guoxin; Luo, Ming

    2015-01-01

    New inhibitors of influenza viruses are needed to combat the potential emergence of novel human influenza viruses. We have identified a class of small molecules that inhibit replication of influenza virus at picomolar concentrations in plaque reduction assays. The compound also inhibits replication of vesicular stomatitis virus. Time of addition and dilution experiments with influenza virus indicated that an early time point of infection was blocked and that inhibitor 136 tightly bound to virions. Using fluorescently labeled influenza virus, inhibition of viral fusion to cellular membranes by blocked lipid mixing was established as the mechanism of action for this class of inhibitors. Stabilization of the neutral pH form of hemagglutinin (HA) was ruled out by trypsin digestion studies in vitro and with conformation specific HA antibodies within cells. Direct visualization of 136 treated influenza virions at pH 7.5 or acidified to pH 5.0 showed that virions remain intact and that glycoproteins become disorganized as expected when HA undergoes a conformational change. This suggests that exposure of the fusion peptide at low pH is not inhibited but lipid mixing is inhibited, a different mechanism than previously reported fusion inhibitors. We hypothesize that this new class of inhibitors intercalate into the virus envelope altering the structure of the viral envelope required for fusion to cellular membranes. PMID:25803288

  6. A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways

    PubMed Central

    Spring, Bryan Q.; Sears, R. Bryan; Zheng, Lei Zak; Mai, Zhiming; Watanabe, Reika; Sherwood, Margaret E.; Schoenfeld, David A.; Pogue, Brian W.; Pereira, Stephen P.; Villa, Elizabeth; Hasan, Tayyaba

    2015-01-01

    Nanoscale drug delivery vehicles can facilitate multimodal therapies of cancer by promoting tumour-selective drug release. However, few are effective because cancer cells develop ways to resist and evade treatment. Here, we introduce a photoactivatable multi-inhibitor nanoliposome (PMIL) that imparts light-induced cytotoxicity in synchrony with photo-initiated and sustained release of inhibitors that suppress tumour regrowth and treatment escape signalling pathways. The PMIL consists of a nanoliposome doped with a photoactivatable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing cabozantinib (XL184)—a multikinase inhibitor—encapsulated inside. Near infrared tumour irradiation, following intravenous PMIL administration, triggers photodynamic damage of tumour cells and microvessels, and simultaneously initiates release of XL184 inside the tumour. A single PMIL treatment achieves prolonged tumour reduction in two mouse models and suppresses metastatic escape in an orthotopic pancreatic tumour model. The PMIL offers new prospects for cancer therapy by enabling spatiotemporal control of drug release whilst reducing systemic drug exposure and associated toxicities. PMID:26780659

  7. A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways

    NASA Astrophysics Data System (ADS)

    Spring, Bryan Q.; Bryan Sears, R.; Zheng, Lei Zak; Mai, Zhiming; Watanabe, Reika; Sherwood, Margaret E.; Schoenfeld, David A.; Pogue, Brian W.; Pereira, Stephen P.; Villa, Elizabeth; Hasan, Tayyaba

    2016-04-01

    Nanoscale drug delivery vehicles can facilitate multimodal therapies of cancer by promoting tumour-selective drug release. However, few are effective because cancer cells develop ways to resist and evade treatment. Here, we introduce a photoactivable multi-inhibitor nanoliposome (PMIL) that imparts light-induced cytotoxicity in synchrony with a photoinitiated and sustained release of inhibitors that suppress tumour regrowth and treatment escape signalling pathways. The PMIL consists of a nanoliposome doped with a photoactivable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing cabozantinib (XL184)—a multikinase inhibitor—encapsulated inside. Near-infrared tumour irradiation, following intravenous PMIL administration, triggers photodynamic damage of tumour cells and microvessels, and simultaneously initiates release of XL184 inside the tumour. A single PMIL treatment achieves prolonged tumour reduction in two mouse models and suppresses metastatic escape in an orthotopic pancreatic tumour model. The PMIL offers new prospects for cancer therapy by enabling spatiotemporal control of drug release while reducing systemic drug exposure and associated toxicities.

  8. Identification of Novel Fusion Inhibitors of Influenza A Virus by Chemical Genetics

    PubMed Central

    Lai, Kin Kui; Cheung, Nam Nam; Yang, Fang; Dai, Jun; Liu, Li; Chen, Zhiwei; Sze, Kong Hung; Chen, Honglin

    2015-01-01

    ABSTRACT A previous screening of more than 50,000 compounds led to the identification of a pool of bioactive small molecules with inhibitory effect on the influenza A virus. One of these compounds, now widely known as nucleozin, is a small molecule that targets the influenza A virus nucleoprotein. Here we identify and characterize two structurally different novel fusion inhibitors of the influenza A virus group 1 hemagglutinin (HA), FA-583 and FA-617, with low nanomolar activities. Escape mutants that are highly resistant to each of these compounds were generated, and both were found to carry mutations localized in close proximity to the B-loop of the hemagglutinin 2 protein, which plays a crucial role in the virion-host cell fusion process. Recombinant virus, generated through reverse genetics, confirmed the resistance phenotype. In addition, the proposed binding pockets predicted by molecular docking studies are in accordance with the resistance-bearing mutation sites. We show through mechanistic studies that FA-583 and FA-617 act as fusion inhibitors by prohibiting the low-pH-induced conformational change of hemagglutinin. Our study has offered concrete biological and mechanistic explorations for the strategic development of novel fusion inhibitors of influenza A viruses. IMPORTANCE Here we report two structurally distinctive novel fusion inhibitors of influenza A virus that act by interfering with the structural change of HA at acidic pH, a process necessary for successful entry of the virus. Mutational and molecular docking studies have identified their binding pockets situated in close proximity to the B-loop region of hemagglutinin 2. The reduced sensitivity of FA-583- or FA-617-associated mutants to another compound suggests a close proximity and even partial overlap of their binding sites on hemagglutinin. Amino acid sequence alignments and crystal structure analyses of group 1 and group 2 hemagglutinins have shed light on the possible binding mode of

  9. Flaviviridae viruses use a common molecular mechanism to escape nucleoside analogue inhibitors.

    PubMed

    Valdés, James J; Butterill, Philip T; Růžek, Daniel

    2017-03-18

    The RNA-dependent RNA polymerases of Flaviviridae viruses are crucial for replication. The Flaviviridae polymerase is organized into structural motifs (A-G), with motifs F, A, C and E containing interrogating, priming and catalytic substrate-interacting sites. Modified nucleoside analogues act as antiviral drugs by targeting Flaviviridae polymerases and integrating into the synthesized product causing premature termination. A threonine mutation of a conserved serine residue in motif B of Flaviviridae polymerases renders resistance to 2'-C-methylated nucleoside analogues. The mechanism how this single mutation causes Flaviviridae viruses to escape nucleoside analogues is not yet known. Given the pivotal position of the serine residue in motif B that supports motif F, we hypothesized the threonine mutation causes alterations in nucleoside exploration within the entry tunnel. Implementing a stochastic molecular software showed the all-atom 2'-C-methylated analogue reaction within the active sites of wild type and serine-threonine mutant polymerases from Hepacivirus and Flavivirus. Compared with the wild type, the serine-threonine mutant polymerases caused a significant decrease of analogue contacts with conserved interrogating residues in motif F and a displacement of metal ion cofactors. The simulations significantly showed that during the analogue exploration of the active site the hydrophobic methyl group in the serine-threonine mutant repels water-mediated hydrogen bonds with the 2'-C-methylated analogue, causing a concentration of water-mediated bonds at the substrate-interacting sites. Collectively, the data are an insight into a molecular escape mechanism by Flaviviridae viruses from 2'-C-methylated nucleoside analogue inhibitors.

  10. Antiviral activity of a Rac GEF inhibitor characterized with a sensitive HIV/SIV fusion assay

    SciTech Connect

    Pontow, Suzanne; Harmon, Brooke; Campbell, Nancy; Ratner, Lee

    2007-11-10

    A virus-dependent fusion assay was utilized to examine the activity of a panel of HIV-1, -2, and SIV isolates of distinct coreceptor phenotypes. This assay allowed identification of entry inhibitors, and characterization of an antagonist of a Rac guanine nucleotide exchange factor, as an inhibitor of HIV-mediated fusion.

  11. Albumin-conjugated C34 Peptide HIV-1 Fusion Inhibitor

    PubMed Central

    Stoddart, Cheryl A.; Nault, Geneviève; Galkina, Sofiya A.; Thibaudeau, Karen; Bakis, Peter; Bousquet-Gagnon, Nathalie; Robitaille, Martin; Bellomo, Maryanne; Paradis, Véronique; Liscourt, Patricia; Lobach, Alexandra; Rivard, Marie-Ève; Ptak, Roger G.; Mankowski, Marie K.; Bridon, Dominique; Quraishi, Omar

    2008-01-01

    Entry inhibitors of human immunodeficiency virus, type 1 (HIV-1) have been the focus of much recent research. C34, a potent fusion inhibitor derived from the HR2 region of gp41, was engineered into a 1:1 human serum albumin conjugate through stable covalent attachment of a maleimido-C34 analog onto cysteine 34 of albumin. This bioconjugate, PC-1505, was designed to require less frequent dosing and less peptide than T-20 and was assessed for its antifusogenic activity both in vitro and in vivo in the SCID-hu Thy/Liv mouse model. PC-1505 was essentially equipotent to the original C34 peptide and to T-20 in vitro. In HIV-1-infected SCID-hu Thy/Liv mice, T-20 lost activity with infrequent dosing, whereas the antiviral potency of PC-1505 was sustained, and PC-1505 was active against T-20-resistant (“DIV”) virus with a G36D substitution in gp41. The in vivo results are the direct result of a significantly improved pharmacokinetic profile for the C34 peptide following albumin conjugation. Contrary to previous reports that the gp41 NHR trimer is poorly accessible to C34 fused to protein cargoes of increasing size (Hamburger, A. E., Kim, S., Welch, B. D., and Kay, M. S. (2005) J. Biol. Chem. 280, 12567–12572), these results are the first demonstration of the capacity for a large, endogenous serum protein to gain unobstructed access to the transient gp41 intermediates that exist during the HIV fusion process, and it supports further development of albumin conjugation as a promising approach to inhibit HIV-1 entry. PMID:18809675

  12. Escape from Human Immunodeficiency Virus Type 1 (HIV-1) Entry Inhibitors

    PubMed Central

    De Feo, Christopher J.; Weiss, Carol D.

    2012-01-01

    The human immunodeficiency virus (HIV) enters cells through a series of molecular interactions between the HIV envelope protein and cellular receptors, thus providing many opportunities to block infection. Entry inhibitors are currently being used in the clinic, and many more are under development. Unfortunately, as is the case for other classes of antiretroviral drugs that target later steps in the viral life cycle, HIV can become resistant to entry inhibitors. In contrast to inhibitors that block viral enzymes in intracellular compartments, entry inhibitors interfere with the function of the highly variable envelope glycoprotein as it continuously adapts to changing immune pressure and available target cells in the extracellular environment. Consequently, pathways and mechanisms of resistance for entry inhibitors are varied and often involve mutations across the envelope gene. This review provides a broad overview of entry inhibitor resistance mechanisms that inform our understanding of HIV entry and the design of new inhibitors and vaccines. PMID:23342377

  13. Serious infection from Staphylococcus aureus in 2 HIV-infected patients receiving fusion inhibitor therapy.

    PubMed

    Gaughan, Elizabeth M; Ritter, Michelle L; Kumar, Princy N; Timpone, Joseph G

    2008-05-01

    Fusion inhibitors are novel antiretroviral agents, administered as subcutaneous injections, approved for use in treatment-experienced HIV-infected patients. HIV-infected patients are at increased risk for Staphylococcus aureus colonization, specifically with methicillin-resistant S aureus (MRSA), and subsequent systemic infection. We present the cases of 2 patients without a history of MRSA infection in whom a series of severe S aureus infections developed after fusion inhibitor therapy.

  14. A generic screening platform for inhibitors of virus induced cell fusion using cellular electrical impedance

    PubMed Central

    Watterson, Daniel; Robinson, Jodie; Chappell, Keith J.; Butler, Mark S.; Edwards, David J.; Fry, Scott R.; Bermingham, Imogen M.; Cooper, Matthew A.; Young, Paul R.

    2016-01-01

    Fusion of the viral envelope with host cell membranes is an essential step in the life cycle of all enveloped viruses. Despite such a clear target for antiviral drug development, few anti-fusion drugs have progressed to market. One significant hurdle is the absence of a generic, high-throughput, reproducible fusion assay. Here we report that real time, label-free measurement of cellular electrical impedance can quantify cell-cell fusion mediated by either individually expressed recombinant viral fusion proteins, or native virus infection. We validated this approach for all three classes of viral fusion and demonstrated utility in quantifying fusion inhibition using antibodies and small molecule inhibitors specific for dengue virus and respiratory syncytial virus. PMID:26976324

  15. Effects of ROCK inhibitor Y-27632 on cell fusion through a microslit.

    PubMed

    Wada, Ken-Ichi; Hosokawa, Kazuo; Ito, Yoshihiro; Maeda, Mizuo

    2015-11-01

    We previously reported a direct cytoplasmic transfer method using a microfluidic device, in which cell fusion was induced through a microslit (slit-through-fusion) by the Sendai virus envelope (HVJ-E) to prevent nuclear mixing. However, the method was impractical due to low efficiency of slit-through-fusion formation and insufficient prevention of nuclear mixing. The purpose of this study was to establish an efficient method for inducing slit-through-fusion without nuclear mixing. We hypothesized that modulation of cytoskeletal component can decrease nuclear migration through the microslit considering its functions. Here we report that supplementation with Y-27632, a specific ROCK inhibitor, significantly enhances cell fusion induction and prevention of nuclear mixing. Supplementation with Y-27632 increased the formation of slit-through-fusion efficiency by more than twofold. Disruption of F-actin by Y-27632 prevented nuclear migration between fused cells through the microslit. These two effects of Y-27632 led to promotion of the slit-through-fusion without nuclear mixing with a 16.5-fold higher frequency compared to our previous method (i.e., cell fusion induction by HVJ-E without supplementation with Y-27632). We also confirmed that mitochondria were successfully transferred to the fusion partner under conditions of Y-27632 supplementation. These findings demonstrate the practicality of our cell fusion system in producing direct cytoplasmic transfer between live cells.

  16. Convenient cell fusion assay for rapid screening for HIV entry inhibitors

    NASA Astrophysics Data System (ADS)

    Jiang, Shibo; Radigan, Lin; Zhang, Li

    2000-03-01

    Human immunodeficiency viruses (HIV)-induced cell fusion is a critical pathway of HIV spread from infected cells to uninfected cells. A rapid and simple assay was established to measure HIV-induce cell fusion. This study is particularly useful to rapid screen for HIV inhibitors that block HIV cell-to-cell transmission. Present study demonstrated that coculture of HIV-infected cells with uninfected cells at 37 degree(s)C for 2 hours resulted in the highest cell fusion rate. Using this cell fusion assay, we have identified several potent HIV inhibitors targeted to the HIV gp41 core. These antiviral agents can be potentially developed as antiviral drugs for chemotherapy and prophylaxis of HIV infection and AIDS.

  17. Identification of a human protein-derived HIV-1 fusion inhibitor targeting the gp41 fusion core structure.

    PubMed

    Chao, Lijun; Lu, Lu; Yang, Hengwen; Zhu, Yun; Li, Yuan; Wang, Qian; Yu, Xiaowen; Jiang, Shibo; Chen, Ying-Hua

    2013-01-01

    The HIV-1 envelope glycoprotein (Env) gp41 plays a crucial role in the viral fusion process. The peptides derived from the C-terminal heptad repeat (CHR) of gp41 are potent HIV fusion inhibitors. However, the activity of these anti-HIV-1 peptides in vivo may be attenuated by their induction of anti-gp41 antibodies. Thus, it is essential to identify antiviral peptides or proteins with low, or no, immunogenicity to humans. Here, we found that the C-terminal fragment (aa 462-521) of the human POB1 (the partner of RalBP1), designated C60, is an HIV-1 fusion inhibitor. It bound to N36, the peptide derived from the N-terminal heptad repeat (NHR) of gp41, and to the six-helix bundle (6-HB) formed by N36 and C34, a CHR-peptide, but it did not bind to C34. Unlike the CHR-peptides, C60 did not block gp41 6-HB formation. Rather, results suggest that C60 inhibits HIV-1 fusion by binding to the 6-HB, in particular, the residues in the gp41 NHR domain that are exposed on the surface of 6-HB. Since 6-HB plays a crucial role in the late stage of fusion between the viral envelope and endosomal membrane during the endocytic process of HIV-1, C60 may serve as a host restriction factor to suppress HIV-1 entry into CD4+ T lymphocytes. Taken together, it can be concluded from these results that C60 can be used as a lead for the development of anti-HIV-1 therapeutics or microbicides for the treatment and prevention of HIV-1 infection, as well as a molecular probe to study the fusogenic mechanism of HIV-1.

  18. Escape from neutralization by the respiratory syncytial virus-specific neutralizing monoclonal antibody palivizumab is driven by changes in on-rate of binding to the fusion protein

    SciTech Connect

    Bates, John T.; Keefer, Christopher J.; Slaughter, James C.; Kulp, Daniel W.; Schief, William R.

    2014-04-15

    The role of binding kinetics in determining neutralizing potency for antiviral antibodies is poorly understood. While it is believed that increased steady-state affinity correlates positively with increased virus-neutralizing activity, the relationship between association or dissociation rate and neutralization potency is unclear. We investigated the effect of naturally-occurring antibody resistance mutations in the RSV F protein on the kinetics of binding to palivizumab. Escape from palivizumab-mediated neutralization of RSV occurred with reduced association rate (K{sub on}) for binding to RSV F protein, while alteration of dissociation rate (K{sub off}) did not significantly affect neutralizing activity. Interestingly, linkage of reduced K{sub on} with reduced potency mirrored the effect of increased K{sub on} found in a high-affinity enhanced potency palivizumab variant (motavizumab). These data suggest that association rate is the dominant factor driving neutralization potency for antibodies to RSV F protein antigenic site A and determines the potency of antibody somatic variants or efficiency of escape of viral glycoprotein variants. - Highlights: • The relationship of affinity to neutralization for virus antibodies is uncertain. • Palivizumab binds to RSV escape mutant fusion proteins, but with reduced affinity. • Association rate (K{sub on}) correlated well with the potency of neutralization.

  19. Trivalency of a Nanobody Specific for the Human Respiratory Syncytial Virus Fusion Glycoprotein Drastically Enhances Virus Neutralization and Impacts Escape Mutant Selection.

    PubMed

    Palomo, Concepción; Mas, Vicente; Detalle, Laurent; Depla, Erik; Cano, Olga; Vázquez, Mónica; Stortelers, Catelijne; Melero, José A

    2016-11-01

    ALX-0171 is a trivalent Nanobody derived from monovalent Nb017 that binds to antigenic site II of the human respiratory syncytial virus (hRSV) fusion (F) glycoprotein. ALX-0171 is about 6,000 to 10,000 times more potent than Nb017 in neutralization tests with strains of hRSV antigenic groups A and B. To explore the effect of this enhanced neutralization on escape mutant selection, viruses resistant to either ALX-0171 or Nb017 were isolated after serial passage of the hRSV Long strain in the presence of suboptimal concentrations of the respective Nanobodies. Resistant viruses emerged notably faster with Nb017 than with ALX-0171 and in both cases contained amino acid changes in antigenic site II of hRSV F. Detailed binding and neutralization analyses of these escape mutants as well as previously described mutants resistant to certain monoclonal antibodies (MAbs) offered a comprehensive description of site II mutations which are relevant for neutralization by MAbs and Nanobodies. Notably, ALX-0171 showed a sizeable neutralization potency with most escape mutants, even with some of those selected with the Nanobody, and these findings make ALX-0171 an attractive antiviral for treatment of hRSV infections.

  20. A novel bispecific peptide HIV-1 fusion inhibitor targeting the N-terminal heptad repeat and fusion peptide domains in gp41.

    PubMed

    Jiang, Xifeng; Jia, Qiyan; Lu, Lu; Yu, Fei; Zheng, Jishen; Shi, Weiguo; Cai, Lifeng; Jiang, Shibo; Liu, Keliang

    2016-12-01

    HIV-1 fusion with the target cell is initiated by the insertion of the gp41 fusion peptide (FP) into the target cell membrane and the interaction between the gp41 N- and C-terminal heptad repeats (NHR and CHR), followed by the formation of the six-helix bundle (6-HB) fusion core. Therefore, both FP and NHR are important targets for HIV-1 fusion inhibitors. Here, we designed and synthesized a dual-target peptidic HIV-1 fusion inhibitor, 4HR-LBD-VIRIP, in which 4HR-LBD is able to bind to the gp41 NHR domain, while VIRIP is able to interact with gp41 FP. We found that 4HR-LBD-VIRIP is about tenfold more potent than 4HR-LBD and VIRIP in inhibiting HIV-1IIIB infection and HIV-1 envelope glycoprotein (Env)-mediated cell-cell fusion, suggesting that this dual-target HIV-1 fusion inhibitor possesses a strong synergistic antiviral effect. A biophysical analysis indicates that 4HR-LBD-VIRIP can interact with N70 peptide that contains the gp41 NHR and FP domains and binds with lipid membrane. This study provides a new approach for designing novel viral fusion inhibitors against HIV and other enveloped viruses with class I membrane fusion proteins.

  1. The current status and challenges in the development of fusion inhibitors as therapeutics for HIV-1 infection.

    PubMed

    Tan, Jian Jun; Ma, Xue Ting; Liu, Chang; Zhang, Xiao Yi; Wang, Cun Xin

    2013-01-01

    HIV-1 membrane fusion as a part of the process of viral entry in the target cells is facilitated by gp41 and gp120, which are encoded by Env gene of HIV-1. Based on the structure and the mechanism researches, new treatment options targeting HIV-1 entry process have been proposed. Enfuvirtide, which mimics amino acid sequences of viral envelope glycoprotein gp41, is the first HIV-1 fusion inhibitor approved by FDA. Although it fulfills vital functions by binding to gp41 and abolishing the membrane fusion reaction when used in combination, it could induce drug resistant virus variants. Currently, a number of design and modification schemes have been presented, a large number of prospective fusion peptides have emerged. For these fusion inhibitors, multiple mutations in gp41 have been associated with the loss of susceptibility to agents. This review reported the current developments and innovative designs of HIV-1 membrane fusion inhibitors.

  2. The use of hairpin DNA duplexes as HIV-1 fusion inhibitors: synthesis, characterization, and activity evaluation.

    PubMed

    Xu, Liang; Jiang, Xifeng; Xu, Xiaoyu; Zheng, Baohua; Chen, Xueliang; Zhang, Tao; Gao, Fang; Cai, Lifeng; Cheng, Maosheng; Keliang Liu

    2014-07-23

    Discovery of new drugs for the treatment of AIDS that possess unique structures associated with novel mechanisms of action are of great importance due the rapidity with which drug-resistant HIV-1 strains evolve. Recently we reported on a novel class of DNA duplex-based HIV-1 fusion inhibitors modified with hydrophobic groups. The present study describes a new category of hairpin fusion inhibitor DNA duplexes bearing a 3 nucleotide loop located at either the hydrophobic or hydrophilic end. The new loop structures were designed to link 2 separate duplex-forming oligodeoxynucleotides (ODNs) to make helix-assembly easier and more thermally stable resulting in a more compact form of DNA duplex based HIV-1 fusion inhibitors. A series of new hairpin duplexes were tested for anti-HIV-1 cell-cell membrane fusion activity. In addition, Tm, CD, fluorescent resonance energy transfer assays, and molecular modeling analyses were carried out to define their structural activity relationships and possible mechanisms of action.

  3. Multimerized HIV-gp41-derived peptides as fusion inhibitors and vaccines.

    PubMed

    Nomura, Wataru; Mizuguchi, Takaaki; Tamamura, Hirokazu

    2016-11-04

    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.

  4. The rigid amphipathic fusion inhibitor dUY11 acts through photosensitization of viruses.

    PubMed

    Vigant, Frederic; Hollmann, Axel; Lee, Jihye; Santos, Nuno C; Jung, Michael E; Lee, Benhur

    2014-02-01

    Rigid amphipathic fusion inhibitors (RAFIs) are lipophilic inverted-cone-shaped molecules thought to antagonize the membrane curvature transitions that occur during virus-cell fusion and are broad-spectrum antivirals against enveloped viruses (Broad-SAVE). Here, we show that RAFIs act like membrane-binding photosensitizers: their antiviral effect is dependent on light and the generation of singlet oxygen ((1)O(2)), similar to the mechanistic paradigm established for LJ001, a chemically unrelated class of Broad-SAVE. Photosensitization of viral membranes is a common mechanism that underlies these Broad-SAVE.

  5. [Isolation and purification of recombinant soluble and non-fusion angiogenesis inhibitor Kringle 5 using chromatography].

    PubMed

    Ma, Lina; Wu, Dan; Bian, Liujiao

    2012-08-01

    The Kringle 5 domain of plasminogen is one of the most potent angiogenesis inhibitors known to date, which can inhibit cell proliferation and migration efficiently. In the study, on the foundation of successful clone and expression of recombinant soluble and non-fusion angiogenesis inhibitor Kringle 5, a two-step chromatographic method, including the use of SP Sepharose Fast Flow cation exchanger and Sephacryl S-100 HR size exclusion chromatography in sequence, was established to separate and purify angiogenesis inhibitor Kringle 5. On the SP Sepharose Fast Flow column, the buffer A consisted of 50.0 mmol/L acetic acid-sodium acetate (pH 5.2), and the buffer B consisted of buffer A with the addition of 0.5 mol/L sodium chloride (pH 5.2); on Sephacryl S-100 HR column, the elution buffer was 5.0 mmol/L phosphate solution (pH 7.0). Through the two-step chromatographic purification process, the purity of the obtained Kringle 5 was more than 98%. In addition, it was found that the obtained Kringle 5 could inhibit the blood vessel growth of chick embryo chorioallantoic membrane effectively. Finally it is concluded that this method can effectively separate active recombinant soluble and non-fusion angiogenesis inhibitor Kringle 5.

  6. Structural Basis of Potent and Broad HIV-1 Fusion Inhibitor CP32M*

    PubMed Central

    Yao, Xue; Chong, Huihui; Zhang, Chao; Qiu, Zonglin; Qin, Bo; Han, Ruiyun; Waltersperger, Sandro; Wang, Meitian; He, Yuxian; Cui, Sheng

    2012-01-01

    CP32M is a newly designed peptide fusion inhibitor possessing potent anti-HIV activity, especially against T20-resistant HIV-1 strains. In this study, we show that CP32M can efficiently inhibit a large panel of diverse HIV-1 variants, including subtype B′, CRF07_BC, and CRF01_AE recombinants and naturally occurring or induced T20-resistant viruses. To elucidate its mechanism of action, we determined the crystal structure of CP32M complexed with its target sequence. Differing from its parental peptide, CP621-652, the 621VEWNEMT627 motif of CP32M folds into two α-helix turns at the N terminus of the pocket-binding domain, forming a novel layer in the six-helix bundle structure. Prominently, the residue Asn-624 of the 621VEWNEMT627 motif is engaged in the polar interaction with a hydrophilic ridge that borders the hydrophobic pocket on the N-terminal coiled coil. The original inhibitor design of CP32M provides several intra- and salt bridge/hydrogen bond interactions favoring the stability of the helical conformation of CP32M and its interactions with N-terminal heptad repeat (NHR) targets. We identified a novel salt bridge between Arg-557 on the NHR and Glu-648 of CP32M that is critical for the binding of CP32M and resistance against the inhibitor. Therefore, our data present important information for developing novel HIV-1 fusion inhibitors for clinical use. PMID:22679024

  7. Improved inhibitor tolerance in xylose-fermenting yeast Spathaspora passalidarum by mutagenesis and protoplast fusion.

    PubMed

    Hou, Xiaoru; Yao, Shuo

    2012-03-01

    The xylose-fermenting yeast Spathaspora passalidarum showed excellent fermentation performance utilizing glucose and xylose under anaerobic conditions. But this yeast is highly sensitive to the inhibitors such as furfural present in the pretreated lignocellulosic biomass. In order to improve the inhibitor tolerance of this yeast, a combination of UV mutagenesis and protoplast fusion was used to construct strains with improved performance. Firstly, UV-induced mutants were screened and selected for improved tolerance towards furfural. The most promised mutant, S. passalidarum M7, produced 50% more final ethanol than the wild-type strain in a synthetic xylose medium containing 2 g/l furfural. However, this mutant was unable to grow in a medium containing 75% liquid fraction of pretreated wheat straw (WSLQ), in which furfural and many other inhibitors were present. Hybrid yeast strains, obtained from fusion of the protoplasts of S. passalidarum M7 and a robust yeast, Saccharomyces cerevisiae ATCC 96581, were able to grow in 75% WSLQ and produce around 0.4 g ethanol/g consumed xylose. Among the selected hybrid strains, the hybrid FS22 showed the best fermentation capacity in 75% WSLQ. Phenotypic and partial molecular analysis indicated that S. passalidarum M7 was the dominant parental contributor to the hybrid. In summary, the hybrids are characterized by desired phenotypes derived from both parents, namely the ability to ferment xylose from S. passalidarum and an increased tolerance to inhibitors from S. cerevisiae ATCC 96581.

  8. Design, synthesis and activity evaluation of novel peptide fusion inhibitors targeting HIV-1 gp41.

    PubMed

    Tan, Jianjun; Su, Min; Zeng, Yi; Wang, Cunxin

    2016-01-15

    Human immunodeficiency virus type 1 (HIV-1), the pathogen of acquired immunodeficiency syndrome (AIDS), causes about 2 million people to death every year. Fusion inhibitors targeted the envelope protein (gp41) represent a novel and alternative approach for anti-AIDS therapy, which terminates the HIV-1 life cycle at an early stage. Using CP621-652 as a template, a series of peptides were designed, synthesized and evaluated in vitro assays. An interesting phenomenon was found that the substitution of hydrophobic residues at solvent accessible sites could increase the anti-HIV activity when the C-terminal sequence was extended with an enough numbers of amino acids. After the active peptides was synthesized and evaluated, peptide 8 showed the best anti-HIV-1 IIIB whole cell activity (MAGI IC50=53.02 nM). Further study indicated that peptide 8 bound with the gp41 NHR helix, and then blocked the conformation of 6-helix, thus inhibited virus-cell membrane fusion. The results would be helpful for the design of peptide fusion inhibitors against HIV-1 infection.

  9. Discovery of HIV fusion inhibitors targeting gp41 using a comprehensive α-helix mimetic library

    PubMed Central

    Whitby, Landon R.; Boyle, Kristopher E.; Cai, Lifeng; Yu, Xiaoqian; Gochin, Miriam; Boger, Dale L.

    2012-01-01

    The evaluation of a comprehensive α-helix mimetic library for binding the gp41 NHR hydrophobic pocket recognizing an intramolecular CHR α-helix provided a detailed depiction of structural features required for binding and led to the discovery of small molecule inhibitors (Ki 0.6–1.3 µM) that not only match or exceed the potency of those disclosed over the past decade, but that also exhibit effective activity in a cell–cell fusion assay (IC50 5–8 µM). PMID:22424973

  10. Conjugation of a nonspecific antiviral sapogenin with a specific HIV fusion inhibitor: a promising strategy for discovering new antiviral therapeutics.

    PubMed

    Wang, Chao; Lu, Lu; Na, Heya; Li, Xiangpeng; Wang, Qian; Jiang, Xifeng; Xu, Xiaoyu; Yu, Fei; Zhang, Tianhong; Li, Jinglai; Zhang, Zhenqing; Zheng, Baohua; Liang, Guodong; Cai, Lifeng; Jiang, Shibo; Liu, Keliang

    2014-09-11

    Triterpene saponins are a major group of active components in natural products with nonspecific antiviral activities, while T20 peptide (enfuvirtide), which contains a helix zone-binding domain (HBD), is a gp41-specific HIV-1 fusion inhibitor. In this paper, we report the design, synthesis, and structure-activity relationship (SAR) of a group of hybrid molecules in which bioactive triterpene sapogenins were covalently attached to the HBD-containing peptides via click chemistry. We found that either the triterpenes or peptide part alone showed weak activity against HIV-1 Env-mediated cell-cell fusion, while the hybrids generated a strong cooperative effect. Among them, P26-BApc exhibited anti-HIV-1 activity against both T20-sensitive and -resistant HIV-1 strains and improved pharmacokinetic properties. These results suggest that this scaffold design is a promising strategy for developing new HIV-1 fusion inhibitors and possibly novel antiviral therapeutics against other viruses with class I fusion proteins.

  11. Reduction of Factor VIII Inhibitor Titers During Immune Tolerance Induction With Recombinant Factor VIII-Fc Fusion Protein.

    PubMed

    Groomes, Charles L; Gianferante, David M; Crouch, Gary D; Parekh, Dina S; Scott, David W; Lieuw, Kenneth

    2016-05-01

    The development of inhibitors toward factor VIII (FVIII) is a common and serious complication of hemophilia A (HA) therapy. Patients with hemophilia who develop inhibitors often undergo time- and resource-intensive immune tolerance induction (ITI) protocols. We report a 15-month-old male with severe HA and a high-titer inhibitor that occurred while receiving prophylactic treatment with recombinant FVIII (rFVIII), in whom significant inhibitor titer reduction was achieved with thrice weekly infusions of a new, prolonged half-life rFVIII-Fc fusion protein product (trade name Eloctate). Further studies are warranted to explore the potential of Eloctate in ITI protocols.

  12. Pyrroloaryls and pyrroloheteroaryls: Inhibitors of the HIV fusion/attachment, reverse transcriptase and integrase.

    PubMed

    Patel, Rahul V; Park, Se Won

    2015-09-01

    Heterocyclic compounds execute a very important role in drug design and discovery. This article provides the basic milestones of the research for pyrroloaryl and pyrroloheteroaryl based components targeting HIV viral replication cycle. Anti-HIV activity is elaborated for several classes of pyrrolo-compounds as pyrrolopyridines, pyrrolopyrimidines, pyrrolopyridazines, pyrrolobenzodiazepinones, pyrrolobenzothiazepines, pyrrolobenzoxazepinones, pyrrolophenanthridines, pyrroloquinoxalines, pyrrolotriazines, pyrroloquinolines, pyrrolopyrazinones, pyrrolothiatriazines, arylthiopyrroles and pyrrolopyrazolones targeting two essential HIV enzymes, reverse transcriptase and integrase as well as attachment/fusion of HIV virons to the host CD-4 cell. Such attempts were resulted in a discovery of highly potent anti-HIV agents suitable for clinical trials, for example, BMS-378806, BMS-585248, BMS-626529, BMS-663068, BMS-488043 and BMS-663749, etc. as anti-HIV attachment agents, triciribine, QX432, BI-1 and BI-2 as HIV RT inhibitors which are in preclinical or clinical development. Mechanism of action of compounds presented in this article towards the suppression of HIV attachment/fusion as well as against the activities of HIV enzymes reverse transcriptase and integrase has been discussed. Relationships of new compounds' molecular framework and HIV viral target has been overviewed in order to facilitate further construction of promising anti-HIV agents in future drug discovery process.

  13. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer

    PubMed Central

    Koivunen, Jussi P.; Mermel, Craig; Zejnullahu, Kreshnik; Murphy, Carly; Lifshits, Eugene; Holmes, Alison J.; Choi, Hwan Geun; Kim, Jhingook; Chiang, Derek; Thomas, Roman; Lee, Jinseon; Richards, William G.; Sugarbaker, David J.; Ducko, Christopher; Lindeman, Neal; Marcoux, J. Paul; Engelman, Jeffrey A.; Gray, Nathanael S.; Lee, Charles; Meyerson, Matthew; Jänne, Pasi A.

    2011-01-01

    Purpose The EML4-ALK fusion gene has been detected in ~7% of Japanese non-small cell lung cancers (NSCLC). We determined the frequency of EML4-ALK in Caucasian NSCLCs and in NSCLC cell lines. We also determined whether TAE684, a specific ALK kinase inhibitor, would inhibit the growth of EML4-ALK containing cell lines in vitro and in vivo. Experimental Design We screened 305 primary NSCLCs (both US (n=138) and Korean (n=167) patients) and 83 NSCLC cell lines using RT-PCR and by exon array analyses. We evaluated the efficacy of TAE684 against NSCLC cell lines in vitro and in vivo. Results We detected 4 different variants, including two novel variants, of EML4-ALK using RT-PCR in 8/305 tumors (3%) and in 3/83 (3.6%) NSCLC cell lines. All EML4-ALK containing tumors and cell lines were adenocarcinomas. EML4-ALK was detected more frequently in NSCLC patients who were never or light (< 10 pack years) cigarette smokers compared to current/former smokers (6% vs. 1%; p=0.049). TAE684 inhibited the growth of 1 of 3 (H3122) EML4-ALK containing cell lines in vitro and in vivo, inhibited Akt phosphorylation and caused apoptosis. In another EML4-ALK cell line, DFCI032, TAE684 was ineffective due to co-activation of EGFR and ERBB2. The combination of TAE684 and CL-387,785 (EGFR/ERBB2 kinase inhibitor), inhibited growth and Akt phosphorylation and led to apoptosis in the DFCI032 cell line. Conclusions EML4-ALK is found in the minority of NSCLCs. ALK kinase inhibitors alone or in combination may nevertheless be clinically effective treatments for NSCLC patients whose tumors contain EML4-ALK. PMID:18594010

  14. A Lipopeptide HIV-1/2 Fusion Inhibitor with Highly Potent in vitro, ex vivo and in vivo Antiviral Activity.

    PubMed

    Chong, Huihui; Xue, Jing; Xiong, Shengwen; Cong, Zhe; Ding, Xiaohui; Zhu, Yuanmei; Liu, Zixuan; Chen, Ting; Feng, Yifan; He, Lei; Guo, Yan; Wei, Qiang; Zhou, Yusen; Qin, Chuan; He, Yuxian

    2017-03-29

    Peptides derived from the C-terminal heptad repeat (CHR) region of the HIV-1 fusogenic protein gp41 are potent viral entry inhibitors, and currently enfuvirtide (T-20) is the only one for clinical use; however, emerging drug-resistance largely limits its efficacy. In this study, we generated a novel lipopeptide inhibitor, named LP-19, by integrating multiple design strategies, including an N-terminal M-T hook structure, HIV-2 sequence, intra-helical salt-bridges, and a membrane-anchoring lipid tail. LP-19 showed stable binding affinity and highly potent, broad and long-lasting antiviral activity. In in vitro studies, LP-19 efficiently inhibited HIV-1, HIV-2 and SIV-mediated cell fusion, viral entry and infection, and it was highly active against diverse subtypes of primary HIV-1 isolates and inhibitor-resistant mutants. The ex vivo studies demonstrated that LP-19 exhibited dramatically increased anti-HIV activity and extended half-life in rhesus macaques. In short-term monotherapy, LP-19 reduced the viral loads to undetectable levels in acutely and chronically SHIV-infected monkeys. Therefore, this study offers an ideal HIV-1/2 fusion inhibitor for clinical development and emphasizes the importance of the viral fusion step as a drug target.IMPORTANCE The peptide drug T-20 is the only viral fusion inhibitor in clinic, which is used in combination therapy of HIV-1 infection; however, it requires high dosage and easily induces drug-resistance, calling for a new drug with significantly improved pharmaceutical profiles. Here, we have developed a short lipopeptide-based fusion inhibitor termed LP-19, which mainly targets the conserved gp41 pocket site and shows highly potent inhibitory activity on HIV-1, HIV-2 and even SIV isolates. LP-19 exhibits dramatically increased antiviral activity and extended half-life in rhesus macaques, and it has potent therapeutic efficacy in SHIV-infected monkeys, highlighting its high potential as a new viral fusion inhibitor for clinical

  15. Abelson Kinase Inhibitors Are Potent Inhibitors of Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus Fusion

    PubMed Central

    Coleman, Christopher M.; Sisk, Jeanne M.; Mingo, Rebecca M.; Nelson, Elizabeth A.; White, Judith M.

    2016-01-01

    ABSTRACT The highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) cause significant morbidity and morality. There is currently no approved therapeutic for highly pathogenic coronaviruses, even as MERS-CoV is spreading throughout the Middle East. We previously screened a library of FDA-approved drugs for inhibitors of coronavirus replication in which we identified Abelson (Abl) kinase inhibitors, including the anticancer drug imatinib, as inhibitors of both SARS-CoV and MERS-CoV in vitro. Here we show that the anti-CoV activity of imatinib occurs at the early stages of infection, after internalization and endosomal trafficking, by inhibiting fusion of the virions at the endosomal membrane. We specifically identified the imatinib target, Abelson tyrosine-protein kinase 2 (Abl2), as required for efficient SARS-CoV and MERS-CoV replication in vitro. These data demonstrate that specific approved drugs can be characterized in vitro for their anticoronavirus activity and used to identify host proteins required for coronavirus replication. This type of study is an important step in the repurposing of approved drugs for treatment of emerging coronaviruses. IMPORTANCE Both SARS-CoV and MERS-CoV are zoonotic infections, with bats as the primary source. The 2003 SARS-CoV outbreak began in Guangdong Province in China and spread to humans via civet cats and raccoon dogs in the wet markets before spreading to 37 countries. The virus caused 8,096 confirmed cases of SARS and 774 deaths (a case fatality rate of ∼10%). The MERS-CoV outbreak began in Saudi Arabia and has spread to 27 countries. MERS-CoV is believed to have emerged from bats and passed into humans via camels. The ongoing outbreak of MERS-CoV has resulted in 1,791 cases of MERS and 640 deaths (a case fatality rate of 36%). The emergence of SARS-CoV and MERS-CoV provides evidence that coronaviruses are currently spreading from zoonotic

  16. Separating myoblast differentiation from muscle cell fusion using IGF-I and the p38 MAP kinase inhibitor SB202190

    PubMed Central

    Gardner, Samantha; Gross, Sean M.; David, Larry L.; Klimek, John E.

    2015-01-01

    The p38 MAP kinases play critical roles in skeletal muscle biology, but the specific processes regulated by these kinases remain poorly defined. Here we find that activity of p38α/β is important not only in early phases of myoblast differentiation, but also in later stages of myocyte fusion and myofibrillogenesis. By treatment of C2 myoblasts with the promyogenic growth factor insulin-like growth factor (IGF)-I, the early block in differentiation imposed by the p38 chemical inhibitor SB202190 could be overcome. Yet, under these conditions, IGF-I could not prevent the later impairment of muscle cell fusion, as marked by the nearly complete absence of multinucleated myofibers. Removal of SB202190 from the medium of differentiating myoblasts reversed the fusion block, as multinucleated myofibers were detected several hours later and reached ∼90% of the culture within 30 h. Analysis by quantitative mass spectroscopy of proteins that changed in abundance following removal of the inhibitor revealed a cohort of upregulated muscle-enriched molecules that may be important for both myofibrillogenesis and fusion. We have thus developed a model system that allows separation of myoblast differentiation from muscle cell fusion and should be useful in identifying specific steps regulated by p38 MAP kinase-mediated signaling in myogenesis. PMID:26246429

  17. Separating myoblast differentiation from muscle cell fusion using IGF-I and the p38 MAP kinase inhibitor SB202190.

    PubMed

    Gardner, Samantha; Gross, Sean M; David, Larry L; Klimek, John E; Rotwein, Peter

    2015-10-01

    The p38 MAP kinases play critical roles in skeletal muscle biology, but the specific processes regulated by these kinases remain poorly defined. Here we find that activity of p38α/β is important not only in early phases of myoblast differentiation, but also in later stages of myocyte fusion and myofibrillogenesis. By treatment of C2 myoblasts with the promyogenic growth factor insulin-like growth factor (IGF)-I, the early block in differentiation imposed by the p38 chemical inhibitor SB202190 could be overcome. Yet, under these conditions, IGF-I could not prevent the later impairment of muscle cell fusion, as marked by the nearly complete absence of multinucleated myofibers. Removal of SB202190 from the medium of differentiating myoblasts reversed the fusion block, as multinucleated myofibers were detected several hours later and reached ∼90% of the culture within 30 h. Analysis by quantitative mass spectroscopy of proteins that changed in abundance following removal of the inhibitor revealed a cohort of upregulated muscle-enriched molecules that may be important for both myofibrillogenesis and fusion. We have thus developed a model system that allows separation of myoblast differentiation from muscle cell fusion and should be useful in identifying specific steps regulated by p38 MAP kinase-mediated signaling in myogenesis.

  18. Structure–Activity Relationship Studies of Indole-Based Compounds as Small Molecule HIV-1 Fusion Inhibitors Targeting Glycoprotein 41

    PubMed Central

    2015-01-01

    We previously described indole-containing compounds with the potential to inhibit HIV-1 fusion by targeting the hydrophobic pocket of transmembrane glycoprotein gp41. Here we report optimization and structure–activity relationship studies on the basic scaffold, defining the role of shape, contact surface area, and molecular properties. Thirty new compounds were evaluated in binding, cell–cell fusion, and viral replication assays. Below a 1 μM threshold, correlation between binding and biological activity was diminished, indicating an amphipathic requirement for activity in cells. The most active inhibitor 6j exhibited 0.6 μM binding affinity and 0.2 μM EC50 against cell–cell fusion and live virus replication and was active against T20 resistant strains. Twenty-two compounds with the same connectivity displayed a consensus pose in docking calculations, with rank order matching the biological activity. The work provides insight into requirements for small molecule inhibition of HIV-1 fusion and demonstrates a potent low molecular weight fusion inhibitor. PMID:24856833

  19. Inducible expression of a fusion gene encoding two proteinase inhibitors leads to insect and pathogen resistance in transgenic rice.

    PubMed

    Quilis, Jordi; López-García, Belén; Meynard, Donaldo; Guiderdoni, Emmanuel; San Segundo, Blanca

    2014-04-01

    Plant proteinase inhibitors (PIs) are considered as candidates for increased insect resistance in transgenic plants. Insect adaptation to PI ingestion might, however, compromise the benefits received by transgenic expression of PIs. In this study, the maize proteinase inhibitor (MPI), an inhibitor of insect serine proteinases, and the potato carboxypeptidase inhibitor (PCI) were fused into a single open reading frame and introduced into rice plants. The two PIs were linked using either the processing site of the Bacillus thuringiensis Cry1B precursor protein or the 2A sequence from the foot-and-mouth disease virus (FMDV). Expression of each fusion gene was driven by the wound- and pathogen-inducible mpi promoter. The mpi-pci fusion gene was stably inherited for at least three generations with no penalty on plant phenotype. An important reduction in larval weight of Chilo suppressalis fed on mpi-pci rice, compared with larvae fed on wild-type plants, was observed. Expression of the mpi-pci fusion gene confers resistance to C. suppressalis (striped stem borer), one of the most important insect pest of rice. The mpi-pci expression systems described may represent a suitable strategy for insect pest control, better than strategies based on the use of single PI genes, by preventing insect adaptive responses. The rice plants expressing the mpi-pci fusion gene also showed enhanced resistance to infection by the fungus Magnaporthe oryzae, the causal agent of the rice blast disease. Our results illustrate the usefulness of the inducible expression of the mpi-pci fusion gene for dual resistance against insects and pathogens in rice plants.

  20. New Small Molecule Entry Inhibitors Targeting Hemagglutinin-Mediated Influenza A Virus Fusion

    PubMed Central

    Antanasijevic, Aleksandar; Wang, Minxiu; Li, Bing; Mills, Debra M.; Ames, Jessica A.; Nash, Peter J.; Williams, John D.; Peet, Norton P.; Moir, Donald T.; Prichard, Mark N.; Keith, Kathy A.; Barnard, Dale L.; Caffrey, Michael; Rong, Lijun; Bowlin, Terry L.

    2014-01-01

    Influenza viruses are a major public health threat worldwide, and options for antiviral therapy are limited by the emergence of drug-resistant virus strains. The influenza virus glycoprotein hemagglutinin (HA) plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion, making it a potential target for the development of anti-influenza drugs. Using pseudotype virus-based high-throughput screens, we have identified several new small molecules capable of inhibiting influenza virus entry. We prioritized two novel inhibitors, MBX2329 and MBX2546, with aminoalkyl phenol ether and sulfonamide scaffolds, respectively, that specifically inhibit HA-mediated viral entry. The two compounds (i) are potent (50% inhibitory concentration [IC50] of 0.3 to 5.9 μM); (ii) are selective (50% cytotoxicity concentration [CC50] of >100 μM), with selectivity index (SI) values of >20 to 200 for different influenza virus strains; (iii) inhibit a wide spectrum of influenza A viruses, which includes the 2009 pandemic influenza virus A/H1N1/2009, highly pathogenic avian influenza (HPAI) virus A/H5N1, and oseltamivir-resistant A/H1N1 strains; (iv) exhibit large volumes of synergy with oseltamivir (36 and 331 μM2 % at 95% confidence); and (v) have chemically tractable structures. Mechanism-of-action studies suggest that both MBX2329 and MBX2546 bind to HA in a nonoverlapping manner. Additional results from HA-mediated hemolysis of chicken red blood cells (cRBCs), competition assays with monoclonal antibody (MAb) C179, and mutational analysis suggest that the compounds bind in the stem region of the HA trimer and inhibit HA-mediated fusion. Therefore, MBX2329 and MBX2546 represent new starting points for chemical optimization and have the potential to provide valuable future therapeutic options and research tools to study the HA-mediated entry process. PMID:24198411

  1. Fusion

    NASA Astrophysics Data System (ADS)

    Herman, Robin

    1990-10-01

    The book abounds with fascinating anecdotes about fusion's rocky path: the spurious claim by Argentine dictator Juan Peron in 1951 that his country had built a working fusion reactor, the rush by the United States to drop secrecy and publicize its fusion work as a propaganda offensive after the Russian success with Sputnik; the fortune Penthouse magazine publisher Bob Guccione sank into an unconventional fusion device, the skepticism that met an assertion by two University of Utah chemists in 1989 that they had created "cold fusion" in a bottle. Aimed at a general audience, the book describes the scientific basis of controlled fusion--the fusing of atomic nuclei, under conditions hotter than the sun, to release energy. Using personal recollections of scientists involved, it traces the history of this little-known international race that began during the Cold War in secret laboratories in the United States, Great Britain and the Soviet Union, and evolved into an astonishingly open collaboration between East and West.

  2. Insights into the Functions of M-T Hook Structure in HIV Fusion Inhibitor Using Molecular Modeling.

    PubMed

    Tan, Jianjun; Yuan, Hongling; Li, Chunhua; Zhang, Xiaoyi; Wang, Cunxin

    2016-04-01

    HIV-1 membrane fusion plays an important role in the process that HIV-1 entries host cells. As a treatment strategy targeting HIV-1 entry process, fusion inhibitors have been proposed. Nevertheless, development of a short peptide possessing high anti-HIV potency is considered a daunting challenge. He et al. found that two residues, Met626 and Thr627, located the upstream of the C-terminal heptad repeat of the gp41, formed a unique hook-like structure (M-T hook) that can dramatically improve the binding stability and anti-HIV activity of the inhibitors. In this work, we explored the molecular mechanism why M-T hook structure could improve the anti-HIV activity of inhibitors. Firstly, molecular dynamic simulation was used to obtain information on the time evolution between gp41 and ligands. Secondly, based on the simulations, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and molecular mechanics Generalized Born surface area (MM-GBSA) methods were used to calculate the binding free energies. The binding free energy of the ligand with M-T hook was considerably higher than the other without M-T. Further studies showed that the hydrophobic interactions made the dominant contribution to the binding free energy. The numbers of Hydrogen bonds between gp41 and the ligand with M-T hook structure were more than the other. These findings should provide insights into the inhibition mechanism of the short peptide fusion inhibitors and be useful for the rational design of novel fusion inhibitors in the future.

  3. A high throughput Cre–lox activated viral membrane fusion assay identifies pharmacological inhibitors of HIV entry

    SciTech Connect

    Esposito, Anthony M.; Cheung, Pamela; Swartz, Talia H.; Li, Hongru; Tsibane, Tshidi; Durham, Natasha D.; Basler, Christopher F.; Felsenfeld, Dan P.; Chen, Benjamin K.

    2016-03-15

    Enveloped virus entry occurs when viral and cellular membranes fuse releasing particle contents into the target cell. Human immunodeficiency virus (HIV) entry occurs by cell-free virus or virus transferred between infected and uninfected cells through structures called virological synapses. We developed a high-throughput cell-based assay to identify small molecule inhibitors of cell-free or virological synapse-mediated entry. An HIV clone carrying Cre recombinase as a Gag-internal gene fusion releases active Cre into cells upon viral entry activating a recombinatorial gene switch changing dsRed to GFP-expression. A screen of a 1998 known-biological profile small molecule library identified pharmacological HIV entry inhibitors that block both cell-free and cell-to-cell infection. Many top hits were noted as HIV inhibitors in prior studies, but not previously recognized as entry antagonists. Modest therapeutic indices for simvastatin and nigericin were observed in confirmatory HIV infection assays. This robust assay is adaptable to study HIV and heterologous viral pseudotypes. - Highlights: • Cre recombinase viral fusion assay screens cell-free or cell–cell entry inhibitors. • This Gag-iCre based assay is specific for the entry step of HIV replication. • Screened a library of known pharmacologic compounds for HIV fusion antagonists. • Many top hits were previously noted as HIV inhibitors, but here are classified as entry antagonists. Many top hits were previously noted as HIV inhibitors, but not as entry antagonists. • The assay is compatible with pseudotyping with HIV and heterologous viruses.

  4. Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion.

    PubMed

    Veazey, Ronald S; Klasse, Per Johan; Schader, Susan M; Hu, Qinxue; Ketas, Thomas J; Lu, Min; Marx, Preston A; Dufour, Jason; Colonno, Richard J; Shattock, Robin J; Springer, Martin S; Moore, John P

    2005-11-03

    Human immunodeficiency virus type 1 (HIV-1) continues to spread, principally by heterosexual sex, but no vaccine is available. Hence, alternative prevention methods are needed to supplement educational and behavioural-modification programmes. One such approach is a vaginal microbicide: the application of inhibitory compounds before intercourse. Here, we have evaluated the microbicide concept using the rhesus macaque 'high dose' vaginal transmission model with a CCR5-receptor-using simian-human immunodeficiency virus (SHIV-162P3) and three compounds that inhibit different stages of the virus-cell attachment and entry process. These compounds are BMS-378806, a small molecule that binds the viral gp120 glycoprotein and prevents its attachment to the CD4 and CCR5 receptors, CMPD167, a small molecule that binds to CCR5 to inhibit gp120 association, and C52L, a bacterially expressed peptide inhibitor of gp41-mediated fusion. In vitro, all three compounds inhibit infection of T cells and cervical tissue explants, and C52L acts synergistically with CMPD167 or BMS-378806 to inhibit infection of cell lines. In vivo, significant protection was achieved using each compound alone and in combinations. CMPD167 and BMS-378806 were protective even when applied 6 h before challenge.

  5. Creating an Artificial Tail Anchor as a Novel Strategy To Enhance the Potency of Peptide-Based HIV Fusion Inhibitors.

    PubMed

    Su, Shan; Zhu, Yun; Ye, Sheng; Qi, Qianqian; Xia, Shuai; Ma, Zhenxuan; Yu, Fei; Wang, Qian; Zhang, Rongguang; Jiang, Shibo; Lu, Lu

    2017-01-01

    20 (enfuvirtide) and other peptides derived from the human immunodeficiency virus type 1 (HIV-1) gp41 C-terminal heptad repeat (CHR) region inhibit HIV fusion by binding to the hydrophobic grooves on the N-terminal heptad repeat (NHR) trimer and blocking six-helix-bundle (6-HB) formation. Several strategies focusing on the binding grooves of the NHR trimer have been adopted to increase the antiviral activity of the CHR peptides. Here, we developed a novel and simple strategy to greatly enhance the potency of the existing peptide-based HIV fusion inhibitors. First, we identified a shallow pocket adjacent to the groove in the N-terminal region of NHR trimer as a new drug target, and then we designed several short artificial peptides to fit this target. After the addition of IDL (Ile-Asp-Leu) to the C terminus of CHR peptide WQ or MT-WQ, the conjugated peptides, WQ-IDL and MT-WQ-IDL, showed much more potent activities than WQ and T20, respectively, in inhibiting HIV-1 IIIB infection. WQ-IDL and MT-WQ-IDL were also more effective than WQ in blocking HIV-1 Env-mediated membrane fusion and had higher levels of binding affinity with NHR peptide N46. We solved the crystal structure of the 6-HB formed by MT-WQ-IDL and N46 and found that, besides the N-terminal MT hook tail, the IDL tail anchor of MT-WQ-IDL also binds with the shallow hydrophobic pocket outside the groove of the NHR trimer, resulting in enhanced inhibition of HIV-1 fusion with the target cell. It is expected that this novel approach can be widely used to improve the potency of peptidic fusion inhibitors against other enveloped viruses with class I fusion proteins.

  6. Functional characterization, localization, and inhibitor sensitivity of the TPR-FGFR1 fusion in 8p11 myeloproliferative syndrome.

    PubMed

    Malli, Theodora; Buxhofer-Ausch, Veronika; Rammer, Melanie; Erdel, Martin; Kranewitter, Wolfgang; Rumpold, Holger; Marschon, Renate; Deutschbauer, Sabine; Simonitsch-Klupp, Ingrid; Valent, Peter; Muellner-Ammer, Kirsten; Sebesta, Christian; Birkner, Thomas; Webersinke, Gerald

    2016-01-01

    Myeloid and lymphoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) abnormalities, also known as 8p11 myeloproliferative syndrome (EMS), represent rare and aggressive disorders, associated with chromosomal aberrations that lead to the fusion of FGFR1 to different partner genes. We report on a third patient with a fusion of the translocated promoter region (TPR) gene, a component of the nuclear pore complex, to FGFR1 due to a novel ins(1;8)(q25;p11p23). The fact that this fusion is a rare but recurrent event in EMS prompted us to examine the localization and transforming potential of the chimeric protein. TPR-FGFR1 localizes in the cytoplasm, although the nuclear pore localization signal of TPR is retained in the fusion protein. Furthermore, TPR-FGFR1 enables cytokine-independent survival, proliferation, and granulocytic differentiation of the interleukin-3 dependent myeloid progenitor cell line 32Dcl3, reflecting the chronic phase of EMS characterized by myeloid hyperplasia. 32Dcl3 cells transformed with the TPR-FGFR1 fusion and treated with increasing concentrations of the tyrosine kinase inhibitors ponatinib (AP24534) and infigratinib (NVP-BGJ398) displayed reduced survival and proliferation with IC50 values of 49.8 and 7.7 nM, respectively. Ponatinib, a multitargeted tyrosine kinase inhibitor, is already shown to be effective against several FGFR1-fusion kinases. Infigratinib, tested only against FGFR1OP2-FGFR1 to date, is also efficient against TPR-FGFR1. Taking its high specificity for FGFRs into account, infigratinib could be beneficial for EMS patients and should be further investigated for the treatment of myeloproliferative neoplasms with FGFR1 abnormalities.

  7. Improved Pharmacological and Structural Properties of HIV Fusion Inhibitor AP3 over Enfuvirtide: Highlighting Advantages of Artificial Peptide Strategy

    DOE PAGES

    Zhu, Xiaojie; Zhu, Yun; Ye, Sheng; ...

    2015-08-19

    Enfuvirtide (T20), is the first HIV fusion inhibitor approved for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, its clinical application is limited because of short half-life, drug resistance and cross-reactivity with the preexisting antibodies in HIV-infected patients. Using an artificial peptide strategy, we designed a peptide with non-native protein sequence, AP3, which exhibited potent antiviral activity against a broad spectrum of HIV-1 strains, including those resistant to T20, and had remarkably longer in vivo half-life than T20. While the preexisting antibodies in HIV-infected patients significantly suppressed T20’s antiviral activity, these antibodies neither recognizedmore » AP3, nor attenuated its anti-HIV-1 activity. Structurally different from T20, AP3 could fold into single-helix and interact with gp41 NHR. The two residues, Met and Thr, at the N-terminus of AP3 form a hook-like structure to stabilize interaction between AP3 and NHR helices. Therefore, AP3 has potential for further development as a new HIV fusion inhibitor with improved antiviral efficacy, resistance profile and pharmacological properties over enfuvirtide. Meanwhile, this study highlighted the advantages of artificially designed peptides, and confirmed that this strategy could be used in developing artificial peptide-based viral fusion inhibitors against HIV and other enveloped viruses.« less

  8. Evaluation of EML4-ALK Fusion Proteins in Non-Small Cell Lung Cancer Using Small Molecule Inhibitors12

    PubMed Central

    Li, Yongjun; Ye, Xiaofen; Liu, Jinfeng; Zha, Jiping; Pei, Lin

    2011-01-01

    The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene resulting from an inversion within chromosome 2p occurs in approximately 5% of non-small cell lung cancer and is mutually exclusive with Ras and EGFR mutations. In this study, we have used a potent and selective ALK small molecule inhibitor, NPV-TAE684, to assess the oncogenic role of EML4-ALK in non-small cell lung cancer (NSCLC). We show here that TAE684 inhibits proliferation and induces cell cycle arrest, apoptosis, and tumor regression in two NSCLC models that harbor EML4-ALK fusions. TAE684 inhibits EML4-ALK activation and its downstream signaling including ERK, AKT, and STAT3. We used microarray analysis to carry out targeted pathway studies of gene expression changes in H2228 NSCLC xenograft model after TAE684 treatment and identified a gene signature of EML4-ALK inhibition. The gene signature represents 1210 known human genes, and the top biologic processes represented by these genes are cell cycle, DNA synthesis, cell proliferation, and cell death. We also compared the effect of TAE684 with PF2341066, a c-Met and ALK small molecule inhibitor currently in clinical trial in cancers harboring ALK fusions, and demonstrated that TAE684 is a much more potent inhibitor of EML4-ALK. Our data demonstrate that EML4-ALK plays an important role in the pathogenesis of a subset of NSCLC and provides insight into the mechanism of EML4-ALK inhibition by a small molecule inhibitor. PMID:21245935

  9. Escape from neutralization by the respiratory syncytial virus-specific neutralizing monoclonal antibody palivizumab is driven by changes in on-rate of binding to the fusion protein.

    PubMed

    Bates, John T; Keefer, Christopher J; Slaughter, James C; Kulp, Daniel W; Schief, William R; Crowe, James E

    2014-04-01

    The role of binding kinetics in determining neutralizing potency for antiviral antibodies is poorly understood. While it is believed that increased steady-state affinity correlates positively with increased virus-neutralizing activity, the relationship between association or dissociation rate and neutralization potency is unclear. We investigated the effect of naturally-occurring antibody resistance mutations in the RSV F protein on the kinetics of binding to palivizumab. Escape from palivizumab-mediated neutralization of RSV occurred with reduced association rate (Kon) for binding to RSV F protein, while alteration of dissociation rate (Koff) did not significantly affect neutralizing activity. Interestingly, linkage of reduced Kon with reduced potency mirrored the effect of increased Kon found in a high-affinity enhanced potency palivizumab variant (motavizumab). These data suggest that association rate is the dominant factor driving neutralization potency for antibodies to RSV F protein antigenic site A and determines the potency of antibody somatic variants or efficiency of escape of viral glycoprotein variants.

  10. Identification and Analysis of Bacterial Protein Secretion Inhibitors Utilizing a SecA-LacZ Reporter Fusion System

    PubMed Central

    Alksne, L. E.; Burgio, P.; Hu, W.; Feld, B.; Singh, M. P.; Tuckman, M.; Petersen, P. J.; Labthavikul, P.; McGlynn, M.; Barbieri, L.; McDonald, L.; Bradford, P.; Dushin, R. G.; Rothstein, D.; Projan, S. J.

    2000-01-01

    Protein secretion is an essential process for bacterial growth, yet there are few if any antimicrobial agents which inhibit secretion. An in vivo, high-throughput screen to detect secretion inhibitors was developed based on the translational autoregulation of one of the central protein components, SecA. The assay makes use of a SecA-LacZ fusion reporter construct in Escherichia coli which is induced when secretion is perturbed. Several compounds, including two natural product extracts, which had the ability to induce the reporter fusion were identified and the MICs of these compounds for Staphylococcus aureus strain MN8 were found to be ≤128 μg/ml. Enzyme-linked immunosorbent assay, Western blotting, and immunoprecipitation techniques were used to analyze the affects of these compounds on protein secretion. Six representative compounds presented here appear to be bona fide secretion inhibitors but were found to have deleterious effects on membranes. It was concluded that, while the method described here for identifying inhibitors of secretion is valid, screens such as this, which are directed against the membrane-bound portion of a pathway, may preferentially identify compounds which affect membrane integrity. PMID:10817687

  11. Rational improvement of gp41-targeting HIV-1 fusion inhibitors: an innovatively designed Ile-Asp-Leu tail with alternative conformations

    PubMed Central

    Zhu, Yun; Su, Shan; Qin, Lili; Wang, Qian; Shi, Lei; Ma, Zhenxuan; Tang, Jianchao; Jiang, Shibo; Lu, Lu; Ye, Sheng; Zhang, Rongguang

    2016-01-01

    Peptides derived from the C-terminal heptad repeat (CHR) of HIV gp41 have been developed as effective fusion inhibitors against HIV-1, but facing the challenges of enhancing potency and stability. Here, we report a rationally designed novel HIV-1 fusion inhibitor derived from CHR-derived peptide (Trp628~Gln653, named CP), but with an innovative Ile-Asp-Leu tail (IDL) that dramatically increased the inhibitory activity by up to 100 folds. We also determined the crystal structures of artificial fusion peptides N36- and N43-L6-CP-IDL. Although the overall structures of both fusion peptides share the canonical six-helix bundle (6-HB) configuration, their IDL tails adopt two different conformations: a one-turn helix with the N36, and a hook-like structure with the longer N43. Structural comparison showed that the hook-like IDL tail possesses a larger interaction interface with NHR than the helical one. Further molecular dynamics simulations of the two 6-HBs and isolated CP-IDL peptides suggested that hook-like form of IDL tail can be stabilized by its binding to NHR trimer. Therefore, CP-IDL has potential for further development as a new HIV fusion inhibitor, and this strategy could be widely used in developing artificial fusion inhibitors against HIV and other enveloped viruses. PMID:27666394

  12. Rational improvement of gp41-targeting HIV-1 fusion inhibitors: an innovatively designed Ile-Asp-Leu tail with alternative conformations

    NASA Astrophysics Data System (ADS)

    Zhu, Yun; Su, Shan; Qin, Lili; Wang, Qian; Shi, Lei; Ma, Zhenxuan; Tang, Jianchao; Jiang, Shibo; Lu, Lu; Ye, Sheng; Zhang, Rongguang

    2016-09-01

    Peptides derived from the C-terminal heptad repeat (CHR) of HIV gp41 have been developed as effective fusion inhibitors against HIV-1, but facing the challenges of enhancing potency and stability. Here, we report a rationally designed novel HIV-1 fusion inhibitor derived from CHR-derived peptide (Trp628~Gln653, named CP), but with an innovative Ile-Asp-Leu tail (IDL) that dramatically increased the inhibitory activity by up to 100 folds. We also determined the crystal structures of artificial fusion peptides N36- and N43-L6-CP-IDL. Although the overall structures of both fusion peptides share the canonical six-helix bundle (6-HB) configuration, their IDL tails adopt two different conformations: a one-turn helix with the N36, and a hook-like structure with the longer N43. Structural comparison showed that the hook-like IDL tail possesses a larger interaction interface with NHR than the helical one. Further molecular dynamics simulations of the two 6-HBs and isolated CP-IDL peptides suggested that hook-like form of IDL tail can be stabilized by its binding to NHR trimer. Therefore, CP-IDL has potential for further development as a new HIV fusion inhibitor, and this strategy could be widely used in developing artificial fusion inhibitors against HIV and other enveloped viruses.

  13. Small-Molecule Fusion Inhibitors Bind the pH-Sensing Stable Signal Peptide-GP2 Subunit Interface of the Lassa Virus Envelope Glycoprotein

    PubMed Central

    Shankar, Sundaresh; Whitby, Landon R.; Casquilho-Gray, Hedi E.; York, Joanne; Boger, Dale L.

    2016-01-01

    ABSTRACT Arenavirus species are responsible for severe life-threatening hemorrhagic fevers in western Africa and South America. Without effective antiviral therapies or vaccines, these viruses pose serious public health and biodefense concerns. Chemically distinct small-molecule inhibitors of arenavirus entry have recently been identified and shown to act on the arenavirus envelope glycoprotein (GPC) to prevent membrane fusion. In the tripartite GPC complex, pH-dependent membrane fusion is triggered through a poorly understood interaction between the stable signal peptide (SSP) and the transmembrane fusion subunit GP2, and our genetic studies have suggested that these small-molecule inhibitors act at this interface to antagonize fusion activation. Here, we have designed and synthesized photoaffinity derivatives of the 4-acyl-1,6-dialkylpiperazin-2-one class of fusion inhibitors and demonstrate specific labeling of both the SSP and GP2 subunits in a native-like Lassa virus (LASV) GPC trimer expressed in insect cells. Photoaddition is competed by the parental inhibitor and other chemically distinct compounds active against LASV, but not those specific to New World arenaviruses. These studies provide direct physical evidence that these inhibitors bind at the SSP-GP2 interface. We also find that GPC containing the uncleaved GP1-GP2 precursor is not susceptible to photo-cross-linking, suggesting that proteolytic maturation is accompanied by conformational changes at this site. Detailed mapping of residues modified by the photoaffinity adducts may provide insight to guide the further development of these promising lead compounds as potential therapeutic agents to treat Lassa hemorrhagic fever. IMPORTANCE Hemorrhagic fever arenaviruses cause lethal infections in humans and, in the absence of licensed vaccines or specific antiviral therapies, are recognized to pose significant threats to public health and biodefense. Lead small-molecule inhibitors that target the

  14. Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models.

    PubMed

    Okamoto, Kiyoshi; Kodama, Kotaro; Takase, Kazuma; Sugi, Naoko Hata; Yamamoto, Yuji; Iwata, Masao; Tsuruoka, Akihiko

    2013-10-28

    RET gene fusions are recurrent oncogenes identified in thyroid and lung carcinomas. Lenvatinib is a multi-tyrosine kinase inhibitor currently under evaluation in several clinical trials. Here we evaluated lenvatinib in RET gene fusion-driven preclinical models. In cellular assays, lenvatinib inhibited auto-phosphorylation of KIF5B-RET, CCDC6-RET, and NcoA4-RET. Lenvatinib suppressed the growth of CCDC6-RET human thyroid and lung cancer cell lines, and as well, suppressed anchorage-independent growth and tumorigenicity of RET gene fusion-transformed NIH3T3 cells. These results demonstrate that lenvatinib can exert antitumor activity against RET gene fusion-driven tumor models by inhibiting oncogenic RET gene fusion signaling.

  15. Effects of sequence changes in the HIV-1 gp41 fusion peptide on CCR5 inhibitor resistance

    SciTech Connect

    Anastassopoulou, Cleo G.; Ketas, Thomas J.; Sanders, Rogier W.; Johan Klasse, Per; Moore, John P.

    2012-07-05

    A rare pathway of HIV-1 resistance to small molecule CCR5 inhibitors such as Vicriviroc (VCV) involves changes solely in the gp41 fusion peptide (FP). Here, we show that the G516V change is critical to VCV resistance in PBMC and TZM-bl cells, although it must be accompanied by either M518V or F519I to have a substantial impact. Modeling VCV inhibition data from the two cell types indicated that G516V allows both double mutants to use VCV-CCR5 complexes for entry. The model further identified F519I as an independent determinant of preference for the unoccupied, high-VCV affinity form of CCR5. From inhibitor-free reversion cultures, we also identified a substitution in the inner domain of gp120, T244A, which appears to counter the resistance phenotype created by the FP substitutions. Examining the interplay of these changes will enhance our understanding of Env complex interactions that influence both HIV-1 entry and resistance to CCR5 inhibitors.

  16. A high throughput Cre-lox activated viral membrane fusion assay identifies pharmacological inhibitors of HIV entry.

    PubMed

    Esposito, Anthony M; Cheung, Pamela; Swartz, Talia H; Li, Hongru; Tsibane, Tshidi; Durham, Natasha D; Basler, Christopher F; Felsenfeld, Dan P; Chen, Benjamin K

    2016-03-01

    Enveloped virus entry occurs when viral and cellular membranes fuse releasing particle contents into the target cell. Human immunodeficiency virus (HIV) entry occurs by cell-free virus or virus transferred between infected and uninfected cells through structures called virological synapses. We developed a high-throughput cell-based assay to identify small molecule inhibitors of cell-free or virological synapse-mediated entry. An HIV clone carrying Cre recombinase as a Gag-internal gene fusion releases active Cre into cells upon viral entry activating a recombinatorial gene switch changing dsRed to GFP-expression. A screen of a 1998 known-biological profile small molecule library identified pharmacological HIV entry inhibitors that block both cell-free and cell-to-cell infection. Many top hits were noted as HIV inhibitors in prior studies, but not previously recognized as entry antagonists. Modest therapeutic indices for simvastatin and nigericin were observed in confirmatory HIV infection assays. This robust assay is adaptable to study HIV and heterologous viral pseudotypes.

  17. A high throughput Cre–lox activated viral membrane fusion assay identifies pharmacological inhibitors of HIV entry

    PubMed Central

    Esposito, Anthony M.; Cheung, Pamela; Swartz, Talia H.; Li, Hongru; Tsibane, Tshidi; Durham, Natasha D.; Basler, Christopher F.; Felsenfeld, Dan P.; Chen, Benjamin K.

    2016-01-01

    Enveloped virus entry occurs when viral and cellular membranes fuse releasing particle contents into the target cell. Human immunodeficiency virus (HIV) entry occurs by cell-free virus or virus transferred between infected and uninfected cells through structures called virological synapses. We developed a high-throughput cell-based assay to identify small molecule inhibitors of cell-free or virological synapse-mediated entry. An HIV clone carrying Cre recombinase as a Gag-internal gene fusion releases active Cre into cells upon viral entry activating a recombinatorial gene switch changing dsRed to GFP-expression. A screen of a 1998 known-biological profile small molecule library identified pharmacological HIV entry inhibitors that block both cell-free and cell-to-cell infection. Many top hits were noted as HIV inhibitors in prior studies, but not previously recognized as entry antagonists. Modest therapeutic indices for simvastatin and nigericin were observed in confirmatory HIV infection assays. This robust assay is adaptable to study HIV and heterologous viral pseudotypes. PMID:26803470

  18. Decoding distinct membrane interactions of HIV-1 fusion inhibitors using a combined atomic force and fluorescence microscopy approach.

    PubMed

    Franquelim, Henri G; Gaspar, Diana; Veiga, A Salomé; Santos, Nuno C; Castanho, Miguel A R B

    2013-08-01

    Enfuvirtide and T-1249 are two potent HIV-1 fusion inhibitor peptides. Recent studies indicate that lipids play an important role in the mode of action of those bioactive molecules. Using a combined tandem atomic force microscopy (AFM)-epifluorescence microscopy approach, we studied the interaction of both enfuvirtide and T-1249 with supported lipid bilayers. Fluid (ld)-gel (so) and ld-liquid ordered (lo) phase-separated membrane systems were tested. Results, especially for T-1249, show significant lipid membrane activity at a 15μM peptide concentration. T-1249, in opposition to enfuvirtide, induces an increase in membrane surface roughness, decrease in membrane fluidity, bilayer thinning at ld domains and disruption of the so domain borders. In terms of structural properties, both enfuvirtide and T-1249 possess distinct functional hydrophobic and amphipathic domains of HIV gp41. While enfuvirtide only yields the tryptophan-rich domain (TRD), T-1249 possesses both TRD and pocket-binding domain (PBD). TRD increases the hydrophobicity of the peptide while PBD enhances the amphipathic characteristics. As such, the enhanced membrane activity of T-1249 may be explained by a synergism between its amphipathic N-terminal segment and its hydrophophic C-terminal. Our findings provide valuable insights on the molecular-level mode of action of HIV-1 fusion inhibitors, unraveling the correlation between their structural properties and membrane interactions as a factor influencing their antiviral activity. Ultimately, this work validates the applicability of a combined AFM and fluorescence approach to evaluate the mechanic and structural properties of supported lipid bilayers upon interaction with membrane-active peptides.

  19. Recombinant protein of heptad-repeat HR212, a stable fusion inhibitor with potent anti-HIV action in vitro

    SciTech Connect

    Pang, Wei; Wang Ruirui; Yang Liumeng; Liu Changmei; Tien Po Zheng Yongtang

    2008-07-20

    HR212, a recombinant protein expressed in Escherichia coli, has been previously reported to inhibit HIV-1 membrane fusion at low nanomolar level. Here we report that HR212 is effective in blocking laboratory strain HIV-1{sub IIIB} entry and replication with EC{sub 50} values of 3.92 {+-} 0.62 and 6.59 {+-} 1.74 nM, respectively, and inhibiting infection by clinic isolate HIV-1{sub KM018} with EC{sub 50} values of 44.44 {+-} 10.20 nM, as well as suppressing HIV-1-induced cytopathic effect with an EC{sub 50} value of 3.04 {+-} 1.20 nM. It also inhibited HIV-2{sub ROD} and HIV-2{sub CBL-20} entry and replication in the {mu}M range. Notably, HR212 was highly effective against T20-resistant strains with EC{sub 50} values ranging from 5.09 to 7.75 nM. Unlike T20, HR212 showed stability sufficient to inhibit syncytia formation in a time-of-addition assay, and was insensitive to proteinase K digestion. These results suggest that HR212 has great potential to be further developed as novel HIV-1 fusion inhibitor for treatment of HIV/AIDS patients, particularly for those infected by T20-resistant variants.

  20. Identification of Nafamostat as a Potent Inhibitor of Middle East Respiratory Syndrome Coronavirus S Protein-Mediated Membrane Fusion Using the Split-Protein-Based Cell-Cell Fusion Assay.

    PubMed

    Yamamoto, Mizuki; Matsuyama, Shutoku; Li, Xiao; Takeda, Makoto; Kawaguchi, Yasushi; Inoue, Jun-Ichiro; Matsuda, Zene

    2016-11-01

    Middle East respiratory syndrome (MERS) is an emerging infectious disease associated with a relatively high mortality rate of approximately 40%. MERS is caused by MERS coronavirus (MERS-CoV) infection, and no specific drugs or vaccines are currently available to prevent MERS-CoV infection. MERS-CoV is an enveloped virus, and its envelope protein (S protein) mediates membrane fusion at the plasma membrane or endosomal membrane. Multiple proteolysis by host proteases, such as furin, transmembrane protease serine 2 (TMPRSS2), and cathepsins, causes the S protein to become fusion competent. TMPRSS2, which is localized to the plasma membrane, is a serine protease responsible for the proteolysis of S in the post-receptor-binding stage. Here, we developed a cell-based fusion assay for S in a TMPRSS2-dependent manner using cell lines expressing Renilla luciferase (RL)-based split reporter proteins. S was stably expressed in the effector cells, and the corresponding receptor for S, CD26, was stably coexpressed with TMPRSS2 in the target cells. Membrane fusion between these effector and target cells was quantitatively measured by determining the RL activity. The assay was optimized for a 384-well format, and nafamostat, a serine protease inhibitor, was identified as a potent inhibitor of S-mediated membrane fusion in a screening of about 1,000 drugs approved for use by the U.S. Food and Drug Administration. Nafamostat also blocked MERS-CoV infection in vitro Our assay has the potential to facilitate the discovery of new inhibitors of membrane fusion of MERS-CoV as well as other viruses that rely on the activity of TMPRSS2.

  1. Influence of hydrophobic and electrostatic residues on SARS-coronavirus S2 protein stability: insights into mechanisms of general viral fusion and inhibitor design.

    PubMed

    Aydin, Halil; Al-Khooly, Dina; Lee, Jeffrey E

    2014-05-01

    Severe acute respiratory syndrome (SARS) is an acute respiratory disease caused by the SARS-coronavirus (SARS-CoV). SARS-CoV entry is facilitated by the spike protein (S), which consists of an N-terminal domain (S1) responsible for cellular attachment and a C-terminal domain (S2) that mediates viral and host cell membrane fusion. The SARS-CoV S2 is a potential drug target, as peptidomimetics against S2 act as potent fusion inhibitors. In this study, site-directed mutagenesis and thermal stability experiments on electrostatic, hydrophobic, and polar residues to dissect their roles in stabilizing the S2 postfusion conformation was performed. It was shown that unlike the pH-independent retroviral fusion proteins, SARS-CoV S2 is stable over a wide pH range, supporting its ability to fuse at both the plasma membrane and endosome. A comprehensive SARS-CoV S2 analysis showed that specific hydrophobic positions at the C-terminal end of the HR2, rather than electrostatics are critical for fusion protein stabilization. Disruption of the conserved C-terminal hydrophobic residues destabilized the fusion core and reduced the melting temperature by 30°C. The importance of the C-terminal hydrophobic residues led us to identify a 42-residue substructure on the central core that is structurally conserved in all existing CoV S2 fusion proteins (root mean squared deviation=0.4 Å). This is the first study to identify such a conserved substructure and likely represents a common foundation to facilitate viral fusion. We have discussed the role of key residues in the design of fusion inhibitors and the potential of the substructure as a general target for the development of novel therapeutics against CoV infections.

  2. Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein.

    PubMed

    Wang, Yu; Ding, Xiwei; Wang, Shaoqing; Moser, Catherine D; Shaleh, Hassan M; Mohamed, Essa A; Chaiteerakij, Roongruedee; Allotey, Loretta K; Chen, Gang; Miyabe, Katsuyuki; McNulty, Melissa S; Ndzengue, Albert; Barr Fritcher, Emily G; Knudson, Ryan A; Greipp, Patricia T; Clark, Karl J; Torbenson, Michael S; Kipp, Benjamin R; Zhou, Jie; Barrett, Michael T; Gustafson, Michael P; Alberts, Steven R; Borad, Mitesh J; Roberts, Lewis R

    2016-09-28

    Cholangiocarcinoma is a highly lethal cancer with limited therapeutic options. Recent genomic analysis of cholangiocarcinoma has revealed the presence of fibroblast growth factor receptor 2 (FGFR2) fusion proteins in up to 13% of intrahepatic cholangiocarcinoma (iCCA). FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers. In this study, we established a novel cholangiocarcinoma patient derived xenograft (PDX) mouse model bearing an FGFR2-CCDC6 fusion protein from a metastatic lung nodule of an iCCA patient. Using this PDX model, we confirmed the ability of the FGFR inhibitors, ponatinib, dovitinib and BGJ398, to modulate FGFR signaling, inhibit cell proliferation and induce cell apoptosis in cholangiocarcinoma tumors harboring FGFR2 fusions. In addition, BGJ398 appeared to be superior in potency to ponatinib and dovitinib in this model. Our findings provide a strong rationale for the investigation of FGFR inhibitors, particularly BGJ398, as a therapeutic option for cholangiocarcinoma patients harboring FGFR2 fusions.

  3. Antiviral Efficacy of a Respiratory Syncytial Virus (RSV) Fusion Inhibitor in a Bovine Model of RSV Infection.

    PubMed

    Jordan, Robert; Shao, Matt; Mackman, Richard L; Perron, Michel; Cihlar, Tomas; Lewis, Sandy A; Eisenberg, Eugene J; Carey, Anne; Strickley, Robert G; Chien, Jason W; Anderson, Mark L; McEligot, Heather A; Behrens, Nicole E; Gershwin, Laurel J

    2015-08-01

    Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants. Effective treatment for RSV infection is a significant unmet medical need. While new RSV therapeutics are now in development, there are very few animal models that mimic the pathogenesis of human RSV, making it difficult to evaluate new disease interventions. Experimental infection of Holstein calves with bovine RSV (bRSV) causes a severe respiratory infection that is similar to human RSV infection, providing a relevant model for testing novel therapeutic agents. In this model, viral load is readily detected in nasal secretions by quantitative real-time PCR (qRT-PCR), and cumulative symptom scoring together with histopathology evaluations of infected tissue allow for the assessment of disease severity. The bovine RSV model was used to evaluate the antiviral activity of an RSV fusion inhibitor, GS1, which blocks virus entry by inhibiting the fusion of the viral envelope with the host cell membrane. The efficacy of GS1, a close structural analog of GS-5806 that is being developed to treat RSV infection in humans was evaluated in two randomized, blind, placebo-controlled studies in bRSV-infected calves. Intravenous administration of GS1 at 4 mg/kg of body weight/day for 7 days starting 24 h or 72 h postinoculation provided clear therapeutic benefit by reducing the viral load, disease symptom score, respiration rate, and lung pathology associated with bRSV infection. These data support the use of the bovine RSV model for evaluation of experimental therapeutics for treatment of RSV.

  4. Enfuvirtide-PEG conjugate: A potent HIV fusion inhibitor with improved pharmacokinetic properties.

    PubMed

    Cheng, Shuihong; Wang, Yan; Zhang, Zhenxing; Lv, Xun; Gao, George F; Shao, Yiming; Ma, Liying; Li, Xuebing

    2016-10-04

    Enfuvirtide (ENF) is a clinically used peptide drug for the treatment of HIV infections, but its poor pharmacokinetic profile (T1/2 = 1.5 h in rats) and low aqueous solubility make the therapy expensive and inconvenience. In this study, we present a simple and practical strategy to address these problems by conjugating ENF with polyethylene glycol (PEG). Site-specific attachment of a 2 kDa PEG at the N-terminus of ENF resulted in an ENF-PEG (EP) conjugate with high solubility (≥3 mg/mL) and long half-life in rats (T1/2 = 16.1 h). This conjugate showed similar antiviral activity to ENF against various primary HIV-1 isolates (EC50 = 6-91 nM). Mechanistic studies suggested the sources of the antiviral potency. The conjugate bound to a functional domain of the HIV gp41 protein in a helical conformation with high affinity (Kd = 307 nM), thereby inhibiting the gp41-mediated fusion of viral and host-cell membranes. As PEG conjugation has advanced many bioactive proteins and peptides into clinical applications, the EP conjugate described here represents a potential new treatment for HIV infections that may address the unmet medical needs associated with the current ENF therapy.

  5. An oncogenic NTRK fusion in a soft tissue sarcoma patient with response to the tropomyosin-related kinase (TRK) inhibitor LOXO-101

    PubMed Central

    Doebele, Robert C.; Davis, Lara E.; Vaishnavi, Aria; Le, Anh T.; Estrada-Bernal, Adriana; Keysar, Stephen; Jimeno, Antonio; Varella-Garcia, Marileila; Aisner, Dara L.; Li, Yali; Stephens, Philip J.; Morosini, Deborah; Tuch, Brian B.; Fernandes, Michele; Nanda, Nisha; Low, Jennifer A.

    2015-01-01

    Oncogenic TRK fusions induce cancer cell proliferation and engage critical cancer-related downstream signaling pathways. These TRK fusions occur rarely, but in a diverse spectrum of tumor histologies. LOXO-101 is an orally administered inhibitor of the TRK kinase, and is highly selective only for the TRK family of receptors. Preclinical models of LOXO-101 using TRK-fusion bearing human-derived cancer cell lines demonstrate inhibition of the fusion oncoprotein and cellular proliferation in vitro, and tumor growth in vivo. The tumor of a 41-year old woman with soft tissue sarcoma metastatic to lung was found to harbor an LMNA-NTRK1 gene fusion encoding a functional LMNA-TRKA fusion oncoprotein as determined by an in situ proximity ligation assay. On a phase 1 study of LOXO-101 (ClinicalTrials.gov no. NCT02122913), this patient’s tumors underwent rapid and substantial tumor regression, with an accompanying improvement in pulmonary dyspnea, oxygen saturation and plasma tumor markers. PMID:26216294

  6. Tropism-independent protection of macaques against vaginal transmission of three SHIVs by the HIV-1 fusion inhibitor T-1249.

    PubMed

    Veazey, Ronald S; Ketas, Thomas A; Klasse, Per Johan; Davison, Donna K; Singletary, Morgan; Green, Linda C; Greenberg, Michael L; Moore, John P

    2008-07-29

    We have assessed the potential of the fusion inhibitory peptide T-1249 for development as a vaginal microbicide to prevent HIV-1 sexual transmission. When formulated as a simple gel, T-1249 provided dose-dependent protection to macaques against high-dose challenge with three different SHIVs that used either CCR5 or CXCR4 for infection (the R5 virus SHIV-162P3, the X4 virus SHIV-KU1 and the R5X4 virus SHIV-89.6P), and it also protected against SIVmac251 (R5). Protection of half of the test animals was estimated by interpolation to occur at T-1249 concentrations of approximately 40-130 muM, whereas complete protection was observed at 0.1-2 mM. In vitro, T-1249 had substantial breadth of activity against HIV-1 strains from multiple genetic subtypes and in a coreceptor-independent manner. Thus, at 1 muM in a peripheral blood mononuclear cell-based replication assay, T-1249 inhibited all 29 R5 viruses, all 12 X4 viruses and all 7 R5X4 viruses in the test panel, irrespective of their genetic subtype. Combining lower concentrations of T-1249 with other entry inhibitors (CMPD-167, BMS-C, or AMD3465) increased the proportion of test viruses that could be blocked. In the PhenoSense assay, T-1249 was active against 636 different HIV-1 Env-pseudotyped viruses of varying tropism and derived from clinical samples, with IC(50) values typically clustered in a 10-fold range approximately 10 nM. Overall, these results support the concept of using T-1249 as a component of an entry inhibitor-based combination microbicide to prevent the sexual transmission of diverse HIV-1 variants.

  7. Inhibition of neuraminidase inhibitor-resistant influenza virus by DAS181, a novel sialidase fusion protein.

    PubMed

    Triana-Baltzer, Gallen B; Gubareva, Larisa V; Klimov, Alexander I; Wurtman, David F; Moss, Ronald B; Hedlund, Maria; Larson, Jeffrey L; Belshe, Robert B; Fang, Fang

    2009-11-06

    Antiviral drug resistance for influenza therapies remains a concern due to the high prevalence of H1N1 2009 seasonal influenza isolates which display H274Y associated oseltamivir-resistance. Furthermore, the emergence of novel H1N1 raises the potential that additional reassortments can occur, resulting in drug resistant virus. Thus, additional antiviral approaches are urgently needed. DAS181 (Fludase), a sialidase fusion protein, has been shown to have inhibitory activity against a large number of seasonal influenza strains and a highly pathogenic avian influenza (HPAI) strain (H5N1). Here, we examine the in vitro activity of DAS181 against a panel of 2009 oseltamivir-resistant seasonal H1N1 clinical isolates. The activity of DAS181 against nine 2009, two 2007, and two 2004 clinical isolates of seasonal IFV H1N1 was examined using plaque number reduction assay on MDCK cells. DAS181 strongly inhibited all tested isolates. EC50 values remained constant against isolates from 2004, 2007, and 2009, suggesting that there was no change in DAS181 sensitivity over time. As expected, all 2007 and 2009 isolates were resistant to oseltamivir, consistent with the identification of the H274Y mutation in the NA gene of all these isolates. Interestingly, several of the 2007 and 2009 isolates also exhibited reduced sensitivity to zanamivir, and accompanying HA mutations near the sialic acid binding site were observed. DAS181 inhibits IFV that is resistant to NAIs. Thus, DAS181 may offer an alternative therapeutic option for seasonal or pandemic IFVs that become resistant to currently available antiviral drugs.

  8. In Vitro Selection and Characterization of HIV-1 Variants with Increased Resistance to Sifuvirtide, a Novel HIV-1 Fusion Inhibitor*

    PubMed Central

    Liu, Zhonghua; Shan, Mei; Li, Li; Lu, Lu; Meng, Shu; Chen, Cheng; He, Yuxian; Jiang, Shibo; Zhang, Linqi

    2011-01-01

    Sifuvirtide, a novel fusion inhibitor against human immunodeficiency virus type I (HIV-1), which is more potent than enfuvirtide (T20) in cell culture, is currently under clinical investigation for the treatment of HIV-1 infection. We now report that in vitro selection of HIV-1 variants resistant to sifuvirtide in the presence of increasing concentrations of sifuvirtide has led to several specific mutations in the gp41 region that had not been previously reported. Many of these substitutions were confined to the N-terminal heptad repeat region at positions 37, 38, 41, and 43, either singly or in combination. A downstream substitution at position 126 (N126K) in the C-terminal heptad repeat region was also found. Site-directed mutagenesis studies have further identified the critical amino acid substitutions and combinations thereof in conferring the resistant genotypes. Furthermore, the mutant viruses demonstrated variable degrees of cross-resistance to enfuvirtide, some of which are preferentially more resistant to sifuvirtide. Impaired infectivity was also found for many of the mutant viruses. Biophysical and structural analyses of the key substitutions have revealed several potential novel mechanisms against sifuvirtide. Our results may help to predict potential resistant patterns in vivo and facilitate the further clinical development and therapeutic utility of sifuvirtide. PMID:21098485

  9. Half-life extension of the HIV-fusion inhibitor peptide TRI-1144 using a novel linker technology.

    PubMed

    Schneider, Eric L; Ashley, Gary W; Dillen, Lieve; Stoops, Bart; Austin, Nigel E; Malcolm, Bruce A; Santi, Daniel V

    2015-06-01

    We have previously developed a linker technology for half-life extension of peptides, proteins and small molecule drugs (1). The linkers undergo β-elimination reactions with predictable cleavage rates to release the native drug. Here we utilize this technology for half-life extension of the 38 amino acid HIV-1 fusion inhibitor TRI-1144. Conjugation of TRI-1144 to 40 kDa PEG by an appropriate β-eliminative linker and i.v. administration of the conjugate increased the in vivo half-life of the released peptide from 4 to 34 h in the rat, and the pharmacokinetic parameters were in excellent accord with a one-compartment model. From these data we simulated the pharmacokinetics of the PEG-TRI-1144 conjugate in humans, predicting a t1/2,β of 70 h for the released peptide, and that a serum concentration of 25 nM could be maintained by weekly doses of 8 μmol of the conjugate. Using a non-circulating carrier (2) similar simulations indicated a t1/2,β of 150 h for the peptide released from the conjugate and that dosing of only 1.8 μmol/week could maintain serum concentrations of TRI-1144 above 25 nM. Hence, releasable β-eliminative linkers provide significant half-life extension to TRI-1144 and would be expected to do likewise for related peptides.

  10. HIV-1 tropism for the central nervous system: Brain-derived envelope glycoproteins with lower CD4 dependence and reduced sensitivity to a fusion inhibitor

    SciTech Connect

    Martin-Garcia, Julio . E-mail: julio.martin-garcia@drexelmed.edu; Cao, Wei; Varela-Rohena, Angel; Plassmeyer, Matthew L.; Gonzalez-Scarano, Francisco

    2006-03-01

    We previously described envelope glycoproteins of an HIV-1 isolate adapted in vitro for growth in microglia that acquired a highly fusogenic phenotype and lower CD4 dependence, as well as resistance to inhibition by anti-CD4 antibodies. Here, we investigated whether similar phenotypic changes are present in vivo. Envelope clones from the brain and spleen of an HIV-1-infected individual with neurological disease were amplified, cloned, and sequenced. Phylogenetic analysis demonstrated clustering of sequences according to the tissue of origin, as expected. Functional clones were then used in cell-to-cell fusion assays to test for CD4 and co-receptor utilization and for sensitivity to various antibodies and inhibitors. Both brain- and spleen-derived envelope clones mediated fusion in cells expressing both CD4 and CCR5 and brain envelopes also used CCR3 as co-receptor. We found that the brain envelopes had a lower CD4 dependence, since they efficiently mediated fusion in the presence of low levels of CD4 on the target cell membrane, and they were significantly more resistant to blocking by anti-CD4 antibodies than the spleen-derived envelopes. In contrast, we observed no difference in sensitivity to the CCR5 antagonist TAK-779. However, brain-derived envelopes were significantly more resistant than those from spleen to the fusion inhibitor T-1249 and concurrently showed slightly greater fusogenicity. Our results suggest an increased affinity for CD4 of brain-derived envelopes that may have originated from in vivo adaptation to replication in microglial cells. Interestingly, we note the presence of envelopes more resistant to a fusion inhibitor in the brain of an untreated, HIV-1-infected individual.

  11. Neutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors

    SciTech Connect

    Pugach, Pavel; Ketas, Thomas J.; Michael, Elizabeth; Moore, John P.

    2008-08-01

    The small molecule CCR5 inhibitors are a new class of drugs for treating infection by human immunodeficiency virus type 1 (HIV-1). They act by binding to the CCR5 co-receptor and preventing its use during HIV-1-cell fusion. Escape mutants can be raised against CCR5 inhibitors in vitro and will arise when these drugs are used clinically. Here, we have assessed the responses of CCR5 inhibitor-resistant viruses to other anti-retroviral drugs that act by different mechanisms, and their sensitivities to neutralizing antibodies (NAbs). The rationale for the latter study is that the resistance pathway for CCR5 inhibitors involves changes in the HIV-1 envelope glycoproteins (Env), which are also targets for NAbs. The escape mutants CC101.19 and D1/85.16 were selected for resistance to AD101 and vicriviroc (VVC), respectively, from the primary R5 HIV-1 isolate CC1/85. Each escape mutant was cross-resistant to other small molecule CCR5 inhibitors (aplaviroc, maraviroc, VVC, AD101 and CMPD 167), but sensitive to protein ligands of CCR5: the modified chemokine PSC-RANTES and the humanized MAb PRO-140. The resistant viruses also retained wild-type sensitivity to the nucleoside reverse transcriptase inhibitor (RTI) zidovudine, the non-nucleoside RTI nevirapine, the protease inhibitor atazanavir and other attachment and fusion inhibitors that act independently of CCR5 (BMS-806, PRO-542 and enfuvirtide). Of note is that the escape mutants were more sensitive than the parental CC1/85 isolate to a subset of neutralizing monoclonal antibodies and to some sera from HIV-1-infected people, implying that sequence changes in Env that confer resistance to CCR5 inhibitors can increase the accessibility of some NAb epitopes. The need to preserve NAb resistance may therefore be a constraint upon how escape from CCR5 inhibitors occurs in vivo.

  12. Neutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors

    PubMed Central

    Pugach, Pavel; Ketas, Thomas J.; Michael, Elizabeth; Moore, John P.

    2008-01-01

    The small molecule CCR5 inhibitors are a new class of drugs for treating infection by human immunodeficiency virus type 1 (HIV-1). They act by binding to the CCR5 co-receptor and preventing its use during HIV-1-cell fusion. Escape mutants can be raised against CCR5 inhibitors in vitro and will arise when these drugs are used clinically. Here, we have assessed the responses of CCR5 inhibitor-resistant viruses to other anti-retroviral drugs that act by different mechanisms, and their sensitivities to neutralizing antibodies (NAbs). The rationale for the latter study is that the resistance pathway for CCR5 inhibitors involves changes in the HIV-1 envelope glycoproteins (Env), which are also targets for NAbs. The escape mutants CC101.19 and D1/85.16 were selected for resistance to AD101 and vicriviroc (VVC), respectively, from the primary R5 HIV-1 isolate CC1/85. Each escape mutant was cross resistant to other small molecule CCR5 inhibitors (aplaviroc, maraviroc, VVC, AD101 and CMPD 167), but sensitive to protein ligands of CCR5: the modified chemokine PSC-RANTES and the humanized MAb PRO 140. The resistant viruses also retained wild-type sensitivity to the nucleoside reverse transcriptase inhibitor (RTI) zidovudine, the non-nucleoside RTI nevirapine, the protease inhibitor atazanavir and other attachment and fusion inhibitors that act independently of CCR5 (BMS-806, PRO-542 and enfuvirtide). Of note is that the escape mutants were more sensitive than the parental CC1/85 isolate to a subset of neutralizing monoclonal antibodies and to some sera from HIV-1-infected people, implying that sequence changes in Env that confer resistance to CCR5 inhibitors can increase the accessibility of some NAb epitopes. The need to preserve NAb resistance may therefore be a constraint upon how escape from CCR5 inhibitors occurs in vivo. PMID:18519143

  13. Dust escape from Io

    NASA Astrophysics Data System (ADS)

    Flandes, Alberto

    2004-08-01

    The Dust ballerina skirt is a set of well defined streams composed of nanometric sized dust particles that escape from the Jovian system and may be accelerated up to >=200 km/s. The source of this dust is Jupiter's moon Io, the most volcanically active body in the Solar system. The escape of dust grains from Jupiter requires first the escape of these grains from Io. This work is basically devoted to explain this escape given that the driving of dust particles to great heights and later injection into the ionosphere of Io may give the particles an equilibrium potential that allow the magnetic field to accelerate them away from Io. The grain sizes obtained through this study match very well to the values required for the particles to escape from the Jovian system.

  14. An evaluation tool for FKBP12-dependent and -independent mTOR inhibitors using a combination of FKBP-mTOR fusion protein, DSC and NMR.

    PubMed

    Sekiguchi, Mitsuhiro; Kobashigawa, Yoshihiro; Kawasaki, Masashi; Yokochi, Masashi; Kiso, Tetsuo; Suzumura, Ken-ichi; Mori, Keitaro; Teramura, Toshio; Inagaki, Fuyuhiko

    2011-11-01

    Mammalian target of rapamycin (mTOR), a large multidomain protein kinase, regulates cell growth and metabolism in response to environmental signals. The FKBP rapamycin-binding (FRB) domain of mTOR is a validated therapeutic target for the development of immunosuppressant and anticancer drugs but is labile and insoluble. Here we designed a fusion protein between FKBP12 and the FRB domain of mTOR. The fusion protein was successfully expressed in Escherichia coli as a soluble form, and was purified by a simple two-step chromatographic procedure. The fusion protein exhibited increased solubility and stability compared with the isolated FRB domain, and facilitated the analysis of rapamycin and FK506 binding using differential scanning calorimetry (DSC) and solution nuclear magnetic resonance (NMR). DSC enabled the rapid observation of protein-drug interactions at the domain level, while NMR gave insights into the protein-drug interactions at the residue level. The use of the FKBP12-FRB fusion protein combined with DSC and NMR provides a useful tool for the efficient screening of FKBP12-dependent as well as -independent inhibitors of the mTOR FRB domain.

  15. Improved Pharmacological and Structural Properties of HIV Fusion Inhibitor AP3 over Enfuvirtide: Highlighting Advantages of Artificial Peptide Strategy

    SciTech Connect

    Zhu, Xiaojie; Zhu, Yun; Ye, Sheng; Wang, Qian; Xu, Wei; Su, Shan; Sun, Zhiwu; Yu, Fei; Liu, Qi; Wang, Chao; Zhang, Tianhong; Zhang, Zhenqing; Zhang, Xiaoyan; Xu, Jianqing; Du, Lanying; Liu, Keliang; Lu, Lu; Zhang, Rongguang; Jiang, Shibo

    2015-08-19

    Enfuvirtide (T20), is the first HIV fusion inhibitor approved for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, its clinical application is limited because of short half-life, drug resistance and cross-reactivity with the preexisting antibodies in HIV-infected patients. Using an artificial peptide strategy, we designed a peptide with non-native protein sequence, AP3, which exhibited potent antiviral activity against a broad spectrum of HIV-1 strains, including those resistant to T20, and had remarkably longer in vivo half-life than T20. While the preexisting antibodies in HIV-infected patients significantly suppressed T20’s antiviral activity, these antibodies neither recognized AP3, nor attenuated its anti-HIV-1 activity. Structurally different from T20, AP3 could fold into single-helix and interact with gp41 NHR. The two residues, Met and Thr, at the N-terminus of AP3 form a hook-like structure to stabilize interaction between AP3 and NHR helices. Therefore, AP3 has potential for further development as a new HIV fusion inhibitor with improved antiviral efficacy, resistance profile and pharmacological properties over enfuvirtide. Meanwhile, this study highlighted the advantages of artificially designed peptides, and confirmed that this strategy could be used in developing artificial peptide-based viral fusion inhibitors against HIV and other enveloped viruses.

  16. Nonneutralizing Antibodies Induced by the HIV-1 gp41 NHR Domain Gain Neutralizing Activity in the Presence of the HIV Fusion Inhibitor Enfuvirtide: a Potential Therapeutic Vaccine Strategy.

    PubMed

    Wang, Qian; Bi, Wenwen; Zhu, Xiaojie; Li, Haoyang; Qi, Qianqian; Yu, Fei; Lu, Lu; Jiang, Shibo

    2015-07-01

    A key barrier against developing preventive and therapeutic human immunodeficiency virus (HIV) vaccines is the inability of viral envelope glycoproteins to elicit broad and potent neutralizing antibodies. However, in the presence of fusion inhibitor enfuvirtide, we show that the nonneutralizing antibodies induced by the HIV type 1 (HIV-1) gp41 N-terminal heptad repeat (NHR) domain (N63) exhibit potent and broad neutralizing activity against laboratory-adapted HIV-1 strains, including the drug-resistant variants, and primary HIV-1 isolates with different subtypes, suggesting the potential of developing gp41-targeted HIV therapeutic vaccines.

  17. THERMALLY DRIVEN ATMOSPHERIC ESCAPE

    SciTech Connect

    Johnson, Robert E.

    2010-06-20

    Accurately determining the escape rate from a planet's atmosphere is critical for determining its evolution. A large amount of Cassini data is now available for Titan's upper atmosphere and a wealth of data is expected within the next decade on escape from Pluto, Mars, and extra-solar planets. Escape can be driven by upward thermal conduction of energy deposited well below the exobase, as well as by nonthermal processes produced by energy deposited in the exobase region. Recent applications of a model for escape driven by upward thermal conduction, called the slow hydrodynamic escape model, have resulted in surprisingly large loss rates for the atmosphere of Titan, Saturn's largest moon. Based on a molecular kinetic simulation of the exobase region, these rates appear to be orders of magnitude too large. Therefore, the slow hydrodynamic model is evaluated here. It is shown that such a model cannot give a reliable description of the atmospheric temperature profile unless it is coupled to a molecular kinetic description of the exobase region. Therefore, the present escape rates for Titan and Pluto must be re-evaluated using the atmospheric model described here.

  18. Recombinant Mucin-Type Fusion Proteins with a Galα1,3Gal Substitution as Clostridium difficile Toxin A Inhibitors

    PubMed Central

    Jin, Chunsheng; Liu, Jining; Karlsson, Niclas G.; Holgersson, Jan

    2016-01-01

    The capability of a recombinant mucin-like fusion protein, P-selectin glycoprotein ligand-1/mouse IgG2b (PSGL-1/mIgG2b), carrying Galα1,3Galβ1,4GlcNAc determinants to bind and inhibit Clostridium difficile toxin A (TcdA) was investigated. The fusion protein, produced by a glyco-engineered stable CHO-K1 cell line and designated C-PGC2, was purified by affinity and gel filtration chromatography from large-scale cultures. Liquid chromatography-mass spectrometry was used to characterize O-glycans released by reductive β-elimination, and new diagnostic ions to distinguish Galα1,3Gal- from Galα1,4Gal-terminated O-glycans were identified. The C-PGC2 cell line, which was 20-fold more sensitive to TcdA than the wild-type CHO-K1, is proposed as a novel cell-based model for TcdA cytotoxicity and neutralization assays. The C-PGC2-produced fusion protein could competitively inhibit TcdA binding to rabbit erythrocytes, making it a high-efficiency inhibitor of the hemagglutination property of TcdA. The fusion protein also exhibited a moderate capability for neutralization of TcdA cytotoxicity in both C-PGC2 and CHO-K1 cells, the former with and the latter without cell surface Galα1,3Galβ1,4GlcNAc sequences. Future studies in animal models of C. difficile infection will reveal its TcdA-inhibitory effect and therapeutic potential in C. difficile-associated diseases. PMID:27456831

  19. The inhibitor of apoptosis protein fusion c-IAP2.MALT1 stimulates NF-kappaB activation independently of TRAF1 AND TRAF2.

    PubMed

    Varfolomeev, Eugene; Wayson, Sarah M; Dixit, Vishva M; Fairbrother, Wayne J; Vucic, Domagoj

    2006-09-29

    The inhibitors of apoptosis (IAPs) are a family of cell death inhibitors found in viruses and metazoans. All members of the IAP family have at least one baculovirus IAP repeat (BIR) motif that is essential for their anti-apoptotic activity. The t(11, 18)(q21;q21) translocation fuses the BIR domains of c-IAP2 with the paracaspase/MALT1 (mucosa-associated lymphoid tissue) protein, a critical mediator of T cell receptor-stimulated activation of NF-kappaB. The c-IAP2.MALT1 fusion protein constitutively activates the NF-kappaB pathway, and this is considered critical to malignant B cell transformation and lymphoma progression. The BIR domains of c-IAP1 and c-IAP2 interact with tumor necrosis factor receptor-associated factors 1 and 2 (TRAF1 and TRAF2). Here we investigated the importance of TRAF1 and TRAF2 for c-IAP2.MALT1-stimulated NF-kappaB activation. We identified a novel epitope within the BIR1 domains of c-IAP1 and c-IAP2 that is crucial for their physical interaction with TRAF1 and TRAF2. The c-IAP2.MALT1 fusion protein associates with TRAF1 and TRAF2 using the same binding site. We explored the functional relevance of this interaction and established that binding to TRAF1 and TRAF2 is not required for c-IAP2.MALT1-stimulated NF-kappaB activation. Furthermore, gene ablation of TRAF2 or combined down-regulation of TRAF1 and TRAF2 did not affect c-IAP2.MALT1-stimulated signaling. However, TRAF1/2-binding mutants of c-IAP2.MALT1 still oligomerize and activate NF-kappaB, suggesting that oligomerization might be important for signaling of the fusion protein. Therefore, the t(11, 18)(q21;q21) translocation creating the c-IAP2.MALT1 fusion protein activates NF-kappaB and contributes to human malignancy in the absence of signaling adaptors that might otherwise regulate its activity.

  20. Synergistic effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway or NUP214-ABL1 fusion protein in human Acute Lymphoblastic Leukemia

    PubMed Central

    Martelli, Alberto M.; Zauli, Giorgio; Milani, Daniela; McCubrey, James A.; Capitani, Silvano; Neri, Luca M.

    2016-01-01

    Philadelphia chromosome-positive (Ph+) Acute Lymphoblastic Leukemia (ALL) accounts for 25–30% of adult ALL and its incidence increases with age in adults >40 years old. Irrespective of age, the ABL1 fusion genes are markers of poor prognosis and amplification of the NUP214-ABL1 oncogene can be detected mainly in patients with T-ALL. T cell malignancies harboring the ABL1 fusion genes are sensitive to many cytotoxic agents, but up to date complete remissions have not been achieved. The PI3K/Akt/mTOR signaling pathway is often activated in leukemias and plays a crucial role in leukemogenesis. We analyzed the effects of three BCR-ABL1 tyrosine kinase inhibitors (TKIs), alone and in combination with a panel of selective PI3K/Akt/mTOR inhibitors, on three NUP214-ABL1 positive T-ALL cell lines that also displayed PI3K/Akt/mTOR activation. Cells were sensitive to anti BCR-ABL1 TKIs Imatinib, Nilotinib and GZD824, that specifically targeted the ABL1 fusion protein, but not the PI3K/Akt/mTOR axis. Four drugs against the PI3K/Akt/mTOR cascade, GSK690693, NVP-BGT226, ZSTK474 and Torin-2, showed marked cytotoxic effects on T-leukemic cells, without affecting the NUP214-ABL1 kinase and related pathway. Dephosphorylation of pAkt and pS6 showed the cytotoxicity of these compounds. Either single or combined administration of drugs against the different targets displayed inhibition of cellular viability associated with a concentration-dependent induction of apoptosis, cell cycle arrest in G0/G1 phase and autophagy, having the combined treatments a significant synergistic cytotoxic effect. Co-targeting NUP214-ABL1 fusion gene and PI3K/Akt/mTOR signaling pathway could represent a new and effective pharmacological strategy to improve the outcome in NUP214-ABL1 positive T-ALL. PMID:27821800

  1. Site-Specific Polymer Attachment to HR2 Peptide Fusion Inhibitors against HIV-1 Decreases Binding Association Rates and Dissociation Rates Rather Than Binding Affinity.

    PubMed

    Danial, Maarten; Stauffer, Angela N; Wurm, Frederik R; Root, Michael J; Klok, Harm-Anton

    2017-03-15

    A popular strategy for overcoming the limited plasma half-life of peptide heptad repeat 2 (HR2) fusion inhibitors against HIV-1 is conjugation with biocompatible polymers such as poly(ethylene glycol) (PEG). However, despite improved resistance to proteolysis and reduced renal elimination, covalent attachment of polymers often causes a loss in therapeutic potency. In this study, we investigated the molecular origins of the loss in potency upon conjugation of linear, midfunctional, and hyperbranched PEG-like polymers to peptides that inhibit HIV-1-host cell membrane fusion. Fluorescence binding assays revealed that polymer conjugation imparted mass transport limitations that manifested as coexistent slower association and dissociation rates from the gp41 target on HIV-1. Furthermore, reduced association kinetics rather than affinity disruption was responsible for the loss in antiviral potency. Finally, the binding assays indicated that the unmodified HR2-derived peptide demonstrated diffusion-limited binding. The observed high potency of the unmodified peptide in HIV-1 inhibition assays was therefore attributed to rapid peptide conformational changes upon binding to the gp41 prehairpin structure. This study emphasizes that the view in which polymer ligation to therapeutic peptides inadvertently leads to loss in potency due to a loss in binding affinity requires scientific verification on a case-by-case basis and that high peptide potency may be due to rapid target-binding events.

  2. Spacecraft Escape Capsule

    NASA Technical Reports Server (NTRS)

    Robertson, Edward A.; Charles, Dingell W.; Bufkin, Ann L.; Rodriggs, Liana M.; Peterson, Wayne; Cuthbert, Peter; Lee, David E.; Westhelle, Carlos

    2006-01-01

    A report discusses the Gumdrop capsule a conceptual spacecraft that would enable the crew to escape safely in the event of a major equipment failure at any time from launch through atmospheric re-entry. The scaleable Gumdrop capsule would comprise a command module (CM), a service module (SM), and a crew escape system (CES). The CM would contain a pressurized crew environment that would include avionic, life-support, thermal control, propulsive attitude control, and recovery systems. The SM would provide the primary propulsion and would also supply electrical power, life-support resources, and active thermal control to the CM. The CES would include a solid rocket motor, embedded within the SM, for pushing the CM away from the SM in the event of a critical thermal-protection-system failure or loss of control. The CM and SM would normally remain integrated with each other from launch through recovery, but could be separated using the CES, if necessary, to enable the safe recovery of the crew in the CM. The crew escape motor could be used, alternatively, as a redundant means of de-orbit propulsion for the CM in the event of a major system failure in the SM.

  3. Activity of c-Met/ALK Inhibitor Crizotinib and Multi-Kinase VEGF Inhibitor Pazopanib in Metastatic Gastrointestinal Neuroectodermal Tumor Harboring EWSR1-CREB1 Fusion.

    PubMed

    Subbiah, Vivek; Holmes, Oliver; Gowen, Kyle; Spritz, Daniel; Amini, Behrang; Wang, Wei-Lien; Schrock, Alexa B; Meric-Bernstam, Funda; Zinner, Ralph; Piha-Paul, Sarina; Zarzour, Maria; Elvin, Julia A; Erlich, Rachel L; Stockman, David L; Vergilio, Jo-Anne; Suh, James H; Stephens, Philip J; Miller, Vincent; Ross, Jeffrey S; Ali, Siraj M

    2016-01-01

    Malignant gastrointestinal neuroectodermal tumor (GNET) is an aggressive rare tumor, primarily occurring in young adults with frequent local-regional metastases and recurrence after local control. The tumor is characterized by the presence of EWSR1-ATF1 or EWSR1-CREB1 and immunohistochemical positivity for S-100 protein without melanocytic marker positivity. Due to poor responses to standard sarcoma regimens, GNET has a poor prognosis, and development of effective systemic therapy is desperately needed to treat these patients. Herein, we present a patient with a small bowel GNET who experienced recurrent hepatic and skeletal metastases after a primary resection. Comprehensive genomic profiling (CGP) in the course of clinical care with DNA and RNA sequencing demonstrated the presence of an exon 7 to exon 6 EWSR1-CREB1 fusion in the context of a diploid genome with no other genomic alterations. In a clinical trial, the patient received a combination of 250 mg crizotinib with 600 mg pazopanib quaque die and achieved partial response and durable clinical benefit for over 2.8 years, and with minimal toxicity from therapy. Using a CGP database of over 50,000 samples, we identified 11 additional cases that harbor EWSR1-CREB1 and report clinicopathologic characteristics, as these patients may also benefit from such a regimen.

  4. The role of blood cell membrane lipids on the mode of action of HIV-1 fusion inhibitor sifuvirtide

    SciTech Connect

    Matos, Pedro M.; Freitas, Teresa; Castanho, Miguel A.R.B.; Santos, Nuno C.

    2010-12-17

    Research highlights: {yields} Sifuvirtide interacts with erythrocyte and lymphocyte membrane in a concentration dependent manner by decreasing its dipole potential. {yields} Dipole potential variations in lipid vesicles show sifuvirtide's lipid selectivity towards saturated phosphatidylcholines. {yields} This peptide-membrane interaction may direct the drug towards raft-like membrane domains where the receptors used by HIV are located, facilitating its inhibitory action. -- Abstract: Sifuvirtide is a gp41 based peptide that inhibits HIV-1 fusion with the host cells and is currently under clinical trials. Previous studies showed that sifuvirtide partitions preferably to saturated phosphatidylcholine lipid membranes, instead of fluid-phase lipid vesicles. We extended the study to the interaction of the peptide with circulating blood cells, by using the dipole potential sensitive probe di-8-ANEPPS. Sifuvirtide decreased the dipole potential of erythrocyte and lymphocyte membranes in a concentration dependent manner, demonstrating its interaction. Also, the lipid selectivity of the peptide towards more rigid phosphatidylcholines was confirmed based on the dipole potential variations. Overall, the interaction of the peptide with the cell membranes is a contribution of different lipid preferences that presumably directs the peptide towards raft-like domains where the receptors are located, facilitating the reach of the peptide to its molecular target, the gp41 in its pre-fusion conformation.

  5. Atmospheric escape from unmagnetized bodies

    NASA Astrophysics Data System (ADS)

    Brain, D. A.; Bagenal, F.; Ma, Y.-J.; Nilsson, H.; Stenberg Wieser, G.

    2016-12-01

    The upper atmospheres of unmagnetized solar system bodies interact more directly with their local plasma environment than their counterparts on magnetized bodies such as Earth. One consequence of this interaction is that atmospheric particles can gain energy from the flowing plasma, as well as solar photons, and escape to space. Escape proceeds through a number of different mechanisms that can remove neutral particles (Jeans escape, photochemical escape, and sputtering) and mechanisms that can remove ions (ion pickup, magnetic shear and tension-related escape, and pressure gradients). Here we discuss the plasma interactions and escape processes and rates from five solar system objects spanning 3 orders of magnitude in size: comets, Pluto, Titan, Mars, and Venus. We describe similarities and differences in escape for the different objects and provide four open questions that should be addressed in the coming years.

  6. Drug Delivery via Cell Membrane Fusion Using Lipopeptide Modified Liposomes

    PubMed Central

    2016-01-01

    Efficient delivery of drugs to living cells is still a major challenge. Currently, most methods rely on the endocytotic pathway resulting in low delivery efficiency due to limited endosomal escape and/or degradation in lysosomes. Here, we report a new method for direct drug delivery into the cytosol of live cells in vitro and invivo utilizing targeted membrane fusion between liposomes and live cells. A pair of complementary coiled-coil lipopeptides was embedded in the lipid bilayer of liposomes and cell membranes respectively, resulting in targeted membrane fusion with concomitant release of liposome encapsulated cargo including fluorescent dyes and the cytotoxic drug doxorubicin. Using a wide spectrum of endocytosis inhibitors and endosome trackers, we demonstrate that the major site of cargo release is at the plasma membrane. This method thus allows for the quick and efficient delivery of drugs and is expected to have many invitro, ex vivo, and invivo applications. PMID:27725960

  7. Orbiter escape pole

    NASA Technical Reports Server (NTRS)

    Goodrich, Winston D. (Inventor); Wesselski, Clarence J. (Inventor); Pelischek, Timothy E. (Inventor); Becker, Bruce H. (Inventor); Kahn, Jon B. (Inventor); Grimaldi, Margaret E. (Inventor); McManamen, John P. (Inventor); Castro, Edgar O. (Inventor)

    1989-01-01

    A Shuttle type of aircraft (10) with an escape hatch (12) has an arcuately shaped pole housing (16) attachable to an interior wall and ceiling with its open end adjacent to the escape hatch. The pole housing 16 contains a telescopically arranged and arcuately shaped primary pole member (22) and extension pole member (23) which are guided by roller assemblies (30,35). The extension pole member (23) is slidable and extendable relative to the primary pole member (22). For actuation, a spring actuated system includes a spring (52) in the pole housing. A locking member (90) engages both pole members (22,23) through notch portions (85,86) in the pole members. The locking member selectively releases the extension pole member (23) and the primary pole member (22). An internal one-way clutch or anti-return mechanism prevents retraction of the extension pole member from an extended position. Shock absorbers (54)(150,152) are for absoring the energy of the springs. A manual backup deployment system is provided which includes a canted ring (104) biased by a spring member (108). A lever member (100) with a slot and pin connection (102) permits the mechanical manipulation of the canted ring to move the primary pole member. The ring (104) also prevents retraction of the main pole. The crew escape mechanism includes a magazine (60) and a number of lanyards (62), each lanyard being mounted by a roller loop (68) over the primary pole member (22). The strap on the roller loop has stitching for controlled release, a protection sheath (74) to prevent tangling and a hook member (69) for attachment to a crew harness.

  8. Treatment with the Fusion Inhibitor Enfuvirtide Influences the Appearance of Mutations in the Human Immunodeficiency Virus Type 1 Regulatory Protein Rev▿

    PubMed Central

    Svicher, Valentina; Alteri, Claudia; D'Arrigo, Roberta; Laganà, Alessandro; Trignetti, Maria; Lo Caputo, Sergio; Callegaro, Anna Paola; Maggiolo, Franco; Mazzotta, Francesco; Ferro, Alfredo; Dimonte, Salvatore; Aquaro, Stefano; di Perri, Giovanni; Bonora, Stefano; Tommasi, Chiara; Trotta, Maria Paola; Narciso, Pasquale; Antinori, Andrea; Perno, Carlo Federico; Ceccherini-Silberstein, Francesca

    2009-01-01

    The gp41-encoding sequence of the env gene contains in two separate regions the Rev-responsive elements (RRE) and the alternative open reading frame of the second exon of the regulatory protein Rev. The binding of Rev to the RRE allows the transport of unspliced/singly spliced viral mRNAs out of the nucleus, an essential step in the life cycle of human immunodeficiency virus type 1 (HIV-1). In this study, we have investigated whether the fusion-inhibitor enfuvirtide (ENF) can induce mutations in Rev and if these mutations correlate with the classical ENF resistance gp41 mutations and with viremia and CD4 cell count. Specific Rev mutations were positively associated with ENF treatment and significantly correlated with classical ENF resistance gp41 mutations. In particular, a cluster was observed for the Rev mutations E57A (E57Arev) and N86Srev with the ENF resistance gp41 mutations Q40H (Q40Hgp41) and L45Mgp41. In addition, the presence at week 48 of the E57Arev correlates with a significant viremia increase from baseline to week 48 and with a CD4 cell count loss from baseline to week 48. By modeling the RRE structure, we found that the Q40gp41 and L45gp41 codons form complementary base pairs in a region of the RRE involved in Rev binding. The conformation of this Rev-binding site is disrupted when Q40Hgp41 and L45Mgp41 occur alone while it is restored when both mutations are present. In conclusion, our study shows that ENF pressure may also affect both Rev and RRE structures and can provide an excellent example of compensatory evolution. This highlights the multiple roles of ENF (and perhaps other entry inhibitors) in modulating the correct interplay between the different HIV-1 genes and proteins during the HIV-1 life cycle. PMID:19124665

  9. Reconstructing the Alcatraz escape

    NASA Astrophysics Data System (ADS)

    Baart, F.; Hoes, O.; Hut, R.; Donchyts, G.; van Leeuwen, E.

    2014-12-01

    In the night of June 12, 1962 three inmates used a raft made of raincoatsto escaped the ultimate maximum security prison island Alcatraz in SanFrancisco, United States. History is unclear about what happened tothe escapees. At what time did they step into the water, did theysurvive, if so, where did they reach land? The fate of the escapees has been the subject of much debate: did theymake landfall on Angel Island, or did the current sweep them out ofthe bay and into the cold pacific ocean? In this presentation, we try to shed light on this historic case using avisualization of a high-resolution hydrodynamic simulation of the San Francisco Bay, combined with historical tidal records. By reconstructing the hydrodynamic conditions and using a particle based simulation of the escapees we show possible scenarios. The interactive model is visualized using both a 3D photorealistic and web based visualization. The "Escape from Alcatraz" scenario demonstrates the capabilities of the 3Di platform. This platform is normally used for overland flooding (1D/2D). The model engine uses a quad tree structure, resulting in an order of magnitude speedup. The subgrid approach takes detailed bathymetry information into account. The inter-model variability is tested by comparing the results with the DFlow Flexible Mesh (DFlowFM) San Francisco Bay model. Interactivity is implemented by converting the models from static programs to interactive libraries, adhering to the Basic ModelInterface (BMI). Interactive models are more suitable for answeringexploratory research questions such as this reconstruction effort. Although these hydrodynamic simulations only provide circumstantialevidence for solving the mystery of what happened during the foggy darknight of June 12, 1962, it can be used as a guidance and provides aninteresting testcase to apply interactive modelling.

  10. Reviving Antibiotics: Efflux Pump Inhibitors That Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump

    SciTech Connect

    Abdali, Narges; Parks, Jerry M.; Haynes, Keith M.; Chaney, Julie L.; Green, Adam T.; Wolloscheck, David; Walker, John K.; Rybenkov, Valentin V.; Baudry, Jerome; Smith, Jeremy C.; Zgurskaya, Helen I.

    2016-10-21

    Antibiotic resistance is a major threat to human welfare. Inhibitors of multidrug efflux pumps (EPIs) are promising alternative therapeutics that could revive activities of antibiotics and reduce bacterial virulence. Identification of new druggable sites for inhibition is critical for developing effective EPIs, especially in light of constantly emerging resistance. We describe new EPIs that interact with and possibly inhibit the function of periplasmic membrane fusion proteins, critical components of efflux pumps that are responsible for the activation of the transporter and the recruitment of the outer-membrane channel. The discovered EPIs bind to AcrA, a component of the prototypical AcrAB-TolC pump, change its structure in vivo, inhibit efflux of fluorescent probes and potentiate the activities of antibiotics in Escherichia coli cells. These findings expand the chemical and mechanistic diversity of EPIs, suggest the mechanism for regulation of the efflux pump assembly and activity, and provide a promising path for reviving the activities of antibiotics in resistant bacteria.

  11. Reviving Antibiotics: Efflux Pump Inhibitors That Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump

    DOE PAGES

    Abdali, Narges; Parks, Jerry M.; Haynes, Keith M.; ...

    2016-10-21

    Antibiotic resistance is a major threat to human welfare. Inhibitors of multidrug efflux pumps (EPIs) are promising alternative therapeutics that could revive activities of antibiotics and reduce bacterial virulence. Identification of new druggable sites for inhibition is critical for developing effective EPIs, especially in light of constantly emerging resistance. We describe new EPIs that interact with and possibly inhibit the function of periplasmic membrane fusion proteins, critical components of efflux pumps that are responsible for the activation of the transporter and the recruitment of the outer-membrane channel. The discovered EPIs bind to AcrA, a component of the prototypical AcrAB-TolC pump,more » change its structure in vivo, inhibit efflux of fluorescent probes and potentiate the activities of antibiotics in Escherichia coli cells. These findings expand the chemical and mechanistic diversity of EPIs, suggest the mechanism for regulation of the efflux pump assembly and activity, and provide a promising path for reviving the activities of antibiotics in resistant bacteria.« less

  12. Quantitative analysis of a novel HIV fusion inhibitor (sifuvirtide) in HIV infected human plasma using high-performance liquid chromatography-electrospray ionization tandem mass spectrometry.

    PubMed

    Che, Jinjing; Meng, Qingfang; Chen, Zhihang; Hou, Yunan; Shan, Chengqi; Cheng, Yuanguo

    2010-03-11

    A sensitive method for measuring sifuvirtide, a novel HIV fusion inhibitor peptide drug in HIV-1(+) human plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. The plasma samples were treated by solvent/detergent (S/D) method to inactivate viral activity before analysis. After protein precipitation sifuvirtide was determined by LC-MS/MS. A structure analog was used as internal standard (IS). The mass spectrometer was operated in positive ion and multiple reaction monitoring mode with transitions m/z 946.3-->159.0 for sifuvirtide and 951.7-->159.2 for IS. The intra-day precision ranged from 2.74% to 7.57% with accuracy from 91.63% to 102.53%. The inter-day precision ranged from 2.65% to 3.58% and the accuracy from 95.53% to 105.28%. Stability studies showed that sifuvirtide was stable both during the assay procedure and long-term storage. The lower limit of quantitation (LLOQ) was 9.75ngml(-1). The method was used for analyzing samples from phase IIa clinical study of sifuvirtide in China.

  13. Activity of fibroblast growth factor receptor inhibitors TKI258, ponatinib and AZD4547 against TPR-FGFR1 fusion

    PubMed Central

    Qiu, Xu-Hua; Li, Feng; Cao, Hong-Qin; Shao, Jing-Jing; Mei, Jian-Gang; Li, Han-Qing; Zhai, Yong-Ping

    2017-01-01

    8p11 myeloproliferative syndrome (EMS) is a rare disease characterized by the constitutive activation of fibroblast growth factor receptor 1 (FGFR1). To date, four cases of EMS with the chromosomal translocation, t(1;8)(q25;p11.2), have been reported. In the present study, TPR-FGFR1-expressing Baf3 cells were established and confirmed by polymerase chain reaction. To identify the most promising drug for EMS, the activities and associated mechanism of three tyrosine kinase inhibitors (TKIs), TKI258, ponatinib and AZD4547, against TPR-FGFR1 were tested by MTT assay, flow cytometry and western blot. The data demonstrated that TPR-FGFR1 was localized in the cytoplasm, and was able to transform interleukin-3-dependent hematopoietic Baf3 cells into growth factor-independent cells. All of the three TKIs markedly inhibited the proliferation of TPR-FGFR1-expressing Baf3 cells, and the activation of FGFR1 and the downstream signaling molecules, extracellular signal-regulated kinase 1/2, phospholipiase Cγ and signal transducer and activator of transcription 5. AZD4547 was the most efficient drug, and TKI258 was the least. By contrast, no significant difference was found among the three drugs on their effect on cell apoptosis. Taken together, the data obtained in the present study suggested that AZD4547 had increased potency, compared with TKI258 and ponatinib, for the treatment of EMS. PMID:28138694

  14. Escape from Vela X

    SciTech Connect

    Hinton, J.; Funk, S.; Parsons, R.D.; Ohm, S.; /Leicester U. /Leeds U.

    2012-02-15

    While the Vela pulsar and its associated nebula are often considered as the archetype of a system powered by a {approx} 10{sup 4} year old isolated neutron star, many features of the spectral energy distribution of this pulsar wind nebula are both puzzling and unusual. Here we develop a model that for the first time relates the main structures in the system, the extended radio nebula (ERN) and the X-ray cocoon through continuous injection of particles with a fixed spectral shape. We argue that diffusive escape of particles from the ERN can explain the steep Fermi-LAT spectrum. In this scenario Vela X should produce a distinct feature in the locally-measured cosmic ray electron spectrum at very high energies. This prediction can be tested in the future using the Cherenkov Telescope Array (CTA). If particles are indeed released early in the evolution of PWNe and can avoid severe adiabatic losses, PWN provide a natural explanation for the rising positron fraction in the local CR spectrum.

  15. Bursty Escape on Mars

    NASA Astrophysics Data System (ADS)

    Dubinin, E.; Fraenz, M.; Woch, J.; Lundin, R.; Wei, J.; Barabash, S.

    2011-10-01

    Bursty or filamentary structuring of plasma flows is a typical feature of the Martian space. This phenomenon is revealed during time periods when MEX-ASPERA- 3 is operating in the high temporal resolution mode. Frequency of oscillations is about 10-50 mHz. Amplitude of flux variations reaches a factor of 10-30. Bursty origin of fluxes of oxygen ions can be the important process for solar wind induced escape on Mars. There are several mechanisms which can be responsible for the observed periodic bursts. Large-amplitude coherent pressure pulses generated by ion beams upstream the bow shock impact the magnetosphere and produce periodic pulses in forces pushing planetary plasma. Pressure pulses can arise downstream the bow shock - in the magnetosheath, which becomes to be decomposed into a sequence of periodic compressive waves. A wavy dynamics can also appear due to a multi-ion origin of the interacting plasmas since such a medium behaves as a specific rotator. At last, not at least, K-H or other types of large-scale MHD instabilities probably excited in the interface region can generate surface waves which will also modulate the tension forces. We present the different observations which can be interpreted in a favor of all the above mechanisms implying a complex and diverse plasma wave environment at Mars.

  16. ESCAPE FROM VELA X

    SciTech Connect

    Hinton, J. A.; Ohm, S.; Funk, S.; Parsons, R. D.

    2011-12-10

    While the Vela pulsar and its associated nebula are often considered as the archetype of a system powered by a {approx}10{sup 4} year old isolated neutron star, many features of the spectral energy distribution of this pulsar wind nebula (PWN) are both puzzling and unusual. Here we develop a model that for the first time relates the main structures in the system, the extended radio nebula (ERN) and the X-ray cocoon through continuous injection of particles with a fixed spectral shape. We argue that diffusive escape of particles from the ERN can explain the steep Fermi-LAT spectrum. In this scenario Vela X should produce a distinct feature in the locally measured cosmic ray (CR) electron spectrum at very high energies. This prediction can be tested in the future using the Cherenkov Telescope Array. If particles are indeed released early in the evolution of PWNe and can avoid severe adiabatic losses, PWN provides a natural explanation for the rising positron fraction in the local CR spectrum.

  17. Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: Implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients.

    PubMed

    Hong, Shaodong; Chen, Nan; Fang, Wenfeng; Zhan, Jianhua; Liu, Qing; Kang, Shiyang; He, Xiaobo; Liu, Lin; Zhou, Ting; Huang, Jiaxing; Chen, Ying; Qin, Tao; Zhang, Yaxiong; Ma, Yuxiang; Yang, Yunpeng; Zhao, Yuanyuan; Huang, Yan; Zhang, Li

    2016-03-01

    Driver mutations were reported to upregulate programmed death-ligand 1 (PD-L1) expression. However, how PD-L1 expression and immune function was affected by ALK-TKIs and anti-PD-1/PD-L1 treatment in ALK positive non-small-cell lung cancer (NSCLC) remains poorly understood. In the present study, western-blot, real-time PCR, flow cytometry and immunofluorescence were employed to explore how PD-L1 was regulated by ALK fusion protein. ALK-TKIs and relevant inhibitors were used to identify the downstream signaling pathways involved in PD-L1 regulation. Cell apoptosis, viability and Elisa test were used to study the immune suppression by ALK activation and immune reactivation by ALK-TKIs and/or PD-1 blocking in tumor cells and DC-CIK cells co-culture system. We found that PD-L1 expression was associated with EGFR mutations and ALK fusion genes in NSCLC cell lines. Over-expression of ALK fusion protein increased PD-L1 expression. PD-L1 mediated by ALK fusion protein increased the apoptosis of T cells in tumor cells and DC-CIK cells co-culture system. Inhibiting ALK by sensitive TKIs could enhance the production of IFNγ. Anti-PD-1 antibody was effective in both crizotinib sensitive and resistant NSCLC cells. Synergistic tumor killing effects were not observed with ALK-TKIs and anti-PD-1 antibody combination in co-culture system. ALK-TKIs not only directly inhibited tumor viability but also indirectly enhanced the antitumor immunity via the downregulation of PD-L1. Anti-PD-1/PD-L1 antibodies could be an optional therapy for crizotinib sensitive, especially crizotinib resistant NSCLC patients with ALK fusion gene. Combination of ALK-TKIs and anti-PD-1/PD-L1 antibodies treatment for ALK positive NSCLC warrants more data before moving into clinical practice.

  18. Evidence that maturation of the N-linked glycans of the respiratory syncytial virus (RSV) glycoproteins is required for virus-mediated cell fusion: The effect of {alpha}-mannosidase inhibitors on RSV infectivity

    SciTech Connect

    McDonald, Terence P.; Jeffree, Chris E.; Li, Ping; Rixon, Helen W. McL.; Brown, Gaie; Aitken, James D.; MacLellan, Kirsty; Sugrue, Richard J. . E-mail: rjsugrue@ntu.edu.sg

    2006-07-05

    Glycan heterogeneity of the respiratory syncytial virus (RSV) fusion (F) protein was demonstrated by proteomics. The effect of maturation of the virus glycoproteins-associated glycans on virus infectivity was therefore examined using the {alpha}-mannosidase inhibitors deoxymannojirimycin (DMJ) and swainsonine (SW). In the presence of SW the N-linked glycans on the F protein appeared in a partially mature form, whereas in the presence of DMJ no maturation of the glycans was observed. Neither inhibitor had a significant effect on G protein processing or on the formation of progeny virus. Although the level of infectious virus and syncytia formation was not significantly affected by SW-treatment, DMJ-treatment correlated with a one hundred-fold reduction in virus infectivity. Our data suggest that glycan maturation of the RSV glycoproteins, in particular those on the F protein, is an important step in virus maturation and is required for virus infectivity.

  19. 42 CFR 84.51 - Entry and escape, or escape only; classification.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... during entry into a hazardous atmosphere, and for escape from a hazardous atmosphere; or (b) Escape only. Respirators designed and approved for use only during escape from a hazardous atmosphere....

  20. 42 CFR 84.51 - Entry and escape, or escape only; classification.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... during entry into a hazardous atmosphere, and for escape from a hazardous atmosphere; or (b) Escape only. Respirators designed and approved for use only during escape from a hazardous atmosphere....

  1. 42 CFR 84.51 - Entry and escape, or escape only; classification.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... during entry into a hazardous atmosphere, and for escape from a hazardous atmosphere; or (b) Escape only. Respirators designed and approved for use only during escape from a hazardous atmosphere....

  2. 42 CFR 84.51 - Entry and escape, or escape only; classification.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... during entry into a hazardous atmosphere, and for escape from a hazardous atmosphere; or (b) Escape only. Respirators designed and approved for use only during escape from a hazardous atmosphere....

  3. 42 CFR 84.51 - Entry and escape, or escape only; classification.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... during entry into a hazardous atmosphere, and for escape from a hazardous atmosphere; or (b) Escape only. Respirators designed and approved for use only during escape from a hazardous atmosphere....

  4. Lise Meitner's escape from Germany

    NASA Astrophysics Data System (ADS)

    Sime, Ruth Lewin

    1990-03-01

    Lise Meitner (1878-1968) achieved prominence as a nuclear physicist in Germany; although of Jewish origin, her Austrian citizenship exempted her from Nazi racial laws until the annexation of Austria in 1938 precipitated her dismissal. Forbidden to emigrate, she narrowly escaped to the Netherlands with the help of concerned friends in the international physics community.

  5. Mechanisms of Ionospheric Mass Escape

    NASA Technical Reports Server (NTRS)

    Moore, T. E.; Khazanov, G. V.

    2010-01-01

    The dependence of ionospheric O+ escape flux on electromagnetic energy flux and electron precipitation into the ionosphere is derived for a hypothetical ambipolar pick-up process, powered the relative motion of plasmas and neutral upper atmosphere, and by electron precipitation, at heights where the ions are magnetized but influenced by photo-ionization, collisions with gas atoms, ambipolar and centrifugal acceleration. Ion pick-up by the convection electric field produces "ring-beam" or toroidal velocity distributions, as inferred from direct plasma measurements, from observations of the associated waves, and from the spectra of incoherent radar echoes. Ring-beams are unstable to plasma wave growth, resulting in rapid relaxation via transverse velocity diffusion, into transversely accelerated ion populations. Ion escape is substantially facilitated by the ambipolar potential, but is only weakly affected by centrifugal acceleration. If, as cited simulations suggest, ion ring beams relax into non-thermal velocity distributions with characteristic speed equal to the local ion-neutral flow speed, a generalized "Jeans escape" calculation shows that the escape flux of ionospheric O+ increases with Poynting flux and with precipitating electron density in rough agreement with observations.

  6. DYNAMICS OF THE ESCAPE RESPONSE.

    DTIC Science & Technology

    requirements. It has been shown that force is a lawful response measure under positive reinforcement (Notterman and Mintz, 1965). Subjects will adjust...concluded that response force in an escape situation is a lawful response measure, and that it operates in a manner similar to force under positive reinforcement .

  7. HIV-1 variants with a single-point mutation in the gp41 pocket region exhibiting different susceptibility to HIV fusion inhibitors with pocket- or membrane-binding domain.

    PubMed

    Lu, Lu; Tong, Pei; Yu, Xiaowen; Pan, Chungen; Zou, Peng; Chen, Ying-Hua; Jiang, Shibo

    2012-12-01

    Enfuvirtide (T20), the first FDA-approved peptide HIV fusion/entry inhibitor derived from the HIV-1 gp41 C-terminal heptad-repeat (CHR) domain, is believed to share a target with C34, another well-characterized CHR-peptide, by interacting with the gp41 N-terminal heptad-repeat (NHR) to form six-helix bundle core. However, our previous studies showed that T20 mainly interacts with the N-terminal region of the NHR (N-NHR) and lipid membranes, while C34 mainly binds to the NHR C-terminal pocket region. But so far, no one has shown that C34 can induce drug-resistance mutation in the gp41 pocket region. In this study, we constructed pseudoviruses in which the Ala at the position of 67 in the gp41 pocket region was substituted with Asp, Gly or Ser, respectively, and found that these mutations rendered the viruses highly resistant to C34, but sensitive to T20. The NHR-peptide N36 with mutations of A67 exhibited reduced anti-HIV-1 activity and decreased α-helicity. The stability of six-helix bundle formed by C34 and N36 with A67 mutations was significantly lower than that formed by C34 and N36 with wild-type sequence. The combination of C34 and T20 resulted in potent synergistic anti-HIV-1 effect against the viruses with mutations in either N- or C-terminal region in NHR. These results suggest that C34 with a pocket-binding domain and T20 containing the N-NHR- and membrane-binding domains inhibit HIV-1 fusion by interacting with different target sites and the combinatorial use of C34 and T20 is expected to be effective against HIV-1 variants resistant to HIV fusion inhibitors.

  8. Fusion reactor pumped laser

    DOEpatents

    Jassby, Daniel L.

    1988-01-01

    A nuclear pumped laser capable of producing long pulses of very high power laser radiation is provided. A toroidal fusion reactor provides energetic neutrons which are slowed down by a moderator. The moderated neutrons are converted to energetic particles capable of pumping a lasing medium. The lasing medium is housed in an annular cell surrounding the reactor. The cell includes an annular reflecting mirror at the bottom and an annular output window at the top. A neutron reflector is disposed around the cell to reflect escaping neutrons back into the cell. The laser radiation from the annular window is focused onto a beam compactor which generates a single coherent output laser beam.

  9. Viral membrane fusion

    PubMed Central

    Harrison, Stephen C

    2008-01-01

    Infection by viruses having lipid-bilayer envelopes proceeds through fusion of the viral membrane with a membrane of the target cell. Viral ‘fusion proteins’ facilitate this process. They vary greatly in structure, but all seem to have a common mechanism of action, in which a ligand-triggered, large-scale conformational change in the fusion protein is coupled to apposition and merger of the two bilayers. We describe three examples—the influenza virus hemagglutinin, the flavivirus E protein and the vesicular stomatitis virus G protein—in some detail, to illustrate the ways in which different structures have evolved to implement this common mechanism. Fusion inhibitors can be effective antiviral agents. PMID:18596815

  10. Blue Origin Conducts Pad Escape Test

    NASA Video Gallery

    Blue Origin conducted a successful pad escape test Oct. 19 at the company's West Texas launch site, firing its pusher escape motor and launching a full-scale suborbital crew capsule from a simulate...

  11. Cold Ion Escape from Mars

    NASA Astrophysics Data System (ADS)

    Fränz, M.; Dubinin, E.; Wei, Y.; Morgan, D.; Andrews, D.; Barabash, S.; Lundin, R.; Fedorov, A.

    2013-09-01

    It has always been challenging to observe the flux of ions with energies of less than 10eV escaping from the planetary ionospheres. We here report on new measurements of the ionospheric ion flows at Mars by the ASPERA-3 experiment on board Mars Express in combination with the MARSIS radar experiment. We first compare calculations of the mean ion flux observed by ASPERA-3 alone with previously published results. We then combine observations of the cold ion velocity by ASPERA-3 with observations of the cold plasma density by MARSIS since ASPERA-3 misses the cold core of the ion distribution. We show that the mean density of the nightside plasma observed by MARSIS is about two orders higher than observed by ASPERA-3 (Fig.1). Combining both datasets we show that the main escape channel is along the shadow boundary on the tailside of Mars (Fig. 2). At a distance of about 0.5 R_M the flux settles at a constant value (Fig. 3) which indicates that about half of the transterminator ionospheric flow escapes from the planet. Possible mechanism to generate this flux can be the ionospheric pressure gradient between dayside and nightside or momentum transfer from the solar wind via the induced magnetic field since the flow velocity is in the Alfvénic regime.

  12. Anticipating and blocking HIV-1 escape by second generation antiviral shRNAs

    PubMed Central

    2010-01-01

    Background RNA interference (RNAi) is an evolutionary conserved gene silencing mechanism that mediates the sequence-specific breakdown of target mRNAs. RNAi can be used to inhibit HIV-1 replication by targeting the viral RNA genome. However, the error-prone replication machinery of HIV-1 can generate RNAi-resistant variants with specific mutations in the target sequence. For durable inhibition of HIV-1 replication the emergence of such escape viruses must be controlled. Here we present a strategy that anticipates HIV-1 escape by designing 2nd generation short hairpin RNAs (shRNAs) that form a complete match with the viral escape sequences. Results To block the two favorite viral escape routes observed when the HIV-1 integrase gene sequence is targeted, the original shRNA inhibitor was combined with two 2nd generation shRNAs in a single lentiviral expression vector. We demonstrate in long-term viral challenge experiments that the two dominant viral escape routes were effectively blocked. Eventually, virus breakthrough did however occur, but HIV-1 evolution was skewed and forced to use new escape routes. Conclusion These results demonstrate the power of the 2nd generation RNAi concept. Popular viral escape routes are blocked by the 2nd generation RNAi strategy. As a consequence viral evolution was skewed leading to new escape routes. These results are of importance for a deeper understanding of HIV-1 evolution under RNAi pressure. PMID:20529316

  13. The discovery of 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 1.

    PubMed

    Bond, Silas; Draffan, Alistair G; Fenner, Jennifer E; Lambert, John; Lim, Chin Yu; Lin, Bo; Luttick, Angela; Mitchell, Jeffrey P; Morton, Craig J; Nearn, Roland H; Sanford, Vanessa; Stanislawski, Pauline C; Tucker, Simon P

    2015-02-15

    Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, young children and adults. Compound 1a (9b-(4-chlorophenyl)-1-(4-fluorobenzoyl)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one) was identified as an inhibitor of A and B strains of RSV targeting the fusion glycoprotein. SAR was developed by systematic exploration of the phenyl (R(1)) and benzoyl (R(2)) groups. Furthermore, introduction of a nitrogen at the 8-position of the tricyclic core resulted in active analogues with improved properties (aqueous solubility, protein binding and logD) and excellent rat pharmacokinetics (e.g., rat oral bioavailability of 89% for compound 17).

  14. Molecular phylogeny of C1 inhibitor depicts two immunoglobulin-like domains fusion in fishes and ray-finned fishes specific intron insertion after separation from zebrafish

    SciTech Connect

    Kumar, Abhishek; Bhandari, Anita; Sarde, Sandeep J.; Goswami, Chandan

    2014-07-18

    Highlights: • C1 inhibitors of fishes have two Ig domains fused in the N-terminal end. • Spliceosomal introns gain in two Ig domains of selected ray-finned fishes. • C1 inhibitors gene is maintained from 450 MY on the same locus. • C1 inhibitors gene is missing in frog and lampreys. • C1 inhibitors of tetrapod and fishes differ in the RCL region. - Abstract: C1 inhibitor (C1IN) is a multi-facet serine protease inhibitor in the plasma cascades, inhibiting several proteases, notably, regulates both complement and contact system activation. Despite huge advancements in the understanding of C1IN based on biochemical properties and its roles in the plasma cascades, the phylogenetic history of C1IN remains uncharacterized. To date, there is no comprehensive study illustrating the phylogenetic history of C1IN. Herein, we explored phylogenetic history of C1IN gene in vertebrates. Fishes have C1IN with two immunoglobulin like domains attached in the N-terminal region. The RCL regions of CIIN from fishes and tetrapod genomes have variations at the positions P2 and P1′. Gene structures of C1IN gene from selected ray-finned fishes varied in the Ig domain region with creation of novel intron splitting exon Im2 into Im2a and Im2b. This intron is limited to ray-finned fishes with genome size reduced below 1 Gb. Hence, we suggest that genome compaction and associated double-strand break repairs are behind this intron gain. This study reveals the evolutionary history of C1IN and confirmed that this gene remains the same locus for ∼450 MY in 52 vertebrates analysed, but it is not found in frogs and lampreys.

  15. On ion escape from Venus

    NASA Astrophysics Data System (ADS)

    Jarvinen, R.

    2011-04-01

    This doctoral thesis is about the solar wind influence on the atmosphere of the planet Venus. A numerical plasma simulation model was developed for the interaction between Venus and the solar wind to study the erosion of charged particles from the Venus upper atmosphere. The developed model is a hybrid simulation where ions are treated as particles and electrons are modelled as a fluid. The simulation was used to study the solar wind induced ion escape from Venus as observed by the European Space Agency's Venus Express and NASA's Pioneer Venus Orbiter spacecraft. Especially, observations made by the ASPERA-4 particle instrument onboard Venus Express were studied. The thesis consists of an introductory part and four peer-reviewed articles published in scientific journals. In the introduction Venus is presented as one of the terrestrial planets in the Solar System and the main findings of the work are discussed within the wider context of planetary physics.Venus is the closest neighbouring planet to the Earth and the most earthlike planet in its size and mass orbiting the Sun. Whereas the atmosphere of the Earth consists mainly of nitrogen and oxygen, Venus has a hot carbon dioxide atmosphere, which is dominated by the greenhouse effect. Venus has all of its water in the atmosphere, which is only a fraction of the Earth's total water supply. Since planets developed presumably in similar conditions in the young Solar System, why Venus and Earth became so different in many respects?One important feature of Venus is that the planet does not have an intrinsic magnetic field. This makes it possible for the solar wind, a continuous stream of charged particles from the Sun, to flow close to Venus and to pick up ions from the planet's upper atmosphere. The strong intrinsic magnetic field of the Earth dominates the terrestrial magnetosphere and deflects the solar wind flow far away from the atmosphere. The region around Venus where the planet's atmosphere interacts with the

  16. On ion escape from Venus

    NASA Astrophysics Data System (ADS)

    Jarvinen, Riku

    2011-04-01

    This doctoral thesis is about the solar wind influence on the atmosphere of the planet Venus. A numerical plasma simulation model was developed for the interaction between Venus and the solar wind to study the erosion of charged particles from the Venus upper atmosphere. The developed model is a hybrid simulation where ions are treated as particles and electrons are modelled as a fluid. The simulation was used to study the solar wind induced ion escape from Venus as observed by the European Space Agency's Venus Express and NASA's Pioneer Venus Orbiter spacecraft. Especially, observations made by the ASPERA-4 particle instrument onboard Venus Express were studied. The thesis consists of an introductory part and four peer-reviewed articles published in scientific journals. In the introduction Venus is presented as one of the terrestrial planets in the Solar System and the main findings of the work are discussed within the wider context of planetary physics. Venus is the closest neighbouring planet to the Earth and the most earthlike planet in its size and mass orbiting the Sun. Whereas the atmosphere of the Earth consists mainly of nitrogen and oxygen, Venus has a hot carbon dioxide atmosphere, which is dominated by the greenhouse effect. Venus has all of its water in the atmosphere, which is only a fraction of the Earth's total water supply. Since planets developed presumably in similar conditions in the young Solar System, why Venus and Earth became so different in many respects? One important feature of Venus is that the planet does not have an intrinsic magnetic field. This makes it possible for the solar wind, a continuous stream of charged particles from the Sun, to flow close to Venus and to pick up ions from the planet's upper atmosphere. The strong intrinsic magnetic field of the Earth dominates the terrestrial magnetosphere and deflects the solar wind flow far away from the atmosphere. The region around Venus where the planet's atmosphere interacts with the

  17. Malaria Parasites: The Great Escape

    PubMed Central

    Rénia, Laurent; Goh, Yun Shan

    2016-01-01

    Parasites of the genus Plasmodium have a complex life cycle. They alternate between their final mosquito host and their intermediate hosts. The parasite can be either extra- or intracellular, depending on the stage of development. By modifying their shape, motility, and metabolic requirements, the parasite adapts to the different environments in their different hosts. The parasite has evolved to escape the multiple immune mechanisms in the host that try to block parasite development at the different stages of their development. In this article, we describe the mechanisms reported thus far that allow the Plasmodium parasite to evade innate and adaptive immune responses. PMID:27872623

  18. Spinal Fusion

    MedlinePlus

    ... concept of fusion is similar to that of welding in industry. Spinal fusion surgery, however, does not ... bone taken from the patient has a long history of use and results in predictable healing. Autograft ...

  19. Obatoclax Inhibits Alphavirus Membrane Fusion by Neutralizing the Acidic Environment of Endocytic Compartments.

    PubMed

    Varghese, Finny S; Rausalu, Kai; Hakanen, Marika; Saul, Sirle; Kümmerer, Beate M; Susi, Petri; Merits, Andres; Ahola, Tero

    2017-03-01

    As new pathogenic viruses continue to emerge, it is paramount to have intervention strategies that target a common denominator in these pathogens. The fusion of viral and cellular membranes during viral entry is one such process that is used by many pathogenic viruses, including chikungunya virus, West Nile virus, and influenza virus. Obatoclax, a small-molecule antagonist of the Bcl-2 family of proteins, was previously determined to have activity against influenza A virus and also Sindbis virus. Here, we report it to be active against alphaviruses, like chikungunya virus (50% effective concentration [EC50] = 0.03 μM) and Semliki Forest virus (SFV; EC50 = 0.11 μM). Obatoclax inhibited viral entry processes in an SFV temperature-sensitive mutant entry assay. A neutral red retention assay revealed that obatoclax induces the rapid neutralization of the acidic environment of endolysosomal vesicles and thereby most likely inhibits viral fusion. Characterization of escape mutants revealed that the L369I mutation in the SFV E1 fusion protein was sufficient to confer partial resistance against obatoclax. Other inhibitors that target the Bcl-2 family of antiapoptotic proteins inhibited neither viral entry nor endolysosomal acidification, suggesting that the antiviral mechanism of obatoclax does not depend on its anticancer targets. Obatoclax inhibited the growth of flaviviruses, like Zika virus, West Nile virus, and yellow fever virus, which require low pH for fusion, but not that of pH-independent picornaviruses, like coxsackievirus A9, echovirus 6, and echovirus 7. In conclusion, obatoclax is a novel inhibitor of endosomal acidification that prevents viral fusion and that could be pursued as a potential broad-spectrum antiviral candidate.

  20. Pleiotropic effects of hemagglutinin amino acid substitutions of H5 influenza escape mutants

    SciTech Connect

    Rudneva, Irina A.; Timofeeva, Tatiana A.; Ignatieva, Anna V.; Shilov, Aleksandr A.; Krylov, Petr S.; Ilyushina, Natalia A.; Kaverin, Nikolai V.

    2013-12-15

    In the present study we assessed pleiotropic characteristics of the antibody-selected mutations. We examined pH optimum of fusion, temperatures of HA heat inactivation, and in vitro and in vivo replication kinetics of the previously obtained influenza H5 escape mutants. Our results showed that HA1 N142K mutation significantly lowered the pH of fusion optimum. Mutations of the escape mutants located in the HA lateral loop significantly affected H5 HA thermostability (P<0.05). HA changes at positions 131, 144, 145, and 156 and substitutions at positions 131, 142, 145, and 156 affected the replicative ability of H5 escape mutants in vitro and in vivo, respectively. Overall, a co-variation between antigenic specificity and different HA phenotypic properties has been demonstrated. We believe that the monitoring of pleiotropic effects of the HA mutations found in H5 escape mutants is essential for accurate prediction of mutants with pandemic potential. - Highlights: • HA1 N142K mutation significantly lowered the pH of fusion optimum. • Mutations located in the HA lateral loop significantly affected H5 HA thermostability. • HA changes at positions 131, 142, 144, 145, and 156 affected the replicative ability of H5 mutants. • Acquisition of glycosylation site could lead to the emergence of multiple pleiotropic effects.

  1. Novel Injury Site Targeted Fusion Protein Comprising Annexin V and Kunitz Inhibitor Domains Ameliorates Ischemia-Reperfusion Injury and Promotes Survival of Ischemic Rat Abdominal Skin Flaps.

    PubMed

    Shyu, Victor Bong-Hang; Hsu, Chung En; Wen, Chih-Jen; Wun, Tze-Chein; Tang, Rui; Achilefu, Samuel; Wei, Fu-Chan; Cheng, Hui-Yun

    2017-03-01

    Appropriate antithrombotic therapy is critical for successful outcomes in reconstructive microsurgical procedures involving free tissue transfer. The annexin V-6L15 (ANV-6L15) fusion protein was developed as a targeted antithrombotic reagent. Annexin V specifically binds to exposed phosphatidylserine on apoptotic or injured cells, and prevents coagulation and cell adhesion, whereas 6L15 inhibits tissue factor-VIIa pathway within the coagulation cascade. The treatment efficacy of ANV-6L15 on rat island muscle and pedicled abdominal fasciocutaneous flaps following ischemic injury and ischemia-reperfusion injury (IRI) was evaluated.

  2. Wind-Induced Atmospheric Escape: Titan

    NASA Technical Reports Server (NTRS)

    Hartle, Richard; Johnson, Robert; Sittler, Edward, Jr.; Sarantos, Menelaos; Simpson, David

    2012-01-01

    Rapid thermospheric flows can significantly enhance the estimates of the atmospheric loss rate and the structure of the atmospheric corona of a planetary body. In particular, rapid horizontal flow at the exobase can increase the corresponding constituent escape rate. Here we show that such corrections, for both thermal and non-thermal escape, cannot be ignored when calculating the escape of methane from Titan, for which drastically different rates have been proposed. Such enhancements are also relevant to Pluto and exoplanets.

  3. Radioscapholunate Fusions

    PubMed Central

    McGuire, Duncan Thomas; Bain, Gregory Ian

    2012-01-01

    Radiocarpal fusions are performed for a variety of indications, most commonly for debilitating painful arthritis. The goal of a wrist fusion is to fuse the painful, diseased joints and to preserve motion through the healthy joints. Depending on the extent of the disease process, radiocarpal fusions may take the form of radiolunate, radioscapholunate, or total wrist fusions. Surgical techniques and instrumentation have advanced over the last few decades, and consequently the functional outcomes have improved and complications decreased. Techniques for partial carpal fusions have improved and now include distal scaphoid and triquetrum excision, which improves range of motion and fusion rates. In this article we discuss the various surgical techniques and fixation methods available and review the corresponding evidence in the literature. The authors' preferred surgical technique of radioscapholunate fusion with distal scaphoid and triquetrum excision is outlined. New implants and new concepts are also discussed. PMID:24179717

  4. FUSION-Guided Hypothesis Development Leads to the Identification of N6,N6-Dimethyladenosine, a Marine-Derived AKT Pathway Inhibitor

    PubMed Central

    Vaden, Rachel M.; Oswald, Nathaniel W.; Potts, Malia B.; MacMillan, John B.; White, Michael A.

    2017-01-01

    Chemicals found in nature have evolved over geological time scales to productively interact with biological molecules, and thus represent an effective resource for pharmaceutical development. Marine-derived bacteria are rich sources of chemically diverse, bioactive secondary metabolites, but harnessing this diversity for biomedical benefit is limited by challenges associated with natural product purification and determination of biochemical mechanism. Using Functional Signature Ontology (FUSION), we report the parallel isolation and characterization of a marine-derived natural product, N6,N6-dimethyladenosine, that robustly inhibits AKT signaling in a variety of non-small cell lung cancer cell lines. Upon validation of the elucidated structure by comparison with a commercially available sample, experiments were initiated to understand the small molecule’s breadth of effect in a biological setting. One such experiment, a reverse phase protein array (RPPA) analysis of >50 kinases, indicated a specific cellular response to treatment. In all, leveraging the FUSION platform allowed for the rapid generation and validation of a biological mechanism of action hypothesis for an unknown natural product and permitted accelerated purification of the bioactive component from a chemically complex fraction. PMID:28294973

  5. Model of a mechanical clock escapement

    NASA Astrophysics Data System (ADS)

    Moline, David; Wagner, John; Volk, Eugene

    2012-07-01

    The mechanical tower clock originated in Europe during the 14th century to sound hourly bells and later display hands on a dial. An important innovation was the escapement mechanism, which converts stored energy into oscillatory motion for fixed time intervals through the pendulum swing. Previous work has modeled the escapement mechanism in terms of inelastic and elastic collisions. We derive and experimentally verify a theoretical model in terms of impulsive differential equations for the Graham escapement mechanism in a Seth Thomas tower clock. The model offers insight into the clock's mechanical behavior and the functionality of the deadbeat escapement mechanism.

  6. Guidance strategies for microburst escape

    NASA Astrophysics Data System (ADS)

    Dogan, Atilla

    This study compares three escape guidance laws for microburst encounters during final landing approach: Altitude-Guidance, Dive-Guidance, and Pitch-Guidance from the point of view of safety. It also introduces Modified Altitude- and Dive-Guidance laws. In this study, we use a full, 6-DOF, nonlinear, rigid-body aircraft model, including the effects of windshear and wind vorticity, and a model of microburst with turbulence. We also model the effect of stall prevention on the escape path. We first construct a new safety metric that quantifies the aircraft upward force capability in a microburst encounter. In the absence of turbulence, the safety factor is analytically proven to be a decreasing function of altitude. This suggests that descending to a low altitude may improve safety in the sense that the aircraft will have more upward force capability to maintain its altitude. In the presence of stochastic turbulence, the safety factor is treated as a random variable and its probability distribution function is analytically approximated as a function of altitude. This approximation reveals that the probability of safety factor being less than a given value has a minimum, i.e. safety increases as the altitude decreases up to a certain altitude, then starts decreasing. In the dissertation, two different approaches are used for comparison. (1) In a sample analysis approach, typical samples of the time histories of various variables are analyzed. Additionally, an animation of an aircraft escaping a microburst is produced and the behavior of the aircraft along with its inertial velocity and airspeed vectors are studied. (2) In a statistical approach, the probability distribution of the minimum altitude is estimated by the Monte Carlo Method when the statistical properties of the microburst parameters are known. Both approaches suggest that, within the modeling assumptions of this dissertation, and in the absence of human factors, altitude and dive guidance with low commanded

  7. Electronic Escape Trails for Firefighters

    NASA Technical Reports Server (NTRS)

    Jorgensen, Charles; Schipper, John; Betts, Bradley

    2008-01-01

    A proposed wireless-communication and data-processing system would exploit recent advances in radio-frequency identification devices (RFIDs) and software to establish information lifelines between firefighters in a burning building and a fire chief at a control station near but outside the building. The system would enable identification of trails that firefighters and others could follow to escape from the building, including identification of new trails should previously established trails become blocked. The system would include a transceiver unit and a computer at the control station, portable transceiver units carried by the firefighters in the building, and RFID tags that the firefighters would place at multiple locations as they move into and through the building (see figure). Each RFID tag, having a size of the order of a few centimeters, would include at least standard RFID circuitry and possibly sensors for measuring such other relevant environmental parameters as temperature, levels of light and sound, concentration of oxygen, concentrations of hazardous chemicals in smoke, and/or levels of nuclear radiation. The RFID tags would be activated and interrogated by the firefighters and control-station transceivers. Preferably, RFID tags would be configured to communicate with each other and with the firefighters units and the control station in an ordered sequence, with built-in redundancy. In a typical scenario, as firefighters moved through a building, they would scatter many RFID tags into smoke-obscured areas by use of a compressed-air gun. Alternatively or in addition, they would mark escape trails by dropping RFID tags at such points of interest as mantraps, hot spots, and trail waypoints. The RFID tags could be of different types, operating at different frequencies to identify their functions, and possibly responding by emitting audible beeps when activated by signals transmitted by transceiver units carried by nearby firefighters.

  8. Proteasome inhibitor MG-132 enhances histone deacetylase inhibitor SAHA-induced cell death of chronic myeloid leukemia cells by an ROS-mediated mechanism and downregulation of the Bcr-Abl fusion protein

    PubMed Central

    ZHOU, WENJING; ZHU, WEIWEI; MA, LIYA; XIAO, FENG; QIAN, WENBIN

    2015-01-01

    Recently, there has been progress in the treatment of chronic myeloid leukemia (CML). However, novel therapeutic strategies are required in order to address the emerging problem of imatinib resistance. Histone deacetylase inhibitors (HDACi) and proteasome inhibitors are promising alternatives, and may be amenable to integration with current therapeutic approaches. However, the mechanisms underlying the interaction between these two agents remain unclear. The present study assessed the cytotoxic effect of the HDACi, suberoylanilide hydroxamic acid (SAHA), in combination with the proteasome inhibitor, MG-132, in imatinib-sensitive K562 and imatinib-resistant K562G cells, and investigated the mechanism underlying this effect. Cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method and protein expression levels were determined by western blotting. Reactive oxygen species (ROS) generation levels were observed under a fluorescence microscope The results indicated that SAHA and MG-132 act in a synergistic manner to induce cell death in K562 and K562G cells. This effect was associated with Bcr-Abl downregulation and the production of ROS. Notably, the ROS scavenger, N-acetyl-L-cysteine, almost fully reversed the cell death and Bcr-Abl downregulation that was induced by the combination of SAHA and MG-132. By contrast, the pan-caspase inhibitor, z-VAD-fmk, only partially reversed the cell death induced by these two drugs in CML cells. These results indicated that increased intracellular ROS levels are important in the induction of cell death and the downregulation of Bcr-Abl. In conclusion, the present results suggested that combined SAHA and MG-132 may be a promising treatment for CML. PMID:26722260

  9. Inhibition of chaotic escape from a potential well by incommensurate escape-suppressing excitations.

    PubMed

    Chacón, R; Martínez, J A

    2002-03-01

    Theoretical results are presented concerning the reduction of chaotic escape from a potential well by means of a harmonic parametric excitation that satisfies an ultrasubharmonic resonance condition with the escape-inducing excitation. The possibility of incommensurate escape-suppressing excitations is demonstrated by studying rational approximations to the irrational escape-suppressing frequency. The analytical predictions for the suitable amplitudes and initial phases of the escape-suppressing excitation are tested against numerical simulations based on a high-resolution grid of initial conditions. These numerical results indicate that the reduction of escape is reliably achieved for small amplitudes and at, and only at, the predicted initial phases. For the case of irrational escape-suppressing frequencies, the effective escape-reducing initial phases are found to lie close to the accumulation points of the set of suitable initial phases that are associated with the complete series of convergents up to the convergent giving the chosen rational approximation.

  10. Escape as Reinforcement and Escape Extinction in the Treatment of Feeding Problems

    ERIC Educational Resources Information Center

    LaRue, Robert H.; Stewart, Victoria; Piazza, Cathleen C.; Volkert, Valerie M.; Patel, Meeta R.; Zeleny, Jason

    2011-01-01

    Given the effectiveness of putative escape extinction as treatment for feeding problems, it is surprising that little is known about the effects of escape as reinforcement for appropriate eating during treatment. In the current investigation, we examined the effectiveness of escape as reinforcement for mouth clean (a product measure of…

  11. Fusion breeder

    SciTech Connect

    Moir, R.W.

    1982-04-20

    The fusion breeder is a fusion reactor designed with special blankets to maximize the transmutation by 14 MeV neutrons of uranium-238 to plutonium or thorium to uranium-233 for use as a fuel for fission reactors. Breeding fissile fuels has not been a goal of the US fusion energy program. This paper suggests it is time for a policy change to make the fusion breeder a goal of the US fusion program and the US nuclear energy program. The purpose of this paper is to suggest this policy change be made and tell why it should be made, and to outline specific research and development goals so that the fusion breeder will be developed in time to meet fissile fuel needs.

  12. Fusion breeder

    SciTech Connect

    Moir, R.W.

    1982-02-22

    The fusion breeder is a fusion reactor designed with special blankets to maximize the transmutation by 14 MeV neutrons of uranium-238 to plutonium or thorium to uranium-233 for use as a fuel for fission reactors. Breeding fissile fuels has not been a goal of the US fusion energy program. This paper suggests it is time for a policy change to make the fusion breeder a goal of the US fusion program and the US nuclear energy program. The purpose of this paper is to suggest this policy change be made and tell why it should be made, and to outline specific research and development goals so that the fusion breeder will be developed in time to meet fissile fuel needs.

  13. Escaping in Literature. Teaching in the Library.

    ERIC Educational Resources Information Center

    Hurst, Carol Otis

    1993-01-01

    Explores the "escape" genre of children's literature, and recommends and describes several books that deal with such topics as escape from prison camps, from slavery, from the Holocaust, from war, and from Utopian societies. These books should provoke meaningful classroom discussions and allow children to view their own world from different…

  14. Submarine 'safe to escape' studies in man.

    PubMed

    Jurd, K M; Seddon, F M; Thacker, J C; Blogg, S L; Stansfield, M R D; White, M G; Loveman, G A M

    2014-01-01

    The Royal Navy requires reliable advice on the safe limits of escape from a distressed submarine (DISSUB). Flooding in a DISSUB may cause a rise in ambient pressure, increasing the risk of decompression sickness (DCS) and decreasing the maximum depth from which it is safe to escape. The aim of this study was to investigate the pressure/depth limits to escape following saturation at raised ambient pressure. Exposure to saturation pressures up to 1.6 bar (a) (160 kPa) (n = 38); escapes from depths down to 120 meters of sea water (msw) (n = 254) and a combination of saturation followed by escape (n = 90) was carried out in the QinetiQ Submarine Escape Simulator, Alverstoke, United Kingdom. Doppler ultrasound monitoring was used to judge the severity of decompression stress. The trials confirmed the previously untested advice, in the Guardbook, that if a DISSUB was lying at a depth of 90 msw, then it was safe to escape when the pressure in the DISSUB was 1.5 bar (a), but also indicated that this advice may be overly conservative. This study demonstrated that the upper DISSUB saturation pressure limit to safe escape from 90 msw was 1.6 bar (a), resulting in two cases of DCS.

  15. 30 CFR 57.11051 - Escape routes.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Escape routes. 57.11051 Section 57.11051 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE... read direction signs that clearly indicate the ways of escape....

  16. 30 CFR 57.11051 - Escape routes.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Escape routes. 57.11051 Section 57.11051 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE... read direction signs that clearly indicate the ways of escape....

  17. Molecular phylogeny of C1 inhibitor depicts two immunoglobulin-like domains fusion in fishes and ray-finned fishes specific intron insertion after separation from zebrafish.

    PubMed

    Kumar, Abhishek; Bhandari, Anita; Sarde, Sandeep J; Goswami, Chandan

    2014-07-18

    C1 inhibitor (C1IN) is a multi-facet serine protease inhibitor in the plasma cascades, inhibiting several proteases, notably, regulates both complement and contact system activation. Despite huge advancements in the understanding of C1IN based on biochemical properties and its roles in the plasma cascades, the phylogenetic history of C1IN remains uncharacterized. To date, there is no comprehensive study illustrating the phylogenetic history of C1IN. Herein, we explored phylogenetic history of C1IN gene in vertebrates. Fishes have C1IN with two immunoglobulin like domains attached in the N-terminal region. The RCL regions of CIIN from fishes and tetrapod genomes have variations at the positions P2 and P1'. Gene structures of C1IN gene from selected ray-finned fishes varied in the Ig domain region with creation of novel intron splitting exon Im2 into Im2a and Im2b. This intron is limited to ray-finned fishes with genome size reduced below 1 Gb. Hence, we suggest that genome compaction and associated double-strand break repairs are behind this intron gain. This study reveals the evolutionary history of C1IN and confirmed that this gene remains the same locus for ∼450 MY in 52 vertebrates analysed, but it is not found in frogs and lampreys.

  18. Atmospheric escape, redox evolution, and planetary habitability

    NASA Astrophysics Data System (ADS)

    Catling, D. C.; Zahnle, K. J.

    2011-12-01

    Through the greenhouse effect, the presence and composition of an atmosphere is critical for defining a (conventional) circumstellar habitable zone in terms of planetary surface temperatures suitable for liquid water. Lack of knowledge of planetary atmospheres is likely to frustrate attempts to say with any certainty whether detected terrestrial-sized exoplanets may or may not be habitable. Perhaps an underappreciated role in such considerations is the evolutionary effect of atmospheric escape for determining atmospheric composition or whether an atmosphere exists in the first place. Whether atmospheres exist at all on planets is demonstrably connected to the effect of integrated atmospheric escape. When we observe our own Solar System and transiting exoplanets, the existence of an atmosphere is clearly delineated by a relative vulnerability to thermal escape and impact erosion. The prevalence of thermal escape as a key evolutionary determinant for the presence of planetary atmosphere is shown by a relationship between the relative solar (or stellar) heating and the escape velocity. Those bodies with too much stellar heating and too smaller escape velocity end up devoid of atmospheres. Impact erosion is evident in the relationship between impact velocity and escape velocity. Escape due to impacts is particularly important for understanding the large differences in the atmospheres of giant planet moons, such as Ganymede versus Titan. It is also significant for Mars-sized planets. The oxidation state of atmospheres is important for some theories of the origin of life (where an early reducing atmosphere is helpful for organic synthesis) and the evolution of advanced life (where free molecular oxygen is the best source of high energy metabolism). Surfaces on some relatively small planets and moons are observed to have evolved to an oxidized state, which theory and observation can explain through atmospheric escape. There are several examples in the Solar System where a

  19. Cross Sections for Planetary Escape

    NASA Astrophysics Data System (ADS)

    Tully, C.

    2001-05-01

    Energetic charged-particle bombardment, dissociative recombination and photodissociation processes produce energetic recoil atoms which heat the thermosphere and can lead to escape from a planet affecting the evolution of the atmosphere. In describing these processes by Monte Carlo methods, many of the critical cross sections are not available in the energy range of interest, a few eV to 1 keV. Here we present our recent results for elastic collision and collisional dissociation cross sections relevant to Titan, Triton, Europa and the terrestrial planets [1,2]. Elastic and diffusion cross sections were calculated using both quantum mechanical techniques and the semiclassical JWKB approximation for the collision of ground state oxygen atoms in the energy range 1-10eV [2]. This involved calculation of phase shifts for each of the 18 molecular energy states of O2 which separate to two ground state O atoms. For an O thermosphere the total elastic cross section is close to that typically assumed but the escape depths are shown to be larger than those typically used. Dissociation cross sections of N + N2 were calculated using a semiclassical method, in the energy range 0-30eV. This required treating the vibrational motion quantum mechanically while the rotational and the relative translational motion were treated classically. The evolution of the system was calculated by simultaneous propagation of the classical as well as the quantal degrees of freedom. The solution to the classical part was carried out by solving Hamilton equations of motion using an effective London-Eyring-Polanyi-Sato potential energy surface, calculated by Laganá et al [3]. Propagation of the quantal wavefunction was carried out by solving the time dependent Schrödinger equation using the split operator technique with the help of the fast fourier transform which was used to calculate the second derivatives arising from the kinetic energy operator. This work was supported by NASA's Planetary

  20. Fusion reactor pumped laser

    DOEpatents

    Jassby, D.L.

    1987-09-04

    A nuclear pumped laser capable of producing long pulses of very high power laser radiation is provided. A toroidal fusion reactor provides energetic neutrons which are slowed down by a moderator. The moderated neutrons are converted to energetic particles capable of pumping a lasing medium. The lasing medium is housed in an annular cell surrounding the reactor. The cell includes an annular reflecting mirror at the bottom and an annular output window at the top. A neutron reflector is disposed around the cell to reflect escaping neutrons back into the cell. The laser radiation from the annular window is focused onto a beam compactor which generates a single coherent output laser beam. 10 figs.

  1. Intellectual property issues of immune checkpoint inhibitors

    PubMed Central

    Storz, Ulrich

    2016-01-01

    Immune checkpoint inhibitors are drugs that interfere with tumor escape responses. Some members of this class are already approved, and expected to be blockbusters in the future. Many companies have developed patent activities in this field. This article focuses on the patent landscape, and discusses key players and cases related to immune checkpoint inhibitors. PMID:26466763

  2. Image fusion

    NASA Technical Reports Server (NTRS)

    Pavel, M.

    1993-01-01

    The topics covered include the following: a system overview of the basic components of a system designed to improve the ability of a pilot to fly through low-visibility conditions such as fog; the role of visual sciences; fusion issues; sensor characterization; sources of information; image processing; and image fusion.

  3. Light weight escape capsule for fighter aircraft

    NASA Technical Reports Server (NTRS)

    Robert, James A.

    1988-01-01

    Emergency crew escape capabilities have been less than adequate for fighter aircraft since before WW II. From the over-the-side bailout of those days through the current ejection seat with a rocket catapult, escaping from a disabled aircraft has been risky at best. Current efforts are underway toward developing a high-tech, smart ejection seat that will give fighter pilots more room to live in the sky, but an escape capsule is needed to meet current and future fighter envelopes. Escape capsules have a bad reputation due to past examples of high weight, poor performance and great complexity. However, the advantages available demand that a capsule be developed. This capsule concept will minimize the inherent disavantages and incorporate the benefits while integrating all aspects of crew station design. The resulting design is appropriate for a crew station of the year 2010 and includes improved combat acceleration protection, chemical or biological combat capability, improved aircraft to escape system interaction, and the highest level of escape performance achievable. The capsule is compact, which can allow a reduced aircraft size and weighs only 1200 lb. The escape system weight penalty is only 120 lb higher than that for the next ejection seat and the capsule has a corresponding increase in performance.

  4. Escape of magnetic toroids from the Sun

    NASA Technical Reports Server (NTRS)

    Bieber, John W.; Rust, David M.

    1995-01-01

    Analysis of heliospheric magnetic fields at 1 AU shows that 10(exp 24) Mx of net azimuthal flux escapes from the Sun per solar cycle. This rate is consistent with rates derived from other indicators of flux escape, including coronal mass ejections and filament eruptions. The toroidal flux escape rate is compared with the apparent rate of flux emergence at the solar surface, and it is concluded that escaping toroids will remove at least 20% of the emerging flux, and may remove as much as 100% of emerging flux if multiple eruptions occur on the toroids. The data imply that flux escapes the Sun with an efficiency far exceeding Parker's upper limit estimate of 3%. Toroidal flux escape is almost certainly the source of the observed overwinding of the interplanetary magnetic field spiral. Two mechanisms to facilitate net flux escape are discussed: helicity charging to push open the fields and flux transport with reconnection to close them off. We estimate the Sun will shed approximately 2 x 10(exp 45) of magnetic helicity per solar cycle, leading to a mean helicity density of 100 Mx(exp 2)cm(exp -3) at 1 AU, which agrees well with observations.

  5. Statin escape phenomenon: Fact or fiction?

    PubMed Central

    Barkas, Fotios; Elisaf, Moses; Klouras, Eleftherios; Dimitriou, Theodora; Tentolouris, Nikolaos; Liberopoulos, Evangelos

    2017-01-01

    AIM To evaluate the presence of the so called “statin escape” phenomenon among hyperlipidemic subjects attending a lipid clinic. METHODS This was a retrospective analysis of 1240 hyperlipidemic individuals followed-up for ≥ 3 years. We excluded those individuals meeting one of the following criteria: Use of statin therapy at baseline visit, discontinuation of statin treatment at most recent visit, change in statin treatment during follow-up and poor compliance to treatment. Statin escape phenomenon was defined as an increase in low-density lipoprotein cholesterol (LDL-C) levels at the most recent visit by > 10% compared with the value at 6 mo following initiation of statin treatment. RESULTS Of 181 eligible subjects, 31% exhibited the statin escape phenomenon. No major differences regarding baseline characteristics were found between statin escapers and non-statin escapers. Both escapers and non-escapers had similar baseline LDL-C levels [174 (152-189) and 177 (152-205) mg/dL, respectively]. In comparison with non-escapers, statin escapers demonstrated lower LDL-C levels at 6 mo after treatment initiation [88 (78-97) mg/dL vs 109 (91-129) mg/dL, P < 0.05], but higher levels at the most recent visit [103 (96-118) mg/dL vs 94 (79-114) mg/dL, P < 0.05]. CONCLUSION These data confirm the existence of an escape phenomenon among statin-treated individuals. The clinical significance of this phenomenon remains uncertain. PMID:28261552

  6. Isotopic Fractionation by Gravitational Escape

    NASA Astrophysics Data System (ADS)

    Lammer, H. S. J.

    2003-04-01

    Present natural data bases for abundances of the isotopic compositions of noble gases, carbon and nitrogen inventories can be found in the Sun, the solar wind, meteorites and the planetary atmospheres and crustal reservoirs. Mass distributions in the various volatile reservoirs provide boundary conditions which must be satisfied in modelling the history of the present atmospheres. Such boundary conditions are constraints posed by comparison of isotopic ratios in primordial volatile sources with the isotopic pattern which was found on the planets and their satellites. Observations from space missions and Earth-based spectroscopic telescope observations of Venus, Mars and Saturn's major satellite Titan show that the atmospheric evolution of these planetary bodies to their present states was affected by processes capable of fractionating their elements and isotopes. The isotope ratios of D/H in the atmospheres of Venus and Mars indicate evidence for their planetary water inventories. Venus' H2O content may have been at least 0.3% of a terrestrial ocean. Analysis of the D/H ratio on Mars imply that a global H2O ocean with a depth of ≤ 30 m was lost since the end of hydrodynamic escape. Calculations of the time evolution of the 15N/14N isotope anomalies in the atmospheres of Mars and Titan show that the Martian atmosphere was at least ≥ 20 times denser than at present and that the mass of Titan's early atmosphere was about 30 times greater than its present value. A detailed study of gravitational fractionation of isotopes in planetary atmospheres furthermore indicates a much higher solar wind mass flux of the early Sun during the first half billion years.

  7. The fast escaping set for quasiregular mappings

    NASA Astrophysics Data System (ADS)

    Bergweiler, Walter; Drasin, David; Fletcher, Alastair

    2014-06-01

    The fast escaping set of a transcendental entire function is the set of all points which tend to infinity under iteration as fast as possible compatible with the growth of the function. We study the analogous set for quasiregular mappings in higher dimensions and show, among other things, that various equivalent definitions of the fast escaping set for transcendental entire functions in the plane also coincide for quasiregular mappings. We also exhibit a class of quasiregular mappings for which the fast escaping set has the structure of a spider's web.

  8. The Neuroethology of C. elegans Escape

    PubMed Central

    Pirri, Jennifer K.; Alkema, Mark J.

    2012-01-01

    Escape behaviors are crucial to survive predator encounters. Touch to the head of C. elegans induces an escape response where the animal rapidly backs away from the stimulus and suppresses foraging head movements. The coordination of head and body movements facilitates escape from predacious fungi that cohabitate with nematodes in organic debris. An appreciation of the natural habitat of laboratory organisms, like C. elegans, enables a comprehensive neuroethological analysis of behavior. In this review we discuss the neuronal mechanisms and the ecological significance of the C. elegans touch response. PMID:22226513

  9. Interspecific evaluation of octopus escape behavior.

    PubMed

    Wood, James B; Anderson, Roland C

    2004-01-01

    The well-known ability of octopuses to escape enclosures is a behavior that can be fatal and, therefore, is an animal welfare issue. This study obtained survey data from 38 participants-primarily scientists and public aquarists who work with octopuses-on 25 described species of octopus. The study demonstrates that the likeliness to escape is species specific (p =.001). The study gives husbandry techniques to keep captive octopuses contained. This first interspecific study of octopus escape behavior allows readers to make informed species-specific husbandry choices.

  10. Two Escape Mechanisms of Influenza A Virus to a Broadly Neutralizing Stalk-Binding Antibody.

    PubMed

    Chai, Ning; Swem, Lee R; Reichelt, Mike; Chen-Harris, Haiyin; Luis, Elizabeth; Park, Summer; Fouts, Ashley; Lupardus, Patrick; Wu, Thomas D; Li, Olga; McBride, Jacqueline; Lawrence, Michael; Xu, Min; Tan, Man-Wah

    2016-06-01

    Broadly neutralizing antibodies targeting the stalk region of influenza A virus (IAV) hemagglutinin (HA) are effective in blocking virus infection both in vitro and in vivo. The highly conserved epitopes recognized by these antibodies are critical for the membrane fusion function of HA and therefore less likely to be permissive for virus mutational escape. Here we report three resistant viruses of the A/Perth/16/2009 strain that were selected in the presence of a broadly neutralizing stalk-binding antibody. The three resistant viruses harbor three different mutations in the HA stalk: (1) Gln387Lys; (2) Asp391Tyr; (3) Asp391Gly. The Gln387Lys mutation completely abolishes binding of the antibody to the HA stalk epitope. The other two mutations, Asp391Tyr and Asp391Gly, do not affect antibody binding at neutral pH and only slightly reduce binding at low pH. Interestingly, they enhance the fusion ability of the HA, representing a novel mechanism that allows productive membrane fusion even in the presence of antibody and hence virus escape from antibody neutralization. Therefore, these mutations illustrate two different resistance mechanisms used by IAV to escape broadly neutralizing stalk-binding antibodies. Compared to the wild type virus, the resistant viruses release fewer progeny viral particles during replication and are more sensitive to Tamiflu, suggesting reduced viral fitness.

  11. Two Escape Mechanisms of Influenza A Virus to a Broadly Neutralizing Stalk-Binding Antibody

    PubMed Central

    Chai, Ning; Swem, Lee R.; Reichelt, Mike; Chen-Harris, Haiyin; Luis, Elizabeth; Park, Summer; Fouts, Ashley; Lupardus, Patrick; Wu, Thomas D.; Li, Olga; McBride, Jacqueline; Lawrence, Michael; Xu, Min; Tan, Man-Wah

    2016-01-01

    Broadly neutralizing antibodies targeting the stalk region of influenza A virus (IAV) hemagglutinin (HA) are effective in blocking virus infection both in vitro and in vivo. The highly conserved epitopes recognized by these antibodies are critical for the membrane fusion function of HA and therefore less likely to be permissive for virus mutational escape. Here we report three resistant viruses of the A/Perth/16/2009 strain that were selected in the presence of a broadly neutralizing stalk-binding antibody. The three resistant viruses harbor three different mutations in the HA stalk: (1) Gln387Lys; (2) Asp391Tyr; (3) Asp391Gly. The Gln387Lys mutation completely abolishes binding of the antibody to the HA stalk epitope. The other two mutations, Asp391Tyr and Asp391Gly, do not affect antibody binding at neutral pH and only slightly reduce binding at low pH. Interestingly, they enhance the fusion ability of the HA, representing a novel mechanism that allows productive membrane fusion even in the presence of antibody and hence virus escape from antibody neutralization. Therefore, these mutations illustrate two different resistance mechanisms used by IAV to escape broadly neutralizing stalk-binding antibodies. Compared to the wild type virus, the resistant viruses release fewer progeny viral particles during replication and are more sensitive to Tamiflu, suggesting reduced viral fitness. PMID:27351973

  12. 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.

  13. Line tension at lipid phase boundaries as driving force for HIV fusion peptide-mediated fusion.

    PubMed

    Yang, Sung-Tae; Kiessling, Volker; Tamm, Lukas K

    2016-04-26

    Lipids and proteins are organized in cellular membranes in clusters, often called 'lipid rafts'. Although raft-constituent ordered lipid domains are thought to be energetically unfavourable for membrane fusion, rafts have long been implicated in many biological fusion processes. For the case of HIV gp41-mediated membrane fusion, this apparent contradiction can be resolved by recognizing that the interfaces between ordered and disordered lipid domains are the predominant sites of fusion. Here we show that line tension at lipid domain boundaries contributes significant energy to drive gp41-fusion peptide-mediated fusion. This energy, which depends on the hydrophobic mismatch between ordered and disordered lipid domains, may contribute tens of kBT to fusion, that is, it is comparable to the energy required to form a lipid stalk intermediate. Line-active compounds such as vitamin E lower line tension in inhomogeneous membranes, thereby inhibit membrane fusion, and thus may be useful natural viral entry inhibitors.

  14. Line tension at lipid phase boundaries as driving force for HIV fusion peptide-mediated fusion

    NASA Astrophysics Data System (ADS)

    Yang, Sung-Tae; Kiessling, Volker; Tamm, Lukas K.

    2016-04-01

    Lipids and proteins are organized in cellular membranes in clusters, often called `lipid rafts'. Although raft-constituent ordered lipid domains are thought to be energetically unfavourable for membrane fusion, rafts have long been implicated in many biological fusion processes. For the case of HIV gp41-mediated membrane fusion, this apparent contradiction can be resolved by recognizing that the interfaces between ordered and disordered lipid domains are the predominant sites of fusion. Here we show that line tension at lipid domain boundaries contributes significant energy to drive gp41-fusion peptide-mediated fusion. This energy, which depends on the hydrophobic mismatch between ordered and disordered lipid domains, may contribute tens of kBT to fusion, that is, it is comparable to the energy required to form a lipid stalk intermediate. Line-active compounds such as vitamin E lower line tension in inhomogeneous membranes, thereby inhibit membrane fusion, and thus may be useful natural viral entry inhibitors.

  15. Evaluating Melanoma Drug Response and Therapeutic Escape with Quantitative Proteomics*

    PubMed Central

    Rebecca, Vito W.; Wood, Elizabeth; Fedorenko, Inna V.; Paraiso, Kim H. T.; Haarberg, H. Eirik; Chen, Yi; Xiang, Yun; Sarnaik, Amod; Gibney, Geoffrey T.; Sondak, Vernon K.; Koomen, John M.; Smalley, Keiran S. M.

    2014-01-01

    The evolution of cancer therapy into complex regimens with multiple drugs requires novel approaches for the development and evaluation of companion biomarkers. Liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM) is a versatile platform for biomarker measurement. In this study, we describe the development and use of the LC-MRM platform to study the adaptive signaling responses of melanoma cells to inhibitors of HSP90 (XL888) and MEK (AZD6244). XL888 had good anti-tumor activity against NRAS mutant melanoma cell lines as well as BRAF mutant cells with acquired resistance to BRAF inhibitors both in vitro and in vivo. LC-MRM analysis showed HSP90 inhibition to be associated with decreased expression of multiple receptor tyrosine kinases, modules in the PI3K/AKT/mammalian target of rapamycin pathway, and the MAPK/CDK4 signaling axis in NRAS mutant melanoma cell lines and the inhibition of PI3K/AKT signaling in BRAF mutant melanoma xenografts with acquired vemurafenib resistance. The LC-MRM approach targeting more than 80 cancer signaling proteins was highly sensitive and could be applied to fine needle aspirates from xenografts and clinical melanoma specimens (using 50 μg of total protein). We further showed MEK inhibition to be associated with signaling through the NFκB and WNT signaling pathways, as well as increased receptor tyrosine kinase expression and activation. Validation studies identified PDGF receptor β signaling as a potential escape mechanism from MEK inhibition, which could be overcome through combined use of AZD6244 and the PDGF receptor inhibitor, crenolanib. Together, our studies show LC-MRM to have unique value as a platform for the systems level understanding of the molecular mechanisms of drug response and therapeutic escape. This work provides the proof-of-principle for the future development of LC-MRM assays for monitoring drug responses in the clinic. PMID:24760959

  16. Exocytotic fusion pores are composed of both lipids and proteins

    PubMed Central

    Bao, Huan; Goldschen-Ohm, Marcel; Jeggle, Pia; Chanda, Baron; Edwardson, J Michael; Chapman, Edwin R

    2016-01-01

    During exocytosis, fusion pores form the first aqueous connection that allows escape of neurotransmitters and hormones from secretory vesicles. Although it is well established that SNARE proteins catalyze fusion, the structure and composition of fusion pores remain unknown. Here, we exploited the rigid framework and defined size of nanodiscs to interrogate the properties of reconstituted fusion pores, using the neurotransmitter glutamate as a content-mixing marker. Efficient Ca2+-stimulated bilayer fusion, and glutamate release, occurred with approximately two molecules of mouse synaptobrevin 2 reconstituted into ~6-nm nanodiscs. The transmembrane domains of SNARE proteins assumed distinct roles in lipid mixing versus content release and were exposed to polar solvent during fusion. Additionally, tryptophan substitutions at specific positions in these transmembrane domains decreased glutamate flux. Together, these findings indicate that the fusion pore is a hybrid structure composed of both lipids and proteins. PMID:26656855

  17. Evolutionary dynamics of escape from biomedical intervention.

    PubMed Central

    Iwasa, Yoh; Michor, Franziska; Nowak, Martin A

    2003-01-01

    Viruses, bacteria, eukaryotic parasites, cancer cells, agricultural pests and other inconvenient animates have an unfortunate tendency to escape from selection pressures that are meant to control them. Chemotherapy, anti-viral drugs or antibiotics fail because their targets do not hold still, but evolve resistance. A major problem in developing vaccines is that microbes evolve and escape from immune responses. The fundamental question is the following: if a genetically diverse population of replicating organisms is challenged with a selection pressure that has the potential to eradicate it, what is the probability that this population will produce escape mutants? Here, we use multi-type branching processes to describe the accumulation of mutants in independent lineages. We calculate escape dynamics for arbitrary mutation networks and fitness landscapes. Our theory shows how to estimate the probability of success or failure of biomedical intervention, such as drug treatment and vaccination, against rapidly evolving organisms. PMID:14728779

  18. Biogeochemistry: Nocturnal escape route for marsh gas

    NASA Astrophysics Data System (ADS)

    Anthony, Katey Walter; MacIntyre, Sally

    2016-07-01

    A field study of methane emissions from wetlands reveals that more of the gas escapes through diffusive processes than was thought, mostly at night. Because methane is a greenhouse gas, the findings have implications for global warming.

  19. Overlapping Patterns of Rapid Evolution in the Nucleic Acid Sensors cGAS and OAS1 Suggest a Common Mechanism of Pathogen Antagonism and Escape

    PubMed Central

    Hancks, Dustin C.; Hartley, Melissa K.; Hagan, Celia; Clark, Nathan L.; Elde, Nels C.

    2015-01-01

    A diverse subset of pattern recognition receptors (PRRs) detects pathogen-associated nucleic acids to initiate crucial innate immune responses in host organisms. Reflecting their importance for host defense, pathogens encode various countermeasures to evade or inhibit these immune effectors. PRRs directly engaged by pathogen inhibitors often evolve under recurrent bouts of positive selection that have been described as molecular ‘arms races.’ Cyclic GMP-AMP synthase (cGAS) was recently identified as a key PRR. Upon binding cytoplasmic double-stranded DNA (dsDNA) from various viruses, cGAS generates the small nucleotide secondary messenger cGAMP to signal activation of innate defenses. Here we report an evolutionary history of cGAS with recurrent positive selection in the primate lineage. Recent studies indicate a high degree of structural similarity between cGAS and 2’-5’-oligoadenylate synthase 1 (OAS1), a PRR that detects double-stranded RNA (dsRNA), despite low sequence identity between the respective genes. We present comprehensive comparative evolutionary analysis of cGAS and OAS1 primate sequences and observe positive selection at nucleic acid binding interfaces and distributed throughout both genes. Our data revealed homologous regions with strong signatures of positive selection, suggesting common mechanisms employed by unknown pathogen encoded inhibitors and similar modes of evasion from antagonism. Our analysis of cGAS diversification also identified alternately spliced forms missing multiple sites under positive selection. Further analysis of selection on the OAS family in primates, which comprises OAS1, OAS2, OAS3 and OASL, suggests a hypothesis where gene duplications and domain fusion events result in paralogs that provide another means of escaping pathogen inhibitors. Together our comparative evolutionary analysis of cGAS and OAS provides new insights into distinct mechanisms by which key molecular sentinels of the innate immune system have

  20. Gated escaping of ligand out of protein

    NASA Astrophysics Data System (ADS)

    Sheu, Sheh-Yi; Yang, Dah-Yen

    2000-01-01

    We construct a new gating model and develop a new theory to study the escaping process of a ligand out of a spherical cavity with a puncture (or gate) on the surface. The gate undulation can be regulated by any time-dependent function and the motion of the ligand inside the spherical cavity is mapped into a two-dimensional entropy potential surface. Hence the driving force of our model is entropy only. For a static gate, the escaping process corresponds to climbing a two-dimensional entropy barrier. When the gate open angle is small, the escaping rate is proportional to the square of the opening angle. The prefactor of the escaping rate constant depends on the curvature of the entropy potential surface. For coherent gating, the survival time depends not only on the gate undulation frequency but also on how the initial state is defined. On the escaping from protein, our escaping rate shows it is qualitatively consistent with the experimental result of ligand recombination in myoglobin.

  1. Polymer escape from a confining potential

    SciTech Connect

    Mökkönen, Harri; Ikonen, Timo; Jónsson, Hannes; Ala-Nissila, Tapio

    2014-02-07

    The rate of escape of polymers from a two-dimensionally confining potential well has been evaluated using self-avoiding as well as ideal chain representations of varying length, up to 80 beads. Long timescale Langevin trajectories were calculated using the path integral hyperdynamics method to evaluate the escape rate. A minimum is found in the rate for self-avoiding polymers of intermediate length while the escape rate decreases monotonically with polymer length for ideal polymers. The increase in the rate for long, self-avoiding polymers is ascribed to crowding in the potential well which reduces the free energy escape barrier. An effective potential curve obtained using the centroid as an independent variable was evaluated by thermodynamic averaging and Kramers rate theory then applied to estimate the escape rate. While the qualitative features are well reproduced by this approach, it significantly overestimates the rate, especially for the longer polymers. The reason for this is illustrated by constructing a two-dimensional effective energy surface using the radius of gyration as well as the centroid as controlled variables. This shows that the description of a transition state dividing surface using only the centroid fails to confine the system to the region corresponding to the free energy barrier and this problem becomes more pronounced the longer the polymer is. A proper definition of a transition state for polymer escape needs to take into account the shape as well as the location of the polymer.

  2. Submarine tower escape decompression sickness risk estimation.

    PubMed

    Loveman, G A M; Seddon, E M; Thacker, J C; Stansfield, M R; Jurd, K M

    2014-01-01

    Actions to enhance survival in a distressed submarine (DISSUB) scenario may be guided in part by knowledge of the likely risk of decompression sickness (DCS) should the crew attempt tower escape. A mathematical model for DCS risk estimation has been calibrated against DCS outcome data from 3,738 exposures of either men or goats to raised pressure. Body mass was used to scale DCS risk. The calibration data included more than 1,000 actual or simulated submarine escape exposures and no exposures with substantial staged decompression. Cases of pulmonary barotrauma were removed from the calibration data. The calibrated model was used to estimate the likelihood of DCS occurrence following submarine escape from the United Kingdom Royal Navy tower escape system. Where internal DISSUB pressure remains at - 0.1 MPa, escape from DISSUB depths < 200 meters is estimated to have DCS risk < 6%. Saturation at raised DISSUB pressure markedly increases risk, with > 60% DCS risk predicted for a 200-meter escape from saturation at 0.21 MPa. Using the calibrated model to predict DCS for direct ascent from saturation gives similar risk estimates to other published models.

  3. Fusion Power.

    ERIC Educational Resources Information Center

    Dingee, David A.

    1979-01-01

    Discusses the extraordinary potential, the technical difficulties, and the financial problems that are associated with research and development of fusion power plants as a major source of energy. (GA)

  4. First fusion proton measurements in TEXTOR plasmas using activation technique

    SciTech Connect

    Bonheure, G.; Wassenhove, G. Van; Mlynar, J.; Hult, M.; Gonzalez de Orduna, R.; Lutter, G.; Vermaercke, P.; Huber, A.; Schweer, B.; Esser, G.; Biel, W.

    2012-10-15

    MeV particle loss measurements from fusion plasmas, in particular alpha particles, remain difficult in large fusion devices and further R and D is needed for ITER. This paper describes the first attempt to measure 3 MeV escaping fusion protons emitted from TEXTOR tokamak plasmas using activation technique. This technique was successfully demonstrated, initially, in 2006 on the JET tokamak. An ion camera equipped with a collimator and several types of activation detectors was installed inside the TEXTOR vacuum vessel to perform these measurements. After irradiation, the detectors were analyzed using ultra low level gamma-ray spectrometry at the HADES underground laboratory. 3 MeV escaping fusion protons were detected in larger number -{approx}6 times more - compared to earlier measurements using this technique on JET. Another major progress was the reduction of the cooling time by a factor of 50, which made possible to detect radionuclides with half-life of less than 90 min.

  5. First fusion proton measurements in TEXTOR plasmas using activation technique.

    PubMed

    Bonheure, G; Mlynar, J; Van Wassenhove, G; Hult, M; González de Orduña, R; Lutter, G; Vermaercke, P; Huber, A; Schweer, B; Esser, G; Biel, W

    2012-10-01

    MeV particle loss measurements from fusion plasmas, in particular alpha particles, remain difficult in large fusion devices and further R&D is needed for ITER. This paper describes the first attempt to measure 3 MeV escaping fusion protons emitted from TEXTOR tokamak plasmas using activation technique. This technique was successfully demonstrated, initially, in 2006 on the JET tokamak. An ion camera equipped with a collimator and several types of activation detectors was installed inside the TEXTOR vacuum vessel to perform these measurements. After irradiation, the detectors were analyzed using ultra low level gamma-ray spectrometry at the HADES underground laboratory. 3 MeV escaping fusion protons were detected in larger number -~6 times more--compared to earlier measurements using this technique on JET. Another major progress was the reduction of the cooling time by a factor of 50, which made possible to detect radionuclides with half-life of less than 90 min.

  6. First fusion proton measurements in TEXTOR plasmas using activation techniquea)

    NASA Astrophysics Data System (ADS)

    Bonheure, G.; Mlynar, J.; Wassenhove, G. Van; Hult, M.; González de Orduña, R.; Lutter, G.; Vermaercke, P.; Huber, A.; Schweer, B.; Esser, G.; Biel, W.

    2012-10-01

    MeV particle loss measurements from fusion plasmas, in particular alpha particles, remain difficult in large fusion devices and further R&D is needed for ITER. This paper describes the first attempt to measure 3 MeV escaping fusion protons emitted from TEXTOR tokamak plasmas using activation technique. This technique was successfully demonstrated, initially, in 2006 on the JET tokamak. An ion camera equipped with a collimator and several types of activation detectors was installed inside the TEXTOR vacuum vessel to perform these measurements. After irradiation, the detectors were analyzed using ultra low level gamma-ray spectrometry at the HADES underground laboratory. 3 MeV escaping fusion protons were detected in larger number -˜6 times more - compared to earlier measurements using this technique on JET. Another major progress was the reduction of the cooling time by a factor of 50, which made possible to detect radionuclides with half-life of less than 90 min.

  7. MEMO: Mars Escape and Magnetic Orbiter

    NASA Astrophysics Data System (ADS)

    Chassefiere, E.; Langlais, B.; Leblanc, F.; Sotin, C.; Barabash, S.; Dehant, V.; Dougherty, M.; Lammer, H.; Mandea, M.; Vennerstrom, S.

    There are several reasons to believe that Mars could have become an Earth like planet rather than the present dry and cold planet. In particular, many elements suggest the presence of liquid water at the Martian surface during a relatively short period at an early stage of its history. Since liquid water may have been the birthplace for life on Earth, the fate of Martian water is one of the major key and yet unanswered question to be solved. Mars Escape and Magnetic Orbiter (MEMO) is a low periapsis orbiter of Mars devoted to the measurement of present escape and the characterization of the fossil magnetic field of Mars. The use of a low periapsis altitude orbit (120-150 km) is required to detect and quantify all populations of atoms and molecules involved in escape. It is also required to measure the magnetic field of Mars with an unprecedented spatial resolution that would allow getting a more precise timing of the dynamo and its disappearance. Achieving a full characterization of atmospheric escape, and extrapolating it back to the past requires: (i) to measure escape fluxes of neutral and ion species, and characterize the dynamics and chemistry of the regions of the atmosphere where escape occurs (thermosphere, ionosphere, exosphere), as well as their responses to solar activity, and (ii) to characterize the lateral variations of the magnetic field of lithospheric origin, and by extension, the timing of the Martian dynamo. Of particular interest is the extinction of the dynamo that is thought to have enhanced the atmospheric escape processes still operating today. The proposed low-periapsis orbiter will consist of the following elements: • An "Escape Package" to characterize by both in-situ and remote measurements the thermosphere, ionosphere, exosphere and solar wind interaction regions (from one hundred to several thousand km), including thermal, suprathermal 1 and energetic particles. • A "Magnetic Field Package", to characterize the magnetization of the

  8. Escaping Antiangiogenic Therapy: Strategies Employed by Cancer Cells

    PubMed Central

    Pinto, Mauricio P.; Sotomayor, Paula; Carrasco-Avino, Gonzalo; Corvalan, Alejandro H.; Owen, Gareth I.

    2016-01-01

    Tumor angiogenesis is widely recognized as one of the “hallmarks of cancer”. Consequently, during the last decades the development and testing of commercial angiogenic inhibitors has been a central focus for both basic and clinical cancer research. While antiangiogenic drugs are now incorporated into standard clinical practice, as with all cancer therapies, tumors can eventually become resistant by employing a variety of strategies to receive nutrients and oxygen in the event of therapeutic assault. Herein, we concentrate and review in detail three of the principal mechanisms of antiangiogenic therapy escape: (1) upregulation of compensatory/alternative pathways for angiogenesis; (2) vasculogenic mimicry; and (3) vessel co-option. We suggest that an understanding of how a cancer cell adapts to antiangiogenic therapy may also parallel the mechanisms employed in the bourgeoning tumor and isolated metastatic cells delivering responsible for residual disease. Finally, we speculate on strategies to adapt antiangiogenic therapy for future clinical uses. PMID:27608016

  9. Escaping Antiangiogenic Therapy: Strategies Employed by Cancer Cells.

    PubMed

    Pinto, Mauricio P; Sotomayor, Paula; Carrasco-Avino, Gonzalo; Corvalan, Alejandro H; Owen, Gareth I

    2016-09-06

    Tumor angiogenesis is widely recognized as one of the "hallmarks of cancer". Consequently, during the last decades the development and testing of commercial angiogenic inhibitors has been a central focus for both basic and clinical cancer research. While antiangiogenic drugs are now incorporated into standard clinical practice, as with all cancer therapies, tumors can eventually become resistant by employing a variety of strategies to receive nutrients and oxygen in the event of therapeutic assault. Herein, we concentrate and review in detail three of the principal mechanisms of antiangiogenic therapy escape: (1) upregulation of compensatory/alternative pathways for angiogenesis; (2) vasculogenic mimicry; and (3) vessel co-option. We suggest that an understanding of how a cancer cell adapts to antiangiogenic therapy may also parallel the mechanisms employed in the bourgeoning tumor and isolated metastatic cells delivering responsible for residual disease. Finally, we speculate on strategies to adapt antiangiogenic therapy for future clinical uses.

  10. Compensatory escape mechanism at low Reynolds number

    PubMed Central

    Gemmell, Brad J.; Sheng, Jian; Buskey, Edward J.

    2013-01-01

    Despite high predation pressure, planktonic copepods remain one of the most abundant groups on the planet. Their escape response provides one of most effective mechanisms to maximize evolutionary fitness. Owing to their small size (100 µm) compared with their predators (>1 mm), increasing viscosity is believed to have detrimental effects on copepods’ fitness at lower temperature. Using high-speed digital holography we acquire 3D kinematics of the nauplius escape including both location and detailed appendage motion. By independently varying temperature and viscosity we demonstrate that at natural thermal extremes, contrary to conventional views, nauplii achieve equivalent escape distance while maintaining optimal velocity. Using experimental results and kinematic simulations from a resistive force theory propulsion model, we demonstrate that a shift in appendage timing creates an increase in power stroke duration relative to recovery stroke duration. This change allows the nauplius to limit losses in velocity and maintain distance during escapes at the lower bound of its natural thermal range. The shift in power stroke duration relative to recovery stroke duration is found to be regulated by the temperature dependence of swimming appendage muscle groups, not a dynamic response to viscosity change. These results show that copepod nauplii have natural adaptive mechanisms to compensate for viscosity variations with temperature but not in situations in which viscosity varies independent of temperature, such as in some phytoplankton blooms. Understanding the robustness of escapes in the wake of environmental changes such as temperature and viscosity has implications in assessing the future health of performance compensation. PMID:23487740

  11. Cerebrospinal Fluid HIV Escape from Antiretroviral Therapy.

    PubMed

    Ferretti, Francesca; Gisslen, Magnus; Cinque, Paola; Price, Richard W

    2015-06-01

    CNS infection is a nearly constant facet of systemic CNS infection and is generally well controlled by suppressive systemic antiretroviral therapy (ART). However, there are instances when HIV can be detected in the cerebrospinal fluid (CSF) despite suppression of plasma viruses below the clinical limits of measurement. We review three types of CSF viral escape: asymptomatic, neuro-symptomatic, and secondary. The first, asymptomatic CSF escape, is seemingly benign and characterized by lack of discernable neurological deterioration or subsequent CNS disease progression. Neuro-symptomatic CSF escape is an uncommon, but important, entity characterized by new or progressive CNS disease that is critical to recognize clinically because of its management implications. Finally, secondary CSF escape, which may be even more uncommon, is defined by an increase of CSF HIV replication in association with a concomitant non-HIV infection, as a consequence of the local inflammatory response. Understanding these CSF escape settings not only is important for clinical diagnosis and management but also may provide insight into the CNS HIV reservoir.

  12. Residential smoke alarms and fire escape plans.

    PubMed Central

    Harvey, P A; Sacks, J J; Ryan, G W; Bender, P F

    1998-01-01

    OBJECTIVE: To estimate the proportion of U.S. homes with installed smoke alarms, smoke alarms on the same floor as occupants' bedrooms, and fire escape plans. METHODS: The authors analyzed data on smoke alarm use and fire escape planning from a 1994 stratified random telephone survey of 5238 U.S. households. RESULTS: Respondents from 91% of surveyed households reported the presence of at least one installed smoke alarm, and 94% of respondents reported having an alarm on the same level of the home as their sleeping area. The prevalence of installed smoke alarms varied by highest education level in the household and income level. Sixty percent of all households had designed or discussed a fire escape plan at least once; only 17% of these households had actually practiced one. CONCLUSIONS: Although overall use of smoke alarms was high, certain population subgroups were less likely to have smoke alarms or to have them installed on the same floor as bedrooms. Fire escape planning, another important safety measure, was somewhat less common, and very few respondents reported having practiced a fire escape plan with the members of their household. PMID:9769771

  13. Genes that escape from X inactivation.

    PubMed

    Berletch, Joel B; Yang, Fan; Xu, Jun; Carrel, Laura; Disteche, Christine M

    2011-08-01

    To achieve a balanced gene expression dosage between males (XY) and females (XX), mammals have evolved a compensatory mechanism to randomly inactivate one of the female X chromosomes. Despite this chromosome-wide silencing, a number of genes escape X inactivation: in women about 15% of X-linked genes are bi-allelically expressed and in mice, about 3%. Expression from the inactive X allele varies from a few percent of that from the active allele to near equal expression. While most genes have a stable inactivation pattern, a subset of genes exhibit tissue-specific differences in escape from X inactivation. Escape genes appear to be protected from the repressive chromatin modifications associated with X inactivation. Differences in the identity and distribution of escape genes between species and tissues suggest a role for these genes in the evolution of sex differences in specific phenotypes. The higher expression of escape genes in females than in males implies that they may have female-specific roles and may be responsible for some of the phenotypes observed in X aneuploidy.

  14. Escape as reinforcement and escape extinction in the treatment of feeding problems.

    PubMed

    LaRue, Robert H; Stewart, Victoria; Piazza, Cathleen C; Volkert, Valerie M; Patel, Meeta R; Zeleny, Jason

    2011-01-01

    Given the effectiveness of putative escape extinction as treatment for feeding problems, it is surprising that little is known about the effects of escape as reinforcement for appropriate eating during treatment. In the current investigation, we examined the effectiveness of escape as reinforcement for mouth clean (a product measure of swallowing), escape as reinforcement for mouth clean plus escape extinction (EE), and EE alone as treatment for the food refusal of 5 children. Results were similar to those of previous studies, in that reinforcement alone did not result in increases in mouth clean or decreases in inappropriate behavior (e.g., Piazza, Patel, Gulotta, Sevin, & Layer, 2003). Increases in mouth clean and decreases in inappropriate behavior occurred when the therapist implemented EE independent of the presence or absence of reinforcement. Results are discussed in terms of the role of negative reinforcement in the etiology and treatment of feeding problems.

  15. Localized reactive oxygen and nitrogen intermediates inhibit escape of Listeria monocytogenes from vacuoles in activated macrophages.

    PubMed

    Myers, Jesse T; Tsang, Albert W; Swanson, Joel A

    2003-11-15

    Listeria monocytogenes (Lm) evades being killed after phagocytosis by macrophages by escaping from vacuoles into cytoplasm. Activated macrophages are listericidal, in part because they can retain Lm in vacuoles. This study examined the contribution of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI) to the inhibition of Lm escape from vacuoles. Lm escaped from vacuoles of nonactivated macrophages within 30 min of infection. Macrophages activated with IFN-gamma, LPS, IL-6, and a neutralizing Ab against IL-10 retained Lm within the vacuoles, and inhibitors of ROI and RNI blocked inhibition of vacuolar escape to varying degrees. Measurements of Lm escape in macrophages from gp91(phox-/-) and NO synthase 2(-/-) mice showed that vacuolar retention required ROI and was augmented by RNI. Live cell imaging with the fluorogenic probe dihydro-2',4,5,6,7,7'-hexafluorofluorescein coupled to BSA (DHFF-BSA) indicated that oxidative chemistries were generated rapidly and were localized to Lm vacuoles. Chemistries that oxidized DHFF-BSA were similar to those that retained Lm in phagosomes. Fluorescent conversion of DHFF-BSA occurred more efficiently in smaller vacuoles, indicating that higher concentrations of ROI or RNI were generated in more confining volumes. Thus, activated macrophages retained Lm within phagosomes by the localization of ROI and RNI to vacuoles, and by their combined actions in a small space

  16. Laser fusion

    SciTech Connect

    Smit, W.A.; Boskma, P.

    1980-12-01

    Unrestricted laser fusion offers nations an opportunity to circumvent arms control agreements and develop thermonuclear weapons. Early laser weapons research sought a clean radiation-free bomb to replace the fission bomb, but this was deceptive because a fission bomb was needed to trigger the fusion reaction and additional radioactivity was induced by generating fast neutrons. As laser-implosion experiments focused on weapons physics, simulating weapons effects, and applications for new weapons, the military interest shifted from developing a laser-ignited hydrogen bomb to more sophisticated weapons and civilian applications for power generation. Civilian and military research now overlap, making it possible for several countries to continue weapons activities and permitting proliferation of nuclear weapons. These countries are reluctant to include inertial confinement fusion research in the Non-Proliferation Treaty. 16 references. (DCK)

  17. Thermal escape from extrasolar giant planets

    PubMed Central

    Koskinen, Tommi T.; Lavvas, Panayotis; Harris, Matthew J.; Yelle, Roger V.

    2014-01-01

    The detection of hot atomic hydrogen and heavy atoms and ions at high altitudes around close-in extrasolar giant planets (EGPs) such as HD209458b implies that these planets have hot and rapidly escaping atmospheres that extend to several planetary radii. These characteristics, however, cannot be generalized to all close-in EGPs. The thermal escape mechanism and mass loss rate from EGPs depend on a complex interplay between photochemistry and radiative transfer driven by the stellar UV radiation. In this study, we explore how these processes change under different levels of irradiation on giant planets with different characteristics. We confirm that there are two distinct regimes of thermal escape from EGPs, and that the transition between these regimes is relatively sharp. Our results have implications for thermal mass loss rates from different EGPs that we discuss in the context of currently known planets and the detectability of their upper atmospheres. PMID:24664923

  18. Thermal escape from extrasolar giant planets.

    PubMed

    Koskinen, Tommi T; Lavvas, Panayotis; Harris, Matthew J; Yelle, Roger V

    2014-04-28

    The detection of hot atomic hydrogen and heavy atoms and ions at high altitudes around close-in extrasolar giant planets (EGPs) such as HD209458b implies that these planets have hot and rapidly escaping atmospheres that extend to several planetary radii. These characteristics, however, cannot be generalized to all close-in EGPs. The thermal escape mechanism and mass loss rate from EGPs depend on a complex interplay between photochemistry and radiative transfer driven by the stellar UV radiation. In this study, we explore how these processes change under different levels of irradiation on giant planets with different characteristics. We confirm that there are two distinct regimes of thermal escape from EGPs, and that the transition between these regimes is relatively sharp. Our results have implications for thermal mass loss rates from different EGPs that we discuss in the context of currently known planets and the detectability of their upper atmospheres.

  19. Statistical theory of asteroid escape rates.

    PubMed

    Jaffé, Charles; Ross, Shane D; Lo, Martin W; Marsden, Jerrold; Farrelly, David; Uzer, T

    2002-07-01

    Transition states in phase space are identified and shown to regulate the rate of escape of asteroids temporarily captured in circumplanetary orbits. The transition states, similar to those occurring in chemical reaction dynamics, are then used to develop a statistical semianalytical theory for the rate of escape of asteroids temporarily captured by Mars. Theory and numerical simulations are found to agree to better than 1%. These calculations suggest that further development of transition state theory in celestial mechanics, as an alternative to large-scale numerical simulations, will be a fruitful approach to mass transport calculations.

  20. Bacillus anthracis factors for phagosomal escape.

    PubMed

    Tonello, Fiorella; Zornetta, Irene

    2012-07-01

    The mechanism of phagosome escape by intracellular pathogens is an important step in the infectious cycle. During the establishment of anthrax, Bacillus anthracis undergoes a transient intracellular phase in which spores are engulfed by local phagocytes. Spores germinate inside phagosomes and grow to vegetative bacilli, which emerge from their resident intracellular compartments, replicate and eventually exit from the plasma membrane. During germination, B. anthracis secretes multiple factors that can help its resistance to the phagocytes. Here the possible role of B. anthracis toxins, phospholipases, antioxidant enzymes and capsules in the phagosomal escape and survival, is analyzed and compared with that of factors of other microbial pathogens involved in the same type of process.

  1. Escape from R-peptide deletion in a {gamma}-retrovirus

    SciTech Connect

    Schneider, Irene C.; Eckhardt, Manon; Brynza, Julia; Collins, Mary K.; Cichutek, Klaus; Buchholz, Christian J.

    2011-09-30

    The R peptide in the cytoplasmic tail (C-tail) of {gamma}-retroviral envelope proteins (Env) prevents membrane fusion before budding. To analyse its role in the formation of replication competent, infectious particles, we developed chimeric murine leukaemia viruses (MLV) with unmodified or R-peptide deleted Env proteins of the gibbon ape leukaemia virus (GaLV). While titres of these viruses were unaffected, R-peptide deficiency led to strongly impaired spreading. Most remarkably, we isolated an escape mutant which had restored an open reading frame for a C-terminal extension of the truncated C-tail. A reconstituted virus encoding this escape C-tail replicated in cell culture. In contrast to R-peptide deficient Env, particle incorporation of the escape Env was effective due to an enhanced protein expression and restored intracellular co-localisation with Gag proteins. Our data demonstrate that the R peptide not only regulates membrane fusion but also mediates efficient Env protein particle incorporation in {gamma}-retrovirus infected cells.

  2. Molecular pathways: targeting ETS gene fusions in cancer.

    PubMed

    Feng, Felix Y; Brenner, J Chad; Hussain, Maha; Chinnaiyan, Arul M

    2014-09-01

    Rearrangements, or gene fusions, involving the ETS family of transcription factors are common driving events in both prostate cancer and Ewing sarcoma. These rearrangements result in pathogenic expression of the ETS genes and trigger activation of transcriptional programs enriched for invasion and other oncogenic features. Although ETS gene fusions represent intriguing therapeutic targets, transcription factors, such as those comprising the ETS family, have been notoriously difficult to target. Recently, preclinical studies have demonstrated an association between ETS gene fusions and components of the DNA damage response pathway, such as PARP1, the catalytic subunit of DNA protein kinase (DNAPK), and histone deactylase 1 (HDAC1), and have suggested that ETS fusions may confer sensitivity to inhibitors of these DNA repair proteins. In this review, we discuss the role of ETS fusions in cancer, the preclinical rationale for targeting ETS fusions with inhibitors of PARP1, DNAPK, and HDAC1, as well as ongoing clinical trials targeting ETS gene fusions.

  3. Martian Atmospheric and Ionospheric plasma Escape

    NASA Astrophysics Data System (ADS)

    Lundin, Rickard

    2016-04-01

    Solar forcing is responsible for the heating, ionization, photochemistry, and erosion processes in the upper atmosphere throughout the lifetime of the terrestrial planets. Of the four terrestrial planets, the Earth is the only one with a fully developed biosphere, while our kin Venus and Mars have evolved into arid inhabitable planets. As for Mars, there are ample evidences for an early Noachian, water rich period on Mars. The question is, what made Mars evolve so differently compared to the Earth? Various hydrosphere and atmospheric evolution scenarios for Mars have been forwarded based on surface morphology, chemical composition, simulations, semi-empiric (in-situ data) models, and the long-term evolution of the Sun. Progress has been made, but the case is still open regarding the changes that led to the present arid surface and tenuous atmosphere at Mars. This presentation addresses the long-term variability of the Sun, the solar forcing impact on the Martian atmosphere, and its interaction with the space environment - an electromagnetic wave and particle interaction with the upper atmosphere that has implications for its photochemistry, composition, and energization that governs thermal and non-thermal escape. Non-thermal escape implies an electromagnetic upward energization of planetary ions and molecules to velocities above escape velocity, a process governed by a combination of solar EUV radiation (ionization), and energy and momentum transfer by the solar wind. The ion escape issue dates back to the early Soviet and US-missions to Mars, but the first more accurate estimates of escape rates came with the Phobos-2 mission in 1989. Better-quality ion composition measurement results of atmospheric/ionospheric ion escape from Mars, obtained from ESA Mars Express (MEX) instruments, have improved our understanding of the ion escape mechanism. With the NASA MAVEN spacecraft orbiting Mars since Sept. 2014, dual in-situ measurement with plasma instruments are now

  4. Spinal fusion

    MedlinePlus

    Liu G, Wong HK. Laminectomy and fusion. In: Shen FH, Samartzis D, Fessler RG, eds. Textbook of the Cervical Spine . Philadelphia, PA: Elsevier Saunders; 2015:chap 34. Wood GW. Arthrodesis of the spine. In: Canale ST, Beaty JH, eds. Campbell's Operative ...

  5. On the escape of CH4 from Pluto's atmosphere

    NASA Astrophysics Data System (ADS)

    Koskinen, T. T.; Erwin, J. T.; Yelle, R. V.

    2015-09-01

    We adapted a multispecies escape model, developed for close-in extrasolar planets, to calculate the escape rates of CH4 and N2 from Pluto. In the absence of escape, CH4 should overtake N2 as the dominant species below the exobase. The CH4 profile depends strongly on the escape rate, however, and the typical escape rates predicted for Pluto lead to a nearly constant mixing ratio of less than 1% below the exobase. In this case the CH4 escape rate is only 5-10% of the N2 escape rate. Observations of the CH4 profile by the New Horizons/ALICE spectrograph can constrain the CH4 escape rate and provide a unique test for escape models.

  6. Photodynamic therapy with simultaneous suppression of multiple treatment escape pathways (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Spring, Bryan Q.; Sears, R. Bryan; Zheng, Lei Z.; Mai, Zhiming; Watanabe, Reika; Sherwood, Margaret E.; Schoenfeld, David A.; Pogue, Brian W.; Pereira, Stephen P.; Villa, Elizabeth; Hasan, Tayyaba

    2016-03-01

    We introduce photoactivatable multi-inhibitor nanoliposomes (PMILs) for photodynamic tumor cell and microvessel damage in synchrony with photo-initiation of tumor-confined, multikinase inhibitor release. The PMIL is a biodegradable delivery system comprised of a nanoliposome carrying a photoactivable chromophore (benzoporphyrin derivative monoacid A, BPD) in its bilayer. A multikinase inhibitor-loaded PEG-PLGA nanoparticle is encapsulated within the liposome, which acts a barrier to nanoparticle erosion and drug release. Following intravenous PMIL administration, near infrared irradiation of tumors triggers photodynamic therapy and initiates tumor-confined drug release from the nanoparticle. This talk presents promising preclinical data in mouse models of pancreatic cancer utilizing this concept to suppress the VEGF and MET signaling pathways—both critical to cancer progression, metastasis and treatment escape. A single PMIL treatment using low doses of a multikanse inhibitor (cabozantinib, XL184) achieves sustained tumor reduction and suppresses metastatic escape, whereas combination therapy by co-administration of the individual agents has significantly reduced efficacy. The PMIL concept is amenable to a number of molecular inhibitors and offers new prospects for spatiotemporal synchronization of combination therapies whilst reducing systemic drug exposure and associated toxicities.

  7. Escape from Albuquerque: An Apache Memorate.

    ERIC Educational Resources Information Center

    Greenfeld, Philip J.

    2001-01-01

    Clarence Hawkins, a White Mountain Apache, escaped from the Albuquerque Indian School around 1920. His 300-mile trip home, made with two other boys, exemplifies the reaction of many Indian youths to the American government's plans for cultural assimilation. The tale is told in the form of traditional Apache narrative. (TD)

  8. Nociception and escape behavior in planarians

    NASA Astrophysics Data System (ADS)

    Schoetz Collins, Eva-Maria

    2015-03-01

    Planarians are famous and widely studied for their regenerative capabilities. When a moving planarian is cut through the middle, the resulting head and tail pieces instantaneously retract and exhibit a characteristic escape response that differs from normal locomotion. In asexual animals, a similar reaction is observed when the planarian undergoes fission, suggesting that reproduction through self-tearing is a rather traumatic event for the animal. Using a multiscale approach, we unravel the dynamics, mechanics, and functional aspects of the planarian escape response. This musculature-driven gait was found to be a dominating response that supersedes the urge to feed or reproduce and quantitatively differs from other modes of planarian locomotion (gliding, peristalsis). We show that this escape gait constitutes the animal's pain response mediated by TRP like receptors and the neurotransmitter histamine, and that it can be induced through adverse thermal, mechanical, electrical or chemical stimuli. Ultimately, we will examine the neuronal subpopulations involved in mediating escape reflexes in planarians and how they are functionally restored during regeneration, thereby gaining mechanistic insight into the neuronal circuits required for specific behaviors. Supported by BWF CASI and Sloan Foundation.

  9. Centrifugally Stimulated Exospheric Ion Escape at Mercury

    NASA Technical Reports Server (NTRS)

    Delcourt, Dominique; Seki, K.; Terada, N.; Moore, Thomas E.

    2012-01-01

    We investigate the transport of ions in the low-altitude magnetosphere magnetosphere of Mercury. We show that, because of small spatial scales, the centrifugal effect due to curvature of the E B drift paths can lead to significant particle energization in the parallel direction. We demonstrate that because of this effect, ions with initial speed smaller than the escape speed such as those produced via thermal desorption can overcome gravity and escape into the magnetosphere. The escape route of this low-energy exosphere originating material is largely controlled by the magnetospheric convection rate. This escape route spreads over a narrower range of altitudes when the convection rate increases. Bulk transport of low-energy planetary material thus occurs within a limited region of space once moderate magnetospheric convection is established. These results suggest that, via release of material otherwise gravitationally trapped, the E B related centrifugal acceleration is an important mechanism for the net supply of plasma to the magnetosphere of Mercury.

  10. Animal escapology II: escape trajectory case studies

    PubMed Central

    Domenici, Paolo; Blagburn, Jonathan M.; Bacon, Jonathan P.

    2011-01-01

    Summary Escape trajectories (ETs; measured as the angle relative to the direction of the threat) have been studied in many taxa using a variety of methodologies and definitions. Here, we provide a review of methodological issues followed by a survey of ET studies across animal taxa, including insects, crustaceans, molluscs, lizards, fish, amphibians, birds and mammals. Variability in ETs is examined in terms of ecological significance and morpho-physiological constraints. The survey shows that certain escape strategies (single ETs and highly variable ETs within a limited angular sector) are found in most taxa reviewed here, suggesting that at least some of these ET distributions are the result of convergent evolution. High variability in ETs is found to be associated with multiple preferred trajectories in species from all taxa, and is suggested to provide unpredictability in the escape response. Random ETs are relatively rare and may be related to constraints in the manoeuvrability of the prey. Similarly, reports of the effect of refuges in the immediate environment are relatively uncommon, and mainly confined to lizards and mammals. This may be related to the fact that work on ETs carried out in laboratory settings has rarely provided shelters. Although there are a relatively large number of examples in the literature that suggest trends in the distribution of ETs, our understanding of animal escape strategies would benefit from a standardization of the analytical approach in the study of ETs, using circular statistics and related tests, in addition to the generation of large data sets. PMID:21753040

  11. Developing the E-Scape Software System

    ERIC Educational Resources Information Center

    Derrick, Karim

    2012-01-01

    Most innovations have contextual pre-cursors that prompt new ways of thinking and in their turn help to give form to the new reality. This was the case with the e-scape software development process. The origins of the system existed in software components and ideas that we had developed through previous projects, but the ultimate direction we took…

  12. Escape driven by α -stable white noises

    NASA Astrophysics Data System (ADS)

    Dybiec, B.; Gudowska-Nowak, E.; Hänggi, P.

    2007-02-01

    We explore the archetype problem of an escape dynamics occurring in a symmetric double well potential when the Brownian particle is driven by white Lévy noise in a dynamical regime where inertial effects can safely be neglected. The behavior of escaping trajectories from one well to another is investigated by pointing to the special character that underpins the noise-induced discontinuity which is caused by the generalized Brownian paths that jump beyond the barrier location without actually hitting it. This fact implies that the boundary conditions for the mean first passage time (MFPT) are no longer determined by the well-known local boundary conditions that characterize the case with normal diffusion. By numerically implementing properly the set up boundary conditions, we investigate the survival probability and the average escape time as a function of the corresponding Lévy white noise parameters. Depending on the value of the skewness β of the Lévy noise, the escape can either become enhanced or suppressed: a negative asymmetry parameter β typically yields a decrease for the escape rate while the rate itself depicts a non-monotonic behavior as a function of the stability index α that characterizes the jump length distribution of Lévy noise, exhibiting a marked discontinuity at α=1 . We find that the typical factor of 2 that characterizes for normal diffusion the ratio between the MFPT for well-bottom-to-well-bottom and well-bottom-to-barrier-top no longer holds true. For sufficiently high barriers the survival probabilities assume an exponential behavior versus time. Distinct non-exponential deviations occur, however, for low barrier heights.

  13. Cold fusion, Alchemist's dream

    SciTech Connect

    Clayton, E.D.

    1989-09-01

    In this report the following topics relating to cold fusion are discussed: muon catalysed cold fusion; piezonuclear fusion; sundry explanations pertaining to cold fusion; cosmic ray muon catalysed cold fusion; vibrational mechanisms in excited states of D{sub 2} molecules; barrier penetration probabilities within the hydrogenated metal lattice/piezonuclear fusion; branching ratios of D{sub 2} fusion at low energies; fusion of deuterons into {sup 4}He; secondary D+T fusion within the hydrogenated metal lattice; {sup 3}He to {sup 4}He ratio within the metal lattice; shock induced fusion; and anomalously high isotopic ratios of {sup 3}He/{sup 4}He.

  14. Escape from viscosity: the kinematics and hydrodynamics of copepod foraging and escape swimming.

    PubMed

    van Duren, Luca A; Videler, John J

    2003-01-01

    Feeding and escape swimming in adult females of the calanoid copepod Temora longicornis Müller were investigated and compared. Swimming velocities were calculated using a 3-D filming setup. Foraging velocities ranged between 2 and 6 mm s(-1), while maximum velocities of up to 80 mm s(-1) were reached during escape responses. Foraging took place at Reynolds numbers between 2 and 6, indicating that viscous forces are considerable during this swimming mode. Inertial forces are much more important during escape responses, when Reynolds numbers of more than 100 are reached. High-speed film recordings at 500 frames s(-1) of the motion pattern of the feeding appendages and the escape movement of the swimming legs revealed that the two swimming modes are essentially very different. While foraging, the first three mouth appendages (antennae, mandibular palps and maxillules) create a backwards motion of water with a metachronal beating pattern. During escape movements the mouth appendages stop moving and the swimming legs beat in a very fast metachronal rhythm, accelerating a jet of water backwards. The large antennules are folded backwards, resulting in a streamlined body shape. Particle image velocimetry analysis of the flow around foraging and escaping copepods revealed that during foraging an asymmetrical vortex system is created on the ventral side of the animal. The feeding motion is steady over a long period of time. The rate of energy dissipation due to viscous friction relates directly to the energetic cost of the feeding current. During escape responses a vortex ring appears behind the animal, which dissipates over time. Several seconds after cessation of swimming leg movements, energy dissipation can still be measured. During escape responses the rate of energy dissipation due to viscous friction increases by up to two orders of magnitude compared to the rate when foraging.

  15. Selection and characterization of human respiratory syncytial virus escape mutants resistant to a polyclonal antiserum raised against the F protein.

    PubMed

    Tomé, Lorena; Frabasile, Sandra; Candia, Claudia; Pittini, Alvaro; Farina, Natalia; Melero, José Antonio; Arbiza, Juan

    2012-06-01

    A human respiratory syncytial virus (HRSV) neutralization escape mutant was obtained after 56 serial passages in the presence of a polyclonal antiserum raised against the F protein. Nucleotide sequence analysis of this escape mutant virus revealed two amino acid substitutions: Asn268Ile and Val533Met. When this virus was allowed to grow in the absence of the anti-F polyclonal serum, only the mutation Asn268Ile was stably maintained. Both the double and single escape mutant viruses lost reactivity with mAbs belonging to antigenic site II of the fusion protein of RSV. Mutation Asn268Ile has already been reported in RS viruses that are resistant to mAbs 47F and 11 and palivizumab (PZ). We have thus identified a novel mutation (Val533Met) in the transmembrane domain of the F protein that was selected under immune pressure.

  16. Escape of asteroids from the main belt

    NASA Astrophysics Data System (ADS)

    Granvik, Mikael; Morbidelli, Alessandro; Vokrouhlický, David; Bottke, William F.; Nesvorný, David; Jedicke, Robert

    2017-01-01

    Aims: We locate escape routes from the main asteroid belt, particularly into the near-Earth-object (NEO) region, and estimate the relative fluxes for different escape routes as a function of object size under the influence of the Yarkovsky semimajor-axis drift. Methods: We integrated the orbits of 78 355 known and 14 094 cloned main-belt objects and Cybele and Hilda asteroids (hereafter collectively called MBOs) for 100 Myr and recorded the characteristics of the escaping objects. The selected sample of MBOs with perihelion distance q > 1.3 au and semimajor axis a < 4.1 au is essentially complete, with an absolute magnitude limit ranging from HV < 15.9 in the inner belt (a < 2.5 au) to HV < 14.4 in the outer belt (2.5 au < a < 4.1 au). We modeled the semimajor-axis drift caused by the Yarkovsky force and assigned four different sizes (diameters of 0.1, 0.3, 1.0, and 3.0 km) and random spin obliquities (either 0 deg or 180 deg) for each test asteroid. Results: We find more than ten obvious escape routes from the asteroid belt to the NEO region, and they typically coincide with low-order mean-motion resonances with Jupiter and secular resonances. The locations of the escape routes are independent of the semimajor-axis drift rate and thus are also independent of the asteroid diameter. The locations of the escape routes are likewise unaffected when we added a model for Yarkovsky-O'Keefe-Radzievskii-Paddack (YORP) cycles coupled with secular evolution of the rotation pole as a result of the solar gravitational torque. A Yarkovsky-only model predicts a flux of asteroids entering the NEO region that is too high compared to the observationally constrained flux, and the discrepancy grows larger for smaller asteroids. A combined Yarkovsky and YORP model predicts a flux of small NEOs that is approximately a factor of 5 too low compared to an observationally constrained estimate. This suggests that the characteristic timescale of the YORP cycle is longer than our canonical

  17. Launch Pad Escape System Design (Human Spaceflight)

    NASA Technical Reports Server (NTRS)

    Maloney, Kelli

    2011-01-01

    A launch pad escape system for human spaceflight is one of those things that everyone hopes they will never need but is critical for every manned space program. Since men were first put into space in the early 1960s, the need for such an Emergency Escape System (EES) has become apparent. The National Aeronautics and Space Administration (NASA) has made use of various types of these EESs over the past 50 years. Early programs, like Mercury and Gemini, did not have an official launch pad escape system. Rather, they relied on a Launch Escape System (LES) of a separate solid rocket motor attached to the manned capsule that could pull the astronauts to safety in the event of an emergency. This could only occur after hatch closure at the launch pad or during the first stage of flight. A version of a LES, now called a Launch Abort System (LAS) is still used today for all manned capsule type launch vehicles. However, this system is very limited in that it can only be used after hatch closure and it is for flight crew only. In addition, the forces necessary for the LES/LAS to get the capsule away from a rocket during the first stage of flight are quite high and can cause injury to the crew. These shortcomings led to the development of a ground based EES for the flight crew and ground support personnel as well. This way, a much less dangerous mode of egress is available for any flight or ground personnel up to a few seconds before launch. The early EESs were fairly simple, gravity-powered systems to use when thing's go bad. And things can go bad very quickly and catastrophically when dealing with a flight vehicle fueled with millions of pounds of hazardous propellant. With this in mind, early EES designers saw such a passive/unpowered system as a must for last minute escapes. This and other design requirements had to be derived for an EES, and this section will take a look at the safety design requirements had to be derived for an EES, and this section will take a look at

  18. 34. VIEW OF SUBMARINE ESCAPE TRAINING TANK PRIOR TO ADDITION ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    34. VIEW OF SUBMARINE ESCAPE TRAINING TANK PRIOR TO ADDITION OF BLISTERS IN 1959, LOOKING SOUTHEAST - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

  19. 23. VIEW OF ESCAPE TRAINING TANK, LOOKING NORTHWEST, SHOWING TWOLOCK ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    23. VIEW OF ESCAPE TRAINING TANK, LOOKING NORTHWEST, SHOWING TWO-LOCK RECOMPRESSION CHAMBER IN PASSAGEWAY FROM ELEVATOR TO CUPOLA - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

  20. 14. DETAIL VIEW OF ESCAPE TRAINING TANK, SHOWING HOLDDOWN RODS, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    14. DETAIL VIEW OF ESCAPE TRAINING TANK, SHOWING HOLD-DOWN RODS, LOOKING SOUTH - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

  1. 15. VIEW OF ESCAPE TRAINING TANK, LOOKING EAST ACROSS MEZZANINE, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    15. VIEW OF ESCAPE TRAINING TANK, LOOKING EAST ACROSS MEZZANINE, SHOWING ENTRANCE TO SUBMARINE SECTION AT 110-FOOT LEVEL - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

  2. 21. VIEW OF ESCAPE TRAINING TANK, SHOWING INTERIOR OF CUPOLA ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    21. VIEW OF ESCAPE TRAINING TANK, SHOWING INTERIOR OF CUPOLA AND TOP OF THE TANK, LOOKING NORTHEAST - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

  3. 18. VIEW OF ESCAPE TRAINING TANK, SHOWING ENCLOSED PASSAGEWAY FROM ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    18. VIEW OF ESCAPE TRAINING TANK, SHOWING ENCLOSED PASSAGEWAY FROM 50-FOOT LOCK TO ELEVATOR, LOOKING WEST - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

  4. 17. VIEW OF ESCAPE TRAINING TANK, SHOWING ENCLOSED PASSAGEWAY FROM ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    17. VIEW OF ESCAPE TRAINING TANK, SHOWING ENCLOSED PASSAGEWAY FROM ELEVATOR TO 18-FOOT LOCK, LOOKING EAST - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

  5. Escape of atmospheres and loss of water

    NASA Technical Reports Server (NTRS)

    Hunten, D. M.; Donahue, T. M.; Walker, J. C. G.; Kasting, J. F.

    1989-01-01

    The properties and limitations of several loss processes for atmospheric gases are presented and discussed. They include thermal loss (Jeans and hydrodynamic); nonthermal loss (all processes involve charged particles); and impact erosion, including thermal escape from a molten body heated by rapid accretion. Hydrodynamic escape, or 'blowoff', is of particular interest because it offers the prospect of processing large quantities of gas and enriching the remainder in heavy elements and isotopes. In a second part, the water budgets and likely evolutionary histories of Venus, Earth and Mars are assessed. Although it is tempting to associate the great D/H enrichment on Venus with loss of a large initial endowment, a steady state with juvenile water (perhaps from comets) is equally probable.

  6. Fixed-ratio escape reinforcement1

    PubMed Central

    Azrin, N. H.; Holz, W. C.; Hake, D. F.; Ayllon, T.

    1963-01-01

    Escape responses of squirrel monkeys were reinforced according to a fixed-ratio schedule. The reinforcement was a period of safety from a stimulus that signalled the delivery of intermittent pain-shocks. When the frequency of shock was gradually reduced, the performance remained at a high level until the shocks were quite infrequent. Similarly, the duration of the period of safety could be reduced to a few seconds with little loss of behavior. Thus, the responses appeared to be reinforced by even a brief period of safety, the actual degree of shock reduction being fairly slight. The changes in responding during this fixed-ratio escape procedure were comparable to the response changes typically obtained during fixed-ratio food procedures. PMID:13965780

  7. Triton: topside ionosphere and nitrogen escape.

    PubMed

    Yung, Y L; Lyons, J R

    1990-09-01

    The principal ion in the ionosphere of Triton is N+. Energetic electrons of magnetospheric origin are the primary source of ionization, with a smaller contribution due to photoionization. To explain the topside plasma scale height, we postulate that N+ ions escape from Triton. The loss rate is 3.4 x 10(7) cm-2 s-1 or 7.9 x 10(24) ions s-1. Dissociative recombination of N2+ produces neutral exothermic fragments that can escape from Triton. The rate is estimated to be 8.6 x 10(6) N cm-2 s-1 or 2.0 x 10(24) atoms s-1. Implications for the magnetosphere of Neptune and Triton's evolution are discussed.

  8. [Escape mutants of hepatitis B virus].

    PubMed

    Jaramillo, Carlos Mario; Navas, María-Cristina

    2015-04-01

    The hepatitis B virus (HBV) infection is a public health problem worldwide. Considering HBV morbidity and mortality and the economic consequences .of this infection, policies and strategies to control it have been implemented, especially in regions where HBV infection is endemic, with high rates of vertical and horizontal infection. One of these strategies is the development of the recombinant vaccine. A 92% of the countries in the world have implemented the vaccine with a global coverage of 69%. The escape variants of HBV correspond to isolates with mutations in the sequence coding for the "a" determinant; these mutations result in changes in the amino acid sequence of the surface antigen (HBsAg) that prevent neutralization of viral particles by antibodies generated in response to vaccination or infection. The escape variants can infect vaccinated individuals and have been identified in the population of countries with different epidemiological patterns.

  9. Dynamic Escape Routes for Naval Ships

    DTIC Science & Technology

    2005-09-01

    3 o Increase the likelihood of successfully salvaging the ship, and o Increase the likelihood that the crew is rescued safely. It will be possible...spans the period before the event that triggers ship abandonment. Escape routes can be configured based on two factors: 6 o “Crew distribution...crewmembers but the guards are resting in cabins and berthing rooms. This is a plausible scenario at night when the ship is in a non-home port. o

  10. 30 CFR 75.382 - Mechanical escape facilities.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Ventilation § 75.382 Mechanical escape facilities. (a) Mechanical escape facilities shall be provided with overspeed, overwind, and automatic stop... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Mechanical escape facilities. 75.382 Section...

  11. 30 CFR 75.382 - Mechanical escape facilities.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Mechanical escape facilities. 75.382 Section 75... HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Ventilation § 75.382 Mechanical escape facilities. (a) Mechanical escape facilities shall be provided with overspeed, overwind, and automatic...

  12. 30 CFR 75.382 - Mechanical escape facilities.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Mechanical escape facilities. 75.382 Section 75... HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Ventilation § 75.382 Mechanical escape facilities. (a) Mechanical escape facilities shall be provided with overspeed, overwind, and automatic...

  13. 30 CFR 75.382 - Mechanical escape facilities.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Mechanical escape facilities. 75.382 Section 75... HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Ventilation § 75.382 Mechanical escape facilities. (a) Mechanical escape facilities shall be provided with overspeed, overwind, and automatic...

  14. 30 CFR 75.382 - Mechanical escape facilities.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Mechanical escape facilities. 75.382 Section 75... HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Ventilation § 75.382 Mechanical escape facilities. (a) Mechanical escape facilities shall be provided with overspeed, overwind, and automatic...

  15. 46 CFR 108.153 - Location of means of escape.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 4 2010-10-01 2010-10-01 false Location of means of escape. 108.153 Section 108.153 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) A-MOBILE OFFSHORE DRILLING UNITS DESIGN AND EQUIPMENT Construction and Arrangement Means of Escape § 108.153 Location of means of escape....

  16. 46 CFR 108.153 - Location of means of escape.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 4 2011-10-01 2011-10-01 false Location of means of escape. 108.153 Section 108.153 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) A-MOBILE OFFSHORE DRILLING UNITS DESIGN AND EQUIPMENT Construction and Arrangement Means of Escape § 108.153 Location of means of escape....

  17. Xenon Fractionation and Archean Hydrogen Escape

    NASA Technical Reports Server (NTRS)

    Zahnle, K. J.

    2015-01-01

    Xenon is the heaviest gas found in significant quantities in natural planetary atmospheres. It would seem the least likely to escape. Yet there is more evidence for xenon escape from Earth than for any element other than helium and perhaps neon. The most straightforward evidence is that most of the radiogenic Xe from the decay of (129)I (half-life 15.7 Myr) and (244)Pu (half-life 81 Myr) that is Earth's birthright is missing. The missing xenon is often attributed to the impact erosion of early atmospheres of Earth and its ancestors. It is obvious that if most of the radiogenic xenon were driven off by impacts, most of the rest of the atmophiles fared the same fate. The other line of evidence is in the nonradiogenic isotopes of xenon and its silent partner, krypton. Atmospheric xenon is strongly mass fractionated (at about 4% per amu) compared to any known solar system source (Figure 1). This is in stark contrast to krypton, which may not be fractionated at all: atmospheric Kr is slightly heavier than solar Kr (at about 0.5% per amu), but it is the same as in carbonaceous chondrites. Nonradiogenic xenon is also under abundant relative to krypton (the so-called "missing xenon" problem). Together these observations imply that xenon has been subject to fractionating escape and krypton not.

  18. Scrunching: a novel escape gait in planarians.

    PubMed

    Cochet-Escartin, Olivier; Mickolajczyk, Keith J; Collins, Eva-Maria S

    2015-09-10

    The ability to escape a predator or other life-threatening situations is central to animal survival. Different species have evolved unique strategies under anatomical and environmental constraints. In this study, we describe a novel musculature-driven escape gait in planarians, 'scrunching', which is quantitatively different from other planarian gaits, such as gliding and peristalsis. We show that scrunching is a conserved gait among different flatworm species, underlying its importance as an escape mechanism. We further demonstrate that it can be induced by a variety of physical stimuli, including amputation, high temperature, electric shock and low pH. We discuss the functional basis for scrunching as the preferential gait when gliding is impaired due to a disruption of mucus production. Finally, we show that the key mechanical features of scrunching are adequately captured by a simple biomechanical model that is solely based on experimental data from traction force microscopy and tissue rheology without fit parameters. Together, our results form a complete description of this novel form of planarian locomotion. Because scrunching has distinct dynamics, this gait can serve as a robust behavioral readout for studies of motor neuron and muscular functions in planarians and in particular the restoration of these functions during regeneration.

  19. Scrunching: a novel escape gait in planarians

    NASA Astrophysics Data System (ADS)

    Cochet-Escartin, Olivier; Mickolajczyk, Keith J.; Collins, Eva-Maria S.

    2015-10-01

    The ability to escape a predator or other life-threatening situations is central to animal survival. Different species have evolved unique strategies under anatomical and environmental constraints. In this study, we describe a novel musculature-driven escape gait in planarians, ‘scrunching’, which is quantitatively different from other planarian gaits, such as gliding and peristalsis. We show that scrunching is a conserved gait among different flatworm species, underlying its importance as an escape mechanism. We further demonstrate that it can be induced by a variety of physical stimuli, including amputation, high temperature, electric shock and low pH. We discuss the functional basis for scrunching as the preferential gait when gliding is impaired due to a disruption of mucus production. Finally, we show that the key mechanical features of scrunching are adequately captured by a simple biomechanical model that is solely based on experimental data from traction force microscopy and tissue rheology without fit parameters. Together, our results form a complete description of this novel form of planarian locomotion. Because scrunching has distinct dynamics, this gait can serve as a robust behavioral readout for studies of motor neuron and muscular functions in planarians and in particular the restoration of these functions during regeneration.

  20. Escape behavior and escape circuit activation in juvenile crayfish during prey-predator interactions.

    PubMed

    Herberholz, Jens; Sen, Marjorie M; Edwards, Donald H

    2004-05-01

    The neural systems that control escape behavior have been studied intensively in several animals, including mollusks, fish and crayfish. Surprisingly little is known, however, about the activation and the utilization of escape circuits during prey-predator interactions. To complement the physiological and anatomical studies with a necessary behavioral equivalent, we investigated encounters between juvenile crayfish and large dragonfly nymphs in freely behaving animals using a combination of high-speed video-recordings and measurements of electric field potentials. During attacks, dragonfly nymphs rapidly extended their labium, equipped with short, sharp palps, to capture small crayfish. Crayfish responded to the tactile stimulus by activating neural escape circuits to generate tail-flips directed away from the predator. Tail-flips were the sole defense mechanism in response to an attack and every single strike was answered by tail-flip escape behavior. Crayfish used all three known types of escape tail-flips during the interactions with the dragonfly nymphs. Tail-flips generated by activity in the giant neurons were predominantly observed to trigger the initial escape responses to an attack, but non-giant mediated tail-flips were often generated to attempt escape after capture. Attacks to the front of the crayfish triggered tail-flips mediated either by the medial giant neuron or by non-giant circuitry, whereas attacks to the rear always elicited tail-flips mediated by the lateral giant neuron. Overall, tail flipping was found to be a successful behavior in preventing predation, and only a small percentage of crayfish were killed and consumed.

  1. Risks incurred by hydrogen escaping from containers and conduits

    SciTech Connect

    Swain, M.R.; Grilliot, E.S.; Swain, M.N.

    1998-08-01

    This paper is a discussion of a method for hydrogen leak classification. Leaks are classified as; gas escapes into enclosed spaces, gas escapes into partially enclosed spaces (vented), and gas escapes into unenclosed spaces. Each of the three enclosure classifications is further divided into two subclasses; total volume of hydrogen escaped and flow rate of escaping hydrogen. A method to aid in risk assessment determination in partially enclosed spaces is proposed and verified for several enclosure geometries. Examples are discussed for additional enclosure geometries.

  2. The Fusion Energy Option

    NASA Astrophysics Data System (ADS)

    Dean, Stephen O.

    2004-06-01

    Presentations from a Fusion Power Associates symposium, The Fusion Energy Option, are summarized. The topics include perspectives on fossil fuel reserves, fusion as a source for hydrogen production, status and plans for the development of inertial fusion, planning for the construction of the International Thermonuclear Experimental Reactor, status and promise of alternate approaches to fusion and the need for R&D now on fusion technologies.

  3. Revitalizing Fusion via Fission Fusion

    NASA Astrophysics Data System (ADS)

    Manheimer, Wallace

    2001-10-01

    Existing tokamaks could generate significant nuclear fuel. TFTR, operating steady state with DT might generate enough fuel for a 300 MW nuclear reactor. The immediate goals of the magnetic fusion program would necessarily shift from a study of advanced plasma regimes in larger sized devices, to mostly known plasmas regimes, but at steady state or high duty cycle operation in DT plasmas. The science and engineering of breeding blankets would be equally important. Follow on projects could possibly produce nuclear fuel in large quantity at low price. Although today there is strong opposition to nuclear power in the United States, in a 21st century world of 10 billion people, all of whom will demand a middle class life style, nuclear energy will be important. Concern over greenhouse gases will also drive the world toward nuclear power. There are studies indicating that the world will need 10 TW of carbon free energy by 2050. It is difficult to see how this can be achieved without the breeding of nuclear fuel. By using the thorium cycle, proliferation risks are minimized. [1], [2]. 1 W. Manheimer, Fusion Technology, 36, 1, 1999, 2.W. Manheimer, Physics and Society, v 29, #3, p5, July, 2000

  4. Heating and acceleration of escaping planetary ions

    NASA Astrophysics Data System (ADS)

    Nilsson, Hans

    2010-05-01

    The magnetic field of the Earth acts like a shield against the solar wind, leading to a magnetopause position many planetary radii away from the planet, in contrast to the situation at non- or weakly magnetized planets such as Mars and Venus. Despite this there is significant ion outflow due to solar wind interaction from the cusp and polar cap regions of the Earth's ionosphere. Effective interaction regions form, in particular in the ionospheric projection of the cusp, where ionospheric plasma flows up along the field-lines in response to magnetospheric energy input. Strong wave-particle interaction at altitudes above the ionosphere further accelerates the particles so that gravity is overcome. For the particles to enter a direct escape path they must be accelerated along open magnetic field lines so that they cross the magnetopause or reach a distance beyond the region of return flow in the tail. This return flow may also be either lost to space or returned to the atmosphere. Throughout this transport chain the heating and acceleration experienced by the particles will have an influence on the final fate of the particles. We will present quantitative estimates of centrifugal acceleration and perpendicular heating along the escape path from the cusp, through the high altitude polar cap/mantle, based on Cluster spacecraft data. We will open up for a discussion on the benefits of a ponderomotive force description of the acceleration affecting the ion circulation and escape. Finally we will compare with the situation at the unmagnetized planets Mars and Venus and discuss to what extent a magnetic field protects an atmosphere from loss through solar wind interaction.

  5. Motor neurons in the escape response circuit of white shrimp (Litopenaeus setiferus)

    PubMed Central

    2015-01-01

    Many decapod crustaceans perform escape tailflips with a neural circuit involving giant interneurons, a specialized fast flexor motor giant (MoG) neuron, populations of larger, less specialized fast flexor motor neurons, and fast extensor motor neurons. These escape-related neurons are well described in crayfish (Reptantia), but not in more basal decapod groups. To clarify the evolution of the escape circuit, I examined the fast flexor and fast extensor motor neurons of white shrimp (Litopenaeus setiferus; Dendrobranchiata) using backfilling. In crayfish, the MoGs in each abdominal ganglion are a bilateral pair of separate neurons. In L. setiferus, the MoGs have massive, possibly syncytial, cell bodies and fused axons. The non-MoG fast flexor motor neurons and fast extensor motor neurons are generally found in similar locations to where they are found in crayfish, but the number of motor neurons in both the flexor and extensor pools is smaller than in crayfish. The loss of fusion in the MoGs and increased number of fast motor neurons in reptantian decapods may be correlated with an increased reliance on non-giant mediated tailflipping. PMID:26244117

  6. Suicide as escape from psychotic panic.

    PubMed

    Goldblatt, Mark J; Ronningstam, Elsa; Schechter, Mark; Herbstman, Benjamin; Maltsberger, John T

    2016-01-01

    Suicides of patients in states of acute persecutory panic may be provoked by a subjective experience of helpless terror threatening imminent annihilation or dismemberment. These patients are literally scared to death and try to run away. They imagine suicide is survivable and desperately attempt to escape from imaginary enemies. These states of terror occur in a wide range of psychotic illnesses and are often associated with command hallucinations and delusions. In this article, the authors consider the subjective experience of persecutory panic and the suicide response as an attempt to flee from danger.

  7. Evolutionary escape from the prisoner's dilemma.

    PubMed

    Worden, Lee; Levin, Simon A

    2007-04-07

    The classic prisoner's dilemma model of game theory is modified by introducing occasional variations on the options available to players. Mutation and selection of game options reliably change the game matrix, gradually, from a prisoner's dilemma game into a byproduct mutualism one, in which cooperation is stable, and "temptation to defect" is replaced by temptation to cooperate. This result suggests that when there are many different potential ways of interacting, exploring those possibilities may make escape from prisoner's dilemmas a common outcome in the world. A consequence is that persistent prisoner's dilemma structures may be less common than one might otherwise expect.

  8. Modeling Fluorescence Escape from Tissue Phantoms

    NASA Astrophysics Data System (ADS)

    Gardner, Craig Morris

    1995-01-01

    This dissertation represents a contribution to the field of quantitative fluorescence spectroscopy of biological tissue. The absorption and scattering properties of a turbid medium affect the propagation of fluorescence to the medium surface. Optical properties also affect the amount of light reaching a detector placed to monitor fluorescence non-invasively. These facts have in part limited fluorescence spectroscopy of turbid media to a qualitative science. To study the general characteristics of turbid medium fluorescence, a Monte Carlo algorithm of fluorescence light propagation was developed. Modifications to the general algorithm were made to study several specific light distribution quantities associated with optical fiber fluorescent measurement devices. The Monte Carlo-based studies were also used to develop simple, accurate expressions describing the one -dimensional distribution of excitation light within a turbid medium and the escape of fluorescence from the medium. The expressions have accuracy comparable to solutions of the radiative transport equation. The two expressions were combined to derive a simple expression relating the fluorescence power escaping a turbid medium due to surface excitation, to the medium intrinsic fluorescence coefficient, as a function of the medium optical properties. Based on this expression and a description of the fluorescence escape power intercepted by a distant detector, a method was developed to recover the intrinsic fluorescence coefficient from surface measurements of fluorescence and optical properties. Experiments with water-based, turbid media verified the recovery method. The method used to recover the intrinsic fluorescence coefficient was modified for use with a clinical measurement geometry, specifically a small diameter optical fiber probe. Modification required a calibration method to estimate two optical property variables from two unique surface measurements of diffuse reflectance made with the optical

  9. 3D Fokker-Planck modeling of axisymmetric collisional losses of fusion products in TFTR

    SciTech Connect

    Goloborod`ko, V.Ya.; Reznik, S.N.; Yavorskij, V.A.; Zweben, S.J.

    1995-10-01

    Results of a 3D (in constants of motion space) Fokker-Planck simulation of collisional losses of fusion products in axisymmetric DT and DD discharges on TFTR are presented. The distributions of escaped ions over poloidal angle, pitch angle, and their energy spectra are obtained. Axisymmetric collisional losses of fusion products are found to be less than (2--5)%. The distribution of confined fusion products is shown to be strongly anisotropic and nonuniform in the radial coordinate mainly for slowed-down fusion products with small longitudinal energy. Comparison of these results of modeling and experimental data is done.

  10. Nosema Tolerant Honeybees (Apis mellifera) Escape Parasitic Manipulation of Apoptosis.

    PubMed

    Kurze, Christoph; Le Conte, Yves; Dussaubat, Claudia; Erler, Silvio; Kryger, Per; Lewkowski, Oleg; Müller, Thomas; Widder, Miriam; Moritz, Robin F A

    2015-01-01

    Apoptosis is not only pivotal for development, but also for pathogen defence in multicellular organisms. Although numerous intracellular pathogens are known to interfere with the host's apoptotic machinery to overcome this defence, its importance for host-parasite coevolution has been neglected. We conducted three inoculation experiments to investigate in the apoptotic respond during infection with the intracellular gut pathogen Nosema ceranae, which is considered as potential global threat to the honeybee (Apis mellifera) and other bee pollinators, in sensitive and tolerant honeybees. To explore apoptotic processes in the gut epithelium, we visualised apoptotic cells using TUNEL assays and measured the relative expression levels of subset of candidate genes involved in the apoptotic machinery using qPCR. Our results suggest that N. ceranae reduces apoptosis in sensitive honeybees by enhancing inhibitor of apoptosis protein-(iap)-2 gene transcription. Interestingly, this seems not be the case in Nosema tolerant honeybees. We propose that these tolerant honeybees are able to escape the manipulation of apoptosis by N. ceranae, which may have evolved a mechanism to regulate an anti-apoptotic gene as key adaptation for improved host invasion.

  11. Nosema Tolerant Honeybees (Apis mellifera) Escape Parasitic Manipulation of Apoptosis

    PubMed Central

    Kurze, Christoph; Le Conte, Yves; Dussaubat, Claudia; Erler, Silvio; Kryger, Per; Lewkowski, Oleg; Müller, Thomas; Widder, Miriam; Moritz, Robin F. A.

    2015-01-01

    Apoptosis is not only pivotal for development, but also for pathogen defence in multicellular organisms. Although numerous intracellular pathogens are known to interfere with the host’s apoptotic machinery to overcome this defence, its importance for host-parasite coevolution has been neglected. We conducted three inoculation experiments to investigate in the apoptotic respond during infection with the intracellular gut pathogen Nosema ceranae, which is considered as potential global threat to the honeybee (Apis mellifera) and other bee pollinators, in sensitive and tolerant honeybees. To explore apoptotic processes in the gut epithelium, we visualised apoptotic cells using TUNEL assays and measured the relative expression levels of subset of candidate genes involved in the apoptotic machinery using qPCR. Our results suggest that N. ceranae reduces apoptosis in sensitive honeybees by enhancing inhibitor of apoptosis protein-(iap)-2 gene transcription. Interestingly, this seems not be the case in Nosema tolerant honeybees. We propose that these tolerant honeybees are able to escape the manipulation of apoptosis by N. ceranae, which may have evolved a mechanism to regulate an anti-apoptotic gene as key adaptation for improved host invasion. PMID:26445372

  12. The effects of steady swimming on fish escape performance.

    PubMed

    Anwar, Sanam B; Cathcart, Kelsey; Darakananda, Karin; Gaing, Ashley N; Shin, Seo Yim; Vronay, Xena; Wright, Dania N; Ellerby, David J

    2016-06-01

    Escape maneuvers are essential to the survival and fitness of many animals. Escapes are frequently initiated when an animal is already in motion. This may introduce constraints that alter the escape performance. In fish, escape maneuvers and steady, body caudal fin (BCF) swimming are driven by distinct patterns of curvature of the body axis. Pre-existing muscle activity may therefore delay or diminish a response. To quantify the performance consequences of escaping in flow, escape behavior was examined in bluegill sunfish (Lepomis macrochirus) in both still-water and during steady swimming. Escapes executed during swimming were kinematically less variable than those made in still-water. Swimming escapes also had increased response latencies and lower peak velocities and accelerations than those made in still-water. Performance was also lower for escapes made up rather than down-stream, and a preference for down-stream escapes may be associated with maximizing performance. The constraints imposed by pre-existing motion and flow, therefore, have the potential to shape predator-prey interactions under field conditions by shifting the optimal strategies for both predators and prey.

  13. Structured Observations Reveal Slow HIV-1 CTL Escape

    PubMed Central

    Roberts, Hannah E.; Hurst, Jacob; Robinson, Nicola; Brown, Helen; Flanagan, Peter; Vass, Laura; Fidler, Sarah; Weber, Jonathan; Babiker, Abdel; Phillips, Rodney E.; McLean, Angela R.; Frater, John

    2015-01-01

    The existence of viral variants that escape from the selection pressures imposed by cytotoxic T-lymphocytes (CTLs) in HIV-1 infection is well documented, but it is unclear when they arise, with reported measures of the time to escape in individuals ranging from days to years. A study of participants enrolled in the SPARTAC (Short Pulse Anti-Retroviral Therapy at HIV Seroconversion) clinical trial allowed direct observation of the evolution of CTL escape variants in 125 adults with primary HIV-1 infection observed for up to three years. Patient HLA-type, longitudinal CD8+ T-cell responses measured by IFN-γ ELISpot and longitudinal HIV-1 gag, pol, and nef sequence data were used to study the timing and prevalence of CTL escape in the participants whilst untreated. Results showed that sequence variation within CTL epitopes at the first time point (within six months of the estimated date of seroconversion) was consistent with most mutations being transmitted in the infecting viral strain rather than with escape arising within the first few weeks of infection. Escape arose throughout the first three years of infection, but slowly and steadily. Approximately one third of patients did not drive any new escape in an HLA-restricted epitope in just under two years. Patients driving several escape mutations during these two years were rare and the median and modal numbers of new escape events in each patient were one and zero respectively. Survival analysis of time to escape found that possession of a protective HLA type significantly reduced time to first escape in a patient (p = 0.01), and epitopes escaped faster in the face of a measurable CD8+ ELISpot response (p = 0.001). However, even in an HLA matched host who mounted a measurable, specific, CD8+ response the average time before the targeted epitope evolved an escape mutation was longer than two years. PMID:25642847

  14. The escape problem for mortal walkers

    NASA Astrophysics Data System (ADS)

    Grebenkov, D. S.; Rupprecht, J.-F.

    2017-02-01

    We introduce and investigate the escape problem for random walkers that may eventually die, decay, bleach, or lose activity during their diffusion towards an escape or reactive region on the boundary of a confining domain. In the case of a first-order kinetics (i.e., exponentially distributed lifetimes), we study the effect of the associated death rate onto the survival probability, the exit probability, and the mean first passage time. We derive the upper and lower bounds and some approximations for these quantities. We reveal three asymptotic regimes of small, intermediate, and large death rates. General estimates and asymptotics are compared to several explicit solutions for simple domains and to numerical simulations. These results allow one to account for stochastic photobleaching of fluorescent tracers in bio-imaging, degradation of mRNA molecules in genetic translation mechanisms, or high mortality rates of spermatozoa in the fertilization process. Our findings provide a mathematical ground for optimizing storage containers and materials to reduce the risk of leakage of dangerous chemicals or nuclear wastes.

  15. F111 Crew Escape Module pilot parachute

    SciTech Connect

    Tadios, E.L.

    1991-01-01

    A successfully deployment of a parachute system highly depends on the efficiency of the deployment device and/or method. There are several existing methods and devices that may be considered for a deployment system. For the F111 Crew Escape Module (CEM), the recovery parachute system deployment is initiated by the firing of a catapult that ejects the complete system from the CEM. At first motion of the pack, a drogue gun is fired, which deploys the pilot parachute system. The pilot parachute system then deploys the main parachute system, which consists of a cluster of three 49-ft diameter parachutes. The pilot parachute system which extracts the F111 Crew Escape Module recovery parachute system must provide reasonable bag strip velocities throughout the flight envelope (10 psf to 300 psf). The pilot parachute system must, therefore, have sufficient drag area at the lower dynamic pressures and a reduced drag area at the high end of the flight envelope. The final design that was developed was a dual parachute system which consists of a 5-ft diameter guide surface parachute tethered inside a 10-ft diameter flat circular parachute. The high drag area is sustained at the low dynamic pressures by keeping both parachutes intact. The drag area is reduced at the higher extreme by allowing the 10-ft parachute attachment to fail. The discussions to follow describe in detail how the system was developed. 4 refs., 10 figs., 2 tabs.

  16. Orbital Effects on Mercury's Escaping Sodium Exosphere

    NASA Technical Reports Server (NTRS)

    Schmidt, Carl A.; Wilson, Jody K.; Baumgardner, Jeffrey; Mendillo, Michael

    2009-01-01

    We present results from coronagraphic imaging of Mercury's sodium tail over a 7 deg field of view. Several sets of observations made at the McDonald Observatory since May 2007 show a tail of neutral sodium atoms stretching more than 1000 Mercury radii (R(sub m)) in length, or a full degree of sky. However, no tail was observed extending beyond 120 R(sub m) during the January 2008 MESSENGER Fly-by period, or during a similar orbital phase of Mercury in July 2008. Large changes in Mercury's heliocentric radial velocity cause Doppler shifts about the Fraunhofer absorption features; the resultant change in solar flux and radiation pressure is the primary cause of the observed variation in tail brightness. Smaller fluctuations in brightness may exist due to changing source rates at the surface, but we have no explicit evidence for such changes in this data set. The effects of radiation pressure on Mercury's escaping atmosphere are investigated using seven observations spanning different orbital phases. Total escape rates of atmospheric sodium are estimated to be between 5 and 13 x 10(exp 23) atoms/s and show a correlation to radiation pressure. Candidate sources of Mercury's sodium exosphere include desorption by UV sunlight, thermal desorption, solar wind channeled along Mercury's magnetic field lines, and micro-meteor impacts. Wide-angle observations of the full extent of Mercury's sodium tail offer opportunities to enhance our understanding of the time histories of these source rates.

  17. Escape mechanisms of dust in Io

    NASA Astrophysics Data System (ADS)

    Flandes, A.

    The injection of material into the jovian magnetosphere through Io's volcanic activity makes possible the formation of structures such as the plasma torus and the dust ballerina skirt. Io's high temperature volcanism produces spectacular plumes, but even the tallest plumes, as those of Pelen Patera, will not produce enough energy to defeat the gravitational attraction of Io. The fact is that dust escapes from Io, which implies that a second mechanism is acting on the grains. Grains brought to the top of the highest plumes by the volcanic forces are still under Io's gravitational pull, but need only a minimum charge (~10-1 4 C) so that the Lorentz force due to the Jovian magnetic field equilibrates this attraction. In the volcanic vents, the escape velocity of the ejected material and its own density produces enough collisions to create charges. On top of the highest plumes (~500km) charged grains are exposed to the plasma torus that co-rotates rigidly with Jupiter and, due to the relative velocity among Io and the torus, the grains will be dragged away from Io. As it is well known, these dust grains will also be dragged away from Jupiter.

  18. A New Maneuver for Escape Trajectories

    NASA Technical Reports Server (NTRS)

    Adams, Robert B.

    2008-01-01

    This presentation put forth a new maneuver for escape trajectories and specifically sought to find an analytical approximation for medium thrust trajectories. In most low thrust derivations the idea is that escape velocity is best achieved by accelerating along the velocity vector. The reason for this is that change in specific orbital energy is a function of velocity and acceleration. However, Levin (1952) suggested that while this is a locally optimal solution it might not be a globally optimal one. Turning acceleration inward would drop periapse giving a higher velocity later in the trajectory. Acceleration at that point would be dotted against a higher magnitude V giving a greater rate of change of mechanical energy. The author then hypothesized that decelerating from the initial orbit and then accelerating at periapse would not lead to a gain in greater specific orbital energy--however, the hypothesis was incorrect. After considerable derivation it was determined that this new maneuver outperforms a direct burn when the overall DeltaV budget exceeds the initial orbital velocity (the author has termed this the Heinlein maneuver). The author provides a physical explanation for this maneuver and presents optimization analyses.

  19. Escape of water molecular from Carbon Nanotubes

    NASA Astrophysics Data System (ADS)

    Li, Jiaxi; Li, Wenfeng; Zhang, Jianwei

    2014-03-01

    Understanding and controlling the transport of water molecules through nanopores have attracted great interest due to potential applications for designing novel nanofluidic devices, machines and sensors. In this work, we theoretically investigate the effects of an external nonuniform electric field on the escape of water molecules through single-walled carbon nanotubes (SWNTs) by using of molecular dynamics (MD) simulations. When polar water molecules are placed in the gradient electric field, the electric force is experienced that can drive the water molecules. Molecular dynamics simulations show that the escape probability of water obeys the Boltzmann distribution. Our results show that energy barrier delta E is independent of temperature which indicates that it is a single-barrier system. From the MD results statistics, the key parameters could be determined such that the relationship between energy barrier delta E and diameter of SWNTs and nozzle distance of the charge r would be revealed that could deepen our current theoretical understanding on transport of water molecular inside SWNTs with the nonuniform electric field.

  20. Effects of escape to alone versus escape to enriched environments on adaptive and aberrant behavior.

    PubMed Central

    Golonka, Z; Wacker, D; Berg, W; Derby, K M; Harding, J; Peck, S

    2000-01-01

    Escape-maintained aberrant behavior may be influenced by two outcomes: (a) a break from the activity and (b) subsequent access to preferred activities. To assess this hypothesis, a treatment was developed that analyzed response allocation across two break options: break alone and break with access to preferred social activities. The break with preferred activities decreased aberrant behavior and increased appropriate behavior. PMID:10885532

  1. Some Possible Cases of Escape Mimicry in Neotropical Butterflies.

    PubMed

    Pinheiro, C E G; Freitas, A V L

    2014-10-01

    The possibility that escape or evasive mimicry evolved in butterflies and other prey insects in a similar fashion to classical Batesian and Müllerian mimicry has long been advanced in the literature. However, there is a general disagreement among lepidopterists and evolutionary biologists on whether or not escape mimicry exists, as well as in which mimicry rings this form of mimicry has evolved. Here, we review some purported cases of escape mimicry in Neotropical butterflies and suggest new mimicry rings involving several species of Archaeoprepona, Prepona, and Doxocopa (the "bright blue bands" ring) and species of Colobura and Hypna (the "creamy bands" ring) where the palatability of butterflies, their ability to escape predator attacks, geographic distribution, relative abundance, and co-occurrence in the same habitats strongly suggest that escape mimicry is involved. In addition, we also indicate other butterfly taxa whose similarities of coloration patterns could be due to escape mimicry and would constitute important case studies for future investigation.

  2. Strong purifying selection at genes escaping X chromosome inactivation.

    PubMed

    Park, Chungoo; Carrel, Laura; Makova, Kateryna D

    2010-11-01

    To achieve dosage balance of X-linked genes between mammalian males and females, one female X chromosome becomes inactivated. However, approximately 15% of genes on this inactivated chromosome escape X chromosome inactivation (XCI). Here, using a chromosome-wide analysis of primate X-linked orthologs, we test a hypothesis that such genes evolve under a unique selective pressure. We find that escape genes are subject to stronger purifying selection than inactivated genes and that positive selection does not significantly affect the evolution of these genes. The strength of selection does not differ between escape genes with similar versus different expression levels in males versus females. Intriguingly, escape genes possessing Y homologs evolve under the strongest purifying selection. We also found evidence of stronger conservation in gene expression levels in escape than inactivated genes. We hypothesize that divergence in function and expression between X and Y gametologs is driving such strong purifying selection for escape genes.

  3. Direct energy conversion system for D(3)-He fusion

    NASA Astrophysics Data System (ADS)

    Tomita, Y.; Shu, L. Y.; Momota, H.

    1993-11-01

    A novel and highly efficient direct energy conversion system is proposed for utilizing D(3)-He fueled fusion. In order to convert kinetic energy of ions, we applied a pair of direct energy conversion systems each of which has a cusp-type DEC and a traveling wave DEC (TWDEC). In a cusp-type DEC, electrons are separated from the escaping ions at the first line-cusp and the energy of thermal ion components is converted at the second cusp DEC. The fusion protons go through the cusp-type DEC and arrive at the TWDEC, which principle is similar to 'LINAC'. The energy of fusion protons is recovered to electricity with an efficiency of more than 70%. These DEC's bring about the high efficient fusion plant.

  4. Fusion energy

    NASA Astrophysics Data System (ADS)

    1990-09-01

    The main purpose of the International Thermonuclear Experimental Reactor (ITER) is to develop an experimental fusion reactor through the united efforts of many technologically advanced countries. The ITER terms of reference, issued jointly by the European Community, Japan, the USSR, and the United States, call for an integrated international design activity and constitute the basis of current activities. Joint work on ITER is carried out under the auspices of the International Atomic Energy Agency (IAEA), according to the terms of quadripartite agreement reached between the European Community, Japan, the USSR, and the United States. The site for joint technical work sessions is at the Max Planck Institute of Plasma Physics. Garching, Federal Republic of Germany. The ITER activities have two phases: a definition phase performed in 1988 and the present design phase (1989 to 1990). During the definition phase, a set of ITER technical characteristics and supporting research and development (R and D) activities were developed and reported. The present conceptual design phase of ITER lasts until the end of 1990. The objectives of this phase are to develop the design of ITER, perform a safety and environmental analysis, develop site requirements, define future R and D needs, and estimate cost, manpower, and schedule for construction and operation. A final report will be submitted at the end of 1990. This paper summarizes progress in the ITER program during the 1989 design phase.

  5. Fusion energy

    SciTech Connect

    Not Available

    1990-09-01

    The main purpose of the International Thermonuclear Experimental Reactor (ITER) is to develop an experimental fusion reactor through the united efforts of many technologically advanced countries. The ITER terms of reference, issued jointly by the European Community, Japan, the USSR, and the United States, call for an integrated international design activity and constitute the basis of current activities. Joint work on ITER is carried out under the auspices of the International Atomic Energy Agency (IAEA), according to the terms of quadripartite agreement reached between the European Community, Japan, the USSR, and the United States. The site for joint technical work sessions is at the MaxPlanck Institute of Plasma Physics. Garching, Federal Republic of Germany. The ITER activities have two phases: a definition phase performed in 1988 and the present design phase (1989--1990). During the definition phase, a set of ITER technical characteristics and supporting research and development (R D) activities were developed and reported. The present conceptual design phase of ITER lasts until the end of 1990. The objectives of this phase are to develop the design of ITER, perform a safety and environmental analysis, develop site requirements, define future R D needs, and estimate cost, manpower, and schedule for construction and operation. A final report will be submitted at the end of 1990. This paper summarizes progress in the ITER program during the 1989 design phase.

  6. The atmospheric escape at Mars: complementing the scenario

    NASA Astrophysics Data System (ADS)

    Lilensten, Jean; Simon, Cyril; Barthélémy, Mathieu; Thissen, Roland; Ehrenreich, David; Gronoff, Guillaume; Witasse, Olivier

    2013-04-01

    In the recent years, the presence of dications in the atmospheres of Mars, Venus, Earth and Titan has been modeled and assessed. These studies also suggested that these ions could participate to the escape of the planetary atmospheres because a large fraction of them is unstable and highly ener- getic. When they dissociate, their internal energy is transformed into kinetic energy which may be larger than the escape energy. This study assesses the impact of the doubly-charged ions in the escape of CO2-dominated planetary atmospheres and to compare it to the escape of thermal photo-ions.We solve a Boltzmann transport equation at daytime taking into account the dissociative states of CO++ for a simplified single constituent atmosphere of a 2 case-study planet. We compute the escape of fast ions using a Beer-Lambert approach. We study three test-cases. On a Mars-analog planet in today's conditions, we retrieve the measured electron escape flux. When comparing the two mechanisms (i.e. excluding solar wind effects, sputtering ...), the escape due to the fast ions issuing from the dissociation of dications may account for up to 6% of the total and the escape of thermal ions for the remaining. We show that these two mechanisms cannot explain the escape of the atmosphere since the magnetic field vanished but complement the other processes and allow writing the scenario of the Mars escape. We show that the atmosphere of a Mars analog planet would empty in another giga years and a half. At Venus orbit, the contribution of the dications in the escape rate is negligible.When simulating the hot Jupiter HD209458b, the two processes cannot explain the measured escape flux of C+.

  7. Feedback regulated escape of ionising radiation from high redshift galaxies

    NASA Astrophysics Data System (ADS)

    Trebitsch, M.; Blaizot, J.

    2016-12-01

    Small galaxies are thought to provide the bulk of the radiation necessary to reionise the Universe by z ˜ 6. Their ionising efficiency is usually quantified by their escape fraction f_{esc}, but it is extremely hard to constrain from observations. With the goal of studying the physical processes that determine the values of the escape fraction, we have run a series of high resolution, cosmological, radiative hydrodynamics simulations centred on three galaxies. We find that the variability of the escape fraction follows that of the star formation rate, and that local feedback is necessary for radiation to escape.

  8. Managing Pacific salmon escapements: The gaps between theory and reality

    USGS Publications Warehouse

    Knudsen, E. Eric; Knudsen, E. Eric; Steward, Cleveland R.; MacDonald, Donald D.; Williams, Jack E.; Reiser, Dudley W.

    1999-01-01

    There are myriad challenges to estimating intrinsic production capacity for Pacific salmon populations that are heavily exploited and/or suffering from habitat alteration. Likewise, it is difficult to determine whether perceived decreases in production are due to harvest, habitat, or hatchery influences, natural variation, or some combination of all four. There are dramatic gaps between the true nature of the salmon spawner/recruit relationship and the theoretical basis for describing and understanding the relationship. Importantly, there are also extensive practical difficulties associated with gathering and interpreting accurate escapement and run-size information and applying it to population management. Paradoxically, certain aspects of salmon management may well be contributing to losses in abundance and biodiversity, including harvesting salmon in mixed population fisheries, grouping populations into management units subject to a common harvest rate, and fully exploiting all available hatchery fish at the expense of wild fish escapements. Information on U.S. Pacific salmon escapement goal-setting methods, escapement data collection methods and estimation types, and the degree to which stocks are subjected to mixed stock fisheries was summarized and categorized for 1,025 known management units consisting of 9,430 known populations. Using criteria developed in this study, only 1% of U.S. escapement goals are by methods rated as excellent. Escapement goals for 16% of management units were rated as good. Over 60% of escapement goals have been set by methods rated as either fair or poor and 22% of management units have no escapement goals at all. Of the 9,430 populations for which any information was available, 6,614 (70%) had sufficient information to categorize the method by which escapement data are collected. Of those, data collection methods were rated as excellent for 1%, good for 1%, fair for 2%, and poor for 52%. Escapement estimates are not made for 44

  9. Fusion-product transport in axisymmetric tokamaks: losses and thermalization

    SciTech Connect

    Hively, L.M.

    1980-01-01

    High-energy fusion-product losses from an axisymmetric tokamak plasma are studied. Prompt-escape loss fluxes (i.e. prior to slowing down) are calculated including the non-separable dependence of flux as a function of poloidal angle and local angle-of-incidence at the first wall. Fusion-product (fp) thermalization and heating are calculated assuming classical slowing down. The present analytical model describes fast ion orbits and their distribution function in realistic, high-..beta.., non-circular tokamak equilibria. First-orbit losses, trapping effects, and slowing-down drifts are also treated.

  10. Simulating dynamical features of escape panic

    NASA Astrophysics Data System (ADS)

    Helbing, Dirk; Farkas, Illés; Vicsek, Tamás

    2000-09-01

    One of the most disastrous forms of collective human behaviour is the kind of crowd stampede induced by panic, often leading to fatalities as people are crushed or trampled. Sometimes this behaviour is triggered in life-threatening situations such as fires in crowded buildings; at other times, stampedes can arise during the rush for seats or seemingly without cause. Although engineers are finding ways to alleviate the scale of such disasters, their frequency seems to be increasing with the number and size of mass events. But systematic studies of panic behaviour and quantitative theories capable of predicting such crowd dynamics are rare. Here we use a model of pedestrian behaviour to investigate the mechanisms of (and preconditions for) panic and jamming by uncoordinated motion in crowds. Our simulations suggest practical ways to prevent dangerous crowd pressures. Moreover, we find an optimal strategy for escape from a smoke-filled room, involving a mixture of individualistic behaviour and collective `herding' instinct.

  11. Energy Release, Acceleration, and Escape of Solar Energetic Ions

    NASA Astrophysics Data System (ADS)

    de Nolfo, G. A.; Ireland, J.; Ryan, J. M.; Young, C. A.

    2013-12-01

    Solar flares are prodigious producers of energetic particles, and thus a rich laboratory for studying particle acceleration. The acceleration occurs through the release of magnetic energy, a significant fraction of which can go into the acceleration of particles. Coronal mass ejections (CMEs) certainly produce shocks that both accelerate particles and provide a mechanism for escape into the interplanetary medium (IP). What is less well understood is whether accelerated particles produced from the flare reconnection process escape, and if so, how these same particles are related to solar energetic particles (SEPs) detected in-situ. Energetic electron SEPs have been shown to be correlated with Type III radio bursts, hard X-ray emission, and EUV jets, making a very strong case for the connection between acceleration at the flare and escape along open magnetic field lines. Because there has not been a clear signature of ion escape, as is the case with the Type III radio emission for electrons, sorting out the avenues of escape for accelerated flare ions and the possible origin of the impulsive SEPs continues to be a major challenge. The key to building a clear picture of particle escape relies on the ability to map signatures of escape such as EUV jets at the Sun and to follow the progression of these escape signatures as they evolve in time. Furthermore, nuclear γ-ray emissions provide critical context relating ion acceleration to that of escape. With the advent observations from Fermi as well as RHESSI and the Solar Dynamics Observatory (SDO), the challenge of ion escape from the Sun can now be addressed. We present a preliminary study of the relationship of EUV jets with nuclear γ-ray emission and Type III radio observations and discuss the implications for possible magnetic topologies that allow for ion escape from deep inside the corona to the interplanetary medium.

  12. Distinct effects of endosomal escape and inhibition of endosomal trafficking on gene delivery via electrotransfection.

    PubMed

    Cervia, Lisa D; Chang, Chun-Chi; Wang, Liangli; Yuan, Fan

    2017-01-01

    A recent theory suggests that endocytosis is involved in uptake and intracellular transport of electrotransfected plasmid DNA (pDNA). The goal of the current study was to understand if approaches used previously to improve endocytosis of gene delivery vectors could be applied to enhancing electrotransfection efficiency (eTE). Results from the study showed that photochemically induced endosomal escape, which could increase poly-L-lysine (PLL)-mediated gene delivery, decreased eTE. The decrease could not be blocked by treatment of cells with endonuclease inhibitors (aurintricarboxylic acid and zinc ion) or antioxidants (L-glutamine and ascorbic acid). Chemical treatment of cells with an endosomal trafficking inhibitor that blocks endosome progression, bafilomycin A1, resulted in a significant decrease in eTE. However, treatment of cells with lysosomotropic agents (chloroquine and ammonium chloride) had little effects on eTE. These data suggested that endosomes played important roles in protecting and intracellular trafficking of electrotransfected pDNA.

  13. Review of fusion synfuels

    SciTech Connect

    Fillo, J.A.

    1980-01-01

    Thermonuclear fusion offers an inexhaustible source of energy for the production of hydrogen from water. Depending on design, electric generation efficiencies of approx. 40 to 60% and hydrogen production efficiencies by high-temperature electrolysis of approx. 50 to 65% are projected for fusion reactors using high-temperatures blankets. Fusion/coal symbiotic systems appear economically promising for the first generation of commercial fusion synfuels plants. Coal production requirements and the environmental effects of large-scale coal usage would be greatly reduced by a fusion/coal system. In the long term, there could be a gradual transition to an inexhaustible energy system based solely on fusion.

  14. Identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line, LC-2/ad.

    PubMed

    Matsubara, Daisuke; Kanai, Yoshihiko; Ishikawa, Shumpei; Ohara, Shiori; Yoshimoto, Taichiro; Sakatani, Takashi; Oguni, Sachiko; Tamura, Tomoko; Kataoka, Hiroaki; Endo, Shunsuke; Murakami, Yoshinori; Aburatani, Hiroyuki; Fukayama, Masashi; Niki, Toshiro

    2012-12-01

    Rearranged during transfection (RET) fusions have been newly identified in approximately 1% of patients with primary lung tumors. However, patient-derived lung cancer cell lines harboring RET fusions have not yet been established or identified, and therefore, the effectiveness of an RET inhibitor on lung tumors with endogenous RET fusion has not yet been studied. In this study, we report identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line LC-2/ad. LC-2/ad showed distinctive sensitivity to the RET inhibitor, vandetanib, among 39 non-small lung cancer cell lines. The xenograft tumor of LC-2/ad showed cribriform acinar structures, a morphologic feature of primary RET fusion-positive lung adenocarcinomas. LC-2/ad cells could provide useful resources to analyze molecular functions of RET-fusion protein and its response to RET inhibitors.

  15. How many ions have escaped the Martian atmosphere?

    NASA Astrophysics Data System (ADS)

    Brain, David; McFadden, James; Halekas, Jasper; Connerney, J. E. P.; Eparvier, Frank; Mitchell, David; Bougher, Stephen W.; Bowers, Charlie; Curry, Shannon; Dong, Chuanfei; Dong, Yaxue; Egan, Hilary; Fang, Xiaohua; Harada, Yuki; Jakosky, Bruce; Lillis, Robert; Luhmann, Janet; Ma, Yingjuan; Modolo, Ronan; Weber, Tristan

    2016-10-01

    The Mars Atmosphere and Volatile EvolutioN (MAVEN) mission has been making science measurements of the Martian upper atmosphere and its escape to space since November 2014. A key part of this effort is the measurement of the escape rates of charged particles (ions) at present and over solar system history. The lack of a global dynamo magnetic field at Mars leaves its upper atmosphere more directly exposed to the impinging solar wind than magnetized planets such as Earth. For this reason it is thought that ion escape at Mars may have played a significant role in long term climate change. MAVEN measures escaping planetary ions directly, with high energy, mass, and time resolution.With nearly two years of observations in hand, we will report the average ion escape rate and the spatial distribution of escaping ions as measured by MAVEN and place them in context with previous measurements of ion loss by other spacecraft (e.g. Phobos 2 and Mars Express). We will then report on the measured variability in ion escape rates with different drivers (e.g. solar EUV, solar wind pressure, etc.). Finally, we will use these results to provide an initial estimate of the total ion escape from Mars over billions of years.

  16. Green Pea Galaxies Reveal Secrets of Lyα Escape

    NASA Astrophysics Data System (ADS)

    Yang, Huan; Malhotra, Sangeeta; Gronke, Max; Rhoads, James E.; Dijkstra, Mark; Jaskot, Anne; Zheng, Zhenya; Wang, Junxian

    2016-04-01

    We analyze archival Lyα spectra of 12 “Green Pea” galaxies observed with the Hubble Space Telescope, model their Lyα profiles with radiative transfer models, and explore the dependence of the Lyα escape fraction on various properties. Green Pea galaxies are nearby compact starburst galaxies with [O iii] λ5007 equivalent widths (EWs) of hundreds of Å. All 12 Green Pea galaxies in our sample show Lyα lines in emission, with an Lyα EW distribution similar to high-redshift Lyα emitters. Combining the optical and UV spectra of Green Pea galaxies, we estimate their Lyα escape fractions and find correlations between Lyα escape fraction and kinematic features of Lyα profiles. The escape fraction of Lyα in these galaxies ranges from 1.4% to 67%. We also find that the Lyα escape fraction depends strongly on metallicity and moderately on dust extinction. We compare their high-quality Lyα profiles with single H i shell radiative transfer models and find that the Lyα escape fraction anticorrelates with the derived H i column densities. Single-shell models fit most Lyα profiles well, but not the ones with the highest escape fractions of Lyα. Our results suggest that low H i column density and low metallicity are essential for Lyα escape and make a galaxy an Lyα emitter.

  17. The Origins and Underpinning Principles of E-Scape

    ERIC Educational Resources Information Center

    Kimbell, Richard

    2012-01-01

    In this article I describe the context within which we developed project e-scape and the early work that laid the foundations of the project. E-scape (e-solutions for creative assessment in portfolio environments) is centred on two innovations. The first concerns a web-based approach to portfolio building; allowing learners to build their…

  18. 46 CFR 116.500 - Means of escape.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... this section, each space accessible to passengers or used by the crew on a regular basis, must have at... escape must be widely separated and, if possible, at opposite ends or sides of the space to minimize the... windows. (d) The number and dimensions of the means of escape from each space must be sufficient for...

  19. 46 CFR 116.500 - Means of escape.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... least two means of escape, one of which must not be a watertight door. (b) The two required means of... clothing, or damage life jackets. (f) The minimum clear opening of a door or passageway used as a means of escape must not be less than 810 millimeters (32 inches) in width, however, doors or passageways...

  20. 7. VIEW OF ESCAPE TRAINING TANK, LOOKING UP SOUTH SIDE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    7. VIEW OF ESCAPE TRAINING TANK, LOOKING UP SOUTH SIDE FROM 50-FOOT PASSAGEWAY, SHOWING 25-FOOT BLISTER AT LEFT, 18-FOOT PASSAGEWAY AND PLATFORM AT RIGHT - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

  1. 22. VIEW OF ESCAPE TRAINING TANK, LOOKING WEST FROM EAST ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    22. VIEW OF ESCAPE TRAINING TANK, LOOKING WEST FROM EAST SIDE OF CUPOLA TOWARD ELEVATOR. TWO-LOCK RECOMPRESSION CHAMBER AT REAR - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

  2. 29. VIEW OF SUBMARINE ESCAPE TRAINING TANK DURING CONSTRUCTION AT ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    29. VIEW OF SUBMARINE ESCAPE TRAINING TANK DURING CONSTRUCTION AT POINT JUST ABOVE THE SUBMARINE SECTION AT THE 110-FOOT LEVEL 1929-1930 - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

  3. 36. VIEW OF CUPOLA, SUBMARINE ESCAPE TRAINING TANK, SHOWING ROVING ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    36. VIEW OF CUPOLA, SUBMARINE ESCAPE TRAINING TANK, SHOWING ROVING RESCUE BELL SUSPENDED ABOVE TANK, WITH TWO-LOCK RECOMPRESSION CHAMBER AT REAR, LOOKING WEST. Photo taken after installation of recompression chamber in 1956. - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

  4. 35. INTERIOR VIEW OF EQUIPMENT HOUSE, SUBMARINE ESCAPE TRAINING TANK, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    35. INTERIOR VIEW OF EQUIPMENT HOUSE, SUBMARINE ESCAPE TRAINING TANK, PRIOR TO ENLARGEMENT OF ROOM AND INSTALLATION OF TRIPLE-LOCK RECOMPRESSION CHAMBER IN 1957 - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

  5. 31. VIEW OF SUBMARINE ESCAPE TRAINING TANK DURING CONSTRUCTION OF ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    31. VIEW OF SUBMARINE ESCAPE TRAINING TANK DURING CONSTRUCTION OF THE ELEVATOR AND PASSAGEWAYS TO THE 18- AND 50-FOOT LOCKS AND CUPOLA 1932 - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

  6. 33 CFR 143.101 - Means of escape.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Means of escape. 143.101 Section 143.101 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OUTER CONTINENTAL SHELF ACTIVITIES DESIGN AND EQUIPMENT OCS Facilities § 143.101 Means of escape. (a) “Primary...

  7. 46 CFR 169.313 - Means of escape.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... a hold-back to hold the scuttle in an open position. (e) The required means of escape must not have... escape is acceptable provided that— (1) There is no source of fire in the space, such as a galley stove... back of the ladder; and (4) Except when unavoidable obstructions are encountered, there must be...

  8. Complete mapping of viral escape from neutralizing antibodies

    PubMed Central

    Hensley, Scott E.

    2017-01-01

    Identifying viral mutations that confer escape from antibodies is crucial for understanding the interplay between immunity and viral evolution. We describe a high-throughput approach to quantify the selection that monoclonal antibodies exert on all single amino-acid mutations to a viral protein. This approach, mutational antigenic profiling, involves creating all replication-competent protein variants of a virus, selecting with antibody, and using deep sequencing to identify enriched mutations. We use mutational antigenic profiling to comprehensively identify mutations that enable influenza virus to escape four monoclonal antibodies targeting hemagglutinin, and validate key findings with neutralization assays. We find remarkable mutation-level idiosyncrasy in antibody escape: for instance, at a single residue targeted by two antibodies, some mutations escape both antibodies while other mutations escape only one or the other. Because mutational antigenic profiling rapidly maps all mutations selected by an antibody, it is useful for elucidating immune specificities and interpreting the antigenic consequences of viral genetic variation. PMID:28288189

  9. Escape rate scaling in infinite measure preserving systems

    NASA Astrophysics Data System (ADS)

    Munday, Sara; Knight, Georgie

    2016-02-01

    We investigate the scaling of the escape rate from piecewise linear dynamical systems displaying intermittency due to the presence of an indifferent fixed point. Strong intermittent behaviour in the dynamics can result in the system preserving an infinite measure. We define a neighbourhood of the indifferent fixed point to be a hole through which points escape and investigate the scaling of the rate of this escape as the length of the hole decreases, both in the finite measure preserving case and infinite measure preserving case. In the infinite measure preserving systems we observe logarithmic corrections to and polynomial scaling of the escape rate with hole length. Finally we conjecture a relationship between the wandering rate and the observed scaling of the escape rate.

  10. Split-second escape decisions in blue tits (Parus caeruleus)

    NASA Astrophysics Data System (ADS)

    Lind, Johan; Kaby, Ulrika; Jakobsson, Sven

    2002-07-01

    Bird mortality is heavily affected by birds of prey. Under attack, take-off is crucial for survival and even minor mistakes in initial escape response can have devastating consequences. Birds may respond differently depending on the character of the predator's attack and these split-second decisions were studied using a model merlin (Falco columbarius) that attacked feeding blue tits (Parus caeruleus) from two different attack angles in two different speeds. When attacked from a low attack angle they took off more steeply than when attacked from a high angle. This is the first study to show that escape behaviour also depends on predator attack speed. The blue tits responded to a high-speed attack by dodging sideways more often than when attacked at a low speed. Escape speed was not significantly affected by the different treatments. Although they have only a split-second before escaping an attack, blue tits do adjust their escape strategy to the prevailing attack conditions.

  11. Viral membrane fusion.

    PubMed

    Harrison, Stephen C

    2015-05-01

    Membrane fusion is an essential step when enveloped viruses enter cells. Lipid bilayer fusion requires catalysis to overcome a high kinetic barrier; viral fusion proteins are the agents that fulfill this catalytic function. Despite a variety of molecular architectures, these proteins facilitate fusion by essentially the same generic mechanism. Stimulated by a signal associated with arrival at the cell to be infected (e.g., receptor or co-receptor binding, proton binding in an endosome), they undergo a series of conformational changes. A hydrophobic segment (a "fusion loop" or "fusion peptide") engages the target-cell membrane and collapse of the bridging intermediate thus formed draws the two membranes (virus and cell) together. We know of three structural classes for viral fusion proteins. Structures for both pre- and postfusion conformations of illustrate the beginning and end points of a process that can be probed by single-virion measurements of fusion kinetics.

  12. Viral membrane fusion

    PubMed Central

    Harrison, Stephen C.

    2015-01-01

    Membrane fusion is an essential step when enveloped viruses enter cells. Lipid bilayer fusion requires catalysis to overcome a high kinetic barrier; viral fusion proteins are the agents that fulfill this catalytic function. Despite a variety of molecular architectures, these proteins facilitate fusion by essentially the same generic mechanism. Stimulated by a signal associated with arrival at the cell to be infected (e.g., receptor or co-receptor binding, proton binding in an endosome), they undergo a series of conformational changes. A hydrophobic segment (a “fusion loop” or “fusion peptide”) engages the target-cell membrane and collapse of the bridging intermediate thus formed draws the two membranes (virus and cell) together. We know of three structural classes for viral fusion proteins. Structures for both pre- and postfusion conformations of illustrate the beginning and end points of a process that can be probed by single-virion measurements of fusion kinetics. PMID:25866377

  13. Immune Escape Strategies of Malaria Parasites

    PubMed Central

    Gomes, Pollyanna S.; Bhardwaj, Jyoti; Rivera-Correa, Juan; Freire-De-Lima, Celio G.; Morrot, Alexandre

    2016-01-01

    Malaria is one of the most life-threatening infectious diseases worldwide. Immunity to malaria is slow and short-lived despite the repeated parasite exposure in endemic areas. Malaria parasites have evolved refined machinery to evade the immune system based on a range of genetic changes that include allelic variation, biomolecular exposure of proteins, and intracellular replication. All of these features increase the probability of survival in both mosquitoes and the vertebrate host. Plasmodium species escape from the first immunological trap in its invertebrate vector host, the Anopheles mosquitoes. The parasites have to pass through various immunological barriers within the mosquito such as anti-microbial molecules and the mosquito microbiota in order to achieve successful transmission to the vertebrate host. Within these hosts, Plasmodium species employ various immune evasion strategies during different life cycle stages. Parasite persistence against the vertebrate immune response depends on the balance among virulence factors, pathology, metabolic cost of the host immune response, and the parasites ability to evade the immune response. In this review we discuss the strategies that Plasmodium parasites use to avoid the vertebrate host immune system and how they promote successful infection and transmission. PMID:27799922

  14. Escaping the resource curse in China.

    PubMed

    Cao, Shixiong; Li, Shurong; Ma, Hua; Sun, Yutong

    2015-02-01

    Many societies face an income gap between rich regions with access to advanced technology and regions that are rich in natural resources but poorer in technology. This "resource curse" can lead to a Kuznets trap, in which economic inequalities between the rich and the poor increase during the process of socioeconomic development. This can also lead to depletion of natural resources, environmental degradation, social instability, and declining socioeconomic development. These problems will jeopardize China's achievements if the current path continues to be pursued without intervention by the government to solve the problems. To mitigate the socioeconomic development gap between western and eastern China, the government implemented its Western Development Program in 2000. However, recent data suggest that this program has instead worsened the resource curse. Because each region has its own unique strengths and weaknesses, China must escape the resource curse by accounting for this difference; in western China, this can be done by improving education, promoting high-tech industry, adjusting its economic strategy to balance regional development, and seeking more sustainable approaches to socioeconomic development.

  15. WANDERING STARS: AN ORIGIN OF ESCAPED POPULATIONS

    SciTech Connect

    Teyssier, Maureen; Johnston, Kathryn V.; Shara, Michael M.

    2009-12-10

    We demonstrate that stars beyond the virial radii of galaxies may be generated by the gravitational impulse received by a satellite as it passes through the pericenter of its orbit around its parent. These stars may become energetically unbound (escaped stars), or may travel to further than a few virial radii for longer than a few Gyr, but still remain energetically bound to the system (wandering stars). Larger satellites (10%-100% the mass of the parent), and satellites on more radial orbits are responsible for the majority of this ejected population. Wandering stars could be observable on Mpc scales via classical novae, and on 100 Mpc scales via Type Ia supernova. The existence of such stars would imply a corresponding population of barely bound, old, high-velocity stars orbiting the Milky Way, generated by the same physical mechanism during the Galaxy's formation epoch. Sizes and properties of these combined populations should place some constraints on the orbits and masses of the progenitor objects from which they came, providing insight into the merging histories of galaxies in general and the Milky Way in particular.

  16. Sensitization of the Tritonia escape swim.

    PubMed

    Frost, W N; Brandon, C L; Mongeluzi, D L

    1998-03-01

    When repeatedly elicited, the oscillatory escape swim of the marine mollusc Tritonia diomedea undergoes habituation of the number of cycles per swim. Previous work has shown that this habituation is accompanied by sensitization of another feature of the behavior: latency to swim onset. Here we focused on the behavioral features of sensitization itself. Test swims elicited 5 min after a strong sensitizing head stimulus differed in several ways from control swims: sensitized animals had shorter latencies for gill and rhinophore withdrawal, a shorter latency for swim onset, a lower threshold for swim initiation, and an increased number of cycles per swim. Sensitized animals did not, however, swim any faster (no change in cycle period). A separate experiment found that swim onset latency also sensitized when Tritonia came into contact with one of their natural predators, the seastar Pycnopodia helianthoides, demonstrating the ecological relevance of this form of nonassociative learning. These results define the set of behavioral changes to be explained by cellular studies of sensitization in Tritonia.

  17. Immune Escape Strategies of Malaria Parasites.

    PubMed

    Gomes, Pollyanna S; Bhardwaj, Jyoti; Rivera-Correa, Juan; Freire-De-Lima, Celio G; Morrot, Alexandre

    2016-01-01

    Malaria is one of the most life-threatening infectious diseases worldwide. Immunity to malaria is slow and short-lived despite the repeated parasite exposure in endemic areas. Malaria parasites have evolved refined machinery to evade the immune system based on a range of genetic changes that include allelic variation, biomolecular exposure of proteins, and intracellular replication. All of these features increase the probability of survival in both mosquitoes and the vertebrate host. Plasmodium species escape from the first immunological trap in its invertebrate vector host, the Anopheles mosquitoes. The parasites have to pass through various immunological barriers within the mosquito such as anti-microbial molecules and the mosquito microbiota in order to achieve successful transmission to the vertebrate host. Within these hosts, Plasmodium species employ various immune evasion strategies during different life cycle stages. Parasite persistence against the vertebrate immune response depends on the balance among virulence factors, pathology, metabolic cost of the host immune response, and the parasites ability to evade the immune response. In this review we discuss the strategies that Plasmodium parasites use to avoid the vertebrate host immune system and how they promote successful infection and transmission.

  18. Dications and thermal ions in planetary atmospheric escape

    NASA Astrophysics Data System (ADS)

    Lilensten, J.; Simon Wedlund, C.; Barthélémy, M.; Thissen, R.; Ehrenreich, D.; Gronoff, G.; Witasse, O.

    2013-01-01

    In the recent years, the presence of dications in the atmospheres of Mars, Venus, Earth and Titan has been modeled and assessed. These studies also suggested that these ions could participate to the escape of the planetary atmospheres because a large fraction of them is unstable and highly energetic. When they dissociate, their internal energy is transformed into kinetic energy which may be larger than the escape energy. The goal of this study is to assess the impact of the doubly-charged ions in the escape of CO2-dominated planetary atmospheres and to compare it to the escape of thermal photo-ions. We solve a Boltzmann transport equation at daytime taking into account the dissociative states of CO2++ for a simplified single constituent atmosphere of a case-study planet. We compute the escape of fast ions using a Beer-Lambert approach. We study three test-cases. On a Mars-analog planet in today's conditions, we retrieve the measured electron escape flux. When comparing the two mechanisms (i.e. excluding solar wind effects, sputtering, etc.), the escape due to the fast ions issuing from the dissociation of dications may account for up to 6% of the total and the escape of thermal ions for the remaining. We show that these two mechanisms cannot explain the escape of the atmosphere since the magnetic field vanished and even contribute only marginally to this loss. We show that with these two mechanisms, the atmosphere of a Mars analog planet would empty in another giga years and a half. At Venus orbit, the contribution of the dications in the escape rate is negligible. When simulating the hot Jupiter HD 209458 b, the two processes cannot explain the measured escape flux of C+. This study shows that the dications may constitute a source of the escape of planetary atmospheres which had not been taken into account until now. This source, although marginal, is not negligible. The influence of the photoionization is of course large, but cannot explain alone the loss of Mars

  19. Cold fusion research

    SciTech Connect

    1989-11-01

    I am pleased to forward to you the Final Report of the Cold Fusion Panel. This report reviews the current status of cold fusion and includes major chapters on Calorimetry and Excess Heat, Fusion Products and Materials Characterization. In addition, the report makes a number of conclusions and recommendations, as requested by the Secretary of Energy.

  20. Magneto-Inertial Fusion

    SciTech Connect

    Wurden, G. A.; Hsu, S. C.; Intrator, T. P.; Grabowski, T. C.; Degnan, J. H.; Domonkos, M.; Turchi, P. J.; Campbell, E. M.; Sinars, D. B.; Herrmann, M. C.; Betti, R.; Bauer, B. S.; Lindemuth, I. R.; Siemon, R. E.; Miller, R. L.; Laberge, M.; Delage, M.

    2015-11-17

    In this community white paper, we describe an approach to achieving fusion which employs a hybrid of elements from the traditional magnetic and inertial fusion concepts, called magneto-inertial fusion (MIF). The status of MIF research in North America at multiple institutions is summarized including recent progress, research opportunities, and future plans.

  1. Lyman-Werner UV escape fractions from primordial haloes

    NASA Astrophysics Data System (ADS)

    Schauer, Anna T. P.; Whalen, Daniel J.; Glover, Simon C. O.; Klessen, Ralf S.

    2015-12-01

    Population III (Pop III) stars can regulate star formation in the primordial Universe in several ways. They can ionize nearby haloes, and even if their ionizing photons are trapped by their own haloes, their Lyman-Werner (LW) photons can still escape and destroy H2 in other haloes, preventing them from cooling and forming stars. LW escape fractions are thus a key parameter in cosmological simulations of early reionization and star formation but have not yet been parametrized for realistic haloes by halo or stellar mass. To do so, we perform radiation hydrodynamical simulations of LW UV escape from 9-120 M⊙ Pop III stars in 105-107 M⊙ haloes with ZEUS-MP. We find that photons in the LW lines (i.e. those responsible for destroying H2 in nearby systems) have escape fractions ranging from 0 to 85 per cent. No LW photons escape the most massive halo in our sample, even from the most massive star. Escape fractions for photons elsewhere in the 11.18-13.6 eV energy range, which can be redshifted into the LW lines at cosmological distances, are generally much higher, being above 60 per cent for all but the least massive stars in the most massive haloes. We find that shielding of H2 by neutral hydrogen, which has been neglected in most studies to date, produces escape fractions that are up to a factor of 3 smaller than those predicted by H2 self-shielding alone.

  2. Modelling the Evolution and Spread of HIV Immune Escape Mutants

    PubMed Central

    Fryer, Helen R.; Frater, John; Duda, Anna; Roberts, Mick G.; Phillips, Rodney E.; McLean, Angela R.

    2010-01-01

    During infection with human immunodeficiency virus (HIV), immune pressure from cytotoxic T-lymphocytes (CTLs) selects for viral mutants that confer escape from CTL recognition. These escape variants can be transmitted between individuals where, depending upon their cost to viral fitness and the CTL responses made by the recipient, they may revert. The rates of within-host evolution and their concordant impact upon the rate of spread of escape mutants at the population level are uncertain. Here we present a mathematical model of within-host evolution of escape mutants, transmission of these variants between hosts and subsequent reversion in new hosts. The model is an extension of the well-known SI model of disease transmission and includes three further parameters that describe host immunogenetic heterogeneity and rates of within host viral evolution. We use the model to explain why some escape mutants appear to have stable prevalence whilst others are spreading through the population. Further, we use it to compare diverse datasets on CTL escape, highlighting where different sources agree or disagree on within-host evolutionary rates. The several dozen CTL epitopes we survey from HIV-1 gag, RT and nef reveal a relatively sedate rate of evolution with average rates of escape measured in years and reversion in decades. For many epitopes in HIV, occasional rapid within-host evolution is not reflected in fast evolution at the population level. PMID:21124991

  3. Efficiently estimating salmon escapement uncertainty using systematically sampled data

    USGS Publications Warehouse

    Reynolds, Joel H.; Woody, Carol Ann; Gove, Nancy E.; Fair, Lowell F.

    2007-01-01

    Fish escapement is generally monitored using nonreplicated systematic sampling designs (e.g., via visual counts from towers or hydroacoustic counts). These sampling designs support a variety of methods for estimating the variance of the total escapement. Unfortunately, all the methods give biased results, with the magnitude of the bias being determined by the underlying process patterns. Fish escapement commonly exhibits positive autocorrelation and nonlinear patterns, such as diurnal and seasonal patterns. For these patterns, poor choice of variance estimator can needlessly increase the uncertainty managers have to deal with in sustaining fish populations. We illustrate the effect of sampling design and variance estimator choice on variance estimates of total escapement for anadromous salmonids from systematic samples of fish passage. Using simulated tower counts of sockeye salmon Oncorhynchus nerka escapement on the Kvichak River, Alaska, five variance estimators for nonreplicated systematic samples were compared to determine the least biased. Using the least biased variance estimator, four confidence interval estimators were compared for expected coverage and mean interval width. Finally, five systematic sampling designs were compared to determine the design giving the smallest average variance estimate for total annual escapement. For nonreplicated systematic samples of fish escapement, all variance estimators were positively biased. Compared to the other estimators, the least biased estimator reduced bias by, on average, from 12% to 98%. All confidence intervals gave effectively identical results. Replicated systematic sampling designs consistently provided the smallest average estimated variance among those compared.

  4. The Impacts of Orbital Distance on Exoplanetary Atmospheric Escape

    NASA Astrophysics Data System (ADS)

    Yang, M.; Guo, J. H.

    2016-11-01

    Driven by the high energy radiation of host stars, atmospheric escape is very important for planet evolution. While the flux drops dramatically with the increase of orbital distance, it is essential to study the impacts of orbital distance on atmospheric escape. We consider the hydrodynamic escape of exoplanets driven by the XUV (X-ray and extreme-ultraviolet) radiation of their host stars. We aim to study the mass-loss rate, the transition of escape mechanism, the structures of temperature and velocity, based on a one-dimensional hydrodynamic model which includes radiative transfer processes and photochemical reactions. As the stellar XUV emission varies with the stellar evolution, we use XSPEC (X-Ray Spectral Fitting Package) to construct the XUV spectra of solar-type stars at different ages. We find that with the increase of orbital distance, the mass-loss rates drop significantly, and when the stellar XUV flux is too small to preserve the hydrodynamic escape, it will turn to Jeans escape. This transition occurs in larger distance for younger and smaller planets. For young planets, hydrodynamic escape can occur in 1-2 au. For very young and close-in planets, the relation between mass-loss rate and stellar flux is not as significant as planets that are not close to their host stars, and the energy-limited equation can lead to large overestimate.

  5. Ion-induced gamma-ray detection of fast ions escaping from fusion plasmas

    SciTech Connect

    Nishiura, M. Mushiake, T.; Doi, K.; Wada, M.; Taniike, A.; Matsuki, T.; Shimazoe, K.; Yoshino, M.; Nagasaka, T.; Tanaka, T.; Kisaki, M.; Fujimoto, Y.; Fujioka, K.; Yamaoka, H.; Matsumoto, Y.

    2014-11-15

    A 12 × 12 pixel detector has been developed and used in a laboratory experiment for lost fast-ion diagnostics. With gamma rays in the MeV range originating from nuclear reactions {sup 9}Be(α, nγ){sup 12}C, {sup 9}Be(d, nγ){sup 12}C, and {sup 12}C(d, pγ){sup 13}C, a high purity germanium (HPGe) detector measured a fine-energy-resolved spectrum of gamma rays. The HPGe detector enables the survey of background-gamma rays and Doppler-shifted photo peak shapes. In the experiments, the pixel detector produces a gamma-ray image reconstructed from the energy spectrum obtained from total photon counts of irradiation passing through the detector's lead collimator. From gamma-ray image, diagnostics are able to produce an analysis of the fast ion loss onto the first wall in principle.

  6. Identification and Characterization of Influenza Virus Entry Inhibitors through Dual Myxovirus High-Throughput Screening

    PubMed Central

    Weisshaar, Marco; Cox, Robert; Morehouse, Zachary; Kumar Kyasa, Shiva; Yan, Dan; Oberacker, Phil; Mao, Shuli; Lowen, Anice C.; Natchus, Michael G.

    2016-01-01

    ABSTRACT Influenza A virus (IAV) infections cause major morbidity and mortality, generating an urgent need for novel antiviral therapeutics. We recently established a dual myxovirus high-throughput screening protocol that combines a fully replication-competent IAV-WSN strain and a respiratory syncytial virus reporter strain for the simultaneous identification of IAV-specific, paramyxovirus-specific, and broad-spectrum inhibitors. In the present study, this protocol was applied to a screening campaign to assess a diverse chemical library with over 142,000 entries. Focusing on IAV-specific hits, we obtained a hit rate of 0.03% after cytotoxicity testing and counterscreening. Three chemically distinct hit classes with nanomolar potency and favorable cytotoxicity profiles were selected. Time-of-addition, minigenome, and viral entry studies demonstrated that these classes block hemagglutinin (HA)-mediated membrane fusion. Antiviral activity extends to an isolate from the 2009 pandemic and, in one case, another group 1 subtype. Target identification through biolayer interferometry confirmed binding of all hit compounds to HA. Resistance profiling revealed two distinct escape mechanisms: primary resistance, associated with reduced compound binding, and secondary resistance, associated with unaltered binding. Secondary resistance was mediated, unusually, through two different pairs of cooperative mutations, each combining a mutation eliminating the membrane-proximal stalk N-glycan with a membrane-distal change in HA1 or HA2. Chemical synthesis of an analog library combined with in silico docking extracted a docking pose for the hit classes. Chemical interrogation spotlights IAV HA as a major druggable target for small-molecule inhibition. Our study identifies novel chemical scaffolds with high developmental potential, outlines diverse routes of IAV escape from entry inhibition, and establishes a path toward structure-aided lead development. IMPORTANCE This study is one of

  7. Mycobacterial escape from macrophage phagosomes to the cytoplasm represents an alternate adaptation mechanism

    PubMed Central

    Jamwal, Shilpa V.; Mehrotra, Parul; Singh, Archana; Siddiqui, Zaved; Basu, Atanu; Rao, Kanury V.S.

    2016-01-01

    Survival of Mycobacterium tuberculosis (Mtb) within the host macrophage is mediated through pathogen-dependent inhibition of phagosome-lysosome fusion, which enables bacteria to persist within the immature phagosomal compartment. By employing ultrastructural examination of different field isolates supported by biochemical analysis, we found that some of the Mtb strains were in fact poorly adapted for subsistence within endocytic vesicles of infected macrophages. Instead, through a mechanism involving activation of host cytosolic phospholipase A2, these bacteria rapidly escaped from phagosomes, and established residence in the cytoplasm of the host cell. Interestingly, by facilitating an enhanced suppression of host cellular autophagy, this translocation served as an alternate virulence acquisition mechanism. Thus, our studies reveal plasticity in the adaptation strategies employed by Mtb, for survival in the host macrophage. PMID:26980157

  8. Magnetized target fusion and fusion propulsion

    NASA Astrophysics Data System (ADS)

    Kirkpatrick, Ronald C.

    2002-01-01

    Magnetized target fusion (MTF) is a thermonuclear fusion concept that is intermediate between the two mainline approaches, magnetic confinement and inertial confinement fusion (MCF and ICF). MTF incorporates some aspects of each and offers advantages over each of the mainline approaches. First, it provides a means of reducing the driver power requirements, thereby admitting a wider range of drivers than ICF. Second, the magnetic field is only used for insulation, not confinement, and the plasma is wall confined, so that plasma instabilities are traded in for hydrodynamic instabilities. However, the degree of compression required to reach fusion condition is lower than for ICF, so that hydrodynamic instabilities are much less threatening. The standoff driver innovation proposes to dynamically form the target plasma and a gaseous shell that compresses and confines the target plasma. Therefore, fusion target fabrication is traded in for a multiplicity of plasma guns, which must work in synchrony. The standoff driver embodiment of MTF leads to a fusion propulsion system concept that is potentially compact and lightweight. We will discuss the underlying physics of MTF and some of the details of the fusion propulsion concept using the standoff driver approach. We discuss here the optimization of an MTF target design for space propulsion. .

  9. 16. INTERIOR VIEW OF SUBMARINE SECTION AT 110FOOT LEVEL, ESCAPE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    16. INTERIOR VIEW OF SUBMARINE SECTION AT 110-FOOT LEVEL, ESCAPE TRAINING TANK, SHOWING LADDER TO ESCAPE TANK, LOOKING SOUTH - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

  10. Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergetics-mitochondrial priming

    PubMed Central

    Zhang, Wei; Shi, Ivy; Bagai, Rakesh; Leahy, Patrick; Feng, Yan; Veigl, Martina; Lindner, Daniel; Danielpour, David; Yin, Lihong; Rosell, Rafael; Bivona, Trever G.; Zhang, Zhenfeng; Ma, Patrick C.

    2016-01-01

    The impact of EGFR-mutant NSCLC precision therapy is limited by acquired resistance despite initial excellent response. Classic studies of EGFR-mutant clinical resistance to precision therapy were based on tumor rebiopsies late during clinical tumor progression on therapy. Here, we characterized a novel non-mutational early adaptive drug-escape in EGFR-mutant lung tumor cells only days after therapy initiation, that is MET-independent. The drug-escape cell states were analyzed by integrated transcriptomic and metabolomics profiling uncovering a central role for autocrine TGFβ2 in mediating cellular plasticity through profound cellular adaptive Omics reprogramming, with common mechanistic link to prosurvival mitochondrial priming. Cells undergoing early adaptive drug escape are in proliferative-metabolic quiescent, with enhanced EMT-ness and stem cell signaling, exhibiting global bioenergetics suppression including reverse Warburg, and are susceptible to glutamine deprivation and TGFβ2 inhibition. Our study further supports a preemptive therapeutic targeting of bioenergetics and mitochondrial priming to impact early drug-escape emergence using EGFR precision inhibitor combined with broad BH3-mimetic to interrupt BCL-2/BCL-xL together, but not BCL-2 alone. PMID:27852038

  11. Ring fusion strategy for the synthesis of anthra[2,3-d]oxazole-2-thione-5,10-dione homologues as DNA topoisomerase inhibitors and as antitumor agents.

    PubMed

    Chen, Chun-Liang; Liu, Fei-Lan; Lee, Chia-Chung; Chen, Tsung-Chih; Chang, Wen-Wei; Guh, Jih-Hwa; Ahmed Ali, Ahmed Atef; Chang, Deh-Ming; Huang, Hsu-Shan

    2014-11-24

    The efficient synthesis of mono-substituted anthraquinones and ring fusion into anthra[2,3-d]oxazole-2-thione-5,10-dione derivatives were developed, and all the compounds were tested for their cytotoxicity against PC-3 cancer cell lines. Compounds 8, 14, 17 and 23 were selected by the NCI and 12, 17 and 19 were evaluated for topoisomerase I-mediated DNA relaxation. Among them, 17 appeared to be the most active compound of this series and not only showed higher inhibition when indicated from the low IC50 values against PC-3 cancer cell line but also attenuated the in vitro topoisomerase I-mediated DNA relaxation at low micromolar concentrations. All test compounds exhibited different cytostatic and cytotoxic activities for further developing potential anticancer drugs.

  12. Viral membrane fusion

    SciTech Connect

    Harrison, Stephen C.

    2015-05-15

    Membrane fusion is an essential step when enveloped viruses enter cells. Lipid bilayer fusion requires catalysis to overcome a high kinetic barrier; viral fusion proteins are the agents that fulfill this catalytic function. Despite a variety of molecular architectures, these proteins facilitate fusion by essentially the same generic mechanism. Stimulated by a signal associated with arrival at the cell to be infected (e.g., receptor or co-receptor binding, proton binding in an endosome), they undergo a series of conformational changes. A hydrophobic segment (a “fusion loop” or “fusion peptide”) engages the target-cell membrane and collapse of the bridging intermediate thus formed draws the two membranes (virus and cell) together. We know of three structural classes for viral fusion proteins. Structures for both pre- and postfusion conformations of illustrate the beginning and end points of a process that can be probed by single-virion measurements of fusion kinetics. - Highlights: • Viral fusion proteins overcome the high energy barrier to lipid bilayer merger. • Different molecular structures but the same catalytic mechanism. • Review describes properties of three known fusion-protein structural classes. • Single-virion fusion experiments elucidate mechanism.

  13. Efficacy of an adapted granzyme B-based anti-CD30 cytolytic fusion protein against PI-9-positive classical Hodgkin lymphoma cells in a murine model.

    PubMed

    Schiffer, S; Hansen, H P; Hehmann-Titt, G; Huhn, M; Fischer, R; Barth, S; Thepen, T

    2013-03-22

    Tumors develop when infiltrating immune cells contribute growth stimuli, and cancer cells are selected to survive within such a cytotoxic microenvironment. One possible immune-escape mechanism is the upregulation of PI-9 (Serpin B9) within cancer cells. This serine proteinase inhibitor selectively inactivates apoptosis-inducing granzyme B (GrB) from cytotoxic granules of innate immune cells. We demonstrate that most classical Hodgkin lymphoma (cHL)-derived cell lines express PI-9, which protects them against the GrB attack and thereby renders them resistant against GrB-based immunotherapeutics. To circumvent this disadvantage, we developed PI-9-insensitive human GrB mutants as fusion proteins to target the Hodgkin-selective receptor CD30. In contrast to the wild-type GrB, a R201K point-mutated GrB construct most efficiently killed PI-9-positive and -negative cHL cells. This was tested in vitro and also in vivo whereby a novel optical imaging-based tumor model with HL cell line L428 was applied. Therefore, this variant, as part of the next generation immunotherapeutics, also named cytolytic fusion proteins showing reduced immunogenicity, is a promising molecule for (targeted) therapy of patients with relapsing malignancies, such as cHL, and possibly other PI-9-positive malignancies, such as breast or lung carcinoma.

  14. 30 CFR 77.1101 - Escape and evacuation; plan.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... alarm signals, and applicable procedures to be followed in case of fire. (c) Plans for escape and evacuation shall include the designation and proper maintenance of adequate means for exit from all...

  15. 30 CFR 77.1101 - Escape and evacuation; plan.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... alarm signals, and applicable procedures to be followed in case of fire. (c) Plans for escape and evacuation shall include the designation and proper maintenance of adequate means for exit from all...

  16. 30 CFR 77.1101 - Escape and evacuation; plan.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... alarm signals, and applicable procedures to be followed in case of fire. (c) Plans for escape and evacuation shall include the designation and proper maintenance of adequate means for exit from all...

  17. Survey of space escape/rescue/survivability capabilities.

    NASA Technical Reports Server (NTRS)

    Fleisig, R.; Bolger, P. H.; Heath, G. W.

    1971-01-01

    Discussion of preventive or remedial systems to achieve safer space flight operations. Escape, rescue, and survival systems are defined by categories: on board, prepositioned aid, and earth-launched concepts. The survey considers separable escape or survival capsules; standby escape or rescue systems; and earth-launched manned and unmanned rescue systems. Reports covering such systems are listed, and the contents are classified as to scope of investigation, space mission, and design approach. Mission classes considered are earth orbit, lunar, and interplanetary. Results of the space escape, rescue, and survivability investigations are summarized in terms of system features and performance, including apparent voids or limitations in rescue capability. Recovery requirements and resources for space rescue are discussed.

  18. Experimental Analysis and Extinction of Self-Injurious Escape Behavior.

    ERIC Educational Resources Information Center

    Iwata, Brian A.; And Others

    1990-01-01

    Three studies investigated environmental correlates of self-injurious behavior in seven developmentally disabled children and adolescents which were then later used for treatment. Correlates investigated included positive reinforcement, negative reinforcement, automatic reinforcement, and control. "Escape extinction" was successfully…

  19. Pilot Fullerton dons ejection escape suit (EES) on middeck

    NASA Technical Reports Server (NTRS)

    1982-01-01

    Pilot Fullerton dons ejection escape suit (EES) (high altitude pressure garment) life preserver unit (LPU) on forward port side of middeck above potable water tank. Fullerton also adjusts lapbelt fitting and helmet holddown strap.

  20. Dissociated neural effects of cortisol depending on threat escapability.

    PubMed

    Montoya, Estrella R; van Honk, Jack; Bos, Peter A; Terburg, David

    2015-11-01

    Evolution has provided us with a highly flexible neuroendocrine threat system which, depending on threat imminence, switches between active escape and passive freezing. Cortisol, the "stress-hormone", is thought to play an important role in both fear behaviors, but the exact mechanisms are not understood. Using pharmacological functional magnetic resonance imaging we investigated how cortisol modulates the brain's fear systems when humans are under virtual-predator attack. We show dissociated neural effects of cortisol depending on whether escape from threat is possible. During inescapable threat cortisol reduces fear-related midbrain activity, whereas in anticipation of active escape cortisol boosts activity in the frontal salience network (insula and anterior cingulate cortex), which is involved in autonomic control, visceral perception and motivated action. Our findings suggest that cortisol adjusts the human neural threat system from passive fear to active escape, which illuminates the hormone's crucial role in the adaptive flexibility of fear behaviors.

  1. Prey escaping wolves, Canis lupus, despite close proximity

    USGS Publications Warehouse

    Nelson, M.E.; Mech, L.D.

    1993-01-01

    We describe attacks by wolf (Canis lupus) packs in Minnesota on a white-tailed deer (Odocoileus virginianus) and a moose (Alces alces) in which wolves were within contact distance of the prey but in which the prey escaped.

  2. 14. View inside Building 802, the "Escape Hatch" at the ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    14. View inside Building 802, the "Escape Hatch" at the rear of the "Sleeping Quarters", facing south. - Naval Air Station Fallon, 100-man Fallout Shelter, 800 Complex, off Carson Road near intersection of Pasture & Berney Roads, Fallon, Churchill County, NV

  3. Electron yields and escape depths from spacecraft materials

    SciTech Connect

    Yang, K.Y.

    1986-01-01

    Secondary electron emission (SEE) characteristics and photoelectron yields were determined for several insulating materials used onboard a space shuttle. These materials are: kapton, teflon, spaceshuttle tiles, and space suit cloth. Secondary electron escape depth and photoelectron escape depth from kapton were calculated from the experimental data. Sternglass' theory and Dionne's method were used in the calculation. Some semi-empirical theories of SEE and three-step theory of photoemission were reviewed. Pulsed beam techniques were used to reduce surface charging problems. Three ..mu..sec pulses of electrons were used in SEE experiments, and 100 msec to 1 sec pulses were used in photoemission experiments. The maximum SEE yields of the materials studied range from 1.75 ro 2.70. The secondary electron escape depth in kapton was calculated to be 55 +/- 5 A. All samples have photoyields lower than 1.0%. The photoelectrons excited by 21-eV photons have 87 +/- 30 A escape depth in kapton.

  4. Oxygen Escape from Venus During High Dynamic Pressure ICMEs

    NASA Astrophysics Data System (ADS)

    McEnulty, Tess; Luhmann, J. G.; Brain, D. A.; Fedorov, A.; Jian, L. K.; Russell, C. T.; Zhang, T.; Möstl, C.; Futaana, Y.; de Pater, I.

    2013-10-01

    Previous studies using data from Pioneer Venus suggested that oxygen ion escape flux may be enhanced by orders of magnitude during Interplanetary Coronal Mass Ejections. However, this large enhancement has been ambiguous in Venus Express ion data - with some analyses showing no flux enhancement or a small enhancement (within 2 times undisturbed cases). One possible explanation is that high escape flux may be due to high dynamic pressure in the solar wind, and the dynamic pressure has been lower during the VEX time period. So, we focus on ICMEs with the largest dynamic pressure and with VEX sampling of the escaping ions during the sheath of the ICMEs (during which the highest dynamic pressures in the solar wind occur). We will show the characteristics of these large events measured by VEX, and compare them to the largest ICMEs measured by PVO. We will then discuss estimates of the oxygen ion escape flux during these events.

  5. Pioneer Venus Orbiter (PVO) Ionosphere Evidence for Atmospheric Escape

    NASA Astrophysics Data System (ADS)

    Grebowsky, J. M.; Hoegy, W. R.

    2009-12-01

    An early estimate of escape of H2O from Venus [McElroy et al., 1982] using observed hot oxygen densities inferred by Nagy et al. [1981] from PVO OUVS 1304 Å dayglow and using ionization rates from photoionization and electron impact. This resulted in an estimated oxygen ionization rate planet-wide above the plasmapause of 3x1025 atoms/s. Based on the energetic O+ being swept up and removed by solar wind, McElroy et al. [1982] gave an estimate of a loss rate for O of 6x106 atoms/cm2/s. Using a different method of estimating escape based data in the ionotail of Venus, Brace et al. [1987] estimated a total planetary O+ escape rate of 5x1025 ions/s. Their estimate was based on PVO measurements of superthermal O+ (energy range 9-16 eV) in the tail ray plasma between 2000 and 3000 km. Their estimated global mean flux was 107 atoms/cm2/s. The two escape rates are remarkably close considering all the errors involved in such estimates of escape. A study of escape by Luhmann et al. [2008] using VEX observations at low solar activity finds modest escape rates, prompting the authors to reconsider the evidence from both PVO and VEX of the possibility of enhanced escape during extreme interplanetary conditions. We reexamine the variation of escape under different solar wind conditions using ion densities and plasma content in the dayside and nightside of Venus using PVO ionosphere density during times of high solar activity. Citations: Brace, L.H., W. T. Kasprzak, H.A. Taylor, R. F. Theis, C. T. Russess, A. Barnes, J. D. Mihalov, and D. M. Hunten, "The Ionotail of Venus: Its Configuration and Evidence for Ion Escape", J. Geophys. Res. 92, 15-26, 1987. Luhmann, J.G., A. Fedorov, S. Barabash, E. Carlsson, Y. Futaana, T.L. Zhang, C.T. Russell, J.G. Lyon, S.A. Ledvina, and D.A. Brain, “Venus Express observations of atmospheric oxygen escape during the passage of several coronal mass ejections”, J. Geophys. Res., 113, 2008. McElroy, M. B., M. J. Prather, J. M. Rodiquez, " Loss

  6. Distinct Requirements for HIV-Cell Fusion and HIV-mediated Cell-Cell Fusion*

    PubMed Central

    Kondo, Naoyuki; Marin, Mariana; Kim, Jeong Hwa; Desai, Tanay M.; Melikyan, Gregory B.

    2015-01-01

    Whether HIV-1 enters cells by fusing with the plasma membrane or with endosomes is a subject of active debate. The ability of HIV-1 to mediate fusion between adjacent cells, a process referred to as “fusion-from-without” (FFWO), shows that this virus can fuse with the plasma membrane. To compare FFWO occurring at the cell surface with HIV-cell fusion through a conventional entry route, we designed an experimental approach that enabled the measurements of both processes in the same sample. The following key differences were observed. First, a very small fraction of viruses fusing with target cells participated in FFWO. Second, whereas HIV-1 fusion with adherent cells was insensitive to actin inhibitors, post-CD4/coreceptor binding steps during FFWO were abrogated. A partial dependence of HIV-cell fusion on actin remodeling was observed in CD4+ T cells, but this effect appeared to be due to the actin dependence of virus uptake. Third, deletion of the cytoplasmic tail of HIV-1 gp41 dramatically enhanced the ability of the virus to promote FFWO, while having a modest effect on virus-cell fusion. Distinct efficiencies and actin dependences of FFWO versus HIV-cell fusion are consistent with the notion that, except for a minor fraction of particles that mediate fusion between the plasma membranes of adjacent cells, HIV-1 enters through an endocytic pathway. We surmise, however, that cell-cell contacts enabling HIV-1 fusion with the plasma membrane could be favored at the sites of high density of target cells, such as lymph nodes. PMID:25589785

  7. Photoelectron escape fluxes over the equatorial and midlatitude regions

    NASA Technical Reports Server (NTRS)

    Narasingarao, B. C.; Singh, R. N.; Maier, E. J.

    1972-01-01

    Satellite measurements of photoelectron escape flux around noontime made by Explorer 31 in 600-800 km altitude range are reported for the equatorial and midlatitude regions. The pitch angle distributions and the spectral distributions are derived from the data. Analyzed data show that the flux for equatorial regions is lower by a factor 2 to 3 in comparison to that of midlatitude regions. Theoretical calculations are also made to compare with observed escape fluxes.

  8. Ion escape from Venus using statistical distribution functions

    NASA Astrophysics Data System (ADS)

    Nordstrom, T.; Stenberg, G.; Nilsson, H.; Barabash, S.; Futaana, Y.

    2012-04-01

    We use more than three years of data from the ASPERA-4 instrument onboard Venus Express to compile statistical distribution functions of ion flux in and around induced magnetosphere of Venus. We present samples of statistical distribution functions, as well average flux patterns in the near Venus space based on the statistical distribution functions. The statistical distribution functions allows for a compensation of biased sampling regarding both position and angular coverage of the instrument. Protons and heavy ions (mass/charge > 16) are the major ion species escaping from Venus. The escape is due to acceleration of planetary ions by energy transfer from the solar wind. The ion escape appears to exclusively take place in the induced magnetotail region and no heavy ions are present in the magnetosheath. Protons of solar wind origin are travelling around the planet and penetrating the tail, resulting in a mix of planetary and solar wind protons inside the induced magnetosphere boundary. The escape rates of ions inside the tail agree with results from recent published studies, where other analysis methods have been used. We also compare our results for Venus with a recent study of ion escape from Mars, where the same analysis method has been applied to data from the ASPERA-3 instrument on Mars Express. Both Mars and Venus are unmagnetized planets and are expected to interact similarly with the solar wind. On Mars the heavy ions are seen escaping in both the magnetosheath and tail regions as opposed to Venus where escape only takes place inside the tail. A possible explanation is that the magnetosphere of Mars is smaller compared to the ion gyroradius, making it easier for the ions to pass through the induced magnetosphere boundary. On both planets the escape rates of heavy ions in the tail are constant with increasing tail distance, verifying that the ions are leaving the planet in this region.

  9. GREEN PEA GALAXIES REVEAL SECRETS OF Lyα ESCAPE

    SciTech Connect

    Yang, Huan; Wang, Junxian; Malhotra, Sangeeta; Rhoads, James E.; Gronke, Max; Dijkstra, Mark; Jaskot, Anne; Zheng, Zhenya E-mail: huan.y@asu.edu E-mail: James.Rhoads@asu.edu

    2016-04-01

    We analyze archival Lyα spectra of 12 “Green Pea” galaxies observed with the Hubble Space Telescope, model their Lyα profiles with radiative transfer models, and explore the dependence of the Lyα escape fraction on various properties. Green Pea galaxies are nearby compact starburst galaxies with [O iii] λ5007 equivalent widths (EWs) of hundreds of Å. All 12 Green Pea galaxies in our sample show Lyα lines in emission, with an Lyα EW distribution similar to high-redshift Lyα emitters. Combining the optical and UV spectra of Green Pea galaxies, we estimate their Lyα escape fractions and find correlations between Lyα escape fraction and kinematic features of Lyα profiles. The escape fraction of Lyα in these galaxies ranges from 1.4% to 67%. We also find that the Lyα escape fraction depends strongly on metallicity and moderately on dust extinction. We compare their high-quality Lyα profiles with single H i shell radiative transfer models and find that the Lyα escape fraction anticorrelates with the derived H i column densities. Single-shell models fit most Lyα profiles well, but not the ones with the highest escape fractions of Lyα. Our results suggest that low H i column density and low metallicity are essential for Lyα escape and make a galaxy an Lyα emitter.

  10. Materials research for fusion

    NASA Astrophysics Data System (ADS)

    Knaster, J.; Moeslang, A.; Muroga, T.

    2016-05-01

    Fusion materials research started in the early 1970s following the observation of the degradation of irradiated materials used in the first commercial fission reactors. The technological challenges of fusion energy are intimately linked with the availability of suitable materials capable of reliably withstanding the extremely severe operational conditions of fusion reactors. Although fission and fusion materials exhibit common features, fusion materials research is broader. The harder mono-energetic spectrum associated with the deuterium-tritium fusion neutrons (14.1 MeV compared to <2 MeV on average for fission neutrons) releases significant amounts of hydrogen and helium as transmutation products that might lead to a (at present undetermined) degradation of structural materials after a few years of operation. Overcoming the historical lack of a fusion-relevant neutron source for materials testing is an essential pending step in fusion roadmaps. Structural materials development, together with research on functional materials capable of sustaining unprecedented power densities during plasma operation in a fusion reactor, have been the subject of decades of worldwide research efforts underpinning the present maturity of the fusion materials research programme.

  11. Optimal escapement in stage-structured fisheries with environmental stochasticity.

    PubMed

    Holden, Matthew H; Conrad, Jon M

    2015-11-01

    Stage-structured population models are commonly used to understand fish population dynamics and additionally for stock assessment. Unfortunately, there is little theory on the optimal harvest of stage-structured populations, especially in the presence of stochastic fluctuations. In this paper, we find closed form optimal equilibrium escapement policies for a three-dimensional, discrete-time, stage-structured population model with linear growth, post-harvest nonlinear recruitment, and stage-specific pricing and extend the analytic results to structured populations with environmental stochasticity. When only fishing reproductive adults, stochasticity does not affect optimal escapement policies. However, when harvesting immature fish, the addition of stochasticity can increase or decrease optimal escapement depending on the second and third derivative of the recruitment function. For logistic recruitment, stochasticity reduces optimal immature escapement by a multiplicative factor of one over one plus the variance of the environmental noise. Using hard clam, Mercenaria mercenaria, as an example and assuming Beverton-Holt recruitment, we show that optimal fishing of hard clam targets the immature stage class exclusively and that environmental stochasticity increases optimal escapement for low discount rates and decreases optimal escapement for high discount rates.

  12. Group chase and escape with sight-limited chasers

    NASA Astrophysics Data System (ADS)

    Wang, Huodong; Han, Wenchen; Yang, Junzhong

    2017-01-01

    We study group chase and escape with sight-limited chasers. Two search strategies, random-walk-strategy and relocation-strategy, are introduced for chasers when escapers are out of their fields of vision. There exist two regimes for the group lifetime of escapers. In the narrow sight regime, the group lifetime is a decreasing function of chasers' sight range. In the wide sight regime, the group lifetime stays at a constant when chasers adopting random-walk-strategy while increases with the sight range when chasers adopting relocation-strategy. The impacts of the two search strategies on group chase and escape are studied by investigating the lifetime distribution of all escapers and the dependence of the minimum lifetime on the number of chasers. We also find that, to reach the most efficient and the lowest energy cost chase for chasers, the ratio between the number of chasers and escapers stays at around 6 under random-walk-strategy. However, the optimal number of chasers vanishes and the energy cost monotonically increases with increasing the number of chasers under relocation-strategy.

  13. Extreme hydrodynamic atmospheric loss near the critical thermal escape regime

    NASA Astrophysics Data System (ADS)

    Erkaev, N. V.; Lammer, H.; Odert, P.; Kulikov, Yu. N.; Kislyakova, K. G.

    2015-04-01

    By considering martian-like planetary embryos inside the habitable zone of solar-like stars we study the behaviour of the hydrodynamic atmospheric escape of hydrogen for small values of the Jeans escape parameter β < 3, near the base of the thermosphere, that is defined as a ratio of the gravitational and thermal energy. Our study is based on a 1D hydrodynamic upper atmosphere model that calculates the volume heating rate in a hydrogen-dominated thermosphere due to the absorption of the stellar soft X-ray and extreme ultraviolet (XUV) flux. In case of a monatomic gas, we find that when the β value near the mesopause/homopause level exceeds a critical value of ˜2.5, there exists a steady hydrodynamic solution with a smooth transition from subsonic to supersonic flow. For a fixed XUV flux, the escape rate of the upper atmosphere is an increasing function of the temperature at the lower boundary. Our model results indicate a crucial enhancement of the atmospheric escape rate, when the Jeans escape parameter β decreases to this critical value. When β becomes ≤2.5, there is no stationary hydrodynamic transition from subsonic to supersonic flow. This is the case of a fast non-stationary atmospheric expansion that results in extreme thermal atmospheric escape rates.

  14. Foraging behavior delays mechanically-stimulated escape responses in fish.

    PubMed

    Bohórquez-Herrera, Jimena; Kawano, Sandy M; Domenici, Paolo

    2013-11-01

    Foraging and the evasion of predators are fundamental for the survival of organisms, but they impose contrasting demands that can influence performance in each behavior. Previous studies suggested that foraging organisms may experience decreased vigilance to attacks by predators; however, little is known about the effect of foraging on escape performance with respect to the kinematics and the timing of the response. This study tested the hypothesis that engaging in foraging activities affected escape performance by comparing fast-start escape responses of silver-spotted sculpins Blepsias cirrhosus under three conditions: (1) control (no foraging involved), (2) while targeting prey, and (3) immediately after capture of prey. Escape response variables (non-locomotor and locomotor) were analyzed from high-speed videos. Responsiveness was lower immediately after capturing a prey item compared with the other two treatments, and latency of performance was higher in the control treatment than in the other two. Locomotor variables such as maximum speed, maximum acceleration, and turning rates did not show statistical differences among the three groups. Our results demonstrate that foraging can negatively affect two fundamental components of the escape response: (1) responsiveness and (2) latency of escape, suggesting that engaging in foraging may decrease an individual's ability to successfully evade predators.

  15. Link between intraphagosomal biotin and rapid phagosomal escape in Francisella

    PubMed Central

    Napier, Brooke A.; Meyer, Lena; Bina, James E.; Miller, Mark A.; Sjöstedt, Anders; Weiss, David S.

    2012-01-01

    Cytosolic bacterial pathogens require extensive metabolic adaptations within the host to replicate intracellularly and cause disease. In phagocytic cells such as macrophages, these pathogens must respond rapidly to nutrient limitation within the harsh environment of the phagosome. Many cytosolic pathogens escape the phagosome quickly (15–60 min) and thereby subvert this host defense, reaching the cytosol where they can replicate. Although a great deal of research has focused on strategies used by bacteria to resist antimicrobial phagosomal defenses and transiently pass through this compartment, the metabolic requirements of bacteria in the phagosome are largely uncharacterized. We previously identified a Francisella protein, FTN_0818, as being essential for intracellular replication and involved in virulence in vivo. We now show that FTN_0818 is involved in biotin biosynthesis and required for rapid escape from the Francisella-containing phagosome (FCP). Addition of biotin complemented the phagosomal escape defect of the FTN_0818 mutant, demonstrating that biotin is critical for promoting rapid escape during the short time that the bacteria are in the phagosome. Biotin also rescued the attenuation of the FTN_0818 mutant during infection in vitro and in vivo, highlighting the importance of this process. The key role of biotin in phagosomal escape implies biotin may be a limiting factor during infection. We demonstrate that a bacterial metabolite is required for phagosomal escape of an intracellular pathogen, providing insight into the link between bacterial metabolism and virulence, likely serving as a paradigm for other cytosolic pathogens. PMID:23071317

  16. FGFR-TACC gene fusions in human glioma.

    PubMed

    Lasorella, Anna; Sanson, Marc; Iavarone, Antonio

    2016-11-16

    Chromosomal translocations joining in-frame members of the fibroblast growth factor receptor-transforming acidic coiled-coil gene families (the FGFR-TACC gene fusions) were first discovered in human glioblastoma multiforme (GBM) and later in many other cancer types. Here, we review this rapidly expanding field of research and discuss the unique biological and clinical features conferred to isocitrate dehydrogenase wild-type glioma cells by FGFR-TACC fusions. FGFR-TACC fusions generate powerful oncogenes that combine growth-promoting effects with aneuploidy through the activation of as yet unclear intracellular signaling mechanisms. FGFR-TACC fusions appear to be clonal tumor-initiating events that confer strong sensitivity to FGFR tyrosine kinase inhibitors. Screening assays have recently been reported for the accurate identification of FGFR-TACC fusion variants in human cancer, and early clinical data have shown promising effects in cancer patients harboring FGFR-TACC fusions and treated with FGFR inhibitors. Thus, FGFR-TACC gene fusions provide a "low-hanging fruit" model for the validation of precision medicine paradigms in human GBM.

  17. Trade-offs between performance and variability in the escape responses of bluegill sunfish (Lepomis macrochirus)

    PubMed Central

    Hitchcock, Amanda C.; Chen, Tiffany; Connolly, Erin; Darakananda, Karin; Jeong, Janet; Quist, Arbor; Robbins, Allison; Ellerby, David J.

    2015-01-01

    Successful predator evasion is essential to the fitness of many animals. Variation in escape behaviour may be adaptive as it reduces predictability, enhancing escape success. High escape velocities and accelerations also increase escape success, but biomechanical factors likely constrain the behavioural range over which performance can be maximized. There may therefore be a trade-off between variation and performance during escape responses. We have used bluegill sunfish (Lepomis macrochirus) escape responses to examine this potential trade-off, determining the full repertoire of escape behaviour for individual bluegill sunfish and linking this to performance as indicated by escape velocity and acceleration. Fish escapes involve an initial C-bend of the body axis, followed by variable steering movements. These generate thrust and establish the escape direction. Directional changes during the initial C-bend were less variable than the final escape angle, and the most frequent directions were associated with high escape velocity. Significant inter-individual differences in escape angles magnified the overall variation, maintaining unpredictability from a predator perspective. Steering in the latter stages of the escape to establish the final escape trajectory also affected performance, with turns away from the stimulus associated with reduced velocity. This suggests that modulation of escape behaviour by steering may also have an associated performance cost. This has important implications for understanding the scope and control of intra- and inter-individual variation in escape behaviour and the associated costs and benefits. PMID:25910940

  18. Muon Catalyzed Fusion

    NASA Technical Reports Server (NTRS)

    Armour, Edward A.G.

    2007-01-01

    Muon catalyzed fusion is a process in which a negatively charged muon combines with two nuclei of isotopes of hydrogen, e.g, a proton and a deuteron or a deuteron and a triton, to form a muonic molecular ion in which the binding is so tight that nuclear fusion occurs. The muon is normally released after fusion has taken place and so can catalyze further fusions. As the muon has a mean lifetime of 2.2 microseconds, this is the maximum period over which a muon can participate in this process. This article gives an outline of the history of muon catalyzed fusion from 1947, when it was first realised that such a process might occur, to the present day. It includes a description of the contribution that Drachrnan has made to the theory of muon catalyzed fusion and the influence this has had on the author's research.

  19. A New Strategy to Reduce Influenza Escape: Detecting Therapeutic Targets Constituted of Invariance Groups.

    PubMed

    Lao, Julie; Vanet, Anne

    2017-03-02

    The pathogenicity of the different flu species is a real public health problem worldwide. To combat this scourge, we established a method to detect drug targets, reducing the possibility of escape. Besides being able to attach a drug candidate, these targets should have the main characteristic of being part of an essential viral function. The invariance groups that are sets of residues bearing an essential function can be detected genetically. They consist of invariant and synthetic lethal residues (interdependent residues not varying or slightly varying when together). We analyzed an alignment of more than 10,000 hemagglutinin sequences of influenza to detect six invariance groups, close in space, and on the protein surface. In parallel we identified five potential pockets on the surface of hemagglutinin. By combining these results, three potential binding sites were determined that are composed of invariance groups located respectively in the vestigial esterase domain, in the bottom of the stem and in the fusion area. The latter target is constituted of residues involved in the spring-loaded mechanism, an essential step in the fusion process. We propose a model describing how this potential target could block the reorganization of the hemagglutinin HA2 secondary structure and prevent viral entry into the host cell.

  20. A New Strategy to Reduce Influenza Escape: Detecting Therapeutic Targets Constituted of Invariance Groups

    PubMed Central

    Lao, Julie; Vanet, Anne

    2017-01-01

    The pathogenicity of the different flu species is a real public health problem worldwide. To combat this scourge, we established a method to detect drug targets, reducing the possibility of escape. Besides being able to attach a drug candidate, these targets should have the main characteristic of being part of an essential viral function. The invariance groups that are sets of residues bearing an essential function can be detected genetically. They consist of invariant and synthetic lethal residues (interdependent residues not varying or slightly varying when together). We analyzed an alignment of more than 10,000 hemagglutinin sequences of influenza to detect six invariance groups, close in space, and on the protein surface. In parallel we identified five potential pockets on the surface of hemagglutinin. By combining these results, three potential binding sites were determined that are composed of invariance groups located respectively in the vestigial esterase domain, in the bottom of the stem and in the fusion area. The latter target is constituted of residues involved in the spring-loaded mechanism, an essential step in the fusion process. We propose a model describing how this potential target could block the reorganization of the hemagglutinin HA2 secondary structure and prevent viral entry into the host cell. PMID:28257108

  1. Magnetic fusion reactor economics

    SciTech Connect

    Krakowski, R.A.

    1995-12-01

    An almost primordial trend in the conversion and use of energy is an increased complexity and cost of conversion systems designed to utilize cheaper and more-abundant fuels; this trend is exemplified by the progression fossil fission {yields} fusion. The present projections of the latter indicate that capital costs of the fusion ``burner`` far exceed any commensurate savings associated with the cheapest and most-abundant of fuels. These projections suggest competitive fusion power only if internal costs associate with the use of fossil or fission fuels emerge to make them either uneconomic, unacceptable, or both with respect to expensive fusion systems. This ``implementation-by-default`` plan for fusion is re-examined by identifying in general terms fusion power-plant embodiments that might compete favorably under conditions where internal costs (both economic and environmental) of fossil and/or fission are not as great as is needed to justify the contemporary vision for fusion power. Competitive fusion power in this context will require a significant broadening of an overly focused program to explore the physics and simbiotic technologies leading to more compact, simplified, and efficient plasma-confinement configurations that reside at the heart of an attractive fusion power plant.

  2. Magnetic-confinement fusion

    NASA Astrophysics Data System (ADS)

    Ongena, J.; Koch, R.; Wolf, R.; Zohm, H.

    2016-05-01

    Our modern society requires environmentally friendly solutions for energy production. Energy can be released not only from the fission of heavy nuclei but also from the fusion of light nuclei. Nuclear fusion is an important option for a clean and safe solution for our long-term energy needs. The extremely high temperatures required for the fusion reaction are routinely realized in several magnetic-fusion machines. Since the early 1990s, up to 16 MW of fusion power has been released in pulses of a few seconds, corresponding to a power multiplication close to break-even. Our understanding of the very complex behaviour of a magnetized plasma at temperatures between 150 and 200 million °C surrounded by cold walls has also advanced substantially. This steady progress has resulted in the construction of ITER, a fusion device with a planned fusion power output of 500 MW in pulses of 400 s. ITER should provide answers to remaining important questions on the integration of physics and technology, through a full-size demonstration of a tenfold power multiplication, and on nuclear safety aspects. Here we review the basic physics underlying magnetic fusion: past achievements, present efforts and the prospects for future production of electrical energy. We also discuss questions related to the safety, waste management and decommissioning of a future fusion power plant.

  3. Escape from the competence state in Streptococcus mutans is governed by the bacterial population density.

    PubMed

    Dufour, D; Villemin, C; Perry, J A; Lévesque, C M

    2016-12-01

    Horizontal gene transfer through natural DNA transformation is an important evolutionary mechanism among bacteria. Transformation requires that the bacteria are physiologically competent to take and incorporate free DNA directly from the environment. Although natural genetic transformation is a remarkable feature of many naturally competent bacteria, the process is energetically expensive for the cells. Consequently, a tight control of the competence state is necessary. The objective of the present work was to help decipher the molecular mechanisms regulating the escape from the competence state in Streptococcus mutans, the principal etiological agent responsible for tooth decay in humans. Our results showed that the cessation of competence in S. mutans was abrupt, and did not involve the accumulation of a competence inhibitor nor the depletion of a competence activator in the extracellular environment. The competence state was repressed at high cell population density via concomitant repression of sigX gene encoding the master regulator of the competence regulon. Co-culture experiments performed with oral and non-oral bacteria showed that S. mutans assesses its own population density and also the microbial density of its surroundings to regulate its competence escape. Interestingly, neither the intra-species and extra-species quorum-sensing systems nor the other 13 two-component regulatory systems identified in S. mutans were involved in the cell-density-dependent escape of the competence state. Altogether, our results suggest a complex mechanism regulating the competence shut-off involving cell-density-dependent repression of sigX through an as yet undefined system, and possibly SigX protein stability.

  4. Green Pea Galaxies Reveal Secrets of Lyα Escape

    NASA Astrophysics Data System (ADS)

    Yang, Huan; Malhotra, Sangeeta; Gronke, Max; Rhoads, James E.; Jaskot, Anne; Zheng, Zhenya; Dijkstra, Mark; Wang, JunXian

    2016-01-01

    In star-forming galaxies, a lot of Lyα photons were generated in HII regions surrounding massive stars. The escape of Lyα photons from galaxies is a key issue in studying high redshift galaxies and probing cosmic reionization with Lyα. To understand Lyα escape, it is valuable to study high quality Lyα profiles in Lyα emitters. However, such studies are rare due to the faintness of high-z Lyα emitters and the lack of local analogs with high Lyα equivalent width. Here we show that "Green Pea" galaxies are the best local analogs of high-z Lyα emitters and their high quality Lyα profiles demonstrate low HI column density is the key to Lyα escape. The Lyα escape fraction shows correlations with the ratio of Lyα blue peak velocity to Hα line width, the normalized flux density at valley of Lyα profile, and a few other features of Lyα profiles. We compared the Lyα profiles with outflowing HI shell radiative transfer model and found that the best-fit HI column density is anti-correlated with the Lyα escape fraction. We also found an anti-correlation between Lyα escape fraction and galactic metallicity. Our results support that LAEs with high Lyα escape fraction have low metallicity, low HI column density, and mild HI gas outflow.

  5. Oxygen or carbogen breathing before simulated submarine escape.

    PubMed

    Gennser, M; Blogg, S L

    2008-01-01

    Raised internal pressure in a distressed submarine increases the risk of bubble formation and decompression illness after submarine escape. The hypothesis that short periods of oxygen breathing before submarine escape would reduce decompression stress was tested, using Doppler-detectable venous gas emboli as a measure. Twelve goats breathed oxygen for 15 min at 0.1 MPa before exposure to a simulated submarine escape profile to and from 2.5 MPa (240 m/seawater), whereas 28 control animals underwent the same dive without oxygen prebreathe. No decompression sickness (DCS) occurred in either of these two groups. Time with high bubble scores (Kisman-Masurel >or=3) was significantly (P < 0.001) shorter in the prebreathe group. In a second series, 30 goats breathed air at 0.2 MPa for 6 h. Fifteen minutes before escape from 2.5 MPa, animals were provided with either air (n = 10), oxygen (n = 12), or carbogen (97.5% O(2) and 2.5% CO(2)) gas (n = 8) as breathing gas. Animals breathed a hyperoxic gas (60% O(2)-40% N(2)) during the escape. Two animals (carbogen group) suffered oxygen convulsions during the escape but recovered on surfacing. Only one case of DCS occurred (carbogen group). The initial bubble score was reduced in the oxygen group (P < 0.001). The period with bubble score of Kisman-Masurel >or=3 was also significantly reduced in the oxygen group (P < 0.001). Oxygen breathing before submarine escape reduces initial bubble scores, although its significance in reducing central nervous system DCS needs to be investigated further.

  6. Fusion of mitochondria in tobacco suspension cultured cells is dependent on the cellular ATP level but not on actin polymerization.

    PubMed

    Wakamatsu, Kairo; Fujimoto, Masaru; Nakazono, Mikio; Arimura, Shin-ichi; Tsutsumi, Nobuhiro

    2010-10-01

    Mitochondria in plant cells undergo fusion and fission frequently. Although the mechanisms and proteins of mitochondrial fusion are well known in yeast and mammalian cells, they remain poorly understood in plant cells. To clarify the physiological requirements for plant mitochondrial fusion, we investigated the fusion frequency of mitochondria in tobacco cultured cells using the photoconvertible fluorescent protein Kaede and some physiological inhibitors. The latter included two uncouplers, 2,4-dinitrophenol (DNP) and carbonyl cyanide m-chlorophenylhydrazone (CCCP), an inhibitor of mitochondrial ATP synthase, oligomycin, and an actin polymerization inhibitor, latrunculin B (Lat B). The frequency of mitochondrial fusion was clearly reduced by DNP, CCCP and oligomycin, but not by Lat B, although Lat B severely inhibited mitochondrial movement. Moreover, DNP, CCCP and oligomycin evidently lowered the cellular ATP levels. These results indicate that plant mitochondrial fusion depends on the cellular ATP level, but not on actin polymerization.

  7. Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation.

    PubMed

    Huber, Veronica; Camisaschi, Chiara; Berzi, Angela; Ferro, Simona; Lugini, Luana; Triulzi, Tiziana; Tuccitto, Alessandra; Tagliabue, Elda; Castelli, Chiara; Rivoltini, Licia

    2017-03-06

    The link between cancer metabolism and immunosuppression, inflammation and immune escape has generated major interest in investigating the effects of low pH on tumor immunity. Indeed, microenvironmental acidity may differentially impact on diverse components of tumor immune surveillance, eventually contributing to immune escape and cancer progression. Although the molecular pathways underlying acidity-related immune dysfunctions are just emerging, initial evidence indicates that antitumor effectors such as T and NK cells tend to lose their function and undergo a state of mostly reversible anergy followed by apoptosis, when exposed to low pH environment. At opposite, immunosuppressive components such as myeloid cells and regulatory T cells are engaged by tumor acidity to sustain tumor growth while blocking antitumor immune responses. Local acidity could also profoundly influence bioactivity and distribution of antibodies, thus potentially interfering with the clinical efficacy of therapeutic antibodies including immune checkpoint inhibitors. Hence tumor acidity is a central regulator of cancer immunity that orchestrates both local and systemic immunosuppression and that may offer a broad panel of therapeutic targets. This review outlines the fundamental pathways of acidity-driven immune dysfunctions and sheds light on the potential strategies that could be envisaged to potentiate immune-mediated tumor control in cancer patients.

  8. Small molecule fusion inhibitors: design, synthesis and biological evaluation of (Z)-3-(5-(3-benzyl-4-oxo-2-thioxothiazolidinylidene)methyl)-N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrroles and related derivatives targeting HIV-1 gp41.

    PubMed

    He, Xiao-Yang; Lu, Lu; Qiu, Jiayin; Zou, Peng; Yu, Fei; Jiang, Xing-Kai; Li, Lin; Jiang, Shibo; Liu, Shuwen; Xie, Lan

    2013-12-01

    By a scaffold elongation strategy, a series of (Z)-3-(5-(3-benzyl-4-oxo-2-thioxothiazolidinylidene)methyl)-N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrroles and related derivatives with a linear multi-aromatic-ring skeleton were designed, synthesized, and evaluated in HIV-1 gp41 and cellular assays. Among them, the most active compounds, 12e, 12g, and 12k with a one-carbon linker (n=1) between the rhodanine (C) and phenyl (D) rings, exhibited very promising inhibitory potency with IC50 values of 1.8-2.6 μM and EC50 values of 0.3-1.5 μM against gp41 6-HB formation and HIV-1 replication in MT-2 cells, respectively. Additionally, they were almost equally effective against both T20-sensitive and resistant strains. The related SAR studies and molecular modeling results provided potential for further developing a new class of non-peptide small molecular fusion inhibitors targeting the HIV-1 gp41.

  9. 1,2,3,9b-Tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 2: identification of BTA9881 as a preclinical candidate.

    PubMed

    Bond, Silas; Draffan, Alistair G; Fenner, Jennifer E; Lambert, John; Lim, Chin Yu; Lin, Bo; Luttick, Angela; Mitchell, Jeffrey P; Morton, Craig J; Nearn, Roland H; Sanford, Vanessa; Anderson, Kelly H; Mayes, Penelope A; Tucker, Simon P

    2015-02-15

    Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, young children and adults. 1,2,3,9b-Tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones with general structure 1 were previously identified as promising inhibitors of RSV targeting the fusion glycoprotein. In particular, the introduction of a nitrogen at the 8-position of the tricyclic core yielded lead compounds 2 and 3. Extensive exploration of the R(2) group established that certain heterocyclic amides conferred potent RSV A&B activity and a good balance of physicochemical and pharmacokinetic properties. The antiviral activity was found to reside in a single enantiomer and compound 33a, (9bS)-9b-(4-chlorophenyl)-1-(pyridin-3-ylcarbonyl)-1,2,3,9b-tetrahydro-5H-imidazo[1',2':1,2]pyrrolo[3,4-c]pyridin-5-one (known as BTA9881), was identified as a candidate for preclinical development.

  10. Cell fusion and nuclear fusion in plants.

    PubMed

    Maruyama, Daisuke; Ohtsu, Mina; Higashiyama, Tetsuya

    2016-12-01

    Eukaryotic cells are surrounded by a plasma membrane and have a large nucleus containing the genomic DNA, which is enclosed by a nuclear envelope consisting of the outer and inner nuclear membranes. Although these membranes maintain the identity of cells, they sometimes fuse to each other, such as to produce a zygote during sexual reproduction or to give rise to other characteristically polyploid tissues. Recent studies have demonstrated that the mechanisms of plasma membrane or nuclear membrane fusion in plants are shared to some extent with those of yeasts and animals, despite the unique features of plant cells including thick cell walls and intercellular connections. Here, we summarize the key factors in the fusion of these membranes during plant reproduction, and also focus on "non-gametic cell fusion," which was thought to be rare in plant tissue, in which each cell is separated by a cell wall.

  11. Single-File Escape of Colloidal Particles from Microfluidic Channels.

    PubMed

    Locatelli, Emanuele; Pierno, Matteo; Baldovin, Fulvio; Orlandini, Enzo; Tan, Yizhou; Pagliara, Stefano

    2016-07-15

    Single-file diffusion is a ubiquitous physical process exploited by living and synthetic systems to exchange molecules with their environment. It is paramount to quantify the escape time needed for single files of particles to exit from constraining synthetic channels and biological pores. This quantity depends on complex cooperative effects, whose predominance can only be established through a strict comparison between theory and experiments. By using colloidal particles, optical manipulation, microfluidics, digital microscopy, and theoretical analysis we uncover the self-similar character of the escape process and provide closed-formula evaluations of the escape time. We find that the escape time scales inversely with the diffusion coefficient of the last particle to leave the channel. Importantly, we find that at the investigated microscale, bias forces as tiny as 10^{-15}  N determine the magnitude of the escape time by drastically reducing interparticle collisions. Our findings provide crucial guidelines to optimize the design of micro- and nanodevices for a variety of applications including drug delivery, particle filtering, and transport in geometrical constrictions.

  12. History of oxygen and carbon escape from the Martian atmosphere

    NASA Technical Reports Server (NTRS)

    Luhmann, J. G.; Zhang, M. H. G.; Johnson, R. E.; Bougher, S. W.; Nagy, A. F.

    1992-01-01

    A fraction of the oxygen in the Martian atmosphere continually escapes to space because dissociative recombination of the O2(+) ions in the ionosphere can impart sufficient energy to the product O atoms. In addition, ionization of the extended atomic oxygen corona resulting from the above process adds to escape since the solar wind can carry away O(+) ions born above a few hundred km altitude. A further by-product of this ion-pickup by the solar wind is an additional population of escaping oxygen atoms that are sputtered from the atmosphere near the exobase by pickup ions that are on reentry rather than escaping trajectories. This sputtering process can also remove carbon in the form of intact or dissociated CO2 since all atoms and molecules in the 'target' gas are subject to the collisional energy transfer that characterizes sputtering. We have estimated the present rates of escape of oxygen and carbon due to these mechanisms, as well as the rates at several epochs in the history of the solar system.

  13. Enhancing Endosomal Escape for Intracellular Delivery of Macromolecular Biologic Therapeutics

    PubMed Central

    Lönn, Peter; Kacsinta, Apollo D.; Cui, Xian-Shu; Hamil, Alexander S.; Kaulich, Manuel; Gogoi, Khirud; Dowdy, Steven F.

    2016-01-01

    Bioactive macromolecular peptides and oligonucleotides have significant therapeutic potential. However, due to their size, they have no ability to enter the cytoplasm of cells. Peptide/Protein transduction domains (PTDs), also called cell-penetrating peptides (CPPs), can promote uptake of macromolecules via endocytosis. However, overcoming the rate-limiting step of endosomal escape into the cytoplasm remains a major challenge. Hydrophobic amino acid R groups are known to play a vital role in viral escape from endosomes. Here we utilize a real-time, quantitative live cell split-GFP fluorescence complementation phenotypic assay to systematically analyze and optimize a series of synthetic endosomal escape domains (EEDs). By conjugating EEDs to a TAT-PTD/CPP spilt-GFP peptide complementation assay, we were able to quantitatively measure endosomal escape into the cytoplasm of live cells via restoration of GFP fluorescence by intracellular molecular complementation. We found that EEDs containing two aromatic indole rings or one indole ring and two aromatic phenyl groups at a fixed distance of six polyethylene glycol (PEG) units from the TAT-PTD-cargo significantly enhanced cytoplasmic delivery in the absence of cytotoxicity. EEDs address the critical rate-limiting step of endosomal escape in delivery of macromolecular biologic peptide, protein and siRNA therapeutics into cells. PMID:27604151

  14. Enhancing Endosomal Escape for Intracellular Delivery of Macromolecular Biologic Therapeutics.

    PubMed

    Lönn, Peter; Kacsinta, Apollo D; Cui, Xian-Shu; Hamil, Alexander S; Kaulich, Manuel; Gogoi, Khirud; Dowdy, Steven F

    2016-09-08

    Bioactive macromolecular peptides and oligonucleotides have significant therapeutic potential. However, due to their size, they have no ability to enter the cytoplasm of cells. Peptide/Protein transduction domains (PTDs), also called cell-penetrating peptides (CPPs), can promote uptake of macromolecules via endocytosis. However, overcoming the rate-limiting step of endosomal escape into the cytoplasm remains a major challenge. Hydrophobic amino acid R groups are known to play a vital role in viral escape from endosomes. Here we utilize a real-time, quantitative live cell split-GFP fluorescence complementation phenotypic assay to systematically analyze and optimize a series of synthetic endosomal escape domains (EEDs). By conjugating EEDs to a TAT-PTD/CPP spilt-GFP peptide complementation assay, we were able to quantitatively measure endosomal escape into the cytoplasm of live cells via restoration of GFP fluorescence by intracellular molecular complementation. We found that EEDs containing two aromatic indole rings or one indole ring and two aromatic phenyl groups at a fixed distance of six polyethylene glycol (PEG) units from the TAT-PTD-cargo significantly enhanced cytoplasmic delivery in the absence of cytotoxicity. EEDs address the critical rate-limiting step of endosomal escape in delivery of macromolecular biologic peptide, protein and siRNA therapeutics into cells.

  15. Single-File Escape of Colloidal Particles from Microfluidic Channels

    NASA Astrophysics Data System (ADS)

    Locatelli, Emanuele; Pierno, Matteo; Baldovin, Fulvio; Orlandini, Enzo; Tan, Yizhou; Pagliara, Stefano

    2016-07-01

    Single-file diffusion is a ubiquitous physical process exploited by living and synthetic systems to exchange molecules with their environment. It is paramount to quantify the escape time needed for single files of particles to exit from constraining synthetic channels and biological pores. This quantity depends on complex cooperative effects, whose predominance can only be established through a strict comparison between theory and experiments. By using colloidal particles, optical manipulation, microfluidics, digital microscopy, and theoretical analysis we uncover the self-similar character of the escape process and provide closed-formula evaluations of the escape time. We find that the escape time scales inversely with the diffusion coefficient of the last particle to leave the channel. Importantly, we find that at the investigated microscale, bias forces as tiny as 10-15 N determine the magnitude of the escape time by drastically reducing interparticle collisions. Our findings provide crucial guidelines to optimize the design of micro- and nanodevices for a variety of applications including drug delivery, particle filtering, and transport in geometrical constrictions.

  16. Enhancing endosomal escape for nanoparticle mediated siRNA delivery

    NASA Astrophysics Data System (ADS)

    Ma, Da

    2014-05-01

    Gene therapy with siRNA is a promising biotechnology to treat cancer and other diseases. To realize siRNA-based gene therapy, a safe and efficient delivery method is essential. Nanoparticle mediated siRNA delivery is of great importance to overcome biological barriers for systemic delivery in vivo. Based on recent discoveries, endosomal escape is a critical biological barrier to be overcome for siRNA delivery. This feature article focuses on endosomal escape strategies used for nanoparticle mediated siRNA delivery, including cationic polymers, pH sensitive polymers, calcium phosphate, and cell penetrating peptides. Work has been done to develop different endosomal escape strategies based on nanoparticle types, administration routes, and target organ/cell types. Also, enhancement of endosomal escape has been considered along with other aspects of siRNA delivery to ensure target specific accumulation, high cell uptake, and low toxicity. By enhancing endosomal escape and overcoming other biological barriers, great progress has been achieved in nanoparticle mediated siRNA delivery.

  17. MAVEN measurements of photochemical escape of oxygen from the Martian atmosphere

    NASA Astrophysics Data System (ADS)

    Lillis, R. J.; Deighan, J.; Fox, J. L.; Bougher, S. W.; Cravens, T. E.; Lee, Y.; Mahaffy, P. R.; Benna, M.; Elrod, M. K.; Andersson, L.; McFadden, J.

    2015-10-01

    One of the primary goals of the Mars Atmosphere and Volatile Evolution Mission (MAVEN) mission is to characterize rates of atmospheric escape at the present epoch and relate those escape rates to solar drivers [1]. One of the major escape processes is known as photochemical escape, which is broadly defined as a process by which a) an exothermic reaction in the atmosphere/ionosphere results in an upward-traveling neutral particle whose velocity exceeds planetary escape velocity and b) the particle is not prevented from escaping through any subsequent collisions[2].At Mars, photochemical escape of oxygen is expected to be a significant channel for atmospheric escape, particularly in the early solar system when extreme ultraviolet (EUV) fluxes were much higher[3]. Thus characterizing this escape process is central to understanding the role escape to space has played in Mars' climate evolution.

  18. Controlled Nuclear Fusion.

    ERIC Educational Resources Information Center

    Glasstone, Samuel

    This publication is one of a series of information booklets for the general public published by The United States Atomic Energy Commission. Among the topics discussed are: Importance of Fusion Energy; Conditions for Nuclear Fusion; Thermonuclear Reactions in Plasmas; Plasma Confinement by Magnetic Fields; Experiments With Plasmas; High-Temperature…

  19. Antiproton catalyzed fusion

    SciTech Connect

    Morgan, D.L. Jr.; Perkins, L.J.; Haney, S.W.

    1995-05-15

    Because of the potential application to power production, it is important to investigate a wide range of possible means to achieve nuclear fusion, even those that may appear initially to be infeasible. In antiproton catalyzed fusion, the negative antiproton shields the repulsion between the positively charged nuclei of hydrogen isotopes, thus allowing a much higher level of penetration through the repulsive Coulomb barrier, and thereby greatly enhancing the fusion cross section. Because of their more compact wave function, the more massive antiprotons offer considerably more shielding than do negative muons. The effects of the shielding on fusion cross sections are most predominate, at low energies. If the antiproton could exist in the ground state with a nucleus for a sufficient time without annihilating, the fusion cross sections are so enhanced that at room temperature energies, values up to about 1,000 barns (that for d+t) would be possible. Unfortunately, the cross section for antiproton annihilation with the incoming nucleus is even higher. A model that provides an upper bound for the fusion to annihilation cross section for all relevant energies indicates that each antiproton will catalyze no more than about one fusion. Because the energy required to make one antiproton greatly exceeds the fusion energy that is released, this level of catalysis is far from adequate for power production.

  20. Fusion Science Education Outreach

    NASA Astrophysics Data System (ADS)

    Danielson, C. A.; DIII-D Education Group

    1996-11-01

    This presentation will focus on education outreach activities at General Atomics that have been expanded to include the general population on science education with a focus on fusion energy. Outreach materials are distributed upon request both nationally and internationally. These materials include a notebook containing copies of DIII--D tour panels, fusion poster, new fusion energy video, new fusion energy brochure, and the electromagnetic spectrum curriculum. The 1996 Fusion Forum (held in the House Caucus Room) included a student/ teacher lunch with Energy Secretary Hazel O'Leary and a private visit to the Forum exhibits. The continuing partnership with Kearny High School includes lectures, job shadowing, internship, equipment donations and an award-winning electric car-racing program. Development of distribution by CD of the existing interactive fusion energy kiosk and a virtual reality tour of the DIII--D facility are underway. The DIII--D fusion education WWW site includes e-mail addresses to ``Ask the Wizard,'' and/or receive GA's outreach materials. Steve Rodecker, a local science teacher, aided by DIII--D fusion staff, won his second Tapestry Award; he also was named the ``1995 National Science Teacher of the Year'' and will be present to share his experiences with the DIII--D educational outreach program.

  1. Two Horizons of Fusion

    ERIC Educational Resources Information Center

    Lo, Mun Ling; Chik, Pakey Pui Man

    2016-01-01

    In this paper, we aim to differentiate the internal and external horizons of "fusion." "Fusion" in the internal horizon relates to the structure and meaning of the object of learning as experienced by the learner. It clarifies the interrelationships among an object's critical features and aspects. It also illuminates the…

  2. Fusion Power Deployment

    SciTech Connect

    J.A. Schmidt; J.M. Ogden

    2002-02-06

    Fusion power plants could be part of a future portfolio of non-carbon dioxide producing energy supplies such as wind, solar, biomass, advanced fission power, and fossil energy with carbon dioxide sequestration. In this paper, we discuss key issues that could impact fusion energy deployment during the last half of this century. These include geographic issues such as resource availability, scale issues, energy storage requirements, and waste issues. The resource needs and waste production associated with fusion deployment in the U.S. should not pose serious problems. One important feature of fusion power is the fact that a fusion power plant should be locatable within most local or regional electrical distribution systems. For this reason, fusion power plants should not increase the burden of long distance power transmission to our distribution system. In contrast to fusion power, regional factors could play an important role in the deployment of renewable resources such as wind, solar and biomass or fossil energy with CO2 sequestration. We examine the role of these regional factors and their implications for fusion power deployment.

  3. Inhibition of Sendai virus fusion with phospholipid vesicles and human erythrocyte membranes by hydrophobic peptides

    SciTech Connect

    Kelsey, D.R.; Flanagan, T.D.; Young, J.E.; Yeagle, P.L. )

    1991-06-01

    Hydrophobic di- and tripeptides which are capable of inhibiting enveloped virus infection of cells are also capable of inhibiting at least three different types of membrane fusion events. Large unilamellar vesicles (LUV) of N-methyl dioleoylphosphatidylethanolamine (N-methyl DOPE), containing encapsulated 1-aminonaphthalene-3,6,8-trisulfonic acid (ANTS) and/or p-xylene bis(pyridinium bromide) (DPX), were formed by extrusion. Vesicle fusion and leakage were then monitored with the ANTS/DPX fluorescence assay. Sendai virus fusion with lipid vesicles and Sendai virus fusion with human erythrocyte membranes were measured by following the relief of fluorescence quenching of virus labeled with octadecylrhodamine B chloride (R18). This study found that the effectiveness of the peptides carbobenzoxy-L-Phe-L-Phe (Z-L-Phe-L-Phe), Z-L-Phe, Z-D-Phe, and Z-Gly-L-Phe-L-Phe in inhibiting N-methyl DOPE LUV fusion or fusion of virus with N-methyl DOPE LUV also paralleled their reported ability to block viral infectivity. Furthermore, Z-D-Phe-L-PheGly and Z-Gly-L-Phe inhibited Sendai virus fusion with human erythrocyte membranes with the same relative potency with which they inhibited vesicle-vesicle and virus-vesicle fusion. The evidence suggests a mechanism by which these peptides exert their inhibition of plaque formation by enveloped viruses. This class of inhibitors apparently acts by inhibiting fusion of the viral envelope with the target cell membrane, thereby preventing viral infection. The physical pathway by which these peptides inhibit membrane fusion was investigated. {sup 31}P nuclear magnetic resonance (NMR) of proposed intermediates in the pathway for membrane fusion in LUV revealed that the potent fusion inhibitor Z-D-Phe-L-PheGly selectively altered the structure (or dynamics) of the hypothesized fusion intermediates and that the poor inhibitor Z-Gly-L-Phe did not.

  4. Angiogenesis Inhibitors

    MedlinePlus

    ... inhibitors: current strategies and future prospects. CA: A Cancer Journal for Clinicians 2010; 60(4):222–243. [PubMed Abstract] Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nature Reviews Clinical Oncology 2009; 6(8):465– ...

  5. Carboxylesterase inhibitors

    PubMed Central

    Hatfield, M. Jason; Potter, Philip M.

    2011-01-01

    Introduction Carboxylesterases play major roles in the hydrolysis of numerous therapeutically active compounds. This is, in part, due to the prevalence of the ester moiety in these small molecules. However, the impact these enzymes may play on drug stability and pharmacokinetics is rarely considered prior to molecule development. Therefore, the application of selective inhibitors of this class of proteins may have utility in modulating the metabolism, distribution and toxicity of agents that are subjected to enzyme hydrolysis. Areas covered This review details the development of all such compounds dating back to 1986, but principally focuses on the very recent identification of selective human carboxylesterases inhibitors. Expert opinion The implementation of carboxylesterase inhibitors may significantly revolutionize drug discovery. Such molecules may allow for improved efficacy of compounds inactivated by this class of enzymes and/or reduce the toxicity of agents that are activated by these proteins. Furthermore, since lack of carboxylesterase activity appears to have no obvious biological consequence, these compounds could be applied in combination with virtually any esterified drug. Therefore, inhibitors of these proteins may have utility in altering drug hydrolysis and distribution in vivo. The characteristics, chemical and biological properties, and potential uses of such agents, are discussed here. PMID:21609191

  6. Escape rate and diffusion of a Stochastically Driven particle

    PubMed Central

    Piscitelli, Antonio; Pica Ciamarra, Massimo

    2017-01-01

    The dynamical properties of a tracer repeatedly colliding with heat bath particles can be described within a Langevin framework provided that the tracer is more massive than the bath particles, and that the collisions are frequent. Here we consider the escape of a particle from a potential well, and the diffusion coefficient in a periodic potential, without making these assumptions. We have thus investigated the dynamical properties of a Stochastically Driven particle that moves under the influence of the confining potential in between successive collisions with the heat bath. In the overdamped limit, both the escape rate and the diffusion coefficient coincide with those of a Langevin particle. Conversely, in the underdamped limit the two dynamics have a different temperature dependence. In particular, at low temperature the Stochastically Driven particle has a smaller escape rate, but a larger diffusion coefficient. PMID:28120904

  7. Mean escape time in a system with stochastic volatility

    NASA Astrophysics Data System (ADS)

    Bonanno, Giovanni; Valenti, Davide; Spagnolo, Bernardo

    2007-01-01

    We study the mean escape time in a market model with stochastic volatility. The process followed by the volatility is the Cox, Ingersoll, and Ross process which is widely used to model stock price fluctuations. The market model can be considered as a generalization of the Heston model, where the geometric Brownian motion is replaced by a random walk in the presence of a cubic nonlinearity. We investigate the statistical properties of the escape time of the returns, from a given interval, as a function of the three parameters of the model. We find that the noise can have a stabilizing effect on the system, as long as the global noise is not too high with respect to the effective potential barrier experienced by a fictitious Brownian particle. We compare the probability density function of the return escape times of the model with those obtained from real market data. We find that they fit very well.

  8. Kramers escape of a self-propelled particle

    NASA Astrophysics Data System (ADS)

    Geiseler, Alexander; Hänggi, Peter; Schmid, Gerhard

    2016-08-01

    We investigate the escape rate of an overdamped, self-propelled spherical Brownian particle on a surface from a metastable potential well. Within a modeling in terms of a 1D constant speed of the particle's active dynamics we consider the associated rate using both numerical and analytical approaches. Regarding the properties of the stationary state in the potential well, two major timescales exist, each governing the translational and the rotational dynamics of the particle, respectively. The particle radius is identified to present the essential quantity in charge of regulating the ratio between those timescales. For very small and very large particle radii, approximate analytic expressions for the particle's escape rate can be derived, which, within their respective range of validity, compare favorably with the precise escape numerics of the underlying full two-dimensional Fokker-Planck description.

  9. Coexisting chaotic and periodic dynamics in clock escapements.

    PubMed

    Moon, Francis C; Stiefel, Preston D

    2006-09-15

    This paper addresses the nature of noise in machines. As a concrete example, we examine the dynamics of clock escapements from experimental, historical and analytical points of view. Experiments on two escapement mechanisms from the Reuleaux kinematic collection at Cornell University are used to illustrate chaotic-like noise in clocks. These vibrations coexist with the periodic dynamics of the balance wheel or pendulum. A mathematical model is presented that shows how self-generated chaos in clocks can break the dry friction in the gear train. This model is shown to exhibit a strange attractor in the structural vibration of the clock. The internal feedback between the oscillator and the escapement structure is similar to anti-control of chaos models.

  10. Social escape behaviors in children with fragile X syndrome.

    PubMed

    Hall, Scott; DeBernardis, Marie; Reiss, Allan

    2006-10-01

    Social escape behavior is a common behavioral feature of individuals with fragile X syndrome (fraX). In this observational study, we examined the effect of antecedent social and performance demands on problem behaviors in four conditions: face-to-face interview, silent reading, oral reading and a singing task. Results showed that problem behaviors were significantly more likely to occur during the interview and singing conditions. Higher levels of salivary cortisol were predictive of higher levels of fidgeting behavior and lower levels of eye contact in male participants. There were no associations between level of FMRP expression and social escape behaviors. These data suggest that specific antecedent biological and environmental factors evoke social escape behaviors in fragile X syndrome.

  11. Exploring the Escape of Hydrogen Ionizing Photons from Local Galaxies

    NASA Astrophysics Data System (ADS)

    Davis, Jesse A.; Rosenberg, Jessica L.; Venkatesan, Aparna; Cannon, John M.; Salzer, John Joseph

    2016-01-01

    Low-mass galaxies dominate the universe by number and many of these systems have large star formation rates per unit mass. Measurements of the escape fraction of ionizing radiation from dwarf galaxies are an important input to cosmological simulations and theoretical studies but are largely unconstrained by observations. As a result, the role of low-mass galaxies in cosmological reionization and the ionization state of the intergalactic medium (IGM) at high and low redshifts remains poorly understood. Here we study a sample of 18 star-forming galaxies (12 from the Lyman-Alpha Reference Sample, Rivera-Thorsen et al. 2015; 6 from the KISS sample, Salzer et al. 2001), some of which are low-mass systems (10 with M_star < 5 x 10^9 M_sun). All of the sample galaxies were observed in the FUV with the HST/COS spectrograph and these measurements were used to derive limits on their escaping Lyman-alpha radiation (Rivera-Thorsen et al. 2015, Wofford et al. 2013). Using the numerical radiative transfer simulations of Yajima et al. 2014, we relate the escape of Lyman-alpha radiation to limits on the fraction of escaping H-ionizing radiation from these galaxies. This correlation is stronger for low-redshift galaxies (Yajima et al. 2014) and these galaxies are more accessible observationally for these studies. Although the Yajima et al. (2014) study focuses on high-mass galaxies, we derive tentative limits on the escape fraction for H-ionizing radiation for all of the galaxies in this sample. From our analysis, we find escape fractions of less than 5% in all but two extreme cases where the escape fractions are greater than 14%. Our sample averaged escape fraction is insufficient for what reionization requires, although our values are likely to be lower limits and the two outliers are two of the lowest mass systems from the LARS sample. We discuss future directions, including further modeling of the radiative transfer and the galaxy's physical conditions, to better understand the

  12. Rapid endosomal escape of prickly nanodiamonds: implications for gene delivery

    NASA Astrophysics Data System (ADS)

    Chu, Zhiqin; Miu, Kaikei; Lung, Pingsai; Zhang, Silu; Zhao, Saisai; Chang, Huan-Cheng; Lin, Ge; Li, Quan

    2015-06-01

    The prickly nanodiamonds easily entered cells via endocytosis followed by unique intracellular translocation characteristics—quick endosomal escape followed by stable residence in cytoplasm. Endosomal membrane rupturing is identified as the major route of nanodiamonds’ escaping the vesicle confinement and to the cytoplasm. Little cytotoxicity is observed to associate with the nanodiamonds’ cytosolic release. Such features enable its application for gene delivery, which requires both effective cellular uptake and cytosolic release of the gene. Taking green fluorescent protein gene as an example, we demonstrate the successful cytosolic delivery and expression of such a gene using the prickly nanodiamonds as carrier.

  13. Case of escape in cassava, Manihot esculenta Crantz.

    PubMed

    Nassar, N M A; Mendonza, M

    2017-02-08

    Two cassava escapes where collected from cultivated fields near natural habitat in Bolivia. They are described morphologically and analyzed cytogenetically in this study. It is suggested that they are the product of backcrosses of cassava interspecific hybrids with the cultigen itself, and that selective conditions have developed in which certain forms of cassava segregates have adapted to grow wildly in natural habitats near cassava fields. These segregates may hybridize with cultivated cassava upon coming in contact with such varieties. Because these escapes have incorporated useful genes from the wild into their genetic structure, they could be used for cassava improvement since their genetic barriers with other forms of cassava are very weak.

  14. Fusion Studies in Japan

    NASA Astrophysics Data System (ADS)

    Ogawa, Yuichi

    2016-05-01

    A new strategic energy plan decided by the Japanese Cabinet in 2014 strongly supports the steady promotion of nuclear fusion development activities, including the ITER project and the Broader Approach activities from the long-term viewpoint. Atomic Energy Commission (AEC) in Japan formulated the Third Phase Basic Program so as to promote an experimental fusion reactor project. In 2005 AEC has reviewed this Program, and discussed on selection and concentration among many projects of fusion reactor development. In addition to the promotion of ITER project, advanced tokamak research by JT-60SA, helical plasma experiment by LHD, FIREX project in laser fusion research and fusion engineering by IFMIF were highly prioritized. Although the basic concept is quite different between tokamak, helical and laser fusion researches, there exist a lot of common features such as plasma physics on 3-D magnetic geometry, high power heat load on plasma facing component and so on. Therefore, a synergetic scenario on fusion reactor development among various plasma confinement concepts would be important.

  15. Indoleamine 2,3-dioxygenase pathways of pathgenic inflammation and immune escape in cancer

    PubMed Central

    Prendergast, George C.; Smith, Courtney; Thomas, Sunil; Mandik-Nayak, Laura; Laury-Kleintop, Lisa; Metz, Richard; Muller, Alexander J.

    2014-01-01

    Genetic and pharmacological studies of indoleamine 2,3-dioxygenase (IDO) have established this tryptophan catabolic enzyme as a central driver of malignant development and progression. IDO acts in tumor, stromal and immune cells to support pathogenic inflammatory processes that engender immune tolerance to tumor antigens. The multifaceted effects of IDO activation in cancer include the suppression of T and NK cells, the generation and activation of T regulatory cells (Treg) and myeloid-derived suppressor cells (MDSC), and the promotion of tumor angiogenesis. Mechanistic investigations have defined the aryl hydrocarbon receptor AhR, the master metabolic regulator mTORC1 and the stress kinase Gcn2 as key effector signaling elements for IDO, which also exerts a non-catalytic role in TGF-β signaling. Small molecule inhibitors of IDO exhibit anticancer activity and cooperate with immunotherapy, radiotherapy or chemotherapy to trigger rapid regression of aggressive tumors otherwise resistant to treatment. Notably, the dramatic antitumor activity of certain targeted therapeutics such as imatinib (Gleevec) in GIST has been traced in part to IDO downregulation. Further, antitumor responses to immune checkpoint inhibitors can be heightened safely by a clinical lead inhibitor of the IDO pathway that relieves IDO-mediated suppression of mTORC1 in T cells. In this personal perspective on IDO as a nodal mediator of pathogenic inflammation and immune escape in cancer, we provide a conceptual foundation for the clinical development of IDO inhibitors as a novel class of immunomodulators with broad application in the treatment of advanced human cancer. PMID:24711084

  16. Particle beam fusion

    SciTech Connect

    1980-12-31

    Today, in keeping with Sandia Laboratories` designation by the Department of Energy as the lead laboratory for the pulsed power approach to fusion, its efforts include major research activities and the construction of new facilities at its Albuquerque site. Additionally, in its capacity as lead laboratory, Sandia coordinates DOE-supported pulsed power fusion work at other government operated laboratories, with industrial contractors, and universities. The beginning of Sandia`s involvement in developing fusion power was an outgrowth of its contributions to the nation`s nuclear weapon program. The Laboratories` work in the early 1960`s emphasized the use of pulsed radiation environments to test the resistance of US nuclear weapons to enemy nuclear bursts. A careful study of options for fusion power indicated that Sandia`s expertise in the pulsed power field could provide a powerful match to ignite fusion fuel. Although creating test environments is an achieved goal of Sandia`s overall program, this work and other military tasks protected by appropriate security regulations will continue, making full use of the same pulsed power technology and accelerators as the fusion-for-energy program. Major goals of Sandia`s fusion program including the following: (1) complete a particle accelerator to deliver sufficient beam energy for igniting fusion targets; (2) obtain net energy gain, this goal would provide fusion energy output in excess of energy stored in the accelerator; (3) develop a technology base for the repetitive ignition of pellets in a power reactor. After accomplishing these goals, the technology will be introduced to the nation`s commercial sector.

  17. Spherical torus fusion reactor

    DOEpatents

    Martin Peng, Y.K.M.

    1985-10-03

    The object of this invention is to provide a compact torus fusion reactor with dramatic simplification of plasma confinement design. Another object of this invention is to provide a compact torus fusion reactor with low magnetic field and small aspect ratio stable plasma confinement. In accordance with the principles of this invention there is provided a compact toroidal-type plasma confinement fusion reactor in which only the indispensable components inboard of a tokamak type of plasma confinement region, mainly a current conducting medium which carries electrical current for producing a toroidal magnet confinement field about the toroidal plasma region, are retained.

  18. Fusion for Space Propulsion

    NASA Technical Reports Server (NTRS)

    Thio, Y. C. Francis; Schafer, Charles (Technical Monitor)

    2001-01-01

    There is little doubt that humans will attempt to explore and develop the solar system in this century. A large amount of energy will be required for accomplishing this. The need for fusion propulsion is discussed. For a propulsion system, there are three important thermodynamical attributes: (1) The absolute amount of energy available, (2) the propellant exhaust velocity, and (3) the jet power per unit mass of the propulsion system (specific power). For human exploration and development of the solar system, propellant exhaust velocity in excess of 100 km/s and specific power in excess of 10 kW/kg are required. Chemical combustion can produce exhaust velocity up to about 5 km/s. Nuclear fission processes typically result in producing energy in the form of heat that needs to be manipulated at temperatures limited by materials to about 2,800 K. Using the energy to heat a hydrogen propellant increases the exhaust velocity by only a factor of about two. Alternatively the energy can be converted into electricity which is then used to accelerate particles to high exhaust velocity. The necessary power conversion and conditioning equipment, however, increases the mass of the propulsion system for the same jet power by more than two orders of magnitude over chemical system, thus greatly limits the thrust-to-weight ratio attainable. The principal advantage of the fission process is that its development is relatively mature and is available right now. If fusion can be developed, fusion appears to have the best of all worlds in terms of propulsion - it can provide the absolute amount, the propellant exhaust velocity, and the high specific jet power. An intermediate step towards pure fusion propulsion is a bimodal system in which a fission reactor is used to provide some of the energy to drive a fusion propulsion unit. The technical issues related to fusion for space propulsion are discussed. The technical priorities for developing and applying fusion for propulsion are

  19. Induction of Cell-Cell Fusion by Ebola Virus Glycoprotein: Low pH Is Not a Trigger.

    PubMed

    Markosyan, Ruben M; Miao, Chunhui; Zheng, Yi-Min; Melikyan, Gregory B; Liu, Shan-Lu; Cohen, Fredric S

    2016-01-01

    Ebola virus (EBOV) is a highly pathogenic filovirus that causes hemorrhagic fever in humans and animals. Currently, how EBOV fuses its envelope membrane within an endosomal membrane to cause infection is poorly understood. We successfully measure cell-cell fusion mediated by the EBOV fusion protein, GP, assayed by the transfer of both cytoplasmic and membrane dyes. A small molecule fusion inhibitor, a neutralizing antibody, as well as mutations in EBOV GP known to reduce viral infection, all greatly reduce fusion. By monitoring redistribution of small aqueous dyes between cells and by electrical capacitance measurements, we discovered that EBOV GP-mediated fusion pores do not readily enlarge-a marked difference from the behavior of other viral fusion proteins. EBOV GP must be cleaved by late endosome-resident cathepsins B or L in order to become fusion-competent. Cleavage of cell surface-expressed GP appears to occur in endosomes, as evidenced by the fusion block imposed by cathepsin inhibitors, agents that raise endosomal pH, or an inhibitor of anterograde trafficking. Treating effector cells with a recombinant soluble cathepsin B or thermolysin, which cleaves GP into an active form, increases the extent of fusion, suggesting that a fraction of surface-expressed GP is not cleaved. Whereas the rate of fusion is increased by a brief exposure to acidic pH, fusion does occur at neutral pH. Importantly, the extent of fusion is independent of external pH in experiments in which cathepsin activity is blocked and EBOV GP is cleaved by thermolysin. These results imply that low pH promotes fusion through the well-known pH-dependent activity of cathepsins; fusion induced by cleaved EBOV GP is a process that is fundamentally independent of pH. The cell-cell fusion system has revealed some previously unappreciated features of EBOV entry, which could not be readily elucidated in the context of endosomal entry.

  20. Development of three-layered rumen escapable capsules for cattle

    PubMed Central

    SEYAMA, Tomohiro; HIRAYASU, Hirofumi; YAMAWAKI, Kenji; ADACHI, Takuhiko; SUGIMOTO, Takayuki; KASAI, Koji

    2016-01-01

    A new rumen escapable tool is presented for cattle in prospect of developing medical treatment or supplementing trace elements for disease prevention. This tool consists of a three-layered capsule that dissolves in the lower digestive tract, but not in the rumen. The capsule was manufactured by capsule-forming techniques through the use of liquid surface tension. This method does not involve high-temperature treatment, so the capsule can contain not only lipophilic substances but also hydrophilic or heat-sensitive substances. Furthermore, the capsule has a specific gravity of 1.3 and diameter of 6.0 mm, which were previously shown to be appropriate to avoid rumination. The objective of this study was to confirm the effectiveness of the capsule pertinent to rumen escaping. In order to validate rumen escape, capsules containing 30 g of water-soluble vitamin (thiamine hydrochloride) per head were administered to four lactating cows assigned in a crossover trial. In the group administered encapsulated thiamine hydrochloride, blood thiamine levels increased from 12.4 ± 1.03 ng/ml before administration to 54.8 ± 2.21 ng/ml at 6 hr following administration, whereas the level remained at 13.3 ± 2.05 ng/ml in the control group administered via aqueous solution. This indicates that the three-layered capsules passed through the rumen and dissolved in the lower digestive tract, thus functioning as a rumen escapable tool. PMID:27546371

  1. 46 CFR 177.500 - Means of escape.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... escape must be widely separated and, if possible, at opposite ends or sides of the space to minimize the... elevator enclosures, elevated stages, bars, and cashier stands, but not including slot machines, tables, or... necessary for handling lifesaving equipment, anchor handling equipment, or line handling gear, or in way...

  2. 46 CFR 177.500 - Means of escape.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... escape must be widely separated and, if possible, at opposite ends or sides of the space to minimize the... elevator enclosures, elevated stages, bars, and cashier stands, but not including slot machines, tables, or... necessary for handling lifesaving equipment, anchor handling equipment, or line handling gear, or in way...

  3. 46 CFR 177.500 - Means of escape.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... escape must be widely separated and, if possible, at opposite ends or sides of the space to minimize the... elevator enclosures, elevated stages, bars, and cashier stands, but not including slot machines, tables, or... necessary for handling lifesaving equipment, anchor handling equipment, or line handling gear, or in way...

  4. 46 CFR 177.500 - Means of escape.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... escape must be widely separated and, if possible, at opposite ends or sides of the space to minimize the... elevator enclosures, elevated stages, bars, and cashier stands, but not including slot machines, tables, or... necessary for handling lifesaving equipment, anchor handling equipment, or line handling gear, or in way...

  5. 46 CFR 177.500 - Means of escape.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... escape must be widely separated and, if possible, at opposite ends or sides of the space to minimize the... elevator enclosures, elevated stages, bars, and cashier stands, but not including slot machines, tables, or... necessary for handling lifesaving equipment, anchor handling equipment, or line handling gear, or in way...

  6. 46 CFR 108.445 - Alarm and means of escape.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 4 2010-10-01 2010-10-01 false Alarm and means of escape. 108.445 Section 108.445 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) A-MOBILE OFFSHORE DRILLING UNITS DESIGN AND EQUIPMENT Fire Extinguishing Systems Fixed Carbon Dioxide Fire Extinguishing Systems §...

  7. Evolving Project E-Scape for National Assessment

    ERIC Educational Resources Information Center

    Kimbell, Richard

    2012-01-01

    In the opening paper in this Special Edition I outlined the major issues that led to the establishment of "project e-scape". The project was intended to develop systems and approaches that enabled learners to build real-time web-based portfolios of their performance (initially) in design & technology and additionally to build systems…

  8. 75 FR 61386 - Emergency Escape Breathing Apparatus Standards

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-05

    ...FRA is proposing to amend its regulations related to occupational safety and health in locomotive cabs in three ways. First and foremost, pursuant to a 2008 Congressional mandate, FRA is proposing to include requirements that railroads provide an appropriate atmosphere-supplying emergency escape breathing apparatus (EEBA) to the members of the train crew and certain other employees while they......

  9. Enuresis Control through Fading, Escape, and Avoidance Training.

    ERIC Educational Resources Information Center

    Hansen, Gordon D.

    1979-01-01

    A twin signal device that provides both escape and avoidance conditioning in enuresis control was documented with case studies of two enuretic children (eight and nine years old). In addition, a technique of fading as an adjunct to the process was utilized with one subject. (Author/SBH)

  10. 46 CFR 169.313 - Means of escape.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 7 2014-10-01 2014-10-01 false Means of escape. 169.313 Section 169.313 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) NAUTICAL SCHOOLS SAILING SCHOOL VESSELS Construction... apart, uniform for the length of the ladder; (3) At least 3 inches from the nearest permanent object...

  11. 46 CFR 169.313 - Means of escape.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 7 2013-10-01 2013-10-01 false Means of escape. 169.313 Section 169.313 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) NAUTICAL SCHOOLS SAILING SCHOOL VESSELS Construction... apart, uniform for the length of the ladder; (3) At least 3 inches from the nearest permanent object...

  12. 12. CLOSEUP VIEW FROM NORTHWEST, SHOWING DETAILS OF FIRE ESCAPE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    12. CLOSE-UP VIEW FROM NORTHWEST, SHOWING DETAILS OF FIRE ESCAPE NEAR CORNER OF MILLS HALL MAIN WING NORTH WALL, AND MILLS HALL NORTH WING WEST WALL. - Mills Hall, Mills College, 5000 MacArthur Boulevard, Oakland, Alameda County, CA

  13. Magnetic buoyancy and the escape of magnetic fields from stars

    NASA Astrophysics Data System (ADS)

    Parker, E. N.

    1984-06-01

    Magnetic buoyancy causes the azimuthal magnetic fields of stars to rise rapidly to the surface, from where they are generally assumed to escape freely into space. However, a closer look at the problem reveals the simple fact that disengagement of the field from the gas, and escape into space, require a convoluted field configuration, producing neutral point reconnection of the flux in the tenuous gas above the surface of the star. Only that flux which reconnects can escape. Recent observations of the magnetic fields emerging through the surface of the Sun show that even at sunspot maximum the gaps in longitude between bipolar magnetic regions are so wide as to limit severely the reconnection between regions. We suggest from the observations that no more than perhaps 3% of the flux that is observed to emerge through the surface is able to reconnect and escape. Hence the surface of the Sun approximates to an impenetrable barrier rather than an open surface, with quantitative consequences for theoretical dynamo models. Recent observations of the retraction of bipolar fields at the end of their appearance at the surface suggest active dynamical control by the convection beneath the surface.

  14. Speed kills: ineffective avian escape responses to oncoming vehicles

    PubMed Central

    DeVault, Travis L.; Blackwell, Bradley F.; Seamans, Thomas W.; Lima, Steven L.; Fernández-Juricic, Esteban

    2015-01-01

    Animal–vehicle collisions cause high levels of vertebrate mortality worldwide, and what goes wrong when animals fail to escape and ultimately collide with vehicles is not well understood. We investigated alert and escape behaviours of captive brown-headed cowbirds (Molothrus ater) in response to virtual vehicle approaches of different sizes and at speeds ranging from 60 to 360 km h−1. Alert and flight initiation distances remained similar across vehicle speeds, and accordingly, alert and flight initiation times decreased at higher vehicle speeds. Thus, avoidance behaviours in cowbirds appeared to be based on distance rather than time available for escape, particularly at 60–150 km h−1; however, at higher speeds (more than or equal to 180 km h−1) no trend in response behaviour was discernible. As vehicle speed increased, cowbirds did not have enough time to assess the approaching vehicle, and cowbirds generally did not initiate flight with enough time to avoid collision when vehicle speed exceeded 120 km h−1. Although potentially effective for evading predators, the decision-making process used by cowbirds in our study appears maladaptive in the context of avoiding fast-moving vehicles. Our methodological approach and findings provide a framework to assess how novel management strategies could affect escape rules, and the sensory and cognitive abilities animals use to avoid vehicle collisions. PMID:25567648

  15. 46 CFR 108.445 - Alarm and means of escape.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 4 2011-10-01 2011-10-01 false Alarm and means of escape. 108.445 Section 108.445 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) A-MOBILE OFFSHORE DRILLING UNITS DESIGN AND EQUIPMENT Fire Extinguishing Systems Fixed Carbon Dioxide Fire Extinguishing Systems §...

  16. 46 CFR 108.445 - Alarm and means of escape.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Alarm and means of escape. (a) Each CO2 system that has a supply of more than 136 kilograms (300 pounds) of CO2, except a system that protects a tank, must have an alarm that sounds for at least 20 seconds before the CO2 is released into the space. (b) Each audible alarm for a CO2 system must have the...

  17. Brain size as a driver of avian escape strategy.

    PubMed

    Samia, Diogo S M; Pape Møller, Anders; Blumstein, Daniel T

    2015-07-03

    After detecting an approaching predator, animals make a decision when to flee. Prey will initiate flight soon after detecting a predator so as to minimize attentional costs related to on-going monitoring of the whereabouts of the predator. Such costs may compete with foraging and other maintenance activities and hence be larger than the costs of immediate flight. The drivers of interspecific variation in escape strategy are poorly known. Here we investigated the morphological, life history and natural history traits that correlate with variation in avian escape strategy across a sample of 96 species of birds. Brain mass, body size, habitat structure and group size were the main predictors of escape strategy. The direction of the effect of these traits was consistent with selection for a reduction of monitoring costs. Therefore, attentional costs depend on relative brain size, which determines the ability to monitor the whereabouts of potential predators and the difficulty of this task as reflected by habitat and social complexity. Thus brain size, and the cognitive functions associated with it, constitute a general framework for explaining the effects of body size, habitat structure and sociality identified as determinants of avian escape strategy.

  18. 46 CFR 108.445 - Alarm and means of escape.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... Alarm and means of escape. (a) Each CO2 system that has a supply of more than 136 kilograms (300 pounds) of CO2, except a system that protects a tank, must have an alarm that sounds for at least 20 seconds before the CO2 is released into the space. (b) Each audible alarm for a CO2 system must have the...

  19. 46 CFR 108.445 - Alarm and means of escape.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Alarm and means of escape. (a) Each CO2 system that has a supply of more than 136 kilograms (300 pounds) of CO2, except a system that protects a tank, must have an alarm that sounds for at least 20 seconds before the CO2 is released into the space. (b) Each audible alarm for a CO2 system must have the...

  20. Spatial and Nonspatial Escape Strategies in the Barnes Maze

    ERIC Educational Resources Information Center

    Harrison, Fiona E.; Reiserer, Randall S.; Tomarken, Andrew J.; McDonald, Michael P.

    2006-01-01

    The Barnes maze is a spatial memory task that requires subjects to learn the position of a hole that can be used to escape the brightly lit, open surface of the maze. Two experiments assessed the relative importance of spatial (extra-maze) versus proximal visible cues in solving the maze. In Experiment 1, four groups of mice were trained either…

  1. Seasonal Dependence of the Escape of Martian Water

    NASA Astrophysics Data System (ADS)

    Clarke, John

    2013-10-01

    This proposal is to obtain ACS/SBC images and STIS spectra of the extended H Ly alpha and O 1304 emissions from H and O atoms in the atmosphere of Mars to study seasonal changes in the escape rate of H and O atoms, and thereby water. Prior HST observations have revealed a surprising rapid change in the H escape rate in late martian summer following a global dust storm, and have shown that STIS spectra can easily detect superthermal O atoms. The relative degree of influence of seasons and dust storms on the H density and escape flux are not known, and little is known about variations in the hot O density and escape rate. The timing of these observations is key to these scientific goals. Mars is now approaching the Sun, HST can observe Mars over a wide range of seasons from April - Nov 2014, and HST will not be able to observe Mars again until after the prime mission of MAVEN. These observations will provide strong support for the NASA MAVEN mission, scheduled to arrive at Mars in Sept. 2014. This proposal is for a single visit of 3 HST orbits in late sprign 2014 to establish the baseline conditions when Mars is far from the Sun.

  2. Solar forcing and planetary ion escape from Mars

    NASA Astrophysics Data System (ADS)

    Lundin, R.; Barabash, S.; Fedorov, A.; Holmström, M.; Nilsson, H.; Sauvaud, J.-A.; Yamauchi, M.

    2008-05-01

    The variability of planetary ion escape from Mars is studied using data from the Ion Mass Analyzer, IMA, on Mars Express (MEX). 42 orbits were selected during 17 months for different solar wind conditions, focusing on the low energy (~30 - 800 eV) heavy ion (e.g. O+, O2 + and CO2 +) outflow. A strong correlation is found between solar wind forcing of the obstacle, the cross-sectional area enclosing the ion outflow from Mars and the total heavy ion escape flux. The at least one order of magnitude changes of the ion outflow on the short term (hours, days), is directly connected with the variability of solar wind, solar soft x-ray and solar EUV (XEUV). The latter was first inferred from an analysis of how the obstacle size changes with changing solar wind and solar XEUV forcing. The 17-month trend of decreasing ion outflow with EUV during a declining phase of solar cycle 23, the EUV determined from the Neutral Particle Imager (NPI) on MEX, illustrates the influence of solar EUV forcing. On the basis of this we conclude that changes in solar wind- and solar XEUV forcing governs the variable ion escape from Mars. Both forcing terms appear to be equally important for the escape rate. Considering the difference in travel time for XEUV and the solar wind to Mars, the XEUV effect will precede the solar wind effect by several (3-9) days.

  3. 46 CFR 116.500 - Means of escape.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... escape must be widely separated and, if possible, at opposite ends or sides of the space to minimize the... millimeters (0.333 inches) multiplied by the number of passengers for which the space is designed. (g) A dead end passageway, or the equivalent, of more than 6.1 meters (20 feet) in length is prohibited. (h)...

  4. 6. UNDERGROUND FIRING CONTROL ROOM, INTERIOR. Looking southeast to escape ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    6. UNDERGROUND FIRING CONTROL ROOM, INTERIOR. Looking southeast to escape tunnel. - Edwards Air Force Base, Air Force Rocket Propulsion Laboratory, Firing Control Building, Test Area 1-100, northeast end of Test Area 1-100 Road, Boron, Kern County, CA

  5. Escaping Embarrassment: Face-Work in the Rap Cipher

    ERIC Educational Resources Information Center

    Lee, Jooyoung

    2009-01-01

    How do individuals escape embarrassing moments in interaction? Drawing from ethnographic fieldwork, in-depth interviews, and video recordings of weekly street corner ciphers (impromptu rap sessions), this paper expands Goffman's theory of defensive and protective face-work. The findings reveal formulaic and indirect dimensions of face-work. First,…

  6. Purinergic inhibition of ENaC produces aldosterone escape.

    PubMed

    Stockand, James D; Mironova, Elena; Bugaj, Vladislav; Rieg, Timo; Insel, Paul A; Vallon, Volker; Peti-Peterdi, Janos; Pochynyuk, Oleh

    2010-11-01

    The mechanisms underlying "aldosterone escape," which refers to the excretion of sodium (Na(+)) during high Na(+) intake despite inappropriately increased levels of mineralocorticoids, are incompletely understood. Because local purinergic tone in the aldosterone-sensitive distal nephron downregulates epithelial Na(+) channel (ENaC) activity, we tested whether this mechanism mediates aldosterone escape. Here, urinary ATP concentration increased with dietary Na(+) intake in mice. Physiologic concentrations of ATP decreased ENaC activity in a dosage-dependent manner. P2Y(2)(-/-) mice, which lack the purinergic receptor, had significantly less increased Na(+) excretion than wild-type mice in response to high-Na(+) intake. Exogenous deoxycorticosterone acetate and deletion of the P2Y(2) receptor each modestly increased the resistance of ENaC to changes in Na(+) intake; together, they markedly increased resistance. Under the latter condition, ENaC could not respond to changes in Na(+) intake. In contrast, as a result of aldosterone escape, wild-type mice had increased Na(+) excretion in response to high-Na(+) intake regardless of the presence of high deoxycorticosterone acetate. These data suggest that control of ENaC by purinergic signaling is necessary for aldosterone escape.

  7. Purinergic Inhibition of ENaC Produces Aldosterone Escape

    PubMed Central

    Mironova, Elena; Bugaj, Vladislav; Rieg, Timo; Insel, Paul A.; Vallon, Volker; Peti-Peterdi, Janos

    2010-01-01

    The mechanisms underlying “aldosterone escape,” which refers to the excretion of sodium (Na+) during high Na+ intake despite inappropriately increased levels of mineralocorticoids, are incompletely understood. Because local purinergic tone in the aldosterone-sensitive distal nephron downregulates epithelial Na+ channel (ENaC) activity, we tested whether this mechanism mediates aldosterone escape. Here, urinary ATP concentration increased with dietary Na+ intake in mice. Physiologic concentrations of ATP decreased ENaC activity in a dosage-dependent manner. P2Y2−/− mice, which lack the purinergic receptor, had significantly less increased Na+ excretion than wild-type mice in response to high-Na+ intake. Exogenous deoxycorticosterone acetate and deletion of the P2Y2 receptor each modestly increased the resistance of ENaC to changes in Na+ intake; together, they markedly increased resistance. Under the latter condition, ENaC could not respond to changes in Na+ intake. In contrast, as a result of aldosterone escape, wild-type mice had increased Na+ excretion in response to high-Na+ intake regardless of the presence of high deoxycorticosterone acetate. These data suggest that control of ENaC by purinergic signaling is necessary for aldosterone escape. PMID:20813869

  8. Plasma amino acid response to graded levels of escape protein.

    PubMed

    Gibb, D J; Klopfenstein, T J; Britton, R A; Lewis, A J

    1992-09-01

    A trial was conducted to examine the potential of using plasma amino acid responses to graded levels of escape protein to determine limiting amino acids in cattle. Growing calves (n = 120; mean BW = 220 +/- 21 kg) were fed a basal diet of corncob:sorghum silage (61:39) and were individually supplemented with distillers' dried grains (DDG), heat-damaged DDG (H-DDG), feather meal (FTH), or urea. The urea supplement was mixed with DDG and H-DDG to allow 0, 20, 35, 50, 65, or 80% of the supplemental CP to come from distillers' protein and maintain an 11.5% CP diet. Urea supplement was mixed with FTH to allow 0, 22, 39, 56, 73, or 90% of the supplemental CP to come from FTH. Dietary CP ranged from 11.5% at the 0% level to 17.3% at the 90% level. Plasma concentration of most essential plasma amino acids responded (P less than .10) linearly and(or) quadratically to increased escape protein. The broken-line response of plasma methionine at low DDG intake suggested that methionine was limiting at low levels of escape protein. An initial decrease followed by a plateau fit by a broken line indicated that histidine became limiting in FTH diets, and lysine eventually became limiting for DDG, H-DDG, and FTH diets before maximum BW gain was reached. Results indicate that plasma amino acid responses may identify amino acids that become limiting with increasing escape protein.

  9. Social Escape Behaviors in Children with Fragile X Syndrome

    ERIC Educational Resources Information Center

    Hall, Scott; DeBernardis, Marie; Reiss, Allan

    2006-01-01

    Social escape behavior is a common behavioral feature of individuals with fragile X syndrome (fraX). In this observational study, we examined the effect of antecedent social and performance demands on problem behaviors in four conditions: face-to-face interview, silent reading, oral reading and a singing task. Results showed that problem behaviors…

  10. 46 CFR 28.390 - Means of escape.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 1 2012-10-01 2012-10-01 false Means of escape. 28.390 Section 28.390 Shipping COAST... emergency exits, passageways, stairways, ladders, deck scuttles, and windows. (b) At least one of the means... suitable for use in emergency conditions and must be of rigid construction. (f) A window or windshield...

  11. 46 CFR 28.390 - Means of escape.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 1 2011-10-01 2011-10-01 false Means of escape. 28.390 Section 28.390 Shipping COAST... emergency exits, passageways, stairways, ladders, deck scuttles, and windows. (b) At least one of the means... suitable for use in emergency conditions and must be of rigid construction. (f) A window or windshield...

  12. 2. WEST REAR, WITH PORTHOLE ESCAPE HATCH ABOVE ENTRY DOOR. ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    2. WEST REAR, WITH PORTHOLE ESCAPE HATCH ABOVE ENTRY DOOR. - Edwards Air Force Base, South Base Sled Track, Firing & Control Blockhouse for 10,000-foot Track, South of Sled Track at midpoint of 20,000-foot track, Lancaster, Los Angeles County, CA

  13. Danger detection and escape behaviour in wood crickets.

    PubMed

    Dupuy, Fabienne; Casas, Jérôme; Body, Mélanie; Lazzari, Claudio R

    2011-07-01

    The wind-sensitive cercal system of Orthopteroid insects that mediates the detection of the approach of a predator is a very sensitive sensory system. It has been intensively analysed from a behavioural and neurobiological point of view, and constitutes a classical model system in neuroethology. The escape behaviour is triggered in orthopteroids by the detection of air-currents produced by approaching objects, allowing these insects to keep away from potential dangers. Nevertheless, escape behaviour has not been studied in terms of success. Moreover, an attacking predator is more than "air movement", it is also a visible moving entity. The sensory basis of predator detection is thus probably more complex than the perception of air movement by the cerci. We have used a piston mimicking an attacking running predator for a quantitative evaluation of the escape behaviour of wood crickets Nemobius sylvestris. The movement of the piston not only generates air movement, but it can be seen by the insect and can touch it as a natural predator. This procedure allowed us to study the escape behaviour in terms of detection and also in terms of success. Our results showed that 5-52% of crickets that detected the piston thrust were indeed touched. Crickets escaped to stimulation from behind better than to a stimulation from the front, even though they detected the approaching object similarly in both cases. After cerci ablation, 48% crickets were still able to detect a piston approaching from behind (compared with 79% of detection in intact insects) and 24% crickets escaped successfully (compared with 62% in the case of intact insects). So, cerci play a major role in the detection of an approaching object but other mechanoreceptors or sensory modalities are implicated in this detection. It is not possible to assure that other sensory modalities participate (in the case of intact animals) in the behaviour; rather, than in the absence of cerci other sensory modalities can

  14. Plasma-induced Escape and Alterations of Planetary Atmospheres

    NASA Astrophysics Data System (ADS)

    Johnson, R. E.; Tucker, O. J.; Ewrin, J.; Cassidy, T. A.; Leblanc, F.

    2009-12-01

    The atmospheres of planets and planetary satellites are typically imbedded in space plasmas. Depending on the interaction with the induced or intrinsic fields energetic ions can have access to the thermosphere and the corona affecting their composition and thermal structure and causing loss to space. These processes are often lumped together as ‘atmospheric sputtering’ (Johnson 1994). In this talk I will review the results of simulations of the plasma bombardment at a number of solar system bodies and use those data to describe the effect on the upper atmosphere and on escape. Of considerable recent interest is the modeling of escape from Titan. Prior to Cassini’s tour of the Saturnian system, plasma-induced escape was suggested to be the dominant loss process, but recent models of enhanced thermal escape, often referred to as ‘slow hydrodynamic’ escape, have been suggested to lead to much larger Titan atmospheric loss rates (Strobel 2008; Cui et al. 2008). Such a process has been suggested to be active at some point in time on a number of solar system bodies. I will present hybrid fluid/ kinetic models of the upper atmosphere of certain bodies in order to test both the plasma-induced and thermal escape processes. Preliminary results suggest that the loss rates estimated using the ‘slow hydrodynamic’ escape process can be orders of magnitude too large. The implications for Mars, Titan and Pluto will be discussed. Background for this talk is contained in the following papers (Johnson 2004; 2009; Chaufray et al. 2007; Johnson et al. 2008; 2009; Tucker and Johnson 2009). References: Chaufray, J.Y., R. Modolo, F. Leblanc, G. Chanteur, R.E. Johnson, and J.G. Luhmann, Mars Solar Wind interaction: formation of the Martian corona and atmosphric loss to space, JGR 112, E09009, doi:10.1029/2007JE002915 (2007) Cui, J., Yelle, R. V., Volk, K. Distribution and escape of molecular hydrogen in Titan's thermosphere and exosphere. J. Geophys. Res. 113, doi:10

  15. Laser-Driven Fusion.

    ERIC Educational Resources Information Center

    Gibson, A. F.

    1980-01-01

    Discusses the present status and future prospects of laser-driven fusion. Current research (which is classified under three main headings: laser-matter interaction processes, compression, and laser development) is also presented. (HM)

  16. Fusion-breeder program

    SciTech Connect

    Moir, R.W.

    1982-11-19

    The various approaches to a combined fusion-fission reactor for the purpose of breeding /sup 239/Pu and /sup 233/U are described. Design aspects and cost estimates for fuel production and electricity generation are discussed. (MOW)

  17. Charged fusion product loss measurements using nuclear activation

    SciTech Connect

    Bonheure, G.; Hult, M.; Gonzalez de Orduna, R.; Wieslander, E.; Arnold, D.; Dombrowski, H.; Laubenstein, M.; Murari, A.; Collaboration: JET-EFDA Contributors

    2010-10-15

    In ITER, {alpha} particle loss measurements will be required in order to understand the alpha particle physics. Techniques capable of operating in a fusion reactor environment need further development. Recent experimental studies on JET demonstrated the potential of nuclear activation to measure the flux of escaping MeV ions. New results from MeV ion induced activation of metallic, ceramic, and crystal samples placed near the plasma edge are reported. Activation products were measured as function of orientation with respect to the magnetic field as well as function of the distance to the plasma. Sample activity was measured using ultralow-level gamma-ray spectrometry. Distribution of 14.68 MeV fusion proton induced activation products is strongly anisotropic in agreement with simulations and falls off sharply with increasing distance to the plasma. Prospects for using the technique in ITER are discussed.

  18. Recording Field Potentials From Zebrafish Larvae During Escape Responses

    PubMed Central

    Monesson-Olson, Bryan D.; Troconis, Eileen L.; Trapani, Josef G.

    2014-01-01

    Among vertebrates, startle responses are a ubiquitous method for alerting, and avoiding or escaping from alarming or dangerous stimuli. In zebrafish larvae, fast escape behavior is easily evoked through either acoustic or tactile stimuli. For example, a light touch to the head will excite trigeminal neurons that in turn excite a large reticulospinal neuron in the hindbrain called the Mauthner cell (M-cell). The M-cell action potential then travels down the contralateral trunk of the larva exciting motoneurons, which subsequently excite the entire axial musculature, producing a large amplitude body bend away from the source of the stimulus. This body conformation is known as the “C-bend” due to the shape of the larva during the behavior. As a result of the semi-synchronized activation of the M-cell, the population of motor neurons, and the axial trunk muscles, a large field potential is generated and can be recorded from free-swimming or fixed-position larvae. Undergraduate laboratories that record field potentials during escape responses in larval zebrafish are relatively simple to setup and allow students to observe and study the escape reflex circuit. Furthermore, by testing hypotheses, analyzing data and writing journal-style laboratory reports, students have multiple opportunities to learn about many neuroscience topics including vertebrate reflexes; sensory transduction; synaptic-, neuro-, and muscle-physiology; the M-cell mediated escape response; and the zebrafish as a model organism. Here, we detail the equipment, software, and recording setup necessary to observe field potentials in an undergraduate teaching lab. Additionally, we discuss potential advanced laboratory exercises and pedagogical outcomes. Finally, we note possible low-cost alternatives for recording field potentials. PMID:25565920

  19. Escape manoeuvres in the spiny dogfish (Squalus acanthias).

    PubMed

    Domenici, Paolo; Standen, Emily M; Levine, Robert P

    2004-06-01

    The locomotor performance of dogfish during escape responses was observed by means of high-speed video. Dogfish show C-type escape responses that are comparable with those shown previously in teleosts. Dogfish show high variability of turning rates of the anterior part of the body (head to centre of mass), i.e. with peak values from 434 to 1023 deg. s(-1). We suggest that this variability may be due to the presence of two types of escape manoeuvres, i.e. responses with high and low turning rates, as previously found in a teleost species. Fast responses (i.e. with high maximum turning rates, ranging between 766 and 1023 deg. s(-1)) showed significantly higher locomotor performance than slow responses (i.e. with low maximum turning rates, ranging between 434 and 593 deg. s(-1)) in terms of distance covered, speed and acceleration, although no differences were found in the turning radius of the centre of mass during the escape manoeuvres. The existence of two types of escape responses would have implications in terms of both neural control and muscular activation patterns. When compared with literature data for the locomotor performance of bony fishes, dogfish showed relatively low speed and acceleration, comparable turning rates and a turning radius that is in the low part of the range when compared with teleosts, indicating relatively high manoeuvrability. The locomotor performance observed in dogfish is consistent with their morphological characteristics: (1) low locomotor performance associated with low thrust developed by their relatively small posterior depth of section and (2) relatively high manoeuvrability associated with their high flexibility.

  20. In situ and remote measurements of ions escaping from Venus

    NASA Astrophysics Data System (ADS)

    Kollmann, P.; Brandt, P. C.

    2013-12-01

    Venus is thought to lose a large fraction of its atmosphere in the form ions, mainly via pickup. The relative loss rate of the exosphere as neutrals or ions is not known, nor is the flux of escaping ions well constrained. Knowledge of these processes will shed light on the role an intrinsic magnetic field has in atmospheric erosion. We use the complementary in-situ plasma and energetic neutral atom (ENA) measurements from the Venus Express (VEx) spacecraft in order to constrain the ion escape. VEx completed about 2500 orbits to date and reached altitudes as low as 200km. The ASPERA/IMA instrument measured directional proton and oxygen ion spectra in the 10eV to 40keV range. We bin the data accumulated over the mission in space and bulk flow direction, yielding a direct measure of the local ion escape flux. While such in-situ measurements provide data without ambiguity, they are limited by the orbital coverage. This is why we include remote ENA measurements from the ASPERA/NPD (100eV to 10keV) instrument to our study. ENAs are created when escaping ions charge exchange with the high atmosphere atoms or molecules. We have done an exhaustive analysis of the data, excluding time periods of instrument contamination. Most ENA emission originates from low altitudes above Venus' limb. These measurements will be compared with the in-situ data, which allows constraining the atmospheric density at high altitudes. Interestingly, there are also ENA emissions from other directions, which were not sampled in-situ. This allows us to put a lower limit to the escape from these regions.

  1. Glossary of fusion energy

    NASA Astrophysics Data System (ADS)

    Whitson, M. O.

    1985-02-01

    The Glossary of Fusion Energy is an attempt to present a concise, yet comprehensive collection of terms that may be beneficial to scientists and laymen who are directly or tangentially concerned with this burgeoning energy enterprise. Included are definitions of terms in theoretical plasma physics, controlled thermonuclear fusion, and some related physics concepts. Also, short descriptions of some of the major thermonuclear experiments currently under way in the world today are included.

  2. Cold nuclear fusion

    SciTech Connect

    Tsyganov, E. N.

    2012-02-15

    Recent accelerator experiments on fusion of various elements have clearly demonstrated that the effective cross-sections of these reactions depend on what material the target particle is placed in. In these experiments, there was a significant increase in the probability of interaction when target nuclei are imbedded in a conducting crystal or are a part of it. These experiments open a new perspective on the problem of so-called cold nuclear fusion.

  3. Fusion ignition research experiment

    SciTech Connect

    Dale Meade

    2000-07-18

    Understanding the properties of high gain (alpha-dominated) fusion plasmas in an advanced toroidal configuration is the largest remaining open issue that must be addressed to provide the scientific foundation for an attractive magnetic fusion reactor. The critical parts of this science can be obtained in a compact high field tokamak which is also likely to provide the fastest and least expensive path to understanding alpha-dominated plasmas in advanced toroidal systems.

  4. Ca-dependent Nonsecretory Vesicle Fusion in a Secretory Cell

    PubMed Central

    Wang, Tzu-Ming; Hilgemann, Donald W.

    2008-01-01

    We have compared Ca-dependent exocytosis in excised giant membrane patches and in whole-cell patch clamp with emphasis on the rat secretory cell line, RBL. Stable patches of 2–4 pF are easily excised from RBL cells after partially disrupting actin cytoskeleton with latrunculin A. Membrane fusion is triggered by switching the patch to a cytoplasmic solution containing 100–200 μM free Ca. Capacitance and amperometric recording show that large secretory granules (SGs) containing serotonin are mostly lost from patches. Small vesicles that are retained (non-SGs) do not release serotonin or other substances detected by amperometry, although their fusion is reduced by tetanus toxin light chain. Non-SG fusion is unaffected by N-ethylmaleimide, phosphatidylinositol-4,5-bis-phosphate (PI(4,5)P2) ligands, such as neomycin, a PI-transfer protein that can remove PI from membranes, the PI(3)-kinase inhibitor LY294002 and PI(4,5)P2, PI(3)P, and PI(4)P antibodies. In patch recordings, but not whole-cell recordings, fusion can be strongly reduced by ATP removal and by the nonspecific PI-kinase inhibitors wortmannin and adenosine. In whole-cell recording, non-SG fusion is strongly reduced by osmotically induced cell swelling, and subsequent recovery after shrinkage is then inhibited by wortmannin. Thus, membrane stretch that occurs during patch formation may be a major cause of differences between excised patch and whole-cell fusion responses. Regarding Ca sensors for non-SG fusion, fusion remains robust in synaptotagmin (Syt) VII−/− mouse embryonic fibroblasts (MEFs), as well as in PLCδ1, PLC δ1/δ4, and PLCγ1−/− MEFs. Thus, Syt VII and several PLCs are not required. Furthermore, the Ca dependence of non-SG fusion reflects a lower Ca affinity (KD ∼71 μM) than expected for these C2 domain–containing proteins. In summary, we find that non-SG membrane fusion behaves and is regulated substantially differently from SG fusion, and we have identified an ATP

  5. Distinct effects of endosomal escape and inhibition of endosomal trafficking on gene delivery via electrotransfection

    PubMed Central

    Chang, Chun-Chi; Wang, Liangli; Yuan, Fan

    2017-01-01

    A recent theory suggests that endocytosis is involved in uptake and intracellular transport of electrotransfected plasmid DNA (pDNA). The goal of the current study was to understand if approaches used previously to improve endocytosis of gene delivery vectors could be applied to enhancing electrotransfection efficiency (eTE). Results from the study showed that photochemically induced endosomal escape, which could increase poly-L-lysine (PLL)-mediated gene delivery, decreased eTE. The decrease could not be blocked by treatment of cells with endonuclease inhibitors (aurintricarboxylic acid and zinc ion) or antioxidants (L-glutamine and ascorbic acid). Chemical treatment of cells with an endosomal trafficking inhibitor that blocks endosome progression, bafilomycin A1, resulted in a significant decrease in eTE. However, treatment of cells with lysosomotropic agents (chloroquine and ammonium chloride) had little effects on eTE. These data suggested that endosomes played important roles in protecting and intracellular trafficking of electrotransfected pDNA. PMID:28182739

  6. Magnetized Target Fusion

    NASA Technical Reports Server (NTRS)

    Griffin, Steven T.

    2002-01-01

    Magnetized target fusion (MTF) is under consideration as a means of building a low mass, high specific impulse, and high thrust propulsion system for interplanetary travel. This unique combination is the result of the generation of a high temperature plasma by the nuclear fusion process. This plasma can then be deflected by magnetic fields to provide thrust. Fusion is initiated by a small traction of the energy generated in the magnetic coils due to the plasma's compression of the magnetic field. The power gain from a fusion reaction is such that inefficiencies due to thermal neutrons and coil losses can be overcome. Since the fusion reaction products are directly used for propulsion and the power to initiate the reaction is directly obtained from the thrust generation, no massive power supply for energy conversion is required. The result should be a low engine mass, high specific impulse and high thrust system. The key is to successfully initiate fusion as a proof-of-principle for this application. Currently MSFC is implementing MTF proof-of-principle experiments. This involves many technical details and ancillary investigations. Of these, selected pertinent issues include the properties, orientation and timing of the plasma guns and the convergence and interface development of the "pusher" plasma. Computer simulations of the target plasma's behavior under compression and the convergence and mixing of the gun plasma are under investigation. This work is to focus on the gun characterization and development as it relates to plasma initiation and repeatability.

  7. ITER Fusion Energy

    ScienceCinema

    Dr. Norbert Holtkamp

    2016-07-12

    ITER (in Latin “the way”) is designed to demonstrate the scientific and technological feasibility of fusion energy. Fusion is the process by which two light atomic nuclei combine to form a heavier over one and thus release energy. In the fusion process two isotopes of hydrogen – deuterium and tritium – fuse together to form a helium atom and a neutron. Thus fusion could provide large scale energy production without greenhouse effects; essentially limitless fuel would be available all over the world. The principal goals of ITER are to generate 500 megawatts of fusion power for periods of 300 to 500 seconds with a fusion power multiplication factor, Q, of at least 10. Q ? 10 (input power 50 MW / output power 500 MW). The ITER Organization was officially established in Cadarache, France, on 24 October 2007. The seven members engaged in the project – China, the European Union, India, Japan, Korea, Russia and the United States – represent more than half the world’s population. The costs for ITER are shared by the seven members. The cost for the construction will be approximately 5.5 billion Euros, a similar amount is foreseen for the twenty-year phase of operation and the subsequent decommissioning.

  8. An Empirical Investigation of Time-Out with and without Escape Extinction to Treat Escape-Maintained Noncompliance

    ERIC Educational Resources Information Center

    Everett, Gregory E.; Olmi, D. Joe; Edwards, Ron P.; Tingstrom, Daniel H.; Sterling-Turner, Heather E.; Christ, Theodore J.

    2007-01-01

    The present study evaluates the effectiveness of two time-out (TO) procedures in reducing escape-maintained noncompliance of 4 children. Noncompliant behavioral function was established via a functional assessment (FA), including indirect and direct descriptive procedures and brief confirmatory experimental analyses. Following FA, parents were…

  9. Formulation of a Cooperative-Confinement-Escape problem of multiple cooperative defenders against an evader escaping from a circular region

    NASA Astrophysics Data System (ADS)

    Li, Wei

    2016-10-01

    In this paper, we propose and formulate the Cooperative-Confinement-Escape (CCE) problem of multiple cooperative defenders against an evader escaping from a circular region, in which the defenders are moving on the circle with attempt to prevent possible escape of a single evader who is initially located inside the circle. The main contributions are summarized as follows: (1) we first provide an effective formulation of the CCE problem, which is an emphasis of this paper, with design of two nonlinear control strategies for the cooperative defenders and the adversarial evader, respectively. Particularly, we consider to include a proper interaction between each pair of the nearest-neighbor defenders, and an adaptive trajectory prediction mechanism in the strategies of the defenders to increase the chance of successful confinement. (2) For the first attempt on analyzing the CCE dynamics which is unavoidably strongly nonlinear, we analyze the minimum energy of the evader for possible escape. (3) For understanding of the behaviors of the system under different parameters, (i) we illustrate the effectiveness of the confinement strategy using the adaptive trajectory prediction mechanism, and (ii) the physical roles of the system parameters with respect to the system dynamics, some of which may be unexpected or not straightforward. A separate paper will be presented for systematic analysis of the agents' behaviors with respect to the large intervals of the parameter settings.

  10. Evolutionary Pressure of a Receptor Competitor Selects Different Subgroup A Avian Leukosis Virus Escape Variants with Altered Receptor Interactions

    PubMed Central

    Melder, Deborah C.; Pankratz, V. Shane; Federspiel, Mark J.

    2003-01-01

    A complex interaction between the retroviral envelope glycoproteins and a specific cell surface protein initiates viral entry into cells. The avian leukosis-sarcoma virus (ALV) group of retroviruses provides a useful experimental system for studying the retroviral entry process and the evolution of receptor usage. In this study, we demonstrate that evolutionary pressure on subgroup A ALV [ALV(A)] entry exerted by the presence of a competitive inhibitor, a soluble form of the ALV(A) Tva receptor linked to a mouse immunoglobulin G tag (quail sTva-mIgG), can select different populations of escape variants. This escape population contained three abundant ALV(A) variant viruses, all with mutations in the surface glycoprotein hypervariable regions: a previously identified variant containing the Y142N mutation in the hr1 region; a new variant with two mutations, W141G in hr1 and K261E in vr3; and another new variant with two mutations, W145R in hr1 and K261E. The W141G K261E and W145R K261E viruses escape primarily by lowering their binding affinities for the quail Tva receptor competitive inhibitor while retaining wild-type levels of binding affinity for the chicken Tva receptor. A secondary phenotype of the new variants was an alteration in receptor interference patterns from that of wild-type ALV(A), indicating that the mutant glycoproteins are possibly interacting with other cellular proteins. One result of these altered interactions was that the variants caused a transient period of cytotoxicity. We could also directly demonstrate that the W141G K261E variant glycoproteins bound significant levels of a soluble form of the TvbS3 ALV receptor in a binding assay. Alterations in the normally extreme specificity of the ALV(A) glycoproteins for Tva may represent an evolutionary first step toward expanding viral receptor usage in response to inefficient viral entry. PMID:12970435

  11. A Generalized Escape System Simulation (GESS) Computer Program: GESS User’s Guide. Version II. Volume 1.

    DTIC Science & Technology

    1983-09-01

    4-14 4-7 Ocupant Alone Variable Fields ......................... 4-15 4-8 Rail Data Variable Fields ............................. 4...civilian management, and Navy personnel with greater ability to: - establish escape system performance requirements, -. . evaluate competitive escape...system proposals, z. evaluate escape system design modifications, ~. monitor escape system test programs, .. prepare fleet information on escape

  12. Late stages of the synchronized macrophage fusion in osteoclast formation depend on dynamin.

    PubMed

    Verma, Santosh K; Leikina, Evgenia; Melikov, Kamran; Chernomordik, Leonid V

    2014-12-15

    Macrophage fusion that leads to osteoclast formation is one of the most important examples of cell-cell fusion in development, tissue homoeostasis and immune response. Protein machinery that fuses macrophages remains to be identified. In the present study, we explored the fusion stage of osteoclast formation for RAW macrophage-like murine cells and for macrophages derived from human monocytes. To uncouple fusion from the preceding differentiation processes, we accumulated fusion-committed cells in the presence of LPC (lysophosphatidylcholine) that reversibly blocks membrane merger. After 16 h, we removed LPC and observed cell fusion events that would normally develop within 16 h develop instead within 30-90 min. Thus, whereas osteoclastogenesis, generally, takes several days, our approach allowed us to focus on an hour in which we observe robust fusion between the cells. Complementing syncytium formation assay with a novel membrane merger assay let us study the synchronized fusion events downstream of a local merger between two plasma membranes, but before expansion of nascent membrane connections and complete unification of the cells. We found that the expansion of membrane connections detected as a growth of multinucleated osteoclasts depends on dynamin activity. In contrast, a merger between the plasma membranes of the two cells was not affected by inhibitors of dynamin GTPase. Thus dynamin that was recently found to control late stages of myoblast fusion also controls late stages of macrophage fusion, revealing an intriguing conserved mechanistic motif shared by diverse cell-cell fusion processes.

  13. Anatomy of an escape tectonic zone: Western Irian Jaya (Indonesia)

    NASA Astrophysics Data System (ADS)

    Pubellier, Manuel; Ego, Frédéric

    2002-07-01

    The western fold-and-thrust belt of New Guinea in Irian Jaya is presently a complex boundary, dominated by the Bird's Head block escape from the collision between the Australian plate and the remnants of volcanic belts carried by the Pacific plate. The escape rate given by geodetic measurements is of the order of 7 cm/yr, and movement is accommodated by a broad shear zone. We analyze this shear pattern using fault slip analyses performed in the field from 1992 to 1996, combined with focal mechanism inversions, moment tensors summations, and surface trace of structures inferred from radar and multispectral satellite images. Time control of the deformation is attained by isotope dating of the recent syntectonic intrusives. The geometry of the macro and microstructures occurred in two stages from the early Pliocene to the Present. The first stage (5 to 2 Ma) is marked by flat-and-ramps structures guided by N60°E lateral ramps associated with a N60°E cleavage, affecting the whole of western Irian Jaya. The second stage (2 Ma to Present) shows the collapse of the western fold-and-thrust belt and the escape of the Bird's Head and the Lengguru belts along N60°E transtensile faults. In the latter stage, the strike-slip offset is distributed on the N60°E schistosity zone along which some fracture planes are reactivated as left-lateral transtensile faults. Shallow earthquakes moment tensors have been inverted for stress and summed to get strain rates to define contrasting structural provinces. The spatial variations in both stress and strain fields from earthquakes and microtectonics show that (1) they are consistent and are assumed to be coeval, (2) they reveal that oblique convergence is partitioned, and (3) they are influenced by the existence of a free boundary. We see no significant rotation of stress axes laterally along the escape zone. Instead, stresses change according to the different orientations of basement structures and thus undergo rapid spatial variations

  14. Fusion for Space Propulsion

    NASA Technical Reports Server (NTRS)

    Thio, Y. C. Francis; Schafer, Charles (Technical Monitor)

    2001-01-01

    There is little doubt that humans will attempt to explore and develop the solar system in this century. A large amount of energy will be required for accomplishing this. The need for fusion propulsion is discussed. For a propulsion system, there are three important thermodynamical attributes: (1) The absolute amount of energy available, (2) the propellant exhaust velocity, and (3) the jet power per unit mass of the propulsion system (specific power). For human exploration and development of the solar system, propellant exhaust velocity in excess of 100 km/s and specific power in excess of 10 kW/kg are required. Chemical combustion can produce exhaust velocity up to about 5 km/s. Nuclear fission processes typically result in producing energy in the form of heat that needs to be manipulated at temperatures limited by materials to about 2,800 K. Using the energy to heat a hydrogen propellant increases the exhaust velocity by only a factor of about two. Alternatively the energy can be converted into electricity which is then used to accelerate particles to high exhaust velocity. The necessary power conversion and conditioning equipment, however, increases the mass of the propulsion system for the same jet power by more than two orders of magnitude over chemical system, thus greatly limits the thrust-to-weight ratio attainable. The principal advantage of the fission process is that its development is relatively mature and is available right now. If fusion can be developed, fusion appears to have the best of all worlds in terms of propulsion - it can provide the absolute amount, the propellant exhaust velocity, and the high specific jet power. An intermediate step towards pure fusion propulsion is a bimodal system in which a fission reactor is used to provide some of the energy to drive a fusion propulsion unit. The technical issues related to fusion for space propulsion are discussed. The technical priorities for developing and applying fusion for propulsion are

  15. 20. DETAIL VIEW IN 18FOOT LOCK, ESCAPE TRAINING TANK, SHOWING ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    20. DETAIL VIEW IN 18-FOOT LOCK, ESCAPE TRAINING TANK, SHOWING DOOR INTO TANK AT RIGHT - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

  16. On the observation of charged particles in cold fusion

    NASA Astrophysics Data System (ADS)

    Sundqvist, Bo U. R.; Håkansson, Per; Hedin, Allan; Bucur, Romulus V.; Johansson, Börje; Wäppling, Roger

    1989-09-01

    With the aim to confirm or reject the recent claim of observation of cold d-d fusion, an experimental effort has been made to try to observe MeV protons which should be emitted as a result of d-d fusion. Pd foils, thin enough to allow all protons produced to escape the foil, were electrolytically charged with deuterium. A Si(SB) detector was placed close to the Pd foil during charging in order to detect any protons emitted. The deuterium content was measured to be the expected 0.7 D per Pd. Monte Carlo simulations were made to estimate the detection efficiency of 3.02 MeV protons produced in the Pd foil. The background in the experiment was so low that fusion rates considerably lower than those reported on by Jones et al. could be detected. A number of experiments have been performed where the charging conditions were varied. In spite of that and the good sensitivity of the experiment no evidence for cold fusion has been found.

  17. Inhibition of the Hantavirus Fusion Process by Predicted Domain III and Stem Peptides from Glycoprotein Gc.

    PubMed

    Barriga, Gonzalo P; Villalón-Letelier, Fernando; Márquez, Chantal L; Bignon, Eduardo A; Acuña, Rodrigo; Ross, Breyan H; Monasterio, Octavio; Mardones, Gonzalo A; Vidal, Simon E; Tischler, Nicole D

    2016-07-01

    Hantaviruses can cause hantavirus pulmonary syndrome or hemorrhagic fever with renal syndrome in humans. To enter cells, hantaviruses fuse their envelope membrane with host cell membranes. Previously, we have shown that the Gc envelope glycoprotein is the viral fusion protein sharing characteristics with class II fusion proteins. The ectodomain of class II fusion proteins is composed of three domains connected by a stem region to a transmembrane anchor in the viral envelope. These fusion proteins can be inhibited through exogenous fusion protein fragments spanning domain III (DIII) and the stem region. Such fragments are thought to interact with the core of the fusion protein trimer during the transition from its pre-fusion to its post-fusion conformation. Based on our previous homology model structure for Gc from Andes hantavirus (ANDV), here we predicted and generated recombinant DIII and stem peptides to test whether these fragments inhibit hantavirus membrane fusion and cell entry. Recombinant ANDV DIII was soluble, presented disulfide bridges and beta-sheet secondary structure, supporting the in silico model. Using DIII and the C-terminal part of the stem region, the infection of cells by ANDV was blocked up to 60% when fusion of ANDV occurred within the endosomal route, and up to 95% when fusion occurred with the plasma membrane. Furthermore, the fragments impaired ANDV glycoprotein-mediated cell-cell fusion, and cross-inhibited the fusion mediated by the glycoproteins from Puumala virus (PUUV). The Gc fragments interfered in ANDV cell entry by preventing membrane hemifusion and pore formation, retaining Gc in a non-resistant homotrimer stage, as described for DIII and stem peptide inhibitors of class II fusion proteins. Collectively, our results demonstrate that hantavirus Gc shares not only structural, but also mechanistic similarity with class II viral fusion proteins, and will hopefully help in developing novel therapeutic strategies against hantaviruses.

  18. Inhibition of the Hantavirus Fusion Process by Predicted Domain III and Stem Peptides from Glycoprotein Gc

    PubMed Central

    Barriga, Gonzalo P.; Villalón-Letelier, Fernando; Márquez, Chantal L.; Bignon, Eduardo A.; Acuña, Rodrigo; Ross, Breyan H.; Monasterio, Octavio; Mardones, Gonzalo A.; Vidal, Simon E.; Tischler, Nicole D.

    2016-01-01

    Hantaviruses can cause hantavirus pulmonary syndrome or hemorrhagic fever with renal syndrome in humans. To enter cells, hantaviruses fuse their envelope membrane with host cell membranes. Previously, we have shown that the Gc envelope glycoprotein is the viral fusion protein sharing characteristics with class II fusion proteins. The ectodomain of class II fusion proteins is composed of three domains connected by a stem region to a transmembrane anchor in the viral envelope. These fusion proteins can be inhibited through exogenous fusion protein fragments spanning domain III (DIII) and the stem region. Such fragments are thought to interact with the core of the fusion protein trimer during the transition from its pre-fusion to its post-fusion conformation. Based on our previous homology model structure for Gc from Andes hantavirus (ANDV), here we predicted and generated recombinant DIII and stem peptides to test whether these fragments inhibit hantavirus membrane fusion and cell entry. Recombinant ANDV DIII was soluble, presented disulfide bridges and beta-sheet secondary structure, supporting the in silico model. Using DIII and the C-terminal part of the stem region, the infection of cells by ANDV was blocked up to 60% when fusion of ANDV occurred within the endosomal route, and up to 95% when fusion occurred with the plasma membrane. Furthermore, the fragments impaired ANDV glycoprotein-mediated cell-cell fusion, and cross-inhibited the fusion mediated by the glycoproteins from Puumala virus (PUUV). The Gc fragments interfered in ANDV cell entry by preventing membrane hemifusion and pore formation, retaining Gc in a non-resistant homotrimer stage, as described for DIII and stem peptide inhibitors of class II fusion proteins. Collectively, our results demonstrate that hantavirus Gc shares not only structural, but also mechanistic similarity with class II viral fusion proteins, and will hopefully help in developing novel therapeutic strategies against hantaviruses

  19. Characterization of CpG sites that escape methylation on the inactive human X-chromosome.

    PubMed

    Moen, Erika L; Litwin, Edward; Arnovitz, Stephen; Zhang, Xu; Zhang, Wei; Dolan, M Eileen; Godley, Lucy A

    2015-01-01

    In many whole genome studies of gene expression or modified cytosines, data from probes localized to the X-chromosome are removed from analyses due to gender bias. Previously, we observed population differences in cytosine modifications between Caucasian and African lymphoblastoid cell lines (LCLs) on the autosomes using whole genome arrays to measure modified cytosines. DNA methylation plays a critical role in establishment and maintenance of X-chromosome inactivation in females. Therefore, we reasoned that by investigating cytosine modification patterns specifically on the X-chromosome, we could obtain valuable information about a chromosome that is often disregarded in genome-wide analyses. We investigated population differences in cytosine modification patterns along the X-chromosome between Caucasian and African LCLs and identified novel sites that escape methylation on the inactive X-chromosome (Xi) in females. We characterized the chromatin state of these loci by incorporating the extensive histone modification ChIP-seq data generated by ENCODE. To explore the relationship between DNA and histone modifications further, we hypothesized that BRD4, a protein that binds acetylated histones, could be preventing some sites from becoming de novo methylated. To test this, we treated 4 female LCLs with JQ1, a small molecule inhibitor of BRD4, but found that JQ1 treatment induced minor changes in cytosine modification levels, and the majority of sites escaping methylation on the Xi remained unmethylated. This suggests that other epigenetic mechanisms or transcription factors are likely playing a larger role in protecting these sites from de novo methylation on the Xi.

  20. Cytokinin is required for escape but not release from auxin mediated apical dominance

    PubMed Central

    Müller, Dörte; Waldie, Tanya; Miyawaki, Kaori; To, Jennifer PC; Melnyk, Charles W; Kieber, Joseph J; Kakimoto, Tatsuo; Leyser, Ottoline

    2015-01-01

    Auxin produced by an active primary shoot apex is transported down the main stem and inhibits the growth of the axillary buds below it, contributing to apical dominance. Here we use Arabidopsis thaliana cytokinin (CK) biosynthetic and signalling mutants to probe the role of CK in this process. It is well established that bud outgrowth is promoted by CK, and that CK synthesis is inhibited by auxin, leading to the hypothesis that release from apical dominance relies on an increased supply of CK to buds. Our data confirm that decapitation induces the expression of at least one ISOPENTENYLTRANSFERASE (IPT) CK biosynthetic gene in the stem. We further show that transcript abundance of a clade of the CK-responsive type-A Arabidopsis response regulator (ARR) genes increases in buds following CK supply, and that, contrary to their typical action as inhibitors of CK signalling, these genes are required for CK-mediated bud activation. However, analysis of the relevant arr and ipt multiple mutants demonstrates that defects in bud CK response do not affect auxin-mediated bud inhibition, and increased IPT transcript levels are not needed for bud release following decapitation. Instead, our data suggest that CK acts to overcome auxin-mediated bud inhibition, allowing buds to escape apical dominance under favourable conditions, such as high nitrate availability. Significance Statement It has been proposed that the release of buds from auxin-mediated apical dominance following decapitation requires increased cytokinin biosynthesis and consequent increases in cytokinin supply to buds. Here we show that in Arabidopsis, increases in cytokinin appear to be unnecessary for the release of buds from apical dominance, but rather allow buds to escape the inhibitory effect of apical auxin, thereby promoting bud activation in favourable growth conditions. PMID:25904120

  1. Myoblast fusion in Drosophila

    SciTech Connect

    Haralalka, Shruti; Abmayr, Susan M.

    2010-11-01

    The body wall musculature of a Drosophila larva is composed of an intricate pattern of 30 segmentally repeated muscle fibers in each abdominal hemisegment. Each muscle fiber has unique spatial and behavioral characteristics that include its location, orientation, epidermal attachment, size and pattern of innervation. Many, if not all, of these properties are dictated by founder cells, which determine the muscle pattern and seed the fusion process. Myofibers are then derived from fusion between a specific founder cell and several fusion competent myoblasts (FCMs) fusing with as few as 3-5 FCMs in the small muscles on the most ventral side of the embryo and as many as 30 FCMs in the larger muscles on the dorsal side of the embryo. The focus of the present review is the formation of the larval muscles in the developing embryo, summarizing the major issues and players in this process. We have attempted to emphasize experimentally-validated details of the mechanism of myoblast fusion and distinguish these from the theoretically possible details that have not yet been confirmed experimentally. We also direct the interested reader to other recent reviews that discuss myoblast fusion in Drosophila, each with their own perspective on the process . With apologies, we use gene nomenclature as specified by Flybase (http://flybase.org) but provide Table 1 with alternative names and references.

  2. Fusion, magnetic confinement

    SciTech Connect

    Berk, H.L.

    1992-08-06

    An overview is presented of the principles of magnetic confinement of plasmas for the purpose of achieving controlled fusion conditions. Sec. 1 discusses the different nuclear fusion reactions which can be exploited in prospective fusion reactors and explains why special technologies need to be developed for the supply of tritium or {sup 3}He, the probable fuels. In Sec. 2 the Lawson condition, a criterion that is a measure of the quality of confinement relative to achieving fusion conditions, is explained. In Sec. 3 fluid equations are used to describe plasma confinement. Specific confinement configurations are considered. In Sec. 4 the orbits of particle sin magneti and electric fields are discussed. In Sec. 5 stability considerations are discussed. It is noted that confinement systems usually need to satisfy stability constraints imposed by ideal magnetohydrodynamic (MHD) theory. The paper culminates with a summary of experimental progress in magnetic confinement. Present experiments in tokamaks have reached the point that the conditions necessary to achieve fusion are being satisfied.

  3. The production and escape of nitrogen atoms on Mars

    NASA Astrophysics Data System (ADS)

    Fox, J. L.

    1993-02-01

    Updated rate coefficients and a revised ionosphere-thermosphere model are used to compute the production rates and densities of odd nitrogen species in the Martian atmosphere. Computed density profiles for N(4S), N(2D), N(2P), and NO are presented. The model NO densities are found to be about a factor of 2-3 less than those measured by the Viking 1 mass spectrometer. Revised values for the escape rates of N atoms from dissociative recombination and ionospheric reactions are also computed. Dissociative recombination is found to be comparable in importance to photodissociation at low solar activity, but it is still the most important escape mechanism for N-14 at high solar activity.

  4. The production and escape of nitrogen atoms on Mars

    NASA Technical Reports Server (NTRS)

    Fox, J. L.

    1993-01-01

    Updated rate coefficients and a revised ionosphere-thermosphere model are used to compute the production rates and densities of odd nitrogen species in the Martian atmosphere. Computed density profiles for N(4S), N(2D), N(2P), and NO are presented. The model NO densities are found to be about a factor of 2-3 less than those measured by the Viking 1 mass spectrometer. Revised values for the escape rates of N atoms from dissociative recombination and ionospheric reactions are also computed. Dissociative recombination is found to be comparable in importance to photodissociation at low solar activity, but it is still the most important escape mechanism for N-14 at high solar activity.

  5. Escape rate of active particles in the effective equilibrium approach

    NASA Astrophysics Data System (ADS)

    Sharma, A.; Wittmann, R.; Brader, J. M.

    2017-01-01

    The escape rate of a Brownian particle over a potential barrier is accurately described by the Kramers theory. A quantitative theory explicitly taking the activity of Brownian particles into account has been lacking due to the inherently out-of-equilibrium nature of these particles. Using an effective equilibrium approach [Farage et al., Phys. Rev. E 91, 042310 (2015), 10.1103/PhysRevE.91.042310] we study the escape rate of active particles over a potential barrier and compare our analytical results with data from direct numerical simulation of the colored noise Langevin equation. The effective equilibrium approach generates an effective potential that, when used as input to Kramers rate theory, provides results in excellent agreement with the simulation data.

  6. Cytosolic amyloid-{beta} peptide 42 escaping from degradation induces cell death

    SciTech Connect

    Lee, Eun Kyung; Park, Yong Wook; Shin, Dong Yeon; Mook-Jung, Inhee; Yoo, Yung Joon . E-mail: yjyoo@gist.ac.kr

    2006-06-02

    Accumulating evidence suggests that intracellular amyloid-{beta} (A{beta}) peptide triggers the early pathological events in Alzheimer's disease (AD). However, little is known about the consequence of cytosolic A{beta}. In this study, we ectopically expressed A{beta}42 in the cytoplasm of SH-SY5Y neuroblastoma cells by expressing a fusion protein of GFP-tagged ubiquitin and A{beta}42 (GFPUb-A{beta}42). Although GFPUb and A{beta}42 are stochastically produced with the same molar ratio in the cytoplasm, A{beta}42 was completely degraded in more than 50% of the GFPUb-expressing cells. However, if A{beta}42 was not degraded in their cytoplasm, then A{beta}42-expressing cells underwent apoptosis. The number of A{beta}42-expressing cells is significantly increased by the inhibition of proteasome with MG132. Cytosolic A{beta}42 which has escaped degradation inhibits proteasome and thereby may accelerate the accumulation of A{beta}42 and its detrimental effects. Our findings suggest that cells have the potential to degrade A{beta}42 in their cytoplasm but if A{beta}42 appears in the cytoplasm due to its incomplete degradation, it accumulates and may trigger the fatal cascade of pathology of AD.

  7. Self-Organizing Reactive Fluid Escape from Dehydrating Rocks

    NASA Astrophysics Data System (ADS)

    John, T.; Pluemper, O.; Podladchikov, Y.; Vrijmoed, J. C.; Scambelluri, M.

    2014-12-01

    Water escape from dehydrating rocks within the Earth's interior is a key process for long-term global water and element cycles, eg. at subduction zones a fluid escape mechanism must exist that prevents ocean water to be drained into the mantle. Existing fluid flow models require a priori physical assumptions (eg. preexisting porosity) and cannot resolve the evolution from initial fluid production to flow channelization. In order to develop a model of this evolution, we need to unravel natural laboratories that display the incipient dehydration stages and the micro- to macro-scale fluid escape route evolution. The Erro-Tobbio meta-serpentinites (Italy) provide a unique snapshot into these early dehydration stages, recording the breakdown of hydrous antigorite to anhydrous olivine plus fluid and the formation of an olivine-vein network. We find that dehydration, fluid pooling, and flow initiation are controlled by micro-scale compositional rock differences. Our model starts with a rock in which all water is stored in solid and any preexisting porosity is negligible (zero-porosity case). As the rock descents into the mantle increasing T will initiate dehydration reactions, dividing the rock continuously into a dry solid and a fluid-filled porosity. Spatially variable reaction progress results in dynamically evolving porosity/permeability and heterogeneous fluid-pore pressure distributions. Fluid-pressure gradient relaxation causes fluid flow and its thermodynamic feedback triggers reactions to progress, resulting in a self-amplifying process. Our new thermodynamic-mechanical model for reaction-porosity waves shows that fluid flow occurs solely in the reaction products and self-organizes into channelized fluid escape networks. This holds the key to formulating future quantitative models that address spatiotemporal processes such as the coupling between fluid release at depth and volcanic eruptions and the amounts of structurally bound water transferred into deep Earth.

  8. On the Relative Contributions of Noncontingent Reinforcement and Escape Extinction in the Treatment of Food Refusal

    ERIC Educational Resources Information Center

    Reed, Gregory K.; Piazza, Cathleen C.; Patel, Meeta R.; Layer, Stacy A.; Bachmeyer, Melanie H.; Bethke, Stephanie D.; Gutshall, Katharine A.

    2004-01-01

    In the current investigation, we evaluated the relative effects of noncontingent reinforcement (NCR), escape extinction, and a combination of NCR and escape extinction as treatment for the feeding problems exhibited by 4 children. For each participant, consumption increased only when escape extinction was implemented, independent of whether NCR…

  9. Escape Geography--Developing Middle-School Students' Sense of Place.

    ERIC Educational Resources Information Center

    Allen, Rodney F.; Molina, Laurie E. S.

    1992-01-01

    Suggests a social studies unit on escaping geography. Examines escape from dangerous places including an airliner, hotel fire, or war zone or from a social situation such as a boring speech or party. Describes historic escapes such as the Underground Railroad and the Berlin Wall. Lists learning strategies such as awareness of space and cognitive…

  10. Autophagy inhibitors.

    PubMed

    Pasquier, Benoit

    2016-03-01

    Autophagy is a lysosome-dependent mechanism of intracellular degradation. The cellular and molecular mechanisms underlying this process are highly complex and involve multiple proteins, including the kinases ULK1 and Vps34. The main function of autophagy is the maintenance of cell survival when modifications occur in the cellular environment. During the past decade, extensive studies have greatly improved our knowledge and autophagy has exploded as a research field. This process is now widely implicated in pathophysiological processes such as cancer, metabolic, and neurodegenerative disorders, making it an attractive target for drug discovery. In this review, we will summarize the different types of inhibitors that affect the autophagy machinery and provide some potential therapeutic perspectives.

  11. CD8 epitope escape and reversion in acute HCV infection.

    PubMed

    Timm, Joerg; Lauer, Georg M; Kavanagh, Daniel G; Sheridan, Isabelle; Kim, Arthur Y; Lucas, Michaela; Pillay, Thillagavathie; Ouchi, Kei; Reyor, Laura L; Schulze zur Wiesch, Julian; Gandhi, Rajesh T; Chung, Raymond T; Bhardwaj, Nina; Klenerman, Paul; Walker, Bruce D; Allen, Todd M

    2004-12-20

    In the setting of acute hepatitis C virus (HCV) infection, robust HCV-specific CD8+ cytotoxic T lymphocyte (CTL) responses are associated with initial control of viremia. Despite these responses, 70-80% of individuals develop persistent infection. Although viral escape from CD8 responses has been illustrated in the chimpanzee model of HCV infection, the effect of CD8 selection pressure on viral evolution and containment in acute HCV infection in humans remains unclear. Here, we examined viral evolution in an immunodominant human histocompatibility leukocyte antigen (HLA)-B8-restricted NS3 epitope in subjects with acute HCV infection. Development of mutations within the epitope coincided with loss of strong ex vivo tetramer and interferon gamma enzyme-linked immunospot responses, and endogenous expression of variant NS3 sequences suggested that the selected mutations altered processing and presentation of the variant epitope. Analysis of NS3 sequences from 30 additional chronic HCV-infected subjects revealed a strong association between sequence variation within this region and expression of HLA-B8, supporting reproducible allele-specific selection pressures at the population level. Interestingly, transmission of an HLA-B8-associated escape mutation to an HLA-B8 negative subject resulted in rapid reversion of the mutation. Together, these data indicate that viral escape from CD8+ T cell responses occurs during human HCV infection and that acute immune selection pressure is of sufficient magnitude to influence HCV evolution.

  12. Comparison of operant escape and reflex tests of nociceptive sensitivity.

    PubMed

    Vierck, Charles J; Yezierski, Robert P

    2015-04-01

    Testing of reflexes such as flexion/withdrawal or licking/guarding is well established as the standard for evaluating nociceptive sensitivity and its modulation in preclinical investigations of laboratory animals. Concerns about this approach have been dismissed for practical reasons - reflex testing requires no training of the animals; it is simple to instrument; and responses are characterized by observers as latencies or thresholds for evocation. In order to evaluate this method, the present review summarizes a series of experiments in which reflex and operant escape responding are compared in normal animals and following surgical models of neuropathic pain or pharmacological intervention for pain. Particular attention is paid to relationships between reflex and escape responding and information on the pain sensitivity of normal human subjects or patients with pain. Numerous disparities between results for reflex and operant escape measures are described, but the results of operant testing are consistent with evidence from humans. Objective reasons are given for experimenters to choose between these and other methods of evaluating the nociceptive sensitivity of laboratory animals.

  13. Oxygen and carbogen breathing following simulated submarine escape.

    PubMed

    Gennser, Mikael; Loveman, Geoff; Seddon, Fiona; Thacker, Julian; Blogg, S Lesley

    2014-01-01

    Escape from a disabled submarine exposes escapers to a high risk of decompression sickness (DCS). The initial bubble load is thought to emanate from the fast tissues; it is this load that should be lowered to reduce risk of serious neurological DCS. The breathing of oxygen or carbogen (5% CO2, 95% O2) post-surfacing was investigated with regard to its ability to reduce the initial bubble load in comparison to air breathing. Thirty-two goats were subject to a dry simulated submarine escape profile to and from 240 meters (2.5 MPa). On surfacing, they breathed air (control), oxygen or carbogen for 30 minutes. Regular Doppler audio bubble grading was carried out, using the Kisman Masurel (KM) scale. One suspected case of DCS was noted. No oxygen toxicity or arterial gas embolism occurred. No significant difference was found between the groups in terms of the median peak KM grade or the period before the KM grade dropped below III. Time to disappearance of bubbles was significantly different between groups; oxygen showed faster bubble resolution than carbogen and air. This reduction in time to bubble resolution may be beneficial in reducing decompression stress, but probably does not affect the risk of fast-tissue DCS.

  14. The C. elegans touch response facilitates escape from predacious fungi

    PubMed Central

    Maguire, Sean M.; Clark, Christopher M.; Nunnari, John; Pirri, Jennifer K.; Alkema, Mark J.

    2012-01-01

    Summary Predator-prey interactions are vital determinants in the natural selection of behavioral traits. However, we have few insights into both the neural mechanisms and the selective advantage of specific behavioral traits. Gentle touch to the anterior half of the body of Caenorhabditis elegans elicits an escape response in which the animal quickly reverses and suppresses exploratory head movements [1]. Even though the C. elegans touch response has provided one of the rare examples of how neural networks translate sensory input to a coordinated motor output [2], the ecological significance of the escape response is unclear. We investigate predator-prey relationships between C. elegans and predacious fungi that catch nematodes using constricting rings as trapping devices. We show that the constricting rings of Drechslerella doedycoides catch early larval stages with a diameter similar to the trap opening. There is a delay between the ring entry and ring closure, which allows the animal to withdraw from the trap before getting caught. Mutants that fail to suppress head movements in response to touch are caught more efficiently than the wild type in constricting fungal rings. Direct competition experiments show that the suppression of head movements in response to touch is an ecologically relevant behavior that allows the C. elegans to smoothly retract from a fungal noose and evade capture. These results suggest that selective pressures imposed by predacious fungi have shaped the evolution of C. elegans escape behavior. PMID:21802299

  15. Fleeing to refuge: Escape decisions in the race for life.

    PubMed

    Cooper, William E

    2016-10-07

    Economic escape theory that predicts that flight initiation distance (FID=predator-prey distance when a prey begins to flee from an approaching predator) increases as predation risk increases has been overwhelmingly supported. However, the vast majority of empirical tests have focused on effects of single predation risk factors. Even studies that have included multiple risk factors have not predicted how they jointly affect FID. I present a model that predicts joint effects of several predation risk factors that affect the outcome of a race between predator and prey to the prey's refuge. As a prey's distance to refuge and predator attack speed increase, and as the prey's location forces it to flee more toward a predator to reach refuge, FID increases. A published model proposed and experiment showed that FID is longer when prey flee directly toward than directly away from a predator to a refuge. We present a new geometric model that predicts FID for all angles between the prey's and predator's paths to refuge, distance of the prey from refuge when escape begins, predator and prey speeds, and a margin of safety allowing the prey to reach refuge before the predator. The model provides many new, testable predictions about relationships among its variables and FID. Most notably, it predicts that FID increases sigmoidally as the angle between predator and prey paths to refuge increases. Although the model is not economic (cost-benefit), we discuss its relationship to economic escape theory.

  16. A Treatment Package without Escape Extinction to Address Food Selectivity.

    PubMed

    Weber, Jessica; Gutierrez, Anibal

    2015-08-21

    Feeding difficulties and feeding disorders are a commonly occurring problem for young children, particularly children with developmental delays including autism. Behavior analytic interventions for the treatment of feeding difficulties oftentimes include escape extinction as a primary component of treatment. The use of escape extinction, while effective, may be problematic as it is also associated with the emergence of challenging behavior (e.g., extinction burst). Such challenging behavior may be an acceptable side effect in treatment cases where feeding problems are severe and chronic (e.g., failure to thrive). However, in more acute cases (e.g., selective eating), the negative side effect may be unwarranted and undesired. More recent research on the behavioral treatment of food selectivity has begun to evaluate treatments for feeding difficulties that do not include escape extinction (e.g., demand fading, behavioral momentum), with some success. However, research to date reveals individual differences in responsiveness to such treatments and no clear preferable treatment has emerged. This manuscript describes a multi-component treatment package that includes shaping, sequential presentation and simultaneous presentation, for the treatment of food selectivity in four young children with developmental delays. This treatment package extends the literature on the behavioral treatment for food selectivity and offers a multi-component treatment protocol that may be clinically applicable across a range of treatment scenarios and settings.

  17. Peaceful Uses of Fusion

    DOE R&D Accomplishments Database

    Teller, E.

    1958-07-03

    Applications of thermonuclear energy for peaceful and constructive purposes are surveyed. Developments and problems in the release and control of fusion energy are reviewed. It is pointed out that the future of thermonuclear power reactors will depend upon the construction of a machine that produces more electric energy than it consumes. The fuel for thermonuclear reactors is cheap and practically inexhaustible. Thermonuclear reactors produce less dangerous radioactive materials than fission reactors and, when once brought under control, are not as likely to be subject to dangerous excursions. The interaction of the hot plasma with magnetic fields opens the way for the direct production of electricity. It is possible that explosive fusion energy released underground may be harnessed for the production of electricity before the same feat is accomplished in controlled fusion processes. Applications of underground detonations of fission devices in mining and for the enhancement of oil flow in large low-specific-yield formations are also suggested.

  18. Spherical torus fusion reactor

    DOEpatents

    Peng, Yueng-Kay M.

    1989-01-01

    A fusion reactor is provided having a near spherical-shaped plasma with a modest central opening through which straight segments of toroidal field coils extend that carry electrical current for generating a toroidal magnet plasma confinement fields. By retaining only the indispensable components inboard of the plasma torus, principally the cooled toroidal field conductors and in some cases a vacuum containment vessel wall, the fusion reactor features an exceptionally small aspect ratio (typically about 1.5), a naturally elongated plasma cross section without extensive field shaping, requires low strength magnetic containment fields, small size and high beta. These features combine to produce a spherical torus plasma in a unique physics regime which permits compact fusion at low field and modest cost.

  19. Spherical torus fusion reactor

    DOEpatents

    Peng, Yueng-Kay M.

    1989-04-04

    A fusion reactor is provided having a near spherical-shaped plasma with a modest central opening through which straight segments of toroidal field coils extend that carry electrical current for generating a toroidal magnet plasma confinement fields. By retaining only the indispensable components inboard of the plasma torus, principally the cooled toroidal field conductors and in some cases a vacuum containment vessel wall, the fusion reactor features an exceptionally small aspect ratio (typically about 1.5), a naturally elongated plasma cross section without extensive field shaping, requires low strength magnetic containment fields, small size and high beta. These features combine to produce a spherical torus plasma in a unique physics regime which permits compact fusion at low field and modest cost.

  20. Ceramics for fusion applications

    SciTech Connect

    Clinard, F.W. Jr.

    1986-01-01

    Ceramics are required for a variety of uses in both near-term fusion devices and in commercial powerplants. These materials must retain adequate structural and electrical properties under conditions of neutron, particle, and ionizing irradiation; thermal and applied stresses; and physical and chemical sputtering. Ceramics such as Al/sub 2/O/sub 3/, MgAl/sub 2/O/sub 4/, BeO, Si/sub 3/N/sub 4/ and SiC are currently under study for fusion applications, and results to date show widely-varying response to the fusion environment. Materials can be identified today which will meet initial operating requirements, but improvements in physical properties are needed to achieve satisfactory lifetimes for critical applications.

  1. Fusion research at ORNL

    SciTech Connect

    Not Available

    1982-03-01

    The ORNL Fusion Program includes the experimental and theoretical study of two different classes of magnetic confinement schemes - systems with helical magnetic fields, such as the tokamak and stellarator, and the ELMO Bumpy Torus (EBT) class of toroidally linked mirror systems; the development of technologies, including superconducting magnets, neutral atomic beam and radio frequency (rf) heating systems, fueling systems, materials, and diagnostics; the development of databases for atomic physics and radiation effects; the assessment of the environmental impact of magnetic fusion; and the design of advanced demonstration fusion devices. The program involves wide collaboration, both within ORNL and with other institutions. The elements of this program are shown. This document illustrates the program's scope; and aims by reviewing recent progress.

  2. Simulation of Fusion Plasmas

    ScienceCinema

    Holland, Chris [UC San Diego, San Diego, California, United States

    2016-07-12

    The upcoming ITER experiment (www.iter.org) represents the next major milestone in realizing the promise of using nuclear fusion as a commercial energy source, by moving into the “burning plasma” regime where the dominant heat source is the internal fusion reactions. As part of its support for the ITER mission, the US fusion community is actively developing validated predictive models of the behavior of magnetically confined plasmas. In this talk, I will describe how the plasma community is using the latest high performance computing facilities to develop and refine our models of the nonlinear, multiscale plasma dynamics, and how recent advances in experimental diagnostics are allowing us to directly test and validate these models at an unprecedented level.

  3. Intense fusion neutron sources

    NASA Astrophysics Data System (ADS)

    Kuteev, B. V.; Goncharov, P. R.; Sergeev, V. Yu.; Khripunov, V. I.

    2010-04-01

    The review describes physical principles underlying efficient production of free neutrons, up-to-date possibilities and prospects of creating fission and fusion neutron sources with intensities of 1015-1021 neutrons/s, and schemes of production and application of neutrons in fusion-fission hybrid systems. The physical processes and parameters of high-temperature plasmas are considered at which optimal conditions for producing the largest number of fusion neutrons in systems with magnetic and inertial plasma confinement are achieved. The proposed plasma methods for neutron production are compared with other methods based on fusion reactions in nonplasma media, fission reactions, spallation, and muon catalysis. At present, intense neutron fluxes are mainly used in nanotechnology, biotechnology, material science, and military and fundamental research. In the near future (10-20 years), it will be possible to apply high-power neutron sources in fusion-fission hybrid systems for producing hydrogen, electric power, and technological heat, as well as for manufacturing synthetic nuclear fuel and closing the nuclear fuel cycle. Neutron sources with intensities approaching 1020 neutrons/s may radically change the structure of power industry and considerably influence the fundamental and applied science and innovation technologies. Along with utilizing the energy produced in fusion reactions, the achievement of such high neutron intensities may stimulate wide application of subcritical fast nuclear reactors controlled by neutron sources. Superpower neutron sources will allow one to solve many problems of neutron diagnostics, monitor nano-and biological objects, and carry out radiation testing and modification of volumetric properties of materials at the industrial level. Such sources will considerably (up to 100 times) improve the accuracy of neutron physics experiments and will provide a better understanding of the structure of matter, including that of the neutron itself.

  4. The Gasdynamic Mirror Fusion Propulsion System -- Revisited

    SciTech Connect

    Kammash, Terry; Tang, Ricky

    2005-02-06

    Many of the previous studies assessing the capability of the gasdynamic mirror (GDM) fusion propulsion system employed analyses that ignored the 'ambipolar' potential. This electrostatic potential arises as a result of the rapid escape of the electrons due to their small mass. As they escape, they leave behind an excess positive charge which manifests itself in an electric field that slows down the electrons while speeding up the ions until their respective axial diffusions are equalized. The indirect effect on the ions is that their confinement time is reduced relative to that of zero potential, and hence the plasma length must be increased to accommodate that change. But as they emerge from the thruster mirror - which serves as a magnetic nozzle - the ions acquire an added energy equal to that of the potential energy, and that in turn manifests itself in increased specific impulse and thrust. We assess the propulsive performance of the GDM thruster, based on the more rigorous theory, by applying it to a round trip Mars mission employing a continuous burn acceleration/deceleration type of trajectory. We find that the length of the device and travel time decrease with increasing plasma density, while the total vehicle mass reaches a minimum at a plasma density of 3 x 1016 cm-3. At such a density, and an initial DT ion temperature of 10 keV, a travel time of 60 days is found to be achievable at GDM propulsion parameters of about 200,000 seconds of specific impulse and approximately 47 kN of thrust.

  5. Atomic data for fusion

    SciTech Connect

    Hunter, H.T.; Kirkpatrick, M.I.; Alvarez, I.; Cisneros, C.; Phaneuf, R.A.; Barnett, C.F.

    1990-07-01

    This report provides a handbook of recommended cross-section and rate-coefficient data for inelastic collisions between hydrogen, helium and lithium atoms, molecules and ions, and encompasses more than 400 different reactions of primary interest in fusion research. Published experimental and theoretical data have been collected and evaluated, and the recommended data are presented in tabular, graphical and parametrized form. Processes include excitation and spectral line emission, charge exchange, ionization, stripping, dissociation and particle interchange reactions. The range of collision energies is appropriate to applications in fusion-energy research.

  6. Fusion welding process

    DOEpatents

    Thomas, Kenneth C.; Jones, Eric D.; McBride, Marvin A.

    1983-01-01

    A process for the fusion welding of nickel alloy steel members wherein a ferrite containing pellet is inserted into a cavity in one member and melted by a welding torch. The resulting weld nugget, a fusion of the nickel containing alloy from the members to be welded and the pellet, has a composition which is sufficiently low in nickel content such that ferrite phases occur within the weld nugget, resulting in improved weld properties. The steel alloys encompassed also include alloys containing carbon and manganese, considered nickel equivalents.

  7. Fusion for Space Propulsion

    NASA Technical Reports Server (NTRS)

    Thio, Y. C. Francis; Schmidt, George R.; Santarius, John F.; Turchi, Peter J.; Siemon, Richard E.; Rodgers, Stephen L. (Technical Monitor)

    2002-01-01

    The need for fusion propulsion for interplanetary flights is discussed. For a propulsion system, there are three important system attributes: (1) The absolute amount of energy available, (2) the propellant exhaust velocity, and (3) the jet power per unit mass of the propulsion system (specific power). For efficient and affordable human exploration of the solar system, propellant exhaust velocity in excess of 100 km/s and specific power in excess of 10 kW/kg are required. Chemical combustion obviously cannot meet the requirement in propellant exhaust velocity. Nuclear fission processes typically result in producing energy in the form of heat that needs to be manipulated at temperatures limited by materials to about 2,800 K. Using the fission energy to heat a low atomic weight propellant produces propellant velocity of the order of 10 kinds. Alternatively the fission energy can be converted into electricity that is used to accelerate particles to high exhaust velocity. However, the necessary power conversion and conditioning equipment greatly increases the mass of the propulsion system. Fundamental considerations in waste heat rejection and power conditioning in a fission electric propulsion system place a limit on its jet specific power to the order of about 0.2 kW/kg. If fusion can be developed for propulsion, it appears to have the best of all worlds - it can provide the largest absolute amount of energy, the propellant exhaust velocity (> 100 km/s), and the high specific jet power (> 10 kW/kg). An intermediate step towards fusion propulsion might be a bimodal system in which a fission reactor is used to provide some of the energy to drive a fusion propulsion unit. There are similarities as well as differences between applying fusion to propulsion and to terrestrial electrical power generation. The similarities are the underlying plasma and fusion physics, the enabling component technologies, the computational and the diagnostics capabilities. These physics and

  8. Development of Lead Compounds as Fusion Inhibitors for Dengue Virus

    DTIC Science & Technology

    2009-08-01

    interactions with transporters and metabolizing enzymes in the gut wall. Important properties for determining permeability seem to be the size of the...molecular properties, such as logD or hydrogen-bonding capacity. However, besides the purely physicochemical component contributing to membrane transport ...many compounds are affected by biological events, including the influence of transporters and metabolism. Many drugs seem to be substrates for

  9. Multisensor data fusion algorithm development

    SciTech Connect

    Yocky, D.A.; Chadwick, M.D.; Goudy, S.P.; Johnson, D.K.

    1995-12-01

    This report presents a two-year LDRD research effort into multisensor data fusion. We approached the problem by addressing the available types of data, preprocessing that data, and developing fusion algorithms using that data. The report reflects these three distinct areas. First, the possible data sets for fusion are identified. Second, automated registration techniques for imagery data are analyzed. Third, two fusion techniques are presented. The first fusion algorithm is based on the two-dimensional discrete wavelet transform. Using test images, the wavelet algorithm is compared against intensity modulation and intensity-hue-saturation image fusion algorithms that are available in commercial software. The wavelet approach outperforms the other two fusion techniques by preserving spectral/spatial information more precisely. The wavelet fusion algorithm was also applied to Landsat Thematic Mapper and SPOT panchromatic imagery data. The second algorithm is based on a linear-regression technique. We analyzed the technique using the same Landsat and SPOT data.

  10. Workmanship standards for fusion welding

    NASA Technical Reports Server (NTRS)

    Phillips, M. D.

    1967-01-01

    Workmanship standards manual defines practices, that adhere to rigid codes and specifications, for fusion welding of component piping, assemblies, and systems. With written and pictorial presentations, it is part of the operating procedure for fusion welding.

  11. Lunar mission safety and rescue: Escape/rescue analysis and plan

    NASA Technical Reports Server (NTRS)

    1971-01-01

    The results are presented of the technical analysis of escape/rescue/survival situations, crew survival techniques, alternate escape/rescue approaches and vehicles, and the advantages and disadvantages of each for advanced lunar exploration. Candidate escape/rescue guidelines are proposed and elements of a rescue plan developed. The areas of discussions include the following: lunar arrival/departure operations, lunar orbiter operations, lunar surface operations, lunar surface base escape/rescue analysis, lander tug location operations, portable airlock, emergency pressure suit, and the effects of no orbiting lunar station, no lunar surface base, and no foreign lunar orbit/surface operations on the escape/rescue plan.

  12. Mutations located on both F1 and F2 subunits of the Newcastle disease virus fusion protein confer resistance to neutralization with monoclonal antibodies.

    PubMed Central

    Neyt, C; Geliebter, J; Slaoui, M; Morales, D; Meulemans, G; Burny, A

    1989-01-01

    The fusion gene sequence of six Newcastle disease virus escape mutants revealed that residues important for the integrity of antigenic site 1 and antigenic site 2 were located, respectively, on the F2 subunit and within the cysteine-rich domain of the F1 subunit. We further report the antibody-binding capacity of these mutants. PMID:2463386

  13. Fusion Engineering Device design description

    SciTech Connect

    Flanagan, C.A.; Steiner, D.; Smith, G.E.

    1981-12-01

    The US Magnetic Fusion Engineering Act of 1980 calls for the operation of a Fusion Engineering Device (FED) by 1990. It is the intent of the Act that the FED, in combination with other testing facilities, will establish the engineering feasibility of magnetic fusion energy. During 1981, the Fusion Engineering Design Center (FEDC), under the guidance of a Technical Management Board (TMB), developed a baseline design for the FED. This design is summarized herein.

  14. Fusion engineering device design description

    SciTech Connect

    Flanagan, C.A.; Steiner, D.; Smith, G.E.

    1981-12-01

    The US Magnetic Fusion Engineering Act of 1980 calls for the operation of a Fusion Engineering Device (FED) by 1990. It is the intent of the Act that the FED, in combination with other testing facilities, will establish the engineering feasibility of magnetic fusion energy. During 1981, the Fusion Engineering Design Center (FEDC), under the guidance of a Technical Management Board (TMB), developed a baseline design for the FED. This design is summarized herein.

  15. Mars manned fusion spaceship

    SciTech Connect

    Hedrick, J.; Buchholtz, B.; Ward, P.; Freuh, J.; Jensen, E.

    1991-01-01

    Fusion Propulsion has an enormous potential for space exploration in the near future. In the twenty-first century, a usable and efficient fusion rocket will be developed and in use. Because of the great distance between other planets and Earth, efficient use of time, fuel, and payload is essential. A nuclear spaceship would provide greater fuel efficiency, less travel time, and a larger payload. Extended missions would give more time for research, experiments, and data acquisition. With the extended mission time, a need for an artificial environment exists. The topics of magnetic fusion propulsion, living modules, artificial gravity, mass distribution, space connection, and orbital transfer to Mars are discussed. The propulsion system is a magnetic fusion reactor based on a tandem mirror design. This allows a faster, shorter trip time and a large thrust to weight ratio. The fuel proposed is a mixture of deuterium and helium. Helium can be obtained from lunar mining. There will be minimal external radiation from the reactor resulting in a safe, efficient propulsion system.

  16. Mars manned fusion spaceship

    NASA Technical Reports Server (NTRS)

    Hedrick, James; Buchholtz, Brent; Ward, Paul; Freuh, Jim; Jensen, Eric

    1991-01-01

    Fusion Propulsion has an enormous potential for space exploration in the near future. In the twenty-first century, a usable and efficient fusion rocket will be developed and in use. Because of the great distance between other planets and Earth, efficient use of time, fuel, and payload is essential. A nuclear spaceship would provide greater fuel efficiency, less travel time, and a larger payload. Extended missions would give more time for research, experiments, and data acquisition. With the extended mission time, a need for an artificial environment exists. The topics of magnetic fusion propulsion, living modules, artificial gravity, mass distribution, space connection, and orbital transfer to Mars are discussed. The propulsion system is a magnetic fusion reactor based on a tandem mirror design. This allows a faster, shorter trip time and a large thrust to weight ratio. The fuel proposed is a mixture of deuterium and helium-3. Helium-3 can be obtained from lunar mining. There will be minimal external radiation from the reactor resulting in a safe, efficient propulsion system.

  17. Auditory Fusion in Children.

    ERIC Educational Resources Information Center

    Davis, Sylvia M.; McCroskey, Robert L.

    1980-01-01

    Focuses on auditory fusion (defined in terms of a listerner's ability to distinguish paired acoustic events from single acoustic events) in 3- to 12-year-old children. The subjects listened to 270 pairs of tones controlled for frequency, intensity, and duration. (CM)

  18. A fusion of minds

    NASA Astrophysics Data System (ADS)

    Corfield, Richard

    2013-02-01

    Mystery still surrounds the visit of the astronomer Sir Bernard Lovell to the Soviet Union in 1963. But his collaboration - and that of other British scientists - eased geopolitical tensions at the height of the Cold War and paved the way for today's global ITER fusion project, as Richard Corfield explains.

  19. Synergetic Multisensor Fusion

    DTIC Science & Technology

    1990-11-30

    technology have led to increased interest in using DEMs for navigation and other applications. In particular, DEMs are attractive for use in aircraft...Multisensor Fusion for Computer Vision [67]. 30 6. POSI!IONAL zSTIM&TION TECEnIQUzs FOR AN OUTDOOR MOBLE ROBOT The autonomous navigation of mobile robots is

  20. Fusion reactor materials

    SciTech Connect

    none,

    1989-01-01

    This paper discuses the following topics on fusion reactor materials: irradiation, facilities, test matrices, and experimental methods; dosimetry, damage parameters, and activation calculations; materials engineering and design requirements; fundamental mechanical behavior; radiation effects; development of structural alloys; solid breeding materials; and ceramics.

  1. Human-Centered Fusion Framework

    SciTech Connect

    Posse, Christian; White, Amanda M.; Beagley, Nathaniel

    2007-05-16

    In recent years the benefits of fusing signatures extracted from large amounts of distributed and/or heterogeneous data sources have been largely documented in various problems ranging from biological protein function prediction to cyberspace monitoring. In spite of significant progress in information fusion research, there is still no formal theoretical framework for defining various types of information fusion systems, defining and analyzing relations among such types, and designing information fusion systems using a formal method approach. Consequently, fusion systems are often poorly understood, are less than optimal, and/or do not suit user needs. To start addressing these issues, we outline a formal humancentered fusion framework for reasoning about fusion strategies. Our approach relies on a new taxonomy for fusion strategies, an alternative definition of information fusion in terms of parameterized paths in signature related spaces, an algorithmic formalization of fusion strategies and a library of numeric and dynamic visual tools measuring the impact as well as the impact behavior of fusion strategies. Using a real case of intelligence analysis we demonstrate that the proposed framework enables end users to rapidly 1) develop and implement alternative fusion strategies, 2) understand the impact of each strategy, 3) compare the various strategies, and 4) perform the above steps without having to know the mathematical foundations of the framework. We also demonstrate that the human impact on a fusion system is critical in the sense that small changes in strategies do not necessarily correspond to small changes in results.

  2. Graphite for fusion energy applications

    SciTech Connect

    Eatherly, W.P.; Clausing, R.E.; Strehlow, R.A.; Kennedy, C.R.; Mioduszewski, P.K.

    1987-03-01

    Graphite is in widespread and beneficial use in present fusion energy devices. This report reflects the view of graphite materials scientists on using graphite in fusion devices. Graphite properties are discussed with emphasis on application to fusion reactors. This report is intended to be introductory and descriptive and is not intended to serve as a definitive information source. (JDH)

  3. Broad CTL Response in Early HIV Infection Drives Multiple Concurrent CTL Escapes.

    PubMed

    Leviyang, Sivan; Ganusov, Vitaly V

    2015-10-01

    Recent studies have highlighted the ability of HIV to escape from cytotoxic T lymphocyte (CTL) responses that concurrently target multiple viral epitopes. Yet, the viral dynamics involved in such escape are incompletely understood. Previous analyses have made several strong assumptions regarding HIV escape from CTL responses such as independent or non-concurrent escape from individual CTL responses. Using experimental data from evolution of HIV half genomes in four patients we observe concurrent viral escape from multiple CTL responses during early infection (first 100 days of infection), providing confirmation of a recent result found in a study of one HIV-infected patient. We show that current methods of estimating CTL escape rates, based on the assumption of independent escapes, are biased and perform poorly when CTL escape proceeds concurrently at multiple epitopes. We propose a new method for analyzing longitudinal sequence data to estimate the rate of CTL escape across multiple epitopes; this method involves few parameters and performs well in simulation studies. By applying our novel method to experimental data, we find that concurrent multiple escapes occur at rates between 0.03 and 0.4 day(-1), a relatively broad range that reflects uncertainty due to sparse sampling and wide ranges of parameter values. However, we show that concurrent escape at rates 0.1-0.2 day(-1) across multiple epitopes is consistent with our patient datasets.

  4. The effects of escape from self and interpersonal relationship on the pathological use of Internet games.

    PubMed

    Kwon, Jung-Hye; Chung, Chung-Suk; Lee, Jung

    2011-02-01

    The purpose of the present study was to examine whether Baumeister's escape from self theory may account for the pathological use of Internet games among Korean adolescents. A sample of 1,136 junior high school students completed measures assessing Internet game addiction (IGA), real-ideal self discrepancy, escape from self, current mood, peer relationships, perceived parent-child relationship, and parental supervision. IGA was significantly correlated with all of these variables. Multiple regression analysis showed that escape from self best explained the adolescents' IGA. A path model yielded significant paths from self-discrepancy to negative mood, from negative mood to escape from self, and from escape from self to IGA. These results support the validity of using the escape from self theory to explain the adolescents' IGA, thereby suggesting that adolescents become addicted to Internet games in an attempt to escape from self and reality.

  5. A comparison of positive and negative reinforcement for compliance to treat problem behavior maintained by escape.

    PubMed

    Slocum, Sarah K; Vollmer, Timothy R

    2015-09-01

    Previous research has shown that problem behavior maintained by escape can be treated using positive reinforcement. In the current study, we directly compared functional (escape) and nonfunctional (edible) reinforcers in the treatment of escape-maintained problem behavior for 5 subjects. In the first treatment, compliance produced a break from instructions. In the second treatment, compliance produced a small edible item. Neither treatment included escape extinction. Results suggested that the delivery of a positive reinforcer for compliance was effective for treating escape-maintained problem behavior for all 5 subjects, and the delivery of escape for compliance was ineffective for 3 of the 5 subjects. Implications and future directions related to the use of positive reinforcers in the treatment of escape behavior are discussed.

  6. Escape erosion and relaxation of craters on Pluto

    NASA Astrophysics Data System (ADS)

    Porter, S.; Zangari, A.; Stern, A.

    2014-07-01

    Pluto and its major satellite Charon will be the most distant objects ever visited when NASA's New Horizons spacecraft flies past them in mid-2015. Both bodies should have suffered impacts from other transneptunian objects, though those impacts are of much lower velocity than typical on giant-planet satellites. New Horizons will image the illuminated hemispheres of Pluto and Charon seen at closest approach at better than 0.5 km/pix and 1.0 km/pix, respectively. We compare new different predictions of the impactor population on Pluto and Charon, including the effects of escape erosion from Pluto, and examine the crater size distributions those impactors would produce over the range observable to the imagers on New Horizons. The impact distribution models diverge the most for craters smaller than 10 km. We expect the crater size distribution on Charon to be determined by the impactor distribution and the rheology of the surface. Inverting the Charon size distribution seen by New Horizons will then constrain the overall size frequency distribution in the Kuiper belt, and the location of any break in that size frequency distribution. However, owing to escape erosion, craters on Pluto may be much more modified than on Charon. To constrain this modification, we present a range of possible Pluto crater distributions, as a function of impactor distribution, atmospheric escape rate, and surface ice viscosity. Pluto's atmosphere is primarily made of molecular nitrogen and is currently escaping at between 10^{27} and 10^{28} N_2/s according to model estimates. To sustain these escape rates for 3.5 billion years, a global layer of N_2 ice 0.3 to 3 km thick would need to have sublimated from the surface. We show that this gradual mass loss could have erased many of the smaller craters on Pluto, especially craters with diameters smaller than 10 km. This sublimation erosion process does not occur on Charon, which has a water ice surface and no observed atmosphere. We also show

  7. Fusogenic activity of reconstituted newcastle disease virus envelopes: a role for the hemagglutinin-neuraminidase protein in the fusion process.

    PubMed

    Cobaleda, C; Muñoz-Barroso, I; Sagrera, A; Villar, E

    2002-04-01

    Enveloped viruses, such as newcastle disease virus (NDV), make their entry into the host cell by membrane fusion. In the case of NDV, the fusion step requires both transmembrane hemagglutinin-neuraminidase (HN) and fusion (F) viral envelope glycoproteins. The HN protein should show fusion promotion activity. To date, the nature of HN-F interactions is a controversial issue. In this work, we aim to clarify the role of the HN glycoprotein in the membrane fusion step. Four types of reconstituted detergent-free NDV envelopes were used, on differing in their envelope protein contents. Fusion of the different virosomes and erythrocyte ghosts was monitored using the octadecyl rhodamine B chloride assay. Only the reconstituted envelopes having the F protein, even in the absence of HN protein, displayed residual fusion activity. Treatment of such virosomes with denaturing agents affecting the F protein abolished fusion, indicating that the fusion detected was viral protein-dependent. Interestingly, the rate of fusion in the reconstituted systems was similar to that of intact viruses in the presence of the inhibitor of HN sialidase activity 2,3-dehydro-2-deoxy-N-acetylneuraminic acid. The results show that the residual fusion activity detected in the reconstituted systems was exclusively due to F protein activity, with no contribution from the fusion promotion activity of HN protein.

  8. Experimental analysis and extinction of self-injurious escape behavior.

    PubMed

    Iwata, B A; Pace, G M; Kalsher, M J; Cowdery, G E; Cataldo, M F

    1990-01-01

    Three studies are presented in which environmental correlates of self-injurious behavior were systematically examined and later used as the basis for treatment. In Study 1, 7 developmentally disabled subjects were exposed to a series of conditions designed to identify factors that maintain self-injurious behavior: attention contingent on self-injurious behavior (positive reinforcement), escape from or avoidance of demands contingent on self-injurious behaviour (negative reinforcement), alone (automatic reinforcement), and play (control). Results of a multielement design showed that each subject's self-injurious behavior occurred more frequently in the demand condition, suggesting that the behavior served an avoidance or escape function. Six of the 7 subjects participated in Study 2. During educational sessions, "escape extinction" was applied as treatment for their self-injurious behavior in a multiple baseline across subjects design. Results showed noticeable reduction or elimination of self-injurious behavior for each subject and an increase in compliance with instructions in all subjects for whom compliance data were taken. The 7th subject, whose self-injurious behavior during Study 1 occurred in response to medical demands (i.e., physical examinations), participated in Study 3. Treatment was comprised of extinction, as in Study 2, plus reinforcement for tolerance of the examination procedure, and was evaluated in a multiple baseline across settings design. Results showed that the treatment was successful in eliminating self-injurious behavior and that its effects transferred across eight new therapists and three physicians. General implications for the design, interpretation, and uses of assessment studies are discussed.

  9. Accelerators for heavy ion fusion

    SciTech Connect

    Bangerter, R.O.

    1985-10-01

    Large fusion devices will almost certainly produce net energy. However, a successful commercial fusion energy system must also satisfy important engineering and economic constraints. Inertial confinement fusion power plants driven by multi-stage, heavy-ion accelerators appear capable of meeting these constraints. The reasons behind this promising outlook for heavy-ion fusion are given in this report. This report is based on the transcript of a talk presented at the Symposium on Lasers and Particle Beams for Fusion and Strategic Defense at the University of Rochester on April 17-19, 1985.

  10. Surgical fusion in childhood spondylolisthesis.

    PubMed

    Stanton, R P; Meehan, P; Lovell, W W

    1985-01-01

    Twenty cases of surgical fusion for spondylolisthesis were reviewed at the Scottish Rite Hospital (Atlanta, GA, U.S.A.) to determine whether a procedure other than a simple posterolateral fusion is necessary for most patients. The patients were treated postoperatively with pantaloon spica cast immobilization. The fusion rate was high (90%), and patient satisfaction was high. One patient developed neurologic loss postoperatively. Two patients' slips progressed greater than 10% before solid fusion occurred. Thus, bilateral posterolateral fusion, followed by pantaloon spica cast immobilization, is effective for patients with symptomatic spondylolisthesis or asymptomatic children with grade 3 or greater slips. Reduction was not performed in this series.

  11. Advanced Crew Escape Suits (ACES): Particle Impact Test

    NASA Technical Reports Server (NTRS)

    Rosales, Keisa R.; Stoltzfus, Joel M.

    2009-01-01

    NASA Johnson Space Center (JSC) requested NASA JSC White Sands Test Facility to assist in determining the effects of impaired anodization on aluminum parts in advanced crew escape suits (ACES). Initial investigation indicated poor anodization could lead to an increased risk of particle impact ignition, and a lack of data was prevalent for particle impact of bare (unanodized) aluminum; therefore, particle impact tests were performed. A total of 179 subsonic and 60 supersonic tests were performed with no ignition of the aluminum targets. Based on the resulting test data, WSTF found no increased particle impact hazard was present in the ACES equipment.

  12. Service-Life Extension of Explosive Escape Devices

    NASA Technical Reports Server (NTRS)

    Bement, L. J.; Schimmel, M. L.

    1987-01-01

    Chemical and functional tests yield conservative service-life estimates. Approach to extension of service lives of explosive devices in aircraft escape system developed, supported by testing of representative candidate devices to evaluate quantitatively effects of service, age, and degradation, and to enable responsible, conservative service-life determinations. Five types of explosive components evaluated: rigid and flexible explosive transfer lines; one-way transfers; flexible, linear-shaped charges; and initiation-handles. Extension of service in realistic manner provides both cost savings and increased system reliability.

  13. The age structure of selected countries in the ESCAP region.

    PubMed

    Hong, S

    1982-01-01

    The study objective was to examine the age structure of selected countries in the Economic and Social Commission for Asia and the Pacific (ESCAP) region, using available data and frequently applied indices such as the population pyramid, aged-child ratio, and median age. Based on the overall picture of the age structure thus obtained, age trends and their implication for the near future were arrived at. Countries are grouped into 4 types based on the fertility and mortality levels. Except for Japan, Hong Kong, and Singapore, the age structure in the 18 ESCAP region countries changed comparatively little over the 1950-80 period. The largest structural change occurred in Singapore, where the proportion of children under age 15 in the population declined significantly from 41-27%, while that of persons 65 years and older more than doubled. This was due primarily to the marked decline in fertility from a total fertility rate (TFR) of 6.7-1.8 during the period. Hong Kong also had a similar major transformation during the same period: the proportion of the old age population increased 2 1/2 times, from 2.5-6.3%. The age structures of the 18 ESCAP countries varied greatly by country. 10 countries of the 2 high fertility and mortality types showed a similar young age structural pattern, i.e., they have higher dependency ratios, a higher proportion of children under 15 years, a lower proportion of population 65 years and older, lower aged-child ratios, and younger median ages than the average countries in the less developed regions of the world. With minimal changes over the 1950-80 period, the gap between these countries and the average of the less developed regions widened. Unlike these 10 (mostly South Asian) countries, moderately low fertility and mortality countries (China, Korea, and Sri Lanka) are located between the world average and the less developed region in most of the indices, particularly during the last decade. Although their rate of population aging is not

  14. Behavioral momentum in the treatment of escape-motivated stereotypy.

    PubMed Central

    Mace, F C; Belfiore, P

    1990-01-01

    Descriptive and experimental analyses of stereotypy by a woman with severe mental retardation showed that the behavior was maintained by escape from demands. A sequence of high-probability requests issued immediately prior to a task-related request established a momentum of compliance that increased compliance with task-related demands. Increases in compliance were accompanied by collateral reductions in stereotypic behavior. A mechanism of response covariation, called functional incompatibility, and an animal analogue study for testing the validity of this mechanism are proposed. PMID:2074239

  15. Astrophysical bounds on photons escaping into extra dimensions.

    PubMed

    Friedland, A; Giannotti, M

    2008-01-25

    In a class of extra-dimensional models with a warped metric and a single brane the photon can be localized on the brane by gravity only. An intriguing feature of these models is the possibility of the photon escaping into the extra dimensions. The search for this effect has motivated the present round of precision ortho-positronium decay experiments. We point out that in this framework a photon in plasma should be metastable, and we consider what this implies for cooling of globular cluster stars and core-collapse supernovae. The resulting bounds on the model parameter exceed the possible reach of ortho-positronium experiments by many orders of magnitude.

  16. First-passage and escape problems in the Feller process

    NASA Astrophysics Data System (ADS)

    Masoliver, Jaume; Perelló, Josep

    2012-10-01

    The Feller process is an one-dimensional diffusion process with linear drift and state-dependent diffusion coefficient vanishing at the origin. The process is positive definite and it is this property along with its linear character that have made Feller process a convenient candidate for the modeling of a number of phenomena ranging from single-neuron firing to volatility of financial assets. While general properties of the process have long been well known, less known are properties related to level crossing such as the first-passage and the escape problems. In this work we thoroughly address these questions.

  17. The path to fusion power.

    PubMed

    Llewellyn Smith, Chris; Ward, David

    2007-04-15

    Fusion is potentially an environmentally responsible and intrinsically safe source of essentially limitless power. It should be possible to build viable fusion power stations, and it looks as if the cost of fusion power will be reasonable. But time is needed to further develop the technology and to test in power station conditions the materials that would be used in their construction. Assuming no major adverse surprises, an orderly fusion development programme could lead to a prototype fusion power station putting electricity into the grid within 30 years, with commercial fusion power following some 10 or more years later. In the second half of the century, fusion could therefore be an important part of the portfolio of measures that are needed to cope with rising demand for energy in an environmentally responsible manner. In this paper, we describe the basics of fusion, its potential attractions, the status of fusion R&D, the remaining challenges and how they will be tackled at the International Tokamak Experimental Reactor and the proposed International Fusion Materials Irradiation Facility, and the timetable for the subsequent commercialization of fusion power.

  18. The Need for Fusion Propulsion

    NASA Technical Reports Server (NTRS)

    Cassibry, Jason

    2005-01-01

    Fusion propulsion is inevitable if the human race remains dedicated to exploration of the solar system. There are fundamental reasons why fusion surpasses more traditional approaches to routine crewed missions to Mars, crewed missions to the outer planets, and deep space high speed robotic missions, assuming that reduced trip times, increased payloads, and higher available power are desired. A recent series of informal discussions were held among members from government, academia, and industry concerning fusion propulsion. We compiled a sufficient set of arguments for utilizing fusion in space. If the U.S. is to lead the effort and produce a working system in a reasonable amount of time, NASA must take the initiative, relying on, but not waiting for, DOE guidance. In this talk those arguments for fusion propulsion are presented, along with fusion enabled mission examples, fusion technology trade space, and a proposed outline for future efforts.

  19. Variable processing and cross-presentation of HIV by dendritic cells and macrophages shapes CTL immunodominance and immune escape.

    PubMed

    Dinter, Jens; Duong, Ellen; Lai, Nicole Y; Berberich, Matthew J; Kourjian, Georgio; Bracho-Sanchez, Edith; Chu, Duong; Su, Hang; Zhang, Shao Chong; Le Gall, Sylvie

    2015-03-01

    Dendritic cells (DCs) and macrophages (Møs) internalize and process exogenous HIV-derived antigens for cross-presentation by MHC-I to cytotoxic CD8⁺ T cells (CTL). However, how degradation patterns of HIV antigens in the cross-presentation pathways affect immunodominance and immune escape is poorly defined. Here, we studied the processing and cross-presentation of dominant and subdominant HIV-1 Gag-derived epitopes and HLA-restricted mutants by monocyte-derived DCs and Møs. The cross-presentation of HIV proteins by both DCs and Møs led to higher CTL responses specific for immunodominant epitopes. The low CTL responses to subdominant epitopes were increased by pretreatment of target cells with peptidase inhibitors, suggestive of higher intracellular degradation of the corresponding peptides. Using DC and Mø cell extracts as a source of cytosolic, endosomal or lysosomal proteases to degrade long HIV peptides, we identified by mass spectrometry cell-specific and compartment-specific degradation patterns, which favored the production of peptides containing immunodominant epitopes in all compartments. The intracellular stability of optimal HIV-1 epitopes prior to loading onto MHC was highly variable and sequence-dependent in all compartments, and followed CTL hierarchy with immunodominant epitopes presenting higher stability rates. Common HLA-associated mutations in a dominant epitope appearing during acute HIV infection modified the degradation patterns of long HIV peptides, reduced intracellular stability and epitope production in cross-presentation-competent cell compartments, showing that impaired epitope production in the cross-presentation pathway contributes to immune escape. These findings highlight the contribution of degradation patterns in the cross-presentation pathway to HIV immunodominance and provide the first demonstration of immune escape affecting epitope cross-presentation.

  20. The Route of HIV Escape from Immune Response Targeting Multiple Sites Is Determined by the Cost-Benefit Tradeoff of Escape Mutations

    PubMed Central

    Batorsky, Rebecca; Sergeev, Rinat A.; Rouzine, Igor M.

    2014-01-01

    Cytotoxic T lymphocytes (CTL) are a major factor in the control of HIV replication. CTL arise in acute infection, causing escape mutations to spread rapidly through the population of infected cells. As a result, the virus develops partial resistance to the immune response. The factors controlling the order of mutating epitope sites are currently unknown and would provide a valuable tool for predicting conserved epitopes. In this work, we adapt a well-established mathematical model of HIV evolution under dynamical selection pressure from multiple CTL clones to include partial impairment of CTL recognition, , as well as cost to viral replication, . The process of escape is described in terms of the cost-benefit tradeoff of escape mutations and predicts a trajectory in the cost-benefit plane connecting sequentially escaped sites, which moves from high recognition loss/low fitness cost to low recognition loss/high fitness cost and has a larger slope for early escapes than for late escapes. The slope of the trajectory offers an interpretation of positive correlation between fitness costs and HLA binding impairment to HLA-A molecules and a protective subset of HLA-B molecules that was observed for clinically relevant escape mutations in the Pol gene. We estimate the value of from published experimental studies to be in the range (0.01–0.86) and show that the assumption of complete recognition loss () leads to an overestimate of mutation cost. Our analysis offers a consistent interpretation of the commonly observed pattern of escape, in which several escape mutations are observed transiently in an epitope. This non-nested pattern is a combined effect of temporal changes in selection pressure and partial recognition loss. We conclude that partial recognition loss is as important as fitness loss for predicting the order of escapes and, ultimately, for predicting conserved epitopes that can be targeted by vaccines. PMID:25356981

  1. Fusion Data Grid Service

    NASA Astrophysics Data System (ADS)

    Shasharina, Svetlana; Wang, Nanbor

    2004-11-01

    Simulations and experiments in the fusion and plasma physics community generate large datasets at remote sites. Visualization and analysis of these datasets are difficult because of the incompatibility among the various data formats adopted by simulation, experiments, and analysis tools, and the large sizes of analyzed data. Grids and Web Services technologies are capable of providing solutions for such heterogeneous settings, but need to be customized to the field-specific needs and merged with distributed technologies currently used by the community. This paper describes how we are addressing these issues in the Fusion Grid Service under development. We also present performance results of relevant data transfer mechanisms including binary SOAP, DIME, GridFTP and MDSplus and CORBA. We will describe the status of data converters (between HDF5 and MDSplus data types), developed in collaboration with MIT (J. Stillerman). Finally, we will analyze bottlenecks of MDSplus data transfer mechanism (work performed in collaboration with General Atomics (D. Schissel and M. Qian).

  2. Experiments in cold fusion

    SciTech Connect

    Palmer, E.P.

    1986-03-28

    The work of Steve Jones and others in muon-catalyzed cold fusion of deuterium and hydrogen suggests the possibility of such fusion catalyzed by ions, or combinations of atoms, or more-or-less free electrons in solid and liquid materials. A hint that this might occur naturally comes from the heat generated in volcanic action in subduction zones on the earth. It is questionable whether the potential energy of material raised to the height of a midocean ridge and falling to the depth of an ocean trench can produce the geothermal effects seen in the volcanoes of subduction zones. If the ridge, the trench, the plates, and the asthenosphere are merely visible effects of deeper density-gradient driven circulations, it is still uncertain that observed energy-concentration effects fit the models.

  3. Fusion pumped laser

    DOEpatents

    Pappas, D.S.

    1987-07-31

    The apparatus of this invention may comprise a system for generating laser radiation from a high-energy neutron source. The neutron source is a tokamak fusion reactor generating a long pulse of high-energy neutrons and having a temperature and magnetic field effective to generate a neutron flux of at least 10/sup 15/ neutrons/cm/sup 2//center dot/s. Conversion means are provided adjacent the fusion reactor at a location operable for converting the high-energy neutrons to an energy source with an intensity and energy effective to excite a preselected lasing medium. A lasing medium is spaced about and responsive to the energy source to generate a population inversion effective to support laser oscillations for generating output radiation. 2 figs., 2 tabs.

  4. Unconventional approaches to fusion

    SciTech Connect

    Brunelli, B.; Leotta, G.G.

    1982-01-01

    This volume is dedicated to unconventional approaches to fusionthose thermonuclear reactors that, in comparison with Tokamak and other main lines, have received little attention in the worldwide scientific community. Many of the approaches considered are still in the embryonic stages. The authors-an international group of active nuclear scientists and engineers-focus on the parameters achieved in the use of these reactors and on the meaning of the most recent physical studies and their implications for the future. They also compare these approaches with conventional ones, the Tokamak in particular, stressing the non-plasma-physics requirements of fusion reactors. Unconventional compact toroids, linear systems, and multipoles are considered, as are the ''almost conventional'' fusion machines: stellarators, mirrors, reversed-field pinches, and EBT.

  5. Maximum Likelihood Fusion Model

    DTIC Science & Technology

    2014-08-09

    data fusion, hypothesis testing,maximum likelihood estimation, mobile robot navigation REPORT DOCUMENTATION PAGE 11. SPONSOR/MONITOR’S REPORT...61 vi 9 Bibliography 62 vii 10 LIST OF FIGURES 1.1 Illustration of mobile robotic agents. Land rovers such as (left) Pioneer robots ...simultaneous localization and mapping 1 15 Figure 1.1: Illustration of mobile robotic agents. Land rovers such as (left) Pioneer robots , (center) Segways

  6. Fusion development and technology

    SciTech Connect

    Montgomery, D.B.

    1992-01-01

    This report discusses the following: superconducting magnet technology; high field superconductors; advanced magnetic system and divertor development; poloidal field coils; gyrotron development; commercial reactor studies--aries; ITER physics: alpha physics and alcator R D for ITER; lower hybrid current drive and heating in the ITER device; ITER superconducting PF scenario and magnet analysis; ITER systems studies; and safety, environmental and economic factors in fusion development.

  7. (Fusion energy research)

    SciTech Connect

    Phillips, C.A.

    1988-01-01

    This report discusses the following topics: principal parameters achieved in experimental devices (FY88); tokamak fusion test reactor; Princeton beta Experiment-Modification; S-1 Spheromak; current drive experiment; x-ray laser studies; spacecraft glow experiment; plasma deposition and etching of thin films; theoretical plasma; tokamak modeling; compact ignition tokamak; international thermonuclear experimental reactor; Engineering Department; Project Planning and Safety Office; quality assurance and reliability; and technology transfer.

  8. Modular Aneutronic Fusion Engine

    SciTech Connect

    Gary Pajer, Yosef Razin, Michael Paluszek, A.H. Glasser and Samuel Cohen

    2012-05-11

    NASA's JUNO mission will arrive at Jupiter in July 2016, after nearly five years in space. Since operational costs tend to rise with mission time, minimizing such times becomes a top priority. We present the conceptual design for a 10MW aneutronic fusion engine with high exhaust velocities that would reduce transit time for a Jupiter mission to eighteen months and enable more challenging exploration missions in the solar system and beyond. __________________________________________________

  9. Inducible renitence limits Listeria monocytogenes escape from vacuoles in macrophages.

    PubMed

    Davis, Michael J; Gregorka, Brian; Gestwicki, Jason E; Swanson, Joel A

    2012-11-01

    Membranes of endolysosomal compartments in macrophages are often damaged by physical or chemical effects of particles ingested through phagocytosis or by toxins secreted by intracellular pathogens. This study identified a novel inducible activity in macrophages that increases resistance of phagosomes, late endosomes, and lysosomes to membrane damage. Pretreatment of murine macrophages with LPS, peptidoglycan, TNF-α, or IFN-γ conferred protection against subsequent damage to intracellular membranes caused by photooxidative chemistries or by phagocytosis of ground silica or silica microspheres. Phagolysosome damage was partially dependent on reactive oxygen species but was independent of the phagocyte oxidase. IFN-γ-stimulated macrophages from mice lacking the phagocyte oxidase inhibited escape from vacuoles by the intracellular pathogen Listeria monocytogenes, which suggested a role for this inducible renitence (resistance to pressure) in macrophage resistance to infection by pathogens that damage intracellular membranes. Renitence and inhibition of L. monocytogenes escape were partially attributable to heat shock protein-70. Thus, renitence is a novel, inducible activity of macrophages that maintains or restores the integrity of endolysosomal membranes.

  10. Numerical simulation of a self-propelled copepod during escape

    NASA Astrophysics Data System (ADS)

    Sotiropoulos, Fotis; Borazjani, Iman; Malkiel, Edwin; Katz, Josef

    2008-11-01

    Obtaining the 3D flow field, forces, and power is essential for understanding the high accelerations of a copepod during the escap. We carry out numerical simulations to study a free swimming copepod using the sharp-interface immersed boundary, fluid-structure interaction (FSI) approach of Borazjani et al. (J Compu Phys, 2008, 227, p 7587-7620). We use our previous tethered copepod model with a realistic copepod-like body, including all the appendages with the appendages motion prescribed from high-resolution, cinematic dual digital holography. The simulations are performed in a frame of reference attached to the copepod whose velocity is calculated by considering the forces acting on the copepod. The self-propelled simulations are challenging due to the destabilizing effects of the large added mass resulting from the low copepod mass and fast acceleration during the escape. Strongly-coupled FSI with under-relaxation and the Aitken acceleration technique is used to obtain stable and robust FSI iterations. The computed results for the self-propelled model are analyzed and compared with our earlier results for the tethered model.

  11. Escape of Hot Oxygen Atoms from the Atmosphere of Mars

    NASA Astrophysics Data System (ADS)

    Rahmati, A.; Croxell, J. A.; Cravens, T.; Pothapragada, S.; Nagy, A. F.; Ledvina, S. A.

    2013-12-01

    The main source of the production of hot oxygen atoms in the Martian atmosphere is the dissociative recombination (DR) reaction of O2+ ions with electrons. In this study, the primary production rate of hot O atoms is found for four energy channels of DR reaction. The one-dimensional energy and altitude dependent up and down flux differential equations are solved using a two-stream transport method, by taking into account the primary, secondary and cascade productions of hot O and also, the interactions with the background atmosphere. The forward and backward scattering probabilities and energy loss coefficients for 12 neutral target species are found using a Monte-Carlo simulation. The neutral target species are H, H2, He, C, N, O, CO, N2, NO, O2, Ar and CO2 for which the density profiles appropriate for Viking landers condition are used. From the up and down fluxes, the energy distribution function of hot O atoms and the escape flux at the exobase of Mars is calculated and by using the Liouville equation, the density profile of hot O is found above the exobase, extending out to several Martian radii. The results are used to study the interaction of escaping hot O atoms with the solar wind and specifically, the fluxes of energetic O+ pickup ions are determined.

  12. Escape of Hydrogen from the Exosphere of Mars

    NASA Astrophysics Data System (ADS)

    Bhattacharyya, Dolon; Clarke, John T.; Bertaux, Jean-Loup; Chaufray, Jean-Yves; Mayyasi-Matta, Majd A.

    2016-10-01

    After decades of exploration, the martian neutral hydrogen exosphere has remained largely uncharacterized even today. In my dissertation I have attempted to constrain the characteristics of the martian hydrogen exosphere using Hubble Space Telescope observations obtained during October-November 2007 and 2014. These observations reveal short-term seasonal changes exhibited by the martian hydrogen exosphere that are inconsistent with the diffusion-limited escape scenario. This seasonal behavior adds a new element towards backtracking the history of water loss from Mars. Modeling of the data also indicates the likely presence of a superthermal population of hydrogen created by non-thermal processes at Mars, another key element to understand the present-day escape. Exploration of the latitudinal symmetry of the martian exosphere indicates that it is symmetric above 2.5 martian radii and asymmetric below this altitude, which could be due to temperature differences between the day and night sides. Finally, the large uncertainties in determining the characteristics of the martian exosphere after decades of exploration is due to various assumptions about the intrinsic characteristics of the martian exosphere in the modeling process, degeneracy in the two modeling parameters temperature and density of the hydrogen atoms, unaccounted seasonal effects, and uncertainties introduced from spacecraft instrumentation as well as their viewing geometry.

  13. Quantification of Nociceptive Escape Response in C.elegans

    NASA Astrophysics Data System (ADS)

    Leung, Kawai; Mohammadi, Aylia; Ryu, William; Nemenman, Ilya

    2013-03-01

    Animals cannot rank and communicate their pain consciously. Thus in pain studies on animal models, one must infer the pain level from high precision experimental characterization of behavior. This is not trivial since behaviors are very complex and multidimensional. Here we explore the feasibility of C.elegans as a model for pain transduction. The nematode has a robust neurally mediated noxious escape response, which we show to be partially decoupled from other sensory behaviors. We develop a nociceptive behavioral response assay that allows us to apply controlled levels of pain by locally heating worms with an IR laser. The worms' motions are captured by machine vision programming with high spatiotemporal resolution. The resulting behavioral quantification allows us to build a statistical model for inference of the experienced pain level from the behavioral response. Based on the measured nociceptive escape of over 400 worms, we conclude that none of the simple characteristics of the response are reliable indicators of the laser pulse strength. Nonetheless, a more reliable statistical inference of the pain stimulus level from the measured behavior is possible based on a complexity-controlled regression model that takes into account the entire worm behavioral output. This work was partially supported by NSF grant No. IOS/1208126 and HFSP grant No. RGY0084/2011.

  14. Interspecific differences in how habitat degradation affects escape response.

    PubMed

    McCormick, Mark I; Allan, Bridie J M

    2017-03-27

    Degradation of habitats is widespread and a leading cause of extinctions. Our study determined whether the change in the chemical landscape associated with coral degradation affected the way three fish species use olfactory information to optimize their fast-start escape response. Water from degraded coral habitats affected the fast-start response of the three closely-related damselfishes, but its effect differed markedly among species. The Ward's damselfish (Pomacentrus wardi) was most affected by water from degraded coral, and displayed shorter distances covered in the fast-start and slower escape speeds compared to fish in water from healthy coral. In the presence of alarm odours, which indicate an imminent threat, the Ambon damsel (P. amboinensis) displayed enhanced fast-start performance in water from healthy coral, but not when in water from degraded coral. In contrast, while the white-tailed damsel (P. chrysurus) was similarly primed by its alarm odour, the elevation of fast start performance was not altered by water from degraded coral. These species-specific responses to the chemistry of degraded water and alarm odours suggest differences in the way alarm odours interact with the chemical landscape, and differences in the way species balance information about threats, with likely impacts on the survival of affected species in degraded habitats.

  15. On the escape of pollutants from urban street canyons

    NASA Astrophysics Data System (ADS)

    Baik, Jong-Jin; Kim, Jae-Jin

    Pollutant transport from urban street canyons is numerically investigated using a two-dimensional flow and dispersion model. The ambient wind blows perpendicular to the street and passive pollutants are released at the street level. Results from the control experiment with a street aspect ratio of 1 show that at the roof level of the street canyon, the vertical turbulent flux of pollutants is upward everywhere and the vertical flux of pollutants by mean flow is upward or downward. The horizontally integrated vertical flux of pollutants by mean flow at the roof level of the street canyon is downward and its magnitude is much smaller than that by turbulent process. These results indicate that pollutants escape from the street canyon mainly by turbulent process and that the net effect of mean flow is to make some escaped pollutants reenter the street canyon. Further experiments with different inflow turbulence intensities, inflow wind speeds, and street aspect ratio confirm the findings from the control experiment. In the case of two isolated buildings, the horizontally integrated vertical flux of pollutants by mean flow is upward due to flow separation but the other main results are the same as those from the control experiment.

  16. Ultra-fast Escape of a Octopus-inspired Rocket

    NASA Astrophysics Data System (ADS)

    Weymouth, Gabriel; Triantafyllou, Michael

    2013-11-01

    The octopus, squid, and other cephalopods inflate with water and then release a jet to accelerate in the opposite direction. This escape mechanism is particularly interesting in the octopus because they become initially quite bluff, yet this does not hinder them in achieving impressive bursts of speed. We examine this somewhat paradoxical maneuver using a simple deflating spheroid model in both potential and viscous flow. We demonstrate that the dynamic reduction of the width of the body completely changes the flow and forces acting on the escaping rocket in three ways. First, a body which reduces in size can generate an added mass thrust which counteracts the added mass inertia. Second, the motion of the shrinking wall acts similar to suction on a static wall, reducing separation and drag forces in a viscous fluid, but that this effects depends on the rate of size change. Third, using a combination of these two features it is possible to initially load the fluid with kinetic energy when heavy and bluff and then recover that energy when streamlined and light, enabling ultra-fast accelerations. As a notable example, these mechanisms allow a shrinking spheroid rocket in a heavy inviscid fluid to achieve speeds greater than an identical rocket in the vacuum of space. Southampton Marine and Maritime Institute.

  17. Slow and Fast Escape for Open Intermittent Maps

    NASA Astrophysics Data System (ADS)

    Demers, Mark F.; Todd, Mike

    2017-04-01

    If a system mixes too slowly, putting a hole in it can completely destroy the richness of the dynamics. Here we study this instability for a class of intermittent maps with a family of slowly mixing measures. We show that there are three regimes: (1) standard hyperbolic-like behavior where the rate of mixing is faster than the rate of escape through the hole, there is a unique limiting absolutely continuous conditionally invariant measure (accim) and there is a complete thermodynamic description of the dynamics on the survivor set; (2) an intermediate regime, where the rate of mixing and escape through the hole coincide, limiting accims exist, but much of the thermodynamic picture breaks down; (3) a subexponentially mixing regime where the slow mixing means that mass simply accumulates on the parabolic fixed point. We give a complete picture of the transitions and stability properties (in the size of the hole and as we move through the family) in this class of open systems. In particular, we are able to recover a form of stability in the third regime above via the dynamics on the survivor set, even when no limiting accim exists.

  18. Tectonic escape in the evolution of the continental crust

    NASA Technical Reports Server (NTRS)

    Burke, K.; Sengor, C.

    1986-01-01

    The continental crust originated by processes similar to those operating today and continents consist of material most of which originated long ago in arc-systems that have later been modified, especially at Andean margins and in continental collisions where crustal thickening is common. Collision-related strike-slip motion is a general process in continental evolution. Because buoyant continental (or arc) material generally moves during collision toward a nearby oceanic margin where less buoyant lithosphere crops out, the process of major strike-slip dominated motion toward a 'free-face' is called 'tectonic escape'. Tectonic escape is and has been an element in continental evolution throughout recorded earth-history. It promotes: (1) rifting and the formation of rift-basins with thinning of thickened crust; (2) pervasive strike-slip faulting late in orogenic history which breaks up mountain belts across strike and may juxtapose unrelated sectors in cross-section; (3) localized compressional mountains and related foreland-trough basins.

  19. Autoimmunity as a result of escape from RNA surveillance.

    PubMed

    Bachmann, Michael P; Bartsch, Holger; Gross, Joanne K; Maier, Shannon M; Gross, Timothy F; Workman, Jennifer L; James, Judith A; Farris, A Darise; Jung, Bettina; Franke, Claudia; Conrad, Karsten; Schmitz, Marc; Büttner, Cordula; Buyon, Jill P; Semsei, Imre; Harley, John B; Rieber, E Peter

    2006-08-01

    In previous studies, we detected a frame shift mutation in the gene encoding the autoantigen La of a patient with systemic lupus erythematosus. The mutant La mRNA contains a premature termination codon. mRNAs that prematurely terminate translation should be eliminated by RNA quality control mechanisms. As we find Abs specific for the mutant La form in approximately 30% of sera from anti-La-positive patients, we expected that mutant La mRNAs circumvent RNA control and the expression of mutant La protein could become harmful. Indeed, real-time PCR, immunostaining, and immunoblotting data of mice transgenic for the mutant La form show that mutant La mRNAs are not repressed in these animals and are translated to mutant La protein. In addition to the mutant La protein, we detected a minor portion of native human La in the mutant La-transgenic mice. Therefore, ribosomal frame shifting may allow the mutant La mRNA to escape from RNA control. Interestingly, expression of the mutant La mRNA results in a lupus-like disease in the experimental mice. Consequently, escape of mutant La mRNA from RNA control can have two effects: it 1) results in the expression of an immunogenic (neo)epitope, and 2) predisposes to autoimmunity.

  20. Autoimmunity as a Result of Escape from RNA Surveillance

    PubMed Central

    Bachmann, Michael P.; Bartsch, Holger; Gross, Joanne K.; Maier, Shannon M.; Gross, Timothy F.; Workman, Jennifer L.; James, Judith A.; Farris, A. Darise; Jung, Bettina; Franke, Claudia; Conrad, Karsten; Schmitz, Marc; Büttner, Cordula; Buyon, Jill P.; Semsei, Imre; Harley, John B.; Rieber, E. Peter

    2006-01-01

    In previous studies we detected a frame shift mutation in the gene encoding the autoantigen La of a patient with systemic lupus erythematosus. The mutant La mRNA contains a premature termination codon. mRNAs that prematurely terminate translation should be eliminated by RNA quality control mechanisms. As we find Abs specific for the mutant La form in about 30% of sera from anti-La positive patients we expected that mutant La mRNAs circumvent RNA control and the expression of mutant La protein could become harmful. Indeed, realtime PCR, immunostaining, and immunoblotting data of mice transgenic for the mutant La form show that mutant La mRNAs are not repressed in these animals and are translated to mutant La protein. In addition to the mutant La protein, we detected a minor portion of native human La in the mutant La transgenic mice. Therefore, ribosomal frame shifting may allow the mutant La mRNA to escape from RNA control. Interestingly, expression of the mutant La mRNA results in a lupus like disease in the experimental mice. Consequently, escape of mutant La mRNA from RNA control can have two effects: It (i) results in the expression of an immunogenic (neo)epitope, and (ii) predisposes to autoimmunity. PMID:16849479