WorldWideScience

Sample records for ctl escape mutations

  1. Broad CTL Response in Early HIV Infection Drives Multiple Concurrent CTL Escapes.

    Science.gov (United States)

    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.

  2. Quantifying factors determining the rate of CTL escape and reversion during acute and chronic phases of HIV infection

    Energy Technology Data Exchange (ETDEWEB)

    Ganusov, Vitaly V [Los Alamos National Laboratory; Korber, Bette M [Los Alamos National Laboratory; Perelson, Alan S [Los Alamos National Laboratory

    2009-01-01

    Human immunodeficiency virus (HIV) often evades cytotoxic T cell (CTL) responses by generating variants that are not recognized by CTLs. However, the importance and quantitative details of CTL escape in humans are poorly understood. In part, this is because most studies looking at escape of HIV from CTL responses are cross-sectional and are limited to early or chronic phases of the infection. We use a novel technique of single genome amplification (SGA) to identify longitudinal changes in the transmitted/founder virus from the establishment of infection to the viral set point at 1 year after the infection. We find that HIV escapes from virus-specific CTL responses as early as 30-50 days since the infection, and the rates of viral escapes during acute phase of the infection are much higher than was estimated in previous studies. However, even though with time virus acquires additional escape mutations, these late mutations accumulate at a slower rate. A poor correlation between the rate of CTL escape in a particular epitope and the magnitude of the epitope-specific CTL response suggests that the lower rate of late escapes is unlikely due to a low efficacy of the HIV-specific CTL responses in the chronic phase of the infection. Instead, our results suggest that late and slow escapes are likely to arise because of high fitness cost to the viral replication associated with such CTL escapes. Targeting epitopes in which virus escapes slowly or does not escape at all by CTL responses may, therefore, be a promising direction for the development of T cell based HIV vaccines.

  3. CTL escape mediated by proteasomal destruction of an HIV-1 cryptic epitope.

    Directory of Open Access Journals (Sweden)

    Sylvain Cardinaud

    2011-05-01

    Full Text Available Cytotoxic CD8+ T cells (CTLs play a critical role in controlling viral infections. HIV-infected individuals develop CTL responses against epitopes derived from viral proteins, but also against cryptic epitopes encoded by viral alternative reading frames (ARF. We studied here the mechanisms of HIV-1 escape from CTLs targeting one such cryptic epitope, Q9VF, encoded by an HIVgag ARF and presented by HLA-B*07. Using PBMCs of HIV-infected patients, we first cloned and sequenced proviral DNA encoding for Q9VF. We identified several polymorphisms with a minority of proviruses encoding at position 5 an aspartic acid (Q9VF/5D and a majority encoding an asparagine (Q9VF/5N. We compared the prevalence of each variant in PBMCs of HLA-B*07+ and HLA-B*07- patients. Proviruses encoding Q9VF/5D were significantly less represented in HLA-B*07+ than in HLA-B*07- patients, suggesting that Q9FV/5D encoding viruses might be under selective pressure in HLA-B*07+ individuals. We thus analyzed ex vivo CTL responses directed against Q9VF/5D and Q9VF/5N. Around 16% of HLA-B*07+ patients exhibited CTL responses targeting Q9VF epitopes. The frequency and the magnitude of CTL responses induced with Q9VF/5D or Q9VF/5N peptides were almost equal indicating a possible cross-reactivity of the same CTLs on the two peptides. We then dissected the cellular mechanisms involved in the presentation of Q9VF variants. As expected, cells infected with HIV strains encoding for Q9VF/5D were recognized by Q9VF/5D-specific CTLs. In contrast, Q9VF/5N-encoding strains were neither recognized by Q9VF/5N- nor by Q9VF/5D-specific CTLs. Using in vitro proteasomal digestions and MS/MS analysis, we demonstrate that the 5N variation introduces a strong proteasomal cleavage site within the epitope, leading to a dramatic reduction of Q9VF epitope production. Our results strongly suggest that HIV-1 escapes CTL surveillance by introducing mutations leading to HIV ARF-epitope destruction by proteasomes.

  4. Within-Epitope Interactions Can Bias CTL Escape Estimation in Early HIV Infection

    Directory of Open Access Journals (Sweden)

    Victor Garcia

    2017-05-01

    Full Text Available As human immunodeficiency virus (HIV begins to replicate within hosts, immune responses are elicited against it. Escape mutations in viral epitopes—immunogenic peptide parts presented on the surface of infected cells—allow HIV to partially evade these responses, and thus rapidly go to fixation. The faster they go to fixation, i.e., the higher their escape rate, the larger the selective pressure exerted by the immune system is assumed to be. This relation underpins the rationale for using escapes to assess the strength of immune responses. However, escape rate estimates are often obtained by employing an aggregation procedure, where several mutations that affect the same epitope are aggregated into a single, composite epitope mutation. The aggregation procedure thus rests upon the assumption that all within-epitope mutations have indistinguishable effects on immune recognition. In this study, we investigate how violation of this assumption affects escape rate estimates. To this end, we extend a previously developed simulation model of HIV that accounts for mutation, selection, and recombination to include different distributions of fitness effects (DFEs and inter-mutational genomic distances. We use this discrete time Wright–Fisher based model to simulate early within-host evolution of HIV for DFEs and apply standard estimation methods to infer the escape rates. We then compare true with estimated escape rate values. We also compare escape rate values obtained by applying the aggregation procedure with values estimated without use of that procedure. We find that across the DFEs analyzed, the aggregation procedure alters the detectability of escape mutations: large-effect mutations are overrepresented while small-effect mutations are concealed. The effect of the aggregation procedure is similar to extracting the largest-effect mutation appearing within an epitope. Furthermore, the more pronounced the over-exponential decay of the DFEs, the

  5. The route of HIV escape from immune response targeting multiple sites is determined by the cost-benefit tradeoff of escape mutations.

    Directory of Open Access Journals (Sweden)

    Rebecca Batorsky

    2014-10-01

    Full Text Available 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, [Formula: see text], as well as cost to viral replication, [Formula: see text]. 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 [Formula: see text] from published experimental studies to be in the range (0.01-0.86 and show that the assumption of complete recognition loss ([Formula: see text] 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

  6. The route of HIV escape from immune response targeting multiple sites is determined by the cost-benefit tradeoff of escape mutations.

    Science.gov (United States)

    Batorsky, Rebecca; Sergeev, Rinat A; Rouzine, Igor M

    2014-10-01

    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, [Formula: see text], as well as cost to viral replication, [Formula: see text]. 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 [Formula: see text] from published experimental studies to be in the range (0.01-0.86) and show that the assumption of complete recognition loss ([Formula: see text]) 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

  7. Impact of immune escape mutations on HIV-1 fitness in the context of the cognate transmitted/founder genome

    Directory of Open Access Journals (Sweden)

    Song Hongshuo

    2012-10-01

    Full Text Available Abstract Background A modest change in HIV-1 fitness can have a significant impact on viral quasispecies evolution and viral pathogenesis, transmission and disease progression. To determine the impact of immune escape mutations selected by cytotoxic T lymphocytes (CTL on viral fitness in the context of the cognate transmitted/founder (T/F genome, we developed a new competitive fitness assay using molecular clones of T/F genomes lacking exogenous genetic markers and a highly sensitive and precise parallel allele-specific sequencing (PASS method. Results The T/F and mutant viruses were competed in CD4+ T-cell enriched cultures, relative proportions of viruses were assayed after repeated cell-free passage, and fitness costs were estimated by mathematical modeling. Naturally occurring HLA B57-restricted mutations involving the TW10 epitope in Gag and two epitopes in Tat/Rev and Env were assessed independently and together. Compensatory mutations which restored viral replication fitness were also assessed. A principal TW10 escape mutation, T242N, led to a 42% reduction in replication fitness but V247I and G248A mutations in the same epitope restored fitness to wild-type levels. No fitness difference was observed between the T/F and a naturally selected variant carrying the early CTL escape mutation (R355K in Env and a reversion mutation in the Tat/Rev overlapping region. Conclusions These findings reveal a broad spectrum of fitness costs to CTL escape mutations in T/F viral genomes, similar to recent findings reported for neutralizing antibody escape mutations, and highlight the extraordinary plasticity and adaptive potential of the HIV-1 genome. Analysis of T/F genomes and their evolved progeny is a powerful approach for assessing the impact of composite mutational events on viral fitness.

  8. Escape of leukemia blasts from HLA-specific CTL pressure in a recipient of HLA one locus-mismatched bone marrow transplantation.

    Science.gov (United States)

    Kato, Tomonori; Terakura, Seitaro; Murata, Makoto; Sugimoto, Kyoko; Murase, Miho; Iriyama, Chisako; Tomita, Akihiro; Abe, Akihiro; Suzuki, Momoko; Nishida, Tetsuya; Naoe, Tomoki

    2012-01-01

    A case of leukemia escape from an HLA-specific cytotoxic T lymphocyte (CTL) response in a recipient of bone marrow transplantation is presented. Only the expression of HLA-B51, which was a mismatched HLA locus in the graft-versus-host direction, was down-regulated in post-transplant leukemia blasts compared with that in pre-transplant blasts. All CTL clones, that were isolated from the recipient's blood when acute graft-versus-host disease developed, recognized the mismatched B(∗)51:01 molecule in a peptide-dependent manner. The pre-transplant leukemia blasts were lysed by CTL clones, whereas the post-transplant leukemia blasts were not lysed by any CTL clones. The IFN-γ ELISPOT assay revealed that B(∗)51:01-reactive T lymphocytes accounted for the majority of the total alloreactive T lymphocytes in the blood just before leukemia relapse. These data suggest that immune escape of leukemia blasts from CTL pressure toward a certain HLA molecule can lead to clinical relapse after bone marrow transplantation. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication of vertically transmitted viruses.

    Science.gov (United States)

    Honegger, Jonathan R; Kim, Seungtaek; Price, Aryn A; Kohout, Jennifer A; McKnight, Kevin L; Prasad, Mona R; Lemon, Stanley M; Grakoui, Arash; Walker, Christopher M

    2013-11-01

    Globally, about 1% of pregnant women are persistently infected with the hepatitis C virus (HCV). Mother-to-child transmission of HCV occurs in 3-5% of pregnancies and accounts for most new childhood infections. HCV-specific CD8(+) cytotoxic T lymphocytes (CTLs) are vital in the clearance of acute HCV infections, but in the 60-80% of infections that persist, these cells become functionally exhausted or select for mutant viruses that escape T cell recognition. Increased HCV replication during pregnancy suggests that maternofetal immune tolerance mechanisms may further impair HCV-specific CTLs, limiting their selective pressure on persistent viruses. To assess this possibility, we characterized circulating viral quasispecies during and after consecutive pregnancies in two women. This revealed a loss of some escape mutations in HLA class I epitopes during pregnancy that was associated with emergence of more fit viruses. CTL selective pressure was reimposed after childbirth, at which point escape mutations in these epitopes again predominated in the quasispecies and viral load dropped sharply. Importantly, the viruses transmitted perinatally were those with enhanced fitness due to reversion of escape mutations. Our findings indicate that the immunoregulatory changes of pregnancy reduce CTL selective pressure on HCV class I epitopes, thereby facilitating vertical transmission of viruses with optimized replicative fitness.

  10. Specific killing of P53 mutated tumor cell lines by a cross-reactive human HLA-A2-restricted P53-specific CTL line

    DEFF Research Database (Denmark)

    Würtzen, P A; Pedersen, L O; Poulsen, H S

    2001-01-01

    , 4 HLA-A2(+) p53-mutated tumor cell lines were lysed by the CTL line, indicating that these peptides are endogenously processed and presented on HLA-A2 molecule. Thus, monocyte-derived DC pulsed with a pool of peptides are able to induce CTL reactivity to wild-type p53 peptides presented by several...

  11. Initiating a watch list for Ebola virus antibody escape mutations

    Directory of Open Access Journals (Sweden)

    Craig R. Miller

    2016-02-01

    Full Text Available The 2014 Ebola virus (EBOV outbreak in West Africa is the largest in recorded history and resulted in over 11,000 deaths. It is essential that strategies for treatment and containment be developed to avoid future epidemics of this magnitude. With the development of vaccines and antibody-based therapies using the envelope glycoprotein (GP of the 1976 Mayinga strain, one important strategy is to anticipate how the evolution of EBOV might compromise these efforts. In this study we have initiated a watch list of potential antibody escape mutations of EBOV by modeling interactions between GP and the antibody KZ52. The watch list was generated using molecular modeling to estimate stability changes due to mutation. Every possible mutation of GP was considered and the list was generated from those that are predicted to disrupt GP-KZ52 binding but not to disrupt the ability of GP to fold and to form trimers. The resulting watch list contains 34 mutations (one of which has already been seen in humans at six sites in the GP2 subunit. Should mutations from the watch list appear and spread during an epidemic, it warrants attention as these mutations may reflect an evolutionary response from the virus that could reduce the effectiveness of interventions such as vaccination. However, this watch list is incomplete and emphasizes the need for more experimental structures of EBOV interacting with antibodies in order to expand the watch list to other epitopes. We hope that this work provokes experimental research on evolutionary escape in both Ebola and other viral pathogens.

  12. Variable epitope library carrying heavily mutated survivin-derived CTL epitope variants as a new class of efficient vaccine immunogen tested in a mouse model of breast cancer.

    Science.gov (United States)

    NoeDominguez-Romero, Allan; Zamora-Alvarado, Rubén; Servín-Blanco, Rodolfo; Pérez-Hernández, Erendira G; Castrillon-Rivera, Laura E; Munguia, Maria Elena; Acero, Gonzalo; Govezensky, Tzipe; Gevorkian, Goar; Manoutcharian, Karen

    2014-01-01

    The antigenic variability of tumor cells leading to dynamic changes in cancer epitope landscape along with escape from immune surveillance by down-regulating tumor antigen expression/presentation and immune tolerance are major obstacles for the design of effective vaccines. We have developed a novel concept for immunogen construction based on introduction of massive mutations within the epitopes targeting antigenically variable pathogens and diseases. Previously, we showed that these immunogens carrying large combinatorial libraries of mutated epitope variants, termed as variable epitope libraries (VELs), induce potent, broad and long lasting CD8+IFN-γ+ T-cell response as well as HIV-neutralizing antibodies. In this proof-of-concept study, we tested immunogenic properties and anti-tumor effects of the VELs bearing survivin-derived CTL epitope (GWEPDDNPI) variants in an aggressive metastatic mouse 4T1 breast tumor model. The constructed VELs had complexities of 10,500 and 8,000 individual members, generated as combinatorial M13 phage display and synthetic peptide libraries, respectively, with structural composition GWXPXDXPI, where X is any of 20 natural amino acids. Statistically significant tumor growth inhibition was observed in BALB/c mice immunized with the VELs in both prophylactic and therapeutic settings. Vaccinated mice developed epitope-specific spleen cell and CD8+ IFN-γ+ T-cell responses that recognize more than 50% of the panel of 87 mutated epitope variants, as demonstrated in T-cell proliferation assays and FACS analysis. These data indicate the feasibility of the application of this new class of immunogens based on VEL concept as an alternative approach for the development of molecular vaccines against cancer.

  13. Dynamics of immune escape during HIV/SIV infection.

    Directory of Open Access Journals (Sweden)

    Christian L Althaus

    Full Text Available Several studies have shown that cytotoxic T lymphocytes (CTLs play an important role in controlling HIV/SIV infection. Notably, the observation of escape mutants suggests a selective pressure induced by the CTL response. However, it remains difficult to assess the definite role of the cellular immune response. We devise a computational model of HIV/SIV infection having a broad cellular immune response targeting different viral epitopes. The CTL clones are stimulated by viral antigen and interact with the virus population through cytotoxic killing of infected cells. Consequently, the virus population reacts through the acquisition of CTL escape mutations. Our model provides realistic virus dynamics and describes several experimental observations. We postulate that inter-clonal competition and immunodominance may be critical factors determining the sequential emergence of escapes. We show that even though the total killing induced by the CTL response can be high, escape rates against a single CTL clone are often slow and difficult to estimate from infrequent sequence measurements. Finally, our simulations show that a higher degree of immunodominance leads to more frequent escape with a reduced control of viral replication but a substantially impaired replicative capacity of the virus. This result suggests two strategies for vaccine design: Vaccines inducing a broad CTL response should decrease the viral load, whereas vaccines stimulating a narrow but dominant CTL response are likely to induce escape but may dramatically reduce the replicative capacity of the virus.

  14. Antigenic drift in the influenza A virus (H3N2) nucleoprotein and escape from recognition by cytotoxic T lymphocytes

    NARCIS (Netherlands)

    T.M. Bestebroer (Theo); N.J. Nieuwkoop; R.A.M. Fouchier (Ron); G.F. Rimmelzwaan (Guus); J.T.M. Voeten; A.D.M.E. Osterhaus (Ab)

    2000-01-01

    textabstractViruses exploit different strategies to escape immune surveillance, including the introduction of mutations in cytotoxic T-lymphocyte (CTL) epitopes. The sequence of these epitopes is critical for their binding to major histocompatibility complex (MHC) class I molecules

  15. Resistance mutations and CTL epitopes in archived HIV-1 DNA of patients on antiviral treatment: toward a new concept of vaccine.

    Directory of Open Access Journals (Sweden)

    Jennifer Papuchon

    Full Text Available Eleven patients responding successfully to first-line antiretroviral therapy (ART were investigated for proviral drug resistance mutations (DRMs in RT by ultra-deep pyrosequencing (UDPS. After molecular typing of the class I alleles A and B, the CTL epitopes in the Gag, Nef and Pol regions of the provirus were sequenced and compared to the reference HXB2 HIV-1 epitopes. They were then matched with the HLA alleles with determination of theoretical affinity (TA. For 3 patients, the results could be compared with an RNA sample of the circulating virus at initiation of therapy. Five out of 11 patients exhibited DRMs by UDPS. The issue is whether a therapeutic switch is relevant in these patients by taking into account the identity of the archived resistance mutations. When the archived CTL epitopes were determined on the basis of the HLA alleles, different patterns were observed. Some epitopes were identical to those reported for the reference with the same TA, while others were mutated with a decrease in TA. In 2 cases, an epitope was observed as a combination of subpopulations at entry and was retrieved as a single population with lower TA at success. With regard to immunological stimulation and given the variability of the archived CTL epitopes, we propose a new concept of curative vaccine based on identification of HIV-1 CTL epitopes after prior sequencing of proviral DNA and matching with HLA class I alleles.

  16. Potential elucidation of a novel CTL epitope in HIV-1 protease by the protease inhibitor resistance mutation L90M.

    Directory of Open Access Journals (Sweden)

    Werner Smidt

    Full Text Available The combination of host immune responses and use of antiretrovirals facilitate partial control of human immunodeficiency virus type 1 (HIV-1 infection and result in delayed progression to Acquired Immunodeficiency Syndrome (AIDS. Both treatment and host immunity impose selection pressures on the highly mutable HIV-1 genome resulting in antiretroviral resistance and immune escape. Researchers have shown that antiretroviral resistance mutations can shape cytotoxic T-lymphocyte immunity by altering the epitope repertoire of HIV infected cells. Here it was discovered that an important antiretroviral resistance mutation, L90M in HIV protease, occurs at lower frequencies in hosts that harbor the B*15, B*48 or A*32 human leukocyte antigen subtypes. A likely reason is the elucidation of novel epitopes by L90M. NetMHCPan predictions reveal increased affinity of the peptide spanning the HIV protease region, PR 89-97 and PR 90-99 to HLA-B*15/B*48 and HLA-A*32 respectively due to the L90M substitution. The higher affinity could increase the chance of the epitope being presented and recognized by Cytotoxic T-lymphocytes and perhaps provide additional immunological pressures in the presence of antiretroviral attenuating mutations. This evidence supports the notion that knowledge of HLA allotypes in HIV infected individuals could augment antiretroviral treatment by the elucidation of epitopes due to antiretroviral resistance mutations in HIV protease.

  17. Mutator suppression and escape from replication error-induced extinction in yeast.

    Directory of Open Access Journals (Sweden)

    Alan J Herr

    2011-10-01

    Full Text Available Cells rely on a network of conserved pathways to govern DNA replication fidelity. Loss of polymerase proofreading or mismatch repair elevates spontaneous mutation and facilitates cellular adaptation. However, double mutants are inviable, suggesting that extreme mutation rates exceed an error threshold. Here we combine alleles that affect DNA polymerase δ (Pol δ proofreading and mismatch repair to define the maximal error rate in haploid yeast and to characterize genetic suppressors of mutator phenotypes. We show that populations tolerate mutation rates 1,000-fold above wild-type levels but collapse when the rate exceeds 10⁻³ inactivating mutations per gene per cell division. Variants that escape this error-induced extinction (eex rapidly emerge from mutator clones. One-third of the escape mutants result from second-site changes in Pol δ that suppress the proofreading-deficient phenotype, while two-thirds are extragenic. The structural locations of the Pol δ changes suggest multiple antimutator mechanisms. Our studies reveal the transient nature of eukaryotic mutators and show that mutator phenotypes are readily suppressed by genetic adaptation. This has implications for the role of mutator phenotypes in cancer.

  18. Vaccination and timing influence SIV immune escape viral dynamics in vivo.

    Directory of Open Access Journals (Sweden)

    Liyen Loh

    2008-01-01

    Full Text Available CD8+ cytotoxic T lymphocytes (CTL can be effective at controlling HIV-1 in humans and SIV in macaques, but their utility is partly offset by mutational escape. The kinetics of CTL escape and reversion of escape mutant viruses upon transmission to MHC-mismatched hosts can help us understand CTL-mediated viral control and the fitness cost extracted by immune escape mutation. Traditional methods for following CTL escape and reversion are, however, insensitive to minor viral quasispecies. We developed sensitive quantitative real-time PCR assays to track the viral load of SIV Gag164-172 KP9 wild-type (WT and escape mutant (EM variants in pigtail macaques. Rapid outgrowth of EM virus occurs during the first few weeks of infection. However, the rate of escape plateaued soon after, revealing a prolonged persistence of WT viremia not detectable by standard cloning and sequencing methods. The rate of escape of KP9 correlated with levels of vaccine-primed KP9-specific CD8+ T cells present at that time. Similarly, when non-KP9 responder (lacking the restricting Mane-A*10 allele macaques were infected with SHIVmn229 stock containing a mixture of EM and WT virus, rapid reversion to WT was observed over the first 2 weeks following infection. However, the rate of reversion to WT slowed dramatically over the first month of infection. The serial quantitation of escape mutant viruses evolving during SIV infection shows that rapid dynamics of immune escape and reversion can be observed in early infection, particularly when CD8 T cells are primed by vaccination. However, these early rapid rates of escape and reversion are transient and followed by a significant slowing in these rates later during infection, highlighting that the rate of escape is significantly influenced by the timing of its occurrence.

  19. A quantitative quasispecies theory-based model of virus escape mutation under immune selection.

    Science.gov (United States)

    Woo, Hyung-June; Reifman, Jaques

    2012-08-07

    Viral infections involve a complex interplay of the immune response and escape mutation of the virus quasispecies inside a single host. Although fundamental aspects of such a balance of mutation and selection pressure have been established by the quasispecies theory decades ago, its implications have largely remained qualitative. Here, we present a quantitative approach to model the virus evolution under cytotoxic T-lymphocyte immune response. The virus quasispecies dynamics are explicitly represented by mutations in the combined sequence space of a set of epitopes within the viral genome. We stochastically simulated the growth of a viral population originating from a single wild-type founder virus and its recognition and clearance by the immune response, as well as the expansion of its genetic diversity. Applied to the immune escape of a simian immunodeficiency virus epitope, model predictions were quantitatively comparable to the experimental data. Within the model parameter space, we found two qualitatively different regimes of infectious disease pathogenesis, each representing alternative fates of the immune response: It can clear the infection in finite time or eventually be overwhelmed by viral growth and escape mutation. The latter regime exhibits the characteristic disease progression pattern of human immunodeficiency virus, while the former is bounded by maximum mutation rates that can be suppressed by the immune response. Our results demonstrate that, by explicitly representing epitope mutations and thus providing a genotype-phenotype map, the quasispecies theory can form the basis of a detailed sequence-specific model of real-world viral pathogens evolving under immune selection.

  20. Investigating the Consequences of Interference between Multiple CD8+ T Cell Escape Mutations in Early HIV Infection.

    Directory of Open Access Journals (Sweden)

    Victor Garcia

    2016-02-01

    Full Text Available During early human immunodeficiency virus (HIV infection multiple CD8+ T cell responses are elicited almost simultaneously. These responses exert strong selective pressures on different parts of HIV's genome, and select for mutations that escape recognition and are thus beneficial to the virus. Some studies reveal that the later these escape mutations emerge, the more slowly they go to fixation. This pattern of escape rate decrease(ERD can arise by distinct mechanisms. In particular, in large populations with high beneficial mutation rates interference among different escape strains--an effect that can emerge in evolution with asexual reproduction and results in delayed fixation times of beneficial mutations compared to sexual reproduction--could significantly impact the escape rates of mutations. In this paper, we investigated how interference between these concurrent escape mutations affects their escape rates in systems with multiple epitopes, and whether it could be a source of the ERD pattern. To address these issues, we developed a multilocus Wright-Fisher model of HIV dynamics with selection, mutation and recombination, serving as a null-model for interference. We also derived an interference-free null model assuming initial neutral evolution before immune response elicitation. We found that interference between several equally selectively advantageous mutations can generate the observed ERD pattern. We also found that the number of loci, as well as recombination rates substantially affect ERD. These effects can be explained by the underexponential decline of escape rates over time. Lastly, we found that the observed ERD pattern in HIV infected individuals is consistent with both independent, interference-free mutations as well as interference effects. Our results confirm that interference effects should be considered when analyzing HIV escape mutations. The challenge in estimating escape rates and mutation-associated selective

  1. Mutations That Alter Use of Hepatitis C Virus Cell Entry Factors Mediate Escape From Neutralizing Antibodies

    Science.gov (United States)

    FAUVELLE, CATHERINE; ZAHID, MUHAMMAD NAUMAN; TUREK, MARINE; HEYDMANN, LAURA; CURY, KARINE; HAYER, JULIETTE; COMBET, CHRISTOPHE; COSSET, FRANÇOIS–LOÏC; PIETSCHMANN, THOMAS; HIET, MARIE–SOPHIE; BARTENSCHLAGER, RALF; HABERSETZER, FRANÇOIS; DOFFOËL, MICHEL; KECK, ZHEN–YONG; FOUNG, STEVEN K. H.; ZEISEL, MIRJAM B.; STOLL–KELLER, FRANÇOISE; BAUMERT, THOMAS F.

    2017-01-01

    BACKGROUND & AIMS The development of vaccines and other strategies to prevent hepatitis C virus (HCV) infection is limited by rapid viral evasion. HCV entry is the first step of infection; this process involves several viral and host factors and is targeted by host-neutralizing responses. Although the roles of host factors in HCV entry have been well characterized, their involvement in evasion of immune responses is poorly understood. We used acute infection of liver graft as a model to investigate the molecular mechanisms of viral evasion. METHODS We studied factors that contribute to evasion of host immune responses using patient-derived antibodies, HCV pseudoparticles, and cell culture–derived HCV that express viral envelopes from patients who have undergone liver transplantation. These viruses were used to infect hepatoma cell lines that express different levels of HCV entry factors. RESULTS By using reverse genetic analyses, we identified altered use of host-cell entry factors as a mechanism by which HCV evades host immune responses. Mutations that alter use of the CD81 receptor also allowed the virus to escape neutralizing antibodies. Kinetic studies showed that these mutations affect virus–antibody interactions during postbinding steps of the HCV entry process. Functional studies with a large panel of patient-derived antibodies showed that this mechanism mediates viral escape, leading to persistent infection in general. CONCLUSIONS We identified a mechanism by which HCV evades host immune responses, in which use of cell entry factors evolves with escape from neutralizing antibodies. These findings advance our understanding of the pathogenesis of HCV infection and might be used to develop antiviral strategies and vaccines. PMID:22503792

  2. Replicative Homeostasis: A fundamental mechanism mediating selective viral replication and escape mutation

    Directory of Open Access Journals (Sweden)

    Sallie Richard

    2005-02-01

    Full Text Available Abstract Hepatitis C (HCV, hepatitis B (HBV, the human immunodeficiency viruses (HIV, and other viruses that replicate via RNA intermediaries, cause an enormous burden of disease and premature death worldwide. These viruses circulate within infected hosts as vast populations of closely related, but genetically diverse, molecules known as "quasispecies". The mechanism(s by which this extreme genetic and antigenic diversity is stably maintained are unclear, but are fundamental to understanding viral persistence and pathobiology. The persistence of HCV, an RNA virus, is especially problematic and HCV stability, maintained despite rapid genomic mutation, is highly paradoxical. This paper presents the hypothesis, and evidence, that viruses capable of persistent infection autoregulate replication and the likely mechanism mediating autoregulation – Replicative Homeostasis – is described. Replicative homeostasis causes formation of stable, but highly reactive, equilibria that drive quasispecies expansion and generates escape mutation. Replicative homeostasis explains both viral kinetics and the enigma of RNA quasispecies stability and provides a rational, mechanistic basis for all observed viral behaviours and host responses. More importantly, this paradigm has specific therapeutic implication and defines, precisely, new approaches to antiviral therapy. Replicative homeostasis may also modulate cellular gene expression.

  3. The circadian Clock mutation increases exploratory activity and escape-seeking behavior.

    Science.gov (United States)

    Easton, A; Arbuzova, J; Turek, F W

    2003-02-01

    Disturbances of circadian rhythms are associated with many types of mood disorders; however, it is unknown whether a dysfunctional circadian pacemaker can be the primary cause of altered emotional behavior. To test this hypothesis, male and female mice carrying a mutation of the circadian gene, Clock, were compared to wild-type mice in an array of behavioral tests used to measure exploratory activity, anxiety, and behavioral despair. Female Clock mutant mice exhibited significantly greater activity and rearing in an open field and a greater number of total arm entries in the elevated plus maze. In addition, female Clock mutant mice spent significantly more time swimming in the forced swim test than wild-type mice on both days of a 2-day test. Male Clock mutant mice also exhibited increased exploration of the open field and increased swimming in the forced swim test; however, behavioral changes were less robust in Clock mutant males compared to Clock mutant females. These changes in behavior were not dependent on the expression of a lengthened free-running period but were more or less striking depending on the testing conditions. These data indicate that the Clock mutation leads to increased exploratory behavior and increased escape-seeking behavior, and, conversely, does not result in increased anxiety or depressive-like behavior. These results suggest that the Clock gene is involved in regulating behavioral arousal, and that Clock may interact with sex hormones to produce these behavioral changes.

  4. CTL ELISPOT assay.

    Science.gov (United States)

    Ranieri, Elena; Popescu, Iulia; Gigante, Margherita

    2014-01-01

    Enzyme-linked immune absorbent spot (Elispot) is a quantitative method for measuring relevant parameters of T cell activation. The sensitivity of Elispot allows the detection of low-frequency antigen-specific T cells that secrete cytokines and effector molecules, such as granzyme B and perforin. Cytotoxic T cell (CTL) studies have taken advantage with this high-throughput technology by providing insights into quantity and immune kinetics. Accuracy, sensitivity, reproducibility, and robustness of Elispot resulted in a wide range of applications in research as well as in diagnostic field. Actually, CTL monitoring by Elispot is a gold standard for the evaluation of antigen-specific T cell immunity in clinical trials and vaccine candidates where the ability to detect rare antigen-specific T cells is of relevance for immune diagnostic. The most utilized Elispot assay is the interferon-gamma (IFN-γ) test, a marker for CD8(+) CTL activation, but Elispot can also be used to distinguish different subsets of activated T cells by using other cytokines such as T-helper (Th) 1-type cells (characterized by the production of IFN-γ, IL-2, IL-6, IL-12, IL-21, and TNF-α), Th2 (producing cytokines like IL-4, IL-5, IL-10, and IL-13), and Th17 (IL-17) cells. The reliability of Elispot-generated data, by the evaluation of T cell frequency recognizing individual antigen/peptide, is the core of this method currently applied widely to investigate specific immune responses in cancer, infections, allergies, and autoimmune diseases. The Elispot assay is competing with other methods measuring single-cell cytokine production, e.g., intracellular cytokine by FACS or Miltenyi cytokine secretion assay. Other types of lymphocyte frequency and function assays include limiting dilution assay (LDA), cytotoxic T cell assay (CTL), and tetramer staining. Compared with respect to sensitivity the Elispot assay is outranking other methods to define frequency of antigen-specific lymphocytes. The method

  5. [HBV vaccine escape mutations in a chronic hepatitis B patient treated with nucleos(t)ide analogues].

    Science.gov (United States)

    Sayan, Murat; Buğdacı, Mehmet Sait

    2013-07-01

    The hepatitis B virus (HBV) polymerase (pol) gene completely overlaps with the envelope (S) gene. Nucleos(t)ide analogue (NA) resistance mutations in the pol gene of HBV, either from selection of primary or secondary resistance mutations, typically result in changes in the overlapping hepatitis B surface antigen (HBsAg). Recent studies have conferred a new acronym to these HBV pol/S gene overlap mutants; ADAPVEMs, for antiviral drug-associated potential vaccine-escape mutants. The present report aimed to assess the determined multiple HBV vaccine-escape mutants in a Turkish patient with chronic hepatitis B (CHB), undergoing NAs treatment. The liver biopsy of HBsAg positive, HBeAg negative 53-year old female patient with CHB, revealed a score as histological activity index; 9 and fibrosis; 2 according to Ishak classification. NA treatment backgrounds consisted of 24 months lamivudine, followed by 18 months entacavir and lastly 3 months tenofovir monotherapies. Since HBV DNA load was determined as 7.030.000 IU/ml at the 4th month of tenofovir therapy, entecavir was added as current treatment regimen, and tenofovir + entecavir therapy decreased the HBV DNA load (400 IU/ml). Sequence analysis was performed for HBV pol/S gene and overlapping pol/S gene amino acid substitutions, primary/compensatory NA resistance mutations and antiviral drug-associated potential vaccine-escape mutations (ADAPVEM) were analysed. The patient isolate was identified as genotype D/subgenotype D1 of HBV. Primary drug resistance mutations (rtV173L + rtL180M + rtM204V) to lamivudine and telbivudine and a compensatory mutation (rtQ215H) to lamivudine and adefovir were described in the HBV pol gene sequence. However, multiple HBV vaccine-escape mutations (sS143T + sD144E + sG145R + sE164D + sI195M) have been determined on the HBV overlapping pol/S gene region. Lamivudine and telbivudine which are the frequently preferred drugs for the treatment of CHB in Turkey, have the potential to lead to

  6. Stable cytotoxic T cell escape mutation in hepatitis C virus is linked to maintenance of viral fitness.

    Directory of Open Access Journals (Sweden)

    Luke Uebelhoer

    Full Text Available Mechanisms by which hepatitis C virus (HCV evades cellular immunity to establish persistence in chronically infected individuals are not clear. Mutations in human leukocyte antigen (HLA class I-restricted epitopes targeted by CD8(+ T cells are associated with persistence, but the extent to which these mutations affect viral fitness is not fully understood. Previous work showed that the HCV quasispecies in a persistently infected chimpanzee accumulated multiple mutations in numerous class I epitopes over a period of 7 years. During the acute phase of infection, one representative epitope in the C-terminal region of the NS3/4A helicase, NS3(1629-1637, displayed multiple serial amino acid substitutions in major histocompatibility complex (MHC anchor and T cell receptor (TCR contact residues. Only one of these amino acid substitutions at position 9 (P9 of the epitope was stable in the quasispecies. We therefore assessed the effect of each mutation observed during in vivo infection on viral fitness and T cell responses using an HCV subgenomic replicon system and a recently developed in vitro infectious virus cell culture model. Mutation of a position 7 (P7 TCR-contact residue, I1635T, expectedly ablated the T cell response without affecting viral RNA replication or virion production. In contrast, two mutations at the P9 MHC-anchor residue abrogated antigen-specific T cell responses, but additionally decreased viral RNA replication and virion production. The first escape mutation, L1637P, detected in vivo only transiently at 3 mo after infection, decreased viral production, and reverted to the parental sequence in vitro. The second P9 variant, L1637S, which was stable in vivo through 7 years of follow-up, evaded the antigen-specific T cell response and did not revert in vitro despite being less optimal in virion production compared to the parental virus. These studies suggest that HCV escape mutants emerging early in infection are not necessarily

  7. Nicotine inhibits memory CTL programming.

    Directory of Open Access Journals (Sweden)

    Zhifeng Sun

    Full Text Available Nicotine is the main tobacco component responsible for tobacco addiction and is used extensively in smoking and smoking cessation therapies. However, little is known about its effects on the immune system. We confirmed that multiple nicotinic receptors are expressed on mouse and human cytotoxic T lymphocytes (CTLs and demonstrated that nicotinic receptors on mouse CTLs are regulated during activation. Acute nicotine presence during activation increases primary CTL expansion in vitro, but impairs in vivo expansion after transfer and subsequent memory CTL differentiation, which reduces protection against subsequent pathogen challenges. Furthermore, nicotine abolishes the regulatory effect of rapamycin on memory CTL programming, which can be attributed to the fact that rapamycin enhances expression of nicotinic receptors. Interestingly, naïve CTLs from chronic nicotine-treated mice have normal memory programming, which is impaired by nicotine during activation in vitro. In conclusion, simultaneous exposure to nicotine and antigen during CTL activation negatively affects memory development.

  8. Nicotine inhibits memory CTL programming.

    Science.gov (United States)

    Sun, Zhifeng; Smyth, Kendra; Garcia, Karla; Mattson, Elliot; Li, Lei; Xiao, Zhengguo

    2013-01-01

    Nicotine is the main tobacco component responsible for tobacco addiction and is used extensively in smoking and smoking cessation therapies. However, little is known about its effects on the immune system. We confirmed that multiple nicotinic receptors are expressed on mouse and human cytotoxic T lymphocytes (CTLs) and demonstrated that nicotinic receptors on mouse CTLs are regulated during activation. Acute nicotine presence during activation increases primary CTL expansion in vitro, but impairs in vivo expansion after transfer and subsequent memory CTL differentiation, which reduces protection against subsequent pathogen challenges. Furthermore, nicotine abolishes the regulatory effect of rapamycin on memory CTL programming, which can be attributed to the fact that rapamycin enhances expression of nicotinic receptors. Interestingly, naïve CTLs from chronic nicotine-treated mice have normal memory programming, which is impaired by nicotine during activation in vitro. In conclusion, simultaneous exposure to nicotine and antigen during CTL activation negatively affects memory development.

  9. Germ line transmission of the Cdk4(R24C) mutation facilitates tumorigenesis and escape from cellular senescence.

    Science.gov (United States)

    Rane, Sushil G; Cosenza, Stephen C; Mettus, Richard V; Reddy, E Premkumar

    2002-01-01

    Mutations in CDK4 and its key kinase inhibitor p16(INK4a) have been implicated in the genesis and progression of familial human melanoma. The importance of the CDK4 locus in human cancer first became evident following the identification of a germ line CDK4-Arg24Cys (R24C) mutation, which abolishes the ability of CDK4 to bind to p16(INK4a). To determine the role of the Cdk4(R24C) germ line mutation in the genesis of other cancer types, we introduced the R24C mutation in the Cdk4 locus of mice by using Cre-loxP-mediated "knock-in" technology. Cdk4(R24C/R24C) mouse embryo fibroblasts (MEFs) displayed increased Cdk4 kinase activity resulting in hyperphosphorylation of all three members of the Rb family, pRb, p107, and p130. MEFs derived from Cdk4(R24C/R24C) mice displayed decreased doubling times, escape from replicative senescence, and escape sensitivity to contact-induced growth arrest. These MEFs also exhibited a high degree of susceptibility to oncogene-induced transformation, suggesting that the Cdk4(R24C) mutation can serve as a primary event in the progression towards a fully transformed phenotype. In agreement with the in vitro data, homozygous Cdk4(R24C/R24C) mice developed tumors of various etiology within 8 to 10 months of their life span. The majority of these tumors were found in the pancreas, pituitary, brain, mammary tissue, and skin. In addition, Cdk4(R24C/R24C) mice showed extraordinary susceptibility to carcinogens and developed papillomas within the first 8 to 10 weeks following cutaneous application of the carcinogens 9,10-di-methyl-1,2-benz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). This report formally establishes that the activation of Cdk4 is sufficient to promote cancer in many tissues. The observation that a wide variety of tumors develop in mice harboring the Cdk4(R24C) mutation offers a genetic proof that Cdk4 activation may constitute a central event in the genesis of many types of cancers in addition to melanoma.

  10. Involvement of a joker mutation in a polymerase-independent lethal mutagenesis escape mechanism.

    Science.gov (United States)

    Agudo, Rubén; de la Higuera, Ignacio; Arias, Armando; Grande-Pérez, Ana; Domingo, Esteban

    2016-07-01

    We previously characterized a foot-and-mouth disease virus (FMDV) with three amino acid replacements in its polymerase (3D) that conferred resistance to the mutagenic nucleoside analogue ribavirin. Here we show that passage of this mutant in the presence of high ribavirin concentrations resulted in selection of viruses with the additional replacement I248T in 2C. This 2C substitution alone (even in the absence of replacements in 3D) increased FMDV fitness mainly in the presence of ribavirin, prevented an incorporation bias in favor of A and U associated with ribavirin mutagenesis, and conferred the ATPase activity of 2C decreased sensitivity to ribavirin-triphosphate. Since in previous studies we described that 2C with I248T was selected under different selective pressures, this replacement qualifies as a joker substitution in FMDV evolution. The results have identified a role of 2C in nucleotide incorporation, and have unveiled a new polymerase-independent mechanism of virus escape to lethal mutagenesis.

  11. CRISPR/Cas9-Derived Mutations Both Inhibit HIV-1 Replication and Accelerate Viral Escape

    Directory of Open Access Journals (Sweden)

    Zhen Wang

    2016-04-01

    Full Text Available Cas9 cleaves specific DNA sequences with the assistance of a programmable single guide RNA (sgRNA. Repairing this broken DNA by the cell’s error-prone non-homologous end joining (NHEJ machinery leads to insertions and deletions (indels that often impair DNA function. Using HIV-1, we have now demonstrated that many of these indels are indeed lethal for the virus, but that others lead to the emergence of replication competent viruses that are resistant to Cas9/sgRNA. This unexpected contribution of Cas9 to the development of viral resistance is facilitated by some indels that are not deleterious for viral replication, but that are refractory to recognition by the same sgRNA as a result of changing the target DNA sequences. This observation illustrates two opposite outcomes of Cas9/sgRNA action, i.e., inactivation of HIV-1 and acceleration of viral escape, thereby potentially limiting the use of Cas9/sgRNA in HIV-1 therapy.

  12. Multi Dimensional CTL and Stratified Datalog

    Directory of Open Access Journals (Sweden)

    Theodore Andronikos

    2010-02-01

    Full Text Available In this work we define Multi Dimensional CTL (MD-CTL in short by extending CTL which is thedominant temporal specification language in practice. The need for Multi Dimensional CTL is mainlydue to the advent of semi-structured data. The common path nature of CTL and XPath which provides asuitable model for semi-structured data, has caused the emergence of work on specifying a relation amongthem aiming at exploiting the nice properties of CTL. Although the advantages of such an approach havealready been noticed [36, 26, 5], no formal definition of MD-CTL has been given. The goal of this workis twofold; a we define MD-CTL and prove that the “nice” properties of CTL (linear model checking andbounded model property transfer also to MD-CTL, b we establish new results on stratified Datalog. Inparticular, we define a fragment of stratified Datalog called Multi Branching Temporal (MBT in shortprograms that has the same expressive power as MD-CTL. We prove that by devising a linear translationbetween MBT and MD-CTL. We actually give the exact translation rules for both directions. We furtherbuild on this relation to prove that query evaluation is linear and checking satisfiability, containment andequivalence are EXPTIME–complete for MBT programs. The class MBT is the largest fragment of stratifiedDatalog for which such results exist in the literature.

  13. Nicotine Inhibits Memory CTL Programming

    OpenAIRE

    Zhifeng Sun; Kendra Smyth; Karla Garcia; Elliot Mattson; Lei Li; Zhengguo Xiao

    2013-01-01

    Nicotine is the main tobacco component responsible for tobacco addiction and is used extensively in smoking and smoking cessation therapies. However, little is known about its effects on the immune system. We confirmed that multiple nicotinic receptors are expressed on mouse and human cytotoxic T lymphocytes (CTLs) and demonstrated that nicotinic receptors on mouse CTLs are regulated during activation. Acute nicotine presence during activation increases primary CTL expansion in vitro, but imp...

  14. Wnt signaling inhibits CTL memory programming.

    Science.gov (United States)

    Xiao, Zhengguo; Sun, Zhifeng; Smyth, Kendra; Li, Lei

    2013-12-01

    Induction of functional CTLs is one of the major goals for vaccine development and cancer therapy. Inflammatory cytokines are critical for memory CTL generation. Wnt signaling is important for CTL priming and memory formation, but its role in cytokine-driven memory CTL programming is unclear. We found that wnt signaling inhibited IL-12-driven CTL activation and memory programming. This impaired memory CTL programming was attributed to up-regulation of eomes and down-regulation of T-bet. Wnt signaling suppressed the mTOR pathway during CTL activation, which was different to its effects on other cell types. Interestingly, the impaired memory CTL programming by wnt was partially rescued by mTOR inhibitor rapamycin. In conclusion, we found that crosstalk between wnt and the IL-12 signaling inhibits T-bet and mTOR pathways and impairs memory programming which can be recovered in part by rapamycin. In addition, direct inhibition of wnt signaling during CTL activation does not affect CTL memory programming. Therefore, wnt signaling may serve as a new tool for CTL manipulation in autoimmune diseases and immune therapy for certain cancers.

  15. Bounded Model Checking of CTL

    Institute of Scientific and Technical Information of China (English)

    Zhi-Hong Tao; Cong-Hua Zhou; Zhong Chen; Li-Fu Wang

    2007-01-01

    Bounded Model Checking has been recently introduced as an efficient verification method for reactive systems.This technique reduces model checking of linear temporal logic to propositional satisfiability.In this paper we first present how quantified Boolean decision procedures can replace BDDs.We introduce a bounded model checking procedure for temporal logic CTL* which reduces model checking to the satisfiability of quantified Boolean formulas.Our new technique avoids the space blow up of BDDs, and extends the concept of bounded model checking.

  16. Bacteriophage ΦM1 of Pectobacterium evolves to escape two bifunctional Type III toxin-antitoxin and abortive infection systems through mutations in a single viral gene.

    Science.gov (United States)

    Blower, Tim R; Chai, Ray; Przybilski, Rita; Chindhy, Shahzad; Fang, Xinzhe; Kidman, Samuel E; Tan, Hui; Luisi, Ben F; Fineran, Peter C; Salmond, George P C

    2017-02-03

    Some bacteria, when infected by their viral parasites (bacteriophages), undergo a suicidal response that also terminates productive viral replication (abortive infection; Abi). This response can be viewed as an altruistic act protecting the uninfected bacterial clonal population. Abortive infection can occur through the action of Type III protein-RNA toxin-antitoxin (TA) systems, such as ToxINPa from the phytopathogen, Pectobacterium atrosepticum Rare spontaneous mutants evolved in the generalized transducing phage, ΦM1, which escaped ToxINPa-mediated abortive infection in P. atrosepticum ΦM1 is a member of the Podoviridae and member of the "KMV-like viruses", a subset of the T7 supergroup. Genomic sequencing of ΦM1 escape mutants revealed single-base changes which clustered in a single open reading frame. The "escape" gene product, M1-23, was highly toxic to the host bacterium when over-expressed, but mutations in M1-23 that enabled an escape phenotype caused M1-23 to be less toxic. M1-23 is encoded within the DNA metabolism modular section of the phage genome, and when it was over-expressed, it co-purified with the host nucleotide excision repair protein, UvrA. While the M1-23 protein interacted with UvrA in co-immunoprecipitation assays, a UvrA mutant strain still aborted ΦM1, suggesting that the interaction is not critical for the Type III TA Abi activity. Additionally, ΦM1 escaped a heterologous Type III TA system (TenpINPl) from Photorhabdus luminescens (reconstituted in P. atrosepticum) through mutations in the same protein, M1-23. The mechanistic action of M1-23 is currently unknown but further analysis of this protein could provide insights into the mode of activation of both systems.

  17. Mutation or loss of Wilms' tumor gene 1 (WT1 are not major reasons for immune escape in patients with AML receiving WT1 peptide vaccination

    Directory of Open Access Journals (Sweden)

    Ochsenreither Sebastian

    2010-01-01

    Full Text Available Abstract Background Efficacy of cancer vaccines may be limited due to immune escape mechanisms like loss or mutation of target antigens. Here, we analyzed 10 HLA-A2 positive patients with acute myeloid leukemia (AML for loss or mutations of the WT1 epitope or epitope flanking sequences that may abolish proper T cell recognition or epitope presentation. Methods All patients had been enrolled in a WT1 peptide phase II vaccination trial (NCT00153582 and ultimately progressed despite induction of a WT1 specific T cell response. Blood and bone marrow samples prior to vaccination and during progression were analyzed for mRNA expression level of WT1. Base exchanges within the epitope sequence or flanking regions (10 amino acids N- and C-terminal of the epitope were assessed with melting point analysis and sequencing. HLA class I expression and WT1 protein expression was analyzed by flow cytometry. Results Only in one patient, downregulation of WT1 mRNA by 1 log and loss of WT1 detection on protein level at time of disease progression was observed. No mutation leading to a base exchange within the epitope sequence or epitope flanking sequences could be detected in any patient. Further, no loss of HLA class I expression on leukemic blasts was observed. Conclusion Defects in antigen presentation caused by loss or mutation of WT1 or downregulation of HLA molecules are not the major basis for escape from the immune response induced by WT1 peptide vaccination.

  18. 乙型肝炎病毒包膜区和核心区CTL抗原表位变异对感染慢性化及疾病转归的影响%Impact of CTL epitope mutations of hepatitis B virus envelope protein and core protein on chronicity and disease prognosis in patients with hepatitis B

    Institute of Scientific and Technical Information of China (English)

    哈明昊; 佘会元; 吴建秋; 孙莉萍; 沈文娟; 黄钟鸣; 陈晓兰; 单文艳; 何慧芳

    2015-01-01

    Objective To investigate the impact of cytotoxic T lymphocyte (CTL) epitope mutation of HBV envelope and core protein on disease progress in patients with hepatitis B. Methods 38 individuals with asymptomatic HBsAg carrier,35 patients with chronic hepatitis B and 23 with liver cirrhosis were recruited in this study. Gene sequencing analysis of HBV core region and envelope region was carried out in all enrolled patients to unveil any possible CTL epitope mutation. Results The mutation rates of locus 41~49,88~96,97~108,172~180 and 185~194 of CTL epitope in HBV envelope region were 48(55.2%),13(14.9%),11(12.6%),9(10.3%) and 6 (6.9%),respectively;60% of mutation at locus 41~49 in patients with chronic hepatitis B and 65.2% in with liver cirrhosis were significantly higher than 31.6% in asymptomatic HBsAg carriers(P<0.05);the mutation rates at 18~27 and 91~95 locus of CTL epitope in HBV core region were 56.2% and 43.8%,respectively;the mutation rates at locus 18~27 were also higher in patients with CHB (20.0%) and LC (30.4%) than that in asymptomatic HBsAg carriers (10.5%,P<0.05);Multivariate analysis showed that locus 41~49 mutation was an independent risk factor for the progress of CHB to LC. Conclusion CTL epitope mutation of HBV is a significant cause for the chronicity of hepatitis B virus infection.%目的:探讨HBV包膜区和核心区细胞毒性T淋巴细胞(CTL)抗原表位变异的规律及对疾病发展转归的影响。方法本研究选择无症状HBsAg携带者(ASC)38例,慢性乙型肝炎(CHB)35例,乙型肝炎肝硬化(LC)23例。采用DNA测序法检测HBV包膜区和核心区病毒序列及表位变异情况,并分析其与临床转归的关系。结果在入组患者中,HBV包膜区CTL抗原表位41~49、88~96、97~108、172~180和185~194变异率分别为48个(55.2%)、13个(14.9%)、11个(12.6%)、9个(10.3%)和6个(6.9%);HBV CTL 41~49位变异率在CHB和肝硬化患者中的变异率分别为60.0%

  19. Engineering a CTL-Tailored Replicon RNA Vaccine against PRRSV

    DEFF Research Database (Denmark)

    Welner, Simon; Werder, Simea; Nielsen, Morten

    The development of vaccines against porcine reproductive and respiratory syndrome virus (PRRSV) has been hampered by the high mutation rate and the multiple immunoevasive strategies of the virus. With the overall aim of designing a broad coverage vaccine that induces an effective CTL response...... detection in the presence of a proteasome inhibitor. Finally, a vaccination-challenge experiment using 18 SLA-matched pigs is currently being conducted until July 2016 in which a test group and a control group are being vaccinated twice with VRPs expressing PRRSV epitopes and non-sense control epitopes...... will be available for IVIS. This study exemplifies how bioinformatics epitope prediction, recombinant SLA molecules and RNA virus replicon design can be used to engineer a replicating non-propagating vaccine tailored to deliver conserved and immunogenic CTL epitopes....

  20. CTL Model Update for System Modifications

    CERN Document Server

    Ding, Yulin; Zhang, Yan; Zhang, Y; 10.1613/jair.2420

    2011-01-01

    Model checking is a promising technology, which has been applied for verification of many hardware and software systems. In this paper, we introduce the concept of model update towards the development of an automatic system modification tool that extends model checking functions. We define primitive update operations on the models of Computation Tree Logic (CTL) and formalize the principle of minimal change for CTL model update. These primitive update operations, together with the underlying minimal change principle, serve as the foundation for CTL model update. Essential semantic and computational characterizations are provided for our CTL model update approach. We then describe a formal algorithm that implements this approach. We also illustrate two case studies of CTL model updates for the well-known microwave oven example and the Andrew File System 1, from which we further propose a method to optimize the update results in complex system modifications.

  1. Prevention of cytotoxic T cell escape using a heteroclitic subdominant viral T cell determinant.

    Directory of Open Access Journals (Sweden)

    Noah S Butler

    2008-10-01

    Full Text Available High affinity antigen-specific T cells play a critical role during protective immune responses. Epitope enhancement can elicit more potent T cell responses and can subsequently lead to a stronger memory pool; however, the molecular basis of such enhancement is unclear. We used the consensus peptide-binding motif for the Major Histocompatibility Complex molecule H-2K(b to design a heteroclitic version of the mouse hepatitis virus-specific subdominant S598 determinant. We demonstrate that a single amino acid substitution at a secondary anchor residue (Q to Y at position 3 increased the stability of the engineered determinant in complex with H-2K(b. The structural basis for this enhanced stability was associated with local alterations in the pMHC conformation as a result of the Q to Y substitution. Recombinant viruses encoding this engineered determinant primed CTL responses that also reacted to the wildtype epitope with significantly higher functional avidity, and protected against selection of virus mutated at a second CTL determinant and consequent disease progression in persistently infected mice. Collectively, our findings provide a basis for the enhanced immunogenicity of an engineered determinant that will serve as a template for guiding the development of heteroclitic T cell determinants with applications in prevention of CTL escape in chronic viral infections as well as in tumor immunity.

  2. Germ Line Transmission of the Cdk4R24C Mutation Facilitates Tumorigenesis and Escape from Cellular Senescence

    OpenAIRE

    Sushil G Rane; Cosenza, Stephen C.; Mettus, Richard V.; Reddy, E. Premkumar

    2002-01-01

    Mutations in CDK4 and its key kinase inhibitor p16INK4a have been implicated in the genesis and progression of familial human melanoma. The importance of the CDK4 locus in human cancer first became evident following the identification of a germ line CDK4-Arg24Cys (R24C) mutation, which abolishes the ability of CDK4 to bind to p16INK4a. To determine the role of the Cdk4R24C germ line mutation in the genesis of other cancer types, we introduced the R24C mutation in the Cdk4 locus of mice by usi...

  3. Pandemic influenza A viruses escape from restriction by human MxA through adaptive mutations in the nucleoprotein.

    Directory of Open Access Journals (Sweden)

    Benjamin Mänz

    2013-03-01

    Full Text Available The interferon-induced dynamin-like MxA GTPase restricts the replication of influenza A viruses. We identified adaptive mutations in the nucleoprotein (NP of pandemic strains A/Brevig Mission/1/1918 (1918 and A/Hamburg/4/2009 (pH1N1 that confer MxA resistance. These resistance-associated amino acids in NP differ between the two strains but form a similar discrete surface-exposed cluster in the body domain of NP, indicating that MxA resistance evolved independently. The 1918 cluster was conserved in all descendent strains of seasonal influenza viruses. Introduction of this cluster into the NP of the MxA-sensitive influenza virus A/Thailand/1(KAN-1/04 (H5N1 resulted in a gain of MxA resistance coupled with a decrease in viral replication fitness. Conversely, introduction of MxA-sensitive amino acids into pH1N1 NP enhanced viral growth in Mx-negative cells. We conclude that human MxA represents a barrier against zoonotic introduction of avian influenza viruses and that adaptive mutations in the viral NP should be carefully monitored.

  4. Escape Mutations, Ganciclovir Resistance, and Teratoma Formation in Human iPSCs Expressing an HSVtk Suicide Gene

    Directory of Open Access Journals (Sweden)

    Andriana G Kotini

    2016-01-01

    Full Text Available Human pluripotent stem cells (hPSCs hold great promise for cell therapy. However, a major concern is the risk of tumor formation by residual undifferentiated cells contaminating the hPSC-derived cell product. Suicide genes could safeguard against such adverse events by enabling elimination of cells gone astray, but the efficacy of this approach has not yet been thoroughly tested. Here, we engineered a lentivirally encoded herpes simplex virus thymidine kinase (HSVtk with expression restricted to undifferentiated hPSCs through regulation by the let7 family of miRNAs. We show that induced pluripotent stem cells (iPSCs expressing a let7-regulated HSVtk transgene are selectively killed by ganciclovir (GCV, whereas differentiated cells are fully protected. However, in contrast to previous studies, we find that in vivo GCV administration results in longer latency but does not prevent teratoma formation by iPSCs expressing either a constitutive or a let7-regulated HSVtk, without evidence of silencing of the HSVtk. Clonal analyses of iPSCs expressing HSVtk revealed frequent emergence of GCV resistance which, at least in some cases, could be attributed to preexisting inactivating mutations in the HSVtk coding sequence, selected for upon GCV treatment. Our findings have important consequences for the future use of suicide genes in hPSC-based cell therapies.

  5. HLA-associated immune escape pathways in HIV-1 subtype B Gag, Pol and Nef proteins.

    Directory of Open Access Journals (Sweden)

    Zabrina L Brumme

    Full Text Available BACKGROUND: Despite the extensive genetic diversity of HIV-1, viral evolution in response to immune selective pressures follows broadly predictable mutational patterns. Sites and pathways of Human Leukocyte-Antigen (HLA-associated polymorphisms in HIV-1 have been identified through the analysis of population-level data, but the full extent of immune escape pathways remains incompletely characterized. Here, in the largest analysis of HIV-1 subtype B sequences undertaken to date, we identify HLA-associated polymorphisms in the three HIV-1 proteins most commonly considered in cellular-based vaccine strategies. Results are organized into protein-wide escape maps illustrating the sites and pathways of HLA-driven viral evolution. METHODOLOGY/PRINCIPAL FINDINGS: HLA-associated polymorphisms were identified in HIV-1 Gag, Pol and Nef in a multicenter cohort of >1500 chronically subtype-B infected, treatment-naïve individuals from established cohorts in Canada, the USA and Western Australia. At q< or =0.05, 282 codons commonly mutating under HLA-associated immune pressures were identified in these three proteins. The greatest density of associations was observed in Nef (where close to 40% of codons exhibited a significant HLA association, followed by Gag then Pol (where approximately 15-20% of codons exhibited HLA associations, confirming the extensive impact of immune selection on HIV evolution and diversity. Analysis of HIV codon covariation patterns identified over 2000 codon-codon interactions at q< or =0.05, illustrating the dense and complex networks of linked escape and secondary/compensatory mutations. CONCLUSIONS/SIGNIFICANCE: The immune escape maps and associated data are intended to serve as a user-friendly guide to the locations of common escape mutations and covarying codons in HIV-1 subtype B, and as a resource facilitating the systematic identification and classification of immune escape mutations. These resources should facilitate

  6. Lack of viral control and development of cART escape mutations in macaques after bone marrow transplantation

    Science.gov (United States)

    PETERSON, Christopher W.; HAWORTH, Kevin G.; POLACINO, Patricia; HUANG, Meei-Li; SYKES, Craig; OBENZA, Willimark M.; REPETTO, Andrea C.; KASHUBA, Angela; BUMGARNER, Roger; DeROSA, Stephen C.; WOOLFREY, Ann E.; JEROME, Keith R.; MULLINS, James I.; HU, Shiu-Lok; KIEM, Hans-Peter

    2015-01-01

    Objective We have previously demonstrated robust control of simian/human immunodeficiency virus (SHIV1157-ipd3N4) viremia following administration of combination antiretroviral therapy (cART) in pigtailed macaques. Here, we sought to determine the safety of hematopoietic stem cell transplantation (HSCT) in cART-suppressed and unsuppressed animals. Design We compared disease progression in animals challenged with SHIV 100 days post-transplant (PT), to controls that underwent transplant following SHIV challenge and stable, cART-dependent viral suppression. Methods SHIV viral load, combination antiretroviral therapy (cART) levels, and anti-SHIV antibodies were measured longitudinally from plasma/serum from each animal. Flow cytometry was used to assess T-cell subset frequencies in peripheral blood and gastrointestinal tract (GI). Deep sequencing was used to identify cART resistance mutations. Results In control animals, virus challenge induced transient peak viremia, viral set point, and durable suppression by cART. Subsequent HSCT was not associated with adverse events in these animals. PT animals were challenged during acute recovery following HSCT, and displayed sustained peak viremia and cART resistance. Although PT animals had comparable plasma levels of antiretroviral drugs and showed no evidence of enhanced infection of myeloid subsets in the periphery, they exhibited a drastic reduction in virus-specific antibody production and decreased T-cell counts. Conclusions These results suggest that virus challenge prior to complete transplant recovery impairs viral control and may promote drug resistance. These findings may also have implications for scheduled treatment interruption (STI) studies in patients on cART during post-HSCT recovery: premature STI could similarly result in lack of viral control and cART resistance. PMID:26372270

  7. Shell Delays CTL Venture with Shenhua

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    @@ Royal Dutch Shell has recently made a decision to postpone a coal-to-liquids (CTL) joint project with Shenhua Group in the Ningxia Hui Autonomous Region."In a period of economic downturn, we have postponed the project due to a number of reasons," Lira Haw Kuang,Executive Chairman of Shell Companies in China, told the news media in mid April without elaborating. But the company will keep playing an active role in China's coal gasification sector, Lim added.

  8. Cytotoxic T lymphocytes and CD4 epitope mutations in the pre-core/core region of hepatitis B virus in chronic hepatitis B carriers in Northeast Iran.

    Science.gov (United States)

    Zhand, Sareh; Tabarraei, Alijan; Nazari, Amineh; Moradi, Abdolvahab

    2017-07-25

    Hepatitis B virus (HBV) is vulnerable to many various mutations. Those within epitopes recognized by sensitized T cells may influence the re-emergence of the virus. This study was designed to investigate the mutation in immune epitope regions of HBV pre-core/core among chronic HBV patients of Golestan province, Northeast Iran. In 120 chronic HBV carriers, HBV DNA was extracted from blood plasma samples and PCR was done using specific primers. Direct sequencing and alignment of the pre-core/core region were applied using reference sequence from Gene Bank database (Accession Number AB033559). The study showed 27 inferred amino acid substitutions, 9 of which (33.3%) were in CD4 and 2 (7.4%) in cytotoxic T lymphocytes' (CTL) epitopes and 16 other mutations (59.2%) were observed in other regions. CTL escape mutations were not commonly observed in pre-core/core sequences of chronic HBV carriers in the locale of study. It can be concluded that most of the inferred amino acid substitutions occur in different immune epitopes other than CTL and CD4.

  9. Functional expression of choline transporter like-protein 1 (CTL1) and CTL2 in human brain microvascular endothelial cells.

    Science.gov (United States)

    Iwao, Beniko; Yara, Miki; Hara, Naomi; Kawai, Yuiko; Yamanaka, Tsuyoshi; Nishihara, Hiroshi; Inoue, Takeshi; Inazu, Masato

    2016-02-01

    In this study, we examined the molecular and functional characterization of choline transporter in human brain microvascular endothelial cells (hBMECs). Choline uptake into hBMECs was a saturable process that was mediated by a Na(+)-independent, membrane potential and pH-dependent transport system. The cells have two different [(3)H]choline transport systems with Km values of 35.0 ± 4.9 μM and 54.1 ± 8.1 μM, respectively. Choline uptake was inhibited by choline, acetylcholine (ACh) and the choline analog hemicholinium-3 (HC-3). Various organic cations also interacted with the choline transport system. Choline transporter-like protein 1 (CTL1) and CTL2 mRNA were highly expressed, while mRNA for high-affinity choline transporter 1 (CHT1) and organic cation transporters (OCTs) were not expressed in hBMECs. CTL1 and CTL2 proteins were localized to brain microvascular endothelial cells in human brain cortical sections. Both CTL1 and CTL2 proteins were expressed on the plasma membrane and mitochondria. CTL1 and CTL2 proteins are mainly expressed in plasma membrane and mitochondria, respectively. We conclude that choline is mainly transported via an intermediate-affinity choline transport system, CTL1 and CTL2, in hBMECs. These transporters are responsible for the uptake of extracellular choline and organic cations. CTL2 participate in choline transport mainly in mitochondria, and may be the major site for the control of choline oxidation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Distributed Maximality based CTL Model Checking

    Directory of Open Access Journals (Sweden)

    Djamel Eddine Saidouni

    2010-05-01

    Full Text Available In this paper we investigate an approach to perform a distributed CTL Model checker algorithm on a network of workstations using Kleen three value logic, the state spaces is partitioned among the network nodes, We represent the incomplete state spaces as a Maximality labeled Transition System MLTS which are able to express true concurrency. we execute in parallel the same algorithm in each node, for a certain property on an incomplete MLTS , this last compute the set of states which satisfy or which if they fail are assigned the value .The third value mean unknown whether true or false because the partial state space lacks sufficient information needed for a precise answer concerning the complete state space .To solve this problem each node exchange the information needed to conclude the result about the complete state space. The experimental version of the algorithm is currently being implemented using the functional programming language Erlang.

  11. Investigating CTL mediated killing with a 3D cellular automaton.

    Directory of Open Access Journals (Sweden)

    Frederik Graw

    2009-08-01

    Full Text Available Cytotoxic T lymphocytes (CTLs are important immune effectors against intra-cellular pathogens. These cells search for infected cells and kill them. Recently developed experimental methods in combination with mathematical models allow for the quantification of the efficacy of CTL killing in vivo and, hence, for the estimation of parameters that characterize the effect of CTL killing on the target cell populations. It is not known how these population-level parameters relate to single-cell properties. To address this question, we developed a three-dimensional cellular automaton model of the region of the spleen where CTL killing takes place. The cellular automaton model describes the movement of different cell populations and their interactions. Cell movement patterns in our cellular automaton model agree with observations from two-photon microscopy. We find that, despite the strong spatial nature of the kinetics in our cellular automaton model, the killing of target cells by CTLs can be described by a term which is linear in the target cell frequency and saturates with respect to the CTL levels. Further, we find that the parameters describing CTL killing on the population level are most strongly impacted by the time a CTL needs to kill a target cell. This suggests that the killing of target cells, rather than their localization, is the limiting step in CTL killing dynamics given reasonable frequencies of CTL. Our analysis identifies additional experimental directions which are of particular importance to interpret estimates of killing rates and could advance our quantitative understanding of CTL killing.

  12. Figuring the Context of CTL under 2013 Curiculum

    Directory of Open Access Journals (Sweden)

    Chairina Nasir

    2017-06-01

    Full Text Available The 2013 curriculum states that the purpose of teaching English for junior high school is to develop students’ communicative competence. In line with this expectation, several learning characteristics have been defined i.e. learning from model, observing, questioning, gathering information, associating, and communicating. Therefore, the teaching approaches that are used by the teacher in teaching English must suit the criteria to promote students' communicative competence. Contextual Teaching and learning (CTL seems to be compatible as an approach since it has the the characteristics of constructivism, questioning, inquiry, learning community, modelling, reflection, and authentic assessment, which are similar to the learning characteristics mentioned above, which are similar to the learning characteristics mentioned above. , which are similar to the learning characteristics mentioned above. Therefore, a qualitative research concerning the issue was conducted to see how CTL approach is implemented under the 2013 curriculum in teaching reading comprehension. From the result of observation, questionnaire, and interview as the instruments, it was found that CTL was implemented properly from phase to phase and is applicable to be implemented under the curriculum. Also, it promotes active and enjoyable learning, facilitates the students to comprehend the material and helps them to implement the knowledge in real life. The. The teacher had implemented all of the procedures of CTL under the instruction of the 2013 curriculum. Thus, applying the CTL CTL approach in the process of teaching for the 2013 curriculum for the 2013 curriculum is recommended since it gives satisfactory benefits for students.

  13. Induction of protective CTL immunity against peptide transporter TAP-deficient tumors through dendritic cell vaccination.

    Science.gov (United States)

    Chambers, Benedict; Grufman, Per; Fredriksson, Vanoohi; Andersson, Kenth; Roseboom, Marjet; Laban, Sandra; Camps, Marcel; Wolpert, Elisabeth Z; Wiertz, Emmanuel J H J; Offringa, Rienk; Ljunggren, Hans-Gustaf; van Hall, Thorbald

    2007-09-15

    A large proportion of human cancers show deficiencies in the MHC class I antigen-processing machinery. Such defects render tumors resistant to immune eradication by tumoricidal CTLs. We recently identified a unique population of CTL that selectively targets tumor immune-escape variants through recognition of MHC-presented peptides, termed TEIPP (T cell epitopes associated with impaired peptide processing), expressed on cells lacking functional TAP-peptide transporters. Previously, we showed that vaccination with TEIPP peptides mediates protection against TAP-deficient tumors. Here, we further explored the concept of TEIPP-targeted therapy using a dendritic cell (DC)-based cellular vaccine. Impairment of TAP function in DC induced the presentation of endogenous TEIPP antigens by MHC class I molecules, and immunization with these DCs protected mice against the outgrowth of TAP-deficient lymphomas and fibrosarcomas. Immune analysis of vaccinated mice revealed strong TEIPP-specific CTL responses, and a crucial role for CD8(+) cells in tumor resistance. Finally, we show that TEIPP antigens could be successfully induced in wild-type DC by introducing the viral TAP inhibitor UL49.5. Our results imply that immune intervention strategies with TAP-inhibited DC could be developed for the treatment of antigen processing-deficient cancers in humans.

  14. Mathematical modeling of escape of HIV from cytotoxic T lymphocyte responses

    Science.gov (United States)

    Ganusov, Vitaly V.; Neher, Richard A.; Perelson, Alan S.

    2013-01-01

    Human immunodeficiency virus (HIV-1 or simply HIV) induces a persistent infection, which in the absence of treatment leads to AIDS and death in almost all infected individuals. HIV infection elicits a vigorous immune response starting about 2-3 weeks postinfection that can lower the amount of virus in the body, but which cannot eradicate the virus. How HIV establishes a chronic infection in the face of a strong immune response remains poorly understood. It has been shown that HIV is able to rapidly change its proteins via mutation to evade recognition by virus-specific cytotoxic T lymphocytes (CTLs). Typically, an HIV-infected patient will generate 4-12 CTL responses specific for parts of viral proteins called epitopes. Such CTL responses lead to strong selective pressure to change the viral sequences encoding these epitopes so as to avoid CTL recognition. Indeed, the viral population ‘escapes’ from about half of the CTL responses by mutation in the first year. Here we review experimental data on HIV evolution in response to CTL pressure, mathematical models developed to explain this evolution, and highlight problems associated with the data and previous modeling efforts. We show that estimates of the strength of the epitope-specific CTL response depend on the method used to fit models to experimental data and on the assumptions made regarding how mutants are generated during infection. We illustrate that allowing CTL responses to decay over time may improve the model fit to experimental data and provides higher estimates of the killing efficacy of HIV-specific CTLs. We also propose a novel method for simultaneously estimating the killing efficacy of multiple CTL populations specific for different epitopes of HIV using stochastic simulations. Lastly, we show that current estimates of the efficacy at which HIV-specific CTLs clear virus-infected cells can be improved by more frequent sampling of viral sequences and by combining data on sequence evolution with

  15. Quantifying the impact of human immunodeficiency virus-1 escape from cytotoxic T-lymphocytes.

    Directory of Open Access Journals (Sweden)

    Ulrich D Kadolsky

    Full Text Available HIV-1 escape from the cytotoxic T-lymphocyte (CTL response leads to a weakening of viral control and is likely to be detrimental to the patient. To date, the impact of escape on viral load and CD4(+ T cell count has not been quantified, primarily because of sparse longitudinal data and the difficulty of separating cause and effect in cross-sectional studies. We use two independent methods to quantify the impact of HIV-1 escape from CTLs in chronic infection: mathematical modelling of escape and statistical analysis of a cross-sectional cohort. Mathematical modelling revealed a modest increase in log viral load of 0.051 copies ml(-1 per escape event. Analysis of the cross-sectional cohort revealed a significant positive association between viral load and the number of "escape events", after correcting for length of infection and rate of replication. We estimate that a single CTL escape event leads to a viral load increase of 0.11 log copies ml(-1 (95% confidence interval: 0.040-0.18, consistent with the predictions from the mathematical modelling. Overall, the number of escape events could only account for approximately 6% of the viral load variation in the cohort. Our findings indicate that although the loss of the CTL response for a single epitope results in a highly statistically significant increase in viral load, the biological impact is modest. We suggest that this small increase in viral load is explained by the small growth advantage of the variant relative to the wildtype virus. Escape from CTLs had a measurable, but unexpectedly low, impact on viral load in chronic infection.

  16. Newly Exerted T Cell Pressures on Mutated Epitopes following Transmission Help Maintain Consensus HIV-1 Sequences.

    Directory of Open Access Journals (Sweden)

    Emily M Eriksson

    Full Text Available CD8+ T cells are important for HIV-1 virus control, but are also a major contributing factor that drives HIV-1 virus sequence evolution. Although HIV-1 cytotoxic T cell (CTL escape mutations are a common aspect during HIV-1 infection, less is known about the importance of T cell pressure in reversing HIV-1 virus back to a consensus sequences. In this study we aimed to assess the frequency with which reversion of transmitted mutations in T cell epitopes were associated with T cell responses to the mutation. This study included 14 HIV-1 transmission pairs consisting of a 'source' (virus-donor and a 'recipient' (newly infected individual. Non-consensus B sequence amino acids (mutations in T cell epitopes in HIV-1 gag regions p17, p24, p2 and p7 were identified in each pair and transmission of mutations to the recipient was verified with population viral sequencing. Longitudinal analyses of the recipient's viral sequence were used to identify whether reversion of mutations back to the consensus B sequence occurred. Autologous 12-mer peptides overlapping by 11 were synthesized, representing the sequence region surrounding each reversion and longitudinal analysis of T cell responses to source-derived mutated and reverted epitopes were assessed. We demonstrated that mutations in the source were frequently transmitted to the new host and on an average 17 percent of mutated epitopes reverted to consensus sequence in the recipient. T cell responses to these mutated epitopes were detected in 7 of the 14 recipients in whom reversion occurred. Overall, these findings indicate that transmitted non-consensus B epitopes are frequently immunogenic in HLA-mismatched recipients and new T cell pressures to T cell escape mutations following transmission play a significant role in maintaining consensus HIV-1 sequences.

  17. Reducing Validity in Epistemic ATL to Validity in Epistemic CTL

    Directory of Open Access Journals (Sweden)

    Dimitar P. Guelev

    2013-03-01

    Full Text Available We propose a validity preserving translation from a subset of epistemic Alternating-time Temporal Logic (ATL to epistemic Computation Tree Logic (CTL. The considered subset of epistemic ATL is known to have the finite model property and decidable model-checking. This entails the decidability of validity but the implied algorithm is unfeasible. Reducing the validity problem to that in a corresponding system of CTL makes the techniques for automated deduction for that logic available for the handling of the apparently more complex system of ATL.

  18. Modulation of the virus-receptor interaction by mutations in the V5 loop of feline immunodeficiency virus (FIV following in vivo escape from neutralising antibody

    Directory of Open Access Journals (Sweden)

    Samman Ayman

    2010-04-01

    Full Text Available Abstract Background In the acute phase of infection with feline immunodeficiency virus (FIV, the virus targets activated CD4+ T cells by utilising CD134 (OX40 as a primary attachment receptor and CXCR4 as a co-receptor. The nature of the virus-receptor interaction varies between isolates; strains such as GL8 and CPGammer recognise a "complex" determinant on CD134 formed by cysteine-rich domains (CRDs 1 and 2 of the molecule while strains such as PPR and B2542 require a more "simple" determinant comprising CRD1 only for infection. These differences in receptor recognition manifest as variations in sensitivity to receptor antagonists. In this study, we ask whether the nature of the virus-receptor interaction evolves in vivo. Results Following infection with a homogeneous viral population derived from a pathogenic molecular clone, a quasispecies emerged comprising variants with distinct sensitivities to neutralising antibody and displaying evidence of conversion from a "complex" to a "simple" interaction with CD134. Escape from neutralising antibody was mediated primarily by length and sequence polymorphisms in the V5 region of Env, and these alterations in V5 modulated the virus-receptor interaction as indicated by altered sensitivities to antagonism by both anti-CD134 antibody and soluble CD134. Conclusions The FIV-receptor interaction evolves under the selective pressure of the host humoral immune response, and the V5 loop contributes to the virus-receptor interaction. Our data are consistent with a model whereby viruses with distinct biological properties are present in early versus late infection and with a shift from a "complex" to a "simple" interaction with CD134 with time post-infection.

  19. 基于非均匀变异和自适应逃逸的果蝇优化算法%Fruit fly optimization algorithm based on non-uniform mutation and adaptive escape

    Institute of Scientific and Technical Information of China (English)

    张彩宏; 潘广贞

    2016-01-01

    Aiming at the problems of low convergence precision and easily relapsing into local extremum caused by olfaction searching random blind and only learning from the optimal fruit fly in basic fruit fly optimization algorithm (FOA),an improved FOA called fruit fly optimization algorithm based on non-uniform mutation and adaptive escape (NAFOA)was proposed.Non-uniform mutation operator was introduced into olfaction searching phase to adj ust dynamically searching step of each iteration. States of population were divided into premature state and normal state by setting threshold.If population was in normal state, basic FOA was adopted to evolve.Otherwise,it fell into premature,perturbations dimension by dimension for the global optimal fruit was adopted to generate new solution.The ability to escape from local optimum was enhanced and the balance between ex-ploring and developing was well processed.Test of six classic functions was designed.Experimental results show that the algo-rithm in terms of accuracy and robustness were better than FOA and other several improved algorithms.%基本果蝇优化算法(FOA)存在嗅觉搜索随机盲目、迭代寻优只学习最优个体的问题,导致收敛精度低、易陷入局部极值,为此提出基于非均匀变异和自适应逃逸的果蝇优化算法(NAFOA)。在嗅觉搜索阶段引入非均匀变异算子,动态调整每次迭代的搜索步长。通过设置阈值将种群划分为“早熟”状态和正常状态,若处于正常状态,采用基本的 FOA模式进化;若处于“早熟”状态,对全局最优果蝇进行逐维扰动,逃离局部最优,平衡果蝇探索和开发的能力。设计实验,测试6个经典函数,实验结果表明,该算法在精度和鲁棒性方面均优于基本的果蝇算法及其它几种改进算法。

  20. Dust escape from Io

    Science.gov (United States)

    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.

  1. Harmful Gas Recognition Exploiting a CTL Sensor Array

    Directory of Open Access Journals (Sweden)

    Yao Zheng

    2013-10-01

    Full Text Available In this paper, a novel cataluminescence (CTL-based sensor array consisting of nine types of catalytic materials is developed for the recognition of several harmful gases, namely carbon monoxide, acetone, chloroform and toluene. First, the experimental setup is constructed by using sensing nanomaterials, a heating plate, a pneumatic pump, a gas flow meter, a digital temperature device, a camera and a BPCL Ultra Weak Chemiluminescence Analyzer. Then, unique CTL patterns for the four types of harmful gas are obtained from the sensor array. The harmful gases are successful recognized by the PCA method. The optimal conditions are also investigated. Finally, experimental results show high sensitivity, long-term stability and good linearity of the sensor array, which combined with simplicity, make our system a promising application in this field.

  2. Contextual Teaching and Learning (CTL dalam Pembelajaran PAI

    Directory of Open Access Journals (Sweden)

    Muhammad Iwan Abdi

    2011-06-01

    Full Text Available Contextual teaching learning (CTL is an educational process that aims to help students see meaning in academic material they are learning by connecting academic subjects with the context of their daily, which is related to personal circumstances, social, and cultural development. In Contextual teaching and learning (CTL takes an approach that is more empowering students with the expectations of students able to construct knowledge in their minds, rather than memorizing facts. Besides, students learn through experience rather than memorize, given knowledge of the facts and not a concept readily accepted but something that must be constructed by the students. To achieve this goal include the eight components of the system, the following: making meaningful connections, doing meaningful work, conduct self-regulated learning, collaborate, think critically and creatively, helping individuals to grow and develop, achieving high standards , and using authentic assessment. In learning PAI, CTL developed by focusing on moral or affective touch protege acquired through personal experience that photographing their daily environment. This touch your heart and thoughts will inspire students to practice it.

  3. Model Checking Electronic Commerce Security Protocols Based on CTL

    Institute of Scientific and Technical Information of China (English)

    XIAO De-qin; ZHANG Huan-guo

    2005-01-01

    We present a model based on Computational Temporal Logic (CTL) methods for verifying security requirements of electronic commerce protocols. The model describes formally the authentication, confidentiality integrity,non-repudiation, denial of service and access control of the electronic commerce protocols. We illustrate as case study a variant of the Lu-Smolka protocol proposed by Lu-Smolka.Moreover, we have discovered two attacks that allow a dishonest user to purchase a good debiting the amount to another user. And also, we compared our work with relative research works and found that the formal way of this paper is more general to specify security protocols for E-Commerce.

  4. CTL Induction of Tumoricidal Nitric Oxide Production by Intratumoral Macrophages Is Critical for Tumor Elimination

    OpenAIRE

    Vicetti Miguel, Rodolfo D.; Cherpes, Thomas L.; Watson, Leah J.; McKenna, Kyle C.

    2010-01-01

    To characterize mechanisms of CTL inhibition within an ocular tumor microenvironment, tumor-specific CTLs were transferred into mice with tumors developing within the anterior chamber of the eye or skin. Ocular tumors were resistant to CTL transfer therapy whereas skin tumors were sensitive. CTLs infiltrated ocular tumors at higher CTL/tumor ratios than in skin tumors and demonstrated comparable ex vivo effector function to CTLs within skin tumors indicating that ocular tumor progression was ...

  5. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells.

    Science.gov (United States)

    Barsoum, Ivraym B; Smallwood, Chelsea A; Siemens, D Robert; Graham, Charles H

    2014-02-01

    Immune escape is a fundamental trait of cancer in which mechanistic knowledge is incomplete. Here, we describe a novel mechanism by which hypoxia contributes to tumoral immune escape from cytotoxic T lymphocytes (CTL). Exposure of human or murine cancer cells to hypoxia for 24 hours led to upregulation of the immune inhibitory molecule programmed cell death ligand-1 (PD-L1; also known as B7-H1), in a manner dependent on the transcription factor hypoxia-inducible factor-1α (HIF-1α). In vivo studies also demonstrated cellular colocalization of HIF-1α and PD-L1 in tumors. Hypoxia-induced expression of PD-L1 in cancer cells increased their resistance to CTL-mediated lysis. Using glyceryl trinitrate (GTN), an agonist of nitric oxide (NO) signaling known to block HIF-1α accumulation in hypoxic cells, we prevented hypoxia-induced PD-L1 expression and diminished resistance to CTL-mediated lysis. Moreover, transdermal administration of GTN attenuated tumor growth in mice. We found that higher expression of PD-L1 induced in tumor cells by exposure to hypoxia led to increased apoptosis of cocultured CTLs and Jurkat leukemia T cells. This increase in apoptosis was prevented by blocking the interaction of PD-L1 with PD-1, the PD-L1 receptor on T cells, or by addition of GTN. Our findings point to a role for hypoxia/HIF-1 in driving immune escape from CTL, and they suggest a novel cancer immunotherapy to block PD-L1 expression in hypoxic-tumor cells by administering NO mimetics.

  6. Escape in Hill's Problem

    CERN Document Server

    Heggie, D C

    2000-01-01

    This didactic paper is motivated by the problem of understanding how stars escape from globular star clusters. One formulation of this problem is known, in dynamical astronomy, as Hill's problem. Originally intended as a model for the motion of the moon around the earth with perturbations by the sun, with simple modifications it also serves as a model for the motion of a star in a star cluster with perturbations by the galaxy. The paper includes introductory sections on the derivation of the equations of motion of Hill's problem, their elementary properties, and extensions to deal with non-point masses and non-circular orbits. We then show how the rate of escape may be calculated numerically and estimated theoretically, and discuss how this simple picture is modified if the stars in a cluster are also undergoing two-body relaxation. Finally we introduce some established ideas for obtaining the distribution of escape times.

  7. Cationic influenza virosomes as an adjuvanted delivery system for CTL induction by DNA vaccination

    NARCIS (Netherlands)

    Jamali, Abbas; Holtrop, Marijke; de Haan, Aalzen; Hashemi, Hamidreza; Shenagari, Mohammad; Memarnejadian, Arash; Roohvand, Farzin; Sabahi, Farzaneh; Kheiri, Masumeh Tavassoti; Huckriede, Anke

    2012-01-01

    DNA vaccines have emerged as an attractive approach to induce CTL responses against cancer and infectious agents in recent years. Although CTL induction by DNA vaccination would be a valuable strategy for controlling viral infections, increasing the potency of DNA vaccines is mandatory before DNA

  8. Strategi Bisnis pada PT CTL Dengan Pendekatan Metode Tows

    Directory of Open Access Journals (Sweden)

    Tjia Fie Tjoe

    2010-11-01

    Full Text Available The purpose of this research is determining direction of the correct business strategy to be applied by PT CTL, a garment company producing cloth for men. Research method used by the author is descriptive analysis with a case study research method. Research is conducted by collecting data obtained through survey by interview and giving questionnaire to all staff and head and also observation by evaluating directly the research object and also through literature study. Data analysis is conducted through input phase by using IFAS and EFAS matrix, adaptation phase with TOWS diagram, TOWS matrix and Internal-External matrix, and also uses SPACE matrix and also BCG matrix to analyse company's finance situation. Based on the conducted analysist the recommended corporation level strategy to be used by the company is diversification strategy direct to growth and stability. 

  9. A dynamical perspective of CTL cross-priming and regulation: implications for cancer immunology.

    Science.gov (United States)

    Wodarz, Dominik; Jansen, Vincent A A

    2003-05-01

    Cytotoxic T lymphocytes (CTL) responses are required to fight many diseases such as viral infections and tumors. At the same time, they can cause disease when induced inappropriately. Which factors regulate CTL and decide whether they should remain silent or react is open to debate. The phenomenon called cross-priming has received attention in this respect. That is, CTL expansion occurs if antigen is recognized on the surface of professional antigen presenting cells (APCs). This is in contrast to direct presentation where antigen is seen on the surface of the target cells (e.g. infected cells or tumor cells). Here we introduce a mathematical model, which takes the phenomenon of cross-priming into account. We propose a new mechanism of regulation which is implicit in the dynamics of the CTL: According to the model, the ability of a CTL response to become established depends on the ratio of cross-presentation to direct presentation of the antigen. If this ratio is relatively high, CTL responses are likely to become established. If this ratio is relatively low, tolerance is the likely outcome. The behavior of the model includes a parameter region where the outcome depends on the initial conditions. We discuss our results with respect to the idea of self/non-self discrimination and the danger signal hypothesis. We apply the model to study the role of CTL in cancer initiation, cancer evolution/progression, and therapeutic vaccination against cancers.

  10. Symbolic Model Checking Algorithm for Temporal Epistemic Logic CTL * K%时态认知逻辑CTL*K的符号化模型检查算法

    Institute of Scientific and Technical Information of China (English)

    陈彬; 王智学

    2009-01-01

    时序认知逻辑是由时序逻辑和认知逻辑组合而成的逻辑,主要应用于多主体系统的规范定义.大多数时序认知逻辑是基于CTL的,表达能力有限.并且已知的一些模型检查算法存在内存不足和状态爆炸等问题.讨论了基于CTL*的时态认知逻辑cTL*K的语法、语义和模型,它能够在表达力很强的时态逻辑CTL*基础上描述智能体的知识、目标等意向特征.并给出了CTL*K的模型检查算法,其核心思想就是将CTL*K公式的检查问题转化为CTL*公式的模型检查问题,可以使检查的系统规模得以大幅度提高.并且将算法编码后容易集成到NuSMV模型检查器.

  11. A Lucky Escape

    Institute of Scientific and Technical Information of China (English)

    王道庚

    2009-01-01

    @@ This story concerns(有关)a spider(蜘蛛)and a certain general of ancient times who had lost a battle and,in the company of(在……陪同下)a faithful(忠诚的)servant,was trying to escape(逃脱)from the enemy.Both were extremely(极度,非常)tired,and both were hungry and thirsty,but they did not dare to go into any town for fear of (担心,害怕)being discovered and captured(捉)by the enemy.Toward evening they arrived at a mountain where there was a small cave.

  12. Building blocks for institutional preparation of CTL019 delivery.

    Science.gov (United States)

    McGuirk, Joseph; Waller, Edmund K; Qayed, Muna; Abhyankar, Sunil; Ericson, Solveig; Holman, Peter; Keir, Christopher; Myers, G Douglas

    2017-09-01

    Chimeric antigen receptor (CAR) T-cell therapy is an investigational immunocellular therapy that reprograms a patient's cytotoxic T cells to engage and eliminate malignant cells. CAR T-cell therapies targeting the CD19 antigen have demonstrated high efficacy in clinical trials for patients with B-cell malignancies and may potentially be available on a broader scale in the future. CAR T-cell therapy begins with the collection of a sufficient number of T cells from a patient's peripheral blood through leukapheresis. Several factors must be considered when patients undergo leukapheresis for CAR T-cell therapy, including age and prior therapies. The leukapheresis material is shipped to a manufacturing facility, followed by return of the CAR T cells to the treatment center. Careful coordination of a multidisciplinary team composed of physicians, nurses, pharmacists and other hospital personnel is critical for the proper care of the patient before, during and after CAR T-cell therapy. CAR T-cell therapy has been associated with adverse events (AEs) such as cytokine release syndrome, which requires rapid attention by the emergency department, intensive care unit and hospital pharmacy. In this review, we discuss several aspects of institutional preparation for leukapheresis, CAR T-cell infusion and AE management based on our experience with clinical trials of the CD19 CAR T-cell therapy CTL019. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  13. Escape from the Alternative

    Directory of Open Access Journals (Sweden)

    Marin Dinu

    2006-12-01

    Full Text Available This paper sets out to elaborate on Romania’s specific agenda regarding the approach to the integration process in the EU as a project of modernization. The focus is on the functional aspects, the type of strategic solutions destined to consolidate the specific transformations belonging to post-communist transition seen as an internal transition, on the one hand and on the other hand to push convergence as the essence of integration, marked by the vision of EU integration as a continuation of change, which is the stage of external transition. Identifying the prominent factors and the pragmatic priorities of the escape from the peripheries of development by engaging in evolution by way of the second modernization constitutes as well a target for analysis. One particularity of the method of analysis is the review if the value-set of the bobsled effect of path dependency – the path of the peripheries – as well as of the set of values of the escape from the peripheries.

  14. Evolutionary escape from the prisoner's dilemma.

    Science.gov (United States)

    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.

  15. Prior population immunity reduces the expected impact of CTL-inducing vaccines for pandemic influenza control.

    Directory of Open Access Journals (Sweden)

    Kirsty J Bolton

    Full Text Available Vaccines that trigger an influenza-specific cytotoxic T cell (CTL response may aid pandemic control by limiting the transmission of novel influenza A viruses (IAV. We consider interventions with hypothetical CTL-inducing vaccines in a range of epidemiologically plausible pandemic scenarios. We estimate the achievable reduction in the attack rate, and, by adopting a model linking epidemic progression to the emergence of IAV variants, the opportunity for antigenic drift. We demonstrate that CTL-inducing vaccines have limited utility for modifying population-level outcomes if influenza-specific T cells found widely in adults already suppress transmission and prove difficult to enhance. Administration of CTL-inducing vaccines that are efficacious in "influenza-experienced" and "influenza-naive" hosts can likely slow transmission sufficiently to mitigate a moderate IAV pandemic. However if neutralising cross-reactive antibody to an emerging IAV are common in influenza-experienced hosts, as for the swine-variant H3N2v, boosting CTL immunity may be ineffective at reducing population spread, indicating that CTL-inducing vaccines are best used against novel subtypes such as H7N9. Unless vaccines cannot readily suppress transmission from infected hosts with naive T cell pools, targeting influenza-naive hosts is preferable. Such strategies are of enhanced benefit if naive hosts are typically intensively mixing children and when a subset of experienced hosts have pre-existing neutralising cross-reactive antibody. We show that CTL-inducing vaccination campaigns may have greater power to suppress antigenic drift than previously suggested, and targeting adults may be the optimal strategy to achieve this when the vaccination campaign does not have the power to curtail the attack rate. Our results highlight the need to design interventions based on pre-existing cellular immunity and knowledge of the host determinants of vaccine efficacy, and provide a framework

  16. Prior Population Immunity Reduces the Expected Impact of CTL-Inducing Vaccines for Pandemic Influenza Control

    Science.gov (United States)

    Bolton, Kirsty J.; McCaw, James M.; Brown, Lorena; Jackson, David; Kedzierska, Katherine; McVernon, Jodie

    2015-01-01

    Vaccines that trigger an influenza-specific cytotoxic T cell (CTL) response may aid pandemic control by limiting the transmission of novel influenza A viruses (IAV). We consider interventions with hypothetical CTL-inducing vaccines in a range of epidemiologically plausible pandemic scenarios. We estimate the achievable reduction in the attack rate, and, by adopting a model linking epidemic progression to the emergence of IAV variants, the opportunity for antigenic drift. We demonstrate that CTL-inducing vaccines have limited utility for modifying population-level outcomes if influenza-specific T cells found widely in adults already suppress transmission and prove difficult to enhance. Administration of CTL-inducing vaccines that are efficacious in "influenza-experienced" and "influenza-naive" hosts can likely slow transmission sufficiently to mitigate a moderate IAV pandemic. However if neutralising cross-reactive antibody to an emerging IAV are common in influenza-experienced hosts, as for the swine-variant H3N2v, boosting CTL immunity may be ineffective at reducing population spread, indicating that CTL-inducing vaccines are best used against novel subtypes such as H7N9. Unless vaccines cannot readily suppress transmission from infected hosts with naive T cell pools, targeting influenza-naive hosts is preferable. Such strategies are of enhanced benefit if naive hosts are typically intensively mixing children and when a subset of experienced hosts have pre-existing neutralising cross-reactive antibody. We show that CTL-inducing vaccination campaigns may have greater power to suppress antigenic drift than previously suggested, and targeting adults may be the optimal strategy to achieve this when the vaccination campaign does not have the power to curtail the attack rate. Our results highlight the need to design interventions based on pre-existing cellular immunity and knowledge of the host determinants of vaccine efficacy, and provide a framework for assessing the

  17. Function of Helper T Cells in the Memory CTL-mediated Anti-tumor Immunity

    Institute of Scientific and Technical Information of China (English)

    高丰光; GermainJ.P.Fernendo; 刘文军

    2004-01-01

    Abstract To investigate the role of CD4+ helper T (Th) cells in the memory CTL-mediated anti-tumor immunity, the RAG-1 gene knock out mice were adoptively transferred with OT-1 cells to generate the memory CTL, the C57B1/6 mice immunized with the epitope peptide of OVA specific Th cells and with different adjuvants were adopfively transferred with these memory-CTLs, and then the animals were challenged with tumor cells EGT. It was found that although the simple immunization of mice with the epitope peptide of the OVA specific Th cells could generate more effect CTL, but this effect was not so strong enough to resist completely the challenges with tumor cells. Nevertheless, the memory CTL-mediated anti-tumor immune effect required the helps of Th1 and Th2 cells. The cross-regulation between Thl and Th2 cells seemed to be beneficial for the host to generate more effector CTL for mounting an efficient anti-tumor response. It concluded that the interaction between Thl and Th2 cells might be more important than the single subset of Th cells in the memory CTL-mediated anti-tumor immune response. More attention should be paid in this regard for the future studies.

  18. Mars - an escaping planet?

    CERN Document Server

    Dvorak, R

    2005-01-01

    The chaotic behaviour of the motion of the planets in our Solar System is well established. Numerical experiments with a modified Solar System consisting of a more massive Earth have shown, that for special values of an enlargement factor K around 5 the dynamical state of a truncated planetary system (excluding Mercury and the outer planets Uranus and Neptune) is highly chaotic. On the contrary for values of the mass of the Earth up to the mass of Saturn no irregular dynamical behaviour was observed. We extended our investigations to the complete planetary system and showed, that this chaotic window found before still exists. Tests in different 'Solar Systems' showed that only including Jupiter and Saturn with their actual masses together with a 'massive' Earth (between 4 and 6 times more massive) destabilize the orbit of Mars so that even escapes from the system are possible.

  19. Induction of systemic CTL responses in melanoma patients by dendritic cell vaccination: Cessation of CTL responses is associated with disease progression

    DEFF Research Database (Denmark)

    Andersen, M.H.; Keikavoussi, P.; Brocker, E.B.

    2001-01-01

    by Western blotting was decreased in PBL at this time. In summary, our data confirm that DC-based vaccinations induce peptide-specific T cells in the peripheral blood of advanced-stage melanoma patients. Although successful induction of systemic tumor antigen-specific CTL may not lead to objective clinical...

  20. Construction and immunogenicity prediction of Plasmodium falciparum CTL epitope minigene vaccine

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The minigenes encoding Plasmodium falciparum CTL epitopesrestricted to human MHC class I molecular HLA-A2 and HLA-B51, which were both at high frequency among Chinese population, were constructed as mono-epitope CTL vaccines named pcDNA3.1/tr and pcDNA3.1/ sh. The minigenes of the two epitopes were then tandem linked to form a dimeric CTL epitope minigene recombinant vaccine. After DNA transfection, the epitope minigenes were expressed respectively in two human cell lines, each bearing one MHC class I molecule named CIR/HLA-A2.1 and K562/HLA-B51. The intracellular expression of the CTL epitope minigenes not only enhanced the stability of HLA-A2.1 and HLA-B51 molecules but also increased the assemblage of MHC class I molecules on cell surfaces, which testified the specific process and presentation of those endogenous expressed epitopes. For the cells transfected with the dimeric minigene encoding two tandem linked epitopes, the expression and presentation of each epitope were also detected on cell membranes that bore different MHC class I molecules. It meant that the adjacency of the two CTL epitopes did not interfere with the specific process and presentation of each epitope. Compared with the ordinary CTL studies that inoculated synthesized epitope peptides with peripheral blood cells, this work aimed to process the epitopes directly inside HLA class I allele specific human cells, and thus theoretically imitated the same procedure in vivo. It was also an economical way to predict the immunogenicity of CTL epitopes at an early stage especially in laboratories with limited financial resource.

  1. Inferring HIV escape rates from multi-locus genotype data

    Directory of Open Access Journals (Sweden)

    Taylor A Kessinger

    2013-09-01

    Full Text Available Cytotoxic T-lymphocytes (CTLs recognize viral protein fragments displayed by major histocompatibility complex (MHC molecules on the surface of virally infected cells and generate an anti-viral response that can kill the infected cells. Virus variants whose protein fragments are not efficiently presented on infected cells or whose fragments are presented but not recognized by CTLs therefore have a competitive advantage and spread rapidly through the population. We present a method that allows a more robust estimation of these escape rates from serially sampled sequence data. The proposed method accounts for competition between multiple escapes by explicitly modeling the accumulation of escape mutations and the stochastic effects of rare multiple mutants. Applying our method to serially sampled HIV sequence data, we estimate rates of HIV escape that are substantially larger than those previously reported. The method can be extended to complex escapes that require compensatory mutations. We expect our method to be applicable in other contexts such as cancer evolution where time series data is also available.

  2. Hepatitis B escape mutants in Scottish blood donors.

    Science.gov (United States)

    Larralde, Osmany; Dow, Brian; Jarvis, Lisa; Davidson, Fiona; Petrik, Juraj

    2013-06-01

    Hepatitis B virus (HBV) remains as the viral infection with the highest risk of transmission by transfusion. This risk is associated with window period donations, occult HBV infection (OBI) and the emergence of escape mutants, which render blood donations false negative for hepatitis B surface antigen (HBsAg) serological testing. A retrospective study was conducted to gain insights into the molecular epidemiology of HBV escape mutants in Scottish blood donors. The criterion for selection was HBV positivity either by serology or nucleic acid testing (NAT). HBsAg detection was compared across several commercial immunoassays. The full length S gene from plasma samples was PCR amplified, cloned and expressed in HepG2 cells. Eight samples showed HBsAg discordant results, while 5 OBI samples were found. Four escape mutants, containing missense mutations in the S gene, are described here. These mutations impaired HBsAg detection both from HBV infected plasma samples and from recombinant proteins derived from its infected donors. Phylogenetic analysis showed that most of the mutants were clustered in the genotype D and were closely related to strains from Asia and the Middle East. We report here a proline substitution, outside the major hydrophilic region, that impaired HBsAg detection in vivo and in vitro, warning about the risk for the emergence of vaccine escape mutants with mutations outside the major neutralisation site.

  3. The CD68 protein as a potential target for leukaemia-reactive CTL.

    Science.gov (United States)

    Sadovnikova, E; Parovichnikova, E N; Savchenko, V G; Zabotina, T; Stauss, H J

    2002-10-01

    CD68, a haematopoietic differentiation marker of the monocyte-macrophage lineage, is expressed in various human malignancies including chronic and acute myeloid leukaemia (AML). While the majority of normal CD34(+) cells are negative for CD68 expression, CD34(+) cells from AML patients produce elevated amounts of this protein. The purpose of this study was to identify CTL epitopes in the human CD68 protein. Mouse CD68 was also analysed to search for epitopes that could be used in murine tumor model. Peptides binding to murine H2(b) class I molecules were identified and used to stimulate CTL responses from allogeneic donor mice to avoid immunological tolerance. High avidity CTL clones specific for three different peptide epitopes did not kill CD68-expressing murine target cells, indicating that endogenous antigen processing failed to produce sufficient amounts of these peptides. In contrast, allo-restricted human CTL specific for an HLA-A2-binding peptide of CD68 recognised not only picomolar concentrations of peptide, but also displayed low levels of killing against HLA-A2-positive K562 and THP-1 leukemia cell lines and blast cells from AML patients. These data suggest that human leukaemia cells express limited amounts of CD68-derived peptides, and that high avidity CTL capable of recognising sub-picomolar concentrations of peptides are required for efficient killing of leukaemia cells.

  4. An escape from crowding.

    Science.gov (United States)

    Freeman, Jeremy; Pelli, Denis G

    2007-10-26

    Crowding occurs when nearby flankers jumble the appearance of a target object, making it hard to identify. Crowding is feature integration over an inappropriately large region. What determines the size of that region? According to bottom-up proposals, the size is that of an anatomically determined isolation field. According to top-down proposals, the size is that of the spotlight of attention. Intriligator and Cavanagh (2001) proposed the latter, but we show that their conclusion rests on an implausible assumption. Here we investigate the role of attention in crowding using the change blindness paradigm. We measure capacity for widely and narrowly spaced letters during a change detection task, both with and without an interstimulus cue. We find that standard crowding manipulations-reducing spacing and adding flankers-severely impair uncued change detection but have no effect on cued change detection. Because crowded letters look less familiar, we must use longer internal descriptions (less compact representations) to remember them. Thus, fewer fit into working memory. The memory limit does not apply to the cued condition because the observer need remember only the cued letter. Cued performance escapes the effects of crowding, as predicted by a top-down account. However, our most parsimonious account of the results is bottom-up: Cued change detection is so easy that the observer can tolerate feature degradation and letter distortion, making the observer immune to crowding. The change detection task enhances the classic partial report paradigm by making the test easier (same/different instead of identifying one of many possible targets), which increases its sensitivity, so it can reveal degraded memory traces.

  5. Induction of cytotoxic T-cell responses by gene gun DNA vaccination with minigenes encoding influenza A virus HA and NP CTL-epitopes

    DEFF Research Database (Denmark)

    Fomsgaard, A; Nielsen, H V; Kirkby, N

    1999-01-01

    degree of controllability. We have examined the induction of murine CTL's by this approach using DNA plasmid minigene vaccines encoding known mouse K(k) minimal CTL epitopes (8 amino acids) from the influenza A virus hemagglutinin and nucleoprotein. We here report that such an approach is feasible...... and that wild type influenza virus flanking amino acid sequences can influence the CTL response but are not essential for optimal CTL induction. We also examined the effect of different new amino acid sequences flanking the CTL epitopes. In one version, two CTL epitopes were linked together as 'string of beads......-induced CTL responses and tested for their protective effect against a lethal influenza A virus infection in mice and no effect was found. We conclude that a specific and highly directed CTL induction is possible by unlinked minigene DNA immunisation, but that CTL induction solely is not always sufficient...

  6. Escape rates for Gibbs measures

    CERN Document Server

    Ferguson, Andrew

    2010-01-01

    We study the asymptotic behaviour of the escape rate of a Gibbs measure supported on a conformal repeller through a small hole. There are additional applications to the convergence of Hausdorff dimension of the survivor set.

  7. Direction of escape in reindeer

    OpenAIRE

    Baskin, Leonid M.; Terje Skogland

    1997-01-01

    We tested the hypothesis that reindeer prefer to run uphill and upwind when escaping from man. Groups of wild and feral reindeer in Norway, Svalbard and on Wrangel Island were approached and their behaviour and direction of escape were recorded. Two stages of interaction with man were studied: first flight and final withdrawal. First flights proved to be away from man, upwind and uphill. Most final withdrawals were in the direction reindeer were moving when first observed.

  8. Direction of escape in reindeer

    Directory of Open Access Journals (Sweden)

    Leonid M. Baskin

    1997-04-01

    Full Text Available We tested the hypothesis that reindeer prefer to run uphill and upwind when escaping from man. Groups of wild and feral reindeer in Norway, Svalbard and on Wrangel Island were approached and their behaviour and direction of escape were recorded. Two stages of interaction with man were studied: first flight and final withdrawal. First flights proved to be away from man, upwind and uphill. Most final withdrawals were in the direction reindeer were moving when first observed.

  9. PEMBELAJARAN CONTEXTUAL TEACHING AND LEARNING (CTL) DAN HASIL BELAJAR MATEMATIKA SISWA SEKOLAH DASAR

    OpenAIRE

    Sunandar Sunandar

    2016-01-01

    The Influences of CTL Teaching-learning on the Learning Achievement of Primary School Students. The main purpose of this study was knowing whether using Contextual Teaching and Learn­ing (CTL) approach was more effective than Textual Teaching and Learning (TTL) approach in mathematics study. The samples of this study were 85 students from class VA and VB of Ngesrep 01/02 Elementary School at Semarang. The instruments in this study were (1) learning achievement test (2) observation sheet of st...

  10. Construction and immunogenicity prediction of Plasmodium falciparum CTL epitope minigene vaccine

    Institute of Scientific and Technical Information of China (English)

    TANG; Yuyang

    2001-01-01

    [1]Hill, A. V., Elvin, J., Willis, A. C. et al., Molecular analysis of the association of HLA-B53 and resistance to severe malaria, Nature, 1992, 360: 434.[2]Perlmann, P., Miller, L., Fogarty/WHO international conference on cellular mechanisms in malaria immunity, Immun. Letter, 1990, 25: 1.[3]Perkus, M. E., Tartaglia, J., Paoletti, E. et al., Poxvirus-based vaccine candidates for cancer, AIDS and other infectious diseases, J. Leukocyte Biol., 1995, 58(1): 1.[4]Shen, H., Slifka, M. K., Matloubian, M. et al., Recombinant Listeria monocytogenes as a live vaccine vehicle for the induction of protective anti-viral cell-mediated immunity, Proc. Natl. Acad. Sci. USA, 1995, 92: 3987.[5]Waine, G. J., McManus, D. P., Nucleic acids: vaccines of the future, Parasitol Today, 1995, 11: 113.[6]Whitton, J. L., Sheng, N., Oldstone, M. B. A. et al., A "string-of beads" vaccine, comprising linked minigenes, confers protection from lethal-dose virus challenge, J. Virol., 1993, 67: 348.[7]Lalvani, A., Aidoo, M., Allsopp, C. E. et al., An-HLA-based approach to design of a CTL-inducing vaccine against Plasmodium falciparum, Res. Immunol., 1994, 145: 461.[8]Sidney, J., Grey, H. M., Kubo, R. T. et al., Practical, biochemical and evolutionary implications of the discovery of HLA class I supermotifs, Immunology Today, 1996, 17: 261.[9]Thomson, S. A., Elliott, S. L., Sherritt, M. A. et al., Recombinant polyepitope vaccines for the delivery of multiple CD8 cytotoxic T cell epitopes, J. Immun., 1996, 157: 822.[10] Hanke, T., Schneider, J., Gilbert, S. C. et al., DNA multi-CTL epitope vaccines for HIV and Plasmodium falciparum: immunogenicity in mice, Vaccine, 1998, 16: 426.[11] Townsend, A. R. M., Rothbard, J., Gotch, F. M. et al., The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides, Cell, 1986, 44: 959.[12] Ojcius, D. M., Abastado, J. P., Casrouge, A. et al., Dissociation of

  11. Plasmodium falciparum CS protein - prime malaria vaccine candidate: definition of the human CTL domain and analysis of its variation

    Directory of Open Access Journals (Sweden)

    Denise L. Doolan

    1992-01-01

    Full Text Available Studies in mice have shown that immunity to malaria sporozoites is mediated primarily by citotoxic T lymphocytes (CTL specific for epitopes within the circumsporozoite (CS protein. Humans, had never been shown to generate CTL against any malaria or other parasite protein. The design of a sub-unit vaccine for humans ralies on the epitopes recognized by CTL being identified and polymorphisms therein being defined. We have developed a novel technique using an entire series of overlapping synthetic peptides to define the epitopes of the Plasmodium falciparum CS protein recognized by human CTL and have analyzed the sequence variation of the protein with respect to the identified CTL epitopic domain. We have demonstrated that some humans can indeed generate CTL. against the P. falciparum CS protein. Furthermore, the extent of variation observed for the CTL recognition domain is finite and the combination of peptides necessary for inclusion in a polyvalent vaccine may be small. If ways can be found to increase immune responsiveness, then a vaccine designed to stimulate CS protein-specific CTL activity may prevent malaria.

  12. Peptide-MHC class I stability is a stronger predictor of CTL immunogenicity than peptide affinity

    DEFF Research Database (Denmark)

    Harndahl, Mikkel Nors; Rasmussen, Michael; Nielsen, Morten

    2012-01-01

    Peptide-MHC class I stability is a stronger predictor of CTL immunogenicity than peptide affinity Mikkel Harndahla, Michael Rasmussena, Morten Nielsenb, Soren Buusa,∗ a Laboratory of Experimental Immunology, Faculty of Health Sciences, University of Copenhagen, Denmark b Center for Biological Seq...... al., 2007. J. Immunol. 178, 7890–7901. doi:10.1016/j.molimm.2012.02.025...

  13. MODEL PEMBELAJARAN EKONOMI SYARI’AH MELALUI CTL PADA JURUSAN PENDIDIKAN EKONOMI UNIVERSITAS NEGERI SURABAYA

    Directory of Open Access Journals (Sweden)

    Yoyok Soesatyo

    2015-09-01

    material given by using direct instructional model is still less than the standard of competencespecified, therefore it is necessary efforts to increase the understanding material through appropriate learning model in this study is a CTL (Contectual Teaching Learning

  14. EFEKTIVITAS PENDEKATAN OPEN-ENDED DAN CTL DITINJAU DARI BERPIKIR KREATIF SISWA KELAS VII

    Directory of Open Access Journals (Sweden)

    Yeni Rahmawati ES

    2016-06-01

    Full Text Available This research aimed to describe the effectiveness of the open-ended and CTL approach in terms of creative thinking. This research was quasi-experimental study design with nonequivalent pretest-posttest design goup. The research population was all students in class VII SMP Negeri 1 Sekampung which consisted of five classes. The research sample consisted of two classes is determined randomly. First experimental group was treated the open-ended and experimental group II were treated CTL approach. The one sample t-test carried out to investigate the effectiveness of the open-ended and CTL approach. Data collection techniques used were tests. Engineering tests used to measure student creative thinking on basic competencies: 1 identify the properties of a rectangle, square, trapezoid, parallelogram, rhombus and a kite; 2 calculate the circumference and area of a rectangle up and use it in problem solving both before and after treatment. The results of the research show that the open-ended and CTL approach is effective in terms of creative thinking. Keywords: open-ended, contextual teaching and learning, creative thinking

  15. Submarine Escape Set Test Facilities

    Directory of Open Access Journals (Sweden)

    G.S.N. Murthy

    2009-07-01

    Full Text Available Submarine Escape Set (SES is used by submariners to escape from a sunken submarine. This set caters for breathing needs of the submariner under water, until he reaches the surface. Evaluation of such life-saving equipment is of paramount importance. This paper describes the submarine escape set and various constructional features and schedules of operation of test facilities designed indegenously and which can evaluate the SES. The test facility is divided into two parts: the reducer test facility, and the breathing bag test facility. The equipment has been rigorously tested and accepted by Indian Navy. Two such test facilities have been developed, one of which is installed at INS Satavahana, Visakhapatnam, and are working satisfactorily.

  16. Identification and enhancement of HLA-A2.1-restricted CTL epitopes in a new human cancer antigen-POTE.

    Directory of Open Access Journals (Sweden)

    Yi-Hsiang Huang

    Full Text Available Identification of CD8(+ T cell epitopes that can induce T cells to kill tumor cells is a fundamental step for development of a peptide cancer vaccine. POTE protein is a newly identified cancer antigen that was found to be expressed in a wide variety of human cancers, including prostate, colon, lung, breast, ovary and pancreas. Here, we determined HLA-A2.1-restricted cytotoxic T lymphocyte (CTL epitopes in the POTE protein, and also designed enhanced epitopes by amino acid (AA substitutions. Five 9-mer peptides were first selected and their binding affinity to HLA-A2 molecules was measured by the T2 binding assay. POTE 272-280 and POTE 323-331 showed the strongest HLA-A2 binding affinity. AA substituted peptides POTE 252-9V (with valine at position 9, POTE 553-1Y (with tyrosine at position 1 and POTE 323-3F (with phenylalanine at position 3 conferred higher affinity for HLA-A2, and induced CTL responses cross-reactive with wild type antigens. While POTE 252-9V was the strongest in this respect, POTE 323-3F had the greatest increase in immunogenicity compared to wild type. Importantly, two modified epitopes (POTE-553-1Y and POTE-323-3F induced CTLs that killed NCI-H522, a POTE-expressing HLA-A2(+ human non-small cell lung cancer cell line, indicating natural endogenous processing of these epitopes. In conclusion, the immunogenicity of POTE epitopes can be enhanced by peptide modification to induce T cells that kill human cancer cells. A combination of POTE 553-1Y and POTE 323-3F epitopes might be an attractive vaccine strategy for HLA-A2 cancer patients to overcome tolerance induced by tumors and prevent escape.

  17. Inhibition of serine-peptidase activity enhances the generation of a survivin-derived HLA-A2-presented CTL epitope in colon-carcinoma cells.

    Science.gov (United States)

    Preta, G; Marescotti, D; Fortini, C; Carcoforo, P; Castelli, C; Masucci, M; Gavioli, R

    2008-12-01

    Cytotoxic T lymphocytes eliminate tumor cells expressing antigenic peptides in the context of MHC-I molecules. Peptides are generated during protein degradation by the proteasome and resulting products, surviving cytosolic amino-peptidases activity, may be presented by MHC-I molecules. The MHC-I processing pathway is altered in a large number of malignancies and modulation of antigen generation is one strategy employed by cells to evade immune control. In this study we analyzed the generation and presentation of a survivin-derived CTL epitope in HLA-A2-positive colon-carcinoma cells. Although all cell lines expressed the anti-apoptotic protein survivin, some tumors were poorly recognized by ELTLGEFLKL (ELT)-specific CTL cultures. The expression of MHC-I or TAP molecules was similar in all cell lines suggesting that tumors not recognized by CTLs may present defects in the generation of the ELT-epitope which could be due either to lack of generation or to subsequent degradation of the epitope. The cells were analyzed for the expression and the activity of extra-proteasomal peptidases. A significant overexpression and higher activity of TPPII was observed in colon-carcinoma cells which are not killed by ELT-specific CTLs, suggesting a possible role of TPPII in the degradation of the ELT-epitope. To confirm the role of TPPII in the degradation of the ELT-peptide, we showed that treatment of colon-carcinoma cells with a TPPII inhibitor resulted in a dose-dependent increased sensitivity to ELT-specific CTLs. These results suggest that TPPII is involved in degradation of the ELT-peptide, and its overexpression may contribute to the immune escape of colon-carcinoma cells.

  18. DYNAMICS OF THE ESCAPE RESPONSE.

    Science.gov (United States)

    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 .

  19. Keefektifan CTL Berbantuan Macromedia Flash Terhadap Kemampuan Berpikir Kritis pada Materi Segiempat

    Directory of Open Access Journals (Sweden)

    O.N. Kusumadewi

    2013-06-01

    Full Text Available Tujuan pada penelitian ini adalah untuk mengetahui nilai rata-rata dan tingkat ketuntasan klasikal pada kemampuan berpikir kritis peserta didik dalam materi segiempat setelah diterapkan model Contextual Teaching and Learning/CTL berbantuan Macromedia Flash 8, dan membandingkan model CTL berbantuan Macromedia Flash 8 dengan model direct instruction pada kemampuan berpikir kritis materi segiempat kelas VII. Populasi pada penelitian ini adalah peserta didik kelas VII SMP Negeri 1 Semarang tahun pelajaran 2012/ 2013. Sampel dipilih dengan menggunakan teknik cluster sampling. Hasil penelitian menunjukkan menunjukkan bahwa rata-rata kemampuan berpikir kritis kelas eksperimen mencapai kriteria ketuntasan minimum (KKM. Persentase banyaknya peserta didik yang tuntas melebihi ketuntasan klasikal minimal. Kemampuan berpikir kritis pada kelas eksperimen lebih baik dibandingkan pada kelas kontrol.  Hal tersebut terlihat dari rata-rata nilai dan persentase peserta didik yang tuntas pada kelas eksperimen lebih tinggi daripada kelas kontrol. Berdasarkan hasil penelitian, dapat disimpulkan bahwa pembelajaran dengan model CTL berbantuan Macromedia Flash 8 efektif terhadap kemampuan berpikir kritis materi segiempat kelas VII.   The purpose of the experiment is to find out the students’ completeness mean score and percentage in critical thinking ability about quadrilateral in CTL model with Macromedia Flash 8, and to compare the CTL model with direct instruction model in students’ critical thinking ability at 7th grade. The popula­tion of this study was 7th grade students of SMP N 1 Semarang academic year 2012/2013. Study learning showed that means score of critical thinking ability in experiment class achieves minimum completeness criteria (KKM. Percentage of students that achieve KKM was also more than minimum classical completeness score. Critical thinking ability of the experiment class is better than control class. It is proven from mean score and

  20. Optimization and immune recognition of multiple novel conserved HLA-A2, human immunodeficiency virus type 1-specific CTL epitopes

    DEFF Research Database (Denmark)

    Corbet, S; Nielsen, HV; Vinner, L;

    2003-01-01

    MHC-I-restricted cytotoxic responses are considered a critical component of protective immunity against viruses, including human immunodeficiency virus type 1 (HIV-1). CTLs directed against accessory and early regulatory HIV-1 proteins might be particularly effective; however, CTL epitopes....... This study demonstrates the potency of ANNs for identifying putative virus CTL epitopes, and the new HIV-1 CTL epitopes identified should have significant implications for HIV-1 vaccine development. As a novel vaccine approach, it is proposed to increase the coverage of HIV variants by including multiple...

  1. Optimization and immune recognition of multiple novel conserved HLA-A2, human immunodeficiency virus type 1-specific CTL epitopes

    DEFF Research Database (Denmark)

    Corbet, S.; Nielsen, H.V.; Vinner, L.;

    2003-01-01

    MHC-I-restricted cytotoxic responses are considered a critical component of protective immunity against viruses, including human immunodeficiency virus type 1 (HIV-1). CTLs directed against accessory and early regulatory HIV-1 proteins might be particularly effective; however, CTL epitopes...... demonstrates the potency of ANNs for identifying putative virus CTL epitopes, and the new HIV-1 CTL epitopes identified should have significant implications for HIV-1 vaccine development. As a novel vaccine approach, it is proposed to increase the coverage of HIV variants by including multiple anchor...

  2. SARS CTL vaccine candidates; HLA supertype-, genome-wide scanning and biochemical validation

    DEFF Research Database (Denmark)

    Sylvester-Hvid, C; Nielsen, M; Lamberth, K;

    2004-01-01

    of the HLA supertypes and identified almost 100 potential vaccine candidates. These should be further validated in SARS survivors and used for vaccine formulation. We suggest that immunobioinformatics may become a fast and valuable tool in rational vaccine design.......An effective Severe Acute Respiratory Syndrome (SARS) vaccine is likely to include components that can induce specific cytotoxic T-lymphocyte (CTL) responses. The specificities of such responses are governed by human leukocyte antigen (HLA)-restricted presentation of SARS-derived peptide epitopes......-CoV) was isolated and full-length sequenced (Marra et al., Science 2003: 300: 1399-404). Here, we have combined advanced bioinformatics and high-throughput immunology to perform an HLA supertype-, genome-wide scan for SARS-specific CTL epitopes. The scan includes all nine human HLA supertypes in total covering >99...

  3. SARS CTL vaccine candidates; HLA supertype-, genome-wide scanning and biochemical validation

    DEFF Research Database (Denmark)

    Sylvester-Hvid, C.; Nielsen, Morten; Lamberth, K.;

    2004-01-01

    of the HLA supertypes and identified almost 100 potential vaccine candidates. These should be further validated in SARS survivors and used for vaccine formulation. We suggest that immunobioinformatics may become a fast and valuable tool in rational vaccine design.......An effective Severe Acute Respiratory Syndrome (SARS) vaccine is likely to include components that can induce specific cytotoxic T-lymphocyte (CTL) responses. The specificities of such responses are governed by human leukocyte antigen (HLA)-restricted presentation of SARS-derived peptide epitopes......-CoV) was isolated and full-length sequenced (Marra et al., Science 2003: 300: 1399404). Here, we have combined advanced bioinformatics and high-throughput immunology to perform an HLA supertype-, genome-wide scan for SARS-specific CTL epitopes. The scan includes all nine human HLA supertypes in total covering >99...

  4. Global stability for delay-dependent HTLV-I model with CTL immune response

    Science.gov (United States)

    Wang, Yan; Liu, Jun

    2016-06-01

    We present a delay-dependent HTLV-I model with CTL immune response. The basic reproduction number is obtained for the existence of positive steady state. By constructing suitable Lyapunov functions, when the basic reproduction number is less than one, the infection-free steady state is globally asymptotically stable; when the basic reproduction number is greater than one, the infected steady state is globally asymptotically stable.

  5. SARS CTL vaccine candidates; HLA supertype-, genome-wide scanning and biochemical validation

    DEFF Research Database (Denmark)

    Sylvester-Hvid, C.; Nielsen, Morten; Lamberth, K.

    2004-01-01

    An effective Severe Acute Respiratory Syndrome (SARS) vaccine is likely to include components that can induce specific cytotoxic T-lymphocyte (CTL) responses. The specificities of such responses are governed by human leukocyte antigen (HLA)-restricted presentation of SARS-derived peptide epitopes...... of the HLA supertypes and identified almost 100 potential vaccine candidates. These should be further validated in SARS survivors and used for vaccine formulation. We suggest that immunobioinformatics may become a fast and valuable tool in rational vaccine design....

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

    Energy Technology Data Exchange (ETDEWEB)

    Rudneva, Irina A.; Timofeeva, Tatiana A.; Ignatieva, Anna V.; Shilov, Aleksandr A.; Krylov, Petr S. [D.I. Ivanovsky Institute of Virology, 123098 Moscow (Russian Federation); Ilyushina, Natalia A., E-mail: Natalia.Ilyushina@fda.hhs.gov [FDA CDER, 29 Lincoln Drive, Bethesda, MD 20892 (United States); Kaverin, Nikolai V., E-mail: nik.kaverin@gmail.com [D.I. Ivanovsky Institute of Virology, 123098 Moscow (Russian Federation)

    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.

  7. CTL responses to Leishmania mexicana gp63-cDNA vaccine in a murine model.

    Science.gov (United States)

    Ali, S A; Rezvan, H; McArdle, S E; Khodadadi, A; Asteal, F A; Rees, R C

    2009-07-01

    Immunity to Leishmania is believed to be strongly dependent upon the activation of Th1 immune responses, although the exact role of cytotoxic T lymphocytes (CTLs) has not yet been determined. The aims of this study were to establish a suitable cytotoxicity assay to measure CTL activity and to compare immunity induced by Leishmania mexicana gp63 cDNA via i.m. injection and gene gun immunization in the BALB/c mouse model. The CTL activity was evaluated by short-term (51)Cr-release cytotoxicity assays against CT26 tumour cells transfected with L. mexicana gp63 cDNA and dendritic cells (DCs) loaded with soluble Leishmania antigen (SLA) as targets. The results clearly demonstrated that higher protection to L. mexicana infection was induced by gene gun DNA-immunization vs. i.m. injection. Cytotoxic T lymphocyte activity of splenocytes was observed in mice immunized either with L. mexicana gp63 cDNA or SLA and long-lived CTL activity was observed in immunized and/or re-challenged mice but not naïve mice infected with the parasite.

  8. PENGARUH PENDEKATAN CONTEXTUAL TEACHING AND LEARNING (CTL BERBANTUAN MEDIA POWERPOINT TERHADAP PENINGKATAN HASIL BELAJAR IPA FISIKA

    Directory of Open Access Journals (Sweden)

    Suprianto Suprianto

    2016-12-01

    Full Text Available Berdasarkan hasil wawancara terbatas dengan sebagian guru IPA fisika MTs di kecamatan Camplong Kabupaten Sampang didapatkan informasi bahwa hasil belajar siswa masih rendah dibawah KKM yang sudah ditentukan pihak sekolah. Hal ini disebabkan karena kurangnya penggunaan media pembelajaran, proses pembelajaran masih bersifat teacher centered sehingga sebagian besar siswa tidak mampu menghubungkan antara apa yang mereka pelajari dengan bagaimana pemanfaatannya dalam kehidupan nyata. Adapun tujuan penelitian ini adalah untuk mengidentifikasi pengaruh pendekatan CTL berbantuan media powerpoint terhadap peningkatan hasil belajar IPA fisika siswa. Metode penelitian yang digunakan adalah metode Quasi Experimen dengan menggunakan Nonrandomized Control Group Pretest-Postest Design dan dibagi menjadi dua kelompok, yaitu kelompok eksperimen dan kelompok kontrol. Instrumen penelitian yang digunakan berupa tes objektif bentuk pilihan ganda. Tes ini terdiri dari empat pilihan (opsi dan hasilnya diuji melalui statistik uji “t”. Dari hasil perhitungan diperoleh nilai thitung sebesar 10,81 sedangkan ttabel sebesar 2,021 pada taraf signifikansi 0,05 atau dapat diketahui thitung > ttabel. Dari perhitungan N-gain, dapat dinyatakan bahwa peningkatan hasil belajar fisika yang diterapkan pendekatan CTL berbantuan media powerpoint lebih tinggi dari pada pembelajaran konvensional yaitu 0,71 > 0,52. Berdasarkan hasil analisis statistika dan deskriptif maka dapat di simpulkan bahwa terdapat pengaruh yang signifikan pendekatan CTL berbantuan media powerpoint terhadap peningkatan hasil belajar fisika siswa di kelas VIII MTs.

  9. Cold Ion Escape from Mars

    Science.gov (United States)

    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.

  10. EscapED: A Framework for Creating Educational Escape Rooms and Interactive Games to For Higher/Further Education.

    Directory of Open Access Journals (Sweden)

    Samantha Jane Clarke

    2017-09-01

    Full Text Available Game-based learning (GBL is often found to be technologically driven and more often than not, serious games for instance, are conceptualised and designed solely for digital platforms and state of the art technologies. To encourage a greater discussion on the potential benefits and challenges of a more holistic approach to developing GBL that promote human centered interactions and play for learning, the authors present the escapED programme. The escapED programme was conceived following the recent entertainment trend of escape rooms and is used for developing non-digital GBL approaches within education. escapED aids the design and creation of educational Escape Rooms and Interactive Gaming Experiences for staff and students in further/higher education settings. The paper first presents a pilot study that was used to assess the feasibility and acceptance of University teaching staff of embedding interactive GBL into a higher education environment. The authors then present the escapED theoretical framework that was used to create the prototype game for the pilot study as a tool to aid future design and development of on-site interactive experiences. The paper also presents an external developer report of using the escapED framework to develop a prototype game for teaching research methods to Southampton University students. Finally, the authors present a discussion on the use of the escapED framework so far and plans for future work and evaluation in order to provide engaging alternatives for learning and soft skills development amongst higher education staff andstudents.

  11. ESCAPE AS REINFORCEMENT AND ESCAPE EXTINCTION IN THE TREATMENT OF FEEDING PROBLEMS

    OpenAIRE

    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 si...

  12. Photochemical Escape of Oxygen from Early Mars

    CERN Document Server

    Zhao, Jinjin

    2015-01-01

    Photochemical escape is an important process for oxygen escape from present Mars. In this work, a 1-D Monte-Carlo Model is developed to calculate escape rates of energetic oxygen atoms produced from O2+ dissociative recombination reactions (DR) under 1, 3, 10, and 20 times present solar XUV fluxes. We found that although the overall DR rates increase with solar XUV flux almost linearly, oxygen escape rate increases from 1 to 10 times present solar XUV conditions but decreases when increasing solar XUV flux further. Analysis shows that atomic species in the upper thermosphere of early Mars increases more rapidly than O2+ when increasing XUV fluxes. While the latter is the source of energetic O atoms, the former increases the collision probability and thus decreases the escape probability of energetic O. Our results suggest that photochemical escape be a less important escape mechanism than previously thought for the loss of water and/or CO2 from early Mars.

  13. Energy-limited escape revised

    CERN Document Server

    Salz, M; Czesla, S; Schmitt, J H M M

    2016-01-01

    Gas planets in close proximity to their host stars experience photoevaporative mass loss. The energy-limited escape concept is generally used to derive estimates for the planetary mass-loss rates. Our photoionization hydrodynamics simulations of the thermospheres of hot gas planets show that the energy-limited escape concept is valid only for planets with a gravitational potential lower than $\\log_\\mathrm{10}\\left( -\\Phi_{\\mathrm{G}}\\right) < 13.11~$erg$\\,$g$^{-1}$ because in these planets the radiative energy input is efficiently used to drive the planetary wind. Massive and compact planets with $\\log_\\mathrm{10}\\left( -\\Phi_{\\mathrm{G}}\\right) \\gtrsim 13.6~$erg$\\,$g$^{-1}$ exhibit more tightly bound atmospheres in which the complete radiative energy input is re-emitted through hydrogen Ly$\\alpha$ and free-free emission. These planets therefore host hydrodynamically stable thermospheres. Between these two extremes the strength of the planetary winds rapidly declines as a result of a decreasing heating eff...

  14. Association between Hepatitis B Virus Chronic Infection and Mutations of Surface Antigen Gene%乙型肝炎病毒慢性感染与其表面抗原基因突变的相关性

    Institute of Scientific and Technical Information of China (English)

    王卫华; 宋建新

    2013-01-01

    目的 基于一个完整的乙型肝炎病毒(HBV)感染自然史的4个时期(免疫耐受期、免疫清除期、不活动期和HBeAg阴性肝炎阶段),研究HBV表面抗原各抗原表位的免疫逃逸突变分布.方法 收集280例患者的临床资料及血清标本,按照HBV自然史的不同时期分为4组,提取DNA并荧光定量,通过巢式PCR扩增HBV表面基因序列,以PCR产物作为模板进行DNA测序.分析比较4组乙肝表面抗原中辅助性T细胞(Th)表位、细胞毒性T淋巴细胞(CTL)表位及B细胞抗原表位的突变差异.结果 Th抗原表位突变中,4组间比较具有差异的是17-31、37-51、67-81等区域,CTL抗原表位突变中具有差异的是14-22、41-49等区域,在B细胞抗原表位区域发现了Q101K、P120S、T126S、Q129H、M133L、M133I、和M133T等7个乙肝表面抗原免疫逃逸突变.结论在HBV感染自然史中,表面抗原突变的累积发生在免疫清除期,突变的产生有利于HBV逃避免疫系统的攻击.%Objective To investigate the distribution of the immune escape mutations of hepatitis B virus surface antigen across the natural history of hepatitis B virus infection. Methods A total of 280 patients were divided into four groups according to the natural history of hepatitis B virus infection. DNA was extracted ,and the gene sequences of hepatitis B virus surface autigen were amplified by using nested PCR. The PCR product served as a template for DNA sequencing. The differences of mutations in epitopes of helper T cells (Th) ,cytotoxic T lymphocytes (CTL ) and B cells were analyzed. Results Among the four groups ,there were significant differences in mutations of epitopes of Th at regions of 17-31 ,37-51 ,67-81 ,and in mutations of epitopes of CTL at regions of 14-22 and 41-49 among the four groups. Immune escape mutations of hepatitis B virus surface an -tigen were found in epitopes of B cells in all four groups , namely Q101K, P120S , T126S , Q129H , M133L,M133I and M133T

  15. Wind-Induced Atmospheric Escape: Titan

    Science.gov (United States)

    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.

  16. Role of RNA secondary structure in emergence of compartment specific hepatitis B virus immune escape variants

    OpenAIRE

    Datta, Sibnarayan; Chakravarty, Runu

    2016-01-01

    AIM To investigate the role of subgenotype specific RNA secondary structure in the compartment specific selection of hepatitis B virus (HBV) immune escape mutations. METHODS This study was based on the analysis of the specific observation of HBV subgenotype A1 in the serum/plasma, while subgenotype A2 with G145R mutation in the peripheral blood leukocytes (PBLs). Genetic variability found among the two subgenotypes was used for prediction and comparison of the full length pregenomic RNA (pgRN...

  17. CTL Responses to Regulatory Proteins Tat and Rev in HIV-1 B'/C Virus-Infected Individuals

    Institute of Scientific and Technical Information of China (English)

    MING-MING JIA; KUN-XUE HONG; JIAN-PING CHEN; HONG-WEI LIU; SHA LIU; XIAO-QING ZHANG; HONG-JING ZHAO; YI-MING SHAO

    2008-01-01

    To characterize HIV-1 specific CTL responses to regulatory proteins Tat and Rev in HIV-B'/C vires-infected ART-naive individuals. Methods HIV-1-specific CTL responses were analyzed by IFN-γ ELISPOT assay using overlapping peptides spanning the consensus sequences of HIV-1 clade C Tat and Rev proteins. Statistical analysis and graphical presentation were performed using SIGMAPLOT 10.0 and SIGMASTAT 3.5. For samples with a positive response, the magnitude of CTL responses was compared between HIV-1 C proteins by Wilcoxon rank sum test, and the significance threshold was P<0.05. Results Tat and Rev were frequently recognized, with 23% and 52% of the tested individuals having detectable responses to these proteins, respectively. Several immunodominant regions were detected in Rev. No significant correlation was observed between the magnitude and breadth of CTL responses to regulatory proteins and the control of virus replication in this study. Conclusion Tat and Rev can serve as targets for HIV-1-specific CTL, and several immunodominant regions are detectable in Rev. Further characterization of epitopes and their role in virus control may shed light on pathogenesis of HIV-1 natural infection and also be useful for the design and testing of candidate vaccines.

  18. Chimeric virus-like particles for the delivery of an inserted conserved influenza A-specific CTL epitope.

    Science.gov (United States)

    Cheong, Wan-Shoo; Reiseger, Jessica; Turner, Stephen John; Boyd, Richard; Netter, Hans-Jürgen

    2009-02-01

    The small hepatitis B virus surface antigens (HBsAg-S) have the ability to self-assemble with host-derived lipids into empty non-infectious virus-like particles (VLPs). HBsAg-S VLPs are the sole component of the licensed hepatitis B vaccine, and they are a useful delivery platform for foreign epitopes. To develop VLPs capable of transporting foreign cytotoxic T lymphocyte (CTL) epitopes, HBsAg-S specific CTL epitopes at various sites were substituted with a conserved CTL epitope derived from the influenza matrix protein. Depending on the insertion site, the introduction of the MHC class I A2.1-restricted influenza epitope was compatible with the secretion competence of HBsAg-S indicating that chimeric VLPs were assembled. Immunizations of transgenic HHDII mice with chimeric VLPs induced anti-influenza CTL responses proving that the inserted foreign epitope can be correctly processed and cross-presented. Chimeric VLPs in the absence of adjuvant were able to induce memory T cell responses, which could be recalled by influenza virus infections in the mouse model system. The ability of chimeric HBsAg-S VLPs to induce anti-foreign CTL responses and also with the proven ability to induce humoral immune responses constitute a highly versatile platform for the delivery of selected multiple epitopes to target disease associated infectious agents.

  19. Co-lethality studied as an asset against viral drug escape: the HIV protease case

    Directory of Open Access Journals (Sweden)

    Ollivier Emmanuelle

    2010-06-01

    Full Text Available Abstract Background Co-lethality, or synthetic lethality is the documented genetic situation where two, separately non-lethal mutations, become lethal when combined in one genome. Each mutation is called a "synthetic lethal" (SL or a co-lethal. Like invariant positions, SL sets (SL linked couples are choice targets for drug design against fast-escaping RNA viruses: mutational viral escape by loss of affinity to the drug may induce (synthetic lethality. Results From an amino acid sequence alignment of the HIV protease, we detected the potential SL couples, potential SL sets, and invariant positions. From the 3D structure of the same protein we focused on the ones that were close to each other and accessible on the protein surface, to possibly bind putative drugs. We aligned 24,155 HIV protease amino acid sequences and identified 290 potential SL couples and 25 invariant positions. After applying the distance and accessibility filter, three candidate drug design targets of respectively 7 (under the flap, 4 (in the cantilever and 5 (in the fulcrum amino acid positions were found. Conclusions These three replication-critical targets, located outside of the active site, are key to our anti-escape strategy. Indeed, biological evidence shows that 2/3 of those target positions perform essential biological functions. Their mutational variations to escape antiviral medication could be lethal, thus limiting the apparition of drug-resistant strains. Reviewers This article was reviewed by Arcady Mushegian, Shamil Sunyaev and Claus Wilke.

  20. ELISPOT Assay for Monitoring Cytotoxic T Lymphocytes (CTL Activity in Cancer Vaccine Clinical Trials

    Directory of Open Access Journals (Sweden)

    Thomas J. Sayers

    2012-05-01

    Full Text Available The profiling and monitoring of immune responses are key elements in the evaluation of the efficacy and development of new biotherapies, and a number of assays have been introduced for analyzing various immune parameters before, during, and after immunotherapy. The choice of immune assays for a given clinical trial depends on the known or suggested immunomodulating mechanisms associated with the tested therapeutic modality. Cell-mediated cytotoxicity represents a key mechanism in the immune response to various pathogens and tumors. Therefore, the selection of monitoring methods for the appropriate assessment of cell-mediated cytotoxicity is thought to be crucial. Assays that can detect both cytotoxic T lymphocytes (CTL frequency and function, such as the IFN-γ enzyme-linked immunospot assay (ELISPOT have gained increasing popularity for monitoring clinical trials and in basic research. Results from various clinical trials, including peptide and whole tumor cell vaccination and cytokine treatment, have shown the suitability of the IFN-γ ELISPOT assay for monitoring T cell responses. However, the Granzyme B ELISPOT assay and Perforin ELISPOT assay may represent a more direct analysis of cell-mediated cytotoxicity as compared to the IFN-γ ELISPOT, since Granzyme B and perforin are the key mediators of target cell death via the granule-mediated pathway. In this review we analyze our own data and the data reported by others with regard to the application of various modifications of ELISPOT assays for monitoring CTL activity in clinical vaccine trials.

  1. Escaping growth arrest in cancer

    NARCIS (Netherlands)

    Kortlever, R.M.

    2008-01-01

    We now have a general idea of which genes and cellular pathways are central in cancer development: uncontrolled growth governs establishment and spread of the disease. Nevertheless, to fully appreciate the consequences of the interplay of driver mutations in this genetic disease it is imperative we

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

    Science.gov (United States)

    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…

  3. Triggering DTH and CTL Activity by fd Filamentous Bacteriophages: Role of CD4+ T Cells in Memory Responses

    Directory of Open Access Journals (Sweden)

    Giovanna Del Pozzo

    2010-01-01

    Full Text Available The ability of fd bacteriophage particles to trigger different arms of the immune system has been previously shown by us with particular emphasis on the ability of phages to raise CTL responses in vitro and in vivo. Here we show that fd virions in the absence of adjuvants are able to evoke a DTH reaction mediated by antigen specific CD8+ T cells. In addition, we analyzed the induction of CTL responses in mice depleted of CD4+ T cells, and we observed that short-term secondary CTL responses were induced in the absence of CD4+ T cells while induction of long-term memory CTLs required the presence of CD4+ T lymphocytes. These results examine the cellular mechanism at the basis of fd efficiency and provide new elements to further validate the use of fd particles for eliciting and monitoring antigen-specific CTLs.

  4. Learning from escaped prescribed fire reviews [Abstract

    Science.gov (United States)

    Anne Black; Dave Thomas; James Saveland

    2011-01-01

    Over the past decade, the wildland fire community has developed a number of innovative methods for conducting a review following escape of a prescribed fire. The stated purpose been to identify methods that not only meet policy requirements, but to reduce future escapes. Implicit is the assumption that a review leads to learning. Yet, as organizational learning expert...

  5. Escape of atmospheric gases from the Moon

    Indian Academy of Sciences (India)

    Da Dao-an; Yang Ya-tian

    2005-12-01

    The escape rate of atmospheric molecules on the Moon is calculated.Based on the assumption that the rates of emission and escape of gases attain equilibrium, the ratio of molecular number densities during day and night, 0/0, can be explained. The plausible emission rate of helium and radioactive elements present in the Moon has also been calculated.

  6. Escaping in Literature. Teaching in the Library.

    Science.gov (United States)

    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…

  7. Statin escape phenomenon: Fact or fiction?

    Science.gov (United States)

    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 statin-treated individuals. The clinical significance of this phenomenon remains uncertain.

  8. CADM1/TSLC1 Identifies HTLV-1-Infected Cells and Determines Their Susceptibility to CTL-Mediated Lysis.

    Directory of Open Access Journals (Sweden)

    Kiruthika Manivannan

    2016-04-01

    Full Text Available Human T cell lymphotropic virus-1 (HTLV-1 primarily infects CD4+ T cells, causing inflammatory disorders or a T cell malignancy in 5% to 10% of carriers. The cytotoxic T lymphocyte (CTL response is a key factor that controls the viral load and thus the risk of disease. The ability to detect the viral protein Tax in primary cells has made it possible to estimate the rate at which Tax-expressing infected cells are eliminated by CTLs in persistently infected people. However, most HTLV-1-infected cells are Tax-at a given time, and their immunophenotype is poorly defined. Here, we aimed to identify a cell-surface molecule expressed by both Tax+ and Tax-HTLV-1-infected cells and use it to analyse the CTL response in fresh peripheral blood mononuclear cells. Cell adhesion molecule 1 (CADM1/TSLC1 was the best single marker of HTLV-1 infection, identifying HTLV-1-infected cells with greater sensitivity and specificity than CD25, CCR4 or ICAM-1. CADM1+CD4+ T cells carried a median of 65% of proviral copies in peripheral blood. In a cohort of 23 individuals, we quantified the rate of CTL-mediated killing of Tax+ and Tax-CADM1+ cells. We show that CADM1 expression is associated with enhanced susceptibility of infected cells to CTL lysis: despite the immunodominance of Tax in the CTL response, Tax+CADM1- cells were inefficiently lysed by CTLs. Upregulation of the CADM1 ligand CRTAM on CD8+ T cells correlated with efficient lysis of infected cells. Tax-CADM1+ cells were lysed at a very low rate by autologous CTLs, however, were efficiently killed when loaded with exogenous peptide antigen. High expression of CADM1 on most HTLV-1-infected cells in the face of enhanced CTL counterselection implies that CADM1 confers a strong benefit on the virus.

  9. Atmospheric escape, redox evolution, and planetary habitability

    Science.gov (United States)

    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

  10. A scallop C-type lectin from Argopecten irradians (AiCTL5) with activities of lipopolysaccharide binding and Gram-negative bacteria agglutination.

    Science.gov (United States)

    Mu, Changkao; Song, Xiaoyan; Zhao, Jianmin; Wang, Lingling; Qiu, Limei; Zhang, Huan; Zhou, Zhi; Wang, Mengqiang; Song, Linsheng; Wang, Chunlin

    2012-05-01

    C-type lectins are a family of calcium-dependent carbohydrate-binding proteins. In the present study, a C-type lectin (designated as AiCTL5) was identified and characterized from Argopecten irradians. The full-length cDNA of AiCTL5 was of 673 bp, containing a 5' untranslated region (UTR) of 24 bp, a 3' UTR of 130 bp with a poly (A) tail, and an open reading frame (ORF) of 519 bp encoding a polypeptide of 172 amino acids with a putative signal peptide of 17 amino acids. A C-type lectin-like domain (CRD) containing 6 conserved cysteines and a putative glycosylation sites were identified in the deduced amino acid sequence of AiCTL5. AiCTL5 shared 11%-27.5% identity with the previous reported C-type lectin from A. irradians. The cDNA fragment encoding the mature peptide of AiCTL5 was recombined into pET-21a (+) with a C-terminal hexa-histidine tag fused in-frame, and expressed in Escherichia coli Origami (DE3). The recombinant AiCTL5 (rAiCTL5) agglutinated Gram-negative E. coli TOP10F' and Listonella anguillarum, but did not agglutinate Gram-positive bacteria Bacillus thuringiensis and Micrococcus luteus, and the agglutination could be inhibited by EDTA, indicating that AiCTL5 was a Ca(2+)-dependent lectin. rAiCTL5 exhibited a significantly strong activity to bind LPS from E. coli, which conformed to the agglutinating activity toward Gram-negative bacteria. Moreover, rAiCTL5 also agglutinated rabbit erythrocytes. These results indicated that AiCTL5 could function as a pattern recognition receptor to protect bay scallop from Gram-negative bacterial infection, and also provide evidence to understand the structural and functional diverse of lectin.

  11. Characterization of the cysK2-ctl1-cysE2 gene cluster involved in sulfur metabolism in Lactobacillus casei.

    Science.gov (United States)

    Bogicevic, Biljana; Irmler, Stefan; Portmann, Reto; Meile, Leo; Berthoud, Hélène

    2012-01-16

    The up- and downstream regions of ctl1 and ctl2 that encode a cystathionine lyase were analyzed in various Lactobacillus casei strains. ctl1 and ctl2 were found to be part of a gene cluster encoding two other open reading frames. One of the two open reading frames precedes ctl1 and encodes a putative cysteine synthase. The other open reading frame lies downstream of ctl1 and encodes a putative serine acetyltransferase. The gene cluster is not present in the publicly available genome sequences of L. casei ATCC 334, BL23 and Zhang. Apparently, the gene cluster was acquired by a horizontal gene transfer event and can also be found in other lactic acid bacteria such as Lactobacillus helveticus, Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus. RT-PCR was used to analyze the expression of the gene cluster. Additionally, an mass spectrometry-based selected reaction monitoring method was developed for quantifying Ctl1 in a cell-free extract of lactic acid bacteria. The gene cluster cysK2-ctl1-cysE2 was expressed as single transcript, and expression was down-regulated by cysteine. In addition, cystathionine lyase activity present in cell-free extracts disappeared when L. casei was grown in the presence of cysteine. Whereas the transcript and the gene product of ctl1 protein were found in all studied ctl1(+)L. casei strains, only the transcript but not the protein or cystathionine lyase activity was detected in L. helveticus FAM2888, L. delbrueckii subsp. bulgaricus ATCC 11842 and S. thermophilus FAM17014, which actually possess a homolog of the cysK2-ctl1-cysE2 gene cluster.

  12. Optimization and immune recognition of multiple novel conserved HLA-A2, human immunodeficiency virus type 1-specific CTL epitopes

    DEFF Research Database (Denmark)

    Corbet, Sylvie; Nielsen, Henrik Vedel; Vinner, Lasse

    2003-01-01

    and more conserved. Such epitope peptides were anchor-optimized to improve immunogenicity and further increase the number of potential vaccine epitopes. About 67 % of anchor-optimized vaccine epitopes induced immune responses against the corresponding non-immunogenic naturally occurring epitopes....... This study demonstrates the potency of ANNs for identifying putative virus CTL epitopes, and the new HIV-1 CTL epitopes identified should have significant implications for HIV-1 vaccine development. As a novel vaccine approach, it is proposed to increase the coverage of HIV variants by including multiple...

  13. Optimal escape theory predicts escape behaviors beyond flight initiation distance: risk assessment and escape by striped plateau lizards Sceloporus virgatus

    Institute of Scientific and Technical Information of China (English)

    William E.COOPER Jr

    2009-01-01

    Escape theory predicts that flight initiation distance (FID=distance between predator and prey when escape begins) is longer when risk is greater and shorter when escape is more costly. A few tests suggest that escape theory applies to distance fled. Escape models have not addressed stochastic variables, such as probability of fleeing and of entering refuge, but their economic logic might be applicable. Experiments on several risk factors in the lizard Sceloporus virgatus confirmed all predictions for the above escape variables. FID was greater when approach was faster and more direct, for lizards on ground than on trees, for lizards rarely exposed to humans, for the second of two approaches, and when the predator turned toward lizards rather than away. Lizards fled further during rapid and second consecutive approaches. They were more likely to flee when approached directly, when a predator turned toward them, and during second approaches. They were more likely to enter refuge when approached rapidly. A novel finding is that perch height in trees was unrelated to FID because lizards escaped by moving out of sight, then moving up or down unpredictably. These findings add to a growing body of evidence supporting predictions of escape theory for FID and distance fled. They show that two probabilistic aspects of escape are predictable based on relative predation risk levels. Because individuals differ in boldness, the assessed optimal FID and threshold risks for fleeing and entering refuge are exceeded for an increasing proportion of individuals as risk increases[Current Zoology 55(2):123-131,2009].

  14. Atmospheric Escape from Hot Jupiters

    CERN Document Server

    Murray-Clay, Ruth; Murray, Norman

    2008-01-01

    Photoionization heating from UV radiation incident on the atmospheres of hot Jupiters may drive planetary mass loss. We construct a model of escape that includes realistic heating and cooling, ionization balance, tidal gravity, and pressure confinement by the host star wind. We show that mass loss takes the form of a hydrodynamic ("Parker") wind, emitted from the planet's dayside during lulls in the stellar wind. When dayside winds are suppressed by the confining action of the stellar wind, nightside winds might pick up if there is sufficient horizontal transport of heat. A hot Jupiter loses mass at maximum rates of ~2 x 10^12 g/s during its host star's pre-main-sequence phase and ~2 x10^10 g/s during the star's main sequence lifetime, for total maximum losses of ~0.06% and ~0.6% of the planet's mass, respectively. For UV fluxes F_UV < 10^4 erg/cm^2/s, the mass loss rate is approximately energy-limited and is proportional to F_UV^0.9. For larger UV fluxes, such as those typical of T Tauri stars, radiative ...

  15. Clusters versus affinity-based approaches in F. tularensis whole genome search of CTL epitopes.

    Directory of Open Access Journals (Sweden)

    Anat Zvi

    Full Text Available Deciphering the cellular immunome of a bacterial pathogen is challenging due to the enormous number of putative peptidic determinants. State-of-the-art prediction methods developed in recent years enable to significantly reduce the number of peptides to be screened, yet the number of remaining candidates for experimental evaluation is still in the range of ten-thousands, even for a limited coverage of MHC alleles. We have recently established a resource-efficient approach for down selection of candidates and enrichment of true positives, based on selection of predicted MHC binders located in high density "hotspots" of putative epitopes. This cluster-based approach was applied to an unbiased, whole genome search of Francisella tularensis CTL epitopes and was shown to yield a 17-25 fold higher level of responders as compared to randomly selected predicted epitopes tested in Kb/Db C57BL/6 mice. In the present study, we further evaluate the cluster-based approach (down to a lower density range and compare this approach to the classical affinity-based approach by testing putative CTL epitopes with predicted IC(50 values of <10 nM. We demonstrate that while the percent of responders achieved by both approaches is similar, the profile of responders is different, and the predicted binding affinity of most responders in the cluster-based approach is relatively low (geometric mean of 170 nM, rendering the two approaches complimentary. The cluster-based approach is further validated in BALB/c F. tularensis immunized mice belonging to another allelic restriction (Kd/Dd group. To date, the cluster-based approach yielded over 200 novel F. tularensis peptides eliciting a cellular response, all were verified as MHC class I binders, thereby substantially increasing the F. tularensis dataset of known CTL epitopes. The generality and power of the high density cluster-based approach suggest that it can be a valuable tool for identification of novel CTLs in

  16. Murine leukemia RL male 1 and sarcoma Meth A antigens recognized by cytotoxic T lymphocytes (CTL).

    Science.gov (United States)

    Uenaka, Akiko; Nakayama, Eiichi

    2003-11-01

    Peptide elution and expression cloning methods have been used to identify T cell-recognized antigens for which no molecular information is available. We identified a unique tumor antigen peptide pRL1a, IPGLPLSL that is recognized by CTL on BALB/c RL male 1 leukemia by peptide elution. The sequence of the peptide corresponded to the normally untranslated 5' region of akt. Cytotoxicity was generated in BALB/c spleen cells by in vivo and in vitro sensitization with pRL1a peptide in the form of multiple antigen peptide (MAP), but not the original form. pRL1a MAP immunization had a significant growth-inhibitory effect. pRL1a MAP was mostly internalized into the endosomal compartment of antigen-presenting cells, leaked to the cytosol, and degraded, and the pRL1a peptide produced was presented through the MHC class I pathway. In vivo depletion of CD4 T cells from tumor-inoculated BALB/c mice caused RL male 1 regression. Overexpression of the RLakt molecule seemed to induce CD4 immunoregulatory cells, which resulted in progressive RL male 1 growth in BALB/c mice. In vivo administration of anti-CD25 mAb (PC61) caused regression of RL male 1, suggesting that CD4(+) CD25(+) immunoregulatory cells were involved in the tumor growth. Recently, we improved the sensitivity and the efficacy of T cell antigen cloning from cDNA expression libraries by using large- and small-scale ELISPOT assays. Using the IFN-gamma ELISPOT method, we obtained a cDNA clone S35 of 937 bp recognized by AT-1 CTL on BALB/c Meth A sarcoma. S35 was a part of the retinoic acid-regulated nuclear matrix-associated protein (ramp). AT-1 CTL recognized the peptide LGAEAIFRL, which was derived from a newly created open reading frame due to the exon 14 extension.

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

    Science.gov (United States)

    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.

  18. Differential requirements for CTL generation by novel immunostimulants: APC tropism, use of the TAP-independent processing pathway, and dependency on CD80/CD86 costimulation.

    NARCIS (Netherlands)

    Sheikh, NA; Attard, GS; Rooijen, van N.; Rajananthanan, P; Hariharan, K; Yang, YW; Morrow, WJ

    2003-01-01

    A major drawback of subunit vaccines is their inability to generate cytolytic T lymphocytes (CTL), a deficit attributed to segregation of the class I and class II antigen-processing pathways. We sought to understand processes involved in CTL induction by three proprietary adjuvants: Tomatine, PROVAX

  19. Quantifying Distributions of Lyman Continuum Escape Fraction

    CERN Document Server

    Cen, Renyue

    2015-01-01

    Simulations have indicated that most of the escaped Lyman continuum photons escape through a minority of solid angles with near complete transparency, with the remaining majority of the solid angles largely opaque, resulting in a very broad and skewed probability distribution function (PDF) of the escape fraction when viewed at different angles. Thus, the escape fraction of Lyman continuum photons of a galaxy observed along a line of sight merely represents the properties of the interstellar medium along that line of sight, which may be an ill-representation of true escape fraction of the galaxy averaged over its full sky. Here we study how Lyman continuum photons escape from galaxies at $z=4-6$, utilizing high-resolution large-scale cosmological radiation-hydrodynamic simulations. We compute the PDF of the mean escape fraction ($\\left$) averaged over mock observational samples, as a function of the sample size, compared to the true mean (had you an infinite sample size). We find that, when the sample size is...

  20. Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape.

    Directory of Open Access Journals (Sweden)

    Katharine J Bar

    Full Text Available Single genome sequencing of early HIV-1 genomes provides a sensitive, dynamic assessment of virus evolution and insight into the earliest anti-viral immune responses in vivo. By using this approach, together with deep sequencing, site-directed mutagenesis, antibody adsorptions and virus-entry assays, we found evidence in three subjects of neutralizing antibody (Nab responses as early as 2 weeks post-seroconversion, with Nab titers as low as 1∶20 to 1∶50 (IC(50 selecting for virus escape. In each of the subjects, Nabs targeted different regions of the HIV-1 envelope (Env in a strain-specific, conformationally sensitive manner. In subject CH40, virus escape was first mediated by mutations in the V1 region of the Env, followed by V3. HIV-1 specific monoclonal antibodies from this subject mapped to an immunodominant region at the base of V3 and exhibited neutralizing patterns indistinguishable from polyclonal antibody responses, indicating V1-V3 interactions within the Env trimer. In subject CH77, escape mutations mapped to the V2 region of Env, several of which selected for alterations of glycosylation. And in subject CH58, escape mutations mapped to the Env outer domain. In all three subjects, initial Nab recognition was followed by sequential rounds of virus escape and Nab elicitation, with Nab escape variants exhibiting variable costs to replication fitness. Although delayed in comparison with autologous CD8 T-cell responses, our findings show that Nabs appear earlier in HIV-1 infection than previously recognized, target diverse sites on HIV-1 Env, and impede virus replication at surprisingly low titers. The unexpected in vivo sensitivity of early transmitted/founder virus to Nabs raises the possibility that similarly low concentrations of vaccine-induced Nabs could impair virus acquisition in natural HIV-1 transmission, where the risk of infection is low and the number of viruses responsible for transmission and productive clinical

  1. Local Model Checking of Weighted CTL with Upper-Bound Constraints

    DEFF Research Database (Denmark)

    Jensen, Jonas Finnemann; Larsen, Kim Guldstrand; Srba, Jiri

    2013-01-01

    graphs. We implement all algorithms in a publicly available tool prototype and evaluate them on several experiments. The principal conclusion is that our local algorithm is the most efficient one with an order of magnitude improvement for model checking problems with a high number of “witnesses”.......We present a symbolic extension of dependency graphs by Liu and Smolka in order to model-check weighted Kripke structures against the logic CTL with upper-bound weight constraints. Our extension introduces a new type of edges into dependency graphs and lifts the computation of fixed-points from...... boolean domain to nonnegative integers in order to cope with the weights. We present both global and local algorithms for the fixed-point computation on symbolic dependency graphs and argue for the advantages of our approach compared to the direct encoding of the model checking problem into dependency...

  2. Peptide‐MHC class I stability is a better predictor than peptide affinity of CTL immunogenicity

    DEFF Research Database (Denmark)

    Harndahl, Mikkel Nors; Rasmussen, Michael; Roder, Gustav

    2012-01-01

    Efficient presentation of peptide‐MHC class I (pMHC‐I) complexes to immune T cells should benefit from a stable peptide‐MHC‐I interaction. However, it has been difficult to distinguish stability from other requirements for MHC‐I binding, for example, affinity. We have recently established a high......‐throughput assay for pMHC‐I stability. Here, we have generated a large database containing stability measurements of pMHC‐I complexes, and re‐examined a previously reported unbiased analysis of the relative contributions of antigen processing and presentation in defining cytotoxic T lymphocyte (CTL) immunogenicity...... [Assarsson et al., J. Immunol. 2007. 178: 7890–7901]. Using an affinity‐balanced approach, we demonstrated that immunogenic peptides tend to be more stably bound to MHC‐I molecules compared with nonimmunogenic peptides. We also developed a bioinformatics method to predict pMHC‐I stability, which suggested...

  3. Residue analysis of a CTL epitope of SARS-CoV spike protein by IFN-gamma production and bioinformatics prediction

    Directory of Open Access Journals (Sweden)

    Huang Jun

    2012-09-01

    Full Text Available Abstract Background Severe acute respiratory syndrome (SARS is an emerging infectious disease caused by the novel coronavirus SARS-CoV. The T cell epitopes of the SARS CoV spike protein are well known, but no systematic evaluation of the functional and structural roles of each residue has been reported for these antigenic epitopes. Analysis of the functional importance of side-chains by mutational study may exaggerate the effect by imposing a structural disturbance or an unusual steric, electrostatic or hydrophobic interaction. Results We demonstrated that N50 could induce significant IFN-gamma response from SARS-CoV S DNA immunized mice splenocytes by the means of ELISA, ELISPOT and FACS. Moreover, S366-374 was predicted to be an optimal epitope by bioinformatics tools: ANN, SMM, ARB and BIMAS, and confirmed by IFN-gamma response induced by a series of S358-374-derived peptides. Furthermore, each of S366-374 was replaced by alanine (A, lysine (K or aspartic acid (D, respectively. ANN was used to estimate the binding affinity of single S366-374 mutants to H-2 Kd. Y367 and L374 were predicated to possess the most important role in peptide binding. Additionally, these one residue mutated peptides were synthesized, and IFN-gamma production induced by G368, V369, A371, T372 and K373 mutated S366-374 were decreased obviously. Conclusions We demonstrated that S366-374 is an optimal H-2 Kd CTL epitope in the SARS CoV S protein. Moreover, Y367, S370, and L374 are anchors in the epitope, while C366, G368, V369, A371, T372, and K373 may directly interact with TCR on the surface of CD8-T cells.

  4. A HLA-A2 restricted human CTL line recognizes a novel tumor cell expressed p53 epitope

    DEFF Research Database (Denmark)

    Würtzen, Peter A; Claesson, Mogens H

    2002-01-01

    line, indicating that this novel p53 peptide epitope is endogenously processed and presented by the HLA-A2 molecules of the tumor cells. In conclusion, CTL reactivity towards a wild-type p53 peptide was revealed through induction with DC pulsed with a pool of HLA-A2 binding p53 peptides. In addition...

  5. Development of oral CTL vaccine using a CTP-integrated Sabin 1 poliovirus-based vector system.

    Science.gov (United States)

    Han, Seung-Soo; Lee, Jinjoo; Jung, Yideul; Kang, Myeong-Ho; Hong, Jung-Hyub; Cha, Min-Suk; Park, Yu-Jin; Lee, Ezra; Yoon, Cheol-Hee; Bae, Yong-Soo

    2015-09-11

    We developed a CTL vaccine vector by modification of the RPS-Vax system, a mucosal vaccine vector derived from a poliovirus Sabin 1 strain, and generated an oral CTL vaccine against HIV-1. A DNA fragment encoding a cytoplasmic transduction peptide (CTP) was integrated into the RPS-Vax system to generate RPS-CTP, a CTL vaccine vector. An HIV-1 p24 cDNA fragment was introduced into the RPS-CTP vector system and a recombinant poliovirus (rec-PV) named vRPS-CTP/p24 was produced. vRPS-CTP/p24 was genetically stable and efficiently induced Th1 immunity and p24-specific CTLs in immunized poliovirus receptor-transgenic (PVR-Tg) mice. In challenge experiments, PVR-Tg mice that were pre-immunized orally with vRPS-CTP/p24 were resistant to challenge with a lethal dose of p24-expressing recombinant vaccinia virus (rMVA-p24). These results suggested that the RPS-CTP vector system had potential for developing oral CTL vaccines against infectious diseases.

  6. The escape velocity and Schwarzschild metric

    CERN Document Server

    Murzagalieva, A G; Murzagaliev, G Z

    2002-01-01

    The escape velocity value in the terms of general relativity by means Schwarzschild metric is provided to make of the motion equation with Friedman cosmological model behavior build in the terms of Robertson-Worker metric. (author)

  7. St.Petersburg Escape Experience Tour

    OpenAIRE

    Palagina, Mariia; Zhak, Svetlana

    2017-01-01

    The growing popularity of Russia as a tourist destination and the high interest towards escape rooms and quests opens new business opportunities and market niches. The aim of this thesis is to develop a tourist product based on the new escape room tourism concept combining the historical, cultural and game experiences. The choice of the theme and destination was determined by the authors’ personal backgrounds and the destination proximity to Finland. The theoretical research was implement...

  8. Polymer escape from a confining potential

    Energy Technology Data Exchange (ETDEWEB)

    Mökkönen, Harri, E-mail: harri.mokkonen@aalto.fi [Department of Applied Physics and COMP CoE, Aalto University School of Science, P.O. Box 11100, FIN-00076 Aalto, Espoo (Finland); Faculty of Physical Sciences, University of Iceland, Reykjavík (Iceland); Ikonen, Timo [Department of Applied Physics and COMP CoE, Aalto University School of Science, P.O. Box 11100, FIN-00076 Aalto, Espoo (Finland); VTT Technical Research Centre of Finland, P.O. Box 1000, FI-02044 VTT (Finland); Jónsson, Hannes [Department of Applied Physics and COMP CoE, Aalto University School of Science, P.O. Box 11100, FIN-00076 Aalto, Espoo (Finland); Faculty of Physical Sciences, University of Iceland, Reykjavík (Iceland); Department of Physics, Brown University, Providence, Rhode Island 02912-1843 (United States); Ala-Nissila, Tapio [Department of Applied Physics and COMP CoE, Aalto University School of Science, P.O. Box 11100, FIN-00076 Aalto, Espoo (Finland); Department of Physics, Brown University, Providence, Rhode Island 02912-1843 (United States)

    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.

  9. Combined Transfection with EBV-Specific Epitopes and HLA-A2 genes is More Effective than Separate Transfection in Promoting CTL Lysis against Nasopharyngeal Carcinoma

    Institute of Scientific and Technical Information of China (English)

    Weijun Ding; Choylen Fong

    2004-01-01

    To augment specific cytotoxic T lymphocyte (CTL) lysis is a promising strategy for cancer therapy. In this study,we examined the boosting effect of CTLs upon autologous lymphoblastoid B cell lines (LCLs) transfected with diverse plasmids, to explore the possible CTL-based immunotherapy of nasopharyngeal carcinoma (NPC).FCM analysis displayed rather high ratio (>30%) of successfully transfected LCLs by utilizing the DMRIE-C kit. CTL assays demonstrated that substantially higher ratio of CTL specific lysis was observed upon the LCLs transfected with both expression vectors encoding EBV-specific epitopes and their presentation molecule HLA-A2, in contrast with those transfected separately. By transfecting the vector encoding HLA-A2 alone, only the LCLs of HLA-A2+ donors elicited markedly higher CTL lysis. CTL assays also showed that there existed no marked differences upon transfection by either different vectors (pcDNA3, pNGVL3 or pNGVL3-hFlex), or different EBV-derived peptides (LMP2Pep1 or LMP2Pep2), or with or without the doubled DNA sequence encoding peptides. This study indicated a promising immunotherapy strategy on NPC through boosting and eliciting the EBV-specific CTL activation by transferring vectors encoding both EBV-specific epitopes and their presentation molecule HLA-A2 into autologous LCL, the presentation cells of MHC/peptide tetrameric complex.

  10. Combined Transfection with EBV-Specific Epitopes and HLA-A2 genes is More Effective than Separate Transfection in Promoting CTL Lysis against Nasopharyngeal Carcinoma

    Institute of Scientific and Technical Information of China (English)

    WeijunDing; ChoylenFong

    2004-01-01

    To augment specific cytotoxic T lymphocyte (CTL) lysis is a promising strategy for cancer therapy. In this study,we examined the boosting effect of CTLs upon autologous lymphoblastoid B cell lines (LCLs) transfected with diverse plasmids, to explore the possible CTL-based immunotherapy of nasopharyngeal carcinoma (NPC).FCM analysis displayed rather high ratio (>30%) of successfully transfected LCLs by utilizing the DMRIE-C kit. CTL assays demonstrated that substantially higher ratio of CTL specific lysis was observed upon the LCLs transfected with both expression vectors encoding EBV-specific epitopes and their presentation molecule HLA-A2, In contrast with those transfected separately. By transfecting the vector encoding HLA-A2 alone, only the LCLs of HLA-A2+ donors elicited markedly higher CTL lysis. CTL assays also showed that there existed no marked differences upon transfection by either different vectors (pcDNA3, pNGVL3 or pNGVL3-hFIex), or different EBV-derived peptides (LMP2Pep1 or LMP2Pep2), or with or without the doubled DNA sequence encoding peptides. This study indicated a promising immunotherapy strategy on NPC through boosting and eliciting the EBV-specific CTL activation by transferring vectors encoding both EBV-specific epitopes and their presentation molecule HLA-A2 into autologous LCL, the presentation cells of MHC/peptide tetrameric complex.

  11. Promiscuous prediction and conservancy analysis of CTL binding epitopes of HCV 3a viral proteome from Punjab Pakistan: an In Silico Approach

    Directory of Open Access Journals (Sweden)

    Idrees Muhammad

    2011-02-01

    Full Text Available Abstract Background HCV is a positive sense RNA virus affecting approximately 180 million people world wide and about 10 million Pakistani populations. HCV genotype 3a is the major cause of infection in Pakistani population. One of the major problems of HCV infection especially in the developing countries that limits the limits the antiviral therapy is the long term treatment, high dosage and side effects. Studies of antigenic epitopes of viral sequences of a specific origin can provide an effective way to overcome the mutation rate and to determine the promiscuous binders to be used for epitope based subunit vaccine design. An in silico approach was applied for the analysis of entire HCV proteome of Pakistani origin, aimed to identify the viral epitopes and their conservancy in HCV genotypes 1, 2 and 3 of diverse origin. Results Immunoinformatic tools were applied for the predictive analysis of HCV 3a antigenic epitopes of Pakistani origin. All the predicted epitopes were then subjected for their conservancy analysis in HCV genotypes 1, 2 and 3 of diverse origin (worldwide. Using freely available web servers, 150 MHC II epitopes were predicted as promiscuous binders against 51 subjected alleles. E2 protein represented the 20% of all the predicted MHC II epitopes. 75.33% of the predicted MHC II epitopes were (77-100% conserve in genotype 3; 47.33% and 40.66% in genotype 1 and 2 respectively. 69 MHC I epitopes were predicted as promiscuous binders against 47 subjected alleles. NS4b represented 26% of all the MHC I predicted epitopes. Significantly higher epitope conservancy was represented by genotype 3 i.e. 78.26% and 21.05% for genotype 1 and 2. Conclusions The study revealed comprehensive catalogue of potential HCV derived CTL epitopes from viral proteome of Pakistan origin. A considerable number of predicted epitopes were found to be conserved in different HCV genotype. However, the number of conserved epitopes in HCV genotype 3 was

  12. Chitinase-like (CTL) and cellulose synthase (CESA) gene expression in gelatinous-type cellulosic walls of flax (Linum usitatissimum L.) bast fibers.

    Science.gov (United States)

    Mokshina, Natalia; Gorshkova, Tatyana; Deyholos, Michael K

    2014-01-01

    Plant chitinases (EC 3.2.1.14) and chitinase-like (CTL) proteins have diverse functions including cell wall biosynthesis and disease resistance. We analyzed the expression of 34 chitinase and chitinase-like genes of flax (collectively referred to as LusCTLs), belonging to glycoside hydrolase family 19 (GH19). Analysis of the transcript expression patterns of LusCTLs in the stem and other tissues identified three transcripts (LusCTL19, LusCTL20, LusCTL21) that were highly enriched in developing bast fibers, which form cellulose-rich gelatinous-type cell walls. The same three genes had low relative expression in tissues with primary cell walls and in xylem, which forms a xylan type of secondary cell wall. Phylogenetic analysis of the LusCTLs identified a flax-specific sub-group that was not represented in any of other genomes queried. To provide further context for the gene expression analysis, we also conducted phylogenetic and expression analysis of the cellulose synthase (CESA) family genes of flax, and found that expression of secondary wall-type LusCESAs (LusCESA4, LusCESA7 and LusCESA8) was correlated with the expression of two LusCTLs (LusCTL1, LusCTL2) that were the most highly enriched in xylem. The expression of LusCTL19, LusCTL20, and LusCTL21 was not correlated with that of any CESA subgroup. These results defined a distinct type of CTLs that may have novel functions specific to the development of the gelatinous (G-type) cellulosic walls.

  13. Chitinase-like (CTL and cellulose synthase (CESA gene expression in gelatinous-type cellulosic walls of flax (Linum usitatissimum L. bast fibers.

    Directory of Open Access Journals (Sweden)

    Natalia Mokshina

    Full Text Available Plant chitinases (EC 3.2.1.14 and chitinase-like (CTL proteins have diverse functions including cell wall biosynthesis and disease resistance. We analyzed the expression of 34 chitinase and chitinase-like genes of flax (collectively referred to as LusCTLs, belonging to glycoside hydrolase family 19 (GH19. Analysis of the transcript expression patterns of LusCTLs in the stem and other tissues identified three transcripts (LusCTL19, LusCTL20, LusCTL21 that were highly enriched in developing bast fibers, which form cellulose-rich gelatinous-type cell walls. The same three genes had low relative expression in tissues with primary cell walls and in xylem, which forms a xylan type of secondary cell wall. Phylogenetic analysis of the LusCTLs identified a flax-specific sub-group that was not represented in any of other genomes queried. To provide further context for the gene expression analysis, we also conducted phylogenetic and expression analysis of the cellulose synthase (CESA family genes of flax, and found that expression of secondary wall-type LusCESAs (LusCESA4, LusCESA7 and LusCESA8 was correlated with the expression of two LusCTLs (LusCTL1, LusCTL2 that were the most highly enriched in xylem. The expression of LusCTL19, LusCTL20, and LusCTL21 was not correlated with that of any CESA subgroup. These results defined a distinct type of CTLs that may have novel functions specific to the development of the gelatinous (G-type cellulosic walls.

  14. Genes that escape from X inactivation.

    Science.gov (United States)

    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.

  15. CD8-dependent CTL require co-engagement of CD8 and the TCR for phosphatidylinositol hydrolysis, but CD8-independent CTL do not and can kill in the absence of phosphatidylinositol hydrolysis.

    Science.gov (United States)

    Knall, C; Smith, P A; Potter, T A

    1995-06-01

    Most instances of MHC class I recognition and target cell killing by CD8+ CTL require the involvement of CD8. The role of CD8 in these events may be both for adhesion of the CTL with the APC, as well as for signal transduction through the TCR. The precise mechanism by which CD8 mediates signal transduction remains enigmatic. Similarly, it is unclear whether only the CD8 molecules which bind to the same class I molecule as the TCR contribute to signaling in the T cell responding to antigen. We have investigated the requirement for co-engagement of CD8 and the TCR in the induction of the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) during the interaction of CTL and APC transfected with either wild-type or mutant (CD8 non-binding) class I molecules. Our results show that for conventional CD8-dependent killing co-engagement of both CD8 and the TCR is required to initiate PIP2 hydrolysis. This requirement for co-engagement, however, can be overcome by a high density of ligand, such as that provided by high concentrations of exogenous peptide. In such situations, the binding of CD8 to non-antigenic class I molecules can elicit PIP2 hydrolysis. Therefore, during interactions between CTL and APC, which generally occur at low concentrations of antigenic peptide, triggering of PIP2 hydrolysis requires TCR and CD8 co-engagement, and the binding of CD8 to non-antigenic class I molecules does not contribute significantly to signaling within the T cell.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Dynamics of a Delayed HIV-1 Infection Model with Saturation Incidence Rate and CTL Immune Response

    Science.gov (United States)

    Guo, Ting; Liu, Haihong; Xu, Chenglin; Yan, Fang

    2016-12-01

    In this paper, we investigate the dynamics of a five-dimensional virus model incorporating saturation incidence rate, CTL immune response and three time delays which represent the latent period, virus production period and immune response delay, respectively. We begin this model by proving the positivity and boundedness of the solutions. Our model admits three possible equilibrium solutions, namely the infection-free equilibrium E0, the infectious equilibrium without immune response E1 and the infectious equilibrium with immune response E2. Moreover, by analyzing corresponding characteristic equations, the local stability of each of the feasible equilibria and the existence of Hopf bifurcation at the equilibrium point E2 are established, respectively. Further, by using fluctuation lemma and suitable Lyapunov functionals, it is shown that E0 is globally asymptotically stable when the basic reproductive numbers for viral infection R0 is less than unity. When the basic reproductive numbers for immune response R1 is less than unity and R0 is greater than unity, the equilibrium point E1 is globally asymptotically stable. Finally, some numerical simulations are carried out for illustrating the theoretical results.

  17. Platelets prevent IFN-alpha/beta-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus.

    Science.gov (United States)

    Iannacone, Matteo; Sitia, Giovanni; Isogawa, Masanori; Whitmire, Jason K; Marchese, Patrizia; Chisari, Francis V; Ruggeri, Zaverio M; Guidotti, Luca G

    2008-01-15

    We found that mice infected with different isolates of lymphocytic choriomeningitis virus (LCMV) develop a mild hemorrhagic anemia, which becomes severe and eventually lethal in animals depleted of platelets or lacking integrin beta3. Lethal hemorrhagic anemia is mediated by virus-induced IFN-alpha/beta that causes platelet dysfunction, mucocutaneous blood loss and suppression of erythropoiesis. In addition to the life-threatening hemorrhagic anemia, platelet-depleted mice fail to mount an efficient cytotoxic T lymphocyte (CTL) response and cannot clear LCMV. Transfusion of functional platelets into these animals reduces hemorrhage, prevents death and restores CTL-induced viral clearance in a manner partially dependent on CD40 ligand (CD40L). These results indicate that, upon activation, platelets expressing integrin beta3 and CD40L are required for protecting the host against the induction of an IFN-alpha/beta-dependent lethal hemorrhagic diathesis and for clearing LCMV infection through CTLs.

  18. Escape statistics for parameter sweeps through bifurcations.

    Science.gov (United States)

    Miller, Nicholas J; Shaw, Steven W

    2012-04-01

    We consider the dynamics of systems undergoing parameter sweeps through bifurcation points in the presence of noise. Of interest here are local codimension-one bifurcations that result in large excursions away from an operating point that is transitioning from stable to unstable during the sweep, since information about these "escape events" can be used for system identification, sensing, and other applications. The analysis is based on stochastic normal forms for the dynamic saddle-node and subcritical pitchfork bifurcations with a time-varying bifurcation parameter and additive noise. The results include formulation and numerical solution for the distribution of escape events in the general case and analytical approximations for delayed bifurcations for which escape occurs well beyond the corresponding quasistatic bifurcation points. These bifurcations result in amplitude jumps encountered during parameter sweeps and are particularly relevant to nano- and microelectromechanical systems, for which noise can play a significant role.

  19. Cosmic ray escape from supernova remnants

    CERN Document Server

    Gabici, Stefano

    2011-01-01

    Galactic cosmic rays are believed to be accelerated at supernova remnants via diffusive shock acceleration. Though this mechanism gives fairly robust predictions for the spectrum of particles accelerated at the shock, the spectrum of the cosmic rays which are eventually injected in the interstellar medium is more uncertain and depends on the details of the process of particle escape from the shock. Knowing the spectral shape of these escaping particles is of crucial importance in order to assess the validity of the supernova remnant paradigm for cosmic ray origin. Moreover, after escaping from a supernova remnant, cosmic rays interact with the surrounding ambient gas and produce gamma rays in the vicinity of the remnant itself. The detection of this radiation can be used as an indirect proof of the fact that the supernova remnant was indeed accelerating cosmic rays in the past.

  20. Thermal escape from extrasolar giant planets.

    Science.gov (United States)

    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.

  1. Mutations and phylogenetic analysis of the equine influenza virus (H3N8 nucleoprotein isolated in Morocco

    Directory of Open Access Journals (Sweden)

    M. Boukharta

    2013-08-01

    Full Text Available The equine influenza (EI is a highly contagious respiratory viral disease of equines. The aim of the present study was to determine the amino acid mutation sequences of the partial nucleoprotein (NP, which includes four epitopes of the equine leucocyte antigen (ELA of A/equine/Nador/1/1997 (H3N8. These epitopes are critical for their binding to major histocompatibility molecule complex (MHC class I and recognition by specific Cytotoxic T Lymphocytes (CTLs. The isolate was subjected to RT-PCR amplifications followed by sequencing analysis. Phylogenetic analysis showed that Moroccan isolate belongs to equine host-specific lineage and more closely related to Italian strains A/equine/Rome/5/1991 and A/equine/Italy/1062/1991. Amino acid sequence comparison of the NP showed that the strain A/equine/Nador/1/1997 has twelve substitutions at the residues T/284/A, A/286/T, R/293/K, I/299/V, V/312/I, N/319/K, S/344/L, V/353/I, M/374/I, C/377/N, N/397/S and R/452/K. All substitutions concerned both the interaction domains NP–NP and NP–PB2. However, the mutation N319 K enhances the NP–PB2 interaction and polymerase activity in mammalian infected cells. S/344/L mutation was located on the FEDLRVSNFI epitope (aa 338–347, this substitution is likely to help the virus to overcome the barrier of cell-mediated immunity of the host. The identified mutations were grouped into two groups, one included residues that facilitate the adaptation and evolution of influenza viruses within the equine lineage such as A/286/T, R/293/K, S/344/L, V/353/I and R/452/K, while the second contained the substitutions which enhance the virulence as polymerase activity (N319 K and mutations that affect CTL epitopes, resulting in an escape from immune surveillance by specific CTLs (S/344/L.

  2. Bacillus anthracis factors for phagosomal escape.

    Science.gov (United States)

    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.

  3. DAI (DLM-1/ZBP1) as a genetic adjuvant for DNA vaccines that promotes effective antitumor CTL immunity.

    Science.gov (United States)

    Lladser, Alvaro; Mougiakakos, Dimitrios; Tufvesson, Helena; Ligtenberg, Maarten A; Quest, Andrew Fg; Kiessling, Rolf; Ljungberg, Karl

    2011-03-01

    DNA vaccination is an attractive approach to induce antigen-specific cytotoxic CD8(+) T lymphocytes (CTLs), which can mediate protective antitumor immunity. The potency of DNA vaccines encoding weakly immunogenic tumor-associated antigens (TAAs) can be enhanced by codelivering gene-encoded adjuvants. Pattern recognition receptors (PRRs) that sense intracellular DNA could potentially be used to harness intrinsic immune-stimulating properties of plasmid DNA vaccines. Consequently, the cytosolic DNA sensor, DNA-dependent activator of interferon (IFN) regulatory factors (DAI), was used as a genetic adjuvant. In vivo electroporation (EP) of mice with a DAI-encoding plasmid (pDAI) promoted transcription of genes encoding type I IFNs, proinflammatory cytokines, and costimulatory molecules. Coimmunization with pDAI and antigen-encoding plasmids enhanced in vivo antigen-specific proliferation, and induction of effector and memory CTLs. Moreover, codelivery of pDAI effectively promoted CTL and CD4(+) Th1 responses to the TAA survivin. The DAI-enhanced CTL induction required nuclear factor κB (NF-κB) activation and type I IFN signaling, but did not involve the IFN regulatory factor 3 (IRF3). Codelivery of pDAI also increased CTL responses to the melanoma-associated antigen tyrosinase-related protein-2 (TRP2), enhanced tumor rejection and conferred long-term protection against B16 melanoma challenge. This study constitutes "proof-of-principle" validating the use of intracellular PRRs as genetic adjuvants to enhance DNA vaccine potency.

  4. Prediction of HLA-A 2.1-restricted CTL epitopes from IGFBP7 antigen of lung carcinoma

    Institute of Scientific and Technical Information of China (English)

    Zhao Weipeng; Long Haixia; Zhu Bo; Duan Yuzhong; Chen Zhengtang

    2009-01-01

    Objective: With the development of peptide-based cancer specific immunotherapy, the prediction of CTL epitopes from insulin-like growth factor-binding protein 7 (IGFBP7) is very important for some research about tumor metastasis. Because HLA-A2.1-expressing individuals cover >50% in the population of China, we aimed at identifying IGFBP7-encoded peptide presented by HLA-A2.1. Methods: In our study, a HLA-A2.1 restricted CTL epitope was identified by using the following two-step procedure: (a) computer-based epitope prediction from the amino acid sequence of IGFBP7 antigen; (b) Validation with epitope molecular modeling. Results: We obtained four epitopes with high immunogenicity scores by all of the three algorithms, i.e., BIMAS, SYFPEITHI and IMTECH. Each of the four candidates satisfied the criteria of the HLA-A2.1-restricted CTL epitopes in molecular modeling analysis. Conclusion: The combination of BIMAS, SYFPEITHI and IMTECH method can improve the prediction efficiency and accuracy. Due to this research herein, this four epitopes have potential value for further studied, also have potential application in peptide-mediated immunotherapy. These epitopes may be useful in the design of therapeutic peptide vaccine for lung carcinoma and as immunotherapeutic strategies against lung carcinoma after identified by immunology experiment.

  5. Is There a Role for HTLV-1-Specific CTL in Adult T-Cell Leukemia/Lymphoma?

    Directory of Open Access Journals (Sweden)

    Aileen G. Rowan

    2012-01-01

    Full Text Available ATLL is an aggressive malignancy of T cells that affects about 5% of individuals infected with HTLV-1. The precise mechanism of oncogenesis is not known, but there is evidence that two regulatory viral proteins, Tax and HBZ, are involved. A high set point proviral load is associated with development of ATLL or a chronic inflammatory condition, HAM/TSP. Several lines of evidence, including HLA class 1 association studies and in vitro killing assays, indicate that cytotoxic T lymphocytes are instrumental in determining this proviral load set point. Prior studies have focused chiefly on the CTL response to the immunodominant Tax protein: efficient lysis of Tax-expressing cells inversely correlates with proviral load in nonmalignant infection. However, a recent study showed that strong binding of peptides from HBZ, but not Tax, to HLA class 1 molecules was associated with a low proviral load and a reduced risk of developing HAM/TSP, indicating an important role for HBZ-specific CTL in determining infection outcome. In comparison with nonmalignant infection, HTLV-1-specific CTLs in ATLL patients are reduced in frequency and functionally deficient. Here we discuss the nature of protective CTL responses in nonmalignant HTLV-1 infection and explore the potential of CTLs to protect against ATLL.

  6. CTL responses of high functional avidity and broad variant cross-reactivity are associated with HIV control.

    Directory of Open Access Journals (Sweden)

    Beatriz Mothe

    Full Text Available Cytotoxic T lymphocyte (CTL responses targeting specific HIV proteins, in particular Gag, have been associated with relative control of viral replication in vivo. However, Gag-specific CTL can also be detected in individuals who do not control the virus and it remains thus unclear how Gag-specific CTL may mediate the beneficial effects in some individuals but not in others. Here, we used a 10mer peptide set spanning HIV Gag-p24 to determine immunogen-specific T-cell responses and to assess functional properties including functional avidity and cross-reactivity in 25 HIV-1 controllers and 25 non-controllers without protective HLA class I alleles. Our data challenge the common belief that Gag-specific T cell responses dominate the virus-specific immunity exclusively in HIV-1 controllers as both groups mounted responses of comparable breadths and magnitudes against the p24 sequence. However, responses in controllers reacted to lower antigen concentrations and recognized more epitope variants than responses in non-controllers. These cross-sectional data, largely independent of particular HLA genetics and generated using direct ex-vivo samples thus identify T cell responses of high functional avidity and with broad variant reactivity as potential functional immune correlates of relative HIV control.

  7. Promiscuous CTL recognition of viral epitopes on multiple human leukocyte antigens: biological validation of the proposed HLA A24 supertype.

    Science.gov (United States)

    Burrows, Scott R; Elkington, Rebecca A; Miles, John J; Green, Katherine J; Walker, Susan; Haryana, Sofia M; Moss, Denis J; Dunckley, Heather; Burrows, Jacqueline M; Khanna, Rajiv

    2003-08-01

    Multiple HLA class I alleles can bind peptides with common sequence motifs due to structural similarities in the peptide binding cleft, and these groups of alleles have been classified into supertypes. Nine major HLA supertypes have been proposed, including an A24 supertype that includes A*2301, A*2402, and A*3001. Evidence for this A24 supertype is limited to HLA sequence homology and/or similarity in peptide binding motifs for the alleles. To investigate the immunological relevance of this proposed supertype, we have examined two viral epitopes (from EBV and CMV) initially defined as HLA-A*2301-binding peptides. The data clearly demonstrate that each peptide could be recognized by CTL clones in the context of A*2301 or A*2402; thus validating the inclusion of these three alleles within an A24 supertype. Furthermore, CTL responses to the EBV epitope were detectable in both A*2301(+) and A*2402(+) individuals who had been previously exposed to this virus. These data substantiate the biological relevance of the A24 supertype, and the identification of viral epitopes with the capacity to bind promiscuously across this supertype could aid efforts to develop CTL-based vaccines or immunotherapy. The degeneracy in HLA restriction displayed by some T cells in this study also suggests that the dogma of self-MHC restriction needs some refinement to accommodate foreign peptide recognition in the context of multiple supertype alleles.

  8. CTL epitopes for influenza A including the H5N1 bird flu; genome-, pathogen-, and HLA-wide screening.

    Science.gov (United States)

    Wang, Mingjun; Lamberth, Kasper; Harndahl, Mikkel; Røder, Gustav; Stryhn, Anette; Larsen, Mette V; Nielsen, Morten; Lundegaard, Claus; Tang, Sheila T; Dziegiel, Morten H; Rosenkvist, Jørgen; Pedersen, Anders E; Buus, Søren; Claesson, Mogens H; Lund, Ole

    2007-04-12

    The purpose of the present study is to perform a global screening for new immunogenic HLA class I (HLA-I) restricted cytotoxic T cell (CTL) epitopes of potential utility as candidates of influenza A-virus diagnostics and vaccines. We used predictions of antigen processing and presentation, the latter encompassing 12 different HLA class I supertypes with >99% population coverage, and searched for conserved epitopes from available influenza A viral protein sequences. Peptides corresponding to 167 predicted peptide-HLA-I interactions were synthesized, tested for peptide-HLA-I interactions in a biochemical assay and for influenza-specific, HLA-I-restricted CTL responses in an IFN-gamma ELISPOT assay. Eighty-nine peptides could be confirmed as HLA-I binders, and 13 could be confirmed as CTL targets. The 13 epitopes, are highly conserved among human influenza A pathogens, and all of these epitopes are present in the emerging bird flu isolates. Our study demonstrates that present technology enables a fast global screening for T cell immune epitopes of potential diagnostics and vaccine interest. This technology includes immuno-bioinformatics predictors with the capacity to perform fast genome-, pathogen-, and HLA-wide searches for immune targets. To exploit this new potential, a coordinated international effort to analyze the precious source of information represented by rare patients, such as the current victims of bird flu, would be essential.

  9. Induction of protective anti-CTL epitope responses against HER-2-positive breast cancer based on multivalent T7 phage nanoparticles.

    Directory of Open Access Journals (Sweden)

    Somayeh Pouyanfard

    Full Text Available We report here the development of multivalent T7 bacteriophage nanoparticles displaying an immunodominant H-2k(d-restricted CTL epitope derived from the rat HER2/neu oncoprotein. The immunotherapeutic potential of the chimeric T7 nanoparticles as anti-cancer vaccine was investigated in BALB/c mice in an implantable breast tumor model. The results showed that T7 phage nanoparticles confer a high immunogenicity to the HER-2-derived minimal CTL epitope, as shown by inducing robust CTL responses. Furthermore, the chimeric nanoparticles protected mice against HER-2-positive tumor challenge in both prophylactic and therapeutic setting. In conclusion, these results suggest that CTL epitope-carrying T7 phage nanoparticles might be a promising approach for development of T cell epitope-based cancer vaccines.

  10. Martian Atmospheric and Ionospheric plasma Escape

    Science.gov (United States)

    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

  11. Influenza A virus hemagglutinin antibody escape promotes neuraminidase antigenic variation and drug resistance.

    Directory of Open Access Journals (Sweden)

    Scott E Hensley

    Full Text Available Drugs inhibiting the influenza A virus (IAV neuraminidase (NA are the cornerstone of anti-IAV chemotherapy and prophylaxis in man. Drug-resistant mutations in NA arise frequently in human isolates, limiting the therapeutic application of NA inhibitors. Here, we show that antibody-driven antigenic variation in one domain of the H1 hemagglutinin Sa site leads to compensatory mutations in NA, resulting in NA antigenic variation and acquisition of drug resistance. These findings indicate that influenza A virus resistance to NA inhibitors can potentially arise from antibody driven HA escape, confounding analysis of influenza NA evolution in nature.

  12. Do the visual conditions at the point of escape affect European sea bass escape behavior?

    Directory of Open Access Journals (Sweden)

    I.E. PAPADAKIS

    2013-04-01

    Full Text Available European sea bass (Dicentrarchus labrax, an important species for the Mediterranean aquaculture industry, has been reported to escape from sea cage installations. Fish escapes are caused mainly by operational and technical failures that eventually result into a creation of a tear. Escapees may interact with wild stocks through interbreeding, transfer of pathogens and competition for food. The aim of this study was to examine at which extent the presence of a visible obstacle close to a tear on the net have an influence on sea bass propensity to escape. Fish were initially confined into small sea cages, with a tear at one side. The escape behavior was tested under experimental conditions. It is clearly demonstrated that sea bass was able to locate a tear on the net pen, immediately after its appearance. Crossings occurred in all cages, in singles or in a series of up to seven individuals. The presence of an obstacle close to the net tear altered the escape behavior of D. labrax resulting in a delay that eventually reduced the escape rate. Concluding, it is highly recommended that sea bass cages should be kept internally the culture array. Furthermore, the placement of artificial obstacles close to the sea cages could be an efficient practice that mitigates the escape risk after severe environmental conditions.

  13. Do the visual conditions at the point of escape affect European sea bass escape behavior?

    Directory of Open Access Journals (Sweden)

    I.E. PAPADAKIS

    2013-03-01

    Full Text Available European sea bass (Dicentrarchus labrax, an important species for the Mediterranean aquaculture industry, has been reported to escape from sea cage installations. Fish escapes are caused mainly by operational and technical failures that eventually result into a creation of a tear. Escapees may interact with wild stocks through interbreeding, transfer of pathogens and competition for food. The aim of this study was to examine at which extent the presence of a visible obstacle close to a tear on the net have an influence on sea bass propensity to escape. Fish were initially confined into small sea cages, with a tear at one side. The escape behavior was tested under experimental conditions. It is clearly demonstrated that sea bass was able to locate a tear on the net pen, immediately after its appearance. Crossings occurred in all cages, in singles or in a series of up to seven individuals. The presence of an obstacle close to the net tear altered the escape behavior of D. labrax resulting in a delay that eventually reduced the escape rate. Concluding, it is highly recommended that sea bass cages should be kept internally the culture array. Furthermore, the placement of artificial obstacles close to the sea cages could be an efficient practice that mitigates the escape risk after severe environmental conditions.

  14. Preferential CTL targeting of Gag is associated with relative viral control in long-term surviving HIV-1 infected former plasma donors from China

    Institute of Scientific and Technical Information of China (English)

    Mingming Jia; Quanbi Zhao; Dan Li; Hong Peng; Marcus Altfeld; Bruce D Walker; Xu G Yu; Yiming Shao; Kunxue Hong; Jianping Chen; Yuhua Ruan; Zhe Wang; Bing Su; Guoliang Ren; Xiaoqing Zhang; Zhen Liu

    2012-01-01

    It is generally believed that CD8+ cytotoxic T lymphocytes (CTLs) play a critical role in limiting the replication of human immunodeficiency virus type 1 (HIV-1) and in determining the outcome of the infection,and this effect may partly depend on which HIV product is preferentially targeted.To address the correlation between HIV-1-specific CTL responses and virus replication in a cohort of former plasma donors (FPDs),143 antiretroviral therapy naive FPDs infected with HIV-1 clade B' strains were assessed for HIV-1-specific CTL responses with an IFN-γElispot assay at single peptide level by using overlapping peptides (OLPs) covering the whole consensus clade B proteome.By using a Spearman's rank correlation analysis,we found that the proportion of Gag-specific CTL responses among the total virus-specific CTL activity was inversely correlated with viral loads while being positively correlated to CD4 counts,as opposed to Pol- and Env-specific responses that were associated with increased viral loads and decreased CD4 counts,In addition,Vpr-specifc CTL responses showed a similar protective effect with Gag responses,but with a much lower frequency of recognition.Significantly,we also observed an association between HLA-A*30/B*13/Cw*06 haplotype and lower viral loads that was probably due to restricted Gag-specific CTL responses.Thus,our data demonstrate the prominent role of Gag-specific CTL responses in disease control.The advantage of HLA-A*30/B*13/Cw*06 haplotype in viral control may be associated with the contribution of Gag-specific CTL responses in the studied individuals.

  15. Do HIV-specific CTL continue to have an antiviral function during antiretroviral therapy? If not, why not, and what can be done about it?

    OpenAIRE

    Dorian eMcIlroy

    2013-01-01

    Pharmacological re-activation of HIV expression from latent proviruses coupled with fully suppressive anti-retroviral therapy (ART) has been suggested as a strategy to eradicate HIV infection. In order for this strategy to be effective, latently infected cells must be killed either by the cytopathic effect of reactivated HIV gene expression, or by HIV-specific CTL. However, a review of current data reveals little evidence that CTL retain an anti-viral effector capacity in patients on fully su...

  16. An integrative approach to CTL epitope prediction: A combined algorithm integrating MHC class I binding, TAP transport efficiency, and proteasomal cleavage predictions

    DEFF Research Database (Denmark)

    Larsen, Mette Voldby; Lundegaard, Claus; Lamberth, K;

    2005-01-01

    Reverse immunogenetic approaches attempt to optimize the selection of candidate epitopes, and thus minimize the experimental effort needed to identify new epitopes. When predicting cytotoxic T cell epitopes, the main focus has been on the highly specific MHC class I binding event. Methods have al.......The method is available at http://www.cbs.dtu.dk/services/NetCTL. Supplementary material is available at http://www.cbs.dtu.dk/suppl/immunology/CTL.php....

  17. Learning from escaped prescribed fire reviews

    Science.gov (United States)

    Anne E. Black; Dave Thomas; James Saveland; Jennifer D. Ziegler

    2011-01-01

    The U.S. wildland fire community has developed a number of innovative methods for conducting a review following escape of a prescribed fire (expanding on the typical regional or local reviews, to include more of a learning focus - expanded After Action Reviews, reviews that incorporate High Reliability Organizing, Facilitated Learning Analyses, etc). The stated purpose...

  18. Centrifugally Stimulated Exospheric Ion Escape at Mercury

    Science.gov (United States)

    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.

  19. Net escapement of Antartic krill in trawls

    DEFF Research Database (Denmark)

    Krafft, B.A.; Krag, Ludvig Ahm; Herrmann, Bent;

    This document describes the aims and methodology of a three year project (commenced in 2012) entitled Net Escapement of Antarctic krill in Trawls (NEAT). The study will include a morphology based mathematical modeling (FISHSELECT) of different sex and maturity groups of Antarctic krill (Euphausia...

  20. Nociception and escape behavior in planarians

    Science.gov (United States)

    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.

  1. Do HIV-specific CTL continue to have an antiviral function during antiretroviral therapy? If not, why not, and what can be done about it?

    Directory of Open Access Journals (Sweden)

    Dorian eMcIlroy

    2013-03-01

    Full Text Available Pharmacological re-activation of HIV expression from latent proviruses coupled with fully suppressive anti-retroviral therapy (ART has been suggested as a strategy to eradicate HIV infection. In order for this strategy to be effective, latently infected cells must be killed either by the cytopathic effect of reactivated HIV gene expression, or by HIV-specific CTL. However, a review of current data reveals little evidence that CTL retain an anti-viral effector capacity in patients on fully suppressive ART, implying that the HIV-specific CTL present in these patients will not be able to eliminate HIV-infected CD4+ T-cells effectively. If this is due to functional impairment or a quantitative deficit of HIV-specific CTL during ART, then therapeutic vaccination may improve the prospects for eradicating latent reservoirs. However, data from the macaque SIV model indicate that in vivo, SIV-specific CTL are only effective during the early stages of the viral replication cycle, and this constitutes an alternative explanation why HIV-specific CTL do not appear to have an impact on HIV reservoirs during ART. In that case, immunotoxins that target HIV-expressing cells may be a more promising approach for HIV eradication.

  2. Enhancing the cellulose-degrading activity of cellulolytic bacteria CTL-6 (Clostridium thermocellum) by co-culture with non-cellulolytic bacteria W2-10 (Geobacillus sp.).

    Science.gov (United States)

    Lü, Yucai; Li, Ning; Yuan, Xufeng; Hua, Binbin; Wang, Jungang; Ishii, Masaharu; Igarashi, Yasuo; Cui, Zongjun

    2013-12-01

    The effect of a non-cellulolytic bacterium W2-10 (Geobacillus sp.) on the cellulose-degrading activity of a cellulolytic bacterium CTL-6 (Clostridium thermocellum) was determined using cellulose materials (paper and straw) in peptone cellulose solution (PCS) medium under aerobic conditions. The results indicated that in the co-culture, addition of W2-10 resulted in a balanced medium pH, and may provide the required anaerobic environment for CTL-6. Overall, addition of W2-10 was beneficial to CTL-6 growth in the adverse environment of the PCS medium. In co-culture with W2-10, the CTL-6 cellulose degradation efficiency of filter paper and alkaline-treated wheat straw significantly increased up to 72.45 and 37.79 %, respectively. The CMCase activity and biomass of CTL-6 also increased from 0.23 U ml(-1) and 45.1 μg ml(-1) (DNA content) up to 0.47 U ml(-1) and 112.2 μg ml(-1), respectively. In addition, co-culture resulted in accumulation of acetate and propionate up to 4.26 and 2.76 mg ml(-1). This was a respective increase of 2.58 and 4.45 times, in comparison to the monoculture with CTL-6.

  3. T-cell receptor (TCR) phenotype of nodal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (CTL): a clinicopathologic study of 39 cases.

    Science.gov (United States)

    Kato, Seiichi; Asano, Naoko; Miyata-Takata, Tomoko; Takata, Katsuyoshi; Elsayed, Ahmed Ali; Satou, Akira; Takahashi, Emiko; Kinoshita, Tomohiro; Nakamura, Shigeo

    2015-04-01

    Among Epstein-Barr virus (EBV)-positive cytotoxic T/NK-cell lymphoma, there are only a few reports on the clinicopathologic features of patients with primary nodal presentation (nodal EBV cytotoxic T-cell lymphoma [CTL]). Here, we compared the clinicopathologic profiles of 39 patients with nodal EBV CTL with those of 27 cases of "extranasal" NK/T-cell lymphoma of nasal type (ENKTL), especially addressing their T-cell receptor (TCR) phenotype. Histologically, 22 of 39 nodal EBV CTL cases (56%) were unique in having centroblastoid appearance, which was contrasted with the lower incidence of this feature in ENKTL (15%, P=0.001). In contrast, pleomorphic appearance was more frequently seen in ENKTL than in nodal EBV CTL (67% vs. 23%, P=0.001). Thirty-three of 39 nodal EBV CTL cases (85%) were of T-cell lineage on the basis of TCR expression and/or TCRγ gene rearrangement; in detail, 18 cases (46%) were TCRβ positive (αβ T), 5 (13%) were TCRγ and/or δ positive (γδ T), and 10 (26%) were TCR-silent type with clonal TCRγ gene rearrangement but no expression of TCRβ, γ, or δ. These results were clearly contrasted by a lower incidence of T-cell lineage in ENKTL (7 cases, 26%, PEBV CTL is distinct from ENKTL.

  4. Therapeutic polypeptides based on HBV core 18-27 epitope can induce CD8+ CTL-mediated cytotoxicity in HLA-A2+ human PBMCs

    Institute of Scientific and Technical Information of China (English)

    Tong-Dong Shi; Yu-Zhang Wu; Zheng-Cai Jia; Li-Yun Zou; Wei Zhou

    2004-01-01

    AIM: To explore how to improve the immunogenicity of HBcAg CTL epitope based polypeptides and to trigger an HBV-specific HLA I-restricted CD8+ T cell response in vitro.METHODS: A new panel of mimetic therapeutic peptides based on the immunodominant B cell epitope of HBV PreS218-24 region, the CTL epitope of HBcAg18-27 and the universal T helper epitope of tetanus toxoid (TT) 830-843was designed using computerized molecular design method and synthesized by Merrifield's solid-phase peptide synthesis.Their immunological properties of stimulating activation and proliferation of lymphocytes, of inducing TH1 polarization,CD8+ T cell magnification and HBV-specific CD8+ CTL mediated cytotoxicity were investigatedin vitro using HLAA2+ human peripheral blood mononuclear cells (PBMCs) from healthy donors and chronic hepatitis B patients.RESULTS: Results demonstrated that the therapeutic polypeptides based on immunodominant HBcAg18-27 CTL,PreS2 B- and universal TH epitopes could stimulate the activation and proliferation of lymphocytes, induce specifically and effectively CD8+ T cell expansion and vigorous HBVspecific CTL-mediated cytotoxicity in human PBMCs.CONCLUSION: It indicated that the introduction of immunodominant T helper plus B-epitopes with short and flexible linkers could dramatically improve the immunogenicity of short CTL epitopes in vitro.

  5. The Escape of Cancer from T Cell-Mediated Immune Surveillance: HLA Class I Loss and Tumor Tissue Architecture

    Science.gov (United States)

    Garrido, Federico; Perea, Francisco; Bernal, Mónica; Sánchez-Palencia, Abel; Aptsiauri, Natalia; Ruiz-Cabello, Francisco

    2017-01-01

    Tumor immune escape is associated with the loss of tumor HLA class I (HLA-I) expression commonly found in malignant cells. Accumulating evidence suggests that the efficacy of immunotherapy depends on the expression levels of HLA class I molecules on tumors cells. It also depends on the molecular mechanism underlying the loss of HLA expression, which could be reversible/“soft” or irreversible/“hard” due to genetic alterations in HLA, β2-microglobulin or IFN genes. Immune selection of HLA-I negative tumor cells harboring structural/irreversible alterations has been demonstrated after immunotherapy in cancer patients and in experimental cancer models. Here, we summarize recent findings indicating that tumor HLA-I loss also correlates with a reduced intra-tumor T cell infiltration and with a specific reorganization of tumor tissue. T cell immune selection of HLA-I negative tumors results in a clear separation between the stroma and the tumor parenchyma with leucocytes, macrophages and other mononuclear cells restrained outside the tumor mass. Better understanding of the structural and functional changes taking place in the tumor microenvironment may help to overcome cancer immune escape and improve the efficacy of different immunotherapeutic strategies. We also underline the urgent need for designing strategies to enhance tumor HLA class I expression that could improve tumor rejection by cytotoxic T-lymphocytes (CTL). PMID:28264447

  6. PD-L1 Expression on Retrovirus-Infected Cells Mediates Immune Escape from CD8+ T Cell Killing.

    Directory of Open Access Journals (Sweden)

    Ilseyar Akhmetzyanova

    2015-10-01

    Full Text Available Cytotoxic CD8+ T Lymphocytes (CTL efficiently control acute virus infections but can become exhausted when a chronic infection develops. Signaling of the inhibitory receptor PD-1 is an important mechanism for the development of virus-specific CD8+ T cell dysfunction. However, it has recently been shown that during the initial phase of infection virus-specific CD8+ T cells express high levels of PD-1, but are fully competent in producing cytokines and killing virus-infected target cells. To better understand the role of the PD-1 signaling pathway in CD8+ T cell cytotoxicity during acute viral infections we analyzed the expression of the ligand on retrovirus-infected cells targeted by CTLs. We observed increased levels of PD-L1 expression after infection of cells with the murine Friend retrovirus (FV or with HIV. In FV infected mice, virus-specific CTLs efficiently eliminated infected target cells that expressed low levels of PD-L1 or that were deficient for PD-L1 but the population of PD-L1high cells escaped elimination and formed a reservoir for chronic FV replication. Infected cells with high PD-L1 expression mediated a negative feedback on CD8+ T cells and inhibited their expansion and cytotoxic functions. These findings provide evidence for a novel immune escape mechanism during acute retroviral infection based on PD-L1 expression levels on virus infected target cells.

  7. The Escape of Cancer from T Cell-Mediated Immune Surveillance: HLA Class I Loss and Tumor Tissue Architecture

    Directory of Open Access Journals (Sweden)

    Federico Garrido

    2017-02-01

    Full Text Available Tumor immune escape is associated with the loss of tumor HLA class I (HLA-I expression commonly found in malignant cells. Accumulating evidence suggests that the efficacy of immunotherapy depends on the expression levels of HLA class I molecules on tumors cells. It also depends on the molecular mechanism underlying the loss of HLA expression, which could be reversible/“soft” or irreversible/“hard” due to genetic alterations in HLA, β2-microglobulin or IFN genes. Immune selection of HLA-I negative tumor cells harboring structural/irreversible alterations has been demonstrated after immunotherapy in cancer patients and in experimental cancer models. Here, we summarize recent findings indicating that tumor HLA-I loss also correlates with a reduced intra-tumor T cell infiltration and with a specific reorganization of tumor tissue. T cell immune selection of HLA-I negative tumors results in a clear separation between the stroma and the tumor parenchyma with leucocytes, macrophages and other mononuclear cells restrained outside the tumor mass. Better understanding of the structural and functional changes taking place in the tumor microenvironment may help to overcome cancer immune escape and improve the efficacy of different immunotherapeutic strategies. We also underline the urgent need for designing strategies to enhance tumor HLA class I expression that could improve tumor rejection by cytotoxic T-lymphocytes (CTL.

  8. Life events and escape in conversion disorder.

    Science.gov (United States)

    Nicholson, T R; Aybek, S; Craig, T; Harris, T; Wojcik, W; David, A S; Kanaan, R A

    2016-09-01

    Psychological models of conversion disorder (CD) traditionally assume that psychosocial stressors are identifiable around symptom onset. In the face of limited supportive evidence such models are being challenged. Forty-three motor CD patients, 28 depression patients and 28 healthy controls were assessed using the Life Events and Difficulties Schedule in the year before symptom onset. A novel 'escape' rating for events was developed to test the Freudian theory that physical symptoms of CD could provide escape from stressors, a form of 'secondary gain'. CD patients had significantly more severe life events and 'escape' events than controls. In the month before symptom onset at least one severe event was identified in 56% of CD patients - significantly more than 21% of depression patients [odds ratio (OR) 4.63, 95% confidence interval (CI) 1.56-13.70] and healthy controls (OR 5.81, 95% CI 1.86-18.2). In the same time period 53% of CD patients had at least one 'high escape' event - again significantly higher than 14% in depression patients (OR 6.90, 95% CI 2.05-23.6) and 0% in healthy controls. Previous sexual abuse was more commonly reported in CD than controls, and in one third of female patients was contextually relevant to life events at symptom onset. The majority (88%) of life events of potential aetiological relevance were not identified by routine clinical assessments. Nine per cent of CD patients had no identifiable severe life events. Evidence was found supporting the psychological model of CD, the Freudian notion of escape and the potential aetiological relevance of childhood traumas in some patients. Uncovering stressors of potential aetiological relevance requires thorough psychosocial evaluation.

  9. Dynamical correlations in the escape strategy of Influenza A virus

    Science.gov (United States)

    Taggi, L.; Colaiori, F.; Loreto, V.; Tria, F.

    2013-03-01

    The evolutionary dynamics of human Influenza A virus presents a challenging theoretical problem. An extremely high mutation rate allows the virus to escape, at each epidemic season, the host immune protection elicited by previous infections. At the same time, at each given epidemic season a single quasi-species, that is a set of closely related strains, is observed. A non-trivial relation between the genetic (i.e., at the sequence level) and the antigenic (i.e., related to the host immune response) distances can shed light into this puzzle. In this paper we introduce a model in which, in accordance with experimental observations, a simple interaction rule based on spatial correlations among point mutations dynamically defines an immunity space in the space of sequences. We investigate the static and dynamic structure of this space and we discuss how it affects the dynamics of the virus-host interaction. Interestingly we observe a staggered time structure in the virus evolution as in the real Influenza evolutionary dynamics.

  10. Timing constraints of in vivo gag mutations during primary HIV-1 subtype C infection.

    Directory of Open Access Journals (Sweden)

    Vladimir Novitsky

    Full Text Available BACKGROUND: Aiming to answer the broad question "When does mutation occur?" this study examined the time of appearance, dominance, and completeness of in vivo Gag mutations in primary HIV-1 subtype C infection. METHODS: A primary HIV-1C infection cohort comprised of 8 acutely and 34 recently infected subjects were followed frequently up to 500 days post-seroconversion (p/s. Gag mutations were analyzed by employing single-genome amplification and direct sequencing. Gag mutations were determined in relation to the estimated time of seroconversion. Time of appearance, dominance, and completeness was compared for different types of in vivo Gag mutations. RESULTS: Reverse mutations to the wild type appeared at a median (IQR of 62 (44;139 days p/s, while escape mutations from the wild type appeared at 234 (169;326 days p/s (p<0.001. Within the subset of mutations that became dominant, reverse and escape mutations appeared at 54 (30;78 days p/s and 104 (47;198 days p/s, respectively (p<0.001. Among the mutations that reached completeness, reverse and escape mutations appeared at 54 (30;78 days p/s and 90 (44;196 days p/s, respectively (p=0.006. Time of dominance for reverse mutations to and escape mutations from the wild type was 58 (44;105 days p/s and 219 (90;326 days p/s, respectively (p<0.001. Time of completeness for reverse and escape mutations was 152 (100;176 days p/s and 243 (101;370 days p/s, respectively (p=0.001. Fitting a Cox proportional hazards model with frailties confirmed a significantly earlier time of appearance (hazard ratio (HR: 2.6; 95% CI: 2.3-3.0, dominance (4.8 (3.4-6.8, and completeness (3.6 (2.3-5.5 of reverse mutations to the wild type Gag than escape mutations from the wild type. Some complex mutational pathways in Gag included sequential series of reversions and escapes. CONCLUSIONS: The study identified the timing of different types of in vivo Gag mutations in primary HIV-1 subtype C infection in relation to the

  11. Launch Pad Escape System Design (Human Spaceflight)

    Science.gov (United States)

    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

  12. Emergence of Ebola Virus Escape Variants in Infected Nonhuman Primates Treated with the MB-003 Antibody Cocktail.

    Science.gov (United States)

    Kugelman, Jeffrey R; Kugelman-Tonos, Johanny; Ladner, Jason T; Pettit, James; Keeton, Carolyn M; Nagle, Elyse R; Garcia, Karla Y; Froude, Jeffrey W; Kuehne, Ana I; Kuhn, Jens H; Bavari, Sina; Zeitlin, Larry; Dye, John M; Olinger, Gene G; Sanchez-Lockhart, Mariano; Palacios, Gustavo F

    2015-09-29

    MB-003, a plant-derived monoclonal antibody cocktail used effectively in treatment of Ebola virus infection in non-human primates, was unable to protect two of six animals when initiated 1 or 2 days post-infection. We characterized a mechanism of viral escape in one of the animals, after observation of two clusters of genomic mutations that resulted in five nonsynonymous mutations in the monoclonal antibody target sites. These mutations were linked to a reduction in antibody binding and later confirmed to be present in a viral isolate that was not neutralized in vitro. Retrospective evaluation of a second independent study allowed the identification of a similar case. Four SNPs in previously identified positions were found in this second fatality, suggesting that genetic drift could be a potential cause for treatment failure. These findings highlight the importance selecting different target domains for each component of the cocktail to minimize the potential for viral escape.

  13. Convergent evolution of escape from hepaciviral antagonism in primates.

    Science.gov (United States)

    Patel, Maulik R; Loo, Yueh-Ming; Horner, Stacy M; Gale, Michael; Malik, Harmit S

    2012-01-01

    The ability to mount an interferon response on sensing viral infection is a critical component of mammalian innate immunity. Several viruses directly antagonize viral sensing pathways to block activation of the host immune response. Here, we show that recurrent viral antagonism has shaped the evolution of the host protein MAVS--a crucial component of the viral-sensing pathway in primates. From sequencing and phylogenetic analyses of MAVS from 21 simian primates, we found that MAVS has evolved under strong positive selection. We focused on how this positive selection has shaped MAVS' susceptibility to Hepatitis C virus (HCV). We functionally tested MAVS proteins from diverse primate species for their ability to resist antagonism by HCV, which uses its protease NS3/4A to cleave human MAVS. We found that MAVS from multiple primates are resistant to inhibition by the HCV protease. This resistance maps to single changes within the protease cleavage site in MAVS, which protect MAVS from getting cleaved by the HCV protease. Remarkably, most of these changes have been independently acquired at a single residue 506 that evolved under positive selection. We show that "escape" mutations lower affinity of the NS3 protease for MAVS and allow it to better restrict HCV replication. We further show that NS3 proteases from all other primate hepaciviruses, including the highly divergent GBV-A and GBV-C viruses, are functionally similar to HCV. We conclude that convergent evolution at residue 506 in multiple primates has resulted in escape from antagonism by hepaciviruses. Our study provides a model whereby insights into the ancient history of viral infections in primates can be gained using extant host and virus genes. Our analyses also provide a means by which primates might clear infections by extant hepaciviruses like HCV.

  14. Conflicting selective forces affect T cell receptor contacts in an immunodominant human immunodeficiency virus epitope

    DEFF Research Database (Denmark)

    Iversen, Astrid K N; Stewart-Jones, Guillaume; Learn, Gerald H

    2006-01-01

    Cytotoxic T lymphocytes (CTLs) are critical for the control of human immunodeficiency virus, but containment of virus replication can be undermined by mutations in CTL epitopes that lead to virus escape. We analyzed the evolution in vivo of an immunodominant, HLA-A2-restricted CTL epitope and fou...

  15. The escape problem for mortal walkers

    CERN Document Server

    Grebenkov, D S

    2016-01-01

    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. This is also a mathematical ground for optimizing stor...

  16. The Escaping Upper Atmospheres of Hot Jupiters

    Science.gov (United States)

    Davidson, Eric; Jones, Gabrielle; Uribe, Ana; Carson, Joseph

    2017-01-01

    Hot Jupiters are massive gaseous planets which orbit closely to their parent star. The strong stellar irradiation at these small orbital separations causes the temperature of the upper atmosphere of the planet to rise. This can cause the planet's atmosphere to escape into space, creating an exoplanet outflow. We ascertained which factors determine the presence and structure of these outflows by creating one dimensional simulations of the density, pressure, velocity, optical depth, and neutral fraction of hot Jupiter atmospheres. This was done for planets of masses and radii ranging from 0.5-1.5 Mj and 0.5-1.5 Rj. We found the outflow rate to be highest for a planet of 0.5 Mj and 1.5 Rj at 5.3×10-14 Mj/Yr. We also found that the higher the escape velocity, the lower the chance of the planet having an outflow.

  17. Escape and Stand of the Pluto Atmosphere

    Institute of Scientific and Technical Information of China (English)

    GAO Chong-Yi

    2002-01-01

    Molar mass μmin of the lightest gas, which will exist "forever" in the atmosphere at the planet surface,can be evaluated by Jeans rule. The μmin of Pluto is 17.3 g@ mol-1. It is evident that both N2 and CO can be major atmospheric composition at the Pluto surface, and will exist "forever". CH4 can only be escaping slowly from Pluto atmosphere, and still holds quite a proportion in current Pluto atmosphere. However, it will not escape from Titan (or Jupiter, Saturn) atmosphere largely, and will exist "forever". Given the quantitylevelof partial pressure of CH4 in Pluto and Titan (or Jupiter, Saturn) original atmosphere is the same, it will be clear that the current partial pressure of CH4 in Pluto surface atmosphere is 10-3 Pa.

  18. ENDOGENOUS EXPRESSION AND HLA STABILIZATION ASSAY OF PLASMODIUM FALCIPARUM CTL EPITOPE MINIGENE IN HUMAN HLA-A2.1 AND HLA-B51 CELLS

    Institute of Scientific and Technical Information of China (English)

    唐玉阳; 王恒

    2001-01-01

    Objective. To evaluate the Plasmodium falciparum CTL epitope vaccines in HLA class I allele specific human cell lines that have high frequency among Chinese population. Methods. Synthesized oligonucleotides encoding for P.f. CTL epitope genes, constructed eukaryotic expression plasmids, transfected the minigenes into HLA class I allele specific human cell lines and identified endogenous expressing of the minigenes by RT-PCR and HLA stabilization assay. Results. Two mini-genes encoding Plasmodium falciparum CTL epitopes were designed and cloned, respectively, into an eukaryotic expressing vector to form TR26 which was restricted to HLA-B51, SH6 which was restricted to HLA-A2.1, and TS, which had the two aforementioned mini-genes fused in tandem. All of these CTL epitope genes were transfected and endogenously expressed in respective cell lines containing appropriate HLA molecules. The obviously increased expressions of HLA class I molecules were detected in the transfected cell lines. It was demonstrated that the two discrete Plasmodium falciparum epitope genes were effectively processed and presented, and the close proximity of the two epitope genes in one chain as in mini-gene TS did not interfere with the processing and presenting of each epitope gene in corresponding cell line. Conclusion. A successful expression and presentation of multiple CTL epitope mini-gene in MHC class I allele specific human cell lines were demonstrated by an in vitro assay, which could be corresponding to the vaccination of CTL vaccines in people with different MHC I molecules. This work also suggested the possibility of constructing a multiple CTL epitope plasmodium falciparum DNA vaccine that could cover most of Chinese population.

  19. Effects of submarine escape training on the pulmonary function and carbon dioxide retention in the escape

    Institute of Scientific and Technical Information of China (English)

    CHEN Rui-yong; WANG Wen-bo; FANG Yi-qun; XU Ji; XU Lin-jun

    2011-01-01

    Objective Fast buoyancy ascent escape used in submarine escape is the most probable choice of survival in case of a submarine accident.Rate of success for escape depends very much on the extent of training,in spite of the fact that rapid compression and decompression pose great challenges to the human body in terms of enormous stresses.To minimize stresses experienced during sub escape training has always been a research subject for us.Lungs are susceptible to rapid change in pressure during escape.Dynamic pulmonary function and the end-tidal PCO2 ( PETCO2 ) might be the best indicator for its effect on the pulmonary function of the submarine escapee.Methods Five male navy divers received submarine escape trainings,at different depths from 3-60 m.They were compressed at different rates (with pressure doubled every 20 s or 30 s),in the simulated submarine escape tower located in the Naval Medical Research Institute.The gas of end-expiration was collected immediately after escape,respiratory rate (RR) and dynamic pulmonary function were closely monitored,and PETCO2 was determined with the mass spectrometer.Results Experimental results showed that forced expiratory volume in 1 second (FEV1.0) tended to increase with increasing depth,and that it increased significantly at 50 m and 60 m,when compared with the basic data (P < 0.05 ),and it was coupled with a decrease in forced expiratory flow at 25 % ( FEF25% ),indicating that it had certain effect on the function of small airways.PETCO2 and RR all elevated markedly following escapes.No significant differences could be seen in RR following escapes at various depths.PETCO2 and depth ( r =0.387,P < 0.01 ) were positively correlated with compression rate ( r =0.459,P < 0.01 ) and RR ( r =0.467,P < 0.01 ).CO2 retention might be attributed to pulmonary ventilation disorder induced by rapid changes in pressure.PETCO2 was within normal range,following escapes at various depths,suggesting that increased RR might be

  20. Monoclonal antibody-escape variant of dengue virus serotype 1: Genetic composition and envelope protein expression.

    Science.gov (United States)

    Chem, Y K; Chua, K B; Malik, Y; Voon, K

    2015-06-01

    Monoclonal antibody-escape variant of dengue virus type 1 (MabEV DEN-1) was discovered and isolated in an outbreak of dengue in Klang Valley, Malaysia from December 2004 to March 2005. This study was done to investigate whether DEN152 (an isolate of MabEV DEN-1) is a product of recombination event or not. In addition, the non-synonymous mutations that correlate with the monoclonal antibody-escape variant were determined in this study. The genomes of DEN152 and two new DEN-1 isolates, DENB04 and DENK154 were completely sequenced, aligned, and compared. Phylogenetic tree was plotted and the recombination event on DEN152 was investigated. DEN152 is sub-grouped under genotype I and is closely related genetically to a DEN-1 isolated in Japan in 2004. DEN152 is not a recombinant product of any parental strains. Four amino acid substitutions were unique only to DEN 152. These amino acid substitutions were (Ser)[326](Leu), (Ser)[340](Leu) at the deduced E protein, (Ile)[250](Thr) at NS1 protein, and (Thr)[41](Ser) at NS5 protein. Thus, DEN152 is an isolate of the emerging monoclonal antibody-escape variant DEN-1 that escaped diagnostic laboratory detection.

  1. Identification of a Peptide-Pheromone that Enhances Listeria monocytogenes Escape from Host Cell Vacuoles

    Science.gov (United States)

    Xayarath, Bobbi; Alonzo, Francis; Freitag, Nancy E.

    2015-01-01

    Listeria monocytogenes is a Gram-positive facultative intracellular bacterial pathogen that invades mammalian cells and escapes from membrane-bound vacuoles to replicate within the host cell cytosol. Gene products required for intracellular bacterial growth and bacterial spread to adjacent cells are regulated by a transcriptional activator known as PrfA. PrfA becomes activated following L. monocytogenes entry into host cells, however the signal that stimulates PrfA activation has not yet been defined. Here we provide evidence for L. monocytogenes secretion of a small peptide pheromone, pPplA, which enhances the escape of L. monocytogenes from host cell vacuoles and may facilitate PrfA activation. The pPplA pheromone is generated via the proteolytic processing of the PplA lipoprotein secretion signal peptide. While the PplA lipoprotein is dispensable for pathogenesis, bacteria lacking the pPplA pheromone are significantly attenuated for virulence in mice and have a reduced efficiency of bacterial escape from the vacuoles of nonprofessional phagocytic cells. Mutational activation of PrfA restores virulence and eliminates the need for pPplA-dependent signaling. Experimental evidence suggests that the pPplA peptide may help signal to L. monocytogenes its presence within the confines of the host cell vacuole, stimulating the expression of gene products that contribute to vacuole escape and facilitating PrfA activation to promote bacterial growth within the cytosol. PMID:25822753

  2. Scrunching: a novel escape gait in planarians

    Science.gov (United States)

    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.

  3. Xenon Fractionation and Archean Hydrogen Escape

    Science.gov (United States)

    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.

  4. Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias.

    Science.gov (United States)

    Dunford, Andrew; Weinstock, David M; Savova, Virginia; Schumacher, Steven E; Cleary, John P; Yoda, Akinori; Sullivan, Timothy J; Hess, Julian M; Gimelbrant, Alexander A; Beroukhim, Rameen; Lawrence, Michael S; Getz, Gad; Lane, Andrew A

    2017-01-01

    There is a striking and unexplained male predominance across many cancer types. A subset of X-chromosome genes can escape X-inactivation, which would protect females from complete functional loss by a single mutation. To identify putative 'escape from X-inactivation tumor-suppressor' (EXITS) genes, we examined somatic alterations from >4,100 cancers across 21 tumor types for sex bias. Six of 783 non-pseudoautosomal region (PAR) X-chromosome genes (ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3) harbored loss-of-function mutations more frequently in males (based on a false discovery rate genes (Fisher's exact P genes that escape X-inactivation were observed in combined analysis across many cancers and in several individual tumor types, suggesting a generalized phenomenon. We conclude that biallelic expression of EXITS genes in females explains a portion of the reduced cancer incidence in females as compared to males across a variety of tumor types.

  5. Hydrodynamical Modeling of Hydrogen Escape from Rocky Planets

    Science.gov (United States)

    Barringer, Daniel; Zugger, M.; Kasting, J.

    2013-01-01

    Hydrogen escape affects both the composition of primitive atmospheres of terrestrial planets and the planet’s state of oxidation. On Mars, hydrogen escape played a critical role in how long the planet remained in a warm wet state amenable to life. For both solar and extrasolar planets, hydrogen-rich atmospheres are better candidates for originating life by way of Miller-Urey-type prebiotic synthesis. However, calculating the rate of atmospheric hydrogen escape is difficult, for a number of reasons. First, the escape can be controlled either by diffusion through the homopause or by conditions in the upper atmosphere, whichever is slower. Second, both thermal and non-thermal escape mechanisms are typically important. Third, thermal escape itself can be subdivided into Jeans escape (thin upper atmosphere), and hydrodynamic escape, and hydrodynamic escape can be further subdivided into transonic escape and slower subsonic escape, depending on whether the exobase occurs above or below the sonic point. Additionally, the rate of escape for real terrestrial planet atmospheres, which are not 100% hydrogen, depends upon the concentration of infrared coolants, and upon heating and photochemistry driven largely by extreme ultraviolet (EUV) radiation. We have modified an existing 1-D model of hydrodynamic escape (F. Tian et al., JGR, 2008) to work in the high- hydrogen regime. Calculations are underway to determine hydrogen escape rates as a function of atmospheric H2 mixing ratio and the solar EUV flux. We will compare these rates with the estimated upper limit on the escape rate based on diffusion. Initial results for early Earth and Mars will later be extended to rocky exoplanets.

  6. The role of mutations in core protein of hepatitis B virus in liver fibrosis

    Directory of Open Access Journals (Sweden)

    Abbasi Shahsanam

    2009-11-01

    Full Text Available Abstract The core protein of hepatitis B virus encompasses B- and T-cell immunodominant epitopes and subdivided into two domains: the N-terminal and the functional C-terminal consisted phosphorylation sites. Mutations of the core gene may change the conformation of the core protein or cause alteration of important epitopes in the host immune response. In this study twenty nine men (mean age 40 ± 9 years old with chronic hepatitis B were recruited for direct sequencing of the core gene. Serum ALT and HBV DNA level were measured at the time of liver biopsy. The effects of core protein mutations on patients' characteristics and subsequently mutations in B cell, T helper and cytotoxic T lymphocyte (CTL epitopes and also C-terminal domain of core protein on the activity of liver disease was evaluated. Liver fibrosis was significantly increased in patients with core protein mutation (1.0 ± 0.8 vs 1.9 ± 1.4 for mean stage of fibrosis P = 0.05. Mutations in CTL epitopes and in phosphorylation sites of C-terminal domain of core protein also were associated with higher liver fibrosis (P = 0.003 and P = 0.04; Fisher's exact test for both. Patients with mutation in C-terminal domain had higher serum ALT (62 ± 17 vs 36 ± 12 IU/l, p = 0.02. Patients with mutations in B cell and T helper epitopes did not show significant difference in the clinical features. Our data suggests that core protein mutations in CTL epitopes and C-terminal domain accompanied with higher stage of liver fibrosis may be due to alterations in the function of core protein.

  7. Risks incurred by hydrogen escaping from containers and conduits

    Energy Technology Data Exchange (ETDEWEB)

    Swain, M.R.; Grilliot, E.S. [Univ. of Miami, Coral Gables, FL (United States); Swain, M.N. [Analytical Technologies, Inc., Miami, FL (United States)

    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.

  8. The cost of the sword: escape performance in male swordtails.

    Directory of Open Access Journals (Sweden)

    Alex Baumgartner

    Full Text Available The handicap theory of sexual selection posits that male display traits that are favored in mate choice come at a significant cost to performance. We tested one facet of this hypothesis in the green swordtail (Xiphophorus helleri. In this species, the lower ray of male caudal fin is extended into a 'sword', which serves to attract potential mates. However, bearing a long sword may increase drag and thus compromise a male's ability to swim effectively. We tested escape performance in this species by eliciting C-start escape responses, an instinctive escape behavior, in males with various sword lengths. We then removed males' swords and retested escape performance. We found no relationship between escape performance and sword length and no effect of sword removal on escape performance. While having a large sword may attract a predator's attention, our results suggest that sword size does not compromise a male's escape performance.

  9. Escape from attracting sets in randomly perturbed systems.

    Science.gov (United States)

    Rodrigues, Christian S; Grebogi, Celso; de Moura, Alessandro P S

    2010-10-01

    The dynamics of escape from an attractive state due to random perturbations is of central interest to many areas in science. Previous studies of escape in chaotic systems have rather focused on the case of unbounded noise, usually assumed to have Gaussian distribution. In this paper, we address the problem of escape induced by bounded noise. We show that the dynamics of escape from an attractor's basin is equivalent to that of a closed system with an appropriately chosen "hole." Using this equivalence, we show that there is a minimum noise amplitude above which escape takes place, and we derive analytical expressions for the scaling of the escape rate with noise amplitude near the escape transition. We verify our analytical predictions through numerical simulations of two well-known two-dimensional maps with noise.

  10. Room escape at class: Escape games activities to facilitate the motivation and learning in computer science

    Directory of Open Access Journals (Sweden)

    Carlos Borrego

    2017-06-01

    Full Text Available Real-life room-escape games are ludic activities in which participants enter a room in order to get out of it only after solving some riddles. In this paper, we explain a Room Escape teaching experience developed in the Engineering School at Universitat Autònoma de Barcelona. The goal of this activity is to increase student’s motivation and to improve their learning on two courses of the second year in the Computer Engineering degree: Computer Networksand Information and Security.

  11. Arduino adventures escape from Gemini station

    CERN Document Server

    Kelly, James Floyd

    2013-01-01

    Arduino Adventures: Escape from Gemini Station provides a fun introduction to the Arduino microcontroller by putting you (the reader) into the action of a science fiction adventure story.  You'll find yourself following along as Cade and Elle explore Gemini Station-an orbiting museum dedicated to preserving and sharing technology throughout the centuries. Trouble ensues. The station is evacuated, including Cade and Elle's class that was visiting the station on a field trip. Cade and Elle don't make it aboard their shuttle and are trapped on the station along with a friendly artificial intellig

  12. Immune escape mechanisms in acute myeloid leukemia

    OpenAIRE

    Kolbeck, Alexandra

    2012-01-01

    Obwohl in den letzten Jahren in der Therapie der AML große Fortschritte erzielt wurden, sind die Ursachen für die hohen Rezidivraten nach allogener SZT weiterhin nicht vollständig geklärt. Als Ursache werden Immune Escape Mechanismen diskutiert, mit deren Hilfe sich Tumorzellen vor der Elimination durch das Immunsystem schützen. Nach einer allogenen Stammzelltransplantation spielen Zytokine bei der Entwicklung einer GvHD, bzw. des GvL-Effektes eine zentrale Rolle. Besonders IFNγ ist ein Schlü...

  13. Serial Escape System For Aircraft Crews

    Science.gov (United States)

    Wood, Kenneth E.

    1990-01-01

    Emergency escape system for aircraft and aerospace vehicles ejects up to seven crewmembers, one by one, within 120 s. Intended for emergencies in which disabled craft still in stable flight at no more than 220 kn (113 m/s) equivalent airspeed and sinking no faster than 110 ft/s (33.5 m/s) at altitudes up to 50,000 ft (15.2 km). Ejection rockets load themselves from magazine after each crewmember ejected. Jumpmaster queues other crewmembers and helps them position themselves on egress ramp. Rockets pull crewmembers clear of aircraft structure. Provides orderly, controlled exit and avoids ditching at sea or landing in rough terrain.

  14. Belt fires and mine escape problems

    Energy Technology Data Exchange (ETDEWEB)

    Kovac, J.G.; Lazzara, C.P. [Bureau of Mines, Pittsburgh, PA (United States); Kravitz, J.H.

    1996-12-31

    A conveyor belt fire in an underground coal mine is a serious threat to life and property. About 30% of the reportable underground coal mine fires from 1988 through 1992 occurred in belt entries. In one instance, a fire started in the drive area of a belt line, spread rapidly, and resulted in seating of the entire mine. Large-scale studies conducted by the U.S. Bureau of Mines in an aboveground fire gallery at Lake Lynn Laboratory clearly show the hazards of conveyor belt fires. Mine conveyor belt formulations which passed the current Federal acceptance test for fire-resistant betting were completely consumed by propagating fires or propagated flame, with flame spread rates ranging from 0.3 to 9 m/min. High downstream temperatures and large quantities of smoke and toxic gases, such as carbon monoxide, were generated as the belting burned. The smoke and gases can be spread by the mine`s ventilation system and can create significant problems for miners in the process of evacuation, such as reduction in visibility and incapacitation. In the aftermath of a belt fire, the atmosphere inside of the mine can become smoke filled or unbreathable, forcing miners to evacuate while wearing Self-Contained Self-Rescuers (SCSR`s), Sometimes there is confusion about how to regard the rated duration of an MSHA/NIOSH-approved 60-min. SCSR, especially when an SCSR is used in a way which takes it outside of the test conditions under which it was approved. As examples, for a mine escape that takes a miner from the deepest point of penetration in the mine to the surface: How long will a 60-min. SCSR actually last? and How many SCSR`s will a miner need? To answer these kinds of questions, in-mine data being gathered on escape times, distance and heart rates using miners escaping on foot and under oxygen. A model will be developed and validated which predicts how much oxygen is actually needed for a mine escape, and compares oxygen consumption bare faced versus wearing an SCSR.

  15. X-chromosome inactivation and escape

    Indian Academy of Sciences (India)

    Christine M. Disteche; Joel B. Berletch

    2015-12-01

    X-chromosome inactivation, which was discovered by Mary Lyon in 1961 results in random silencing of one X chromosome in female mammals. This review is dedicated to Mary Lyon, who passed away last year. She predicted many of the features of X inactivation, for e.g., the existence of an X inactivation center, the role of L1 elements in spreading of silencing and the existence of genes that escape X inactivation. Starting from her published work here we summarize advances in the field.

  16. An Approach for a Synthetic CTL Vaccine Design against Zika Flavivirus Using Class I and Class II Epitopes Identified by Computer Modeling

    Directory of Open Access Journals (Sweden)

    Edecio Cunha-Neto

    2017-06-01

    Full Text Available The threat posed by severe congenital abnormalities related to Zika virus (ZKV infection during pregnancy has turned development of a ZKV vaccine into an emergency. Recent work suggests that the cytotoxic T lymphocyte (CTL response to infection is an important defense mechanism in response to ZKV. Here, we develop the rationale and strategy for a new approach to developing cytotoxic T lymphocyte (CTL vaccines for ZKV flavivirus infection. The proposed approach is based on recent studies using a protein structure computer model for HIV epitope selection designed to select epitopes for CTL attack optimized for viruses that exhibit antigenic drift. Because naturally processed and presented human ZKV T cell epitopes have not yet been described, we identified predicted class I peptide sequences on ZKV matching previously identified DNV (Dengue class I epitopes and by using a Major Histocompatibility Complex (MHC binding prediction tool. A subset of those met the criteria for optimal CD8+ attack based on physical chemistry parameters determined by analysis of the ZKV protein structure encoded in open source Protein Data File (PDB format files. We also identified candidate ZKV epitopes predicted to bind promiscuously to multiple HLA class II molecules that could provide help to the CTL responses. This work suggests that a CTL vaccine for ZKV may be possible even if ZKV exhibits significant antigenic drift. We have previously described a microsphere-based CTL vaccine platform capable of eliciting an immune response for class I epitopes in mice and are currently working toward in vivo testing of class I and class II epitope delivery directed against ZKV epitopes using the same microsphere-based vaccine.

  17. Unsuccessful CTL transfusion in a case of post-BMT Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD).

    Science.gov (United States)

    Imashuku, S; Goto, T; Matsumura, T; Naya, M; Yamori, M; Hojo, M; Hibi, S; Todo, S

    1997-08-01

    A patient with AML (FAB M4Eo) developed EBV-LPD 1.5 months after allogeneic BMT from his one locus-mismatched mother, the diagnosis being confirmed on day +82. Attempts to eradicate the monoclonally proliferating LPD using chemotherapy (VP16/dexamethasone) followed by two doses of EBV-specific CTL and one dose of unstimulated donor leukocytes were not successful. We assume delay of infusions (day +100, +107) and insufficient CTL cell doses (total 9.2 x 10(6)) may have been responsible for the poor outcome in this case.

  18. CD40 agonist converting CTL exhaustion via the activation of the mTORC1 pathway enhances PD-1 antagonist action in rescuing exhausted CTLs in chronic infection.

    Science.gov (United States)

    Xu, Aizhang; Wang, Rong; Freywald, Andrew; Stewart, Kristoffor; Tikoo, Suresh; Xu, Jianqing; Zheng, Changyu; Xiang, Jim

    2017-03-11

    Expansion of PD-1-expressing CD8(+) cytotoxic T lymphocytes (CTLs) and associated CTL exhaustion are chief issues for ineffective virus-elimination in chronic infectious diseases. PD-1 blockade using antagonistic anti-PD-L1 antibodies results in a moderate conversion of CTL exhaustion. We previously demonstrated that CD40L signaling of ovalbumin (OVA)-specific vaccine, OVA-Texo, converts CTL exhaustion via the activation of the mTORC1 pathway in OVA-expressing adenovirus (AdVova)-infected B6 mice showing CTL inflation and exhaustion. Here, we developed AdVova-infected B6 and transgenic CD11c-DTR (termed AdVova-B6 and AdVova-CD11c-DTR) mice with chronic infection, and assessed a potential effect of CD40 agonist on the conversion of CTL exhaustion and on a potential enhancement of PD-1 antagonist action in rescuing exhausted CTLs in our chronic infection models. We demonstrate that a single dose of anti-CD40 alone can effectively convert CTL exhaustion by activating the mTORC1 pathway, leading to CTL proliferation, up-regulation of an effector-cytokine IFN-γ and the cytolytic effect in AdVova-B6 mice. Using anti-CD4 antibody and diphtheria toxin (DT) to deplete CD4(+) T-cells and dendritic cells (DCs), we discovered that the CD40 agonist-induced conversion in AdVova-B6 and AdVova-CD11c-DTR mice is dependent upon host CD4(+) T-cell and DC involvements. Moreover, CD40 agonist significantly enhances PD-1 antagonist effectiveness in rescuing exhausted CTLs in chronic infection. Taken together, our data demonstrate the importance of CD40 signaling in the conversion of CTL exhaustion and its ability to enhance PD-1 antagonist action in rescuing exhausted CTLs in chronic infection. Therefore, our findings may positively impact the design of new therapeutic strategies for chronic infectious diseases.

  19. Molecular Dications in Planetary Atmospheric Escape

    Directory of Open Access Journals (Sweden)

    Stefano Falcinelli

    2016-08-01

    Full Text Available Fundamental properties of multiply charged molecular ions, such as energetics, structure, stability, lifetime and fragmentation dynamics, are relevant to understand and model the behavior of gaseous plasmas as well as ionosphere and astrophysical environments. Experimental determinations of the Kinetic Energy Released (KER for ions originating from dissociations reactions, induced by Coulomb explosion of doubly charged molecular ions (molecular dications produced by double photoionization of CO2, N2O and C2H2 molecules of interest in planetary atmospheres, are reported. The KER measurement as a function of the ultraviolet (UV photon energy in the range of 28–65 eV was extracted from the electron-ion-ion coincidence spectra obtained by using tunable synchrotron radiation coupled with ion imaging techniques at the ELETTRA Synchrotron Light Laboratory Trieste, Italy. These experiments, coupled with a computational analysis based on a Monte Carlo trajectory simulation, allow assessing the probability of escape for simple ionic species in the upper atmosphere of Mars, Venus and Titan. The measured KER in the case of H+, C+, CH+, CH2+, N+, O+, CO+, N2+ and NO+ fragment ions range between 1.0 and 5.5 eV, being large enough to allow these ionic species to participate in the atmospheric escape from such planets into space. In the case of Mars, we suggest a possible explanation for the observed behavior of the O+ and CO22+ ion density profiles.

  20. Escape mechanisms of dust in Io

    Science.gov (United States)

    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.

  1. Escape of water molecular from Carbon Nanotubes

    Science.gov (United States)

    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.

  2. Fast escaping points of entire functions

    CERN Document Server

    Rippon, P J

    2010-01-01

    Let $f$ be a transcendental entire function and let $A(f)$ denote the set of points that escape to infinity `as fast as possible' under iteration. By writing $A(f)$ as a countable union of closed sets, called `levels' of $A(f)$, we obtain a new understanding of the structure of this set. For example, we show that if $U$ is a Fatou component in $A(f)$, then $\\partial U\\subset A(f)$ and this leads to significant new results and considerable improvements to existing results about $A(f)$. In particular, we study functions for which $A(f)$, and each of its levels, has the structure of an `infinite spider's web'. We show that there are many such functions and that they have a number of strong dynamical properties. This new structure provides an unexpected connection between a conjecture of Baker concerning the components of the Fatou set and a conjecture of Eremenko concerning the components of the escaping set.

  3. Uremic escape of renal allograft rejection

    Energy Technology Data Exchange (ETDEWEB)

    van Schilfgaarde, R. (Rijksuniversiteit Leiden (Netherlands). Academisch Ziekenhuis); van Breda Vriesman, P.J.C. (Rijksuniversiteit Limburg Maastricht (Netherlands). Dept. of Immunopathology)

    1981-10-01

    It is demonstrated in rats that, in the presence of early postoperative severe but transient uremia, the survival of first set Brown-Norway (BN) renal allografts in Lewis (LEW) recipients is at least three times prolonged when compared to non-uremic controls. This phenomenon is called 'uremic escape of renal allograft rejection'. By means of lethal X-irradiation of donors of BN kidneys transplanted into transiently uremic and non-uremic LEW recipients, the presence of passenger lymphocyte immunocompetence is demonstrated to be obilgatory for this phenomenon to occur. As a result of mobile passenger lymphocyte immunocompetence, a graft-versus-host (GVH) reaction is elicited in the spleens of LEW recipients of BN kidneys which amplifies the host response. The splenomegaly observed in LEW recipients of BN kidneys is caused not only by this GVH reaction, which is shown to be exquisitely sensitive to even mild uremia. It is also contributed to by a proliferative response of the host against the graft (which latter response is equated with an in vivo equivalent of a unilateral mixed lymphocyte reaction (MLR)), since the reduction in spleen weights caused by abrogation of mobile passenger lymphocyte immunocompetence brought about by lethal donor X-irradiation is increased significantly by early postoperative severe but transient uremia. It is concluded that in uremic escape of renal allograft rejection both reactions are suppressed by uremia during the early post-operative period.

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

    NARCIS (Netherlands)

    van Duren, LA; Videler, JJ

    2003-01-01

    Feeding and escape swimming in adult females of the calanoid copepod. Temora lopgicornis Muller were investigated and compared. Swimming velocities were calculated using a 3-D filming setup., Foraging velocities ranged between 2 and 6 min s(-1), while maximum velocities of up to 80 mm s(-1) were rea

  5. Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import

    Science.gov (United States)

    Götz, Veronika; Magar, Linda; Dornfeld, Dominik; Giese, Sebastian; Pohlmann, Anne; Höper, Dirk; Kong, Byung-Whi; Jans, David A.; Beer, Martin; Haller, Otto; Schwemmle, Martin

    2016-01-01

    To establish a new lineage in the human population, avian influenza A viruses (AIV) must overcome the intracellular restriction factor MxA. Partial escape from MxA restriction can be achieved when the viral nucleoprotein (NP) acquires the critical human-adaptive amino acid residues 100I/V, 283P, and 313Y. Here, we show that introduction of these three residues into the NP of an avian H5N1 virus renders it genetically unstable, resulting in viruses harboring additional single mutations, including G16D. These substitutions restored genetic stability yet again yielded viruses with varying degrees of attenuation in mammalian and avian cells. Additionally, most of the mutant viruses lost the capacity to escape MxA restriction, with the exception of the G16D virus. We show that MxA escape is linked to attenuation by demonstrating that the three substitutions promoting MxA escape disturbed intracellular trafficking of incoming viral ribonucleoprotein complexes (vRNPs), thereby resulting in impaired nuclear import, and that the additional acquired mutations only partially compensate for this import block. We conclude that for adaptation to the human host, AIV must not only overcome MxA restriction but also an associated block in nuclear vRNP import. This inherent difficulty may partially explain the frequent failure of AIV to become pandemic. PMID:26988202

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

    Science.gov (United States)

    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.

  7. Interplay and escape in three-body scattering.

    Science.gov (United States)

    Shebalin, J. V.; Tippens, A. L.

    1996-05-01

    The problem of three gravitationally interacting bodies, with total energy less than zero, is investigated numerically. After introducing the concepts of `periastron graphs' and `composite binaries', time-of-escape and interplay are precisely defined. These definitions are useful in characterizing the complete scattering process: escape to t=-{infinity}, interplay, and escape to t=+{infinity}. These definitions are also useful for the efficient and automatic termination of a numerical simulation of interplay.

  8. Experimental self-punishment and superstitious escape behavior.

    Science.gov (United States)

    MIGLER, B

    1963-07-01

    Rats were trained to escape from shock by pressing a bar. Bar holding was subsequently punished with very brief shocks. This treatment failed to depress bar-holding behavior. In some cases, although the escape shocks were delivered very infrequently, bar holding was maintained and resulted in the delivery of several thousand punishments per session. These and other effects of the punishment treatment were investigated. Finally, some of the possibilities of superstitious escape responding were explored by presenting inescapable shocks to rats that had been trained to escape shock by lever pressing. Although responding during these shocks had no programmed consequences, responding was sustained.

  9. Cockroaches keep predators guessing by using preferred escape trajectories

    Science.gov (United States)

    Domenici, P.; Booth, D.; Blagburn, J.M.; Bacon, J. P.

    2009-01-01

    Summary Anti-predator behaviour is vital for most animals, and calls for accurate timing and swift motion. While fast reaction times [1] and predictable, context-dependent, escape initiation distances [2] are common features of most escape systems, previous work has highlighted the need for unpredictability in escape directions, in order to prevent predators from learning a repeated, fixed pattern [3–5]. Ultimate unpredictability would result from random escape trajectories. Although this strategy would deny any predictive power to the predator, it would also result in some escape trajectories towards the threat. Previous work has shown that escape trajectories are in fact generally directed away from the threat, although with a high variability [5–8]. However, the rules governing this variability are largely unknown. Here, we demonstrate tha t individual cockroaches (Periplaneta americana, a much studied model prey species [9–14]) keep each escape unpredictable by running along one of a set of preferred trajectories at fixed angles from the direction of the threatening stimulus. These results provide a new paradigm for understanding the behavio ural strategies for escape responses, underscoring the need to revisit the neural mechanisms controlling escape directions in the cockroach and similar animal models, and the evolutionary forces driving unpredictable, or “protean” [3], anti-predator behaviour. PMID:19013065

  10. Identification of a cyclin B1-derived CTL epitope eliciting spontaneous responses in both cancer patients and healthy donors

    DEFF Research Database (Denmark)

    Andersen, Rikke Sick; Sørensen, Rikke Bæk; Ritter, Cathrin

    2011-01-01

    was verified in an HLA stabilization assay. By stimulation with peptide-loaded dendritic cells a CTL clone was established, which was able to kill two breast cancer cell lines in an HLA-A2-dependent and peptide-specific manner, demonstrating presentation of the peptide on the surface of cancer cells....... Furthermore, blood from cancer patients and healthy donors was screened for spontaneous T-cell reactivity against the peptide in IFN-γ ELISPOT assays. Patients with breast cancer, malignant melanoma, or renal cell carcinoma hosted powerful and high-frequency T-cell responses against the peptide. In addition......, when blood from healthy donors was tested, similar responses were observed. Ultimately, serum from cancer patients and healthy donors was analyzed for anti-cyclin B1 antibodies. Humoral responses against cyclin B1 were frequently detected in both cancer patients and healthy donors. In conclusion...

  11. Identification of a cyclin B1-derived CTL epitope eliciting spontaneous responses in both cancer patients and healthy donors

    DEFF Research Database (Denmark)

    Andersen, Rikke Sick; Sørensen, Rikke Bæk; Ritter, Cathrin

    2011-01-01

    was verified in an HLA stabilization assay. By stimulation with peptide-loaded dendritic cells a CTL clone was established, which was able to kill two breast cancer cell lines in an HLA-A2-dependent and peptide-specific manner, demonstrating presentation of the peptide on the surface of cancer cells....... Furthermore, blood from cancer patients and healthy donors was screened for spontaneous T-cell reactivity against the peptide in IFN-¿ ELISPOT assays. Patients with breast cancer, malignant melanoma, or renal cell carcinoma hosted powerful and high-frequency T-cell responses against the peptide. In addition......, when blood from healthy donors was tested, similar responses were observed. Ultimately, serum from cancer patients and healthy donors was analyzed for anti-cyclin B1 antibodies. Humoral responses against cyclin B1 were frequently detected in both cancer patients and healthy donors. In conclusion...

  12. Model Pembelajaran CTL (Contextual Teaching and Learning dalam Meningkatkan Hasil Belajar Mahasiswa PGSD Pada MataKuliah Konsep IPS Dasar

    Directory of Open Access Journals (Sweden)

    Wahyu Susiloningsih

    2016-03-01

    Full Text Available Hasil belajar adalah suatu proses perubahan tingkah laku dalam pengetahuan, sikap, dan ketrampilan yang diperoleh dalam jangka waktu yang lama.Mata kuliah Konsep IPS Dasar merupakan mata kuliah yang memberikan pemahaman kepada mahasiswa PGSD tentang konsep dasar IPS sebagai landasan kajian yang bahannya bersumber dari kehidupan manusia di masyarakat, yang aspek-aspeknya meliputi social science (ilmu sosial, social studies (studi sosial, Ilmu Pengetahuan Sosial (IPS. IPS merupakan pembelajaran pada tingkat sekolah yang berperan mengfungsionalkan ilmu-ilmu sosial yang bersifat teoritik dalam kehidupan nyata dalam masyarakat. Model pembelajaran CTL adalah model pembelajaran yang menuntut kreatifitas guru dalam mengaitkan subject matter dengan kehidupan nyata mahasiswa guna membantu mahasiswa untuk lebih mudah memaknai materi tersebut.

  13. PEMBELAJARAN PENJUMLAHAN BILANGAN PECAHAN DENGAN METODE CONTEXTUAL TEACHING AND LEARNING (CTL DI SD MUHAMMADIYAH PROGRAM KHUSUS, KOTA BARAT, SURAKARTA

    Directory of Open Access Journals (Sweden)

    Yulia Maftuhah Hidayati

    2015-07-01

    Full Text Available This study is aimed to describe the lesson plan, teaching learning process of sum of fractions based of Contextual Teaching and Learning (CTL, and the motivation of learners attend classes in learning. This study used a qualitative approach. The type of research is a case study. Validation of data is done through triangulation. Data were collected through interviews, observation, documentation, and testing. The technique of data analysis is descriptive, entrepretative. The results of this study indicate that (1 the development of lesson plan has been implemented routinely in every new school year, (2 the process of learning mathematics goes through three stages, namely preinstructional phase (preliminary / initial activity, instructional phase (core activities, and appraisal, (3 during the learning process, the students have a high motivation to participate in activities  because of the method used by teachers is fun and enjoyable

  14. A replicating cytomegalovirus-based vaccine encoding a single Ebola virus nucleoprotein CTL epitope confers protection against Ebola virus.

    Directory of Open Access Journals (Sweden)

    Yoshimi Tsuda

    2011-08-01

    Full Text Available BACKGROUND: Human outbreaks of Ebola virus (EBOV are a serious human health concern in Central Africa. Great apes (gorillas/chimpanzees are an important source of EBOV transmission to humans due to increased hunting of wildlife including the 'bush-meat' trade. Cytomegalovirus (CMV is an highly immunogenic virus that has shown recent utility as a vaccine platform. CMV-based vaccines also have the unique potential to re-infect and disseminate through target populations regardless of prior CMV immunity, which may be ideal for achieving high vaccine coverage in inaccessible populations such as great apes. METHODOLOGY/PRINCIPAL FINDINGS: We hypothesize that a vaccine strategy using CMV-based vectors expressing EBOV antigens may be ideally suited for use in inaccessible wildlife populations. To establish a 'proof-of-concept' for CMV-based vaccines against EBOV, we constructed a mouse CMV (MCMV vector expressing a CD8+ T cell epitope from the nucleoprotein (NP of Zaire ebolavirus (ZEBOV (MCMV/ZEBOV-NP(CTL. MCMV/ZEBOV-NP(CTL induced high levels of long-lasting (>8 months CD8+ T cells against ZEBOV NP in mice. Importantly, all vaccinated animals were protected against lethal ZEBOV challenge. Low levels of anti-ZEBOV antibodies were only sporadically detected in vaccinated animals prior to ZEBOV challenge suggesting a role, at least in part, for T cells in protection. CONCLUSIONS/SIGNIFICANCE: This study demonstrates the ability of a CMV-based vaccine approach to protect against an highly virulent human pathogen, and supports the potential for 'disseminating' CMV-based EBOV vaccines to prevent EBOV transmission in wildlife populations.

  15. The Fastest Saccadic Responses Escape Visual Masking

    DEFF Research Database (Denmark)

    M. Crouzet, Sébastien; Overgaard, Morten; Busch, Niko A.

    2014-01-01

    , which gives access to very early stages of visual processing, target visibility was reduced either by OSM, conventional backward masking, or low stimulus contrast. A general reduction of performance was observed in all three conditions. However, the fastest saccades did not show any sign of interference......Object-substitution masking (OSM) occurs when a briefly presented target in a search array is surrounded by small dots that remain visible after the target disappears. The reduction of target visibility occurring after OSM has been suggested to result from a specific interference with reentrant...... visual processing while the initial feedforward processing is thought to be left intact. We tested a prediction derived from this hypothesis: the fastest responses, being triggered before the beginning of reentrant processing, should escape the OSM interference. In a saccadic choice reaction time task...

  16. Escape dynamics through a continuously growing leak

    Science.gov (United States)

    Kovács, Tamás; Vanyó, József

    2017-06-01

    We formulate a model that describes the escape dynamics in a leaky chaotic system in which the size of the leak depends on the number of the in-falling particles. The basic motivation of this work is the astrophysical process, which describes the planetary accretion. In order to study the dynamics generally, the standard map is investigated in two cases when the dynamics is fully hyperbolic and in the presence of Kolmogorov-Arnold-Moser islands. In addition to the numerical calculations, an analytic solution to the temporal behavior of the model is also derived. We show that in the early phase of the leak expansion, as long as there are enough particles in the system, the number of survivors deviates from the well-known exponential decay. Furthermore, the analytic solution returns the classical result in the limiting case when the number of particles does not affect the leak size.

  17. Antimelanoma CTL recognizes peptides derived from an ORF transcribed from the antisense strand of the 3′ untranslated region of TRIT1

    Directory of Open Access Journals (Sweden)

    Rolf K Swoboda

    2014-01-01

    Full Text Available Noncoding regions of the genome play an important role in tumorigenesis of cancer. Using expression cloning, we have identified a cytotoxic T lymphocyte (CTL–defined antigen that recognizes a protein sequence derived from an open reading frame transcribed from the reverse strand in the 3′ untranslated region of tRNA isopentenyltransferase 1 (TRIT1. A peptide derived from this open reading frame (ORF sequence and predicted to bind to HLA-B57, sensitized HLA-B57+ tumor cells to lysis by CTL793. The peptide also induced a CTL response in peripheral blood mononuclear cells (PBMC of patient 793 and in two other melanoma patients. The CTL lysed peptide-pulsed HLA-B57+ target cells and melanoma cells with endogenous antigen expression. The recognition of this antigen is not limited to HLA-B57-restricted CTLs. An HLA-A2 peptide derived from the ORF was able to induce CTLs in PBMC of 2 HLA-A2+ patients. This study describes for the first time a CTL-defined melanoma antigen that is derived from an ORF on the reverse strand of the putative tumor suppressor gene TRIT1. This antigen has potential use as a vaccine or its ability to induce CTLs in vitro could be used as a predictive biomarker.

  18. Broadly Immunogenic HLA Class I Supertype-Restricted Elite CTL Epitopes Recognized in a Diverse Population Infected with Different HIV-1 Subtypes

    DEFF Research Database (Denmark)

    Pérez, Carina L; Larsen, Mette Voldby; Gustafsson, Rasmus

    2008-01-01

    The genetic variations of the HIV-1 virus and its human host constitute major obstacles for obtaining potent HIV-1-specific CTL responses in individuals of diverse ethnic backgrounds infected with different HIV-1 variants. In this study, we developed and used a novel algorithm to select 184 predi...

  19. Yersinia pestis IS1541 transposition provides for escape from plague immunity.

    Science.gov (United States)

    Cornelius, Claire A; Quenee, Lauriane E; Elli, Derek; Ciletti, Nancy A; Schneewind, Olaf

    2009-05-01

    Yersinia pestis is perhaps the most feared infectious agent due to its ability to cause epidemic outbreaks of plague disease in animals and humans with high mortality. Plague infections elicit strong humoral immune responses against the capsular antigen (fraction 1 [F1]) of Y. pestis, and F1-specific antibodies provide protective immunity. Here we asked whether Y. pestis generates mutations that enable bacterial escape from protective immunity and isolated a variant with an IS1541 insertion in caf1A encoding the F1 outer membrane usher. The caf1A::IS1541 insertion prevented assembly of F1 pili and provided escape from plague immunity via F1-specific antibodies without a reduction in virulence in mouse models of bubonic or pneumonic plague. F1-specific antibodies interfere with Y. pestis type III transport of effector proteins into host cells, an inhibitory effect that was overcome by the caf1A::IS1541 insertion. These findings suggest a model in which IS1541 insertion into caf1A provides for reversible changes in envelope structure, enabling Y. pestis to escape from adaptive immune responses and plague immunity.

  20. Prediction and in vitro verification of potential CTL epitopes conserved among PRRSV-2 strains

    DEFF Research Database (Denmark)

    Welner, Simon; Nielsen, Morten; Rasmussen, Michael

    2017-01-01

    mutation rate, has hampered the development of safe and broadly protective vaccines. Aiming at a vaccine inducing an effective cytotoxic T cell response, a bioinformatics approach was taken to identify conserved PRRSV-derived peptides predicted to react broadly with common swine leukocyte antigen (SLA......) class I alleles. Briefly, all possible 9- and 10-mer peptides were generated from 104 complete PRRSV type 2 genomes of confirmed high quality, and peptides with high binding affinity to five common SLAs were identified combining the NetMHCpan and positional scanning combinatorial peptide libraries...... binding predictions. Predicted binders were prioritized according to genomic conservation and SLA coverage using the PopCover algorithm. From this, 53 peptides were acquired for further analysis. Binding affinity and stability of a subset of 101 peptide-SLA combinations were validated in vitro for 4...

  1. Regulatory B cells inhibit cytotoxic T lymphocyte (CTL activity and elimination of infected CD4 T cells after in vitro reactivation of HIV latent reservoirs.

    Directory of Open Access Journals (Sweden)

    Basile Siewe

    Full Text Available During HIV infection, IL-10/IL-10 receptor and programmed death-1 (PD-1/programmed death-1-ligand (PD-L1 interactions have been implicated in the impairment of cytotoxic T lymphocyte (CTL activity. Despite antiretroviral therapy (ART, attenuated anti-HIV CTL functions present a major hurdle towards curative measures requiring viral eradication. Therefore, deeper understanding of the mechanisms underlying impaired CTL is crucial before HIV viral eradication is viable. The generation of robust CTL activity necessitates interactions between antigen-presenting cells (APC, CD4+ and CD8+ T cells. We have shown that in vitro, IL-10hiPD-L1hi regulatory B cells (Bregs directly attenuate HIV-specific CD8+-mediated CTL activity. Bregs also modulate APC and CD4+ T cell function; herein we characterize the Breg compartment in uninfected (HIVNEG, HIV-infected "elite controllers" (HIVEC, ART-treated (HIVART, and viremic (HIVvir, subjects, and in vitro, assess the impact of Bregs on anti-HIV CTL generation and activity after reactivation of HIV latent reservoirs using suberoylanilide hydroxamic acid (SAHA. We find that Bregs from HIVEC and HIVART subjects exhibit comparable IL-10 expression levels significantly higher than HIVNEG subjects, but significantly lower than HIVVIR subjects. Bregs from HIVEC and HIVART subjects exhibit comparable PD-L1 expression, significantly higher than in HIVVIR and HIVNEG subjects. SAHA-treated Breg-depleted PBMC from HIVEC and HIVART subjects, displayed enhanced CD4+ T-cell proliferation, significant upregulation of antigen-presentation molecules, increased frequency of CD107a+ and HIV-specific CD8+ T cells, associated with efficient elimination of infected CD4+ T cells, and reduction in integrated viral DNA. Finally, IL-10-R and PD-1 antibody blockade partially reversed Breg-mediated inhibition of CD4+ T-cell proliferation. Our data suggest that, possibly, via an IL-10 and PD-L1 synergistic mechanism; Bregs likely inhibit APC

  2. Escape behaviour in the stomatopod crustacean Squilla mantis, and the evolution of the caridoid escape reaction.

    Science.gov (United States)

    Heitler, W J; Fraser, K; Ferrero, E A

    2000-01-01

    The mantis shrimp Squilla mantis shows a graded series of avoidance/escape responses to visual and mechanical (vibration and touch) rostral stimuli. A low-threshold response is mediated by the simultaneous protraction of the thoracic walking legs and abdominal swimmerets and telson, producing a backwards 'lurch' or jump that can displace the animal by up to one-third of its body length, but leaves it facing in the same direction. A stronger response starts with similar limb protraction, but is followed by partial abdominal flexion. The maximal response also consists of limb protraction followed by abdominal flexion, but in this case the abdominal flexion is sufficiently vigorous to pull the animal into a tight vertical loop, which leaves it inverted and facing away from the stimulus. The animal then swims forward (away from the stimulus) and rights itself by executing a half-roll. A bilaterally paired, large-diameter, rapidly conducting axon in the dorsal region of the ventral nerve excites swimmeret protractor motoneurons in several ganglia and is likely to be the driver neuron for the limb-protraction response. The same neuron also excites unidentified abdominal trunk motoneurons, but less reliably. The escape response is a key feature of the malacostracan caridoid facies, and we provide the first detailed description of this response in a group that diverged early in malacostracan evolution. We show that the components of the escape response contrast strongly with those of the full caridoid reaction, and we provide physiological and behavioural evidence for the biological plausibility of a limb-before-tail thesis for the evolution of the escape response.

  3. Whole-genome immunoinformatic analysis of F. tularensis: predicted CTL epitopes clustered in hotspots are prone to elicit a T-cell response.

    Directory of Open Access Journals (Sweden)

    Anat Zvi

    Full Text Available The cellular arm of the immune response plays a central role in the defense against intracellular pathogens, such as F. tularensis. To date, whole genome immunoinformatic analyses were limited either to relatively small genomes (e.g. viral or to preselected subsets of proteins in complex pathogens. Here we present, for the first time, an unbiased bacterial global immunoinformatic screen of the 1740 proteins of F. tularensis subs. holarctica (LVS, aiming at identification of immunogenic peptides eliciting a CTL response. The very large number of predicted MHC class I binders (about 100,000, IC(50 of 1000 nM or less required the design of a strategy for further down selection of CTL candidates. The approach developed focused on mapping clusters rich in overlapping predicted epitopes, and ranking these "hotspot" regions according to the density of putative binding epitopes. Limited by the experimental load, we selected to screen a library of 1240 putative MHC binders derived from 104 top-ranking highly dense clusters. Peptides were tested for their ability to stimulate IFNγ secretion from splenocytes isolated from LVS vaccinated C57BL/6 mice. The majority of the clusters contained one or more CTL responder peptides and altogether 127 novel epitopes were identified, of which 82 are non-redundant. Accordingly, the level of success in identification of positive CTL responders was 17-25 fold higher than that found for a randomly selected library of 500 predicted MHC binders (IC(50 of 500 nM or less. Most proteins (ca. 2/3 harboring the highly dense hotspots are membrane-associated. The approach for enrichment of true positive CTL epitopes described in this study, which allowed for over 50% increase in the dataset of known T-cell epitopes of F. tularensis, could be applied in immunoinformatic analyses of many other complex pathogen genomes.

  4. The Origins and Underpinning Principles of E-Scape

    Science.gov (United States)

    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…

  5. How many ions have escaped the Martian atmosphere?

    Science.gov (United States)

    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.

  6. Entrapment and escape of liquid lubricant in metal forming

    DEFF Research Database (Denmark)

    Bech, Jakob Ilsted; Bay, Niels; Eriksen, Morten

    1999-01-01

    Using a transparent tool entrapment, compression and eventual escape of liquid lubricant in surface pockets is observed in plane strip drawing. The two mechanisms of lubricant escape. Micro Plasto HydroDynamic and Hydrostatic Lubrication (MPHDL and MPHSL), are observed and quantified experimentally...

  7. 46 CFR 169.313 - Means of escape.

    Science.gov (United States)

    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. 46 CFR 177.500 - Means of escape.

    Science.gov (United States)

    2010-10-01

    ...) There is no stove, heater, or other source of fire in the space; (3) The means of escape is located as... 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...

  9. Behavioural asymmetry affects escape performance in a teleost fish

    NARCIS (Netherlands)

    Dadda, Marco; Koolhaas, Wouter H.; Domenici, Paolo

    2010-01-01

    Escape performance is fundamental for survival in fish and most other animals. While previous work has shown that both intrinsic (e.g. size, shape) and extrinsic (e.g. temperature, hypoxia) factors can affect escape performance, the possibility that behavioural asymmetry may affect timing and locomo

  10. Green Pea Galaxies Reveal Secrets of Lyα Escape

    Science.gov (United States)

    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.

  11. Escape response of planktonic protists to fluid mechanical signals

    DEFF Research Database (Denmark)

    Jakobsen, Hans Henrik

    2001-01-01

    The escape response to fluid mechanical signals was examined in 6 protists, 4 ciliates and 2 dinoflagellates. When exposed to a siphon flow. 3 species of ciliates, Balanion comatum, Strobilidium sp., and Mesodinium pulex, responded with escape jumps. The threshold deformation rates required...

  12. Alanine mutagenesis of the primary antigenic escape residue cluster, c1, of apical membrane antigen 1.

    Science.gov (United States)

    Dutta, Sheetij; Dlugosz, Lisa S; Clayton, Joshua W; Pool, Christopher D; Haynes, J David; Gasser, Robert A; Batchelor, Adrian H

    2010-02-01

    Antibodies against apical membrane antigen 1 (AMA1) inhibit invasion of Plasmodium merozoites into red cells, and a large number of single nucleotide polymorphisms on AMA1 allow the parasite to escape inhibitory antibodies. The availability of a crystal structure makes it possible to test protein engineering strategies to develop a monovalent broadly reactive vaccine. Previously, we showed that a linear stretch of polymorphic residues (amino acids 187 to 207), localized within the C1 cluster on domain 1, conferred the highest level of escape from inhibitory antibodies, and these were termed antigenic escape residues (AER). Here we test the hypothesis that immunodampening the C1 AER will divert the immune system toward more conserved regions. We substituted seven C1 AER of the FVO strain Plasmodium falciparum AMA1 with alanine residues (ALA). The resulting ALA protein was less immunogenic than the native protein in rabbits. Anti-ALA antibodies contained a higher proportion of cross-reactive domain 2 and domain 3 antibodies and had higher avidity than anti-FVO. No overall enhancement of cross-reactive inhibitory activity was observed when anti-FVO and anti-ALA sera were compared for their ability to inhibit invasion. Alanine mutations at the C1 AER had shifted the immune response toward cross-strain-reactive epitopes that were noninhibitory, refuting the hypothesis but confirming the importance of the C1 cluster as an inhibitory epitope. We further demonstrate that naturally occurring polymorphisms that fall within the C1 cluster can predict escape from cross-strain invasion inhibition, reinforcing the importance of the C1 cluster genotype for antigenic categorization and allelic shift analyses in future phase 2b trials.

  13. Escape for the Slow Solar Wind

    Science.gov (United States)

    Kohler, Susanna

    2017-05-01

    Plasma from the Sun known as the slow solar wind has been observed far away from where scientists thought it was produced. Now new simulations may have resolved the puzzle of where the slow solar wind comes from and how it escapes the Sun to travel through our solar system.An Origin PuzzleA full view of a coronal hole (dark portion) from SDO. The edges of the coronal hole mark the boundary between open and closed magnetic field lines. [SDO; adapted from Higginson et al. 2017]The Suns atmosphere, known as the corona, is divided into two types of regions based on the behavior of magnetic field lines. In closed-field regions, the magnetic field is firmly anchored in the photosphere at both ends of field lines, so traveling plasma is confined to coronal loops and must return to the Suns surface. In open-field regions, only one end of each magnetic field line is anchored in the photosphere, so plasma is able to stream from the Suns surface out into the solar system.This second type of region known as a coronal hole is thought to be the origin of fast-moving plasma measured in our solar system and known as the fast solar wind. But we also observe a slow solar wind: plasma that moves at speeds of less than 500 km/s.The slow solar wind presents a conundrum. Its observational properties strongly suggest it originates in the hot, closed corona rather than the cooler, open regions. But if the slow solar wind plasma originates in closed-field regions of the Suns atmosphere, then how does it escape from the Sun?Slow Wind from Closed FieldsA team of scientists led by Aleida Higginson (University of Michigan) has now used high-resolution, three-dimensional magnetohydrodynamic simulations to show how the slow solar wind can be generated from plasma that starts outin closed-field parts of the Sun.A simulated heliospheric arc, composed of open magnetic field lines. [Higginson et al. 2017]Motions on the Suns surface near the boundary between open and closed-field regions the boundary

  14. Escaping in couples facilitates evacuation: Experimental study and modeling

    CERN Document Server

    Guo, Ning; Hu, Mao-Bin; Ding, Jian-Xun; Ding, Zhong-Jun

    2015-01-01

    In this paper, the impact of escaping in couples on the evacuation dynamics has been investigated via experiments and modeling. Two sets of experiments have been implemented, in which pedestrians are asked to escape either in individual or in couples. The experiments show that escaping in couples can decrease the average evacuation time. Moreover, it is found that the average evacuation time gap is essentially constant, which means that the evacuation speed essentially does not depend on the number of pedestrians that have not yet escaped. To model the evacuation dynamics, an improved social force model has been proposed, in which it is assumed that the driving force of a pedestrian cannot be fulfilled when the composition of physical forces exceeds a threshold because the pedestrian cannot keep his/her body balance under this circumstance. To model the effect of escaping in couples, attraction force has been introduced between the partners. Simulation results are in good agreement with the experimental ones.

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

    Science.gov (United States)

    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.

  16. Hepatitis B virus S gene escape mutants

    Directory of Open Access Journals (Sweden)

    Purdy Michael

    2007-01-01

    Full Text Available Hepatitis B virus (HBV can be classified into nine immunological subtypes or eight genotypes. The most prevalent genotypes in Asia are genotypes B and C. HBV is transmitted parenteraly and can produce either asymptomatic or symptomatic disease. Although the consequences of acute hepatitis B can be severe, serious sequelae are associated with chronic infections. HBV seroprevalence ranges from intermediate (2%-7% to high (≥8% levels in Asia. Several strategies for the control and prevention of HBV infection have been found to be efficacious. They include vaccination and the administration of HBIG, interferon-a and nucleoside/nucleotide analogues. However, these procedures also apply selective pressures on HBV in infected individuals leading to the generation and accumulation of mutations in the S gene. Most of these mutations occur in the major hydrophilic region (MHR of the S gene. These mutations create public health concerns as they can be responsible for reactivation of hepatitis B and occult hepatitis B infection. The inability to detect occult infections means that these individuals may become blood donors. This suggests that new strategies for donor evaluation and selection may need to be developed to protect the blood supply.

  17. The fastest saccadic responses escape visual masking.

    Directory of Open Access Journals (Sweden)

    Sébastien M Crouzet

    Full Text Available Object-substitution masking (OSM occurs when a briefly presented target in a search array is surrounded by small dots that remain visible after the target disappears. The reduction of target visibility occurring after OSM has been suggested to result from a specific interference with reentrant visual processing while the initial feedforward processing is thought to be left intact. We tested a prediction derived from this hypothesis: the fastest responses, being triggered before the beginning of reentrant processing, should escape the OSM interference. In a saccadic choice reaction time task, which gives access to very early stages of visual processing, target visibility was reduced either by OSM, conventional backward masking, or low stimulus contrast. A general reduction of performance was observed in all three conditions. However, the fastest saccades did not show any sign of interference under either OSM or backward masking, as they did under the low-contrast condition. This finding supports the hypothesis that masking interferes mostly with reentrant processing at later stages, while leaving early feedforward processing largely intact.

  18. Immune Escape Strategies of Malaria Parasites

    Science.gov (United States)

    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

  19. Candida albicans escapes from mouse neutrophils.

    Science.gov (United States)

    Ermert, David; Niemiec, Maria J; Röhm, Marc; Glenthøj, Andreas; Borregaard, Niels; Urban, Constantin F

    2013-08-01

    Candida albicans, the most commonly isolated human fungal pathogen, is able to grow as budding yeasts or filamentous forms, such as hyphae. The ability to switch morphology has been attributed a crucial role for the pathogenesis of C. albicans. To mimic disseminated candidiasis in humans, the mouse is the most widely used model organism. Neutrophils are essential immune cells to prevent opportunistic mycoses. To explore potential differences between the rodent infection model and the human host, we compared the interactions of C. albicans with neutrophil granulocytes from mice and humans. We revealed that murine neutrophils exhibited a significantly lower ability to kill C. albicans than their human counterparts. Strikingly, C. albicans yeast cells formed germ tubes upon internalization by murine neutrophils, eventually rupturing the neutrophil membrane and thereby, killing the phagocyte. On the contrary, growth and subsequent escape of C. albicans are blocked inside human neutrophils. According to our findings, this blockage in human neutrophils might be a result of higher levels of MPO activity and the presence of α-defensins. We therefore outline differences in antifungal immune defense between humans and mouse strains, which facilitates a more accurate interpretation of in vivo results.

  20. Escaping the resource curse in China.

    Science.gov (United States)

    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.

  1. A Single Amino Acid Difference within the α-2 Domain of Two Naturally Occurring Equine MHC Class I Molecules Alters the Recognition of Gag and Rev Epitopes by Equine Infectious Anemia Virus-Specific CTL1

    Science.gov (United States)

    Mealey, Robert H.; Lee, Jae-Hyung; Leib, Steven R.; Littke, Matt H.; McGuire, Travis C.

    2012-01-01

    Although CTL are critical for control of lentiviruses, including equine infectious anemia virus, relatively little is known regarding the MHC class I molecules that present important epitopes to equine infectious anemia virus-specific CTL. The equine class I molecule 7-6 is associated with the equine leukocyte Ag (ELA)-A1 haplotype and presents the Env-RW12 and Gag-GW12 CTL epitopes. Some ELA-A1 target cells present both epitopes, whereas others are not recognized by Gag-GW12-specific CTL, suggesting that the ELA-A1 haplotype comprises functionally distinct alleles. The Rev-QW11 CTL epitope is also ELA-A1-restricted, but the molecule that presents Rev-QW11 is unknown. To determine whether functionally distinct class I molecules present ELA-A1-restricted CTL epitopes, we sequenced and expressed MHC class I genes from three ELA-A1 horses. Two horses had the 7-6 allele, which when expressed, presented Env-RW12, Gag-GW12, and Rev-QW11 to CTL. The other horse had a distinct allele, designated 141, encoding a molecule that differed from 7-6 by a single amino acid within the α-2 domain. This substitution did not affect recognition of Env-RW12, but resulted in more efficient recognition of Rev-QW11. Significantly, CTL recognition of Gag-GW12 was abrogated, despite Gag-GW12 binding to 141. Molecular modeling suggested that conformational changes in the 141/Gag-GW12 complex led to a loss of TCR recognition. These results confirmed that the ELA-A1 haplotype is comprised of functionally distinct alleles, and demonstrated for the first time that naturally occurring MHC class I molecules that vary by only a single amino acid can result in significantly different patterns of epitope recognition by lentivirus-specific CTL. PMID:17082657

  2. Efficiently estimating salmon escapement uncertainty using systematically sampled data

    Science.gov (United States)

    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.

  3. Lyman-Werner UV escape fractions from primordial haloes

    Science.gov (United States)

    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.

  4. A new paradigm for evaluating avoidance/escape motivation.

    Science.gov (United States)

    Tsutsui-Kimura, Iku; Bouchekioua, Youcef; Mimura, Masaru; Tanaka, Kenji F

    2017-05-06

    Organisms have evolved to approach pleasurable opportunities and to avoid or escape from aversive experiences. These two distinct motivations are referred to as approach and avoidance/escape motivations and are both considered vital for survival. Despite several recent advances in understanding the neurobiology of motivation, most studies addressed approach but not avoidance/escape motivation. Here we develop a new experimental paradigm to quantify avoidance/escape motivation and examine the pharmacological validity. We set up an avoidance variable ratio 5 (VR-5) task in which mice were required to press a lever for variable times to avoid an upcoming aversive stimulus (foot shock) or to escape the ongoing aversive event if mice failed to avoid it. We intraperitoneally injected ketamine (0, 1, or 5 mg/kg) or buspirone (0, 5, or 10 mg/kg) 20 or 30 minutes before the behavioral task in order to see if ketamine enhanced avoidance/escape behavior and buspirone diminished it as previously reported. We found that the performance on the avoidance VR-5 task was sensitive to the intensity of the aversive stimulus. Treatment with ketamine increased, while that with buspirone decreased, the probability of avoidance from an aversive stimulus in the VR-5 task, being consistent with previous reports. Our new paradigm will prove usefulness for quantifying avoidance/escape motivation and will contribute to a more comprehensive understanding of motivation.

  5. A Bioinformatics Pipeline for the Analyses of Viral Escape Dynamics and Host Immune Responses during an Infection

    Directory of Open Access Journals (Sweden)

    Preston Leung

    2014-01-01

    Full Text Available Rapidly mutating viruses, such as hepatitis C virus (HCV and HIV, have adopted evolutionary strategies that allow escape from the host immune response via genomic mutations. Recent advances in high-throughput sequencing are reshaping the field of immuno-virology of viral infections, as these allow fast and cheap generation of genomic data. However, due to the large volumes of data generated, a thorough understanding of the biological and immunological significance of such information is often difficult. This paper proposes a pipeline that allows visualization and statistical analysis of viral mutations that are associated with immune escape. Taking next generation sequencing data from longitudinal analysis of HCV viral genomes during a single HCV infection, along with antigen specific T-cell responses detected from the same subject, we demonstrate the applicability of these tools in the context of primary HCV infection. We provide a statistical and visual explanation of the relationship between cooccurring mutations on the viral genome and the parallel adaptive immune response against HCV.

  6. Xenon Fractionation, Hydrogen Escape, and the Oxidation of the Earth

    Science.gov (United States)

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

    2014-12-01

    Xenon in Earth's atmosphere is severely mass fractionated and depleted compared to any plausible solar system source material, yet Kr is unfractionated. These observations seem to imply that Xe has escaped from Earth. Vigorous hydrodynamic hydrogen escape can produce mass fractionation in heavy gases. The required hydrogen flux is very high but within the range permitted by solar EUV heating when Earth was 100 Myrs old or younger. However this model cannot explain why Xe escapes but Kr does not. Recently, what appears to be ancient atmospheric xenon has been recovered from several very ancient (3-3.5 Ga) terrestrial hydrothermal barites and cherts (Pujol 2011, 2013). What is eye-catching about this ancient Xe is that it is less fractionated that Xe in modern air. In other words, it appears that a process was active on Earth some 3 to 3.5 billion years ago that caused xenon to fractionate. By this time the Sun was no longer the EUV source that it used to be. If xenon was being fractionated by escape — currently the only viable hypothesis — it had to be in Earth's Archean atmosphere and under rather modest levels of EUV forcing. It should be possible for Xe, but not Kr, to escape from Earth as an ion. In a hydrodynamically escaping hydrogen wind the hydrogen is partially ionized. The key concepts are that ions are much more strongly coupled to the escaping flow than are neutrals (so that a relatively modest flow of H and H+ to space could carry Xe+ along with it, the flux can be small enough to be consistent with diffusion-limited flux), and that Xe alone among the noble gases is more easily ionized than hydrogen. This sort of escape is possible along the polar field lines, although a weak or absent magnetic field would likely work as well. The extended history of hydrogen escape implicit in Xe escape in the Archean is consistent with other suggestions that hydrogen escape in the Archean was considerable. Hydrogen escape plausibly played the key role in creating

  7. Escape of Hydrogen from HD209458b

    Science.gov (United States)

    Erwin, Justin; Yelle, Roger; Koskinen, Tommi

    2017-04-01

    Recent modeling of the atmosphere of HD209458b has been used to interpret the Lyman-α line and other observations during transits. Koskinen et al. (2010) used a hydrostatic density profile in the thermosphere combined with the Voigt profile to estimate the Lyman-alpha transit depths for an array of model parameters. A detailed photochemical-dynamical model of the thermosphere was developed by Koskinen et al. (2013a) and used to again estimate model parameters to fit not only the Lyman-alpha transits, but also the transits in the O I, C II and Si III lines (Koskinen et al., 2013b). Recently, Bourrier and Lecavelier (2013) modeled the escape of hydrogen from the extended atmospheres of HD209458b and HD189733b and used the results to interpret Lyman-alpha observations. They included acceleration of hydrogen by radiation pressure and stellar wind protons to simulate the high velocity tails of the velocity distribution, arguing that the observations are explained by high velocity gas in the system while Voigt broadening is negligible. In this work we connect a free molecular flow (FMF) model similar to Bourrier and Lecavelier (2013) to the results of Koskinen et al. (2013b) and properly include absorption by the extended thermosphere in the transit model. In this manner, we can interpret the necessity of the various physical processes in matching the observed line profiles. Furthermore, the transit depths of this model can be used to re-evaluate the atmospheric model parameters to determine if they need to be adjusted due

  8. THE PROFILE OF STUDENT ACTIVITIES IN LEARNING BASIC NATURAL SCIENCE CONCEPTS THROUGH THE CONTEXTUAL TEACHING AND LEARNING (CTL APPROACH WITH GROUP INVESTIGATION (GI MODEL

    Directory of Open Access Journals (Sweden)

    Muhammad Minan Chusni

    2017-05-01

    Full Text Available Science learning essentially requires students to cultivate curiosity so that it triggers to conduct investigations by doing science activities. The purpose of this research is to know the profile of student activity in learning basic concept of IPA through contextual teaching and learning approach (CTL with group investigation (GI model.The subject of this research is Program of primary teacher education UMMGL students consisting of two classes with 83 people. The research method is descriptive. Data collection techniques were conducted by setting the focus of research, selecting informants as data sources, collecting data, assessing data quality, analyzing data, interpreting data, and drawing conclusions on the findings.From the research results can be concluded that the profile of student activity in learning basic concept of science through CTL approach with the average GI model is in very good category.

  9. Exhaustion of CTL memory and recrudescence of viremia in lymphocytic choriomeningitis virus-infected MHC class II-deficient mice and B cell-deficient mice

    DEFF Research Database (Denmark)

    Thomsen, Allan Randrup; Johansen, J; Marker, O

    1996-01-01

    To study the contribution of CD4+ T cells and B cells to antiviral immunity and long term virus control, MHC class II-deficient and B cell-deficient mice were infected with lymphocytic choriomeningitis virus. In class II-deficient mice, which lack CD4+ T cells, the primary CTL response is virtually...... this phenomenon could reflect participation of B cells and/or Abs in long term virus control, similar experiments were performed with mice that do not have mature B cells because of a disrupted membrane exon of the mu chain gene. In these mice, the cell-mediated immune response was slightly delayed, but transient...... and that in their absence, the virus-specific CTL potential becomes exhausted. Together our results indicate that while CD8+ cells play a dominant role in acute virus control, all three major components of the immune system are required for long term virus control....

  10. Comparison of CTL reactivity in the spleen and draining lymph nodes after immunization with peptides pulsed on dendritic cells or mixed with Freund's incomplete adjuvant

    DEFF Research Database (Denmark)

    Wang, Ming-Jun; Nissen, Mogens Holst; Buus, Søren

    2003-01-01

    OBJECTIVE: To compare CTL reactivity in the spleen and the draining lymph nodes (LN) from C57BL/6 mice after immunization with self and non-self peptides pulsed on autologous dendritic cells (DC) or mixed with Freund's incomplete adjuvant (FIA). METHODS: Peptides showing high to low binding...... in the draining LN, whereas non-self peptides mixed with FIA generated the strongest response in the spleen. CONCLUSIONS: DC-based immunization with non-self and self peptides is more efficient than immunization based on peptides mixed with FIA. DC-based immunization focuses the CTL response towards the spleen....... Immunization based on FIA focuses the response against self peptides towards the draining LN and non-self peptides towards the spleen....

  11. HTLV-1 Tax-Specific CTL Epitope-Pulsed Dendritic Cell Therapy Reduces Proviral Load in Infected Rats with Immune Tolerance against Tax.

    Science.gov (United States)

    Ando, Satomi; Hasegawa, Atsuhiko; Murakami, Yuji; Zeng, Na; Takatsuka, Natsuko; Maeda, Yasuhiro; Masuda, Takao; Suehiro, Youko; Kannagi, Mari

    2017-02-01

    Adult T cell leukemia/lymphoma (ATL), a CD4(+) T cell malignancy with a poor prognosis, is caused by human T cell leukemia virus type 1 (HTLV-1) infection. High proviral load (PVL) is a risk factor for the progression to ATL. We previously reported that some asymptomatic carriers had severely reduced functions of CTLs against HTLV-1 Tax, the major target Ag. Furthermore, the CTL responses tended to be inversely correlated with PVL, suggesting that weak HTLV-1-specific CTL responses may be involved in the elevation of PVL. Our previous animal studies indicated that oral HTLV-1 infection, the major route of infection, caused persistent infection with higher PVL in rats compared with other routes. In this study, we found that Tax-specific CD8(+) T cells were present, but not functional, in orally infected rats as observed in some human asymptomatic carriers. Even in the infected rats with immune unresponsiveness against Tax, Tax-specific CTL epitope-pulsed dendritic cell (DC) therapy reduced the PVL and induced Tax-specific CD8(+) T cells capable of proliferating and producing IFN-γ. Furthermore, we found that monocyte-derived DCs from most infected individuals still had the capacity to stimulate CMV-specific autologous CTLs in vitro, indicating that DC therapy may be applicable to most infected individuals. These data suggest that peptide-pulsed DC immunotherapy will be useful to induce functional HTLV-1-specific CTLs and decrease PVL in infected individuals with high PVL and impaired HTLV-1-specific CTL responses, thereby reducing the risk of the development of ATL. Copyright © 2017 by The American Association of Immunologists, Inc.

  12. Behavior of the Escape Rate Function in Hyperbolic Dynamical Systems

    CERN Document Server

    Demers, Mark

    2011-01-01

    For a fixed initial reference measure, we study the dependence of the escape rate on the hole for a smooth or piecewise smooth hyperbolic map. First, we prove the existence and Holder continuity of the escape rate for systems with small holes admitting Young towers. Then we consider general holes for Anosov diffeomorphisms, without size or Markovian restrictions. We prove bounds on the upper and lower escape rates using the notion of pressure on the survivor set and show that a variational principle holds under generic conditions. However, we also show that the escape rate function forms a devil's staircase with jumps along sequences of regular holes and present examples to elucidate some of the difficulties involved in formulating a general theory.

  13. On the large escape of ionizing radiation from GEHRs

    CERN Document Server

    Castellanos, M; Tenorio-Tagle, G

    2001-01-01

    A thorough analysis of well studied giant HII regions on galactic discs for which we know the ionizing stellar population, the gas metallicity and the Wolf-Rayet population, leads to photoionization models which can only match all observed line intensity ratios ([OIII], [OII], [NII], [SII] and [SIII] with respect to the intensity of H$\\beta$), as well as the H$\\beta$ luminosity and equivalent width if one allows for an important escape of energetic ionizing radiation. For the three regions presented here, the fractions of escaping Lyman continuum photons amount to 10 to 73 % and, in all cases, the larger fraction of escaping photons has energies between 13.6 and 24.4 eV. These escaping photons clearly must have an important impact as a source of ionization of the diffuse ionized gas (DIG) found surrounding many galaxies, as well as of the intergalactic medium (IGM).

  14. Theoretical Study on Ion Escape in Martian Atmosphere

    Institute of Scientific and Technical Information of China (English)

    SHI Jian-Kui; LIU Zhen-Xing; Klaus TORKAR; Tielong ZHANG

    2007-01-01

    @@ Based on the observation that Martian magnetic moment is gradually reducing from the ancient to the present,we investigate the O+ ion flux distribution along magnetic field lines and the ion escaping flux in Martian tail with different assumed Martian magnetic moments. The results show that the O+ ion flux along magnetic field lines decreases with distance from Mars; the ion flux along the field line decreases more quickly if the magnetic moment is larger; the larger the magnetic moment, the smaller the ion escaping flux in the Martian tail. The ion escaping flux depends on Z-coordinate in the Martian tail. With decrease of the magnetic moment, the ion escaping flux in the Martian tail increases. The results are significant for studying the water loss from Mars surface.

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

    Science.gov (United States)

    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…

  16. Amplitude modulation control of escape from a potential well

    Energy Technology Data Exchange (ETDEWEB)

    Chacón, R. [Departamento de Física Aplicada, Escuela de Ingenierías Industriales, Universidad de Extremadura, Apartado Postal 382, E-06006 Badajoz (Spain); Martínez García-Hoz, A. [Departamento de Física Aplicada, Escuela Universitaria Politécnica, Universidad de Castilla-La Mancha, E-13400 Almadén (Ciudad Real) (Spain); Miralles, J.J. [Departamento de Física Aplicada, Escuela de Ingenieros Industriales, Universidad de Castilla-La Mancha, E-02071 Albacete (Spain); Martínez, P.J. [Departamento de Física Aplicada, E.I.N.A., Universidad de Zaragoza, E-50018 Zaragoza (Spain); Instituto de Ciencia de Materiales de Aragón, CSIC – Universidad de Zaragoza, E-50009 Zaragoza (Spain)

    2014-03-01

    We demonstrate the effectiveness of periodic amplitude modulations in controlling (suppressing and enhancing) escape from a potential well through the universal model of a damped Helmholtz oscillator subjected to an external periodic excitation (the escape-inducing excitation) whose amplitude is periodically modulated (the escape-controlling excitation). Analytical and numerical results show that this multiplicative control works reliably for different subharmonic resonances between the two periodic excitations involved, and that its effectiveness is comparable to those of different methods of additive control. Additionally, we demonstrate the robustness of the multiplicative control against the presence of low-intensity Gaussian noise. -- Highlights: •Multiplicative control of escape from a potential well has been demonstrated. •Theoretical predictions are obtained from a Melnikov analysis. •It has been shown the robustness of the multiplicative control against noise.

  17. Oxygen Escape from Venus During High Dynamic Pressure ICMEs

    Science.gov (United States)

    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.

  18. Estimation of coho salmon escapement in the Ugashik lakes

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — From 26 July to 24 September 2002, hourly counts were conducted from counting towers to estimate the escapement of coho salmon Oncorhynchus kisutch into the Ugashik...

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

    Science.gov (United States)

    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

  20. Response of ELA-A1 horses immunized with lipopeptide containing an equine infectious anemia virus ELA-A1-restricted CTL epitope to virus challenge.

    Science.gov (United States)

    Ridgely, Sherritta L; Zhang, Baoshan; McGuire, Travis C

    2003-01-17

    Lipopeptide containing an ELA-A1-restricted cytotoxic T lymphocyte (CTL) epitope from the envelope surface unit (SU) protein of the EIAV(WSU5) strain was used to immunize three horses having the ELA-A1 haplotype. Peptide-specific ELA-A1-restricted CTL were induced in all three horses, although these were present transiently in PBMC. These horses were further immunized with lipopeptide containing the corresponding CTL epitope from the EIAV(PV) strain. Then, the three immunized horses and three non-immunized horses were challenged by intravenous inoculation with 300 TCID(50) EIAV(PV). All horses developed cell free viremia, fever and thrombocytopenia. However, there was a statistically lower fever and thrombocytopenia severity score in the immunized group. Shorter duration of plasma viral load in two of the three immunized horses likely explains the less severe clinical disease in this group. Results indicate that lipopeptide immunization had a protective effect against development of clinical disease following virus challenge.

  1. GREEN PEA GALAXIES REVEAL SECRETS OF Lyα ESCAPE

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Huan; Wang, Junxian [CAS Key Laboratory for Research in Galaxies and Cosmology, Department of Astronomy, University of Science and Technology of China (China); Malhotra, Sangeeta; Rhoads, James E. [Arizona State University, School of Earth and Space Exploration (United States); Gronke, Max; Dijkstra, Mark [Institute of Theoretical Astrophysics, University of Oslo (Norway); Jaskot, Anne [Smith College, Northampton, MA (United States); Zheng, Zhenya, E-mail: yanghuan@mail.ustc.edu.cn, E-mail: huan.y@asu.edu, E-mail: Sangeeta.Malhotra@asu.edu, E-mail: James.Rhoads@asu.edu [Pontificia Universidad Católica de Chile, Santiago (Chile)

    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.

  2. Purinergic Inhibition of ENaC Produces Aldosterone Escape

    OpenAIRE

    Stockand, James D.; Mironova, Elena; Bugaj, Vladislav; Rieg, Timo; Insel, Paul A.; Vallon, Volker; Peti-Peterdi, Janos; Pochynyuk, Oleh

    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 concentrat...

  3. Group chase and escape with sight-limited chasers

    Science.gov (United States)

    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.

  4. Green Pea Galaxies Reveal Secrets of Ly$\\alpha$ Escape

    CERN Document Server

    Yang, Huan; Gronke, Max; Rhoads, James E; Jaskot, Anne; Zheng, Zhenya; Dijkstra, Mark

    2015-01-01

    Star-formation in galaxies generates a lot of Ly$\\alpha$ photons. Understanding the escape of Ly$\\alpha$ photons from galaxies is a key issue in studying high redshift galaxies and probing cosmic reionization with Ly$\\alpha$. To understand Ly$\\alpha$ escape, it is valuable to study analogs of high redshift Ly$\\alpha$ emitters in nearby universe. However, most nearby analogs have too small a Ly$\\alpha$ equivalent width and escape fraction compared to high redshift Ly$\\alpha$ emitters. One different group of nearby analogs are "Green Pea" galaxies, selected by their high equivalent width optical emission lines. Here we show that Green Pea galaxies have strong Ly$\\alpha$ emission lines and high Ly$\\alpha$ escape fraction (see also Henry et al. 2015), providing an opportunity to solve Ly$\\alpha$ escape problem. Green Peas have a Ly$\\alpha$ equivalent width distribution similar to high redshift Ly$\\alpha$ emitters. The Ly$\\alpha$ escape fraction correlates with many quantities of Ly$\\alpha$ profile, especially the...

  5. Lyman-Werner UV Escape Fractions from Primordial Halos

    CERN Document Server

    Schauer, Anna T P; Glover, Simon C O; Klessen, Ralf S

    2015-01-01

    Population III stars can regulate star formation in the primordial Universe in several ways. They can ionize nearby halos, and even if their ionizing photons are trapped by their own halos, their Lyman-Werner (LW) photons can still escape and destroy H$_2$ in other halos, 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 halos by halo or stellar mass. To do so, we perform radiation hydrodynamical simulations of LW UV escape from 9--120 M$_{\\odot}$ Pop III stars in $10^5$ to $10^7$ M$_{\\odot}$ halos with ZEUS-MP. We find that photons in the LW lines (i.e. those responsible for destroying H$_{2}$ in nearby systems) have escape fractions ranging from 0% to 85%. 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 t...

  6. Escape dynamics and fractal basin boundaries in Seyfert galaxies

    CERN Document Server

    Zotos, Euaggelos E

    2015-01-01

    The escape dynamics in a simple analytical gravitational model which describes the motion of stars in a Seyfert galaxy is investigated in detail. We conduct a thorough numerical analysis distinguishing between regular and chaotic orbits as well as between trapped and escaping orbits, considering only unbounded motion for several energy levels. In order to distinguish safely and with certainty between ordered and chaotic motion, we apply the Smaller ALingment Index (SALI) method. It is of particular interest to locate the escape basins through the openings around the collinear Lagrangian points $L_1$ and $L_2$ and relate them with the corresponding spatial distribution of the escape times of the orbits. Our exploration takes place both in the physical $(x,y)$ and in the phase $(x,\\dot{x})$ space in order to elucidate the escape process as well as the overall orbital properties of the galactic system. Our numerical analysis reveals the strong dependence of the properties of the considered escape basins with the...

  7. Recognition of HIV-1 peptides by host CTL is related to HIV-1 similarity to human proteins.

    Directory of Open Access Journals (Sweden)

    Morgane Rolland

    Full Text Available BACKGROUND: While human immunodeficiency virus type 1 (HIV-1-specific cytotoxic T lymphocytes preferentially target specific regions of the viral proteome, HIV-1 features that contribute to immune recognition are not well understood. One hypothesis is that similarities between HIV and human proteins influence the host immune response, i.e., resemblance between viral and host peptides could preclude reactivity against certain HIV epitopes. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the extent of similarity between HIV-1 and the human proteome. Proteins from the HIV-1 B consensus sequence from 2001 were dissected into overlapping k-mers, which were then probed against a non-redundant database of the human proteome in order to identify segments of high similarity. We tested the relationship between HIV-1 similarity to host encoded peptides and immune recognition in HIV-infected individuals, and found that HIV immunogenicity could be partially modulated by the sequence similarity to the host proteome. ELISpot responses to peptides spanning the entire viral proteome evaluated in 314 individuals showed a trend indicating an inverse relationship between the similarity to the host proteome and the frequency of recognition. In addition, analysis of responses by a group of 30 HIV-infected individuals against 944 overlapping peptides representing a broad range of individual HIV-1B Nef variants, affirmed that the degree of similarity to the host was significantly lower for peptides with reactive epitopes than for those that were not recognized. CONCLUSIONS/SIGNIFICANCE: Our results suggest that antigenic motifs that are scarcely represented in human proteins might represent more immunogenic CTL targets not selected against in the host. This observation could provide guidance in the design of more effective HIV immunogens, as sequences devoid of host-like features might afford superior immune reactivity.

  8. Prognostic Factors Related to Clinical Response in Patients with Metastatic MelanomaTreated by CTL-Associated Antigen-4 Blockade

    Science.gov (United States)

    Downey, Stephanie G.; Klapper, Jacob A.; Smith, Franz O.; C.Yang, James; Sherry, Richard M.; Royal, Richard E.; Kammula, Udai S.; Hughes, Marybeth S.; Allen, Tamika E.; Levy, Catherine L.; Michael, Yellin; Nichol, Geoffrey; E.White, Donald; Steinberg, Seth M.; Rosenberg, Steven A.

    2007-01-01

    Purpose CTL-associated antigen 4 (CTLA-4) can inhibit T-cell activation and helps maintain peripheral self-tolerance. Previously, we showed immune-related adverse events (IRAE) and objective, durable clinical responses in patients with metastatic melanoma treated with CTLA-4 blockade.We have now treated139 patients in two trials and have sufficient follow-up to examine factors associated with clinical response. Experimental Design A total of 139 patients with metastatic melanoma were treated: 54 patients received ipilimumab in conjunction with peptide vaccinations and 85 patients were treated with intrapatient dose escalation of ipilimumab and randomized to receive peptides in accordance with HLA-A*0201status. Results Three patients achieved complete responses (CR; ongoing at 29+, 52+, and 53+ months); an additional 20 patients achieved partial responses (PR) for an overall objective response rate of 17%. The majority of patients (62%, 86 of 139) developed some form of IRAE, which was associated with a greater probability of objective antitumor response (P = 0.0004); all patients with CR had more severe IRAEs. Prior therapy with IFNα-2b was a negative prognostic factor, whereas prior high-dose interleukin-2 did not significantly affect the probability of response. There were no significant differences in the rate of clinical response or development of IRAEs between the two trials. The duration of tumor response was not affected by the use of high-dose steroids for abrogation of treatment-related toxicities (P = 0.23). There were no treatment-related deaths. Conclusion In patients with metastatic melanoma, ipilimumab can induce durable objective clinical responses, which are related to the induction of IRAEs. PMID:17982122

  9. A new vaccine escape mutant of hepatitis B virus causes occult infection.

    Science.gov (United States)

    Ye, Qing; Shang, Shi-Qiang; Li, Wei

    2015-01-01

    There is growing public concern regarding assay sensitivity to HBsAg mutants in clinical diagnosis and vaccine escape. The aim of this study is to introduce a new HBsAg mutant strain. The serum samples were those of patient X at the age of 3 months and 3 years respectively, and of her mother immediately before parturition, which were used to amplify the HBsAg-coding DNA fragments by PCR. The HBsAg DNA sequences were translated into their corresponding amino acid sequences and then aligned in pubmed with nucleotide blast. The sequencing data of S coding regions shows that patient X has been infected by a new HBV variant with an A to C substitution at nt431, resulting in an Asp(GAC)to Ala(GCC) substitution at aa144 of major protein; CC to AA substitution at nt359 and nt360, resulting in an Pro(CCC) to Gln(CAA) substitution at aa120 of pre "a" epitope; A to G substitution at nt491, resulting in an Glu(GAG) to Gly(GGG) substitution at aa164 of post "a" epitope. Three new mutations (S171F, S174N and Q181R) at the antigenic epitopes of HBV presented by HLA class I molecules are found. The HBV mutant strain causes vaccine escape and occult infection.

  10. Early endosomal escape of a cyclic cell-penetrating peptide allows effective cytosolic cargo delivery.

    Science.gov (United States)

    Qian, Ziqing; LaRochelle, Jonathan R; Jiang, Bisheng; Lian, Wenlong; Hard, Ryan L; Selner, Nicholas G; Luechapanichkul, Rinrada; Barrios, Amy M; Pei, Dehua

    2014-06-24

    Cyclic heptapeptide cyclo(FΦRRRRQ) (cFΦR4, where Φ is l-2-naphthylalanine) was recently found to be efficiently internalized by mammalian cells. In this study, its mechanism of internalization was investigated by perturbing various endocytic events through the introduction of pharmacologic agents and genetic mutations. The results show that cFΦR4 binds directly to membrane phospholipids, is internalized into human cancer cells through endocytosis, and escapes from early endosomes into the cytoplasm. Its cargo capacity was examined with a wide variety of molecules, including small-molecule dyes, linear and cyclic peptides of various charged states, and proteins. Depending on the nature of the cargos, they may be delivered by endocyclic (insertion of cargo into the cFΦR4 ring), exocyclic (attachment of cargo to the Gln side chain), or bicyclic approaches (fusion of cFΦR4 and cyclic cargo rings). The overall delivery efficiency (i.e., delivery of cargo into the cytoplasm and nucleus) of cFΦR4 was 4-12-fold higher than those of nonaarginine, HIV Tat-derived peptide, or penetratin. The higher delivery efficiency, coupled with superior serum stability, minimal toxicity, and synthetic accessibility, renders cFΦR4 a useful transporter for intracellular cargo delivery and a suitable system for investigating the mechanism of endosomal escape.

  11. 78 FR 54585 - Safety Zone; Escape to Miami Triathlon, Biscayne Bay, Miami, FL

    Science.gov (United States)

    2013-09-05

    ... SECURITY Coast Guard 33 CFR Part 165 RIN 1625-AA00 Safety Zone; Escape to Miami Triathlon, Biscayne Bay... during the Publix Escape to Miami Triathlon. The Publix Escape to Miami Triathlon is scheduled to take... of life on navigable waters of the United States during the Publix Escape to Miami Triathlon....

  12. Structural controls on fluid escape from the subduction interface

    Science.gov (United States)

    Reynard, Bruno; Tauzin, Benoit; Bodin, Thomas; Perrillat, Jean-Philippe; Debayle, Eric

    2017-04-01

    Seismic activity and non-volcanic tremors are often associated with fluid circulation resulting from the dehydration of subducting plates. Tremors in the overriding continental crust of several subduction zones suggest fluid circulation at shallower depths, but potential fluid pathways are still poorly documented. Fluids are also released at different depths in hot and cold subduction zones, which may result in different schemes of fluid escape. We document potential fluid pathways in Cascadia, one of the hottest subduction zone, using receiver function analysis. We provide evidence for a seismic discontinuity near 15 km depth in the crust of the overriding North American plate. This interface is segmented, and its interruptions are spatially correlated with conductive regions of the forearc and shallow swarms of seismicity and non-volcanic tremors. The comparison of seismological and electrical conductivity profiles suggests that fluid escape is controlled by fault zones between blocks of accreted terranes in the overriding plate. These zones constitute fluid escape routes that may influence the seismic cycle by releasing fluid pressure from the megathrust. Results on Cascadia are compared to fluid escape routes suggested by former geophysical observations in NE Japan, one of the coldest subduction zones. Links between fluid escape, permeability and fluid-rock reactions at or above the plate interface are discussed.

  13. Comparison of spacecraft crew escape systems through dynamic optimization

    Science.gov (United States)

    Hart, William G., III

    Crew escape systems have been a vital component of ensuring safety onboard manned spacecraft. Although there have been only a few aborts involving their use, their operation helps decrease risk in what is known to be a hazardous field. But despite their high reliability, crew escape systems typically suffer from heavy weight, lack of control and hazardous chemical propellants. Hybrid propulsion systems could be a viable solution to all of these problems. With their inert components, ability to throttle and higher specific impulse than solids, hybrids have obtained interest in recent years. This dissertation presents a method that can be used to compare solid and hybrid propulsion systems for the crew escape systems of spacecraft. The concepts of dynamic optimization, Monte Carlo simulation and propulsion system design are combined to produce a tool which can predict the probability of survival for a given abort scenario. The method can also determine the effect of uncertain variables, such as reaction time or the payload of the vehicle, in the safety of the crew. The method is then used to compare crew escape systems for two separate vehicles: a separable crew cabin proposed for the Space Shuttle Launch Vehicle and the Launch Escape System for the Crew Exploration Vehicle scheduled to begin operation in 2012. The effects of uncertain parameters are also studied. The results show the utility of this method and the objective function, and how it could be used in the design process for future space vehicles.

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

    Science.gov (United States)

    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.

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

    CERN Document Server

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

    2015-01-01

    By considering martian-like planetary embryos inside the habitable zone of solar-like stars we study the behavior of the hydrodynamic atmospheric escape of hydrogen for small values of the Jeans escape parameter $\\beta < 3$, near the base of the thermosphere, that is defined as a ratio of the gravitational and thermal energy. Our study is based on a 1-D 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. We find that when the $\\beta$ value near the mesopause/homopause level exceeds a critical value of $\\sim$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 $\\beta$ decr...

  16. Immunosuppressive cells in tumor immune escape and metastasis.

    Science.gov (United States)

    Liu, Yang; Cao, Xuetao

    2016-05-01

    Tumor immune escape and the initiation of metastasis are critical steps in malignant progression of tumors and have been implicated in the failure of some clinical cancer immunotherapy. Tumors develop numerous strategies to escape immune surveillance or metastasize: Tumors not only modulate the recruitment and expansion of immunosuppressive cell populations to develop the tumor microenvironment or pre-metastatic niche but also switch the phenotype and function of normal immune cells from a potentially tumor-reactive state to a tumor-promoting state. Immunosuppressive cells facilitate tumor immune escape by inhibiting antitumor immune responses and furthermore promote tumor metastasis by inducing immunosuppression, promoting tumor cell invasion and intravasation, establishing a pre-metastatic niche, facilitating epithelial-mesenchymal transition, and inducing angiogenesis at primary tumor or metastatic sites. Numerous translational studies indicate that it is possible to inhibit tumor immune escape and prevent tumor metastasis by blocking immunosuppressive cells and eliminating immunosuppressive mechanisms that are induced by either immunosuppressive cells or tumor cells. Furthermore, many clinical trials targeting immunosuppressive cells have also achieved good outcome. In this review, we focus on the underlying mechanisms of immunosuppressive cells in promoting tumor immune escape and metastasis, discuss our current understanding of the interactions between immunosuppressive cells and tumor cells in the tumor microenvironment, and suggest future research directions as well as potential clinical strategies in cancer immunotherapy.

  17. Escape dynamics in a binary system of interacting galaxies

    CERN Document Server

    Zotos, Euaggelos E

    2016-01-01

    The escape dynamics in an analytical gravitational model which describes the motion of stars in a binary system of interacting dwarf spheroidal galaxies is investigated in detail. We conduct a numerical analysis distinguishing between regular and chaotic orbits as well as between trapped and escaping orbits, considering only unbounded motion for several energy levels. In order to distinguish safely and with certainty between ordered and chaotic motion, we apply the Smaller ALingment Index (SALI) method. It is of particular interest to locate the escape basins through the openings around the collinear Lagrangian points $L_1$ and $L_2$ and relate them with the corresponding spatial distribution of the escape times of the orbits. Our exploration takes place both in the configuration $(x,y)$ and in the phase $(x,\\dot{x})$ space in order to elucidate the escape process as well as the overall orbital properties of the galactic system. Our numerical analysis reveals the strong dependence of the properties of the con...

  18. Enhancing endosomal escape for nanoparticle mediated siRNA delivery

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  20. Behavior of Ants Escaping from a Single-Exit Room

    Science.gov (United States)

    Wang, Shujie; Lv, Wei; Song, Weiguo

    2015-01-01

    To study the rules of ant behavior and group-formation phenomena, we examined the behaviors of Camponotus japonicus, a species of large ant, in a range of situations. For these experiments, ants were placed inside a rectangular chamber with a single exit that also contained a filter paper soaked in citronella oil, a powerful repellent. The ants formed several groups as they moved toward the exit to escape. We measured the time intervals between individual escapes in six versions of the experiment, each containing an exit of a different width, to quantify the movement of the groups. As the ants exited the chamber, the time intervals between individual escapes changed and the frequency distribution of the time intervals exhibited exponential decay. We also investigated the relationship between the number of ants in a group and the group flow rate. PMID:26125191

  1. Escape probability of the super-Penrose process

    CERN Document Server

    Ogasawara, Kota; Miyamoto, Umpei; Igata, Takahisa; Patil, Mandar

    2016-01-01

    We consider a head-on collision of two massive particles that move in the equatorial plane of an extremal Kerr black hole, which results in the production of two massless particles. Focusing a typical case, where both of the colliding particles have zero angular momenta, we show that a massless particle produced in such a collision can escape to infinity with arbitrarily large energy in the near-horizon limit of the collision point. Furthermore, if we assume that the emission of the produced massless particles is isotropic in the center-of-mass frame but confined to the equatorial plane, the escape probability of the produced massless particle approaches $5/12$ and almost all escaping massless particles have arbitrarily large energy at infinity and an impact parameter approaching $2M$.

  2. Escape rate and diffusion of a Stochastically Driven particle

    Science.gov (United States)

    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

  3. Second site escape of a T20-dependent HIV-1 variant by a single amino acid change in the CD4 binding region of the envelope glycoprotein

    Directory of Open Access Journals (Sweden)

    Berkhout Ben

    2006-11-01

    Full Text Available Abstract Background We previously described the selection of a T20-dependent human immunodeficiency virus type-1 (HIV-1 variant in a patient on T20 therapy. The fusion inhibitor T20 targets the viral envelope (Env protein by blocking a conformational switch that is critical for viral entry into the host cell. T20-dependent viral entry is the result of 2 mutations in Env (GIA-SKY, creating a protein that undergoes a premature conformational switch, and the presence of T20 prevents this premature switch and rescues viral entry. In the present study, we performed 6 independent evolution experiments with the T20-dependent HIV-1 variant in the absence of T20, with the aim to identify second site compensatory changes, which may provide new mechanistic insights into Env function and the T20-dependence mechanism. Results Escape variants with improved replication capacity appeared within 42 days in 5 evolution cultures. Strikingly, 3 cultures revealed the same single amino acid change in the CD4 binding region of Env (glycine at position 431 substituted for arginine: G431R. This mutation was sufficient to abolish the T20-dependence phenotype and restore viral replication in the absence of T20. The GIA-SKY-G431R escape variant produces an Env protein that exhibits reduced syncytia formation and reduced cell-cell fusion activity. The escape variant was more sensitive to an antibody acting on an early gp41 intermediate, suggesting that the G431R mutation helps preserve a pre-fusion Env conformation, similar to T20 action. The escape variant was also less sensitive to soluble CD4, suggesting a reduced CD4 receptor affinity. Conclusion The forced evolution experiments indicate that the premature conformational switch of the T20-dependent HIV-1 Env variant (GIA-SKY can be corrected by a second site mutation in Env (GIA-SKY-G431R that affects the interaction with the CD4 receptor.

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

    Science.gov (United States)

    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.

  5. Escape probability based routing for ad hoc networks

    Institute of Scientific and Technical Information of China (English)

    Zhang Xuanping; Qin Zheng; Li Xin

    2006-01-01

    Routes in an ad hoc network may fail frequently because of node mobility. Stability therefore can be an important element in the design of routing protocols. The node escape probability is introduced to estimate the lifetime and stability of link between neighboring nodes and the escape probability based routing (EPBR) scheme to discover stable routes is proposed. Simulation results show that the EPBR can discover stable routes to reduce the number of route rediscovery, and is applicable for the situation that has highly dynamic network topology with broad area of communication.

  6. Escape of protists in predator-generated feeding currents

    DEFF Research Database (Denmark)

    Jakobsen, Hans Henrik

    2002-01-01

    The ciliate Strobilidium sp. and 2 flagellates, Chrysochromulina simplex and Gymnodinium sp., were exposed to predator-generated feeding currents, and their escape responses were quantified using 2- and 3-dimensional video techniques. All 3 studied organisms responded by escaping at a defined...... of Strobilidium sp. to the copepod Temora longicornis. The predicted reaction distance fit closely that measured, When the flagellates were exposed to the flow field of the ciliate Uronema filificum, they both responded up-stream to the feeding current. From the distance at which the flagellates responded...

  7. Development of a Luminex Bead Based Assay for Diagnosis of Toxocariasis Using Recombinant Antigens Tc-CTL-1 and Tc-TES-26.

    Science.gov (United States)

    Anderson, John P; Rascoe, Lisa N; Levert, Keith; Chastain, Holly M; Reed, Matthew S; Rivera, Hilda N; McAuliffe, Isabel; Zhan, Bin; Wiegand, Ryan E; Hotez, Peter J; Wilkins, Patricia P; Pohl, Jan; Handali, Sukwan

    2015-01-01

    The clinical spectrum of human disease caused by the roundworms Toxocara canis and Toxocara cati ranges from visceral and ocular larva migrans to covert toxocariasis. The parasite is not typically recovered in affected tissues, so detection of parasite-specific antibodies is usually necessary for establishing a diagnosis. The most reliable immunodiagnostic methods use the Toxocara excretory-secretory antigens (TES-Ag) in ELISA formats to detect Toxocara-specific antibodies. To eliminate the need for native parasite materials, we identified and purified immunodiagnostic antigens using 2D gel electrophoresis followed by electrospray ionization mass spectrometry. Three predominant immunoreactive proteins were found in the TES; all three had been previously described in the literature: Tc-CTL-1, Tc-TES-26, and Tc-MUC-3. We generated Escherichia coli expressed recombinant proteins for evaluation in Luminex based immunoassays. We were unable to produce a functional assay with the Tc-MUC-3 recombinant protein. Tc-CTL-1 and Tc-TES-26 were successfully coupled and tested using defined serum batteries. The use of both proteins together generated better results than if the proteins were used individually. The sensitivity and specificity of the assay for detecting visceral larval migrans using Tc-CTL-1 plus Tc-TES-26 was 99% and 94%, respectively; the sensitivity for detecting ocular larval migrans was 64%. The combined performance of the new assay was superior to the currently available EIA and could potentially be employed to replace current assays that rely on native TES-Ag.

  8. Chimeric flagellin expressed by Salmonella typhimurium induces an ESAT-6-specific Th 1-type immune response and CTL effects following intranasal immunization

    Institute of Scientific and Technical Information of China (English)

    Hui Zhang; Liu Liu; Ke Wen; Jinlin Huang; Shizhong Geng; Junsong Shen; Zhiming Pan; Xinan Jiao

    2011-01-01

    The flagellin component FliC of Salmonella typhimurium is capable of activating the innate immune system via specific interactions with TLR5 and can also act as a carrier of foreign antigen to elicit antigen-specific immune responses.Thus,we constructed an attenuated Salmonella strain SL5928(fliC/esat) expressing chimeric flagellin that contained the ESAT-6 antigen coding sequence of Mycobacterium tuberculosis inserted into the highly variable region of the Salmonella flagellin coding gene fliCi.The chimeric flagellin functioned normally,as demonstrated using a flagella swarming assay and electron microscopy.To analyze the effects of chimeric flagellin,the cell-mediated immune response and cytotoxic T lymphocyte (CTL) effects specific for ESAT-6antigen were tested after intranasal immunization of mice with flagellated Salmonella SL5928(fliC/esat).The results showed that SL5928(fliC/esat) intranasal immunization can strongly elicit an ESAT-6-specific T helper (Th) 1-type immune response in mucosal lymphoid tissues,such as nasopharynx-associated lymph nodes,lung and Peyer's patches,and a Th 1/Th2 response was elicited in spleen and mesenteric lymph nodes.Furthermore,intranasal immunization of SL5928(fliC/esat) produced efficient CTL effects,as demonstrated using a 5-and 6-carboxyfluorescein diacetate succinimidyl ester (CFSE) assay.Thus,our study revealed that Salmonella flagellin acts as a carrier for foreign antigen and triggers strong Th 1 and CTL responses during intranasal immunization.Chimeric flagellin is potentially an effective strategy for the development of novel vaccines against tuberculosis in humans and animals.

  9. PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25(Hi) regulatory T cells.

    Science.gov (United States)

    Wang, Wenshi; Lau, Roy; Yu, Daohai; Zhu, Weiwei; Korman, Alan; Weber, Jeffrey

    2009-09-01

    Regulatory CD4(+)CD25(Hi) T cells (Treg) and programmed death-1 (PD-1) molecule have emerged as pivotal players in immune regulation. However, the underlying mechanisms by which they impact antigen-specific CD8(+) immune responses in cancer patients and how they interact with each other under physiologic conditions remain unclear. Herein, we examined the relationship of PD-1 and its abrogation to the function of Treg in patients with melanoma using short-term in vitro assays to generate melanoma-specific T cells. We identified Treg in the circulation of vaccinated melanoma patients and detected PD-1 expression on vaccine-induced melanoma antigen-specific CTLs, as well as on and within Treg from patients' peripheral blood. Programmed death ligand (PD-L) 1 expression was also detected on patients' Treg. PD-1 blockade promoted the generation of melanoma antigen-specific CTLs and masked their inhibition by Treg. The mechanisms by which PD-1 blockade mediated immune enhancement included direct augmentation of melanoma antigen-specific CTL proliferation, heightening their resistance to inhibition by Treg and direct limitation of the inhibitory ability of Treg. PD-1 blockade reversed the increased expression of PD-1 and PD-L1 on melanoma antigen-specific CTL by Treg, rescued INF-gamma and IL-2 or INF-gamma and tumor necrosis factor-alpha co-expression and expression of IL-7 receptor by melanoma antigen-specific CTL which were diminished by Treg. PD-1 blockade also resulted in down-regulation of intracellular FoxP3 expression by Treg. These data suggest that PD-1 is importantly implicated in the regulation of Treg function in melanoma patients.

  10. PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+CD25Hi regulatory T cells

    Science.gov (United States)

    Lau, Roy; Yu, Daohai; Zhu, Weiwei; Korman, Alan; Weber, Jeffrey

    2009-01-01

    Regulatory CD4+CD25Hi T cells (Treg) and programmed death-1 (PD-1) molecule have emerged as pivotal players in immune regulation. However, the underlying mechanisms by which they impact antigen-specific CD8+ immune responses in cancer patients and how they interact with each other under physiologic conditions remain unclear. Herein, we examined the relationship of PD-1 and its abrogation to the function of Treg in patients with melanoma using short-term in vitro assays to generate melanoma-specific T cells. We identified Treg in the circulation of vaccinated melanoma patients and detected PD-1 expression on vaccine-induced melanoma antigen-specific CTLs, as well as on and within Treg from patients’ peripheral blood. Programmed death ligand (PD-L) 1 expression was also detected on patients’ Treg. PD-1 blockade promoted the generation of melanoma antigen-specific CTLs and masked their inhibition by Treg. The mechanisms by which PD-1 blockade mediated immune enhancement included direct augmentation of melanoma antigen-specific CTL proliferation, heightening their resistance to inhibition by Treg and direct limitation of the inhibitory ability of Treg. PD-1 blockade reversed the increased expression of PD-1 and PD-L1 on melanoma antigen-specific CTL by Treg, rescued INF-γ and IL-2 or INF-γ and tumor necrosis factor-α co-expression and expression of IL-7 receptor by melanoma antigen-specific CTL which were diminished by Treg. PD-1 blockade also resulted in down-regulation of intracellular FoxP3 expression by Treg. These data suggest that PD-1 is importantly implicated in the regulation of Treg function in melanoma patients. PMID:19651643

  11. Autologous HIV-1 neutralizing antibodies: emergence of neutralization-resistant escape virus and subsequent development of escape virus neutralizing antibodies

    DEFF Research Database (Denmark)

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

    1992-01-01

    The capacity of consecutive human sera to neutralize sequentially obtained autologous virus isolates was studied. HIV-1 was isolated three times over a 48-164-week period from three individuals immediately after seroconversion and from two individuals in later stages of infection. Development of ...... escape virus may be part of the explanation of the apparent failure of the immune system to control HIV infection.......The capacity of consecutive human sera to neutralize sequentially obtained autologous virus isolates was studied. HIV-1 was isolated three times over a 48-164-week period from three individuals immediately after seroconversion and from two individuals in later stages of infection. Development...... of neutralizing antibodies to the primary virus isolates was detected 13-45 weeks after seroconversion. Emergence of escape virus with reduced sensitivity to neutralization by autologous sera was demonstrated. The patients subsequently developed neutralizing antibodies against the escape virus but after a delay...

  12. Occult hepatitis B virus infection and S gene escape mutants in HIV-infected patients after hepatitis B virus vaccination.

    Science.gov (United States)

    Aghakhani, Arezoo; Mohraz, Minoo; Aghasadeghi, Mohammad Reza; Banifazl, Mohammad; Vahabpour, Rouhollah; Karami, Afsaneh; Foroughi, Maryam; Ramezani, Amitis

    2016-10-01

    Hepatitis B virus (HBV) vaccination is recommended for HIV patients. Despite the relative success of HBV vaccination, breakthrough infections can occur infrequently in patients, and it can be due to occult HBV infection, vaccine unresponsiveness and/or emergence of escape mutants. This study assessed the presence of occult HBV infection and S gene escape mutants in HIV-positive patients after HBV vaccination. Ninety-two HIV-positive patients were enrolled in this study, including 52 responders to HBV vaccine and 40 non-responders. All of the cases received HBV vaccine according to routine HBV vaccination protocols. The presence of HBV-DNA was determined by real-time polymerase chain reaction (PCR). In HBV-DNA positive samples, the most conserved regions of S gene sequences were amplified by nested PCR and PCR products were sequenced. Occult HBV infection was detected in two cases. Glycine to arginine mutation at residue 145 (G145R) within the 'a' region of the S gene was detected in one of the occult HBV infection cases who was in the non-responder group. This study showed that the prevalence of occult HBV infection and vaccine escape mutants was low in our HBV-vaccinated HIV-positive patients in both responder and non-responder groups, so there was no alarming evidence indicating breakthrough HBV infection in our vaccinated HIV-positive cases. © The Author(s) 2016.

  13. Rapid selection of escape mutants by the first CD8 T cell responses in acute HIV-1 infection

    Energy Technology Data Exchange (ETDEWEB)

    Korber, Bette Tina Marie [Los Alamos National Laboratory

    2008-01-01

    The recent failure of a vaccine that primes T cell responses to control primary HIV-1 infection has raised doubts about the role of CD8+ T cells in early HIV-1 infection. We studied four patients who were identified shortly after HIV-1 infection and before seroconversion. In each patient there was very rapid selection of multiple HIV-1 escape mutants in the transmitted virus by CD8 T cells, including examples of complete fixation of non-synonymous substitutions within 2 weeks. Sequencing by single genome amplification suggested that the high rate of virus replication in acute infection gave a selective advantage to virus molecules that contained simultaneous and gained sequential T cell escape mutations. These observations show that whilst early HIV-1 specific CD8 T cells can act against virus, rapid escape means that these T cell responses are unlikely to benefit the patient and may in part explain why current HIV-1 T cell vaccines may not be protective.

  14. Purinergic inhibition of ENaC produces aldosterone escape.

    Science.gov (United States)

    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.

  15. The Dutch approach to the escape from large compartments

    NARCIS (Netherlands)

    Janse, E.W.; Leur, P.H.E. van de

    1999-01-01

    In the Netherlands, the building regulations have no design mies for large fire compartments (over 1000 m2). With respect to the ability of people to escape from a fire in such large spaces, the Centre for Fire Research of TNO Building and Construction Research has developed a guideline that integra

  16. Entropy, Lyapunov Exponents and Escape Rates in Open Systems

    CERN Document Server

    Demers, Mark; Young, Lai-Sang

    2011-01-01

    We study the relation between escape rates and pressure in general dynamical systems with holes, where pressure is defined to be the difference between entropy and the sum of positive Lyapunov exponents. Central to the discussion is the formulation of a class of invariant measures supported on the survivor set over which we take the supremum to measure the pressure. Upper bounds for escape rates are proved for general diffeomorphisms of manifolds, possibly with singularities, for arbitrary holes and natural initial distributions including Lebesgue and SRB measures. Lower bounds do not hold in such generality, but for systems admitting Markov tower extensions with spectral gaps, we prove the equality of the escape rate with the absolute value of the pressure and the existence of an invariant measure realizing the escape rate, i.e. we prove a full variational principle. As an application of our results, we prove a variational principle for the billiard map associated with a planar Lorentz gas of finite horizon ...

  17. Brain size as a driver of avian escape strategy.

    Science.gov (United States)

    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. Escaping Embarrassment: Face-Work in the Rap Cipher

    Science.gov (United States)

    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,…

  19. A Slam Simulation Base Escape Model Using Response Surface Methodology.

    Science.gov (United States)

    1986-03-01

    OS/84D-8. School of Engineering, Air Force Institute of Technology (AU), Wright-Patterson AFB, OH December 1984. 19. Modianos , Doan T. and others...Pritsker & Associates, Inc, West Lafayette, In--ana, 1984. 21. Patrick , Rayford P. Nuclear Hardness and Base Escape, Engineering Report No. S-112. Omaha

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

    Science.gov (United States)

    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)

  1. The spectrum of Cosmic Rays escaping from relativistic shocks

    CERN Document Server

    Katz, Boaz; Waxman, Eli

    2010-01-01

    We derive expressions for the time integrated spectrum of Cosmic Rays (CRs) that are accelerated in a decelerating relativistic shock wave and escape ahead of the shock. It is assumed that at any given time the CRs have a power law form, carry a constant fraction of the energy E_tot of the shocked plasma, and escape continuously at the maximal energy attainable. The spectrum of escaping particles is highly sensitive to the instantaneous spectral index due to the fact that the minimal energy, E_min ~ \\Gamma^2 m_pc^2 where \\Gamma is the shock Lorentz factor, changes with time. In particular, the escaping spectrum may be considerably harder than the canonical N(E)\\propto E^-2 spectrum. For a shock expanding into a plasma of density n, a spectral break is expected at the maximal energy attainable at the transition to non relativistic velocities, E ~ 10^19 (\\epsilon_B/0.1)(n/1 cm^-3)^(1/6)(E_tot/10^51 erg)^(1/3) eV where \\epsilon_B is the fraction of the energy flux carried by the magnetic field. If ultra-high ene...

  2. Spatial and Nonspatial Escape Strategies in the Barnes Maze

    Science.gov (United States)

    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…

  3. Escaping Embarrassment: Face-Work in the Rap Cipher

    Science.gov (United States)

    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,…

  4. Plasma-induced Escape and Alterations of Planetary Atmospheres

    Science.gov (United States)

    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

  5. Escape chambers in the German coal mining industry. Fluchtkammern im deutschen Steinkohlenbergbau

    Energy Technology Data Exchange (ETDEWEB)

    Kock, F.J.; Langer, G. (Bergbau-Forschung G.m.b.H. - Forschungsinstitut des Steinkohlenbergbauvereins, Essen (Germany, F.R.). Hauptstelle fuer das Grubenrettungswesen); Velsen-Zerweck, R. von; Boettcher, K. (Bergbau AG Westfalen, Dortmund (Germany, F.R.). Hauptabteilung Sicherheitswesen)

    1989-08-17

    Escape chambers are used in special cases in German mines for self-rescue of the work force. On the basis of the newly laid down requirements concerning escape chambers a specification for mobile escape chambers was drawn up. The Safety Department of Bergbau AG Westfalen purchased two escape chambers of different manufacturers for 10 persons in each case, which are curently being tested at collieries of Bergbau AG Westfalen. The German coal mining industry thus has escape chambers at its disposal to make self-rescue of the work force even safer in the event of difficult and long escape routes. (orig.).

  6. Viral escape from HIV-1 neutralizing antibodies drives increased plasma neutralization breadth through sequential recognition of multiple epitopes and immunotypes.

    Directory of Open Access Journals (Sweden)

    Constantinos Kurt Wibmer

    2013-10-01

    Full Text Available Identifying the targets of broadly neutralizing antibodies to HIV-1 and understanding how these antibodies develop remain important goals in the quest to rationally develop an HIV-1 vaccine. We previously identified a participant in the CAPRISA Acute Infection Cohort (CAP257 whose plasma neutralized 84% of heterologous viruses. In this study we showed that breadth in CAP257 was largely due to the sequential, transient appearance of three distinct broadly neutralizing antibody specificities spanning the first 4.5 years of infection. The first specificity targeted an epitope in the V2 region of gp120 that was also recognized by strain-specific antibodies 7 weeks earlier. Specificity for the autologous virus was determined largely by a rare N167 antigenic variant of V2, with viral escape to the more common D167 immunotype coinciding with the development of the first wave of broadly neutralizing antibodies. Escape from these broadly neutralizing V2 antibodies through deletion of the glycan at N160 was associated with exposure of an epitope in the CD4 binding site that became the target for a second wave of broadly neutralizing antibodies. Neutralization by these CD4 binding site antibodies was almost entirely dependent on the glycan at position N276. Early viral escape mutations in the CD4 binding site drove an increase in wave two neutralization breadth, as this second wave of heterologous neutralization matured to recognize multiple immunotypes within this site. The third wave targeted a quaternary epitope that did not overlap any of the four known sites of vulnerability on the HIV-1 envelope and remains undefined. Altogether this study showed that the human immune system is capable of generating multiple broadly neutralizing antibodies in response to a constantly evolving viral population that exposes new targets as a consequence of escape from earlier neutralizing antibodies.

  7. The prevalence of mutations in the major hydrophilic region of the surface antigen of hepatitis B virus varies with subgenotype.

    Science.gov (United States)

    Wang, X Y; Harrison, T J; He, X; Chen, Q Y; Li, G J; Liu, M H; Li, H; Yang, J Y; Fang, Z L

    2015-12-01

    Mutations in the major hydrophilic region (MHR) of the surface antigen of hepatitis B virus (HBV) may result in vaccine escape, failure of immunotherapy and antiviral resistance. These mutants may be transmitted and constitute a public health threat. We aimed to determine the prevalence of MHR mutations of HBV in areas of high endemicity in Guangxi, China. HBV surface gene was analysed from 278 HBsAg-positive asymptomatic individuals recruited from Guangxi using cluster sampling. Three genotypes, B, C and I, were identified. The overall prevalence of MHR mutations is 17·6%. The prevalence of MHR mutations in genotype B (15·1%) is not significantly different from that in genotype C (16·4%). However, the prevalence in subgenotype C5 (31·1%) is significantly higher than in subgenotype C2 (13·0%) (χ 2 = 6·997, P subgenotype C5 is significantly higher than in subgenotypes B2 and C2. In total, 7·9% of MHR mutants are escape mutations and 72·1% of MHR mutations produced amino-acid changes in the overlapping polymerase, including resistance mutations to entecavir. Our results suggest that the prevalence of MHR mutations varies with subgenotype. The prevalence of escape mutations and polymerase mutations may be associated with subgenotype.

  8. A strategy for efficient cross-presentation of CTL-epitope peptides leading to enhanced induction of in vivo tumor immunity.

    Science.gov (United States)

    Hayashi, Akira; Wakita, Hisashi; Yoshikawa, Tomoaki; Nakanishi, Tsuyoshi; Tsutsumi, Yasuo; Mayumi, Tadanori; Mukai, Yohei; Yoshioka, Yasuo; Okada, Naoki; Nakagawa, Shinsaku

    2007-01-22

    The activation of antitumor cytotoxic T-lymphocytes (CTLs) depends on how efficiently the relevant tumor antigen peptides are delivered into the major histocompatibility complex (MHC) class I presentation pathway in antigen presenting cells (APCs). An elegant approach to promote the peptide-MHC class I association has been described for enhanced peptide transportation into the endoplasmic reticulum (ER) by adding an ER insertion signal sequence (Eriss). Nevertheless, this approach does not appear potent enough to induce in vivo tumor protective immunity. Herein, we present a novel peptide-vaccine strategy based on the combined utilization of Eriss and fusogenic liposomes (FLs) capable of directly introducing encapsulated CTL-epitope peptides into the MHC class I pathway of APCs. APCs pulsed with free peptides, FL-encapsulated peptides, or FL-encapsulated Eriss-conjugated peptides exhibited comparable levels of antigen-presenting activity at early phases after pulsing. Interestingly, whereas in the first two methods the APC ability began to decline 40 to 60 h after pulsing, FL-encapsulated Eriss(+) peptides allowed APCs to retain peptide-presentation activity for at least 140 h. This advantage of FL-encapsulated Eriss(+) peptides correlated with the induction of more potent antitumor immunity compared with soluble Eriss(+) or Eriss(-) peptides or FL-encapsulated Eriss(-) peptides when they were administered in vivo. Thus, Eriss-conjugated CTL-epitope peptides encapsulated in FLs provide a highly efficient tumor-vaccine to enhance the induction of in vivo tumor immunity.

  9. Sequence conservation, HLA-E-Restricted peptide, and best-defined CTL/CD8+ epitopes in gag P24 (capsid) of HIV-1 subtype B

    Science.gov (United States)

    Prasetyo, Afiono Agung; Dharmawan, Ruben; Sari, Yulia; Sariyatun, Ratna

    2017-02-01

    Human immunodeficiency virus type 1 (HIV-1) remains a cause of global health problem. Continuous studies of HIV-1 genetic and immunological profiles are important to find strategies against the virus. This study aimed to conduct analysis of sequence conservation, HLA-E-restricted peptide, and best-defined CTL/CD8+ epitopes in p24 (capsid) of HIV-1 subtype B worldwide. The p24-coding sequences from 3,557 HIV subtype B isolates were aligned using MUSCLE and analysed. Some highly conserved regions (sequence conservation ≥95%) were observed. Two considerably long series of sequences with conservation of 100% was observed at base 349-356 and 550-557 of p24 (HXB2 numbering). The consensus from all aligned isolates was precisely the same as consensus B in the Los Alamos HIV Database. The HLA-E-restricted peptide in amino acid (aa) 14-22 of HIV-1 p24 (AISPRTLNA) was found in 55.9% (1,987/3,557) of HIV-1 subtype B worldwide. Forty-four best-defined CTL/CD8+ epitopes were observed, in which VKNWMTETL epitope (aa 181-189 of p24) restricted by B*4801 was the most frequent, as found in 94.9% of isolates. The results of this study would contribute information about HIV-1 subtype B and benefits for further works willing to develop diagnostic and therapeutic strategies against the virus.

  10. Formulation of a Cooperative-Confinement-Escape problem of multiple cooperative defenders against an evader escaping from a circular region

    Science.gov (United States)

    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.

  11. An Empirical Investigation of Time-Out with and without Escape Extinction to Treat Escape-Maintained Noncompliance

    Science.gov (United States)

    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…

  12. Emerging pathogens: Dynamics, mutation and drug resistance

    Energy Technology Data Exchange (ETDEWEB)

    Perelson, A.S.; Goldstein, B.; Korber, B.T. [and others

    1997-10-01

    This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at Los Alamos National Laboratory (LANL). The objectives of this project were to develop models of the spread of pathogens, such as HIV-1 and influenza, in humans, and then to use the models to address the possibility of designing appropriate drug therapies that may limit the ability of the pathogen to escape treatment by mutating into a drug resistant form. We have developed a model of drug-resistance to amantidine and rimantadine, the two major antiviral drugs used to treat influenza, and have used the model to suggest treatment strategies during an epidemic.

  13. Sequence conservation of subdominant HLA-A2-binding CTL epitopes in HIV-1 clinical isolates and CD8+ T-lymphocyte cross-recognition may explain the immune reaction in infected individuals

    DEFF Research Database (Denmark)

    Thorn, Mette; Tang, Sheila; Therrien, Dominic;

    2007-01-01

    Cytotoxic T-lymphocytes (CTL) are critical for immune control of infection with human immunodeficiency virus type-1 (HIV-1) and searches for relevant CTL epitopes for immune therapy are ongoing. Recently, we identified 28 HLA-A2-binding HIV-1 CTL epitopes (1). In this follow-up study we fully...... genome sequenced HIV-1 from 11 HLA-A2(+) patients to examine the sequence variation of these natural epitopes and compared them with the patient's CD8(+) T-cell recall response. Often the epitope was conserved but only a few patients showed a CD8(+) T-cell recall response. This infrequent targeting may...... be explained by immune subdominance. CD8(+) T-cell recall response to a natural epitope could be measured despite sequence differences in the patient's virus. T-cell cross-reaction between such variants could be demonstrated in HLA-A2 transgenic mice. Nine infrequently targeted but conserved or cross...

  14. Th cells promote CTL survival and memory via acquired pMHC-I and endogenous IL-2 and CD40L signaling and by modulating apoptosis-controlling pathways.

    Directory of Open Access Journals (Sweden)

    Channakeshava Sokke Umeshappa

    Full Text Available Involvement of CD4(+ helper T (Th cells is crucial for CD8(+ cytotoxic T lymphocyte (CTL-mediated immunity. However, CD4(+ Th's signals that govern CTL survival and functional memory are still not completely understood. In this study, we assessed the role of CD4(+ Th cells with acquired antigen-presenting machineries in determining CTL fates. We utilized an adoptive co-transfer into CD4(+ T cell-sufficient or -deficient mice of OTI CTLs and OTII Th cells or Th cells with various gene deficiencies pre-stimulated in vitro by ovalbumin (OVA-pulsed dendritic cell (DCova. CTL survival was kinetically assessed in these mice using FITC-anti-CD8 and PE-H-2K(b/OVA257-264 tetramer staining by flow cytometry. We show that by acting via endogenous CD40L and IL-2, and acquired peptide-MHC-I (pMHC-I complex signaling, CD4(+ Th cells enhance survival of transferred effector CTLs and their differentiation into the functional memory CTLs capable of protecting against highly-metastasizing tumor challenge. Moreover, RT-PCR, flow cytometry and Western blot analysis demonstrate that increased survival of CD4(+ Th cell-helped CTLs is matched with enhanced Akt1/NF-κB activation, down-regulation of TRAIL, and altered expression profiles with up-regulation of prosurvival (Bcl-2 and down-regulation of proapoptotic (Bcl-10, Casp-3, Casp-4, Casp-7 molecules. Taken together, our results reveal a previously unexplored mechanistic role for CD4(+ Th cells in programming CTL survival and memory recall responses. This knowledge could also aid in the development of efficient adoptive CTL cancer therapy.

  15. Stream life of spawning pink salmon and the method of escapement enumeration by aerial survey: Draft

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Aerial surveys are currently used as the method tor escapement enumeration of pink salmon throughout Alaska. Other escapement enumeration methods cannot be...

  16. Parameter Optimization on Experimental Study to Reduce Ammonia Escape in CO2 Absorption by Ammonia Scrubbing

    Institute of Scientific and Technical Information of China (English)

    Hao Leng; Jianmin Gao; Mingyue He; Min Xie; Qian Du; Rui Sun; Shaohua Wu

    2016-01-01

    In order to research ammonia escape in CO2 absorption by ammonia scrubbing, ammonia escape was studied in CO2 absorption process using the bubbling reactor in different conditions as gas flow rate, CO2 ratio, absorbent temperature and ammonia concentration and quantity of escaped ammonia was measured by chemical titration. The results indicated that, the amount of ammonia escape can be around 20% of original amount in 90 min and the escaped amount will increase with the rise of gas flow rate, absorbent temperature, concentration of ammonia while decrease as CO2 ratio goes up. Through the analysis of the law of ammonia escape, at the same time, combined with ammonia escape and the influence of the relationship between the CO2 absorption efficiency, reducing ammonia escape working condition parameter optimization is given.

  17. Genetic reconstitution of the human Adenovirus type 2 temperature-sensitive 1 mutant defective in endosomal escape

    Directory of Open Access Journals (Sweden)

    Gastaldelli Michele

    2009-10-01

    Full Text Available Abstract Human Adenoviruses infect the upper and lower respiratory tracts, the urinary and digestive tracts, lymphoid systems and heart, and give rise to epidemic conjunctivitis. More than 51 human serotypes have been identified to-date, and classified into 6 species A-F. The species C Adenoviruses Ad2 and Ad5 (Ad2/5 cause upper and lower respiratory disease, but how viral structure relates to the selection of particular infectious uptake pathways is not known. An adenovirus mutant, Ad2-ts1 had been isolated upon chemical mutagenesis in the past, and shown to have unprocessed capsid proteins. Ad2-ts1 fails to package the viral protease L3/p23, and Ad2-ts1 virions do not efficiently escape from endosomes. It had been suggested that the C22187T point mutation leading to the substitution of the conserved proline 137 to leucine (P137L in the L3/p23 protease was at least in part responsible for this phenotype. To clarify if the C22187T mutation is necessary and sufficient for the Ad2-ts1 phenotype, we sequenced the genes encoding the structural proteins of Ad2-ts1, and confirmed that the Ad2-ts1 DNA carries the point mutation C22187T. Introduction of C22187T to the wild-type Ad2 genome in a bacterial artificial chromosome (Ad2-BAC gave Ad2-BAC46 virions with the full Ad2-ts1 phenotype. Reversion of Ad2-BAC46 gave wild-type Ad2 particles indicating that P137L is necessary and sufficient for the Ad2-ts1 phenotype. The kinetics of Ad2-ts1 uptake into cells were comparable to Ad2 suggesting similar endocytic uptake mechanisms. Surprisingly, infectious Ad2 or Ad5 but not Ad2-ts1 uptake required CALM (clathrin assembly lymphoid myeloid protein, which controls clathrin-mediated endocytosis and membrane transport between endosomes and the trans-Golgi-network. The data show that no other mutations than P137L in the viral protease are necessary to give rise to particles that are defective in capsid processing and endosomal escape. This provides a basis for

  18. Bacillus anthracis Factors for Phagosomal Escape

    Directory of Open Access Journals (Sweden)

    Irene Zornetta

    2012-07-01

    Full Text Available 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.

  19. Dynamics of the verge and foliot clock escapement

    CERN Document Server

    Hoyng, P

    2016-01-01

    The verge and foliot escapement has received relatively little attention in horology, despite the fact that it has been used in clocks for ages. We analyse the operation of a verge and foliot escapement in stationary swing. It is driven by a torque $m=\\pm\\mu$, switching sign at fixed swing angles $\\pm\\phi_0$, and $\\mu$ is taken to be constant. Friction is assumed to exert a torque proportional to the angular speed. We determine the shape of the swing angle $\\varphi(t)$, and compute the period and the swing amplitude of the foliot as a function of the model parameters. We find that the period of the foliot scales as $P\\propto\\mu^{-1}$ for weak driving, gradually changing into $P\\propto\\mu^{-1/3}$ for strong driving (large $\\mu$), which underlines that the motion of the foliot is not isochonous.

  20. Quantum and thermal phase escape in extended Josephson systems

    Energy Technology Data Exchange (ETDEWEB)

    Kemp, A.

    2006-07-12

    In this work I examine phase escape in long annular Josephson tunnel junctions. The sine-Gordon equation governs the dynamics of the phase variable along the junction. This equation supports topological soliton solutions, which correspond to quanta of magnetic flux trapped in the junction barrier. For such Josephson vortices an effective potential is formed by an external magnetic field, while a bias current acts as a driving force. Both together form a metastable potential well, which the vortex is trapped in. When the driving force exceeds the pinning force of the potential, the vortex escapes and the junction switches to the voltage state. At a finite temperature the driving force fluctuates. If the junction's energy scale is small, the phase variable can undergo a macroscopic quantum tunneling (MQT) process at temperatures below the crossover temperature. Without a vortex trapped, the metastable state is not a potential minimum in space, but a potential minimum at zero phase difference. (orig.)

  1. Escape Time of Josephson Junctions for Signal Detection

    CERN Document Server

    Addesso, P; Pierro, V

    2014-01-01

    In this Chapter we investigate with the methods of signal detection the response of a Josephson junction to a perturbation to decide if the perturbation contains a coherent oscillation embedded in the background noise. When a Josephson Junction is irradiated by an external noisy source, it eventually leaves the static state and reaches a steady voltage state. The appearance of a voltage step allows to measure the time spent in the metastable state before the transition to the running state, thus defining an escape time. The distribution of the escape times depends upon the characteristics of the noise and the Josephson junction. Moreover, the properties of the distribution depends on the features of the signal (amplitude, frequency and phase), which can be therefore inferred through the appropriate signal processing methods. Signal detection with JJ is interesting for practical purposes, inasmuch as the superconductive elements can be (in principle) cooled to the absolute zero and therefore can add (in practi...

  2. Behavioral analysis of the escape response in larval zebrafish

    Science.gov (United States)

    Feng, Ruopei; Girdhar, Kiran; Chemla, Yann; Gruebele, Martin

    The behavior of larval zebrafish is of great interest because the limited number of locomotor neurons in larval zebrafish couples with its rich repertoire of movements as a vertebrate animal. Current research uses a priori-selected parameters to describe their swimming behavior while our lab has built a parameter-free model based on singular value decomposition analysis to characterize it. Our previous work has analyzed the free swimming of larval zebrafish and presented a different picture from the current classification of larval zebrafish locomotion. Now we are extending this work to the studies of their escape response to acoustic stimulus. Analysis has shown intrinsic difference in the locomotion between escape response and free swimming.

  3. Escape rate of active particles in the effective equilibrium approach

    Science.gov (United States)

    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.

  4. Partial control of chaotic transients using escape times

    Energy Technology Data Exchange (ETDEWEB)

    Sabuco, Juan; Zambrano, Samuel; Sanjuan, Miguel A F, E-mail: juan.sabuco@urjc.e [Departamento de Fisica, Universidad Rey Juan Carlos, Tulipan s/n, 28933 Mostoles, Madrid (Spain)

    2010-11-15

    The partial control technique allows one to keep the trajectories of a dynamical system inside a region where there is a chaotic saddle and from which nearly all the trajectories diverge. Its main advantage is that this goal is achieved even if the corrections applied to the trajectories are smaller than the action of environmental noise on the dynamics, a counterintuitive result that is obtained by using certain safe sets. Using the Henon map as a paradigm, we show here the deep relationship between the safe sets and the sets of points with different escape times, the escape time sets. Furthermore, we show that it is possible to find certain extended safe sets that can be used instead of the safe sets in the partial control technique. Numerical simulations confirm our findings and show that in some situations, the use of extended safe sets can be more advantageous.

  5. Failed Escape: Solid Surfaces Prevent Tumbling of Escherichia coli

    Science.gov (United States)

    Molaei, Mehdi; Barry, Michael; Stocker, Roman; Sheng, Jian

    2014-08-01

    Understanding how bacteria move close to surfaces is crucial for a broad range of microbial processes including biofilm formation, bacterial dispersion, and pathogenic infections. We used digital holographic microscopy to capture a large number (>103) of three-dimensional Escherichia coli trajectories near and far from a surface. We found that within 20 μm from a surface tumbles are suppressed by 50% and reorientations are largely confined to surface-parallel directions, preventing escape of bacteria from the near-surface region. A hydrodynamic model indicates that the tumble suppression is likely due to a surface-induced reduction in the hydrodynamic force responsible for the flagellar unbundling that causes tumbling. These findings imply that tumbling does not provide an effective means to escape trapping near surfaces.

  6. Escape of Mars atmospheric carbon through time by photochemical means

    Science.gov (United States)

    Luhmann, J. G.; Kim, J.; Nagy, A. F.

    Luhmann et al. recently suggested that sputtering of the Martian atmosphere by re-entering O(+) pickup ions could have provided a significant route of escape for CO2 and its products throughout Mars' history. They estimated that the equivalent of C in an approximately 140-mbar CO2 atmosphere should have been lost this way if the Sun and solar wind evolved according to available models. Another source of escaping C (and O) that is potentially important is the dissociative recombination of ionospheric CO(+) near the exobase. We have evaluated the loss rates due to this process for 'ancient' solar EUV radiation fluxes of 1, 3, and 6 times the present flux in order to calculate the possible cumulative loss over the last 3.5 Gyr.

  7. The C. elegans touch response facilitates escape from predacious fungi

    OpenAIRE

    Maguire, Sean M.; Clark, Christopher M.; Nunnari, John; Pirri, Jennifer K.; Alkema, Mark J.

    2011-01-01

    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 ne...

  8. On the Relative Contributions of Noncontingent Reinforcement and Escape Extinction in the Treatment of Food Refusal

    Science.gov (United States)

    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. 46 CFR 56.50-25 - Safety and relief valve escape piping.

    Science.gov (United States)

    2010-10-01

    ... 46 Shipping 2 2010-10-01 2010-10-01 false Safety and relief valve escape piping. 56.50-25 Section 56.50-25 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PIPING SYSTEMS AND APPURTENANCES Design Requirements Pertaining to Specific Systems § 56.50-25 Safety and relief valve escape piping. (a) Escape piping...

  10. Escape Geography--Developing Middle-School Students' Sense of Place.

    Science.gov (United States)

    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…

  11. EB病毒免疫逃逸的分子机制%Molecular mechanism for EB virus escape from host cell defense

    Institute of Scientific and Technical Information of China (English)

    刘愿(综述); 刘卓然(审校)

    2016-01-01

    EB病毒( Epstein-Barr vius, EBV)是一种最广泛的对人类感染的γ疱疹病毒,与人类多种疾病尤其是恶性肿瘤有关。其致病的一个重要条件是能够在人体B细胞中长期潜伏,并且在人体免疫力低下时被激活并增殖,这表明EB病毒存在逃逸宿主细胞免疫的机制。从潜伏期EB病毒基因表达的下调、干扰抗原加工和提呈、调节细胞毒性T细胞( Cytotoxic lymphocyte, CTL)免疫应答、干扰细胞因子的作用、干扰CTL的活动及抑制宿主细胞凋亡、抑制辅助性T细胞1(Helper T cell 1, Th1)免疫应答等方面,对EB病毒免疫逃逸的分子机制作一简要综述。%Epstein-Barr virus ( EBV) is a kind of human gamma herpesvirus that infects extensively to human beings, it is associated with human diseases, especially malignant tumor. An important condition for the pathogenesis of EBV is it in a latent form to parasitize inside human B cells for a long time, in addition, EBV will be activated and proliferate when the human immunity is deficient, which shows that EBV has a mechanism to evade from host cell immunity. Thus a brief sum-mary will focus on the molecular mechanism for EBV immune escape, including down regulation gene expression of viral an-tigen in a latent state, interference with antigen processing and presenting, interference with regulation of cytotoxic lympho-cyte ( CTL) response, interference with cytokine effect, and inhibition of target cell apoptosis, inhibition of Th1 response and so on.

  12. MAVEN in situ measurements of photochemical escape of oxygen from Mars

    Science.gov (United States)

    Lillis, Robert; Deighan, Justin; Fox, Jane; Bougher, Stephen; Lee, Yuni; Cravens, Thomas; Rahmati, Ali; Mahaffy, Paul; Benna, Mehdi; Groller, Hannes; Jakosky, Bruce

    2016-04-01

    One of the primary goals of the MAVEN mission is to characterize rates of atmospheric escape from Mars at the present epoch and relate those escape rates to solar drivers. One of the known escape processes is photochemical escape, where a) an exothermic chemical reaction in the atmosphere results in an upward-traveling neutral particle whose velocity exceeds planetary escape velocity and b) the particle is not prevented from escaping through subsequent collisions. 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. Thus characterizing this escape process and its variability with solar drivers is central to understanding the role escape to space has played in Mars' climate evolution. We use near-periapsis (atoms. The second is a Monte Carlo hot atom transport model that takes that distribution of initial O energies and the measured neutral density profiles and calculates the probability that a hot atom born at that altitude will escape. The third takes the measured electron and ion densities and electron temperatures and calculates the production rate of hot O atoms. We then multiply together the profiles of hot atom production and escape probability to get profiles of the production rate of escaping atoms. We integrate with respect to altitude to give us the escape flux of hot oxygen atoms for that periapsis pass. We have sufficient coverage in solar zenith angle (SZA) to estimate total escape rates for two intervals with the obvious assumption that escape rates are the same at all points with the same SZA. We estimate total escape rates of 3.5-5.8 x 1025 s-1 for Ls = 289° to 319° and 1.6-2.6 x 1025 s-1 for Ls = 326° to 348°. The latter is the most directly comparable to previous model-based estimates and is roughly in line with several of them. Total photochemical loss over Mars history is not very useful to

  13. Impact of Mutation Weights on Training Backpropagation Neural Networks

    Directory of Open Access Journals (Sweden)

    Lamia Abed Noor Muhammed

    2014-07-01

    Full Text Available Neural network is a computational approach, which based on the simulation of biology neural network. This approach is conducted by several parameters; learning rate, initialized weights, network architecture, and so on. However, this paper would be focused on one of these parameters that is weights. The aim is to shed lights on the mutation weights through training network and its effects on the results. The experiment was done using backpropagation neural network with one hidden layer. The results reveal the role of mutation in escape from the local minima and making the change

  14. Parkinson's disease brain mitochondria have impaired respirasome assembly, age-related increases in distribution of oxidative damage to mtDNA and no differences in heteroplasmic mtDNA mutation abundance

    Directory of Open Access Journals (Sweden)

    Keeney Paula M

    2009-09-01

    Full Text Available Abstract Background Sporadic Parkinson's disease (sPD is a nervous system-wide disease that presents with a bradykinetic movement disorder and is frequently complicated by depression and cognitive impairment. sPD likely has multiple interacting causes that include increased oxidative stress damage to mitochondrial components and reduced mitochondrial bioenergetic capacity. We analyzed mitochondria from postmortem sPD and CTL brains for evidence of oxidative damage to mitochondrial DNA (mtDNA, heteroplasmic mtDNA point mutations and levels of electron transport chain proteins. We sought to determine if sPD brains possess any mtDNA genotype-respiratory phenotype relationships. Results Treatment of sPD brain mtDNA with the mitochondrial base-excision repair enzyme 8-oxyguanosine glycosylase-1 (hOGG1 inhibited, in an age-dependent manner, qPCR amplification of overlapping ~2 kbase products; amplification of CTL brain mtDNA showed moderate sensitivity to hOGG1 not dependent on donor age. hOGG1 mRNA expression was not different between sPD and CTL brains. Heteroplasmy analysis of brain mtDNA using Surveyor nuclease® showed asymmetric distributions and levels of heteroplasmic mutations across mtDNA but no patterns that statistically distinguished sPD from CTL. sPD brain mitochondria displayed reductions of nine respirasome proteins (respiratory complexes I-V. Reduced levels of sPD brain mitochondrial complex II, III and V, but not complex I or IV proteins, correlated closely with rates of NADH-driven electron flow. mtDNA levels and PGC-1α expression did not differ between sPD and CTL brains. Conclusion PD brain mitochondria have reduced mitochondrial respiratory protein levels in complexes I-V, implying a generalized defect in respirasome assembly. These deficiencies do not appear to arise from altered point mutational burden in mtDNA or reduction of nuclear signaling for mitochondrial biogenesis, implying downstream etiologies. The origin of age

  15. Luria-delbruck estimation of turnip mosaic virus mutation rate in vivo.

    Science.gov (United States)

    de la Iglesia, Francisca; Martínez, Fernando; Hillung, Julia; Cuevas, José M; Gerrish, Philip J; Daròs, José-Antonio; Elena, Santiago F

    2012-03-01

    A potential drawback of recent antiviral therapies based on the transgenic expression of artificial microRNAs is the ease with which viruses may generate escape mutations. Using a variation of the classic Luria-Delbrück fluctuation assay, we estimated that the spontaneous mutation rate in the artificial microRNA (amiR) target of a plant virus was ca. 6 × 10(-5) per replication event.

  16. 煤制油项目饱和蒸汽余热利用研究%Study on Saturated Steam Waste Heat Utilization of CTL Project

    Institute of Scientific and Technical Information of China (English)

    周翔

    2016-01-01

    Take a CTL project as an example, the paper mainly introduces the installed capacity and type of saturated steam turbogenerator by calculating plantwide steam balance, and presents the issues needing attention in type selection of saturated steam turbogenerator by analyzing variables like exhaust pressure, exhaust dryness, relative internal efficiency and so on of saturated steam turbogenerator.%以某干粉气化间接合成油项目为例,通过全厂蒸汽平衡的计算,确定了饱和余热发电机组的装机容量和形式;分析了饱和余热发电汽轮机的排汽压力、排汽干度、相对内效率等变量,提出了饱和余热汽轮机选型中应注意的问题。

  17. Rapid progressing allele HLA-B35 Px restricted anti-HIV-1 CD8+ T cells recognize vestigial CTL epitopes.

    Directory of Open Access Journals (Sweden)

    Christian B Willberg

    Full Text Available The HLA-B*35-Px allele has been associated with rapid disease progression in HIV-1 infection, in contrast to the HLA-B*35-Py allele.Immune responses to two HLA-B*35 restricted HIV-1 specific CTL epitopes and their variants were followed longitudinally during early HIV-1 infection in 16 HLA-B*35+ individuals. Subjects expressing HLA-B*35-Px alleles showed no difference in response to the consensus epitopes compared to individuals with HLA-B*35-Py alleles. Surprisingly, all the HLA-B*35-Px+ individuals responded to epitope-variants even in the absence of a consensus response. Sequencing of the viral population revealed no evidence of variant virus in any of the individuals.This demonstrates a novel phenomenon that distinguishes individuals with the HLA-B*35-Px rapid progressing allele and those with the HLA-B*35-Py slower progressing allele.

  18. Recognition of melanoma-derived antigens by CTL: possible mechanisms involved in down-regulating anti-tumor T-cell reactivity

    DEFF Research Database (Denmark)

    Rivoltini, L; Loftus, D J; Squarcina, P

    1998-01-01

    Several T cell-recognized epitopes presented by melanoma cells have been identified recently. Despite the large array of epitopes potentially available for clinical use, it is still unclear which of these antigens could be effective in mediating anti-tumor responses when used as a vaccine...... (detected as increased antigen-specific CTL activity in peripheral blood) was obtained by vaccinating HLA-A2.1+ melanoma patients with the immunodominant epitope (residues 27-35) of the differentiation antigen MART-1, but this immunization was not accompanied by a significant clinical response. To implement...... immunotherapeuties capable of significantly impacting disease outcome, it is necessary to identify the potential mechanisms responsible for the failure of some antigens to mediate significant anti-tumor responses in vivo. In the case of the MART-1(27-35) epitope, we hypothesize that one of these mechanisms may...

  19. Therapy of established B16-F10 melanoma tumors by a single vaccination of CTL/T helper peptides in VacciMax®

    Directory of Open Access Journals (Sweden)

    Korets-Smith Ella

    2007-04-01

    Full Text Available Abstract Background Melanoma tumors are known to express antigens that usually induce weak immune responses of short duration. Expression of both tumor-associated antigens p53 and TRP2 by melanoma cells raises the possibility of simultaneously targeting more than one antigen in a therapeutic vaccine. In this report, we show that VacciMax® (VM, a novel liposome-based vaccine delivery platform, can increase the immunogenicity of melanoma associated antigens, resulting in tumor elimination. Methods C57BL/6 mice bearing B16-F10 melanoma tumors were vaccinated subcutaneously 6 days post tumor implantation with a mixture of synthetic peptides (modified p53: 232–240, TRP-2: 181–188 and PADRE and CpG. Tumor growth was monitored and antigen-specific splenocyte responses were assayed by ELISPOT. Results Vaccine formulated in VM increased the number of both TRP2- and p53-specific IFN-γ producing splenocytes following a single vaccination. Vaccine formulated without VM resulted only in enhanced IFN-γ producing splenocytes to one CTL epitopes (TRP2:180–188, suggesting that VM overcomes antigen dominance and enhances immunogenicity of multiple epitopes. Vaccination of mice bearing 6-day old B16-F10 tumors with both TRP2 and p53-peptides formulated in VM successfully eradicated tumors in all mice. A control vaccine which contained all ingredients except liposomes resulted in eradication of tumors in no more than 20% of mice. Conclusion A single administration of VM is capable of inducing an effective CTL response to multiple tumor-associated antigens. The responses generated were able to reject 6-day old B16-F10 tumors.

  20. Effect of insulin on functional status of cord blood-derived dendritic cells and on dendritic cell-induced CTL cytotoxicity against pancreatic cancer cell lines

    Institute of Scientific and Technical Information of China (English)

    Qiu-Liang Liu; Yi-Sheng Wang; Jia-Xiang Wang

    2009-01-01

    BACKGROUND: Dendritic cells (DCs) are the most important antigen-presenting cells in the human body, and DCs with different mature status possess different or even opposite functions. This study was designed to explore the influence of insulin on the functional status of cord blood-derived DCs and on DC-induced cytotoxic T lymphocyte (CTL) activity against pancreatic cancer cell lines. METHODS: Mononuclear cells were isolated from fresh cord blood. Interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were used to induce or stimulate the mononuclear cells. Insulin at different concentrations served to modify DCs, and then DC morphology, number, and growth status were assessed. The DC immunophenotype was detected with a flow cytometer. The IL-12 in DC supernatant was determined by ELISA. DC functional status was evaluated by the autologous mixed lymphocyte reaction. T lymphocytes were induced by insulin-modified DCs to become CTLs. The CTL cytotoxicity against pancreatic cancer cell lines was determined. RESULTS:  Mononuclear cells from cord blood can be differentiated into DCs by cytokine induction and insulin modification. With the increase in insulin concentration (2.5-25 mg/L), the expression of DC HLA-DR, CD1α, CD80, and CD83 was significantly increased, the DC ability to secrete IL-12 was significantly improved, DC function to activate autologous lymphocytes was significantly enhanced, and the cytotoxicity of CTLs induced by insulin-modified DCs against pancreatic cancer cell lines was significantly strengthened. CONCLUSIONS: Insulin may facilitate DC induction and maturation, and improve the reproductive activity of autologous lymphocytes. The cytotoxicity of CTLs induced by insulin-modified DCs against pancreatic cancer cell lines was significantly enhanced. Insulin may serve as a factor modifying DCs and inducing CTLs in vitro in insulin biotherapy.

  1. Increased PRAME-specific CTL killing of acute myeloid leukemia cells by either a novel histone deacetylase inhibitor chidamide alone or combined treatment with decitabine.

    Directory of Open Access Journals (Sweden)

    Yushi Yao

    Full Text Available As one of the best known cancer testis antigens, PRAME is overexpressed exclusively in germ line tissues such as the testis as well as in a variety of solid and hematological malignant cells including acute myeloid leukemia. Therefore, PRAME has been recognized as a promising target for both active and adoptive anti-leukemia immunotherapy. However, in most patients with PRAME-expressing acute myeloid leukemia, PRAME antigen-specific CD8(+ CTL response are either undetectable or too weak to exert immune surveillance presumably due to the inadequate PRAME antigen expression and PRAME-specific antigen presentation by leukemia cells. In this study, we observed remarkably increased PRAME mRNA expression in human acute myeloid leukemia cell lines and primary acute myeloid leukemia cells after treatment with a novel subtype-selective histone deacetylase inhibitor chidamide in vitro. PRAME expression was further enhanced in acute myeloid leukemia cell lines after combined treatment with chidamide and DNA demethylating agent decitabine. Pre-treatment of an HLA-A0201(+ acute myeloid leukemia cell line THP-1 with chidamide and/or decitabine increased sensitivity to purified CTLs that recognize PRAME(100-108 or PRAME(300-309 peptide presented by HLA-A0201. Chidamide-induced epigenetic upregulation of CD86 also contributed to increased cytotoxicity of PRAME antigen-specific CTLs. Our data thus provide a new line of evidence that epigenetic upregulation of cancer testis antigens by a subtype-selective HDAC inhibitor or in combination with hypomethylating agent increases CTL cytotoxicity and may represent a new opportunity in future design of treatment strategy targeting specifically PRAME-expressing acute myeloid leukemia.

  2. CF Mutation Panel

    Science.gov (United States)

    ... Testing; Cystic Fibrosis Transmembrane Conductance Regulator Mutation Analysis; CFTR Mutation Analysis Formal name: Cystic Fibrosis Gene Mutation ... an elevated immunoreactive trypsinogen (IRT) or positive sweat chloride test , to confirm the diagnosis of cystic fibrosis. ...

  3. A comparison of positive and negative reinforcement for compliance to treat problem behavior maintained by escape.

    Science.gov (United States)

    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.

  4. The HIV-1 V3 domain on field isolates: participation in generation of escape virus in vivo and accessibility to neutralizing antibodies

    DEFF Research Database (Denmark)

    Arendrup, M; Akerblom, L; Heegaard, P M

    1995-01-01

    The V3 domain is highly variable and induces HIV neutralizing antibodies (NA). Here we addressed the issues of 1) the participation of mutations in V3 in generation of neutralization resistant escape virus in vivo and 2) the applicability of synthetic V3 peptides corresponding to field isolates...... to induce neutralizing immune sera. Seven peptides corresponding to the V3 region of primary and escape virus from 3 HIV-1 infected patients were synthesized and used for antibody (Abs) studies and immunizations. The anti-V3 Abs titre in patient serum was generally low against peptides corresponding...... to autologous virus isolated later than the serum sample in contrast to the titre against peptides corresponding to virus isolated earlier than the serum sample. Furthermore, neutralizing anti-V3 monoclonal antibodies (MAbs) raised against V3 peptides from laboratory strains of HIV-1 showed distinct binding...

  5. Escaping the Self: Identity, Group Identification and Violence

    Directory of Open Access Journals (Sweden)

    James Hardie-Bick

    2016-12-01

    Full Text Available This article draws on the early work of Erich Fromm. In Escape from Freedom Fromm (1969 [1941] directly addressed the psychological mechanisms of escape modern individuals employ to protect themselves from feelings of ontological insecurity and existential estrangement. The article builds on Fromm’s analysis by discussing the significance of his escape mechanisms for understanding the dynamic psychological attractions of identifying with entitative groups. Fromm’s work will be discussed in relation to Hogg’s recent work on uncertainty-identity theory. The aim of the article is to examine the advantages of combining Fromm’s psychoanalytic analysis with Hogg’s uncertainty-identity theory and to highlight the potential this approach has for understanding why groups engage in violent and destructive behaviour. Este artículo se inspira en las primeras obras de Erich Fromm. En El miedo a la libertad, Fromm (1969 [1941] abordó directamente los mecanismos psicológicos de evasión que los individuos modernos emplean para protegerse de los sentimientos de inseguridad ontológica y distanciamiento existencial. Este artículo se basa en el análisis de Fromm exponiendo el significado de sus mecanismos de evasión para entender las atracciones psicológicas dinámicas de identificación con grupos entitativos. Se analizará la obra de Fromm en relación con la obra reciente de Hogg sobre la teoría de incertidumbre identitaria. El objetivo del artículo es examinar las ventajas de combinar el análisis psicoanalítico de Fromm con la teoría de incertidumbre identitaria de Hogg, y destacar el potencial que tiene esta aproximación para comprender por qué los grupos adoptan un comportamiento violento y destructivo. DOWNLOAD THIS PAPER FROM SSRN: https://ssrn.com/abstract=2875737

  6. Experimental analysis and extinction of self-injurious escape behavior.

    Science.gov (United States)

    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.

  7. Experimental study of subsonic microjet escaping from a rectangular nozzle

    Science.gov (United States)

    Aniskin, V. M.; Maslov, A. A.; Mukhin, K. A.

    2016-10-01

    The first experiments on the subsonic laminar microjets escaping from the nozzles of rectangular shape are carried out. The nozzle size is 83.3x3823 microns. Reynolds number calculated by the nozzle height and the average flow velocity at the nozzle exit ranged from 58 to 154. The working gas was air at room temperature. The velocity decay and velocity fluctuations along the center line of the jet are determined. The fundamental difference between the laminar microjets characteristics and subsonic turbulent jets of macro size is shown. Based on measurements of velocity fluctuations it is shown the presence of laminar-turbulent transition in microjets and its location is determined.

  8. The mirror of the escaped God – Alejandra Pizarnik

    Directory of Open Access Journals (Sweden)

    Mariano Carou

    2015-04-01

    Full Text Available Alejandra Pizarnik (1936-1972 shows many different stands regarding to “God’s escape” in her poetry and his diaries: from the psalmist’s request to the more combative atheism. There is, however, a constant development of a symbolic constellation to speak about God’s mistery, and the certitude –inherited from German romanticism– that the poet has always something to say about God’s escape, searching for a new hope in which is maybe a new form of mysticism.

  9. First-passage and escape problems in the Feller process

    CERN Document Server

    Masoliver, Jaume

    2012-01-01

    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 are well known since long, 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.

  10. First-passage and escape problems in the Feller process

    Science.gov (United States)

    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.

  11. Chases and escapes the mathematics of pursuit and evasion

    CERN Document Server

    Nahin, Paul J

    2012-01-01

    We all played tag when we were kids. What most of us don't realize is that this simple chase game is in fact an application of pursuit theory, and that the same principles of games like tag, dodgeball, and hide-and-seek are also at play in military strategy, high-seas chases by the Coast Guard, and even romantic pursuits. In Chases and Escapes, Paul Nahin gives us the first complete history of this fascinating area of mathematics, from its classical analytical beginnings to the present day. Drawing on game theory, geometry, linear algebra, target-tracking algorithms, and much

  12. Test of time: what if little Albert had escaped?

    Science.gov (United States)

    Field, Andy P; Nightingale, Zoë C

    2009-04-01

    Watson and Rayner's (1920) ;Little Albert' experiment has become one of the most famous studies in psychology. It is a staple of many general psychology textbooks and is part of the very fabric of the discipline's folklore. Despite this fame, the study has been widely criticized in the nearly 90 years since it was published for its lack of methodological rigour. This article attempts to evaluate the contribution of the ;little Albert' study to modern clinical psychology by speculating on what theories and treatments of child anxiety would look like in a parallel universe in which the study never took place because ;little Albert' escaped from the hospital in which Watson tested him.

  13. A mechanistic understanding of allosteric immune escape pathways in the HIV-1 envelope glycoprotein.

    Directory of Open Access Journals (Sweden)

    Anurag Sethi

    Full Text Available The HIV-1 envelope (Env spike, which consists of a compact, heterodimeric trimer of the glycoproteins gp120 and gp41, is the target of neutralizing antibodies. However, the high mutation rate of HIV-1 and plasticity of Env facilitates viral evasion from neutralizing antibodies through various mechanisms. Mutations that are distant from the antibody binding site can lead to escape, probably by changing the conformation or dynamics of Env; however, these changes are difficult to identify and define mechanistically. Here we describe a network analysis-based approach to identify potential allosteric immune evasion mechanisms using three known HIV-1 Env gp120 protein structures from two different clades, B and C. First, correlation and principal component analyses of molecular dynamics (MD simulations identified a high degree of long-distance coupled motions that exist between functionally distant regions within the intrinsic dynamics of the gp120 core, supporting the presence of long-distance communication in the protein. Then, by integrating MD simulations with network theory, we identified the optimal and suboptimal communication pathways and modules within the gp120 core. The results unveil both strain-dependent and -independent characteristics of the communication pathways in gp120. We show that within the context of three structurally homologous gp120 cores, the optimal pathway for communication is sequence sensitive, i.e. a suboptimal pathway in one strain becomes the optimal pathway in another strain. Yet the identification of conserved elements within these communication pathways, termed inter-modular hotspots, could present a new opportunity for immunogen design, as this could be an additional mechanism that HIV-1 uses to shield vulnerable antibody targets in Env that induce neutralizing antibody breadth.

  14. A Novel Cell Type Enables B. subtilis To Escape From Unsuccessful Sporulation In Minimal Medium

    Directory of Open Access Journals (Sweden)

    Herve Joel Defeu Soufo

    2016-11-01

    Full Text Available Sporulation is the most enduring survival strategy developed by several bacterial species. However, spore development of the model organism Bacillus subtilis has mainly been studied by means of media or conditions optimized for the induction of sporogenesis. Here, I show that during prolonged growth during stationary phase in minimal medium, B. subtilis undergoes an asymmetric cell division that produces small and round-shaped, DNA containing cells. In contrast to wild-type cells, mutants harboring spo0A or spoIIIE/sftA double mutations neither sporulate nor produce this special cell type, providing evidence that the small round cells emerge from the abortion of endospore formation. In most cases observed, the small round cells arise in the presence of sigma H but absence of sigma F activity, different from cases of abortive sporulation described for rich media. These data suggest that in minimal media, many cells are able to initiate but fail to complete spore development, and therefore return to normal growth as rods. This work reveals that the continuation of asymmetric cell division, which results in the formation of the small round cells, is a way for cells to delay or escape from - unsuccessful - sporulation. Based on these findings, I suggest to name the here described cell type as dwarf cells to distinguish them from the well-known minicells observed in mutants defective in septum placement or proper chromosome partitioning.

  15. Phagocytosis escape by a Staphylococcus aureus protein that connects complement and coagulation proteins at the bacterial surface.

    Science.gov (United States)

    Ko, Ya-Ping; Kuipers, Annemarie; Freitag, Claudia M; Jongerius, Ilse; Medina, Eva; van Rooijen, Willemien J; Spaan, András N; van Kessel, Kok P M; Höök, Magnus; Rooijakkers, Suzan H M

    2013-01-01

    Upon contact with human plasma, bacteria are rapidly recognized by the complement system that labels their surface for uptake and clearance by phagocytic cells. Staphylococcus aureus secretes the 16 kD Extracellular fibrinogen binding protein (Efb) that binds two different plasma proteins using separate domains: the Efb N-terminus binds to fibrinogen, while the C-terminus binds complement C3. In this study, we show that Efb blocks phagocytosis of S. aureus by human neutrophils. In vitro, we demonstrate that Efb blocks phagocytosis in plasma and in human whole blood. Using a mouse peritonitis model we show that Efb effectively blocks phagocytosis in vivo, either as a purified protein or when produced endogenously by S. aureus. Mutational analysis revealed that Efb requires both its fibrinogen and complement binding residues for phagocytic escape. Using confocal and transmission electron microscopy we show that Efb attracts fibrinogen to the surface of complement-labeled S. aureus generating a 'capsule'-like shield. This thick layer of fibrinogen shields both surface-bound C3b and antibodies from recognition by phagocytic receptors. This information is critical for future vaccination attempts, since opsonizing antibodies may not function in the presence of Efb. Altogether we discover that Efb from S. aureus uniquely escapes phagocytosis by forming a bridge between a complement and coagulation protein.

  16. Slow and Fast Escape for Open Intermittent Maps

    Science.gov (United States)

    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.

  17. Ultra-fast Escape of a Octopus-inspired Rocket

    Science.gov (United States)

    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.

  18. Escape of Hydrogen from the Exosphere of Mars

    Science.gov (United States)

    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.

  19. Random fluctuation leads to forbidden escape of particles.

    Science.gov (United States)

    Rodrigues, Christian S; de Moura, Alessandro P S; Grebogi, Celso

    2010-08-01

    A great number of physical processes are described within the context of Hamiltonian scattering. Previous studies have rather been focused on trajectories starting outside invariant structures, since the ones starting inside are expected to stay trapped there forever. This is true though only for the deterministic case. We show however that, under finitely small random fluctuations of the field, trajectories starting inside Kolmogorov-Arnold-Moser (KAM) islands escape within finite time. The nonhyperbolic dynamics gains then hyperbolic characteristics due to the effect of the random perturbed field. As a consequence, trajectories which are started inside KAM curves escape with hyperboliclike time decay distribution, and the fractal dimension of a set of particles that remain in the scattering region approaches that for hyperbolic systems. We show a universal quadratic power law relating the exponential decay to the amplitude of noise. We present a random walk model to relate this distribution to the amplitude of noise, and investigate these phenomena with a numerical study applying random maps.

  20. Numerical simulation of a self-propelled copepod during escape

    Science.gov (United States)

    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.

  1. Metastatic Tumor Dormancy in Cutaneous Melanoma: Does Surgery Induce Escape?

    Energy Technology Data Exchange (ETDEWEB)

    Tseng, William W. [Department of Surgery, University of California at San Francisco, 513 Parnassus Avenue, Room S-321, San Francisco, CA 94143 (United States); Fadaki, Niloofar; Leong, Stanley P., E-mail: leongsx@cpmcri.org [Department of Surgery and Center for Melanoma Research and Treatment, California Pacific Medical Center and Research Institute, 2340 Clay Street, 2nd floor, San Francisco, CA 94115 (United States)

    2011-02-21

    According to the concept of tumor dormancy, tumor cells may exist as single cells or microscopic clusters of cells that are clinically undetectable, but remain viable and have the potential for malignant outgrowth. At metastatic sites, escape from tumor dormancy under more favorable local microenvironmental conditions or through other, yet undefined stimuli, may account for distant recurrence after supposed “cure” following surgical treatment of the primary tumor. The vast majority of evidence to date in support of the concept of tumor dormancy originates from animal studies; however, extensive epidemiologic data from breast cancer strongly suggests that this process does occur in human disease. In this review, we aim to demonstrate that metastatic tumor dormancy does exist in cutaneous melanoma based on evidence from mouse models and clinical observations of late recurrence and occult transmission by organ transplantation. Experimental data underscores the critical role of impaired angiogenesis and immune regulation as major mechanisms for maintenance of tumor dormancy. Finally, we examine evidence for the role of surgery in promoting escape from tumor dormancy at metastatic sites in cutaneous melanoma.

  2. Metastatic Tumor Dormancy in Cutaneous Melanoma: Does Surgery Induce Escape?

    Directory of Open Access Journals (Sweden)

    William W. Tseng

    2011-02-01

    Full Text Available According to the concept of tumor dormancy, tumor cells may exist as single cells or microscopic clusters of cells that are clinically undetectable, but remain viable and have the potential for malignant outgrowth. At metastatic sites, escape from tumor dormancy under more favorable local microenvironmental conditions or through other, yet undefined stimuli, may account for distant recurrence after supposed “cure” following surgical treatment of the primary tumor. The vast majority of evidence to date in support of the concept of tumor dormancy originates from animal studies; however, extensive epidemiologic data from breast cancer strongly suggests that this process does occur in human disease. In this review, we aim to demonstrate that metastatic tumor dormancy does exist in cutaneous melanoma based on evidence from mouse models and clinical observations of late recurrence and occult transmission by organ transplantation. Experimental data underscores the critical role of impaired angiogenesis and immune regulation as major mechanisms for maintenance of tumor dormancy. Finally, we examine evidence for the role of surgery in promoting escape from tumor dormancy at metastatic sites in cutaneous melanoma.

  3. The C. elegans touch response facilitates escape from predacious fungi.

    Science.gov (United States)

    Maguire, Sean M; Clark, Christopher M; Nunnari, John; Pirri, Jennifer K; Alkema, Mark J

    2011-08-09

    Predator-prey interactions are vital determinants in the natural selection of 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, 2]. Here, we investigate the ecological significance of the touch response in predator-prey interactions between C. elegans and predacious fungi that catch nematodes using constricting hyphal rings. 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 being caught. Mutants that fail to suppress head movements in response to touch are caught more efficiently than the wild-type. This demonstrates that the coordination of motor programs allows C. elegans to smoothly retract from a fungal noose and evade capture. Our results suggest that selective pressures imposed by predacious fungi have shaped the evolution of C. elegans escape behavior.

  4. Tectonic escape in the evolution of the continental crust

    Science.gov (United States)

    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.

  5. Autologous HIV-1 neutralizing antibodies: emergence of neutralization-resistant escape virus and subsequent development of escape virus neutralizing antibodies

    DEFF Research Database (Denmark)

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

    1992-01-01

    The capacity of consecutive human sera to neutralize sequentially obtained autologous virus isolates was studied. HIV-1 was isolated three times over a 48-164-week period from three individuals immediately after seroconversion and from two individuals in later stages of infection. Development of ...... escape virus may be part of the explanation of the apparent failure of the immune system to control HIV infection.......The capacity of consecutive human sera to neutralize sequentially obtained autologous virus isolates was studied. HIV-1 was isolated three times over a 48-164-week period from three individuals immediately after seroconversion and from two individuals in later stages of infection. Development...

  6. The specificity and polymorphism of the MHC class I prevents the global adaptation of HIV-1 to the monomorphic proteasome and TAP.

    Directory of Open Access Journals (Sweden)

    Boris V Schmid

    Full Text Available The large diversity in MHC class I molecules in a population lowers the chance that a virus infects a host to which it is pre-adapted to escape the MHC binding of CTL epitopes. However, viruses can also lose CTL epitopes by escaping the monomorphic antigen processing components of the pathway (proteasome and TAP that create the epitope precursors. If viruses were to accumulate escape mutations affecting these monomorphic components, they would become pre-adapted to all hosts regardless of the MHC polymorphism. To assess whether viruses exploit this apparent vulnerability, we study the evolution of HIV-1 with bioinformatic tools that allow us to predict CTL epitopes, and quantify the frequency and accumulation of antigen processing escapes. We found that within hosts, proteasome and TAP escape mutations occur frequently. However, on the population level these escapes do not accumulate: the total number of predicted epitopes and epitope precursors in HIV-1 clade B has remained relatively constant over the last 30 years. We argue that this lack of adaptation can be explained by the combined effect of the MHC polymorphism and the high specificity of individual MHC molecules. Because of these two properties, only a subset of the epitope precursors in a host are potential epitopes, and that subset differs between hosts. We estimate that upon transmission of a virus to a new host 39%-66% of the mutations that caused epitope precursor escapes are released from immune selection pressure.

  7. Nurse Scheduling by Cooperative GA with Effective Mutation Operator

    Science.gov (United States)

    Ohki, Makoto

    In this paper, we propose an effective mutation operators for Cooperative Genetic Algorithm (CGA) to be applied to a practical Nurse Scheduling Problem (NSP). The nurse scheduling is a very difficult task, because NSP is a complex combinatorial optimizing problem for which many requirements must be considered. In real hospitals, the schedule changes frequently. The changes of the shift schedule yields various problems, for example, a fall in the nursing level. We describe a technique of the reoptimization of the nurse schedule in response to a change. The conventional CGA is superior in ability for local search by means of its crossover operator, but often stagnates at the unfavorable situation because it is inferior to ability for global search. When the optimization stagnates for long generation cycle, a searching point, population in this case, would be caught in a wide local minimum area. To escape such local minimum area, small change in a population should be required. Based on such consideration, we propose a mutation operator activated depending on the optimization speed. When the optimization stagnates, in other words, when the optimization speed decreases, the mutation yields small changes in the population. Then the population is able to escape from a local minimum area by means of the mutation. However, this mutation operator requires two well-defined parameters. This means that user have to consider the value of these parameters carefully. To solve this problem, we propose a periodic mutation operator which has only one parameter to define itself. This simplified mutation operator is effective over a wide range of the parameter value.

  8. Selective translational repression of truncated proteins from frameshift mutation-derived mRNAs in tumors.

    Directory of Open Access Journals (Sweden)

    Kwon Tae You

    2007-05-01

    Full Text Available Frameshift and nonsense mutations are common in tumors with microsatellite instability, and mRNAs from these mutated genes have premature termination codons (PTCs. Abnormal mRNAs containing PTCs are normally degraded by the nonsense-mediated mRNA decay (NMD system. However, PTCs located within 50-55 nucleotides of the last exon-exon junction are not recognized by NMD (NMD-irrelevant, and some PTC-containing mRNAs can escape from the NMD system (NMD-escape. We investigated protein expression from NMD-irrelevant and NMD-escape PTC-containing mRNAs by Western blotting and transfection assays. We demonstrated that transfection of NMD-irrelevant PTC-containing genomic DNA of MARCKS generates truncated protein. In contrast, NMD-escape PTC-containing versions of hMSH3 and TGFBR2 generate normal levels of mRNA, but do not generate detectable levels of protein. Transfection of NMD-escape mutant TGFBR2 genomic DNA failed to generate expression of truncated proteins, whereas transfection of wild-type TGFBR2 genomic DNA or mutant PTC-containing TGFBR2 cDNA generated expression of wild-type protein and truncated protein, respectively. Our findings suggest a novel mechanism of gene expression regulation for PTC-containing mRNAs in which the deleterious transcripts are regulated either by NMD or translational repression.

  9. Momentum versus extinction effects in the treatment of self-injurious escape behavior.

    OpenAIRE

    Zarcone, J R; Iwata, B A; Hughes, C.E; Vollmer, T R

    1993-01-01

    An individual's self-injurious escape behavior was treated using a high-probability instructional sequence with and without extinction. When presented alone, the high-probability sequence did not reduce self-injurious behavior. When escape extinction was implemented either alone or in combination with the high-probability sequence, self-injury decreased and compliance increased, suggesting that extinction may be a necessary component of the treatment for behavior problems maintained by escape.

  10. On the relative contributions of positive reinforcement and escape extinction in the treatment of food refusal.

    OpenAIRE

    Piazza, Cathleen C; Patel, Meeta R; Gulotta, Charles S; Sevin, Bari M; Layer, Stacy A

    2003-01-01

    We compared the effects of positive reinforcement alone, escape extinction alone, and positive reinforcement with escape extinction in the treatment of the food and fluid refusal of 4 children who had been diagnosed with a pediatric feeding disorder. Consumption did not increase when positive reinforcement was implemented alone. By contrast, consumption increased for all participants when escape extinction was implemented, independent of the presence or absence of positive reinforcement. Howe...

  11. Mutations in the gene region of hepatitis B virus genotype in Turkish patients

    Indian Academy of Sciences (India)

    Mehmet Özaslan; Ersan Özaslan; Arzu Barsgan; Mehmet Koruk

    2007-12-01

    The gene region of the hepatitis B virus (HBV) is responsible for the expression of surface antigens and includes the ‘a’-determinant region. Thus, mutation(s) in this region would afford HBV variants a distinct survival advantage, permitting the mutant virus to escape from the immune system. The aim of this study was to search for mutations of the gene region in different patient groups infected with genotype variants of HBV, and to analyse the biological significance of these mutations. Moreover, we investigated gene mutation inductance among family members. Forty HBV-DNA-positive patients were determined among 132 hepatitis B surface antigen (HbsAg) carriers by the first stage of seminested PCR. Genotypes and subtypes were established by sequencing of the amplified S gene regions. Variants were compared with original sequences of these serotypes, and mutations were identified. All variants were designated as genotype and subtype ayw3. Ten kinds of point mutations were identified within the region. The highest rates of mutation were found in chronic hepatitis patients and their family members. The amino acid mutations 125 (M → T) and 127 (T → P) were found on the first loop of ‘a’-determinant. The other consequence was mutation inductance in a family member. We found some mutations in the S gene region known to be stable and observed that some of these mutations affected gene expression.

  12. Viral escape in the CNS with multidrug-resistant HIV-1

    Directory of Open Access Journals (Sweden)

    Charles Béguelin

    2014-11-01

    Full Text Available Introduction: HIV-1 viral escape in the cerebrospinal fluid (CSF despite viral suppression in plasma is rare [1,2]. We describe the case of a 50-year-old HIV-1 infected patient who was diagnosed with HIV-1 in 1995. Antiretroviral therapy (ART was started in 1998 with a CD4 T cell count of 71 cells/ìL and HIV-viremia of 46,000 copies/mL. ART with zidovudine (AZT, lamivudine (3TC and efavirenz achieved full viral suppression. After the patient had interrupted ART for two years, treatment was re-introduced with tenofovir (TDF, emtricitabin (FTC and ritonavir boosted atazanavir (ATVr. This regimen suppressed HIV-1 in plasma for nine years and CD4 cells stabilized around 600 cells/ìL. Since July 2013, the patient complained about severe gait ataxia and decreased concentration. Materials and Methods: Additionally to a neurological examination, two lumbar punctures, a cerebral MRI and a neuropsycological test were performed. HIV-1 viral load in plasma and in CSF was quantified using Cobas TaqMan HIV-1 version 2.0 (Cobas Ampliprep, Roche diagnostic, Basel, Switzerland with a detection limit of 20 copies/mL. Drug resistance mutations in HIV-1 reverse transcriptase and protease were evaluated using bulk sequencing. Results: The CSF in January 2014 showed a pleocytosis with 75 cells/ìL (100% mononuclear and 1,184 HIV-1 RNA copies/mL, while HIV-1 in plasma was below 20 copies/mL. The resistance testing of the CSF-HIV-1 RNA showed two NRTI resistance-associated mutations (M184V and K65R and one NNRTI resistance-associated mutation (K103N. The cerebral MRI showed increased signal on T2-weighted images in the subcortical and periventricular white matter, in the basal ganglia and thalamus. Four months after ART intensification with AZT, 3TC, boosted darunavir and raltegravir, the pleocytosis in CSF cell count normalized to 1 cell/ìL and HIV viral load was suppressed. The neurological symptoms improved; however, equilibrium disturbances and impaired memory

  13. Common mutations of hepatitis B virus and their clinical significance

    Directory of Open Access Journals (Sweden)

    HU Airong

    2016-06-01

    Full Text Available Hepatitis B virus (HBV tends to mutate easily due to its special structure and life cycle. Mutation changes the biological behavior of HBV and its sensitivity to antiviral drugs and even affects therapeutic effect and accelerate disease progression. The point mutations are commonly see in the pre-S/S open reading frame (ORF, which may be associated with immune escape and occult HBV infection. The G1896A mutation is often observed in the pre-C/C-ORF and is associated with the development of HBeAg-negative chronic hepatitis B (CHB, hepatocellular carcinoma (HCC, and severe chronic hepatitis (liver failure. The mutations in P-ORF mainly occur in the reverse transcriptase (RT domain and are closely related to the resistance to nucleos(tide analogues. The A1762T and G1764A mutations occur in the basal core promoter (BCP, which overlaps with X-ORF, and may be associated with HBeAg-negative CHB, HCC, and severe chronic hepatitis (liver failure. Clarification of the association between these mutations and diseases helps to develop tailor-made diagnostic and therapeutic regimens for patients with HBV infection.

  14. Characterization of escape times of Josephson junctions for signal detection.

    Science.gov (United States)

    Addesso, Paolo; Filatrella, Giovanni; Pierro, Vincenzo

    2012-01-01

    The measurement of the escape time of a Josephson junction might be used to detect the presence of a sinusoidal signal embedded in noise when use of standard signal processing tools can be prohibitive due to the extreme weakness of the source or to the huge amount of data. In this paper we show that the prescriptions for the experimental setup and some physical behaviors depend on the detection strategy. More specifically, by exploitation of the sample mean of escape times to perform detection, two resonant regions are identified. At low frequencies there is a stochastic resonance or activation phenomenon, while near the plasma frequency a geometric resonance appears. Furthermore, detection performance in the geometric resonance region is maximized at the prescribed value of the bias current. The naive sample mean detector is outperformed, in terms of error probability, by the optimal likelihood ratio test. The latter exhibits only geometric resonance, showing monotonically increasing performance as the bias current approaches the junction critical current. In this regime the escape times are vanishingly small and therefore performance is essentially limited by measurement electronics. The behavior of the likelihood ratio and sample mean detector for different values of incoming signal to noise ratio is discussed, and a relationship with the error probability is found. Detectors based on the likelihood ratio test could be employed also to estimate unknown parameters in the applied input signal. As a prototypical example we study the phase estimation problem of a sinusoidal current, which is accomplished by using the filter bank approach. Finally we show that for a physically feasible detector the performances are found to be very close to the Cramer-Rao theoretical bound. Applications might be found, for example, in some astronomical detection problems (where the all-sky gravitational and/or radio wave search for pulsars requires the analysis of nearly sinusoidal

  15. Experiment for Development of Simple Escape Countermeasures for Frogs Falling into Concrete Canals

    Science.gov (United States)

    Watabe, Keiji; Mori, Atsushi; Koizumi, Noriyuki; Takemura, Takeshi; Park, Myeong Soo

    Three prototype escape countermeasures for frogs that can be easily installed in U-shaped canals with widths of 30-50 cm and depths of 30-50 cm were experimentally produced because frogs cannot escape from agricultural canals with deep concrete walls after falling into the canal. The differences of effectiveness of the 3 prototypes in places for the countermeasures (1 and 2) and flow conditions (dry and water running) were investigated for 2 frog species (Tokyo Daruma Pond Frog and Japanese Brown Frog). The brown frogs escaped from the canals more easily than the pond frogs. The brown frogs escaped regardless of their body size, but the small pond frogs escaped more easily than the large pond frogs. The prototype with slopes beside both canal walls and a net spread across the center line of the canal enabled frogs to escape from the canal more easily than the prototypes with only slopes or nets beside both canal walls. Increasing the number of places for the countermeasures enhanced frog escape. The differences in frog escape between dry canals and canals with water running were not significant. Therefore, the prototypes were confirmed sufficient as escape countermeasures that is inexpensive and can be easily placed in and removed from agricultural canals.

  16. Sharks modulate their escape behavior in response to predator size, speed and approach orientation.

    Science.gov (United States)

    Seamone, Scott; Blaine, Tristan; Higham, Timothy E

    2014-12-01

    Escape responses are often critical for surviving predator-prey interactions. Nevertheless, little is known about how predator size, speed and approach orientation impact escape performance, especially in larger prey that are primarily viewed as predators. We used realistic shark models to examine how altering predatory behavior and morphology (size, speed and approach orientation) influences escape behavior and performance in Squalus acanthias, a shark that is preyed upon by apex marine predators. Predator models induced C-start escape responses, and increasing the size and speed of the models triggered a more intense response (increased escape turning rate and acceleration). In addition, increased predator size resulted in greater responsiveness from the sharks. Among the responses, predator approach orientation had the most significant impact on escapes, such that the head-on approach, as compared to the tail-on approach, induced greater reaction distances and increased escape turning rate, speed and acceleration. Thus, the anterior binocular vision in sharks renders them less effective at detecting predators approaching from behind. However, it appears that sharks compensate by performing high-intensity escapes, likely induced by the lateral line system, or by a sudden visual flash of the predator entering their field of view. Our study reveals key aspects of escape behavior in sharks, highlighting the modulation of performance in response to predator approach.

  17. Improving escape panel selectivity in Nephrops directed fisheries by actively stimulating fish behaviour

    DEFF Research Database (Denmark)

    Krag, Ludvig Ahm; Herrmann, Bent; Feekings, Jordan P.

    2016-01-01

    with it. To increase the efficiency of such panels, the contact probability needs to be improved. In this study, we investigate to what extent the efficiency of escape panels can be improved by actively stimulating the escape behaviour of fish. The performance of two identical panel sections was compared...... in a twin-trawl system, one with and one without a stimulation device. A new coupled analysis method was used to explicitly quantify the improvements in contact probability and release efficiency for the escape panel. The results demonstrate that by actively stimulating escape behaviour, the contact...

  18. Ancient village fire escape path planning based on improved ant colony algorithm

    Science.gov (United States)

    Xia, Wei; Cao, Kang; Hu, QianChuan

    2017-06-01

    The roadways are narrow and perplexing in ancient villages, it brings challenges and difficulties for people to choose route to escape when a fire occurs. In this paper, a fire escape path planning method based on ant colony algorithm is presented according to the problem. The factors in the fire environment which influence the escape speed is introduced to improve the heuristic function of the algorithm, optimal transfer strategy, and adjustment pheromone volatile factor to improve pheromone update strategy adaptively, improve its dynamic search ability and search speed. Through simulation, the dynamic adjustment of the optimal escape path is obtained, and the method is proved to be feasible.

  19. Antibody escape kinetics of equine infectious anemia virus infection of horses.

    Science.gov (United States)

    Schwartz, Elissa J; Nanda, Seema; Mealey, Robert H

    2015-07-01

    Lentivirus escape from neutralizing antibodies (NAbs) is not well understood. In this work, we quantified antibody escape of a lentivirus, using antibody escape data from horses infected with equine infectious anemia virus. We calculated antibody blocking rates of wild-type virus, fitness costs of mutant virus, and growth rates of both viruses. These quantitative kinetic estimates of antibody escape are important for understanding lentiviral control by antibody neutralization and in developing NAb-eliciting vaccine strategies. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  20. On the relative contributions of positive reinforcement and escape extinction in the treatment of food refusal.

    Science.gov (United States)

    Piazza, Cathleen C; Patel, Meeta R; Gulotta, Charles S; Sevin, Bari M; Layer, Stacy A

    2003-01-01

    We compared the effects of positive reinforcement alone, escape extinction alone, and positive reinforcement with escape extinction in the treatment of the food and fluid refusal of 4 children who had been diagnosed with a pediatric feeding disorder. Consumption did not increase when positive reinforcement was implemented alone. By contrast, consumption increased for all participants when escape extinction was implemented, independent of the presence or absence of positive reinforcement. However, the addition of positive reinforcement to escape extinction was associated with beneficial effects (e.g., greater decreases in negative vocalizations and inappropriate behavior) for some participants.

  1. Detection and molecular characterisation of a diagnosis escape variant associated with occult hepatitis B virus in Brazil

    Directory of Open Access Journals (Sweden)

    Ricardo Wagner de Almeida

    Full Text Available BACKGROUND Many studies have identified mutations in the hepatitis B surface antigen (HBsAg as important factors limiting the ability of commercial serological assays to detect this viral antigen. However, an association between mutations in the HBsAg gene and the occurrence of occult HBV infection (OBI in patients has not been established. OBJECTIVES To detect hepatitis B virus (HBV DNA in patients with anti-HBc as a unique serological marker, a previously published, cost-effective TaqMan-based real-time polymerase chain reaction (PCR test with minor groove binding probes was adapted for use in this study. The current study also aimed to investigate HBsAg mutations and genotypes of HBV in OBI at the Viral Hepatitis Ambulatory Clinic in Rio de Janeiro to determine any possible association. METHODS Intra-assay and inter-assay reproducibility were determined, and the mean coefficient of variation values obtained were 2.07 and 3.5, respectively. Probit analysis indicated that the 95% detection level was 25 IU/mL. The prevalence of OBI was investigated in 35 serum samples with an ‘anti-HBc alone’ profile from individuals who attended our clinic between 2011 and 2013. FINDINGS HBV DNA was detected in only one sample, resulting in an OBI rate of 2.9%. Nucleotide sequencing of the pre-S/S region was performed to genotype and analyse mutations within the HBsAg gene of this HBV DNA. The HBV in the OBI case was classified as sub-genotype A1, and a sequence analysis of the small S gene revealed 12 mutations in the major hydrophilic region compared to the consensus A1 sequence. Most of these mutations occurred in amino acid residues that have been reported as clinically relevant because they have been implicated in vaccine escape and/or inability to detect HBsAg by commercial serological assays. MAIN CONCLUSIONS Our study suggests the importance of specific HBsAg mutations, different from those in D, B, and C genotypes, in sub-genotype A1 HBV associated

  2. Escape and avoidance learning in the earthworm Eisenia hortensis

    Directory of Open Access Journals (Sweden)

    W. Jeffrey Wilson

    2014-01-01

    Full Text Available Interest in instrumental learning in earthworms dates back to 1912 when Yerkes concluded that they can learn a spatial discrimination in a T-maze. Rosenkoetter and Boice determined in the 1970s that the “learning” that Yerkes observed was probably chemotaxis and not learning at all. We examined a different form of instrumental learning: the ability to learn both to escape and to avoid an aversive stimulus. Freely moving “master” worms could turn off an aversive white light by increasing their movement; the behavior of yoked controls had no effect on the light. We demonstrate that in as few as 12 trials the behavior of the master worms comes under the control of this contingency.

  3. Will 3552 Don Quixote escape from the Solar System?

    Directory of Open Access Journals (Sweden)

    Suryadi Siregar

    2011-05-01

    Full Text Available Asteroid 1983 SA, well known as 3552 Don Quixote, is one of Near Earth Asteroids (NEAs which is the most probable candidate for the cometary origin, or otherwise as Jupiter-Family-Comets (JFCs. The aim of this study is to investigate the possibility of 3552 Don Quixote to be ejected from the Solar System. This paper presents an orbital evolution of 100 hypothetical asteroids generated by cloning 3552 Don Quixote. Investigation of its orbital evolution is conducted by using the SWIFT subroutine package, where the gravitational perturbations of eight major planets in the Solar System are considered. Over very short time scales (220 kyr relative to the Solar System life time (10 Gyr, the asteroid 3552 Don Quixote gave an example of chaotic motion that can cause asteroid to move outward and may be followed by escaping from the Solar System. Probability of ejection within the 220 kyr time scale is 50%.

  4. Novel Anti-Melanoma Immunotherapies: Disarming Tumor Escape Mechanisms

    Directory of Open Access Journals (Sweden)

    Sivan Sapoznik

    2012-01-01

    Full Text Available The immune system fights cancer and sometimes temporarily eliminates it or reaches an equilibrium stage of tumor growth. However, continuous immunological pressure also selects poorly immunogenic tumor variants that eventually escape the immune control system. Here, we focus on metastatic melanoma, a highly immunogenic tumor, and on anti-melanoma immunotherapies, which recently, especially following the FDA approval of Ipilimumab, gained interest from drug development companies. We describe new immunomodulatory approaches currently in the development pipeline, focus on the novel CEACAM1 immune checkpoint, and compare its potential to the extensively described targets, CTLA4 and PD1. This paper combines multi-disciplinary approaches and describes anti-melanoma immunotherapies from molecular, medical, and business angles.

  5. Escape of Mycobacterium tuberculosis from oxidative killing by neutrophils.

    Science.gov (United States)

    Corleis, Björn; Korbel, Daniel; Wilson, Robert; Bylund, Johan; Chee, Ronnie; Schaible, Ulrich E

    2012-07-01

    Neutrophils enter sites of infection, where they can eliminate pathogenic bacteria in an oxidative manner. Despite their predominance in active tuberculosis lesions, the function of neutrophils in this important human infection is still highly controversial. We observed that virulent Mycobacterium tuberculosis survived inside human neutrophils despite prompt activation of these defence cells' microbicidal effectors. Survival of M. tuberculosis was accompanied by necrotic cell death of infected neutrophils. Necrotic cell death entirely depended on radical oxygen species production since chronic granulomatous disease neutrophils were protected from M. tuberculosis-triggered necrosis. More, importantly, the M. tuberculosis ΔRD1 mutant failed to induce neutrophil necrosis rendering this strain susceptible to radical oxygen species-mediated killing. We conclude that this virulence function is instrumental for M. tuberculosis to escape killing by neutrophils and contributes to pathogenesis in tuberculosis.

  6. Escaping Antiangiogenic Therapy: Strategies Employed by Cancer Cells

    Directory of Open Access Journals (Sweden)

    Mauricio P. Pinto

    2016-09-01

    Full Text Available 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.

  7. The structure of spider's web fast escaping sets

    CERN Document Server

    Osborne, J W

    2010-01-01

    Building on recent work by Rippon and Stallard, we explore the intricate structure of the spider's web fast escaping sets associated with certain transcendental entire functions. Our results are expressed in terms of the components of the complement of the set (the 'holes' in the web). We describe the topology of such components and give a characterisation of their possible orbits under iteration. We show that there are uncountably many components having each of a number of orbit types, and we prove that components with bounded orbits are quasiconformally homeomorphic to components of the filled Julia set of a polynomial. We also show that there are singleton periodic components and that these are dense in the Julia set.

  8. Bacillus cereus immune escape: a journey within macrophages.

    Science.gov (United States)

    Tran, Seav-Ly; Ramarao, Nalini

    2013-10-01

    During bacterial infection, professional phagocytes are attracted to the site of infection, where they constitute a first line of host cell defense. Their function is to engulf and destroy the pathogens. Thus, bacteria must withstand the bactericidal activity of professional phagocytes, including macrophages to counteract the host immune system. Bacillus cereus infections are characterized by bacteremia despite the accumulation of inflammatory cells at the site of infection. This implies that the bacteria have developed means of resisting the host immune system. Bacillus cereus spores survive, germinate, and multiply in contact with macrophages, eventually producing toxins that kill these cells. However, the exact mechanism by which B. cereus evades immune attack remains unclear. This review addresses the interaction between B. cereus and macrophages, highlighting, in particular, the ways in which the bacteria escape the microbicidal activities of professional phagocytes.

  9. An Introduction to Survival, Evasion, Resistance, and Escape (SERE) Medicine.

    Science.gov (United States)

    Smith, Michael B

    2013-01-01

    When an individual finds himself/herself in a survival, evasion, resistance, or escape (SERE) scenario, the ability to treat injuries/illnesses can be the difference between life and death. SERE schools are responsible for preparing military members for these situations, but the concept of SERE medicine is not particularly well defined. To provide a comprehensive working description of SERE medicine, operational and training components were examined. Evidence suggests that SERE medicine is diverse, injury/illness patterns are situationally dependent, and treatment options often differ from conventional clinical medicine. Ideally, medical lessons taught in SERE training are based on actual documented events. Unfortunately, the existing body of literature is dated and does not appear to be expanding. In this article, four distinct facets of SERE medicine are presented to establish a basis for future discussion and research. Recommendations to improve SERE medical curricula and data-gathering processes are also provided.

  10. On Escaping a Galaxy Cluster in an Accelerating Universe

    CERN Document Server

    Stark, Alejo; Gifford, Daniel

    2016-01-01

    We derive the escape velocity profile for an Einasto density field in an accelerating universe and demonstrate its physical viability by comparing theoretical expectations to both light-cone data generated from N-body simulations and archival data on 20 galaxy clusters. We demonstrate that the projection function ($g(\\beta )$) is deemed physically viable only for the theoretical expectation that includes a cosmology-dependent term. Using simulations, we show that the inferred velocity anisotropy is more than 6{\\sigma} away from the expected value for the theoretical profile that ignores the acceleration of the universe. In the archival data, we constrain the average velocity anisotropy parameter of a sample of 20 clusters to be $\\beta ={0.248}_{-0.360}^{+0.164}$ at the 68% confidence level. Lastly, we briefly discuss how our analytic model may be used as a novel cosmological probe based on galaxy clusters.

  11. Fast Escape from Quantum Mazes in Integrated Photonics

    CERN Document Server

    Caruso, Filippo; Ciriolo, Anna Gabriella; Sciarrino, Fabio; Osellame, Roberto

    2015-01-01

    Escaping from a complex maze, by exploring different paths with several decision-making branches in order to reach the exit, has always been a very challenging and fascinating task. Wave field and quantum objects may explore a complex structure in parallel by interference effects, but without necessarily leading to more efficient transport. Here, inspired by recent observations in biological energy transport phenomena, we demonstrate how a quantum walker can efficiently reach the output of a maze by partially suppressing the presence of interference. In particular, we show theoretically an unprecedented improvement in transport efficiency for increasing maze size with respect to purely quantum and classical approaches. In addition, we investigate experimentally these hybrid transport phenomena, by mapping the maze problem in an integrated waveguide array, probed by coherent light, hence successfully testing our theoretical results. These achievements may lead towards future bio-inspired photonics technologies...

  12. RpoS controls the Vibrio cholerae mucosal escape response.

    Directory of Open Access Journals (Sweden)

    Alex Toftgaard Nielsen

    2006-10-01

    Full Text Available Vibrio cholerae causes a severe diarrhoeal disease by secreting a toxin during colonization of the epithelium in the small intestine. Whereas the initial steps of the infectious process have been intensively studied, the last phases have received little attention. Confocal microscopy of V. cholerae O1-infected rabbit ileal loops captured a distinctive stage in the infectious process: 12 h post-inoculation, bacteria detach from the epithelial surface and move into the fluid-filled lumen. Designated the "mucosal escape response," this phenomenon requires RpoS, the stationary phase alternative sigma factor. Quantitative in vivo localization assays corroborated the rpoS phenotype and showed that it also requires HapR. Expression profiling of bacteria isolated from ileal loop fluid and mucus demonstrated a significant RpoS-dependent upregulation of many chemotaxis and motility genes coincident with the emigration of bacteria from the epithelial surface. In stationary phase cultures, RpoS was also required for upregulation of chemotaxis and motility genes, for production of flagella, and for movement of bacteria across low nutrient swarm plates. The hapR mutant produced near-normal numbers of flagellated cells, but was significantly less motile than the wild-type parent. During in vitro growth under virulence-inducing conditions, the rpoS mutant produced 10- to 100-fold more cholera toxin than the wild-type parent. Although the rpoS mutant caused only a small over-expression of the genes encoding cholera toxin in the ileal loop, it resulted in a 30% increase in fluid accumulation compared to the wild-type. Together, these results show that the mucosal escape response is orchestrated by an RpoS-dependent genetic program that activates chemotaxis and motility functions. This may furthermore coincide with reduced virulence gene expression, thus preparing the organism for the next stage in its life cycle.

  13. Whole-body volume regulation and escape from antidiuresis.

    Science.gov (United States)

    Verbalis, Joseph G

    2006-07-01

    Both individual cells and organs regulate their volume in response to sustained hypo-osmolality via solute and water losses. Similar processes occur in the whole body to regulate the volumes of extracellular fluid (ECF) and intravascular spaces toward normal levels. Body water losses occur via the phenomena "escape from antidiuresis"; solute losses occur through the secondary natriuresis induced by water retention. As a result of resistance to arginine vasopressin (AVP) signaling, escape from antidiuresis is caused by downregulation of kidney aquaporin-2 expression despite high AVP plasma levels. Recent data have implicated downregulation of vasopressin V2R as a potential mechanism of resistance, and suggest that this may be a result of decreased intrarenal angiotensin II signaling in combination with increased intrarenal nitric oxide and prostaglandin E2 signaling. The natriuresis that results in volume regulation of the ECF and vascular spaces is the result of intrarenal hemodynamic changes produced by volume expansion, but the degree to which these effects are modulated by aldosterone secretion and the activity of distal sodium cotransporters and channels remains to be elucidated. The clinical implication of these volume-regulatory processes is that the chronic hyponatremic state is one of water retention and solute losses from intracellular fluid and ECF compartments. The degree to which solute losses versus water retention contribute to hyponatremia will vary in association with many factors, including the etiology of the hyponatremia, the rapidity of development of the hyponatremia, the chronicity of the hyponatremia, the volume of daily water loading, and individual variability. Understanding these volume-regulatory processes allows a better understanding of many aspects of the conundrum of patients with "clinical euvolemia" and dilutional hyponatremia from AVP-induced water retention.

  14. RpoS controls the Vibrio cholerae mucosal escape response.

    Directory of Open Access Journals (Sweden)

    Alex Toftgaard Nielsen

    2006-10-01

    Full Text Available Vibrio cholerae causes a severe diarrhoeal disease by secreting a toxin during colonization of the epithelium in the small intestine. Whereas the initial steps of the infectious process have been intensively studied, the last phases have received little attention. Confocal microscopy of V. cholerae O1-infected rabbit ileal loops captured a distinctive stage in the infectious process: 12 h post-inoculation, bacteria detach from the epithelial surface and move into the fluid-filled lumen. Designated the "mucosal escape response," this phenomenon requires RpoS, the stationary phase alternative sigma factor. Quantitative in vivo localization assays corroborated the rpoS phenotype and showed that it also requires HapR. Expression profiling of bacteria isolated from ileal loop fluid and mucus demonstrated a significant RpoS-dependent upregulation of many chemotaxis and motility genes coincident with the emigration of bacteria from the epithelial surface. In stationary phase cultures, RpoS was also required for upregulation of chemotaxis and motility genes, for production of flagella, and for movement of bacteria across low nutrient swarm plates. The hapR mutant produced near-normal numbers of flagellated cells, but was significantly less motile than the wild-type parent. During in vitro growth under virulence-inducing conditions, the rpoS mutant produced 10- to 100-fold more cholera toxin than the wild-type parent. Although the rpoS mutant caused only a small over-expression of the genes encoding cholera toxin in the ileal loop, it resulted in a 30% increase in fluid accumulation compared to the wild-type. Together, these results show that the mucosal escape response is orchestrated by an RpoS-dependent genetic program that activates chemotaxis and motility functions. This may furthermore coincide with reduced virulence gene expression, thus preparing the organism for the next stage in its life cycle.

  15. Escaped and Trapped Emission of Organic Light-Emitting Diodes

    Institute of Scientific and Technical Information of China (English)

    LIANG Shi-Xiong; WU Zhao-Xin; ZHAO Xuan-Ke; HOU Xun

    2012-01-01

    By locating the emitters around the first and second antinode of the metal electrode, the escaped and trapped emission of small molecule based bottom emission organic light-emitting diodes is investigated by using an integrating sphere, a fiber spectrometer and a glass hemisphere. It is found that the external coupling ratio by locating the emitters at the second antinode (at a distance of 220 nm from the cathode) is 70%, which is higher than that of an emitter at the first antinode (60 nm from the cathode) in theory and experiment. Extending the "half-space" dipole model by taking the dipole radiation pattern into account, we also calculate the optical coupling efficiency for the emitter at both the first and second antinode. Our experimental and theoretical results will benefit the optimization of device structures for the higher out-coupling efficiency.%By locating the emitters around the first and second antinode of the metal electrode,the escaped and trapped emission of small molecule based bottom emission organic light-emitting diodes is investigated by using an integrating sphere,a fiber spectrometer and a glass hemisphere.It is found that the external coupling ratio by locating the emitters at the second antinode (at a distance of 220 nm from the cathode) is 70%,which is higher than that of an emitter at the first antinode (60nm from the cathode) in theory and experiment.Extending the "half-space" dipole model by taking the dipole radiation pattern into account,we also calculate the optical coupling efficiency for the emitter at both the first and second antinode.Our experimental and theoretical results will benefit the optimization of device structures for the higher out-coupling efficiency.

  16. Phenotypic mismatches reveal escape from arms-race coevolution.

    Science.gov (United States)

    Hanifin, Charles T; Brodie, Edmund D; Brodie, Edmund D

    2008-03-11

    Because coevolution takes place across a broad scale of time and space, it is virtually impossible to understand its dynamics and trajectories by studying a single pair of interacting populations at one time. Comparing populations across a range of an interaction, especially for long-lived species, can provide insight into these features of coevolution by sampling across a diverse set of conditions and histories. We used measures of prey traits (tetrodotoxin toxicity in newts) and predator traits (tetrodotoxin resistance of snakes) to assess the degree of phenotypic mismatch across the range of their coevolutionary interaction. Geographic patterns of phenotypic exaggeration were similar in prey and predators, with most phenotypically elevated localities occurring along the central Oregon coast and central California. Contrary to expectations, however, these areas of elevated traits did not coincide with the most intense coevolutionary selection. Measures of functional trait mismatch revealed that over one-third of sampled localities were so mismatched that reciprocal selection could not occur given current trait distributions. Estimates of current locality-specific interaction selection gradients confirmed this interpretation. In every case of mismatch, predators were "ahead" of prey in the arms race; the converse escape of prey was never observed. The emergent pattern suggests a dynamic in which interacting species experience reciprocal selection that drives arms-race escalation of both prey and predator phenotypes at a subset of localities across the interaction. This coadaptation proceeds until the evolution of extreme phenotypes by predators, through genes of large effect, allows snakes to, at least temporarily, escape the arms race.

  17. Phenotypic mismatches reveal escape from arms-race coevolution.

    Directory of Open Access Journals (Sweden)

    Charles T Hanifin

    2008-03-01

    Full Text Available Because coevolution takes place across a broad scale of time and space, it is virtually impossible to understand its dynamics and trajectories by studying a single pair of interacting populations at one time. Comparing populations across a range of an interaction, especially for long-lived species, can provide insight into these features of coevolution by sampling across a diverse set of conditions and histories. We used measures of prey traits (tetrodotoxin toxicity in newts and predator traits (tetrodotoxin resistance of snakes to assess the degree of phenotypic mismatch across the range of their coevolutionary interaction. Geographic patterns of phenotypic exaggeration were similar in prey and predators, with most phenotypically elevated localities occurring along the central Oregon coast and central California. Contrary to expectations, however, these areas of elevated traits did not coincide with the most intense coevolutionary selection. Measures of functional trait mismatch revealed that over one-third of sampled localities were so mismatched that reciprocal selection could not occur given current trait distributions. Estimates of current locality-specific interaction selection gradients confirmed this interpretation. In every case of mismatch, predators were "ahead" of prey in the arms race; the converse escape of prey was never observed. The emergent pattern suggests a dynamic in which interacting species experience reciprocal selection that drives arms-race escalation of both prey and predator phenotypes at a subset of localities across the interaction. This coadaptation proceeds until the evolution of extreme phenotypes by predators, through genes of large effect, allows snakes to, at least temporarily, escape the arms race.

  18. ESCAP holds expert group meeting on population issues facing adolescents.

    Science.gov (United States)

    1997-01-01

    This article summarizes the activities at the ESCAP Population Division Expert Group Meeting on Adolescents that was held during September-October 1997 in Bangkok, Thailand. The meeting was a follow-up to the 1994 International Conference on Population and Development (ICPD). The meeting considered 1) the ICPD recommendations; 2) the recommendations contained in the Jakarta Plan of Action on Human Resource Development; and 3) the Proposals for Action on Human Resources Development for Youth in Asia and the Pacific. Participants included about 25 people from Australia, Bangladesh, China, India, Indonesia, Philippines, Sri Lanka, and Thailand. The conference relied on 8 invited experts, two resource persons, advisors from the UNFPA Country Support Team for East and Southeast Asia, and representatives of UNFPA, the Population Council, and the East-West Center. A concern was the declining age of menarche of girls in the ESCAP region and the increasing age of marriage. During the time of menarche and marriage, girls are migrating and moving away from their family and community in rural areas. Family structure and relationships are changing. Increases are observed in adolescent premarital sexual activity, the incidence of sexually transmitted diseases, substance abuse, teenage pregnancy, and abortion. The mass media and information technologies have both a positive and a negative influence on adolescents. Parent-child communication exchanges and teacher-student exchanges are "less than ideal." Old traditions and practices change slower than people change. Boys and girls are affected differently by the sociocultural and economic environment. The societal norms set expectations for behavior that may conflict with individual beliefs and practices. Changes brought by globalization and rapid economic growth provide greater opportunity for young girls and women to obtain employment and autonomy.

  19. In vivo CD8+ T-cell suppression of siv viremia is not mediated by CTL clearance of productively infected cells.

    Directory of Open Access Journals (Sweden)

    Joseph K Wong

    2010-01-01

    Full Text Available The CD8+ T-cell is a key mediator of antiviral immunity, potentially contributing to control of pathogenic lentiviral infection through both innate and adaptive mechanisms. We studied viral dynamics during antiretroviral treatment of simian immunodeficiency virus (SIV infected rhesus macaques following CD8+ T-cell depletion to test the importance of adaptive cytotoxic effects in clearance of cells productively infected with SIV. As previously described, plasma viral load (VL increased following CD8+ T-cell depletion and was proportional to the magnitude of CD8+ T-cell depletion in the GALT, confirming a direct relationship between CD8+ T-cell loss and viral replication. Surprisingly, first phase plasma virus decay following administration of antiretroviral drugs was not slower in CD8+ T-cell depleted animals compared with controls indicating that the short lifespan of the average productively infected cell is not a reflection of cytotoxic T-lymphocyte (CTL killing. Our findings support a dominant role for non-cytotoxic effects of CD8+ T-cells on control of pathogenic lentiviral infection and suggest that cytotoxic effects, if present, are limited to early, pre-productive stages of the viral life cycle. These observations have important implications for future strategies to augment immune control of HIV.

  20. 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

    Energy Technology Data Exchange (ETDEWEB)

    Bates, John T. [The Vanderbilt Vaccine Center, Departments of Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN (United States); Keefer, Christopher J. [The Vanderbilt Vaccine Center, Departments of Pediatrics, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN (United States); Slaughter, James C. [The Vanderbilt Vaccine Center, Departments of Biostatistics and Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN (United States); Kulp, Daniel W. [IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (United States); Schief, William R. [IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (United States); Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA (United States); Crowe, James E., E-mail: james.crowe@vanderbilt.edu [The Vanderbilt Vaccine Center, Departments of Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN (United States); The Vanderbilt Vaccine Center, Departments of Pediatrics, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN (United States)

    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.

  1. T-cell-receptor engagement and tumor ICAM-1 up-regulation are required to by-pass low susceptibility of melanoma cells to autologous CTL-mediated lysis.

    Science.gov (United States)

    Anichini, A; Mortarini, R; Alberti, S; Mantovani, A; Parmiani, G

    1993-04-01

    Tumor-specific and non-specific CD3+, TcR alpha beta+, CD8+ cytotoxic T-cell (CTL) clones, isolated from tumor-infiltrating lymphocytes (TIL) or peripheral blood lymphocytes (PBL) of a melanoma patient and allogeneic LAK cells, were used to investigate the requirements for bypassing the low lysability of some melanoma clones derived from an s.c. metastasis from which highly lysable clones were also obtained. Cytofluorimetric analysis showed that all melanoma clones expressed ICAM-1, although to different extents, reaching a 10-fold difference in fluorescence units, while HLA class-I antigens were similarly expressed. The differences in expression of ICAM-1 among tumor clones correlated with differences in lysability, by both specific and non-specific CTL, but were not large enough to affect lymphocyte-tumor conjugate formation. Cytokine- or gene-transfer-mediated up-regulation of ICAM-1 did not induce de novo lysis of ICAM-1low tumor cells; however, it markedly enhanced a low level of killing of the same cells by tumor-specific, TcR-dependent and HLA-restricted CTL clones but not by non-specific, TcR-independent effectors. In addition, lysis of melanoma clones by any effector was similarly inhibited by anti-ICAM-1 and anti-LFA-1 antibodies. This indicates that by-pass of low lysability of ICAM-1low melanoma clones by CTL clones, after ICAM-1 up-regulation, is possible only if simultaneous LFA-1 and TcR engagement takes place. In addition, these results suggest that the constitutive high level of expression of ICAM-1 on the subset of ICAM-1high melanoma cells must be only one of the factors contributing to the high lysability of these cells by any effector.

  2. Cornelia de Lange individuals with new and recurrent SMC1A mutations enhance delineation of mutation repertoire and phenotypic spectrum.

    Science.gov (United States)

    Gervasini, Cristina; Russo, Silvia; Cereda, Anna; Parenti, Ilaria; Masciadri, Maura; Azzollini, Jacopo; Melis, Daniela; Aravena, Teresa; Doray, Bérénice; Ferrarini, Alessandra; Garavelli, Livia; Selicorni, Angelo; Larizza, Lidia

    2013-11-01

    We report on the clinical and molecular characterization of eight patients, one male and seven females, with clinical diagnosis of Cornelia de Lange syndrome (CdLS), who were found to carry distinct mutations of the SMC1A gene. Five of the eight mutations are novel, with two involving amino acid residues previously described as altered in a different way. The other three have been reported each in a single case. Comparison of pairs of individuals with the same mutation indicates only partial overlap of their clinical phenotypes. The following novel missense mutations, all affecting highly conserved amino acid residues, were found: p.R398G in the N-terminal coiled-coil domain, p.V651M in the C-terminal coiled-coil/hinge junction, p.R693G in the C-terminal coiled-coil, and p.N1166T and p.L1189F in the C-terminal ABC cassette. The latter is localized in the H-loop, and represents the first mutation involving a functional motif of SMC1A protein. The effect of the mutations on SMC1A protein function has been predicted using four bioinformatic tools. All mutations except p.V651M were scored as pathogenic by three or four of the tools. p.V651M was found in the only male individual of our cohort, who presented with the most severe phenotype. This raises the issue of gender effect when addressing mutation-phenotype correlation for genes such as SMC1A, which incompletely escapes X-inactivation. Our clinical and molecular findings expand the total number of characterized SMC1A-mutated patients (from 44 to 52) and the restricted repertoire of SMC1A mutations (from 29 to 34), contributing to the molecular and clinical signature of SMC1A-based CdLS. © 2013 Wiley Periodicals, Inc.

  3. Transgenic Animal Mutation Assays

    Institute of Scientific and Technical Information of China (English)

    Tao Chen; Ph.D.D.A.B.T.

    2005-01-01

    @@ The novel transgenic mouse and rat mutation assays have provided a tool for analyzing in vivo mutation in any tissue, thus permitting the direct comparison of cancer incidence with mutant frequency.

  4. Functional analysis of 'a' determinant mutations associated with occult HBV in HIV-positive South Africans.

    Science.gov (United States)

    Powell, Eleanor A; Boyce, Ceejay L; Gededzha, Maemu P; Selabe, Selokela G; Mphahlele, M Jeffrey; Blackard, Jason T

    2016-07-01

    Occult hepatitis B is defined by the presence of hepatitis B virus (HBV) DNA in the absence of hepatitis B surface antigen (HBsAg). Occult HBV is associated with the development of hepatocellular carcinoma, reactivation during immune suppression, and virus transmission. Viral mutations contribute significantly to the occult HBV phenotype. Mutations in the 'a' determinant of HBsAg are of particular interest, as these mutations are associated with immune escape, vaccine escape and diagnostic failure. We examined the effects of selected occult HBV-associated mutations identified in a population of HIV-positive South Africans on HBsAg production in vitro. Mutations were inserted into two different chronic HBV backbones and transfected into a hepatocyte-derived cell line. HBsAg levels were quantified by enzyme-linked immunosorbent assay (ELISA), while the detectability of mutant HBsAg was determined using an HA-tagged HBsAg expression system. Of the seven mutations analysed, four (S132P, C138Y, N146D and C147Y) resulted in decreased HBsAg expression in one viral background but not in the second viral background. One mutation (N146D) led to a decrease in HBsAg detected as compared to HA-tag, indicating that this mutation compromises the ability of the ELISA to detect HBsAg. The contribution of occult-associated mutations to the HBsAg-negative phenotype of occult HBV cannot be determined adequately by testing the effect of the mutation in a single viral background, and rigorous analysis of these mutations is required.

  5. Interdisciplinary Analysis of HIV-Specific CD8(+) T Cell Responses against Variant Epitopes Reveals Restricted TCR Promiscuity

    DEFF Research Database (Denmark)

    Hoof, Ilka; Perez, C.L.; Buggert, M.

    2010-01-01

    HIV-1 specific CTL responses play a key role in limiting viral replication. CTL responses are sensitive to viral escape mutations, which influence recognition of the virus. Although CTLs have been shown to recognize epitope variants, the extent of this cross-reactivity has not been quantitatively...... are useful to study the complex pattern of CTL responses exhibited by an HIV-1 infected patient cohort and for identification of optimal targets for novel therapeutic or vaccine approaches. The Journal of Immunology, 2010, 184: 5383-5391.......HIV-1 specific CTL responses play a key role in limiting viral replication. CTL responses are sensitive to viral escape mutations, which influence recognition of the virus. Although CTLs have been shown to recognize epitope variants, the extent of this cross-reactivity has not been quantitatively...... investigated in a genetically diverse cohort of HIV-1 infected patients. Using a novel bioinformatic binding prediction method, we aimed to explain the pattern of epitope-specific CTL responses based on the patients' HLA genotype and autologous virus sequence quantitatively. Sequences covering predicted...

  6. Hepatitis A Virus Vaccine Escape Variants and Potential New Serotype Emergence

    Science.gov (United States)

    Pérez-Sautu, Unai; Costafreda, M. Isabel; Caylà, Joan; Tortajada, Cecilia; Lite, Josep; Bosch, Albert

    2011-01-01

    Six hepatitis A virus antigenic variants that likely escaped the protective effect of available vaccines were isolated, mostly from men who have sex with men. The need to complete the proper vaccination schedules is critical, particularly in the immunocompromised population, to prevent the emergence of vaccine-escaping variants. PMID:21470474

  7. Hepatitis A Virus Vaccine Escape Variants and Potential New Serotype Emergence

    OpenAIRE

    Pérez-Sautu, Unai; Costafreda, M. Isabel; Caylà, Joan; Tortajada, Cecilia; Lite, Josep; Bosch, Albert; Rosa M Pintó

    2011-01-01

    Six hepatitis A virus antigenic variants that likely escaped the protective effect of available vaccines were isolated, mostly from men who have sex with men. The need to complete the proper vaccination schedules is critical, particularly in the immunocompromised population, to prevent the emergence of vaccine-escaping variants.

  8. Computer Self-Efficacy, Competitive Anxiety and Flow State: Escaping from Firing Online Game

    Science.gov (United States)

    Hong, Jon-Chao; Pei-Yu, Chiu; Shih, Hsiao-Feng; Lin, Pei-Shin; Hong, Jon-Chao

    2012-01-01

    Flow state in game playing affected by computer self-efficacy and game competitive anxiety was studied. In order to examine the effect of those constructs with high competition, this study select "Escaping from firing online game" which require college students to escape from fire and rescue people and eliminate the fire damage along the way of…

  9. Hepatitis A Virus Vaccine Escape Variants and Potential New Serotype Emergence

    OpenAIRE

    Pérez-Sautu, Unai; Costafreda, M. Isabel; Caylà, Joan; Tortajada, Cecilia; Lite, Josep; Bosch, Albert; Pintó, Rosa M.

    2011-01-01

    Six hepatitis A virus antigenic variants that likely escaped the protective effect of available vaccines were isolated, mostly from men who have sex with men. The need to complete the proper vaccination schedules is critical, particularly in the immunocompromised population, to prevent the emergence of vaccine-escaping variants.

  10. The Effects of Fixed-Time Escape on Inappropriate and Appropriate Classroom Behavior

    Science.gov (United States)

    Waller, Rachael D.; Higbee, Thomas S.

    2010-01-01

    Few studies have explored the effects of fixed-time (FT) reinforcement on escape-maintained behavior of students in a classroom setting. We measured the effects of an FT schedule on the disruptive and appropriate academic behaviors of 2 junior high students in a public school setting. Results demonstrated that FT escape from tasks resulted in a…

  11. Competing Contingencies for Escape Behavior: Effects of Negative Reinforcement Magnitude and Quality

    Science.gov (United States)

    Hammond, Jennifer L.

    2009-01-01

    Previous research has shown that problem behavior maintained by social-negative reinforcement can be treated without escape extinction by enhancing the quality of positive reinforcement for an appropriate alternative response such as compliance. By contrast, negative reinforcement (escape) for compliance generally has been ineffective in the…

  12. Spoon Distance Fading with and without Escape Extinction as Treatment for Food Refusal

    Science.gov (United States)

    Rivas, Kristi D.; Piazza, Cathleen C.; Patel, Meeta R.; Bachmeyer, Melanie H.

    2010-01-01

    Little is known about the characteristics of meals that serve as motivating operations (MOs) for escape behavior. In the current investigation, we showed that the distance at which a therapist held a spoon from a child's lips served as an MO for escape behavior. Based on these results, we implemented spoon distance fading, compared fading with and…

  13. HIV-1 Viral Escape in Cerebrospinal Fluid of Subjects on Suppressive Antiretroviral Treatment

    OpenAIRE

    Edén, Arvid; Fuchs, Dietmar; Hagberg, Lars; Nilsson, Staffan; Spudich, Serena; SVENNERHOLM, BO; Price, Richard W.; Gisslén, Magnus

    2010-01-01

    Background. Occasional cases of viral escape in cerebrospinal fluid (CSF) despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA have been reported. We investigated CSF viral escape in subjects treated with commonly used antiretroviral therapy regimens in relation to intrathecal immune activation and central nervous system penetration effectiveness (CPE) rank.

  14. Treatment of Escape-Maintained Behavior with Positive Reinforcement: The Role of Reinforcement Contingency and Density

    Science.gov (United States)

    Ingvarsson, Einar T.; Hanley, Gregory P.; Welter, Katherine M.

    2009-01-01

    Functional analyses suggested that the disruptive behavior of three preschool children was maintained by escape from demands. While keeping the escape contingency intact, we conducted (a) a density analysis in which the children earned preferred items for task completion according to two schedules that varied in reinforcement density, and (b) a…

  15. Identification of genes escaping X inactivation by allelic expression analysis in a novel hybrid mouse model.

    Science.gov (United States)

    Berletch, Joel B; Ma, Wenxiu; Yang, Fan; Shendure, Jay; Noble, William S; Disteche, Christine M; Deng, Xinxian

    2015-12-01

    X chromosome inactivation (XCI) is a female-specific mechanism that serves to balance gene dosage between the sexes whereby one X chromosome in females is inactivated during early development. Despite this silencing, a small portion of genes escape inactivation and remain expressed from the inactive X (Xi). Little is known about the distribution of escape from XCI in different tissues in vivo and about the mechanisms that control tissue-specific differences. Using a new binomial model in conjunction with a mouse model with identifiable alleles and skewed X inactivation we are able to survey genes that escape XCI in vivo. We show that escape from X inactivation can be a common feature of some genes, whereas others escape in a tissue specific manner. Furthermore, we characterize the chromatin environment of escape genes and show that expression from the Xi correlates with factors associated with open chromatin and that CTCF co-localizes with escape genes. Here, we provide a detailed description of the experimental design and data analysis pipeline we used to assay allele-specific expression and epigenetic characteristics of genes escaping X inactivation. The data is publicly available through the GEO database under ascension numbers GSM1014171, GSE44255, and GSE59779. Interpretation and discussion of these data are included in a previously published study (Berletch et al., 2015) [1].

  16. Farming-up coastal fish assemblages through a massive aquaculture escape event.

    Science.gov (United States)

    Toledo-Guedes, Kilian; Sanchez-Jerez, Pablo; Benjumea, María E; Brito, Alberto

    2014-07-01

    We investigated the changes on the mean trophic level of fish assemblages across different spatiotemporal scales, before and after a massive escape event occurred off La Palma (Canary Islands), which resulted in the release of 1.5 million fish (mostly Dicentrarchus labrax) into the wild. The presence of escaped fish altered significantly the mean trophic level of fish assemblages in shallow coastal waters. This alteration was exacerbated by the massive escape. A nearby marine protected area buffered the changes in mean trophic level but exhibited the same temporal patterns as highly fished areas. Moreover, escaped fish exploited natural resources according to their total length and possibly, time since escapement. New concerns arise as a "farming up" process is detected in shallow coastal fish assemblages where marine aquaculture is established.

  17. Heterochromatic Genes Undergo Epigenetic Changes and Escape Silencing in Immunodeficiency, Centromeric Instability, Facial Anomalies (ICF) Syndrome

    Science.gov (United States)

    Brun, Marie-Elisabeth; Lana, Erica; Rivals, Isabelle; Lefranc, Gérard; Sarda, Pierre; Claustres, Mireille; Mégarbané, André; De Sario, Albertina

    2011-01-01

    Immunodeficiency, Centromeric Instability, Facial Anomalies (ICF) syndrome is a rare autosomal recessive disorder that is characterized by a marked immunodeficiency, severe hypomethylation of the classical satellites 2 and 3 associated with disruption of constitutive heterochromatin, and facial anomalies. Sixty percent of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B) gene, encoding a de novo DNA methyltransferase. In the present study, we have shown that, in ICF lymphoblasts and peripheral blood, juxtacentromeric heterochromatic genes undergo dramatic changes in DNA methylation, indicating that they are bona fide targets of the DNMT3B protein. DNA methylation in heterochromatic genes dropped from about 80% in normal cells to approximately 30% in ICF cells. Hypomethylation was observed in five ICF patients and was associated with activation of these silent genes. Although DNA hypomethylation occurred in all the analyzed heterochromatic genes and in all the ICF patients, gene expression was restricted to some genes, every patient having his own group of activated genes. Histone modifications were preserved in ICF patients. Heterochromatic genes were associated with histone modifications that are typical of inactive chromatin: they had low acetylation on H3 and H4 histones and were slightly enriched in H3K9Me3, both in ICF and controls. This was also the case for those heterochromatic genes that escaped silencing. This finding suggests that gene activation was not generalized to all the cells, but rather was restricted to a clonal cell population that may contribute to the phenotypic variability observed in ICF syndrome. A slight increase in H3K27 monomethylation was observed both in heterochromatin and active euchromatin in ICF patients; however, no correlation between this modification and activation of heterochromatic genes was found. PMID:21559330

  18. Heterochromatic genes undergo epigenetic changes and escape silencing in immunodeficiency, centromeric instability, facial anomalies (ICF syndrome.

    Directory of Open Access Journals (Sweden)

    Marie-Elisabeth Brun

    Full Text Available Immunodeficiency, Centromeric Instability, Facial Anomalies (ICF syndrome is a rare autosomal recessive disorder that is characterized by a marked immunodeficiency, severe hypomethylation of the classical satellites 2 and 3 associated with disruption of constitutive heterochromatin, and facial anomalies. Sixty percent of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B gene, encoding a de novo DNA methyltransferase. In the present study, we have shown that, in ICF lymphoblasts and peripheral blood, juxtacentromeric heterochromatic genes undergo dramatic changes in DNA methylation, indicating that they are bona fide targets of the DNMT3B protein. DNA methylation in heterochromatic genes dropped from about 80% in normal cells to approximately 30% in ICF cells. Hypomethylation was observed in five ICF patients and was associated with activation of these silent genes. Although DNA hypomethylation occurred in all the analyzed heterochromatic genes and in all the ICF patients, gene expression was restricted to some genes, every patient having his own group of activated genes. Histone modifications were preserved in ICF patients. Heterochromatic genes were associated with histone modifications that are typical of inactive chromatin: they had low acetylation on H3 and H4 histones and were slightly enriched in H3K9Me(3, both in ICF and controls. This was also the case for those heterochromatic genes that escaped silencing. This finding suggests that gene activation was not generalized to all the cells, but rather was restricted to a clonal cell population that may contribute to the phenotypic variability observed in ICF syndrome. A slight increase in H3K27 monomethylation was observed both in heterochromatin and active euchromatin in ICF patients; however, no correlation between this modification and activation of heterochromatic genes was found.

  19. Natural Killer Cells and Neuroblastoma: tumor recognition, escape mechanisms and possible novel immunotherapeutic approaches

    Directory of Open Access Journals (Sweden)

    Cristina eBottino

    2014-02-01

    Full Text Available Neuroblastoma (NB is the most common extra-cranial solid tumor of childhood and arises from developing sympathetic nervous system. Most primary tumors localize in the abdomen, the adrenal gland or lumbar sympathetic ganglia. Amplification in tumor cells of MYCN, the major oncogenic driver, patients’ age over 18 months and the presence at diagnosis of a metastatic disease (stage IV, M identify NB at high risk of treatment failure. Conventional therapies did not significantly improve the overall survival of these patients. Moreover, the limited landscape of somatic mutations detected in NB is hampering the development of novel pharmacological approaches. Major efforts aim to identify novel NB-associated surface molecules that activate immune responses and/or direct drugs to tumor cells and tumor-associated vessels. PVR (Poliovirus Receptor and B7-H3 are promising targets, since they are expressed by most high-risk NB, are upregulated in tumor vasculature and are essential for tumor survival/invasiveness. PVR is a ligand of DNAM-1 activating receptor that triggers the cytolytic activity of Natural Killer (NK cells against NB. In animal models targeting of PVR with an attenuated oncolytic poliovirus induced tumor regression and elimination. Also B7-H3 was successfully targeted in preclinical studies and is now being tested in phase I/II clinical trials. B7-H3 down-regulates NK cytotoxicity, providing NB with a mechanism of escape from immune response. The immunosuppressive potential of NB can be enhanced by the release of soluble factors that impair NK cell function and/or recruitment. Among these, TGF-β1 modulates the cytotoxicity receptors and the chemokine receptor repertoire of NK cells.Here, we summarize the current knowledge on the main cell surface molecules and soluble mediators that modulate the function of NK cells in NB, considering the pros and cons that must be taken into account in the design of novel NK cell-based immunotherapeutic

  20. Role of AmiA in the morphological transition of Helicobacter pylori and in immune escape.

    Directory of Open Access Journals (Sweden)

    Catherine Chaput

    2006-09-01

    Full Text Available The human gastric pathogen Helicobacter pylori is responsible for peptic ulcers and neoplasia. Both in vitro and in the human stomach it can be found in two forms, the bacillary and coccoid forms. The molecular mechanisms of the morphological transition between these two forms and the role of coccoids remain largely unknown. The peptidoglycan (PG layer is a major determinant of bacterial cell shape, and therefore we studied H. pylori PG structure during the morphological transition. The transition correlated with an accumulation of the N-acetyl-D-glucosaminyl-beta(1,4-N-acetylmuramyl-L-Ala-D-Glu (GM-dipeptide motif. We investigated the molecular mechanisms responsible for the GM-dipeptide motif accumulation, and studied the role of various putative PG hydrolases in this process. Interestingly, a mutant strain with a mutation in the amiA gene, encoding a putative PG hydrolase, was impaired in accumulating the GM-dipeptide motif and transforming into coccoids. We investigated the role of the morphological transition and the PG modification in the biology of H. pylori. PG modification and transformation of H. pylori was accompanied by an escape from detection by human Nod1 and the absence of NF-kappaB activation in epithelial cells. Accordingly, coccoids were unable to induce IL-8 secretion by AGS gastric epithelial cells. amiA is, to our knowledge, the first genetic determinant discovered to be required for this morphological transition into the coccoid forms, and therefore contributes to modulation of the host response and participates in the chronicity of H. pylori infection.

  1. Microdeletion of the escape genes KDM5C and IQSEC2 in a girl with severe intellectual disability and autistic features.

    Science.gov (United States)

    Fieremans, Nathalie; Van Esch, Hilde; de Ravel, Thomy; Van Driessche, Jozef; Belet, Stefanie; Bauters, Marijke; Froyen, Guy

    2015-05-01

    Intellectual disability (ID) is a very heterogeneous disorder with over 100 ID genes located on the X chromosome alone. Of these, KDM5C and IQSEC2 are located adjacent to each other at the Xp11.22 locus. While mutations in either of these genes are associated with severe ID in males, female carriers are mostly unaffected. Here, we report on a female patient with severe ID and autistic features carrying a de novo 0.4 Mb deletion containing six coding genes including KDM5C and IQSEC2. X-inactivation analysis revealed skewing in a lymphocyte-derived cell line from this patient with preferential inactivation of the mutant X chromosome. As the brain-expressed KDM5C and IQSEC2 genes escape X-inactivation, deletion of these alleles could still be detrimental despite skewing of X-inactivation. Indeed, mutations in either of both genes have been reported in a few female ID patients. Expression analysis in the patients' cell line revealed decreased KDM5C mRNA levels compared to female controls. IQSEC2 levels could not be compared due to very low expression in blood. Overall, our data suggest that heterozygous loss-of-function of the escape genes KDM5C and/or IQSEC2 can contribute to severe ID in female patients and should be taken into account in diagnostics.

  2. DR-induced escape of O and C from early Mars

    Science.gov (United States)

    Zhao, Jinjin; Tian, Feng; Ni, Yufang; Huang, Xiaomeng

    2017-03-01

    Energetic particles produced in Dissociative recombination (DR) reactions could escape planets with low gravity, such as Mars, if they could overcome collisions with the surrounding background gases. In this work, a 3-D Monte Carlo model is developed to study these photochemical escape processes on early Mars. Although the DR reaction rates of O2+, CO2+, and CO+ increase monotonically with solar soft X-ray and extreme ultraviolet (XUV) flux, the peak of the calculated DR-induced escape rates of O is near 3 × XUV, and the DR-induced escape rates of C increase with XUV until 10 × XUV. The non-monotonic behavior can be explained by the increased column densities of background species in high XUV conditions, which can deflect energetic particles through collisions more efficiently. At 20 × XUV, CO+ DR is the main source of escaping O and C, and the escape of secondary particles could contribute to 30∼40% and 10% of the total escape of O and C respectively. The time-integrated DR-induced escape of O and C is equivalent to 1 m of H2O and 20 mbar of CO2 escaping early Mars since 4.5 billion years ago. The accumulated CO2 loss is much lower than what's needed to explain the carbon isotopic ratios on Mars and much lower than the total CO2 needed to warm up early Mars. If more vigorous escape mechanisms were absent on early Mars, substantial inventories of volatiles have not been detected yet.

  3. Photochemical escape of oxygen from the Martian atmosphere: new insights from MAVEN

    Science.gov (United States)

    Lillis, R. J.; Deighan, J.; Bougher, S. W.; Cravens, T.; Fox, J. L.; Lee, Y.; Rahmati, A.; McFadden, J. P.; Benna, M.; Mahaffy, P. R.; Elrod, M. K.; Andersson, L.; Fowler, C. M.; Curry, S.; Gröller, H.; Jakosky, B. M.

    2015-12-01

    One of the primary goals of the MAVEN mission is to characterize rates of atmospheric escape from Mars at the present epoch and relate those escape rates to solar drivers. One of the known escape processes is photochemical escape, where a) an exothermic chemical reaction in the atmosphere 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. Because escaping hot atoms are not directly measured, models of production and transport (through the atmosphere) of such atoms must be used to constrain photochemical escape rates. These models require altitude profiles of neutral densities and electron and ion densities and temperatures, as well as compositional information, all of which are measured by MAVEN instruments at the relevant altitudes (150-300 km). For every altitude profile: Profiles of O2+ dissociative recombination (DR) rates will be calculated from electron temperature, electron density and O2+ density. Profiles of energy distributions of hot O atoms will be calculated from profiles of electron and ion temperatures. Profiles of all neutral densities will be input into models of hot O transport in order to calculate photochemical escape fluxes from DR of O2+. We will present photochemical escape fluxes as a function of several factors, in particular solar zenith angle and EUV flux. This, combined with further simulations with progressively higher EUV fluxes, will eventually enable a total integrated loss estimate over the course of Martian history and hence a determination of the impact of this loss process on the evolution of the Martian climate.

  4. Non-random escape pathways from a broadly neutralizing human monoclonal antibody map to a highly conserved region on the hepatitis C virus E2 glycoprotein encompassing amino acids 412-423.

    Directory of Open Access Journals (Sweden)

    Zhen-yong Keck

    2014-08-01

    Full Text Available A challenge for hepatitis C virus (HCV vaccine development is to define epitopes that are able to elicit protective antibodies against this highly diverse virus. The E2 glycoprotein region located at residues 412-423 is conserved and antibodies to 412-423 have broadly neutralizing activities. However, an adaptive mutation, N417S, is associated with a glycan shift in a variant that cannot be neutralized by a murine but by human monoclonal antibodies (HMAbs against 412-423. To determine whether HCV escapes from these antibodies, we analyzed variants that emerged when cell culture infectious HCV virions (HCVcc were passaged under increasing concentrations of a specific HMAb, HC33.1. Multiple nonrandom escape pathways were identified. Two pathways occurred in the context of an N-glycan shift mutation at N417T. At low antibody concentrations, substitutions of two residues outside of the epitope, N434D and K610R, led to variants having improved in vitro viral fitness and reduced sensitivity to HC33.1 binding and neutralization. At moderate concentrations, a S419N mutation occurred within 412-423 in escape variants that have greatly reduced sensitivity to HC33.1 but compromised viral fitness. Importantly, the variants generated from these pathways differed in their stability. N434D and K610R-associated variants were stable and became dominant as the virions were passaged. The S419N mutation reverted back to N419S when immune pressure was reduced by removing HC33.1. At high antibody concentrations, a mutation at L413I was observed in variants that were resistant to HC33.1 neutralization. Collectively, the combination of multiple escape pathways enabled the virus to persist under a wide range of antibody concentrations. Moreover, these findings pose a different challenge to vaccine development beyond the identification of highly conserved epitopes. It will be necessary for a vaccine to induce high potency antibodies that prevent the formation of escape

  5. RNA Viruses and RNAi: Quasispecies Implications for Viral Escape

    Directory of Open Access Journals (Sweden)

    John B. Presloid

    2015-06-01

    Full Text Available Due to high mutation rates, populations of RNA viruses exist as a collection of closely related mutants known as a quasispecies. A consequence of error-prone replication is the potential for rapid adaptation of RNA viruses when a selective pressure is applied, including host immune systems and antiviral drugs. RNA interference (RNAi acts to inhibit protein synthesis by targeting specific mRNAs for degradation and this process has been developed to target RNA viruses, exhibiting their potential as a therapeutic against infections. However, viruses containing mutations conferring resistance to RNAi were isolated in nearly all cases, underlining the problems of rapid viral evolution. Thus, while promising, the use of RNAi in treating or preventing viral diseases remains fraught with the typical complications that result from high specificity of the target, as seen in other antiviral regimens.

  6. Understanding Amino Acid Mutations in Hepatitis B Virus Proteins for Rational Design of Vaccines and Drugs.

    Science.gov (United States)

    Shen, Ke; Shen, Li; Wang, Jing; Jiang, Zhi; Shen, Bairong

    2015-01-01

    The hepatitis B virus (HBV) genome encodes four proteins, i.e., DNA polymerase, surface protein, X, and core proteins. HBV undergoes different selective pressures for drug resistance and immune/vaccine escape and mutations are common for the HBV proteins. We here collected all the reported amino acid mutations happened in these four HBV proteins and studied their patterns. The relationship between the mutations and epitopic functions are investigated with bioinformatics tools, based on their sequence information. Some interesting results are observed for the mutation patterns, such as we found the serine and threonine are both for frequently mutated residues and mutant residues, while the tryptophan and methionine have low mutability. The results provide important information for the understanding of the molecular mechanism of virus evolution and therefore will facilitate the future rational design of HBV vaccines or drugs.

  7. Maize Mutator transposon

    Institute of Scientific and Technical Information of China (English)

    Yijun WANG; Mingliang XU; Dexiang DENG; Yunlong BIAN

    2008-01-01

    Transposable elements are widely distributed in eukaryotes. Due to its high copy numbers, high forward mutation rate and preferential insertion into low-copy DNA sequences, among others, the Mutator system has been widely used as a mutagen in genomic research. The discovery, classification, transposition specificity and epige-netic regulation of Mutator transposons were described. The application of Mutator tagging in plant genomic research was also presented. The role of Mu-like elements in genome evolution was briefly depicted. Moreover, the direction of Mutator transposon research in the future was discussed.

  8. Complex Economies Have a Lateral Escape from the Poverty Trap

    Science.gov (United States)

    Pugliese, Emanuele; Chiarotti, Guido L.; Zaccaria, Andrea; Pietronero, Luciano

    2017-01-01

    We analyze the decisive role played by the complexity of economic systems at the onset of the industrialization process of countries over the past 50 years. Our analysis of the input growth dynamics, considering a further dimension through a recently introduced measure of economic complexity, reveals that more differentiated and more complex economies face a lower barrier (in terms of GDP per capita) when starting the transition towards industrialization. As a consequence, we can extend the classical concept of a one-dimensional poverty trap, by introducing a two-dimensional poverty trap: a country will start the industrialization process if it is rich enough (as in neo-classical economic theories), complex enough (using this new dimension and laterally escaping from the poverty trap), or a linear combination of the two. This naturally leads to the proposal of a Complex Index of Relative Development (CIRD) which shows, when analyzed as a function of the growth due to input, a shape of an upside down parabola similar to that expected from the standard economic theories when considering only the GDP per capita dimension. PMID:28072867

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Christoph Kurze

    Full Text Available 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. Complex Economies Have a Lateral Escape from the Poverty Trap.

    Science.gov (United States)

    Pugliese, Emanuele; Chiarotti, Guido L; Zaccaria, Andrea; Pietronero, Luciano

    2017-01-01

    We analyze the decisive role played by the complexity of economic systems at the onset of the industrialization process of countries over the past 50 years. Our analysis of the input growth dynamics, considering a further dimension through a recently introduced measure of economic complexity, reveals that more differentiated and more complex economies face a lower barrier (in terms of GDP per capita) when starting the transition towards industrialization. As a consequence, we can extend the classical concept of a one-dimensional poverty trap, by introducing a two-dimensional poverty trap: a country will start the industrialization process if it is rich enough (as in neo-classical economic theories), complex enough (using this new dimension and laterally escaping from the poverty trap), or a linear combination of the two. This naturally leads to the proposal of a Complex Index of Relative Development (CIRD) which shows, when analyzed as a function of the growth due to input, a shape of an upside down parabola similar to that expected from the standard economic theories when considering only the GDP per capita dimension.

  12. Escape of the martian protoatmosphere and initial water inventory

    CERN Document Server

    Erkaev, N V; Elkins-Tanton, L; Stökl, A; Odert, P; Marcq, E; Dorfi, E A; Kislyakova, K G; Kulikov, Yu N; Leitzinger, M; Güdel, M

    2013-01-01

    Latest research in planet formation indicate that Mars formed within a few million years (Myr) and remained a planetary embryo that never grew to a more massive planet. It can also be expected from dynamical models, that most of Mars' building blocks consisted of material that formed in orbital locations just beyond the ice line which could have contained ~0.1-0.2 wt. % of H2O. By using these constraints, we estimate the nebula-captured and catastrophically outgassed volatile contents during the solidification of Mars' magma ocean and apply a hydrodynamic upper atmosphere model for the study of the soft X-ray and extreme ultraviolet (XUV) driven thermal escape of the martian protoatmosphere during the early active epoch of the young Sun. The amount of gas that has been captured from the protoplanetary disk into the planetary atmosphere is calculated by solving the hydrostatic structure equations in the protoplanetary nebula. Depending on nebular properties such as the dust grain depletion factor, planetesimal...

  13. Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice

    Science.gov (United States)

    Panigrahy, Dipak; Edin, Matthew L.; Lee, Craig R.; Huang, Sui; Bielenberg, Diane R.; Butterfield, Catherine E.; Barnés, Carmen M.; Mammoto, Akiko; Mammoto, Tadanori; Luria, Ayala; Benny, Ofra; Chaponis, Deviney M.; Dudley, Andrew C.; Greene, Emily R.; Vergilio, Jo-Anne; Pietramaggiori, Giorgio; Scherer-Pietramaggiori, Sandra S.; Short, Sarah M.; Seth, Meetu; Lih, Fred B.; Tomer, Kenneth B.; Yang, Jun; Schwendener, Reto A.; Hammock, Bruce D.; Falck, John R.; Manthati, Vijaya L.; Ingber, Donald E.; Kaipainen, Arja; D’Amore, Patricia A.; Kieran, Mark W.; Zeldin, Darryl C.

    2011-01-01

    Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They are lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs that raise EET levels are in clinical trials for the treatment of hypertension and many other diseases. However, despite their pleiotropic effects on cells, little is known about the role of these epoxyeicosanoids in cancer. Here, using genetic and pharmacological manipulation of endogenous EET levels, we demonstrate that EETs are critical for primary tumor growth and metastasis in a variety of mouse models of cancer. Remarkably, we found that EETs stimulated extensive multiorgan metastasis and escape from tumor dormancy in several tumor models. This systemic metastasis was not caused by excessive primary tumor growth but depended on endothelium-derived EETs at the site of metastasis. Administration of synthetic EETs recapitulated these results, while EET antagonists suppressed tumor growth and metastasis, demonstrating in vivo that pharmacological modulation of EETs can affect cancer growth. Furthermore, inhibitors of soluble epoxide hydrolase (sEH), the enzyme that metabolizes EETs, elevated endogenous EET levels and promoted primary tumor growth and metastasis. Thus, our data indicate a central role for EETs in tumorigenesis, offering a mechanistic link between lipid signaling and cancer and emphasizing the critical importance of considering possible effects of EET-modulating drugs on cancer. PMID:22182838

  14. Intertextuality in Novel: An Escape from Patriarchal Soliloquy

    Directory of Open Access Journals (Sweden)

    Nargess Bagheri

    2015-12-01

    Full Text Available Hypertextuality is one of the intertextual relationships introduced by Gerard Genette. According to him, hypertextuality includes all the relationships which the hypertext has with the previous text, i.e. the hypotext. However, he does not consider the relationship between these two texts to be in such a way that the hypertext is the interpretation of the hypotext. On the other hand, other theorizers including Bakhtin, regard the conversation between texts a way to escape a one-voiced and dominant discourse. From this viewpoint, the intertextual relationships of Sadegh Hedayat’s The Blind Owl, with Shahrnoush Parsipour’s The Blue Mind and Abbas Maroufi’s The Body of Farhad are in such a way that The Blind Owl can be regarded as a hypotext for the other 2 novels but these two novels interpret the text differently. The present study aims to examine the intertextual relationships between these 3 novels and explore how a multiple-voiced conversation is formed between them.

  15. Modified guidance laws to escape microbursts with turbulence

    Directory of Open Access Journals (Sweden)

    Atilla Dogan

    2002-01-01

    Full Text Available This paper introduces Modified Altitude- and Dive-Guidance laws for escaping a microburst with turbulence. The goal is to develop a procedure to estimate the highest altitude at which an aircraft can fly through a microburst without running into stall. First, a new metric is constructed that quantifies the aircraft upward force capability in a microburst encounter. In the absence of turbulence, the metric is shown 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 metric is treated as a random variable and its probability distribution function is analytically approximated as a function of altitude. This approximation allows us to determine the highest safe altitude at which the aircraft may descend, hence avoiding to descend too low. This highest safe altitude is used as the commanded altitude in Modified Altitude- and Dive-Guidance. Monte Carlo simulations show that these Modified Altitude- and Dive-Guidance strategies can decrease the probability of minimum altitude being lower than a given value without significantly increasing the probability of crash.

  16. Breakdown of the escape dynamics in Josephson junctions

    Science.gov (United States)

    Massarotti, D.; Stornaiuolo, D.; Lucignano, P.; Galletti, L.; Born, D.; Rotoli, G.; Lombardi, F.; Longobardi, L.; Tagliacozzo, A.; Tafuri, F.

    2015-08-01

    We have identified anomalous behavior of the escape rate out of the zero-voltage state in Josephson junctions with a high critical current density Jc. For this study we have employed YBa2Cu3O7 -x grain boundary junctions, which span a wide range of Jc and have appropriate electrodynamical parameters. Such high Jc junctions, when hysteretic, do not switch from the superconducting to the normal state following the expected stochastic Josephson distribution, despite having standard Josephson properties such as a Fraunhofer magnetic field pattern. The switching current distributions (SCDs) are consistent with nonequilibrium dynamics taking place on a local rather than a global scale. This means that macroscopic quantum phenomena seem to be practically unattainable for high Jc junctions. We argue that SCDs are an accurate means to measure nonequilibrium effects. This transition from global to local dynamics is of relevance for all kinds of weak links, including the emergent family of nanohybrid Josephson junctions. Therefore caution should be applied in the use of such junctions in, for instance, the search for Majorana fermions.

  17. Rejection of large HPV-16 expressing tumors in aged mice by a single immunization of VacciMax® encapsulated CTL/T helper peptides

    Directory of Open Access Journals (Sweden)

    MacDonald Lisa

    2007-06-01

    Full Text Available Abstract The incidence of cancer increases significantly in later life, yet few pre-clinical studies of cancer immunotherapy use mice of advanced age. A novel vaccine delivery platform (VacciMax®,VM is described that encapsulates antigens and adjuvants in multilamellar liposomes in a water-in-oil emulsion. The therapeutic potential of VM-based vaccines administered as a single dose was tested in HLA-A2 transgenic mice of advanced age (48–58 weeks old bearing large palpable TC1/A2 tumors. The VM-based vaccines contained one or more peptides having human CTL epitopes derived from HPV 16 E6 and E7. VM formulations contained a single peptide, a mixture of four peptides or the same four peptides linked together in a single long peptide. All VM formulations contained PADRE and CpG as adjuvants and ISA51 as the hydrophobic component of the water-in-oil emulsion. VM-formulated vaccines containing the four peptides as a mixture or linked together in one long peptide eradicated 19-day old established tumors within 21 days of immunization. Peptide-specific cytotoxic cellular responses were confirmed by ELISPOT and intracellular staining for IFN-γ producing CD8+ T cells. Mice rendered tumor-free by vaccination were re-challenged in the opposite flank with 10 million HLF-16 tumor cells, another HLA-A2/E6/E7 expressing tumor cell line. None of these mice developed tumors following the re-challenge. In summary, this report describes a VM-formulated therapeutic vaccine with the following unprecedented outcome: a eradication of large tumors (> 700 mm3 b in mice of advanced age c in less than three weeks post-immunization d following a single vaccination.

  18. Review of One Illness Away: Why People Become Poor and How They Escape Poverty

    OpenAIRE

    Afia B. Yamoah

    2011-01-01

    Afia B. Yamoah reviews One Illness Away: Why People Become Poor and How They Escape Poverty, by Anirudh Krishna. Krishna argues that poverty policy needs to address reasons why people become poor and how they can escape poverty.

  19. Glycan shifting on hepatitis C virus (HCV) E2 glycoprotein is a mechanism for escape from broadly neutralizing antibodies.

    Science.gov (United States)

    Pantua, Homer; Diao, Jingyu; Ultsch, Mark; Hazen, Meredith; Mathieu, Mary; McCutcheon, Krista; Takeda, Kentaro; Date, Shailesh; Cheung, Tommy K; Phung, Qui; Hass, Phil; Arnott, David; Hongo, Jo-Anne; Matthews, David J; Brown, Alex; Patel, Arvind H; Kelley, Robert F; Eigenbrot, Charles; Kapadia, Sharookh B

    2013-06-12

    Hepatitis C virus (HCV) infection is a major cause of liver disease and hepatocellular carcinoma. Glycan shielding has been proposed to be a mechanism by which HCV masks broadly neutralizing epitopes on its viral glycoproteins. However, the role of altered glycosylation in HCV resistance to broadly neutralizing antibodies is not fully understood. Here, we have generated potent HCV neutralizing antibodies hu5B3.v3 and MRCT10.v362 that, similar to the previously described AP33 and HCV1, bind to a highly conserved linear epitope on E2. We utilize a combination of in vitro resistance selections using the cell culture infectious HCV and structural analyses to identify mechanisms of HCV resistance to hu5B3.v3 and MRCT10.v362. Ultra deep sequencing from in vitro HCV resistance selection studies identified resistance mutations at asparagine N417 (N417S, N417T and N417G) as early as 5days post treatment. Comparison of the glycosylation status of soluble versions of the E2 glycoprotein containing the respective resistance mutations revealed a glycosylation shift from N417 to N415 in the N417S and N417T E2 proteins. The N417G E2 variant was glycosylated neither at residue 415 nor at residue 417 and remained sensitive to MRCT10.v362. Structural analyses of the E2 epitope bound to hu5B3.v3 Fab and MRCT10.v362 Fab using X-ray crystallography confirmed that residue N415 is buried within the antibody-peptide interface. Thus, in addition to previously described mutations at N415 that abrogate the β-hairpin structure of this E2 linear epitope, we identify a second escape mechanism, termed glycan shifting, that decreases the efficacy of broadly neutralizing HCV antibodies.

  20. Reporter Assay for Endo/Lysosomal Escape of Toxin-Based Therapeutics

    Directory of Open Access Journals (Sweden)

    Roger Gilabert-Oriol

    2014-05-01

    Full Text Available Protein-based therapeutics with cytosolic targets are capable of exhibiting their therapeutic effect once they have escaped from the endosomes or lysosomes. In this study, the reporters—horseradish peroxidase (HRP, Alexa Fluor 488 (Alexa and ricin A-chain (RTA—were investigated for their capacity to monitor the endo/lysosomal escape of the ribosome-inactivating protein, saporin. The conjugates—saporin-HRP, Alexasaporin and saporin-KQ-RTA—were constructed, and the endo/lysosomal escape of these conjugates alone (lack of endo/lysosomal release or in combination with certain structurally-specific triterpenoidal saponins (efficient endo/lysosomal escape was characterized. HRP failed in reporting the endo/lysosomal escape of saporin. Contrastingly, Alexa Fluor 488 successfully allowed the report of the process at a toxin concentration of 1000 nM. In addition, single endo/lysosome analysis facilitated the determination of the amount of Alexasaporin released from each vesicle. RTA was also successful in reporting the endo/lysosomal escape of the enzymatically inactive mutant, saporin-KQ, but in this case, the sensitivity of the method reached a toxin concentration of 10 nM. In conclusion, the simultaneous usage of Alexa Fluor 488 and RTA as reporters may provide the possibility of monitoring the endo/lysosomal escape of protein-based therapeutics in the concentration range of 10–1000 nM.

  1. Heterochrony and the development of the escape response: prehatching movements in the rainbow trout Oncorhynchus mykiss.

    Science.gov (United States)

    Gibb, Alice C; Liu, Corina; Swanson, Brook O

    2007-10-01

    Teleost fishes produce coordinated escape responses (C-starts) at hatching. This implies that essential swimming morphologies and motor behaviors develop during the incubation interval while the embryo is in the chorion. We examined prehatching motor behaviors in rainbow trout Oncorhycus mykiss (considered morphologically mature at hatching) and compared this species with zebrafish Danio rerio (considered morphologically immature) and assessed two hypotheses concerning the development of escape behavior. (1) Escape behavior is associated with the formation of key elements of the musculoskeletal and nervous systems; thus, the escape response appears early in ontogeny, when these elements form. (2) Escape behavior is not directly associated with the formation of underlying morphological elements; instead, it appears at hatching (i.e. when needed). We find that rainbow trout, like zebrafish, respond to touch early in the incubation interval, but do not demonstrate a complete C-start (including the second, propulsive stage) until shortly before hatching. At hatching, rainbow trout and zebrafish are similar in the degree of development of the chondocranium, paired fins and visceral arches (which comprise the larval jaw and gill support); however, rainbow trout have incipient rays in their unpaired fins (dorsal, anal and caudal), whereas zebrafish retain the embryonic fin fold. Although rainbow trout are more mature in axial swimming morphology at hatching, the essential neural and musculoskeletal systems that produce a coordinated escape response are functional at hatching in both species. This finding supports the evolutionary hypothesis that an effective escape response is critical for the survival of newly hatched teleost fishes.

  2. Failure of rats to escape from a potentially lethal microwave field

    Energy Technology Data Exchange (ETDEWEB)

    Carroll, D.R.; Levinson, D.M.; Justesen, D.R.; Clarke, R.L.

    1980-01-01

    Ocularly pigmented rats, all mature females of the Long-Evans strain, were repeatedly presented an opportunity to escape from an intense 918-MHz field (whole-body dose rate . 60 mW/g) to a field of lower intensity (40, 30, 20, or 2 mW/g) by performing a simple locomotor response. Other rats could escape 800-microamperemeter faradic shock to the feet and tail by performing the same response in the same milieu, a multimode cavity. None of 20 irradiated rats learned to associate entry into a visually well-demarcated area of the cavity with immediate reduction of dose rate, in spite of field-induced elevations of body temperature to levels that exceeded 41 degrees C and would have been lethal but for a limit on durations of irradiation. In contrast, all of ten rats motivated by faradic shock rapidly learned to escape. The failure of escape learning by irradiated animals probably arose from deficiencies of motivation and, especially, sensory feedback. Whole-body hyperthermia induced by a multipath field may lack the painful or directional sensory properties that optimally promote the motive to escape. Moreover, a decline of body temperature after an escape-response-contingent reduction of field strength will be relatively slow because of the large thermal time constants of mammalian tissues. Without timely sensory feedback, which is an essential element of negative reinforcement, stimulus-response associability would be imparied, which could retard or preclude learning of an escape response.

  3. Reporter assay for endo/lysosomal escape of toxin-based therapeutics.

    Science.gov (United States)

    Gilabert-Oriol, Roger; Thakur, Mayank; von Mallinckrodt, Benedicta; Bhargava, Cheenu; Wiesner, Burkhard; Eichhorst, Jenny; Melzig, Matthias F; Fuchs, Hendrik; Weng, Alexander

    2014-05-22

    Protein-based therapeutics with cytosolic targets are capable of exhibiting their therapeutic effect once they have escaped from the endosomes or lysosomes. In this study, the reporters-horseradish peroxidase (HRP), Alexa Fluor 488 (Alexa) and ricin A-chain (RTA)-were investigated for their capacity to monitor the endo/lysosomal escape of the ribosome-inactivating protein, saporin. The conjugates-saporin-HRP, (Alexa)saporin and saporin-KQ-RTA-were constructed, and the endo/lysosomal escape of these conjugates alone (lack of endo/lysosomal release) or in combination with certain structurally-specific triterpenoidal saponins (efficient endo/lysosomal escape) was characterized. HRP failed in reporting the endo/lysosomal escape of saporin. Contrastingly, Alexa Fluor 488 successfully allowed the report of the process at a toxin concentration of 1000 nM. In addition, single endo/lysosome analysis facilitated the determination of the amount of (Alexa)saporin released from each vesicle. RTA was also successful in reporting the endo/lysosomal escape of the enzymatically inactive mutant, saporin-KQ, but in this case, the sensitivity of the method reached a toxin concentration of 10 nM. In conclusion, the simultaneous usage of Alexa Fluor 488 and RTA as reporters may provide the possibility of monitoring the endo/lysosomal escape of protein-based therapeutics in the concentration range of 10-1000 nM.

  4. H Escape Rates Inferred from MAVEN/IUVS Observations of the Mars Hydrogen Corona

    Science.gov (United States)

    Chaffin, Michael S.; Chaufray, Jean-Yves; Deighan, Justin; Schneider, Nicholas M.; McClintock, William; Stewart, A. Ian F.; Thiemann, E. M.; Clarke, John T.; Holsclaw, Gregory; Jain, Sonal Kumar; Crismani, Matteo; Stiepen, Arnaud; Montmessin, Franck; Eparvier, Francis; Jakosky, Bruce

    2016-10-01

    H escape oxidizes and dessicates the Mars atmosphere and surface, providing a key control on the present-day chemistry and long-term evolution of the planet. Recently, large variations in the escape rate of H as a function of season have been reported by several studies, making continued observation of the variation a high priority. We present escape rates derived from Mars Atmosphere and Volatile EvolutioN (MAVEN) mission Imaging UltraViolet Spectrograph (IUVS) observations of the extended atmosphere of Mars at H Lyman alpha (121.6 nm), which must be interpreted with a coupled density/radiative transfer model owing to the optically thick nature of the emission and the small fraction of H present in the corona on escaping trajectories. We recover densities, temperatures, and escape rates under the assumption of spherical symmetry for multiple periods across MAVEN's mission so far, beginning in December 2014 (escape rates ~4e8/cm2/s). We describe the observed variation and compare it with previously observed seasonal variation in retrieved H escape rates, providing a necessary input for future photochemical modeling studies and estimates of water loss from Mars over its history.

  5. Do malaria parasites manipulate the escape behaviour of their avian hosts? An experimental study.

    Science.gov (United States)

    Garcia-Longoria, Luz; Møller, Anders P; Balbontín, Javier; de Lope, Florentino; Marzal, Alfonso

    2015-12-01

    Escape behaviour is the behaviour that birds and other animals display when already caught by a predator. An individual exhibiting higher intensity of such anti-predator behaviour could have greater probabilities of escape from predators. Parasites are known to affect different aspects of host behaviour to increase their own fitness. Vector-transmitted parasites such as malaria parasites should gain by manipulating their hosts to enhance the probability of transmission. Several studies have shown that malaria parasites can manipulate their vectors leading to increased transmission success. However, little is known about whether malaria parasites can manipulate escape behaviour of their avian hosts thereby increasing the spread of the parasite. Here we used an experimental approach to explore if Plasmodium relictum can manipulate the escape behaviour of one of its most common avian hosts, the house sparrow Passer domesticus. We experimentally tested whether malaria parasites manipulate the escape behaviour of their avian host. We showed a decrease in the intensity of biting and tonic immobility after removal of infection with anti-malaria medication compared to pre-experimental behaviour. These outcomes suggest that infected sparrows performed more intense escape behaviour, which would increase the likelihood of individuals escaping from predators, but also benefit the parasite by increasing its transmission opportunities.

  6. The impact of escaped farmed Atlantic salmon (Salmo salar L. on catch statistics in Scotland.

    Directory of Open Access Journals (Sweden)

    Darren M Green

    Full Text Available In Scotland and elsewhere, there are concerns that escaped farmed Atlantic salmon (Salmo salar L. may impact on wild salmon stocks. Potential detrimental effects could arise through disease spread, competition, or inter-breeding. We investigated whether there is evidence of a direct effect of recorded salmon escape events on wild stocks in Scotland using anglers' counts of caught salmon (classified as wild or farmed and sea trout (Salmo trutta L.. This tests specifically whether documented escape events can be associated with reduced or elevated escapes detected in the catch over a five-year time window, after accounting for overall variation between areas and years. Alternate model frameworks were somewhat inconsistent, however no robust association was found between documented escape events and higher proportion of farm-origin salmon in anglers' catch, nor with overall catch size. A weak positive correlation was found between local escapes and subsequent sea trout catch. This is in the opposite direction to what would be expected if salmon escapes negatively affected wild fish numbers. Our approach specifically investigated documented escape events, contrasting with earlier studies examining potentially wider effects of salmon farming on wild catch size. This approach is more conservative, but alleviates some potential sources of confounding, which are always of concern in observational studies. Successful analysis of anglers' reports of escaped farmed salmon requires high data quality, particularly since reports of farmed salmon are a relatively rare event in the Scottish data. Therefore, as part of our analysis, we reviewed studies of potential sensitivity and specificity of determination of farmed origin. Specificity estimates are generally high in the literature, making an analysis of the form we have performed feasible.

  7. Escape forces and trajectories in optical tweezers and their effect on calibration.

    Science.gov (United States)

    Bui, Ann A M; Stilgoe, Alexander B; Khatibzadeh, Nima; Nieminen, Timo A; Berns, Michael W; Rubinsztein-Dunlop, Halina

    2015-09-21

    Whether or not an external force can make a trapped particle escape from optical tweezers can be used to measure optical forces. Combined with the linear dependence of optical forces on trapping power, a quantitative measurement of the force can be obtained. For this measurement, the particle is at the edge of the trap, away from the region near the equilbrium position where the trap can be described as a linear spring. This method provides the ability to measure higher forces for the same beam power, compared with using the linear region of the trap, with lower risk of optical damage to trapped specimens. Calibration is typically performed by using an increasing fluid flow to exert an increasing force on a trapped particle until it escapes. In this calibration technique, the particle is usually assumed to escape along a straight line in the direction of fluid-flow. Here, we show that the particle instead follows a curved trajectory, which depends on the rate of application of the force (i.e., the acceleration of the fluid flow). In the limit of very low acceleration, the particle follows the surface of zero axial optical force during the escape. The force required to produce escape depends on the trajectory, and hence the acceleration. This can result in variations in the escape force of a factor of two. This can have a major impact on calibration to determine the escape force efficiency. Even when calibration measurements are all performed in the low acceleration regime, variations in the escape force efficiency of 20% or more can still occur. We present computational simulations using generalized Lorenz-Mie theory and experimental measurements to show how the escape force efficiency depends on rate of increase of force and trapping power, and discuss the impact on calibration.

  8. Turning pain into cues for goal-directed behavior : Implementation intentions reduce escape-avoidance behavior on a painful task

    NARCIS (Netherlands)

    Karsdorp, P.A.; Geenen, R.; Kroese, F.M.; Vlaeyen, J.W.S.

    2016-01-01

    Pain automatically elicits escape-avoidance behavior to avert bodily harm. In patients with chronic pain, long-term escape-avoidance behavior may increase the risk of chronic disability. The aim of the presents study was to examine whether implementation intentions reduce escape-avoidance behavior d

  9. Escape of the martian protoatmosphere and initial water inventory.

    Science.gov (United States)

    Erkaev, N V; Lammer, H; Elkins-Tanton, L T; Stökl, A; Odert, P; Marcq, E; Dorfi, E A; Kislyakova, K G; Kulikov, Yu N; Leitzinger, M; Güdel, M

    2014-08-01

    Latest research in planet formation indicates that Mars formed within a few million years (Myr) and remained as a planetary embryo that never grew to a more massive planet. It can also be expected from dynamical models that most of Mars' building blocks consisted of material that formed in orbital locations just beyond the ice line which could have contained [Formula: see text] of H2O. By using these constraints, we estimate the nebula-captured and catastrophically outgassed volatile contents during the solidification of Mars' magma ocean and apply a hydrodynamic upper atmosphere model for the study of the soft X-ray and extreme ultraviolet (XUV) driven thermal escape of the martian protoatmosphere during the early active epoch of the young Sun. The amount of gas that has been captured from the protoplanetary disk into the planetary atmosphere is calculated by solving the hydrostatic structure equations in the protoplanetary nebula. Depending on nebular properties such as the dust grain depletion factor, planetesimal accretion rates and luminosities, hydrogen envelopes with masses [Formula: see text] to [Formula: see text] could have been captured from the nebula around early Mars. Depending on the before mentioned parameters, due to the planets low gravity and a solar XUV flux that was [Formula: see text] times stronger compared to the present value, our results indicate that early Mars would have lost its nebular captured hydrogen envelope after the nebula gas evaporated, during a fast period of [Formula: see text]. After the solidification of early Mars' magma ocean, catastrophically outgassed volatiles with the amount of [Formula: see text] H2O and [Formula: see text] CO2 could have been lost during [Formula: see text], if the impact related energy flux of large planetesimals and small embryos to the planet's surface lasted long enough, that the steam atmosphere could have been prevented from condensing. If this was not the case, then our results suggest that

  10. Optimal search and ambush for a hider who can escape the search region

    OpenAIRE

    Alpern, Steve; Fokkink, Robbert; Simanjuntak, Martin

    2016-01-01

    Search games for a mobile or immobile hider traditionally have the hider permanently confined to a compact ‘search region’ making eventual capture inevitable. Hence the payoff can be taken as time until capture. However in many real life search problems it is possible for the hider to escape an area in which he was known to be located (e.g. Bin Laden from Tora Bora) or for a prey animal to escape a predator’s hunting territory. We model and solve such continuous time problems with escape wher...

  11. Mean Exit Time and Escape Probability for a Tumor Growth System under Non-Gaussian Noise

    CERN Document Server

    Ren, Jian; Gao, Ting; Kan, Xingye; Duan, Jinqiao

    2011-01-01

    Effects of non-Gaussian $\\alpha-$stable L\\'evy noise on the Gompertz tumor growth model are quantified by considering the mean exit time and escape probability of the cancer cell density from inside a safe or benign domain. The mean exit time and escape probability problems are formulated in a differential-integral equation with a fractional Laplacian operator. Numerical simulations are conducted to evaluate how the mean exit time and escape probability vary or bifurcates when $\\alpha$ changes. Some bifurcation phenomena are observed and their impacts are discussed.

  12. TP53 and Beta-catenin mutations in liver tumours

    Directory of Open Access Journals (Sweden)

    Pierre Hainaut

    2007-02-01

    Full Text Available

    HBV and HCV play key roles in the etiopathogenesis of Hepatocellular carcinoma (HCC . Studies mostly based on cases from Western countries suggest distinct genetic pathways of carcinogenesis involving either TP53 or CTTNB1 mutations. Inappropriate reactivation of Wnt pathway due to mutations in CTNNB1 (Beta-Catenin gene itself is also frequently reported. Mutant Beta-catenin escapes to ubiquitination and down regulation by GSK3-B, it accumulates and trans-activates variety of oncogenes involved in neoplasmic transformation mimicking Wnt pathway activation. Taking into consideration viral infection, chromosome instability and TP53 /Beta-catenin alterations, Laurent-Puig et al. described two distinct HCC profiles in a serie of 137 HCC cases , the first one associates HBV infection with frequent chromosomal alteration and distributes with TP53 mutations, the second would be observed in HBV negative large sized tumors and distributes with Beta-catenin mutations. We have investigated the status of HBV and HCV infections and of genetic alterations in TP53 and CTTNB1 in 26 patients with HCC from Thailand. In tumours, HBV DNA was found in 19 cases (73% and HCV RNA in 4 cases (15.4% cases, 3 of whom were co-infected. Among the 19 HBV positive cases, sequencing of S gene showed genotype C in 82% and genotype B in 18%. Furthermore, 5/19 cases were negative for HBsAg and were categorized as occult HBV infections. TP53 mutations were detected in 9 cases (34,6% including 7 mutations at codon 249 (AGG to AGT, arginine to serine, considered as ";fingerprint"; of mutagenesis by aflatoxin metabolites. All cases with 249ser mutation had overt HBV infection.

    CTNNB1 mutations were found in 6/26 cases (23%, 4 of whom also had TP53 mutation. There was no significant association between CTTNB1

  13. Three kinds of mutation

    CERN Document Server

    Buan, Aslak Bakke; Thomas, Hugh

    2010-01-01

    For a finite dimensional hereditary algebra, we consider: exceptional sequences in the category of finite dimensional modules, silting objects in the bounded derived category, and m-cluster tilting objects in the m-cluster category. There are mutation operations on both the set of m-cluster tilting objects and the set of exceptional sequences. It is also possible to define a mutation operation for silting objects. We compare these three different notions of mutation.

  14. JC polyomavirus mutants escape antibody-mediated neutralization.

    Science.gov (United States)

    Ray, Upasana; Cinque, Paola; Gerevini, Simonetta; Longo, Valeria; Lazzarin, Adriano; Schippling, Sven; Martin, Roland; Buck, Christopher B; Pastrana, Diana V

    2015-09-23

    JC polyomavirus (JCV) persistently infects the urinary tract of most adults. Under conditions of immune impairment, JCV causes an opportunistic brain disease, progressive multifocal leukoencephalopathy (PML). JCV strains found in the cerebrospinal fluid of PML patients contain distinctive mutations in surface loops of the major capsid protein, VP1. We hypothesized that VP1 mutations might allow the virus to evade antibody-mediated neutralization. Consistent with this hypothesis, neutralization serology revealed that plasma samples from PML patients neutralized wild-type JCV strains but failed to neutralize patient-cognate PML-mutant JCV strains. This contrasted with serological results for healthy individuals, most of whom robustly cross-neutralized all tested JCV variants. Mice administered a JCV virus-like particle (VLP) vaccine initially showed neutralizing "blind spots" (akin to those observed in PML patients) that closed after booster immunization. A PML patient administered an experimental JCV VLP vaccine likewise showed markedly increased neutralizing titer against her cognate PML-mutant JCV. The results indicate that deficient humoral immunity is a common aspect of PML pathogenesis and that vaccination may overcome this humoral deficiency. Thus, vaccination with JCV VLPs might prevent the development of PML.

  15. Unsteady motion: escape jumps in planktonic copepods, their kinematics and energetics

    DEFF Research Database (Denmark)

    Kiørboe, Thomas; Andersen, Anders Peter; Langlois, Vincent J.;

    2010-01-01

    estimate the force and power output needed to accelerate and overcome drag. Both are very high compared with those of other organisms, as are the escape velocities in comparison to startle velocities of other aquatic animals. Thus, the maximum weight-specific force, which for muscle motors of other animals...... has been found to be near constant at 57 N (kg muscle)−1, is more than an order of magnitude higher for the escaping copepods. We argue that this is feasible because most copepods have different systems for steady propulsion (feeding appendages) and intensive escapes (swimming legs), with the muscular...... arrangement of the latter probably adapted for high force production during short-lasting bursts. The resulting escape velocities scale with body length to power 0.65, different from the size-scaling of both similar sized and larger animals moving at constant velocity, but similar to that found for startle...

  16. Escape dynamics in collinear atomic-like three mass point systems

    CERN Document Server

    Pasca, Daniel; Stoica, Cristina

    2009-01-01

    The present paper studies the escape mechanism in collinear three point mass systems with small-range-repulsive/large-range-attractive pairwise-interaction. Specifically, we focus on systems with non-negative total energy. We show that on the zero energy level set, most of the orbits lead to binary escape configurations and the set of initial conditions leading to escape configurations where all three separations infinitely increase as $t \\to \\infty 1$ has zero Lebesgue measure. We also give numerical evidence of the existence of a periodic orbit for the case when the two outer masses are equal. For positive energies, we prove that the set of initial conditions leading to escape configurations where all three separations infinitely increase as $t \\to \\infty$ has positive Lebesgue measure. Keywords: linear three point

  17. Escape of an inertial Lévy flight particle from a truncated quartic potential well

    Science.gov (United States)

    Bai, Zhan-Wu; Hu, Meng

    2017-08-01

    Motivated by that the quartic potential can confined Lévy flights, we investigate the escape rate of an inertial Lévy particle from a truncated quartic potential well via Langevin simulation. The escape rate still depends on the noise intensity in a power-law form in low noise intensity, but the exponent and the inverse coefficient vary significantly for different Lévy indexes compared with previous works. Trimodal structure of the probability density function was found in simulations. The probability density function in a quasi-stable state exhibits transition among unimodal, bimodal, and trimodal structures. A metastable state by stable state approach is developed to calculate the escape rate analytically, which may be applied to extensive escape problems. The theoretical approach is confirmed by Langevin simulation for the Cauchy case of Lévy flight in the applied potential.

  18. Escaping the poverty trap: modeling the interplay between economic growth and the ecology of infectious disease

    CERN Document Server

    Goerg, Georg M; Hébert-Dufresne, Laurent; Althouse, Benjamin M

    2013-01-01

    The dynamics of economies and infectious disease are inexorably linked: economic well-being influences health (sanitation, nutrition, treatment capacity, etc.) and health influences economic well-being (labor productivity lost to sickness and disease). Often societies are locked into ``poverty traps'' of poor health and poor economy. Here, using a simplified coupled disease-economic model with endogenous capital growth we demonstrate the formation of poverty traps, as well as ways to escape them. We suggest two possible mechanisms of escape both motivated by empirical data: one, through an influx of capital (development aid), and another through changing the percentage of GDP spent on healthcare. We find that a large influx of capital is successful in escaping the poverty trap, but increasing health spending alone is not. Our results demonstrate that escape from a poverty trap may be possible, and carry important policy implications in the world-wide distribution of aid and within-country healthcare spending.

  19. Effect Of Feedback On The Escape Of Ionizing Radiation From High-Z Galaxies

    Science.gov (United States)

    Trebitsch, Maxime; Blaizot, Jérémy; Rosdahl, Joakim; Devriendt, Julien; Slyz, Adrianne

    2017-06-01

    Quantifying how much of the ionizing radiation produced in high-redshift galaxies escapes in the IGM is one of the main challenges in understanding the sources of reionization. We investigate the radiative properties of simulated low mass galaxies (halos of a few 109 Msun at z=6), where radiation is modelled on-the-fly, and different sources of feedback (from stars and AGN) are included. Using radiation-hydrodynamic simulations performed with Ramses-RT we study how the energy and momentum input from supernovae and black hole activity modulates the properties of the interstellar medium and therefore how, and how many, photons can escape from the galaxy. I will present simulations showing (Trebitsch et al. 2017, https://arxiv.org/abs/1705.00941) that stellar feedback has a pivotal role in regulating the escape fraction in dwarf galaxies. Supernovae carve holes in the gas distribution, through which ionizing photons can escape.

  20. Pizza or Pancake? Formation Models of Gas Escape Biosignatures in Terrestrial and Martian Sediments

    Science.gov (United States)

    Bonaccorsi, R.; Fairen, A. G.; Baker, L.; McKay, C. P.; Willson, D.

    2016-05-01

    Fine-grained sedimentary hollowed structures were imaged in Gale Crater, but no biomarkers identified to support biology. Our observation-based (gas escape) terrestrial model could inform on possible martian paleoenvironments at time of formation.

  1. Choices between positive and negative reinforcement during treatment for escape-maintained behavior.

    OpenAIRE

    DeLeon, I G; Neidert, P L; Anders, B M; Rodriguez-Catter, V

    2001-01-01

    Positive reinforcement was more effective than negative reinforcement in promoting compliance and reducing escape-maintained problem behavior for a child with autism. Escape extinction was then added while the child was given a choice between positive or negative reinforcement for compliance and the reinforcement schedule was thinned. When the reinforcement requirement reached 10 consecutive tasks, the treatment effects became inconsistent and reinforcer selection shifted from a strong prefer...

  2. Influence of throat configuration and fish density on escapement of channel catfish from hoop nets

    Science.gov (United States)

    Porath, Mark T.; Pape, Larry D.; Richters, Lindsey K.

    2011-01-01

    In recent years, several state agencies have adopted the use of baited, tandemset hoop nets to assess lentic channel catfish Ictalurus punctatus populations. Some level of escapement from the net is expected because an opening exists in each throat of the net, although factors influencing rates of escapement from hoop nets have not been quantified. We conducted experiments to quantify rates of escapement and to determine the influence of throat configuration and fish density within the net on escapement rates. An initial experiment to determine the rate of escapement from each net compartment utilized individually tagged channel catfish placed within the entrance (between the two throats) and cod (within the second throat) compartments of a single hoop net for overnight sets. From this experiment, the mean rate (±SE) of channel catfish escaping was 4.2% (±1.5) from the cod (cod throat was additionally restricted from the traditionally manufactured product), and 74% (±4.2) from the entrance compartments. In a subsequent experiment, channel catfish were placed only in the cod compartment with different throat configurations (restricted or unrestricted) and at two densities (low [6 fish per net] and high [60 fish per net]) for overnight sets to determine the influence of fish density and throat configuration on escapement rates. Escapement rates between throat configurations were doubled at low fish density (13.3 ± 5.4% restricted versus 26.7 ± 5.6% unrestricted) and tripled at high fish density (14.3 ± 4.9% restricted versus 51.9 ± 5.0% unrestricted). These results suggest that retention efficiency is high from cod compartments with restricted throat entrances. However, managers and researchers need to be aware that modification to the cod throats (restrictions) is needed for hoop nets ordered from manufacturers. Managers need to be consistent in their use and reporting of cod end throat configurations when using this gear.

  3. THE EFFECTS OF FIXED-TIME ESCAPE ON INAPPROPRIATE AND APPROPRIATE CLASSROOM BEHAVIOR

    OpenAIRE

    Waller, Rachael D; Higbee, Thomas S.

    2010-01-01

    Few studies have explored the effects of fixed-time (FT) reinforcement on escape-maintained behavior of students in a classroom setting. We measured the effects of an FT schedule on the disruptive and appropriate academic behaviors of 2 junior high students in a public school setting. Results demonstrated that FT escape from tasks resulted in a substantial decrease in disruptive behavior and an increase in time engaged in tasks for both participants.

  4. Choices between positive and negative reinforcement during treatment for escape-maintained behavior.

    Science.gov (United States)

    DeLeon, I G; Neidert, P L; Anders, B M; Rodriguez-Catter, V

    2001-01-01

    Positive reinforcement was more effective than negative reinforcement in promoting compliance and reducing escape-maintained problem behavior for a child with autism. Escape extinction was then added while the child was given a choice between positive or negative reinforcement for compliance and the reinforcement schedule was thinned. When the reinforcement requirement reached 10 consecutive tasks, the treatment effects became inconsistent and reinforcer selection shifted from a strong preference for positive reinforcement to an unstable selection pattern.

  5. Solution of the boundary value problem for optimal escape in continuous stochastic systems and maps.

    OpenAIRE

    S; Beri; Mannella, R.; Luchinsky, Dmitry G.; Silchenko, A. N.; McClintock, Peter V. E.

    2005-01-01

    Topologies of invariant manifolds and optimal trajectories are investigated in stochastic continuous systems and maps. A topological method is introduced that simplifies the solution of boundary value problems: The activation energy is calculated as a function of a set of parameters characterizing the initial conditions of the escape path. The method is applied explicitly to compute the optimal escape path and the activation energy for a variety of dynamical systems and maps.

  6. The role of TH cells in memory CTL mediated tumor protection%TH细胞在记忆性CTL介导的肿瘤抑制中的作用研究

    Institute of Scientific and Technical Information of China (English)

    高丰光; Germain J.P.Fernando; 刘文军

    2005-01-01

    目的观察记忆性CTL的抑瘤作用是否需要抗原特异性TH细胞的辅助. 方法表达OVA T 细胞表位SIINFEKL特异性TCR的T细胞转输RAG-/-小鼠,经相应T细胞表位多肽刺激后产生记忆性CTL,将此记忆性CTL转输已产生特异性和非特异性TH细胞的C57BL/6小鼠体内并接种肿瘤细胞EG7. 结果经T细胞表位多肽免疫后,SIINFEKL特异性TCR T细胞成功在RAG-/-小鼠体内增殖并分化为记忆性CTL;抗原特异性TH细胞可辅助产生较多效应性CTL但并没有完全的肿瘤抑制作用;记忆性CTL的完全抑瘤活性需要抗原特异性TH细胞的辅助. 结论机体对肿瘤的长期完全杀伤作用不但需要肿瘤特异性抗原诱导产生的记忆性CTL,而且需要特异性TH细胞的辅助,肿瘤疫苗的设计必须包括特异性的CTL表位多肽和辅助性TH细胞多肽.

  7. Gestational mutations in radiation carcinogenesis

    Science.gov (United States)

    Meza, R.; Luebeck, G.; Moolgavkar, S.

    Mutations in critical genes during gestation could increase substantially the risk of cancer. We examine the consequences of such mutations using the Luebeck-Moolgavkar model for colorectal cancer and the Lea-Coulson modification of the Luria-Delbruck model for the accumulation of mutations during gestation. When gestational mutation rates are high, such mutations make a significant contribution to cancer risk even for adult tumors. Furthermore, gestational mutations ocurring at distinct times during emryonic developmemt lead to substantially different numbers of mutated cells at birth, with early mutations leading to a large number (jackpots) of mutated cells at birth and mutation occurring late leading to only a few mutated cells. Thus gestational mutations could confer considerable heterogeneity of the risk of cancer. If the fetus is exposed to an environmental mutagen, such as ionizing radiation, the gestational mutation rate would be expected to increase. We examine the consequences of such exposures during gestation on the subsequent development of cancer.

  8. The relationship between migration and development in the ESCAP region.

    Science.gov (United States)

    Skeldon, R

    1991-01-01

    The relationship between migration and development in the ESCAP region including southeast and south Asian countries and the Pacific island of Fiji, Papua New Guinea, Vanuatu, Kiribati, Samoa, and the Solomon Islands is discussed in terms of mobility transition and origin and destination factors. The changing patterns of mobility in Asia are further delineated in the discussion of internal movements and international movement. Emigration in the smaller countries of the Pacific are treated separately. Future predictions are that the Asia Pacific region will experience continued fertility decline and stabilization of low rates over the next 20 years. The declines will result in slow labor force growth, and increased demand for labor in traditional core and neocore countries as defined and presented in table form by Friedman will be heightened. International movements are likely to increase in large urban areas within destination countries. Tokyo and Singapore are the principal cities in Asia. Tokyo by restrictive government policy has limited immigration, but future labor shortages of unskilled labor from southeast Asia and China are expected. Singapore is already dependent on foreign labor by 10%. Current labor shortages have led to the creation of a growth triangle between Singapore, Indonesia, and Malaysia. Other cities expected to emerge as primary cities in international regional complexes with spillover into the hinterlands include the Hong Kong, Guangzhou, and Macau triangle in the Pearl River delta, Taipei and Seoul, and possibly Kuala Lumpur. Internal migration is expected to increase in the capital cities of Bangkok, Manila,j and centers such as Shanghai, Beijing, and other large cities of southeast Asia. These cities will be linked through the flows of skilled international migrants, which began in the 1960s and is expected to become a future major flow. Recreational and resource niches will be left in much of the Pacific, the Himalayan Kingdoms, and

  9. Escape-Route Planning of Underground Coal Mine Based on Improved Ant Algorithm

    Directory of Open Access Journals (Sweden)

    Guangwei Yan

    2013-01-01

    Full Text Available When a mine disaster occurs, to lessen disaster losses and improve survival chances of the trapped miners, good escape routes need to be found and used. Based on the improved ant algorithm, we proposed a new escape-route planning method of underground mines. At first, six factors which influence escape difficulty are evaluated and a weight calculation model is built to form a weighted graph of the underground tunnels. Then an improved ant algorithm is designed and used to find good escape routes. We proposed a tunnel network zoning method to improve the searching efficiency of the ant algorithm. We use max-min ant system method to optimize the meeting strategy of ants and improve the performance of the ant algorithm. In addition, when a small part of the mine tunnel network changes, the system may fix the optimal routes and avoid starting a new processing procedure. Experiments show that the proposed method can find good escape routes efficiently and can be used in the escape-route planning of large and medium underground coal mines.

  10. Fundamental Experiment to Determine Escape Countermeasures for Frogs Falling into Agricultural Canals

    Science.gov (United States)

    Watabe, Keiji; Mori, Atsushi; Koizumi, Noriyuki; Takemura, Takeshi

    Frogs often drown in agricultural canals with deep concrete walls, which are installed commonly in paddy fields after land improvement projects in Japan, because they cannot escape after falling into the canal. Therefore, countermeasures that enable frogs to escape from canals are required in some rural areas. An experimental canal with partially sloped walls was used as an escape countermeasure to investigate the preferable angle of slope for the walls, water depth and flow velocity that enables Tokyo Daruma Pond Frogs (Rana porosa porosa), which have no adhesive discs, to easily escape. Walls with slopes of 30-45 degrees allowed 50-60% of frogs to escape from the experimental canals, frogs especially easily climbed the 30 degree sloped walls. When the water depth was 5 cm or flow velocity was greater than 20 cm/s, approximately 80% of the frogs moved downstream and reached the sloped walls because the frogs' toes did not reach the bottom of the canal. However, if the depth was 2 cm and the flow velocity was 5 cm/s, only 4% of the frogs climbed the sloped walls because they could move freely. The frogs appeared to not be good at long-distance swimming and could not remain a long-time under running water. Therefore, walls sloped less than 30 degrees and control of both water depth and flow velocity appears important for enabling frogs to easily escape from canals.

  11. CD4 binding site broadly neutralizing antibody selection of HIV-1 escape mutants.

    Science.gov (United States)

    Dreja, Hanna; Pade, Corinna; Chen, Lei; McKnight, Áine

    2015-07-01

    All human immunodeficiency virus type-1 (HIV-1) viruses use CD4 to enter cells. Consequently, the viral envelope CD4-binding site (CD4bs) is relatively conserved, making it a logical neutralizing antibody target. It is important to understand how CD4-binding site variation allows for escape from neutralizing antibodies. Alanine scanning mutagenesis identifies residues in antigenic sites, whereas escape mutant selection identifies viable mutants. We selected HIV-1 to escape CD4bs neutralizing mAbs b12, A12 and HJ16. Viruses that escape from A12 and b12 remained susceptible to HJ16, VRC01 and J3, whilst six different viruses that escape HJ16 remained sensitive to A12, b12 and J3. In contrast, their sensitivity to VRC01 was variable. Triple HJ16/A12/b12-resistant virus proved that HIV-1 could escape multiple broadly neutralizing monoclonal antibodies, but still retain sensitivity to VRC01 and the llama-derived J3 nanobody. This antigenic variability may reflect that occurring in circulating viruses, so studies like this can predict immunologically relevant antigenic forms of the CD4bs for inclusion in HIV-1 vaccines.

  12. Effects of Serotonergic and Opioidergic Drugs on Escape Behaviors and Social Status of Male Crickets

    Science.gov (United States)

    Dyakonova, V. E.; Schürmann, F.-W.; Sakharov, D. A.

    We examined the effects of selective serotonin depletion and opioid ligands on social rank and related escape behavior of the cricket Gryllus bimaculatus. Establishment of social rank in a pair of males affected their escape reactions. Losers showed a lower and dominants a higher percentage of jumps in response to tactile cercal stimulation than before a fight. The serotonin-depleting drug α-methyltryptophan (AMTP) caused an activation of the escape reactivity in socially naive crickets. AMTP-treated animals also showed a lower ability to become dominants. With an initial 51.6+/-3.6% of wins in the AMTP group, the percentage decreased to 26+/-1.6% on day 5 after injection. The opiate receptor antagonist naloxone affected fight and escape similarly as AMTP. In contrast to naloxone, the opioid agonist [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin decreased escape responsiveness to cercal stimulation in naive and subordinate crickets. We suggest that serotonergic and opioid systems are involved in the dominance induced depression of escape behavior.

  13. Heat-induced symmetry breaking in ant (Hymenoptera: Formicidae) escape behavior.

    Science.gov (United States)

    Chung, Yuan-Kai; Lin, Chung-Chi

    2017-01-01

    The collective egress of social insects is important in dangerous situations such as natural disasters or enemy attacks. Some studies have described the phenomenon of symmetry breaking in ants, with two exits induced by a repellent. However, whether symmetry breaking occurs under high temperature conditions, which are a common abiotic stress, remains unknown. In our study, we deposited a group of Polyrhachis dives ants on a heated platform and counted the number of escaping ants with two identical exits. We discovered that ants asymmetrically escaped through two exits when the temperature of the heated platform was >32.75°C. The degree of asymmetry increased linearly with the temperature of the platform. Furthermore, the higher the temperature of heated platform was, the more ants escaped from the heated platform. However, the number of escaping ants decreased for 3 min when the temperature was higher than the critical thermal limit (39.46°C), which is the threshold for ants to endure high temperature without a loss of performance. Moreover, the ants tended to form small groups to escape from the thermal stress. A preparatory formation of ant grouping was observed before they reached the exit, indicating that the ants actively clustered rather than accidentally gathered at the exits to escape. We suggest that a combination of individual and grouping ants may help to optimize the likelihood of survival during evacuation.

  14. Escape of Mars' CO2 atmosphere by suprathermal atoms during the past 4 Gyrs

    Science.gov (United States)

    Amerstorfer, Ute; Gröller, Hannes; Lichtenegger, Herbert; Lammer, Helmut; Tian, Feng

    2016-04-01

    The escape of atmospheric particles plays a crucial role in the evolution of the atmosphere of Mars. Especially, the escape of oxygen and carbon is thought to have influenced its amount of CO2. With a Monte-Carlo model we investigate the escape of hot oxygen and carbon from the martian atmosphere for three points in time in its history corresponding to 3, 10, and 20 times the present EUV level. We study and discuss different possible sources of hot oxygen and carbon atoms in the thermosphere and their changing importance with the EUV flux. We find that the escape due to photodissociation increases with increasing EUV level, as is a commonly assumed opinion. However, for the escape via other reactions, e.g. dissociative recombination, this is only true until the EUV level reaches 10 times the present EUV flux, but then the rates start to decrease. Our results thus suggest that some escape mechanisms related to the loss of CO2 are less important than previously thought for atmospheres exposed to higher EUV radiation. This work receives funding from the Austrian Science Fund (FWF): P 24247-N16.

  15. Orbital and escape dynamics in barred galaxies - I. The 2D system

    CERN Document Server

    Jung, Christof

    2016-01-01

    In this paper we use the two-dimensional (2D) version of a new analytical gravitational model in order to explore the orbital as well as the escape dynamics of the stars in a barred galaxy composed of a spherically symmetric central nucleus, a bar, a flat disk and a dark matter halo component. A thorough numerical investigation is conducted for distinguishing between bounded and escaping motion. Furthermore bounded orbits are further classified into non-escaping regular and trapped chaotic using the Smaller ALingment Index (SALI) method. Our aim is to determine the basins of escape through the two symmetrical escape channels around the Lagrange points $L_2$ and $L_3$ and also to relate them with the corresponding distribution of the escape rates of the orbits. We integrate initial conditions of orbits in several types of planes so as to obtain a more complete view of the overall orbital properties of the dynamical system. We also present evidence that the unstable manifolds which guide the orbits in and out t...

  16. Lobelia siphilitica plants that escape herbivory in time also have reduced latex production.

    Directory of Open Access Journals (Sweden)

    Amy L Parachnowitsch

    Full Text Available Flowering phenology is an important determinant of a plant's reproductive success. Both assortative mating and niche construction can result in the evolution of correlations between phenology and other reproductive, functional, and life history traits. Correlations between phenology and herbivore defence traits are particularly likely because the timing of flowering can allow a plant to escape herbivory. To test whether herbivore escape and defence are correlated, we estimated phenotypic and genetic correlations between flowering phenology and latex production in greenhouse-grown Lobelia siphilitica L. (Lobeliaceae. Lobelia siphilitica plants that flower later escape herbivory by a specialist pre-dispersal seed predator, and thus should invest fewer resources in defence. Consistent with this prediction, we found that later flowering was phenotypically and genetically correlated with reduced latex production. To test whether herbivore escape and latex production were costly, we also measured four fitness correlates. Flowering phenology was negatively genetically correlated with three out of four fitness estimates, suggesting that herbivore escape can be costly. In contrast, we did not find evidence for costs of latex production. Generally, our results suggest that herbivore escape and defence traits will not evolve independently in L. siphilitica.

  17. Lévy noise-induced escape in an excitable system

    Science.gov (United States)

    Cai, Rui; Chen, Xiaoli; Duan, Jinqiao; Kurths, Jürgen; Li, Xiaofan

    2017-06-01

    This paper considers the dynamics of escape in the stochastic FitzHugh-Nagumo (FHN) neuronal model driven by symmetric α-stable Lévy noise. External or internal stimulation may make the excitable system produce a pulse or not, which can be interpreted as an escape problem. A new method to analyse the state transition from the rest state to the excitatory state is presented. This approach consists of two deterministic indices: the first escape probability (FEP) and the mean first exit time (MFET). We find that higher FEP in the rest state (equilibrium) promotes such a transition and MFET reflects the stability of the rest state directly with the selected escape region. The developed two dimensional numerical simulation method to calculate FEP and MFET can not only avoid a dimension reduction, but is also applicable for the cases with large noise. In addition, FEP provides us with a new perspective to understand the seperatrix of the stochastic FHN model. It can be seen that smaller jumps of the Lévy motion and relatively small noise intensity are conducive to the production of spikes. In order to characterize the effect of noise on the selected escape region in which the equilibrium lies, the area of higher FEP and MFET in the escape region are calculated. Meanwhile, Brownian motion as a special case is also taken into account for comparison. This work was partly supported by the NSF grant 1620449, and NSFC grants 11531006, 11371367 and 11271290.

  18. Hot oxygen escape from Mars: Simple scaling with solar EUV irradiance

    Science.gov (United States)

    Cravens, T. E.; Rahmati, A.; Fox, Jane L.; Lillis, R.; Bougher, S.; Luhmann, J.; Sakai, S.; Deighan, J.; Lee, Yuni; Combi, M.; Jakosky, B.

    2017-01-01

    The evolution of the atmosphere of Mars and the loss of volatiles over the lifetime of the solar system is a key topic in planetary science. An important loss process for atomic species, such as oxygen, is ionospheric photochemical escape. Dissociative recombination of O2+ ions (the major ion species) produces fast oxygen atoms, some of which can escape from the planet. Many theoretical hot O models have been constructed over the years, although a number of uncertainties are present in these models, particularly concerning the elastic cross sections of O atoms with CO2. Recently, the Mars Atmosphere and Volatile Evolution mission has been rapidly improving our understanding of the upper atmosphere and ionosphere of Mars and its interaction with the external environment (e.g., solar wind), allowing a new assessment of this important loss process. The purpose of the current paper is to take a simple analytical approach to the oxygen escape problem in order to (1) study the role that variations in solar radiation or solar wind fluxes could have on escape in a transparent fashion and (2) isolate the effects of uncertainties in oxygen cross sections on the derived oxygen escape rates. In agreement with several more elaborate numerical models, we find that the escape flux is directly proportional to the incident solar extreme ultraviolet irradiance and is inversely proportional to the backscatter elastic cross section. The amount of O lost due to ion transport in the topside ionosphere is found to be about 5-10% of the total.

  19. Quantifying the Escape Mortality of Trawl Caught Antarctic Krill (Euphausia superba)

    Science.gov (United States)

    Krafft, Bjørn A.; Krag, Ludvig A.; Engås, Arill; Nordrum, Sigve; Bruheim, Inge; Herrmann, Bent

    2016-01-01

    Antarctic krill (Euphausia superba) is an abundant fishery resource, the harvest levels of which are expected to increase. However, many of the length classes of krill can escape through commonly used commercial trawl mesh sizes. A vital component of the overall management of a fishery is to estimate the total fishing mortality and quantify the mortality rate of individuals that escape from fishing gear. The methods for determining fishing mortality in krill are still poorly developed. We used a covered codend sampling technique followed by onboard observations made in holding tanks to monitor mortality rates of escaped krill. Haul duration, hydrological conditions, maximum fishing depth and catch composition all had no significant effect on mortality of krill escaping 16 mm mesh size nets, nor was any further mortality associated with the holding tank conditions. A non- parametric Kaplan-Meier analysis was used to model the relationship between mortality rates of escapees and time. There was a weak tendency, though not significant, for smaller individuals to suffer higher mortality than larger individuals. The mortality of krill escaping the trawl nets in our study was 4.4 ± 4.4%, suggesting that krill are fairly tolerant of the capture-and-escape process in trawls. PMID:27622510

  20. Chaotic escape from an open vase-shaped cavity. I. Numerical and experimental results

    Science.gov (United States)

    Novick, Jaison; Keeler, Matthew L.; Giefer, Joshua; Delos, John B.

    2012-01-01

    We present part I in a two-part study of an open chaotic cavity shaped as a vase. The vase possesses an unstable periodic orbit in its neck. Trajectories passing through this orbit escape without return. For our analysis, we consider a family of trajectories launched from a point on the vase boundary. We imagine a vertical array of detectors past the unstable periodic orbit and, for each escaping trajectory, record the propagation time and the vertical detector position. We find that the escape time exhibits a complicated recursive structure. This recursive structure is explored in part I of our study. We present an approximation to the Helmholtz equation for waves escaping the vase. By choosing a set of detector points, we interpolate trajectories connecting the source to the different detector points. We use these interpolated classical trajectories to construct the solution to the wave equation at a detector point. Finally, we construct a plot of the detector position versus the escape time and compare this graph to the results of an experiment using classical ultrasound waves. We find that generally the classical trajectories organize the escaping ultrasound waves.