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Sample records for doublecortin-expressing cells persist

  1. Developmental Patterns of Doublecortin Expression and White Matter Neuron Density in the Postnatal Primate Prefrontal Cortex and Schizophrenia

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    Fung, Samantha J.; Joshi, Dipesh; Allen, Katherine M.; Sivagnanasundaram, Sinthuja; Rothmond, Debora A.; Saunders, Richard; Noble, Pamela L.; Webster, Maree J.; Shannon Weickert, Cynthia

    2011-01-01

    Postnatal neurogenesis occurs in the subventricular zone and dentate gyrus, and evidence suggests that new neurons may be present in additional regions of the mature primate brain, including the prefrontal cortex (PFC). Addition of new neurons to the PFC implies local generation of neurons or migration from areas such as the subventricular zone. We examined the putative contribution of new, migrating neurons to postnatal cortical development by determining the density of neurons in white matter subjacent to the cortex and measuring expression of doublecortin (DCX), a microtubule-associated protein involved in neuronal migration, in humans and rhesus macaques. We found a striking decline in DCX expression (human and macaque) and density of white matter neurons (humans) during infancy, consistent with the arrival of new neurons in the early postnatal cortex. Considering the expansion of the brain during this time, the decline in white matter neuron density does not necessarily indicate reduced total numbers of white matter neurons in early postnatal life. Furthermore, numerous cells in the white matter and deep grey matter were positive for the migration-associated glycoprotein polysialiated-neuronal cell adhesion molecule and GAD65/67, suggesting that immature migrating neurons in the adult may be GABAergic. We also examined DCX mRNA in the PFC of adult schizophrenia patients (n = 37) and matched controls (n = 37) and did not find any difference in DCX mRNA expression. However, we report a negative correlation between DCX mRNA expression and white matter neuron density in adult schizophrenia patients, in contrast to a positive correlation in human development where DCX mRNA and white matter neuron density are higher earlier in life. Accumulation of neurons in the white matter in schizophrenia would be congruent with a negative correlation between DCX mRNA and white matter neuron density and support the hypothesis of a migration deficit in schizophrenia. PMID

  2. Developmental patterns of doublecortin expression and white matter neuron density in the postnatal primate prefrontal cortex and schizophrenia.

    Directory of Open Access Journals (Sweden)

    Samantha J Fung

    Full Text Available Postnatal neurogenesis occurs in the subventricular zone and dentate gyrus, and evidence suggests that new neurons may be present in additional regions of the mature primate brain, including the prefrontal cortex (PFC. Addition of new neurons to the PFC implies local generation of neurons or migration from areas such as the subventricular zone. We examined the putative contribution of new, migrating neurons to postnatal cortical development by determining the density of neurons in white matter subjacent to the cortex and measuring expression of doublecortin (DCX, a microtubule-associated protein involved in neuronal migration, in humans and rhesus macaques. We found a striking decline in DCX expression (human and macaque and density of white matter neurons (humans during infancy, consistent with the arrival of new neurons in the early postnatal cortex. Considering the expansion of the brain during this time, the decline in white matter neuron density does not necessarily indicate reduced total numbers of white matter neurons in early postnatal life. Furthermore, numerous cells in the white matter and deep grey matter were positive for the migration-associated glycoprotein polysialiated-neuronal cell adhesion molecule and GAD65/67, suggesting that immature migrating neurons in the adult may be GABAergic. We also examined DCX mRNA in the PFC of adult schizophrenia patients (n = 37 and matched controls (n = 37 and did not find any difference in DCX mRNA expression. However, we report a negative correlation between DCX mRNA expression and white matter neuron density in adult schizophrenia patients, in contrast to a positive correlation in human development where DCX mRNA and white matter neuron density are higher earlier in life. Accumulation of neurons in the white matter in schizophrenia would be congruent with a negative correlation between DCX mRNA and white matter neuron density and support the hypothesis of a migration deficit in

  3. Novel protocol for persister cells isolation.

    Directory of Open Access Journals (Sweden)

    Silvia J Cañas-Duarte

    Full Text Available Bacterial persistence, where a fraction of a population presents a transient resistance to bactericidal substances, has great medical importance due to its relation with the appearance of antibiotic resistances and untreatable bacterial chronic infections. The mechanisms behind this phenomenon remain largely unknown in spite of recent advances, in great part because of the difficulty in isolating the very small fraction of the population that is in this state at any given time. Current protocols for persister isolation have resulted in possible biases because of the induction of this state by the protocol itself. Here we present a novel protocol that allows rapid isolation of persister cells both from exponential and stationary phase. Moreover, it is capable of differentiating between type I and type II persister cells, which should allow the field to move beyond its current state of studying only one type. While this protocol prompts a revision of many of the current results, it should greatly facilitate further advances in the field.

  4. Effects of interferon on cultured cells persistently infected with viruses

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    Crespi, M

    1986-01-01

    The role of interferon (IFN) in viral persistence at the cellular level was investigated. Two types of persistent infections were chosen. The first type was cell lines which contained hepatitis B virus (HBV) DNA (PLC/PRF/5 and Hep 3B cells) uninfected control hepatoma cells, (Mahlavu, HA22T and Hep G2 cells) or simian virus 40 (SV40) DNA (C2, C6, C11 cells) and control uninfected (CV-1 cells). In the second type of infection Vero cells persistently infected with SSPE or Sendai virus were used. The aim of this work was to determine what effect IFN had in these infections in terms of its antiviral and antiproliferative effects; which of the two major IFN-induced pathways, E enzyme or protein kinase were induced; whether there were any differences in sensitivity to IFN between the DNA and RNA virus persistent infections. The anti-viral effect of IFN was examined by its ability to inhibit Sindbis virus replication using a radioimmunoassay system. The antiproliferative effect of IFN was determined by cell counting and /sup 3/H-thymidine incorporation. The activation of the ribonuclease F, determined by the inhibition of /sup 3/H-leucine incorporation after introduction of 2-5 actin into the cells, was variable, being activated in all cell lines with the exception of the PLC/PRF/5, Hep 3B and Hep G2 cells. Major differences between the two DNA persistent infections and the two RNA persistent infections were found. No correlation was found between the presence of HBV or SV40 persistent infections and the sensitivity of the cell lines to IFN. Both the SSPE and Sendai virus persistent infections were resistant to the antiviral and antiproliferative effect of IFN.

  5. Pregnancy persistently affects memory T cell populations

    NARCIS (Netherlands)

    Kieffer, Tom E. C.; Faas, Marijke M.; Scherjon, Sicco A.; Prins, Jelmer R.

    Pregnancy is an immune challenge to the maternal immune system. The effects of pregnancy on maternal immunity and particularly on memory T cells during and after pregnancy are not fully known. This observational study aims to show the short term and the long term effects of pregnancy on the

  6. DNA-crosslinker cisplatin eradicates bacterial persister cells.

    Science.gov (United States)

    Chowdhury, Nityananda; Wood, Thammajun L; Martínez-Vázquez, Mariano; García-Contreras, Rodolfo; Wood, Thomas K

    2016-09-01

    For all bacteria, nearly every antimicrobial fails since a subpopulation of the bacteria enter a dormant state known as persistence, in which the antimicrobials are rendered ineffective due to the lack of metabolism. This tolerance to antibiotics makes microbial infections the leading cause of death worldwide and makes treating chronic infections, including those of wounds problematic. Here, we show that the FDA-approved anti-cancer drug cisplatin [cis-diamminodichloroplatinum(II)], which mainly forms intra-strand DNA crosslinks, eradicates Escherichia coli K-12 persister cells through a growth-independent mechanism. Additionally, cisplatin is more effective at killing Pseudomonas aeruginosa persister cells than mitomycin C, which forms inter-strand DNA crosslinks, and cisplatin eradicates the persister cells of several pathogens including enterohemorrhagic E. coli, Staphylococcus aureus, and P. aeruginosa. Cisplatin was also highly effective against clinical isolates of S. aureus and P. aeruginosa. Therefore, cisplatin has broad spectrum activity against persister cells. Biotechnol. Bioeng. 2016;113: 1984-1992. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  7. Autocatalytic polymerization generates persistent random walk of crawling cells.

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    Sambeth, R; Baumgaertner, A

    2001-05-28

    The autocatalytic polymerization kinetics of the cytoskeletal actin network provides the basic mechanism for a persistent random walk of a crawling cell. It is shown that network remodeling by branching processes near the cell membrane is essential for the bimodal spatial stability of the network which induces a spontaneous breaking of isotropic cell motion. Details of the phenomena are analyzed using a simple polymerization model studied by analytical and simulation methods.

  8. Transmission of persistent ionizing radiation-induced foci through cell division in human primary cells

    Energy Technology Data Exchange (ETDEWEB)

    Vaurijoux, Aurelie, E-mail: aurelie.vaurijoux@irsn.fr [Institut de Radioprotection et de Sureté Nucléaire (IRSN), Laboratoire de Dosimétrie Biologique, BP 17, 92262 Fontenay aux roses cedex (France); Voisin, Pascale; Freneau, Amelie [Institut de Radioprotection et de Sureté Nucléaire (IRSN), Laboratoire de Dosimétrie Biologique, BP 17, 92262 Fontenay aux roses cedex (France); Barquinero, Joan Francesc [Universitat Autònoma de Barcelona, Faculty of Biosciences, 08193 Cerdanyola del Vallès (Spain); Gruel, Gaetan [Institut de Radioprotection et de Sureté Nucléaire (IRSN), Laboratoire de Dosimétrie Biologique, BP 17, 92262 Fontenay aux roses cedex (France)

    2017-03-15

    Highlights: • Persistent IRIF do not permanently block cell proliferation. • Persistent IRIF are transmitted in part and sometimes asymmetrically to daughter cells. • IRIF differ in their nature before and after the first cell division. - Abstract: Unrepaired DNA double-strand breaks (DSBs) induced by ionizing radiation are associated with lethal effects and genomic instability. After the initial breaks and chromatin destabilization, a set of post-translational modifications of histones occurs, including phosphorylation of serine 139 of histone H2AX (γH2AX), which leads to the formation of ionizing radiation-induced foci (IRIF). DSB repair results in the disappearance of most IRIF within hours after exposure, although some remain 24 h after irradiation. Their relation to unrepaired DSBs is generally accepted but still controversial. This study evaluates the frequency and kinetics of persistent IRIF and analyzes their impact on cell proliferation. We observed persistent IRIF up to 7 days postirradiation, and more than 70% of cells exposed to 5 Gy had at least one of these persistent IRIF 24 h after exposure. Moreover we demonstrated that persistent IRIF did not block cell proliferation definitively. The frequency of IRIF was lower in daughter cells, due to asymmetric distribution of IRIF between some of them. We report a positive association between the presence of IRIF and the likelihood of DNA missegregation. Hence, the structure formed after the passage of a persistent IRI focus across the S and G2 phases may impede the correct segregation of the affected chromosome's sister chromatids. The ensuing abnormal resolution of anaphase might therefore cause the nature of IRIF in daughter-cell nuclei to differ before and after the first cell division. The resulting atypical chromosomal assembly may be lethal or result in a gene dosage imbalance and possibly enhanced genomic instability, in particular in the daughter cells.

  9. Transmission of persistent ionizing radiation-induced foci through cell division in human primary cells

    International Nuclear Information System (INIS)

    Vaurijoux, Aurelie; Voisin, Pascale; Freneau, Amelie; Barquinero, Joan Francesc; Gruel, Gaetan

    2017-01-01

    Highlights: • Persistent IRIF do not permanently block cell proliferation. • Persistent IRIF are transmitted in part and sometimes asymmetrically to daughter cells. • IRIF differ in their nature before and after the first cell division. - Abstract: Unrepaired DNA double-strand breaks (DSBs) induced by ionizing radiation are associated with lethal effects and genomic instability. After the initial breaks and chromatin destabilization, a set of post-translational modifications of histones occurs, including phosphorylation of serine 139 of histone H2AX (γH2AX), which leads to the formation of ionizing radiation-induced foci (IRIF). DSB repair results in the disappearance of most IRIF within hours after exposure, although some remain 24 h after irradiation. Their relation to unrepaired DSBs is generally accepted but still controversial. This study evaluates the frequency and kinetics of persistent IRIF and analyzes their impact on cell proliferation. We observed persistent IRIF up to 7 days postirradiation, and more than 70% of cells exposed to 5 Gy had at least one of these persistent IRIF 24 h after exposure. Moreover we demonstrated that persistent IRIF did not block cell proliferation definitively. The frequency of IRIF was lower in daughter cells, due to asymmetric distribution of IRIF between some of them. We report a positive association between the presence of IRIF and the likelihood of DNA missegregation. Hence, the structure formed after the passage of a persistent IRI focus across the S and G2 phases may impede the correct segregation of the affected chromosome's sister chromatids. The ensuing abnormal resolution of anaphase might therefore cause the nature of IRIF in daughter-cell nuclei to differ before and after the first cell division. The resulting atypical chromosomal assembly may be lethal or result in a gene dosage imbalance and possibly enhanced genomic instability, in particular in the daughter cells.

  10. Persistent photovoltage in methylammonium lead iodide perovskite solar cells

    Directory of Open Access Journals (Sweden)

    A. Baumann

    2014-08-01

    Full Text Available We herein perform open circuit voltage decay (OCVD measurements on methylammonium lead iodide (CH3NH3PbI3 perovskite solar cells to increase the understanding of the charge carrier recombination dynamics in this emerging technology. Optically pulsed OCVD measurements are conducted on CH3NH3PbI3 solar cells and compared to results from another type of thin-film photovoltaics, namely, the two reference polymer–fullerene bulk heterojunction solar cell devices based on P3HT:PC60BM and PTB7:PC70BM blends. We observe two very different time domains of the voltage transient in the perovskite solar cell with a first drop on a short time scale that is similar to the decay in the studied organic solar cells. However, 65%–70% of the maximum photovoltage persists on much longer timescales in the perovskite solar cell than in the organic devices. In addition, we find that the recombination dynamics in all time regimes are dependent on the starting illumination intensity, which is also not observed in the organic devices. We then discuss the potential origins of these unique behaviors.

  11. Persistent Fatigue in Hematopoietic Stem Cell Transplantation Survivors.

    Science.gov (United States)

    Hacker, Eileen Danaher; Fink, Anne M; Peters, Tara; Park, Chang; Fantuzzi, Giamila; Rondelli, Damiano

    Fatigue is highly prevalent after hematopoietic stem cell transplantation (HCT). It has been described as intense and may last for years following treatment. The aim of this study is to compare fatigue, physical activity, sleep, emotional distress, cognitive function, and biological measures in HCT survivors with persistent fatigue (n = 25) with age- and gender-matched healthy controls with occasional tiredness (n = 25). Data were collected using (a) objective, real-time assessments of physical activity and sleep over 7 days; (b) patient-reported fatigue assessments; (c) computerized objective testing of cognitive functioning; and (d) biological measures. Differences between groups were examined using multivariate analysis of variance. Survivors of HCT reported increased physical (P < .001), mental (P < .001), and overall (P < .001) fatigue as well as increased anxiety (P < .05) and depression (P < .01) compared with healthy controls. Red blood cell (RBC) levels were significantly lower in HCT survivors (P < .001). Levels of RBC for both groups, however, were in the normal range. Tumor necrosis factor-α (P < .001) and interleukin-6 (P < .05) levels were significantly higher in HCT survivors. Persistent fatigue in HCT survivors compared with healthy controls with occasional tiredness is accompanied by increased anxiety and depression along with decreased RBC counts. Elevated tumor necrosis factor-α and interleukin-6 levels may be important biomarkers. This study provides preliminary support for the conceptualization of fatigue as existing on a continuum, with tiredness anchoring one end and exhaustion the other. Persistent fatigue experienced by HCT survivors is more severe than the occasional tiredness of everyday life.

  12. Biosynthesis of measles virus hemagglutinin in persistently infected cells

    International Nuclear Information System (INIS)

    Bellini, W.J.; Silver, G.D.; McFarlin, D.E.

    1983-01-01

    The synthesis of the hemagglutinin (HA) glycoprotein of measles virus was investigated in a persistently infected cell line using a monoclonal anti-HA. The synthesis of the HA protein was shown to be associated with the rough endoplasmic reticulum. The unglycosylated (HA 0 ) apoprotein is synthesized as a 65.000 dalton peptide and is inserted into the rough endoplasmic reticulum as a transmembrane protein with approximately 2 to 3000 daltons of the peptide exposed to the cytoplasmic membrane surface. Primary glycosylation of the HA protein was found to occur through the lipid-linked carrier, dolichol-phosphate, as determined by inhibition of glycosylation by tunicamycin. Glycosylation, however, was not a prerequisite for membrane insertion. Endo-β-N-acetyl-Glucosaminidase H digestion of the fully glycosylated HA protein indicated that both simple and complex oligosaccharides are present on the surface glycoprotein. (Author)

  13. Impact of persistent cytomegalovirus infection on human neuroblastoma cell gene expression

    International Nuclear Information System (INIS)

    Hoever, Gerold; Vogel, Jens-Uwe; Lukashenko, Polina; Hofmann, Wolf-Karsten; Komor, Martina; Doerr, Hans Wilhelm; Cinatl, Jindrich

    2005-01-01

    In a model of human neuroblastoma (NB) cell lines persistently infected with human cytomegalovirus (HCMV) we previously showed that persistent HCMV infection is associated with an increased malignant phenotype, enhanced drug resistance, and invasive properties. To gain insights into the mechanisms of increased malignancy we analyzed the global changes in cellular gene expression induced by persistent HCMV infection of human neuroblastoma cells by use of high-density oligonucleotide microarrays (HG-U133A, Affymetrix) and RT-PCR. Comparing the gene expression of different NB cell lines with persistently infected cell sub-lines revealed 11 host cell genes regulated in a similar manner throughout all infected samples. Nine of these 11 genes may contribute to the previously observed changes in malignant phenotype of persistently HCMV infected NB cells by influencing invasive growth, apoptosis, angiogenesis, and proliferation. Thus, this work provides the basis for further functional studies

  14. Recombinant cells and organisms having persistent nonstandard amino acid dependence and methods of making them

    Science.gov (United States)

    Church, George M.; Mandell, Daniel J.; Lajoie, Marc J.

    2017-12-05

    Recombinant cells and recombinant organisms persistently expressing nonstandard amino acids (NSAAs) are provided. Methods of making recombinant cells and recombinant organisms dependent on persistently expressing NSAAs for survival are also provided. These methods may be used to make safe recombinant cells and recombinant organisms and/or to provide a selective pressure to maintain one or more reassigned codon functions in recombinant cells and recombinant organisms.

  15. Rapid Elimination of the Persistent Synergid through a Cell Fusion Mechanism

    KAUST Repository

    Maruyama, Daisuke

    2015-05-01

    In flowering plants, fertilization-dependent degeneration of the persistent synergid cell ensures one-on-one pairings of male and female gametes. Here, we report that the fusion of the persistent synergid cell and the endosperm selectively inactivates the persistent synergid cell in Arabidopsis thaliana. The synergid-endosperm fusion causes rapid dilution of pre-secreted pollen tube attractant in the persistent synergid cell and selective disorganization of the synergid nucleus during the endosperm proliferation, preventing attractions of excess number of pollen tubes (polytubey). The synergid-endosperm fusion is induced by fertilization of the central cell, while the egg cell fertilization predominantly activates ethylene signaling, an inducer of the synergid nuclear disorganization. Therefore, two female gametes (the egg and the central cell) control independent pathways yet coordinately accomplish the elimination of the persistent synergid cell by double fertilization. Two female gametes (the egg cell and the central cell) in flowering plants coordinately prevent attractions of excess number of pollen tubes via two mechanisms to inactivate persistent synergid cell. © 2015 Elsevier Inc.

  16. Mib1 contributes to persistent directional cell migration by regulating the Ctnnd1-Rac1 pathway.

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    Mizoguchi, Takamasa; Ikeda, Shoko; Watanabe, Saori; Sugawara, Michiko; Itoh, Motoyuki

    2017-10-31

    Persistent directional cell migration is involved in animal development and diseases. The small GTPase Rac1 is involved in F-actin and focal adhesion dynamics. Local Rac1 activity is required for persistent directional migration, whereas global, hyperactivated Rac1 enhances random cell migration. Therefore, precise control of Rac1 activity is important for proper directional cell migration. However, the molecular mechanism underlying the regulation of Rac1 activity in persistent directional cell migration is not fully understood. Here, we show that the ubiquitin ligase mind bomb 1 (Mib1) is involved in persistent directional cell migration. We found that knockdown of MIB1 led to an increase in random cell migration in HeLa cells in a wound-closure assay. Furthermore, we explored novel Mib1 substrates for cell migration and found that Mib1 ubiquitinates Ctnnd1. Mib1-mediated ubiquitination of Ctnnd1 K547 attenuated Rac1 activation in cultured cells. In addition, we found that posterior lateral line primordium cells in the zebrafish mib1 ta52b mutant showed increased random migration and loss of directional F-actin-based protrusion formation. Knockdown of Ctnnd1 partially rescued posterior lateral line primordium cell migration defects in the mib1 ta52b mutant. Taken together, our data suggest that Mib1 plays an important role in cell migration and that persistent directional cell migration is regulated, at least in part, by the Mib1-Ctnnd1-Rac1 pathway. Published under the PNAS license.

  17. Poliovirus mutants excreted by a chronically infected hypogammaglobulinemic patient establish persistent infections in human intestinal cells

    International Nuclear Information System (INIS)

    Labadie, Karine; Pelletier, Isabelle; Saulnier, Aure; Martin, Javier; Colbere-Garapin, Florence

    2004-01-01

    Immunodeficient patients whose gut is chronically infected by vaccine-derived poliovirus (VDPV) may excrete large amounts of virus for years. To investigate how poliovirus (PV) establishes chronic infections in the gut, we tested whether it is possible to establish persistent VDPV infections in human intestinal Caco-2 cells. Four type 3 VDPV mutants, representative of the viral evolution in the gut of a hypogammaglobulinemic patient over almost 2 years [J. Virol. 74 (2000) 3001], were used to infect both undifferentiated, dividing cells, and differentiated, polarized enterocytes. A VDPV mutant excreted 36 days postvaccination by the patient was lytic in both types of intestinal cell cultures, like the parental Sabin 3 (S3) strain. In contrast, three VDPVs excreted 136, 442, and 637 days postvaccination, established persistent infections both in undifferentiated cells and in enterocytes. Thus, viral determinants selected between day 36 and 136 conferred on VDPV mutants the capacity to infect intestinal cells persistently. The percentage of persistently VDPV-infected cultures was higher in enterocytes than in undifferentiated cells, implicating cellular determinants involved in the differentiation of enterocytes in persistent VDPV infections. The establishment of persistent infections in enterocytes was not due to poor replication of VDPVs in these cells, but was associated with reduced viral adsorption to the cell surface

  18. Saffold Virus Type 3 (SAFV-3) Persists in HeLa Cells

    Science.gov (United States)

    Himeda, Toshiki; Hosomi, Takushi; Okuwa, Takako; Muraki, Yasushi; Ohara, Yoshiro

    2013-01-01

    Saffold virus (SAFV) was identified as a human cardiovirus in 2007. Although several epidemiological studies have been reported, they have failed to provide a clear picture of the relationship between SAFV and human diseases. SAFV genotype 3 has been isolated from the cerebrospinal fluid specimen of patient with aseptic meningitis. This finding is of interest since Theiler’s murine encephalomyelitis virus (TMEV), which is the closely related virus, is known to cause a multiple sclerosis-like syndrome in mice. TMEV persistently infects in mouse macrophage cells in vivo and in vitro, and the viral persistence is essential in TMEV-induced demyelinating disease. The precise mechanism(s) of SAFV infection still remain unclear. In order to clarify the SAFV pathogenicity, in the present study, we studied the possibilities of the in vitro persistent infection of SAFV. The two distinct phenotypes of HeLa cells, HeLa-N and HeLa-R, were identified. In these cells, the type of SAFV-3 infection was clearly different. HeLa-N cells were lyticly infected with SAFV-3 and the host suitable for the efficient growth. On the other hand, HeLa-R cells were persistently infected with SAFV-3. In addition, the SAFV persistence in HeLa-R cells is independent of type I IFN response of host cells although the TMEV persistence in mouse macrophage cells depends on the response. Furthermore, it was suggested that SAFV persistence may be influenced by the expression of receptor(s) for SAFV infection on the host cells. The present findings on SAFV persistence will provide the important information to encourage the research of SAFV pathogenicity. PMID:23308162

  19. Cell motility as persistent random motion: Theories from experiments

    DEFF Research Database (Denmark)

    Selmeczi, D.; Mosler, S.; Hagedorn, P.H.

    2005-01-01

    Experimental time series for trajectories of motile cells may contain so much information that a systematic analysis will yield cell-type- specific motility models. Here we demonstrate how, using human keratinocytes and fibroblasts as examples. The two resulting models reflect the cells' differen...

  20. Prophages and growth dynamics confound experimental results with antibiotic-tolerant persister cells

    DEFF Research Database (Denmark)

    Harms, Alexander; Fino, Cinzia; Sørensen, Michael Askvad

    2017-01-01

    the validity of our model of persister formation in a refined assay setup that uses robust culture conditions and unravels the dynamics of persister cells through all bacterial growth stages. Our results confirm the importance of (p)ppGpp and Lon but no longer support a role of TA modules in E. coli persister......) modules. This model found considerable support among researchers studying persisters but also generated controversy as part of recent debates in the field. In this study, we therefore used our previous work as a model to critically examine common experimental procedures to understand and overcome......-tolerant persisters via induction of cryptic prophages. Similarly, the inadvertent infection of mutant strains with bacteriophage φ80, a notorious laboratory contaminant, apparently caused several of the phenotypes that we reported in our previous studies. We therefore reconstructed all infected mutants and probed...

  1. Foxp3+ regulatory T cells control persistence of viral CNS infection.

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    Dajana Reuter

    Full Text Available We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically unmodified mice and recombinant measles virus (MV. Using this model infection we investigated the role of regulatory T cells (Tregs as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be modulated by manipulation of Tregs in the periphery. CD4(+ CD25(+ Foxp3(+ Tregs were expanded or depleted during the persistent phase of the CNS infection, and the consequences for the virus-specific immune response and the extent of persistent infection were analyzed. Virus-specific CD8(+ T cells predominantly recognising the H-2D(b-presented viral hemagglutinin epitope MV-H(22-30 (RIVINREHL were quantified in the brain by pentamer staining. Expansion of Tregs after intraperitoneal (i.p. application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT in DEREG (depletion of regulatory T cells-mice induced an increase of virus-specific CD8(+ effector T cells in the brain and caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be utilized to regulate virus persistence in the CNS.

  2. Polypeptide synthesis in alphavirus-infected aedes albopictus cells during the establishment of persistent infection

    International Nuclear Information System (INIS)

    Richardson, M.A.; Boulton, R.W.; Raghow, R.S.; Dalgarno, L.

    1980-01-01

    Polypeptide synthesis was examined in mosquito cells during the establishment of a persistent infection with two alphaviruses, Ross River virus (RRV) and Semliki Forest virus (SFV), and in vertebrate cells cytopathically-infected with the same viruses. In Aedes albopictus cells, RRV reached peak titres at 34-48 hours p.i. At 12 hours 85 per cent of cells assayed as infected by infective centre assay; by 48 hours when persistence was established, virus production was reduced and <5 per cent of cells assayed as infected. There was not shutdown of host polypeptide synthesis during infection. Viral polypeptide synthesis was maximal between 10 and 24 hours p.i. The major viral polypeptides labelled were nucleocapsid protein and envelope protein(s).The precursor polypeptide p95 which was prominent in infected BHK cells was not detected in mosquito cells. Similar results were obtained on SFV infection. During the establishment of persistence there was a coordinate decline in the synthesis of RRV polypeptides, reaching undetectable levels by 72 hours p.i. Subculturing persistently-infected cells led to a small increase in viral polypeptide synthesis and virus titre. In contrast, during RRV growth in BHK cells host protein synthesis was severely inhibited and by 9-11 hours p.i. virus-specific polypeptide synthesis represented more than 90 per cent of total protein synthetic activity. (author)

  3. HTLV-1 Alters T Cells for Viral Persistence and Transmission

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    Azusa Tanaka

    2018-03-01

    Full Text Available Human T-cell leukemia virus type 1 (HTLV-1 was the first retrovirus to be discovered as a causative agent of adult T-cell leukemia-lymphoma (ATL and chronic inflammatory diseases. Two viral factors, Tax and HTLV-1 bZIP factor (HBZ, are thought to be involved in the leukemogenesis of ATL. Tax expression is frequently lost due to DNA methylation in the promoter region, genetic changes to the tax gene, and deletion of the 5′ long terminal repeat (LTR in approximately half of all ATL cases. On the other hand, HBZ is expressed in all ATL cases. HBZ is known to function in both protein form and mRNA form, and both forms play an important role in the oncogenic process of HTLV-1. HBZ protein has a variety of functions, including the suppression of apoptosis, the promotion of proliferation, and the impairment of anti-viral activity, through the interaction with several host cellular proteins including p300/CBP, Foxp3, and Foxo3a. These functions dramatically modify the transcriptional profiling of host T cells. HBZ mRNA also promotes T cell proliferation and viability. HBZ changes infected T cells to CCR4+TIGIT+CD4+ effector/memory T cells. This unique immunophenotype enables T cells to migrate into various organs and tissues and to survive in vivo. In this review, we summarize how HBZ hijacks the transcriptional networks and immune systems of host T cells to contribute to HTLV-1 pathogenesis on the basis of recent new findings about HBZ and tax.

  4. Zika Virus Persistently Infects and Is Basolaterally Released from Primary Human Brain Microvascular Endothelial Cells

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    Megan C. Mladinich

    2017-07-01

    Full Text Available Zika virus (ZIKV is a mosquito-borne Flavivirus that has emerged as the cause of encephalitis and fetal microencephaly in the Americas. ZIKV uniquely persists in human bodily fluids for up to 6 months, is sexually transmitted, and traverses the placenta and the blood-brain barrier (BBB to damage neurons. Cells that support persistent ZIKV replication and mechanisms by which ZIKV establishes persistence remain enigmatic but central to ZIKV entry into protected neuronal compartments. The endothelial cell (EC lining of capillaries normally constrains transplacental transmission and forms the BBB, which selectively restricts access of blood constituents to neurons. We found that ZIKV (strain PRVABC59 persistently infects and continuously replicates in primary human brain microvascular ECs (hBMECs, without cytopathology, for >9 days and following hBMEC passage. ZIKV did not permeabilize hBMECs but was released basolaterally from polarized hBMECs, suggesting a direct mechanism for ZIKV to cross the BBB. ZIKV-infected hBMECs were rapidly resistant to alpha interferon (IFN-α and transiently induced, but failed to secrete, IFN-β and IFN-λ. Global transcriptome analysis determined that ZIKV constitutively induced IFN regulatory factor 7 (IRF7, IRF9, and IFN-stimulated genes (ISGs 1 to 9 days postinfection, despite persistently replicating in hBMECs. ZIKV constitutively induced ISG15, HERC5, and USP18, which are linked to hepatitis C virus (HCV persistence and IFN regulation, chemokine CCL5, which is associated with immunopathogenesis, as well as cell survival factors. Our results reveal that hBMECs act as a reservoir of persistent ZIKV replication, suggest routes for ZIKV to cross hBMECs into neuronal compartments, and define novel mechanisms of ZIKV persistence that can be targeted to restrict ZIKV spread.

  5. The in vivo activation of persistent nanophosphors for optical imaging of vascularization, tumours and grafted cells

    Science.gov (United States)

    Maldiney, Thomas; Bessière, Aurélie; Seguin, Johanne; Teston, Eliott; Sharma, Suchinder K.; Viana, Bruno; Bos, Adrie J. J.; Dorenbos, Pieter; Bessodes, Michel; Gourier, Didier; Scherman, Daniel; Richard, Cyrille

    2014-04-01

    Optical imaging for biological applications requires more sensitive tools. Near-infrared persistent luminescence nanoparticles enable highly sensitive in vivo optical detection and complete avoidance of tissue autofluorescence. However, the actual generation of persistent luminescence nanoparticles necessitates ex vivo activation before systemic administration, which prevents long-term imaging in living animals. Here, we introduce a new generation of optical nanoprobes, based on chromium-doped zinc gallate, whose persistent luminescence can be activated in vivo through living tissues using highly penetrating low-energy red photons. Surface functionalization of this photonic probe can be adjusted to favour multiple biomedical applications such as tumour targeting. Notably, we show that cells can endocytose these nanoparticles in vitro and that, after intravenous injection, we can track labelled cells in vivo and follow their biodistribution by a simple whole animal optical detection, opening new perspectives for cell therapy research and for a variety of diagnosis applications.

  6. Persistent Inflammation Alters the Function of the Endogenous Brain Stem Cell Compartment

    OpenAIRE

    Pluchino, Stefano; Muzio, Luca; Alfaro-Cervello, Clara; Salani, Giuliana; Porcheri, Cristina; Brambilla, Elena; Cavasinni, Francesca; Bergamaschi, Andrea; Garcia-Verdugo, Jose Manuel; Comi, Giancarlo; Martino, Gianvito; Imitola, Jaime; Deleidi, Michela; Khoury, Samia Joseph

    2008-01-01

    Endogenous neural stem/precursor cells (NPCs) are considered a functional reservoir for promoting tissue homeostasis and repair after injury, therefore regenerative strategies that mobilize these cells have recently been proposed. Despite evidence of increased neurogenesis upon acute inflammatory insults (e.g. ischaemic stroke), the plasticity of the endogenous brain stem cell compartment in chronic CNS inflammatory disorders remains poorly characterized. Here we show that persistent brain in...

  7. Persistence of Yellow Fever vaccine-induced antibodies after cord blood stem cell transplant.

    Science.gov (United States)

    Avelino-Silva, Vivian Iida; Freire, Marcos da Silva; Rocha, Vanderson; Rodrigues, Celso Arrais; Novis, Yana Sarkis; Sabino, Ester C; Kallas, Esper Georges

    2016-04-02

    We report the case of a cord blood haematopoietic stem cell transplant recipient who was vaccinated for Yellow Fever (YF) 7 days before initiating chemotherapy and had persistent YF antibodies more than 3 years after vaccination. Since the stem cell donor was never exposed to wild YF or to the YF vaccine, and our patient was not exposed to YF or revaccinated, this finding strongly suggests the persistence of recipient immunity. We briefly discuss potential consequences of incomplete elimination of recipient's leukocytes following existing haematopoietic cancer treatments.

  8. Persistent pulmonary interstitial emphysema in a case of Langerhans cell histiocytosis

    International Nuclear Information System (INIS)

    Abbey, Pooja; Narula, Mahender K.; Anand, Rama; Chandra, Jagdish

    2014-01-01

    We present the case of a 10-month-old boy with multisystem Langerhans cell histiocytosis showing thin-walled lung cysts along with computed tomography (CT) evidence of persistent pulmonary interstitial emphysema (PPIE), in the absence of pneumothorax or pneumomediastinum. Follow-up CT performed after 6 months demonstrated complete resolution of interstitial emphysema

  9. Redirection to the bone marrow improves T cell persistence and antitumor functions.

    Science.gov (United States)

    Khan, Anjum B; Carpenter, Ben; Santos E Sousa, Pedro; Pospori, Constandina; Khorshed, Reema; Griffin, James; Velica, Pedro; Zech, Mathias; Ghorashian, Sara; Forrest, Calum; Thomas, Sharyn; Gonzalez Anton, Sara; Ahmadi, Maryam; Holler, Angelika; Flutter, Barry; Ramirez-Ortiz, Zaida; Means, Terry K; Bennett, Clare L; Stauss, Hans; Morris, Emma; Lo Celso, Cristina; Chakraverty, Ronjon

    2018-05-01

    A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that redirecting T cells to specialized niches in the BM that support memory differentiation would confer increased therapeutic efficacy. We show that overexpression of chemokine receptor CXCR4 in CD8+ T cells (TCXCR4) enhanced their migration toward vascular-associated CXCL12+ cells in the BM and increased their local engraftment. Increased access of TCXCR4 to the BM microenvironment induced IL-15-dependent homeostatic expansion and promoted the differentiation of memory precursor-like cells with low expression of programmed death-1, resistance to apoptosis, and a heightened capacity to generate polyfunctional cytokine-producing effector cells. Following transfer to lymphoma-bearing mice, TCXCR4 showed a greater capacity for effector expansion and better tumor protection, the latter being independent of changes in trafficking to the tumor bed or local out-competition of regulatory T cells. Thus, redirected homing of T cells to the BM confers increased memory differentiation and antitumor immunity, suggesting an innovative solution to increase the persistence and functions of therapeutic T cells.

  10. Long-term Persistence of Innate Lymphoid Cells in the Gut After Intestinal Transplantation.

    Science.gov (United States)

    Weiner, Joshua; Zuber, Julien; Shonts, Brittany; Yang, Suxiao; Fu, Jianing; Martinez, Mercedes; Farber, Donna L; Kato, Tomoaki; Sykes, Megan

    2017-10-01

    Little is known about innate lymphoid cell (ILC) populations in the human gut, and the turnover of these cells and their subsets after transplantation has not been described. Intestinal samples were taken from 4 isolated intestine and 3 multivisceral transplant recipients at the time of any operative resection, such as stoma closure or revision. ILCs were isolated and analyzed by flow cytometry. The target population was defined as being negative for lineage markers and double-positive for CD45/CD127. Cells were further stained to define ILC subsets and a donor-specific or recipient-specific HLA marker to analyze chimerism. Donor-derived ILCs were found to persist greater than 8 years after transplantation. Additionally, the percentage of cells thought to be lymphoid tissue inducer cells among donor ILCs was far higher than that among recipient ILCs. Our findings demonstrate that donor-derived ILCs persist long-term after transplantation and support the notion that human lymphoid tissue inducer cells may form in the fetus and persist throughout life, as hypothesized in rodents. Correlation between chimerism and rejection, graft failure, and patient survival requires further study.

  11. B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers.

    Science.gov (United States)

    Fukazawa, Yoshinori; Lum, Richard; Okoye, Afam A; Park, Haesun; Matsuda, Kenta; Bae, Jin Young; Hagen, Shoko I; Shoemaker, Rebecca; Deleage, Claire; Lucero, Carissa; Morcock, David; Swanson, Tonya; Legasse, Alfred W; Axthelm, Michael K; Hesselgesser, Joseph; Geleziunas, Romas; Hirsch, Vanessa M; Edlefsen, Paul T; Piatak, Michael; Estes, Jacob D; Lifson, Jeffrey D; Picker, Louis J

    2015-02-01

    Chronic-phase HIV and simian immunodeficiency virus (SIV) replication is reduced by as much as 10,000-fold in elite controllers (ECs) compared with typical progressors (TPs), but sufficient viral replication persists in EC tissues to allow viral sequence evolution and induce excess immune activation. Here we show that productive SIV infection in rhesus monkey ECs, but not TPs, is markedly restricted to CD4(+) follicular helper T (TFH) cells, suggesting that these EC monkeys' highly effective SIV-specific CD8(+) T cells can effectively clear productive SIV infection from extrafollicular sites, but their relative exclusion from B cell follicles prevents their elimination of productively infected TFH cells. CD8(+) lymphocyte depletion in EC monkeys resulted in a dramatic re-distribution of productive SIV infection to non-TFH cells, with restriction of productive infection to TFH cells resuming upon CD8(+) T cell recovery. Thus, B cell follicles constitute 'sanctuaries' for persistent SIV replication in the presence of potent anti-viral CD8(+) T cell responses, potentially complicating efforts to cure HIV infection with therapeutic vaccination or T cell immunotherapy.

  12. Altered T cell memory and effector cell development in chronic lymphatic filarial infection that is independent of persistent parasite antigen.

    Directory of Open Access Journals (Sweden)

    Cathy Steel

    2011-04-01

    Full Text Available Chronic lymphatic filarial (LF infection is associated with suppression of parasite-specific T cell responses that persist even following elimination of infection. While several mechanisms have been implicated in mediating this T cell specific downregulation, a role for alterations in the homeostasis of T effector and memory cell populations has not been explored. Using multiparameter flow cytometry, we investigated the role of persistent filarial infection on the maintenance of T cell memory in patients from the filarial-endemic Cook Islands. Compared to filarial-uninfected endemic normals (EN, microfilaria (mf positive infected patients (Inf had a reduced CD4 central memory (T(CM compartment. In addition, Inf patients tended to have more effector memory cells (T(EM and fewer effector cells (T(EFF than did ENs giving significantly smaller T(EFF:T(EM ratios. These contracted T(CM and T(EFF populations were still evident in patients previously mf+ who had cleared their infection (CLInf. Moreover, the density of IL-7Rα, necessary for T memory cell maintenance (but decreased in T effector cells, was significantly higher on memory cells of Inf and CLInf patients, although there was no evidence for decreased IL-7 or increased soluble IL7-Rα, both possible mechanisms for signaling defects in memory cells. However, effector cells that were present in Inf and CLInf patients had lower percentages of HLA-DR suggesting impaired function. These changes in T cell populations appear to reflect chronicity of infection, as filarial-infected children, despite the presence of active infection, did not show alterations in the frequencies of these T cell phenotypes. These data indicate that filarial-infected patients have contracted T(CM compartments and a defect in effector cell development, defects that persist even following clearance of infection. The fact that these global changes in memory and effector cell compartments do not yet occur in infected children

  13. Tissue-resident memory T cells in tissue homeostasis, persistent infection, and cancer surveillance.

    Science.gov (United States)

    Gebhardt, Thomas; Palendira, Umaimainthan; Tscharke, David C; Bedoui, Sammy

    2018-05-01

    A large proportion of memory T cells disseminated throughout the body are non-recirculating cells whose maintenance and function is regulated by tissue-specific environmental cues. These sessile cells are referred to as tissue-resident memory T (T RM ) cells and similar populations of non-recirculating cells also exist among unconventional T cells and innate lymphocyte cells. The pool of T RM cells is highly diverse with respect to anatomical positioning, phenotype, molecular regulation and effector function. Nevertheless, certain transcriptional programs are shared and appear as important unifying features for the overall population of T RM cells and tissue-resident lymphocytes. It is now widely appreciated that T RM cells are a critical component of our immune defense by acting as peripheral sentinels capable of rapidly mobilizing protective tissue immunity upon pathogen recognition. This function is of particular importance in anatomical sites that are not effectively surveilled by blood-borne memory T cells in absence of inflammation, such as neuronal tissues or epithelial compartments in skin and mucosae. Focusing on the well-characterized subtype of CD8 +  CD69 +  CD103 + T RM cells, we will review current concepts on the generation, persistence and function of T RM cells and will summarize commonly used tools to study these cells. Furthermore, we will discuss accumulating data that emphasize localized T RM responses as an important determinant of tissue homeostasis and immune defense in the context of microbiota-immune interactions, persistent infections and cancer surveillance. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. A pharmacological study of Arabidopsis cell fusion between the persistent synergid and endosperm.

    Science.gov (United States)

    Motomura, Kazuki; Kawashima, Tomokazu; Berger, Frédéric; Kinoshita, Tetsu; Higashiyama, Tetsuya; Maruyama, Daisuke

    2018-01-29

    Cell fusion is a pivotal process in fertilization and multinucleate cell formation. A plant cell is ubiquitously surrounded by a hard cell wall, and very few cell fusions have been observed except for gamete fusions. We recently reported that the fertilized central cell (the endosperm) absorbs the persistent synergid, a highly differentiated cell necessary for pollen tube attraction. The synergid-endosperm fusion (SE fusion) appears to eliminate the persistent synergid from fertilized ovule in Arabidopsis thaliana Here, we analyzed the effects of various inhibitors on SE fusion in an in vitro culture system. Different from other cell fusions, neither disruption of actin polymerization nor protein secretion impaired SE fusion. However, transcriptional and translational inhibitors decreased the SE fusion success rate and also inhibited endosperm division. Failures of SE fusion and endosperm nuclear proliferation were also induced by roscovitine, an inhibitor of cyclin-dependent kinases (CDK). These data indicate unique aspects of SE fusion such as independence of filamentous actin support and the importance of CDK-mediated mitotic control. © 2018. Published by The Company of Biologists Ltd.

  15. Extinct type of human parvovirus B19 persists in tonsillar B cells

    OpenAIRE

    Pyöriä, Lari; Toppinen, Mari; Mantyla, Elina; Hedman, Lea; Aaltonen, Leena-Maija; Vihinen-Ranta, Maija; Ilmarinen, Taru; Soderlund-Venermo, Maria; Hedman, Klaus; Perdomo, Maria

    2017-01-01

    Parvovirus B19 (B19V) DNA persists lifelong in human tissues, but the cell type harbouring it remains unclear. We here explore B19V DNA distribution in B, T and monocyte cell lineages of recently excised tonsillar tissues from 77 individuals with an age range of 2?69 years. We show that B19V DNA is most frequent and abundant among B cells, and within them we find a B19V genotype that vanished from circulation >40 years ago. Since re-infection or re-activation are unlikely with this virus type...

  16. Persistence of Coxsackievirus B4 in pancreatic ductal-like cells results in cellular and viral changes.

    Science.gov (United States)

    Alidjinou, E K; Engelmann, I; Bossu, J; Villenet, C; Figeac, M; Romond, M-B; Sané, F; Hober, D

    2017-10-03

    Although known as cytolytic viruses, group B coxackieviruses (CVB) are able to establish a persistent infection in vitro and in vivo. Viral persistence has been reported as a key mechanism in the pathogenesis of CVB-associated chronic diseases such as type 1 diabetes (T1D). The impact of CVB4 persistence on human pancreas ductal-like cells was investigated. A persistent CVB4 infection was established in ductal-like cells. PDX-1 expression, resistance to CVB4-induced lysis and CAR expression were evaluated. The profile of cellular microRNAs (miRNAs) was investigated through miRNA-sequencing. Viral phenotypic changes were examined, and genomic modifications were assessed by sequencing of the viral genome. The CVB4 persistence in ductal-like cells was productive, with continuous release of infectious particles. Persistently infected cells displayed a resistance to CVB4-induced lysis upon superinfection and expression of PDX-1 and CAR was decreased. These changes were maintained even after virus clearance. The patterns of cellular miRNA expression in mock-infected and in CVB4-persistently infected ductal-like cells were clearly different. The persistent infection-derived virus (PIDV) was still able to induce cytopathic effect but its plaques were smaller than the parental virus. Several mutations appeared in various PIDV genome regions, but amino acid substitutions did not affect the predicted site of interaction with CAR. Cellular and viral changes occur during persistent infection of human pancreas ductal-like cells with CVB4. The persistence of cellular changes even after virus clearance supports the hypothesis of a long-lasting impact of persistent CVB infection on the cells.

  17. Impaired antibody response causes persistence of prototypic T cell-contained virus.

    Directory of Open Access Journals (Sweden)

    Andreas Bergthaler

    2009-04-01

    Full Text Available CD8 T cells are recognized key players in control of persistent virus infections, but increasing evidence suggests that assistance from other immune mediators is also needed. Here, we investigated whether specific antibody responses contribute to control of lymphocytic choriomeningitis virus (LCMV, a prototypic mouse model of systemic persistent infection. Mice expressing transgenic B cell receptors of LCMV-unrelated specificity, and mice unable to produce soluble immunoglobulin M (IgM exhibited protracted viremia or failed to resolve LCMV. Virus control depended on immunoglobulin class switch, but neither on complement cascades nor on Fc receptor gamma chain or Fc gamma receptor IIB. Cessation of viremia concurred with the emergence of viral envelope-specific antibodies, rather than with neutralizing serum activity, and even early nonneutralizing IgM impeded viral persistence. This important role for virus-specific antibodies may be similarly underappreciated in other primarily T cell-controlled infections such as HIV and hepatitis C virus, and we suggest this contribution of antibodies be given consideration in future strategies for vaccination and immunotherapy.

  18. Inhibition of HAS2 induction enhances the radiosensitivity of cancer cells via persistent DNA damage

    International Nuclear Information System (INIS)

    Shen, Yan Nan; Shin, Hyun-Jin; Joo, Hyun-Yoo; Park, Eun-Ran; Kim, Su-Hyeon; Hwang, Sang-Gu; Park, Sang Jun; Kim, Chun-Ho; Lee, Kee-Ho

    2014-01-01

    Highlights: •HAS2 may be a promising target for the radiosensitization of human cancer. •HAS2 is elevated (up to ∼10-fold) in irradiated radioresistant and -sensitive cancer cells. •HAS2 knockdown sensitizes cancer cells to radiation. •HAS2 knockdown potentiates irradiation-induced DNA damage and apoptotic death. •Thus, the irradiation-induced up-regulation of HAS2 contributes to the radioresistance of cancer cells. -- Abstract: Hyaluronan synthase 2 (HAS2), a synthetic enzyme for hyaluronan, regulates various aspects of cancer progression, including migration, invasion and angiogenesis. However, the possible association of HAS2 with the response of cancer cells to anticancer radiotherapy, has not yet been elucidated. Here, we show that HAS2 knockdown potentiates irradiation-induced DNA damage and apoptosis in cancer cells. Upon exposure to radiation, all of the tested human cancer cell lines exhibited marked (up to 10-fold) up-regulation of HAS2 within 24 h. Inhibition of HAS2 induction significantly reduced the survival of irradiated radioresistant and -sensitive cells. Interestingly, HAS2 depletion rendered the cells to sustain irradiation-induced DNA damage, thereby leading to an increase of apoptotic death. These findings indicate that HAS2 knockdown sensitizes cancer cells to radiation via persistent DNA damage, further suggesting that the irradiation-induced up-regulation of HAS2 contributes to the radioresistance of cancer cells. Thus, HAS2 could potentially be targeted for therapeutic interventions aimed at radiosensitizing cancer cells

  19. Persistence and Adaptation in Immunity: T Cells Balance the Extent and Thoroughness of Search.

    Directory of Open Access Journals (Sweden)

    G Matthew Fricke

    2016-03-01

    Full Text Available Effective search strategies have evolved in many biological systems, including the immune system. T cells are key effectors of the immune response, required for clearance of pathogenic infection. T cell activation requires that T cells encounter antigen-bearing dendritic cells within lymph nodes, thus, T cell search patterns within lymph nodes may be a crucial determinant of how quickly a T cell immune response can be initiated. Previous work suggests that T cell motion in the lymph node is similar to a Brownian random walk, however, no detailed analysis has definitively shown whether T cell movement is consistent with Brownian motion. Here, we provide a precise description of T cell motility in lymph nodes and a computational model that demonstrates how motility impacts T cell search efficiency. We find that both Brownian and Lévy walks fail to capture the complexity of T cell motion. Instead, T cell movement is better described as a correlated random walk with a heavy-tailed distribution of step lengths. Using computer simulations, we identify three distinct factors that contribute to increasing T cell search efficiency: 1 a lognormal distribution of step lengths, 2 motion that is directionally persistent over short time scales, and 3 heterogeneity in movement patterns. Furthermore, we show that T cells move differently in specific frequently visited locations that we call "hotspots" within lymph nodes, suggesting that T cells change their movement in response to the lymph node environment. Our results show that like foraging animals, T cells adapt to environmental cues, suggesting that adaption is a fundamental feature of biological search.

  20. Persistence and Adaptation in Immunity: T Cells Balance the Extent and Thoroughness of Search

    Science.gov (United States)

    Fricke, G. Matthew; Letendre, Kenneth A.; Moses, Melanie E.; Cannon, Judy L.

    2016-01-01

    Effective search strategies have evolved in many biological systems, including the immune system. T cells are key effectors of the immune response, required for clearance of pathogenic infection. T cell activation requires that T cells encounter antigen-bearing dendritic cells within lymph nodes, thus, T cell search patterns within lymph nodes may be a crucial determinant of how quickly a T cell immune response can be initiated. Previous work suggests that T cell motion in the lymph node is similar to a Brownian random walk, however, no detailed analysis has definitively shown whether T cell movement is consistent with Brownian motion. Here, we provide a precise description of T cell motility in lymph nodes and a computational model that demonstrates how motility impacts T cell search efficiency. We find that both Brownian and Lévy walks fail to capture the complexity of T cell motion. Instead, T cell movement is better described as a correlated random walk with a heavy-tailed distribution of step lengths. Using computer simulations, we identify three distinct factors that contribute to increasing T cell search efficiency: 1) a lognormal distribution of step lengths, 2) motion that is directionally persistent over short time scales, and 3) heterogeneity in movement patterns. Furthermore, we show that T cells move differently in specific frequently visited locations that we call “hotspots” within lymph nodes, suggesting that T cells change their movement in response to the lymph node environment. Our results show that like foraging animals, T cells adapt to environmental cues, suggesting that adaption is a fundamental feature of biological search. PMID:26990103

  1. Human T cell aging and the impact of persistent viral infections

    Directory of Open Access Journals (Sweden)

    Tamas eFulop

    2013-09-01

    Full Text Available Aging is associated with a dysregulation of the immune response, loosely termed immunosenescence. Each part of the immune system is influenced to some extent by the aging process. However, adaptive immunity seems more extensively affected and among all participating cells it is the T cells that are most altered. There is a large body of experimental work devoted to the investigation of age-associated differences in T cell phenotypes and functions in young and old individuals, but few longitudinal studies in humans actually delineating changes at the level of the individual. In most studies, the number and proportion of late-differentiated T cells, especially CD8+ T cells, is reported to be higher in the elderly than in the young. Limited longitudinal studies suggest that accumulation of these cells is a dynamic process and does indeed represent an age-associated change. Accumulations of such late-stage cells may contribute to the enhanced systemic pro-inflammatory milieu commonly seen in older people. We do not know exactly what causes these observed changes, but an understanding of the possible causes is now beginning to emerge. A favored hypothesis is that these events are at least partly due to the effects of the maintenance of essential immune surveillance against persistent viral infections, notably Cytomegalovirus (CMV, which may exhaust the immune system over time. It is still a matter of debate as to whether these changes are compensatory and beneficial or pathological and detrimental to the proper functioning of the immune system and whether they impact longevity. Here, we will review present knowledge of T cell changes with aging and their relation to chronic viral and possibly other persistent infections.

  2. Effect of Apoptotic Cell Recognition on Macrophage Polarization and Mycobacterial Persistence

    Science.gov (United States)

    de Oliveira Fulco, Tatiana; Andrade, Priscila Ribeiro; de Mattos Barbosa, Mayara Garcia; Pinto, Thiago Gomes Toledo; Ferreira, Paula Fernandez; Ferreira, Helen; da Costa Nery, José Augusto; Real, Suzana Côrte; Borges, Valéria Matos; Moraes, Milton Ozório; Sarno, Euzenir Nunes; Sampaio, Elizabeth Pereira

    2014-01-01

    Intracellular Mycobacterium leprae infection modifies host macrophage programming, creating a protective niche for bacterial survival. The milieu regulating cellular apoptosis in the tissue plays an important role in defining susceptible and/or resistant phenotypes. A higher density of apoptotic cells has been demonstrated in paucibacillary leprosy lesions than in multibacillary ones. However, the effect of apoptotic cell removal on M. leprae-stimulated cells has yet to be fully elucidated. In this study, we investigated whether apoptotic cell removal (efferocytosis) induces different phenotypes in proinflammatory (Mϕ1) and anti-inflammatory (Mϕ2) macrophages in the presence of M. leprae. We stimulated Mϕ1 and Mϕ2 cells with M. leprae in the presence or absence of apoptotic cells and subsequently evaluated the M. leprae uptake, cell phenotype, and cytokine pattern in the supernatants. In the presence of M. leprae and apoptotic cells, Mϕ1 macrophages changed their phenotype to resemble the Mϕ2 phenotype, displaying increased CD163 and SRA-I expression as well as higher phagocytic capacity. Efferocytosis increased M. leprae survival in Mϕ1 cells, accompanied by reduced interleukin-15 (IL-15) and IL-6 levels and increased transforming growth factor beta (TGF-β) and IL-10 secretion. Mϕ1 cells primed with M. leprae in the presence of apoptotic cells induced the secretion of Th2 cytokines IL-4 and IL-13 in autologous T cells compared with cultures stimulated with M. leprae or apoptotic cells alone. Efferocytosis did not alter the Mϕ2 cell phenotype or cytokine secretion profile, except for TGF-β. Based on these data, we suggest that, in paucibacillary leprosy patients, efferocytosis contributes to mycobacterial persistence by increasing the Mϕ2 population and sustaining the infection. PMID:25024361

  3. Basic Fibroblast Growth Factor Regulates Persistent ERK Osciliations in Premaligant but not Malignant JB6 Cells

    Energy Technology Data Exchange (ETDEWEB)

    Weber, Thomas J.; Shankaran, Harish; Wiley, H. S.; Opresko, Lee K.; Chrisler, William B.; Quesenberry, Ryan D.

    2010-05-02

    basic fibroblast growth factor (bFGF or FGF2) plays an important role in epidermal wound healing in vivo and is associated with a persistent increased in the extracellular signal-regulated kinase (ERK) pathway in vitro. Here we have examined whether bFGF induces the closure of an experimental scratch wound in JB6 mouse epidermal cells and have explored the regulation of the ERK pathway by bFGF in the context of kinase oscillations. bFGF stimulation is associated with increases in cellular phospho-ERK and phospho-c-Jun levels. In addition, bFGF increases cell proliferation and a change in cell morphology (stellate appearance) in a dose-dependent fashion (0.1 – 100 ng/ml). bFGF treatment also promoted the closure of an experimental scratch wound in vitro. JB6 cells were stably transfected with an ERK1-GFP chimera to follow temporal ERK subcellular distribution patterns. We observe a persistent upregulation of the ERK pathway, as evidenced by a significant increase in nuclear ERK1-GFP levels at time points up to 24 hr after bFGF treatment. Interestingly, at the single cell level, ERK is observed to oscillate between nuclear and cytosolic compartments in response to bFGF treatment. Because this oscillatory behavior is asynchronous in the cell population, it is only clearly resolved at the single cell level. Collectively, data presented here are consistent with an important role for bFGF in wound healing and suggest a more complex regulation of the ERK pathway by bFGF than has previously been appreciated.

  4. Listeria monocytogenes switches from dissemination to persistence by adopting a vacuolar lifestyle in epithelial cells

    Science.gov (United States)

    Mitchell, Gabriel

    2017-01-01

    Listeria monocytogenes causes listeriosis, a foodborne disease that poses serious risks to fetuses, newborns and immunocompromised adults. This intracellular bacterial pathogen proliferates in the host cytosol and exploits the host actin polymerization machinery to spread from cell-to-cell and disseminate in the host. Here, we report that during several days of infection in human hepatocytes or trophoblast cells, L. monocytogenes switches from this active motile lifestyle to a stage of persistence in vacuoles. Upon intercellular spread, bacteria gradually stopped producing the actin-nucleating protein ActA and became trapped in lysosome-like vacuoles termed Listeria-Containing Vacuoles (LisCVs). Subpopulations of bacteria resisted degradation in LisCVs and entered a slow/non-replicative state. During the subculture of host cells harboring LisCVs, bacteria showed a capacity to cycle between the vacuolar and the actin-based motility stages. When ActA was absent, such as in ΔactA mutants, vacuolar bacteria parasitized host cells in the so-called “viable but non-culturable” state (VBNC), preventing their detection by conventional colony counting methods. The exposure of infected cells to high doses of gentamicin did not trigger the formation of LisCVs, but selected for vacuolar and VBNC bacteria. Together, these results reveal the ability of L. monocytogenes to enter a persistent state in a subset of epithelial cells, which may favor the asymptomatic carriage of this pathogen, lengthen the incubation period of listeriosis, and promote bacterial survival during antibiotic therapy. PMID:29190284

  5. Decreased Siglec-9 Expression on Natural Killer Cell Subset Associated With Persistent HBV Replication

    Directory of Open Access Journals (Sweden)

    Di Zhao

    2018-05-01

    Full Text Available Siglec-9 is an MHC-independent inhibitory receptor selectively expressed on CD56dim NK cells. Its role in infection diseases has not been investigated yet. Here, we studied the potential regulatory roles of NK Siglec-9 in the pathogenesis of chronic hepatitis B (CHB infection. Flow cytometry evaluated the expression of Siglec-9 and other receptors on peripheral NK cells. Immunofluorescence staining was used to detect Siglec-9 ligands on liver biopsy tissues and cultured hepatocyte cell lines. Siglec-9 blocking assay was carried out and cytokine synthesis and CD107a degranulation was detected by flow cytometry. Compared to healthy donors, CHB patients had decreased Siglec-9+ NK cells, which reversely correlated with serum hepatitis B e antigen and HBV DNA titer. Siglec-9 expression on NK cells from patients achieving sustained virological response recovered to the level of normal donors. Neutralization of Siglec-9 restored cytokine synthesis and degranulation of NK cells from CHB patients. Immunofluorescence staining showed increased expression of Siglec-9 ligands in liver biopsy tissues from CHB patients and in hepatocyte cell lines infected with HBV or stimulated with inflammatory cytokines (IL-6 or TGF-β. These findings identify Siglec-9 as a negative regulator for NK cells contributing to HBV persistence and the intervention of Siglec-9 signaling might be of potentially translational significance.

  6. Local Inflammatory Cues Regulate Differentiation and Persistence of CD8+ Tissue-Resident Memory T Cells

    Directory of Open Access Journals (Sweden)

    Tessa Bergsbaken

    2017-04-01

    Full Text Available Many pathogens initiate infection at mucosal surfaces, and tissue-resident memory T (Trm cells play an important role in protective immunity, yet the tissue-specific signals that regulate Trm differentiation are poorly defined. During Yersinia infection, CD8+ T cell recruitment to areas of inflammation within the intestine is required for differentiation of the CD103−CD69+ Trm subset. Intestinal proinflammatory microenvironments have elevated interferon (IFN-β and interleukin-12 (IL-12, which regulated Trm markers, including CD103. Type I interferon-receptor- or IL-12-receptor-deficient T cells functioned similarly to wild-type (WT cells during infection; however, the inability of T cells to respond to inflammation resulted in defective differentiation of CD103−CD69+ Trm cells and reduced Trm persistence. Intestinal macrophages were the main producers of IFN-β and IL-12 during infection, and deletion of CCR2+ IL-12-producing cells reduced the size of the CD103− Trm population. These data indicate that intestinal inflammation drives phenotypic diversity and abundance of Trm cells for optimal tissue-specific immunity.

  7. Quorum Sensing-Regulated Phenol-Soluble Modulins Limit Persister Cell Populations in Staphylococcus aureus

    DEFF Research Database (Denmark)

    Bojer, Martin S; Lindemose, Søren; Vestergaard, Martin

    2018-01-01

    Incomplete killing of bacterial pathogens by antibiotics is an underlying cause of treatment failure and accompanying complications. Among those avoiding chemotherapy are persisters being individual cells in a population that for extended periods of time survive high antibiotic concentrations...... proposedly by being in a quiescent state refractory to antibiotic killing. While investigating the human pathogenStaphylococcus aureusand the influence of growth phase on persister formation, we noted that spent supernatants of stationary phase cultures ofS. aureusorS. epidermidis, but not of distantly...... related bacteria, significantly reduced the persister cell frequency upon ciprofloxacin challenge when added to exponentially growing and stationary phaseS. aureuscells. Curiously, the persister reducing activity ofS. aureussupernatants was also effective against persisters formed by eitherS. carnosusor...

  8. Genetic relationship of lactation persistency with milk yield, somatic cell score, reproductive traits, and longevity in Slovak Holstein cattle

    OpenAIRE

    Strapáková, Eva; Candrák, Juraj; Strapák, Peter

    2016-01-01

    The objective of this study was to estimate the breeding values (BVs) of lactation persistency, the test day of milk yield, the somatic cell score, reproductive traits (calving interval, days open), longevity in Slovak Holstein dairy cattle. BVs were used for the detection of relationships among the persistency of lactation and other selected traits. Data for the estimation of BVs of milk production and somatic cell score were collected from 855 240 cows. BVs for reproductive t...

  9. Persisting fetal clonotypes influence the structure and overlap of adult human T cell receptor repertoires.

    Directory of Open Access Journals (Sweden)

    Mikhail V Pogorelyy

    2017-07-01

    Full Text Available The diversity of T-cell receptors recognizing foreign pathogens is generated through a highly stochastic recombination process, making the independent production of the same sequence rare. Yet unrelated individuals do share receptors, which together constitute a "public" repertoire of abundant clonotypes. The TCR repertoire is initially formed prenatally, when the enzyme inserting random nucleotides is downregulated, producing a limited diversity subset. By statistically analyzing deep sequencing T-cell repertoire data from twins, unrelated individuals of various ages, and cord blood, we show that T-cell clones generated before birth persist and maintain high abundances in adult organisms for decades, slowly decaying with age. Our results suggest that large, low-diversity public clones are created during pre-natal life, and survive over long periods, providing the basis of the public repertoire.

  10. Design approach for solar cell and battery of a persistent solar powered GPS tracker

    Science.gov (United States)

    Sahraei, Nasim; Watson, Sterling M.; Pennes, Anthony; Marius Peters, Ian; Buonassisi, Tonio

    2017-08-01

    Sensors with wireless communication can be powered by photovoltaic (PV) devices. However, using solar power requires thoughtful design of the power system, as well as a careful management of the power consumption, especially for devices with cellular communication (because of their higher power consumption). A design approach can minimize system size, weight, and/or cost, while maximizing device performance (data transmission rate and persistence). In this contribution, we describe our design approach for a small form-factor, solar-powered GPS tracker with cellular communication. We evaluate the power consumption of the device in different stages of operation. Combining measured power consumption and the calculated energy-yield of a solar cell, we estimate the battery capacity and solar cell area required for 5 years of continuous operation. We evaluate trade-offs between PV and battery size by simulating the battery state of charge. The data show a trade-off between battery capacity and solar-cell area for given target data transmission rate and persistence. We use this analysis to determine the combination of solar panel area and battery capacity for a given application and the data transmission rate that results in minimum cost or total weight of the system.

  11. Persistent response of Fanconi anemia haematopoietic stem and progenitor cells to oxidative stress.

    Science.gov (United States)

    Li, Yibo; Amarachintha, Surya; Wilson, Andrew F; Li, Xue; Du, Wei

    2017-06-18

    Oxidative stress is considered as an important pathogenic factor in many human diseases including Fanconi anemia (FA), an inherited bone marrow failure syndrome with extremely high risk of leukemic transformation. Members of the FA protein family are involved in DNA damage and other cellular stress responses. Loss of FA proteins renders cells hypersensitive to oxidative stress and cancer transformation. However, how FA cells respond to oxidative DNA damage remains unclear. By using an in vivo stress-response mouse strain expressing the Gadd45β-luciferase transgene, we show here that haematopoietic stem and progenitor cells (HSPCs) from mice deficient for the FA gene Fanca or Fancc persistently responded to oxidative stress. Mechanistically, we demonstrated that accumulation of unrepaired DNA damage, particularly in oxidative damage-sensitive genes, was responsible for the long-lasting response in FA HSPCs. Furthermore, genetic correction of Fanca deficiency almost completely abolished the persistent oxidative stress-induced G 2 /M arrest and DNA damage response in vivo. Our study suggests that FA pathway is an integral part of a versatile cellular mechanism by which HSPCs respond to oxidative stress.

  12. Persistent expression of BMP-4 in embryonic chick adrenal cortical cells and its role in chromaffin cell development

    Directory of Open Access Journals (Sweden)

    Halbach Oliver

    2008-10-01

    Full Text Available Abstract Background Adrenal chromaffin cells and sympathetic neurons both originate from the neural crest, yet signals that trigger chromaffin development remain elusive. Bone morphogenetic proteins (BMPs emanating from the dorsal aorta are important signals for the induction of a sympathoadrenal catecholaminergic cell fate. Results We report here that BMP-4 is also expressed by adrenal cortical cells throughout chick embryonic development, suggesting a putative role in chromaffin cell development. Moreover, bone morphogenetic protein receptor IA is expressed by both cortical and chromaffin cells. Inhibiting BMP-4 with noggin prevents the increase in the number of tyrosine hydroxylase positive cells in adrenal explants without affecting cell proliferation. Hence, adrenal BMP-4 is likely to induce tyrosine hydroxylase in sympathoadrenal progenitors. To investigate whether persistent BMP-4 exposure is able to induce chromaffin traits in sympathetic ganglia, we locally grafted BMP-4 overexpressing cells next to sympathetic ganglia. Embryonic day 8 chick sympathetic ganglia, in addition to principal neurons, contain about 25% chromaffin-like cells. Ectopic BMP-4 did not increase this proportion, yet numbers and sizes of 'chromaffin' granules were significantly increased. Conclusion BMP-4 may serve to promote specific chromaffin traits, but is not sufficient to convert sympathetic neurons into a chromaffin phenotype.

  13. Interpreting phenotypic antibiotic tolerance and persister cells as evolution via epigenetic inheritance.

    Science.gov (United States)

    Day, Troy

    2016-04-01

    Epigenetic inheritance is the transmission of nongenetic material such as gene expression levels, RNA and other biomolecules from parents to offspring. There is a growing realization that such forms of inheritance can play an important role in evolution. Bacteria represent a prime example of epigenetic inheritance because a large array of cellular components is transmitted to offspring, in addition to genetic material. Interestingly, there is an extensive and growing empirical literature showing that many bacteria can form 'persister' cells that are phenotypically resistant or tolerant to antibiotics, but most of these results are not interpreted within the context of epigenetic inheritance. Instead, persister cells are usually viewed as a genetically encoded bet-hedging strategy that has evolved in response to a fluctuating environment. Here I show, using a relatively simple model, that many of these empirical findings can be more simply understood as arising from a combination of epigenetic inheritance and cellular noise. I therefore suggest that phenotypic drug tolerance in bacteria might represent one of the best-studied examples of evolution under epigenetic inheritance. © 2016 John Wiley & Sons Ltd.

  14. Persistence of human parvovirus B19 in multipotent mesenchymal stromal cells expressing the erythrocyte P antigen: implications for transplantation

    Science.gov (United States)

    Sundin, Mikael; Lindblom, Anna; Örvell, Claes; Barrett, A.John; Sundberg, Berit; Watz, Emma; Wikman, Agneta; Broliden, Kristina; Le Blanc, Katarina

    2014-01-01

    Multipotent mesenchymal stromal cells (MSC) are used to improve the outcome of hematopoietic stem cell transplantation and in regenerative medicine. However, MSC may harbor persistent viruses that may compromise their clinical benefit. Retrospectively screened, 1 of 20 MSC from healthy donors contained parvovirus B19 (B19) DNA. We found that MSC express the B19 receptor (the globoside P antigen) and a co-receptor (Ku 80), and can transmit B19 to bone marrow cells in vitro, suggesting that the virus can persist in the marrow stroma of healthy individuals. Two stem cell transplant patients received the B19 positive MSC as treatment for graft-versus-host disease. Neither developed viremia nor symptomatic B19 infection. These results demonstrate for the first time that persistent B19 in MSC can infect hematopoietic cells and underscore the importance of monitoring B19 transmission by MSC products. PMID:18804048

  15. Persistent STAT3 Activation in Colon Cancer Is Associated with Enhanced Cell Proliferation and Tumor Growth

    Directory of Open Access Journals (Sweden)

    Florian M. Corvinus

    2005-06-01

    Full Text Available Colorectal carcinoma (CRC is a major cause of morbidity and mortality in Western countries. It has so far been molecularly defined mainly by alterations of the Wnt pathway. We show here for the first time that aberrant activities of the signal transducer and activator of transcription STAT3 actively contribute to this malignancy and, thus, are a potential therapeutic target for CRC. Constitutive STAT3 activity was found to be abundant in dedifferentiated cancer cells and infiltrating lymphocytes of CRC samples, but not in non-neoplastic colon epithelium. Cell lines derived from malignant colorectal tumors lost persistent STAT3 activity in culture. However, implantation of colon carcinoma cells into nude mice resulted in restoration of STAT3 activity, suggesting a role of an extracellular stimulus within the tumor microenvironment as a trigger for STAT activation. STAT3 activity in CRC cells triggered through interleukin-6 or through a constitutively active STAT3 mutant promoted cancer cell multiplication, whereas STAT3 inhibition through a dominant-negative variant impaired IL-6-driven proliferation. Blockade of STAT3 activation in CRCderived xenograft tumors slowed down their development, arguing for a contribution of STAT3 to colorectal tumor growth.

  16. Pilot study of a cell phone-based exercise persistence intervention post-rehabilitation for COPD

    Directory of Open Access Journals (Sweden)

    Huong Q Nguyen

    2009-08-01

    Full Text Available Huong Q Nguyen1, Dawn P Gill1, Seth Wolpin1, Bonnie G Steele2, Joshua O Benditt11University of Washington, seattle, WA, USA; 2VA Puget Sound Health Care System, Seattle, WA, USAObjective: To determine the feasibility and efficacy of a six-month, cell phone-based exercise persistence intervention for patients with chronic obstructive pulmonary disease (COPD following pulmonary rehabilitation.Methods: Participants who completed a two-week run-in were randomly assigned to either MOBILE-Coached (n = 9 or MOBILE-Self-Monitored (n = 8. All participants met with a nurse to develop an individualized exercise plan, were issued a pedometer and exercise booklet, and instructed to continue to log their daily exercise and symptoms. MOBILE-Coached also received weekly reinforcement text messages on their cell phones; reports of worsening symptoms were automatically flagged for follow-up. Usability and satisfaction were assessed. Participants completed incremental cycle and six minute walk (6MW tests, wore an activity monitor for 14 days, and reported their health-related quality of life (HRQL at baseline, three, and six months.Results: The sample had a mean age of 68 ± 11 and forced expiratory volume in one second (FEV1 of 40 ± 18% predicted. Participants reported that logging their exercise and symptoms was easy and that keeping track of their exercise helped them remain active. There were no differences between groups over time in maximal workload, 6MW distance, or HRQL (p > 0.05; however, MOBILE-Self-Monitored increased total steps/day whereas MOBILE-Coached logged fewer steps over six months (p = 0.04.Conclusions: We showed that it is feasible to deliver a cell phone-based exercise persistence intervention to patients with COPD post-rehabilitation and that the addition of coaching appeared to be no better than self-monitoring. The latter finding needs to be interpreted with caution since this was a purely exploratory study.Trial registration: Clinical

  17. Regulatory T cell suppressive potency dictates the balance between bacterial proliferation and clearance during persistent Salmonella infection.

    Directory of Open Access Journals (Sweden)

    Tanner M Johanns

    2010-08-01

    Full Text Available The pathogenesis of persistent infection is dictated by the balance between opposing immune activation and suppression signals. Herein, virulent Salmonella was used to explore the role and potential importance of Foxp3-expressing regulatory T cells in dictating the natural progression of persistent bacterial infection. Two distinct phases of persistent Salmonella infection are identified. In the first 3-4 weeks after infection, progressively increasing bacterial burden was associated with delayed effector T cell activation. Reciprocally, at later time points after infection, reductions in bacterial burden were associated with robust effector T cell activation. Using Foxp3(GFP reporter mice for ex vivo isolation of regulatory T cells, we demonstrate that the dichotomy in infection tempo between early and late time points is directly paralleled by drastic changes in Foxp3(+ Treg suppressive potency. In complementary experiments using Foxp3(DTR mice, the significance of these shifts in Treg suppressive potency on infection outcome was verified by enumerating the relative impacts of regulatory T cell ablation on bacterial burden and effector T cell activation at early and late time points during persistent Salmonella infection. Moreover, Treg expression of CTLA-4 directly paralleled changes in suppressive potency, and the relative effects of Treg ablation could be largely recapitulated by CTLA-4 in vivo blockade. Together, these results demonstrate that dynamic regulation of Treg suppressive potency dictates the course of persistent bacterial infection.

  18. Postembryonic Nephrogenesis and Persistence of Six2-Expressing Nephron Progenitor Cells in the Reptilian Kidney

    Science.gov (United States)

    Camarata, Troy; Howard, Alexis; Elsey, Ruth M.; Raza, Sarah; O’Connor, Alice; Beatty, Brian; Conrad, Jack; Solounias, Nikos; Chow, Priscilla; Mukta, Saima; Vasilyev, Aleksandr

    2016-01-01

    New nephron formation (nephrogenesis) ceases in mammals around birth and is completely absent in adults. In contrast, postembryonic nephrogenesis is well documented in the mesonephric kidneys of fishes and amphibians. The transient mesonephros in reptiles (including birds) and mammals is replaced by the metanephros during embryogenesis. Thus, one may speculate that postembryonic nephrogenesis is restricted to the mesonephric kidney. Previous reports have suggested the metanephros of non-avian reptiles (hereafter reptiles) may continually form nephrons throughout life. We investigated the presence of adult nephrogenesis in reptiles by examining adult kidneys from several species including Trachemys scripta, Chrysemys picta, Boa constrictor, Tupinambis tegu, Anolis carolinensis, and Alligator mississipiensis among others. We found that all major reptilian groups (Testudines, Crocodylia, and Squamates) showed the presence of adult nephrogenesis. The total amount of nephrogenesis varied greatly between species with turtles displaying the highest density of nephrogenesis. In contrast, we were unable to detect adult nephrogenesis in monotremes, and in the iguanid A. carolinensis. Nephron progenitor cells express the transcription factor Six2, which in mammals, becomes downregulated as the progenitor cell population is exhausted and nephrogenesis ends. Using the alligator as a model, we were able to detect Six2-positive cap mesenchyme cells in the adult kidney, which spatially correlated with areas of nephrogenesis. These results suggest that the metanephric kidney of reptiles has maintained the ability to continually grow new nephrons during postembryonic life, a process lost early in mammalian evolution, likely due to the persistence of a Six2-expressing progenitor cell population. PMID:27144443

  19. Postembryonic Nephrogenesis and Persistence of Six2-Expressing Nephron Progenitor Cells in the Reptilian Kidney.

    Science.gov (United States)

    Camarata, Troy; Howard, Alexis; Elsey, Ruth M; Raza, Sarah; O'Connor, Alice; Beatty, Brian; Conrad, Jack; Solounias, Nikos; Chow, Priscilla; Mukta, Saima; Vasilyev, Aleksandr

    2016-01-01

    New nephron formation (nephrogenesis) ceases in mammals around birth and is completely absent in adults. In contrast, postembryonic nephrogenesis is well documented in the mesonephric kidneys of fishes and amphibians. The transient mesonephros in reptiles (including birds) and mammals is replaced by the metanephros during embryogenesis. Thus, one may speculate that postembryonic nephrogenesis is restricted to the mesonephric kidney. Previous reports have suggested the metanephros of non-avian reptiles (hereafter reptiles) may continually form nephrons throughout life. We investigated the presence of adult nephrogenesis in reptiles by examining adult kidneys from several species including Trachemys scripta, Chrysemys picta, Boa constrictor, Tupinambis tegu, Anolis carolinensis, and Alligator mississipiensis among others. We found that all major reptilian groups (Testudines, Crocodylia, and Squamates) showed the presence of adult nephrogenesis. The total amount of nephrogenesis varied greatly between species with turtles displaying the highest density of nephrogenesis. In contrast, we were unable to detect adult nephrogenesis in monotremes, and in the iguanid A. carolinensis. Nephron progenitor cells express the transcription factor Six2, which in mammals, becomes downregulated as the progenitor cell population is exhausted and nephrogenesis ends. Using the alligator as a model, we were able to detect Six2-positive cap mesenchyme cells in the adult kidney, which spatially correlated with areas of nephrogenesis. These results suggest that the metanephric kidney of reptiles has maintained the ability to continually grow new nephrons during postembryonic life, a process lost early in mammalian evolution, likely due to the persistence of a Six2-expressing progenitor cell population.

  20. Role of denileukin diftitox in the treatment of persistent or recurrent cutaneous T-cell lymphoma

    International Nuclear Information System (INIS)

    Lansigan, Frederick; Stearns, Diane M; Foss, Francine

    2010-01-01

    Denileukin diftitox (Ontak ® ) is indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL), a rare lymphoproliferative disorder of the skin. Denileukin diftitox was the first fusion protein toxin approved for the treatment of a human disease. This fusion protein toxin combines the IL2 protein with diphtheria toxin, and targets the CD25 subunit of the IL2 receptor, resulting in the unique delivery of a cytocidal agent to CD-25 bearing T-cells. Historically, immunotherapy targeting malignant T-cells including monoclonal antibodies has been largely ineffective as cytocidal agents compared to immunotherapy directed against B-cells such as rituximab. This review will summarize the development of denileukin diftitox, its proposed mechanism of action, the pivotal clinical trials that led to its FDA approval, the improvements in quality of life, and the common toxicities experienced during the treatment of patients with CTCL. CTCL is often a chronic progressive lymphoma requiring the sequential use of treatments such as retinoids, traditional chemotherapy, or biological response modifiers. The incorporation of the immunotoxin denileukin diftitox into the sequential or combinatorial treatment of CTCL will also be addressed

  1. Daikenchuto ameliorates muscle hypercontractility in a murine T-cell-mediated persistent gut motor dysfunction model.

    Science.gov (United States)

    Akiho, Hirotada; Nakamura, Kazuhiko

    2011-01-01

    Low-grade inflammation and immunological alterations are evident in functional gastrointestinal disorders such as irritable bowel syndrome (IBS). We evaluated the effects of daikenchuto (DKT), a pharmaceutical grade Japanese herbal medicine, on the hypercontractility of intestinal smooth muscle persisting after acute inflammation induced by a T-cell-activating anti-CD3 antibody (αCD3). BALB/c mice were injected with αCD3 (12.5 μg, i.p.), and DKT (2.7 g/kg) was administered orally once daily for 1 week. The contraction of isolated small intestinal muscle strips and muscle cells was examined on day 7 after αCD3 injection. The gene and protein expressions in the small intestines were evaluated by real-time PCR and multiplex immunoassays, respectively, on days 1, 3 and 7 after αCD3 injection. αCD3 injection resulted in significant increases in carbachol-evoked contractility in the muscle strips and isolated smooth muscle cells on day 7. DKT ameliorated the αCD3-induced muscle hypercontractility on day 7 in both the muscle strips and smooth muscle cells. αCD3 injection rapidly up- and downregulated the mRNA and protein expressions of pro- and anti-inflammatory cytokines, respectively. Although the influence of DKT on the mRNA expressions was moderate, the protein expressions of IL-13 and IL-17 were significantly decreased. We observed changes in the intestinal muscle contractility in muscle strips and muscle cells following resolution of inflammation in a T-cell-mediated model of enteropathy. The observed modulation of cytokine expression and function by DKT may lead to the development of new pharmacotherapeutic strategies aimed at a wide variety of gut motor dysfunction disorders. Copyright © 2011 S. Karger AG, Basel.

  2. Persistent DNA Damage in Spermatogonial Stem Cells After Fractionated Low-Dose Irradiation of Testicular Tissue

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    Grewenig, Angelika; Schuler, Nadine; Rübe, Claudia E., E-mail: claudia.ruebe@uks.eu

    2015-08-01

    Purpose: Testicular spermatogenesis is extremely sensitive to radiation-induced damage, and even low scattered doses to testis from radiation therapy may pose reproductive risks with potential treatment-related infertility. Radiation-induced DNA double-strand breaks (DSBs) represent the greatest threat to the genomic integrity of spermatogonial stem cells (SSCs), which are essential to maintain spermatogenesis and prevent reproduction failure. Methods and Materials: During daily low-dose radiation with 100 mGy or 10 mGy, radiation-induced DSBs were monitored in mouse testis by quantifying 53 binding protein 1 (53BP-1) foci in SSCs within their stem cell niche. The accumulation of DSBs was correlated with proliferation, differentiation, and apoptosis of testicular germ cell populations. Results: Even very low doses of ionizing radiation arrested spermatogenesis, primarily by inducing apoptosis in spermatogonia. Eventual recovery of spermatogenesis depended on the survival of SSCs and their functional ability to proliferate and differentiate to provide adequate numbers of differentiating spermatogonia. Importantly, apoptosis-resistant SSCs resulted in increased 53BP-1 foci levels during, and even several months after, fractionated low-dose radiation, suggesting that surviving SSCs have accumulated an increased load of DNA damage. Conclusions: SSCs revealed elevated levels of DSBs for weeks after radiation, and if these DSBs persist through differentiation to spermatozoa, this may have severe consequences for the genomic integrity of the fertilizing sperm.

  3. Persistent DNA Damage in Spermatogonial Stem Cells After Fractionated Low-Dose Irradiation of Testicular Tissue

    International Nuclear Information System (INIS)

    Grewenig, Angelika; Schuler, Nadine; Rübe, Claudia E.

    2015-01-01

    Purpose: Testicular spermatogenesis is extremely sensitive to radiation-induced damage, and even low scattered doses to testis from radiation therapy may pose reproductive risks with potential treatment-related infertility. Radiation-induced DNA double-strand breaks (DSBs) represent the greatest threat to the genomic integrity of spermatogonial stem cells (SSCs), which are essential to maintain spermatogenesis and prevent reproduction failure. Methods and Materials: During daily low-dose radiation with 100 mGy or 10 mGy, radiation-induced DSBs were monitored in mouse testis by quantifying 53 binding protein 1 (53BP-1) foci in SSCs within their stem cell niche. The accumulation of DSBs was correlated with proliferation, differentiation, and apoptosis of testicular germ cell populations. Results: Even very low doses of ionizing radiation arrested spermatogenesis, primarily by inducing apoptosis in spermatogonia. Eventual recovery of spermatogenesis depended on the survival of SSCs and their functional ability to proliferate and differentiate to provide adequate numbers of differentiating spermatogonia. Importantly, apoptosis-resistant SSCs resulted in increased 53BP-1 foci levels during, and even several months after, fractionated low-dose radiation, suggesting that surviving SSCs have accumulated an increased load of DNA damage. Conclusions: SSCs revealed elevated levels of DSBs for weeks after radiation, and if these DSBs persist through differentiation to spermatozoa, this may have severe consequences for the genomic integrity of the fertilizing sperm

  4. Persistence of DNA damage following exposure of human bladder cells to chronic monomethylarsonous acid

    International Nuclear Information System (INIS)

    Wnek, S.M.; Medeiros, M.K.; Eblin, K.E.; Gandolfi, A.J.

    2009-01-01

    Malignant transformation was demonstrated in UROtsa cells following 52-weeks of exposure to 50 nM monomethylarsonous acid (MMA III ); the result was the malignantly transformed cell line, URO-MSC. URO-MSC cells were used to study the induction of DNA damage and the alteration of DNA repair enzymes in both the presence of MMA III [URO-MSC(+)] and after subsequent removal of MMA III [URO-MSC(-)] following chronic, low-level exposure. In the presence of MMA III , URO-MSC(+) cells demonstrated a sustained increase in DNA damage following 12-weeks of exposure; in particular, a significant increase in DNA single-strand breaks at 12-weeks of exposure consistently elevated through 52 weeks. The persistence of DNA damage in URO-MSC cells was assessed after a 2-week removal of MMA III . URO-MSC(-) cells demonstrated a decrease in DNA damage compared to URO-MSC(+); however, DNA damage in URO-MSC(-) remained significantly elevated when compared to untreated UROtsa and increased in a time-dependent manner. Reactive oxygen species (ROS) were demonstrated to be a critical component in the generation of DNA damage determined through the incubation of ROS scavengers with URO-MSC cells. Poly (ADP-ribose) polymerase (PARP) is a key repair enzyme in DNA single-strand break repair. URO-MSC(+) resulted in a slight increase in PARP activity after 36-weeks of MMA III exposure, suggesting the presence of MMA III is inhibiting the increase in PARP activity. In support, PARP activity in URO-MSC(-) increased significantly, coinciding with a subsequent decrease in DNA damage demonstrated in URO-MSC(-) compared to URO-MSC(+). These data demonstrate that chronic, low-level exposure of UROtsa cells to 50 nM MMA III results in: the induction of DNA damage that remains elevated upon removal of MMA III ; increased levels of ROS that play a role in MMA III induced-DNA damage; and decreased PARP activity in the presence of MMA III .

  5. Postembryonic Nephrogenesis and Persistence of Six2-Expressing Nephron Progenitor Cells in the Reptilian Kidney.

    Directory of Open Access Journals (Sweden)

    Troy Camarata

    Full Text Available New nephron formation (nephrogenesis ceases in mammals around birth and is completely absent in adults. In contrast, postembryonic nephrogenesis is well documented in the mesonephric kidneys of fishes and amphibians. The transient mesonephros in reptiles (including birds and mammals is replaced by the metanephros during embryogenesis. Thus, one may speculate that postembryonic nephrogenesis is restricted to the mesonephric kidney. Previous reports have suggested the metanephros of non-avian reptiles (hereafter reptiles may continually form nephrons throughout life. We investigated the presence of adult nephrogenesis in reptiles by examining adult kidneys from several species including Trachemys scripta, Chrysemys picta, Boa constrictor, Tupinambis tegu, Anolis carolinensis, and Alligator mississipiensis among others. We found that all major reptilian groups (Testudines, Crocodylia, and Squamates showed the presence of adult nephrogenesis. The total amount of nephrogenesis varied greatly between species with turtles displaying the highest density of nephrogenesis. In contrast, we were unable to detect adult nephrogenesis in monotremes, and in the iguanid A. carolinensis. Nephron progenitor cells express the transcription factor Six2, which in mammals, becomes downregulated as the progenitor cell population is exhausted and nephrogenesis ends. Using the alligator as a model, we were able to detect Six2-positive cap mesenchyme cells in the adult kidney, which spatially correlated with areas of nephrogenesis. These results suggest that the metanephric kidney of reptiles has maintained the ability to continually grow new nephrons during postembryonic life, a process lost early in mammalian evolution, likely due to the persistence of a Six2-expressing progenitor cell population.

  6. Cigarette Smoke-Induced Cell Death Causes Persistent Olfactory Dysfunction in Aged Mice

    Directory of Open Access Journals (Sweden)

    Rumi Ueha

    2018-06-01

    Full Text Available Introduction: Exposure to cigarette smoke is a cause of olfactory dysfunction. We previously reported that in young mice, cigarette smoke damaged olfactory progenitors and decreased mature olfactory receptor neurons (ORNs, then, mature ORNs gradually recovered after smoking cessation. However, in aged populations, the target cells in ORNs by cigarette smoke, the underlying molecular mechanisms by which cigarette smoke impairs the regenerative ORNs, and the degree of ORN regeneration after smoking cessation remain unclear.Objectives: To explore the effects of cigarette smoke on the ORN cell system using an aged mouse model of smoking, and to investigate the extent to which smoke-induced damage to ORNs recovers following cessation of exposure to cigarette smoke in aged mice.Methods: We intranasally administered a cigarette smoke solution (CSS to 16-month-old male mice over 24 days, then examined ORN existence, cell survival, changes of inflammatory cytokines in the olfactory epithelium (OE, and olfaction using histological analyses, gene analyses and olfactory habituation/dishabituation tests.Results: CSS administration reduced the number of mature ORNs in the OE and induced olfactory dysfunction. These changes coincided with an increase in the number of apoptotic cells and Tumor necrosis factor (TNF expression and a decrease in Il6 expression. Notably, the reduction in mature ORNs did not recover even on day 28 after cessation of treatment with CSS, resulting in persistent olfactory dysfunction.Conclusion: In aged mice, by increasing ORN death, CSS exposure could eventually overwhelm the regenerative capacity of the OE, resulting in continued reduction in the number of mature ORNs and olfactory dysfunction.

  7. Persistence of radiation-induced chromosome aberrations in a long-term cell culture.

    Science.gov (United States)

    Duran, Assumpta; Barquinero, Joan Francesc; Caballín, María Rosa; Ribas, Montserrat; Barrios, Leonardo

    2009-04-01

    The aim of the present study was to evaluate the persistence of chromosome aberrations induced by X rays. FISH painting and mFISH techniques were applied to long-term cultures of irradiated cells. With painting, at 2 Gy the frequency of apparently simple translocations remained almost invariable during all the culture, whereas at 4 Gy a rapid decline was observed between the first and the second samples, followed by a slight decrease until the end of the culture. Apparently simple dicentrics and complex aberrations disappeared after the first sample at 2 and 4 Gy. By mFISH, at 2 Gy the frequency of complete plus one-way translocations remained invariable between the first and last sample, but at 4 Gy a 60% decline was observed. True incomplete simple translocations disappeared at 2 and 4 Gy, indicating that incompleteness could be a factor to consider when the persistence of translocations is analyzed. The analysis by mFISH showed that the frequency of complex aberrations and their complexity increased with dose and tended to disappear in the last sample. Our results indicate that the influence of dose on the decrease in the frequency of simple translocations with time postirradiation cannot be fully explained by the disappearance of true incomplete translocations and complex aberrations. The chromosome involvement was random for radiation-induced exchange aberrations and non-random for total aberrations. Chromosome 7 showed the highest deviations from expected, being less and more involved than expected in the first and last samples, respectively. Some preferential chromosome-chromosome associations were observed, including a coincidence with a cluster from radiogenic chromosome aberrations described in other studies.

  8. Understanding effects of matrix protease and matrix organization on directional persistence and translational speed in three-dimensional cell migration.

    Science.gov (United States)

    Zaman, Muhammad H; Matsudaira, Paul; Lauffenburger, Douglas A

    2007-01-01

    Recent studies have shown significant differences in migration mechanisms between two- and three-dimensional environments. While experiments have suggested a strong dependence of in vivo migration on both structure and proteolytic activity, the underlying biophysics of such dependence has not been studied adequately. In addition, the existing models of persistent random walk migration are primarily based on two-dimensional movement and do not account for the effect of proteolysis or matrix inhomogeneity. Using lattice Monte Carlo methods, we present a model to study the role of matrix metallo-proteases (MMPs) on directional persistence and speed. The simulations account for a given cell's ability to deform as well as to digest the matrix as the cell moves in three dimensions. Our results show a bimodal dependence of speed and persistence on matrix pore size and suggest high sensitivity on MMP activity, which is in very good agreement with experimental studies carried out in 3D matrices.

  9. Resting regulatory CD4 T cells: a site of HIV persistence in patients on long-term effective antiretroviral therapy.

    Directory of Open Access Journals (Sweden)

    Tu-Anh Tran

    Full Text Available BACKGROUND: In HIV-infected patients on long-term HAART, virus persistence in resting long-lived CD4 T cells is a major barrier to curing the infection. Cell quiescence, by favouring HIV latency, reduces the risk of recognition and cell destruction by cytotoxic lymphocytes. Several cell-activation-based approaches have been proposed to disrupt cell quiescence and then virus latency, but these approaches have not eradicated the virus. CD4+CD25+ regulatory T cells (Tregs are a CD4+ T-cell subset with particular activation properties. We investigated the role of these cells in virus persistence in patients on long-term HAART. METHODOLOGY/PRINCIPAL FINDINGS: We found evidence of infection of resting Tregs (HLADR(-CD69(-CD25(hiFoxP3+CD4+ T cells purified from patients on prolonged HAART. HIV DNA harbouring cells appear more abundant in the Treg subset than in non-Tregs. The half-life of the Treg reservoir was estimated at 20 months. Since Tregs from patients on prolonged HAART showed hyporesponsiveness to cell activation and inhibition of HIV-specific cytotoxic T lymphocyte-related functions upon activation, therapeutics targeting cell quiescence to induce virus expression may not be appropriate for purging the Treg reservoir. CONCLUSIONS: Our results identify Tregs as a particular compartment within the latent reservoir that may require a specific approach for its purging.

  10. Bacterial biofilm mechanical properties persist upon antibiotic treatment and survive cell death

    International Nuclear Information System (INIS)

    Zrelli, K; Galy, O; Henry, N; Latour-Lambert, P; Ghigo, J M; Beloin, C; Kirwan, L

    2013-01-01

    Bacteria living on surfaces form heterogeneous three-dimensional consortia known as biofilms, where they exhibit many specific properties one of which is an increased tolerance to antibiotics. Biofilms are maintained by a polymeric network and display physical properties similar to that of complex fluids. In this work, we address the question of the impact of antibiotic treatment on the physical properties of biofilms based on recently developed tools enabling the in situ mapping of biofilm local mechanical properties at the micron scale. This approach takes into account the material heterogeneity and reveals the spatial distribution of all the small changes that may occur in the structure. With an Escherichia coli biofilm, we demonstrate using in situ fluorescent labeling that the two antibiotics ofloxacin and ticarcillin—targeting DNA replication and membrane assembly, respectively—induced no detectable alteration of the biofilm mechanical properties while they killed the vast majority of the cells. In parallel, we show that a proteolytic enzyme that cleaves extracellular proteins into short peptides, but does not alter bacterial viability in the biofilm, clearly affects the mechanical properties of the biofilm structure, inducing a significant increase of the material compliance. We conclude that conventional biofilm control strategy relying on the use of biocides targeting cells is missing a key target since biofilm structural integrity is preserved. This is expected to efficiently promote biofilm resilience, especially in the presence of persister cells. In contrast, the targeting of polymer network cross-links—among which extracellular proteins emerge as major players—offers a promising route for the development of rational multi-target strategies to fight against biofilms. (paper)

  11. Bacterial biofilm mechanical properties persist upon antibiotic treatment and survive cell death

    Science.gov (United States)

    Zrelli, K.; Galy, O.; Latour-Lambert, P.; Kirwan, L.; Ghigo, J. M.; Beloin, C.; Henry, N.

    2013-12-01

    Bacteria living on surfaces form heterogeneous three-dimensional consortia known as biofilms, where they exhibit many specific properties one of which is an increased tolerance to antibiotics. Biofilms are maintained by a polymeric network and display physical properties similar to that of complex fluids. In this work, we address the question of the impact of antibiotic treatment on the physical properties of biofilms based on recently developed tools enabling the in situ mapping of biofilm local mechanical properties at the micron scale. This approach takes into account the material heterogeneity and reveals the spatial distribution of all the small changes that may occur in the structure. With an Escherichia coli biofilm, we demonstrate using in situ fluorescent labeling that the two antibiotics ofloxacin and ticarcillin—targeting DNA replication and membrane assembly, respectively—induced no detectable alteration of the biofilm mechanical properties while they killed the vast majority of the cells. In parallel, we show that a proteolytic enzyme that cleaves extracellular proteins into short peptides, but does not alter bacterial viability in the biofilm, clearly affects the mechanical properties of the biofilm structure, inducing a significant increase of the material compliance. We conclude that conventional biofilm control strategy relying on the use of biocides targeting cells is missing a key target since biofilm structural integrity is preserved. This is expected to efficiently promote biofilm resilience, especially in the presence of persister cells. In contrast, the targeting of polymer network cross-links—among which extracellular proteins emerge as major players—offers a promising route for the development of rational multi-target strategies to fight against biofilms.

  12. Circulating immune cell subpopulations in pestivirus persistently infected calves and non-infected calves varying in immune status.

    Science.gov (United States)

    Circulating immune cell subpopulations in cattle representing varying stages of immune status categorized as; colostrum deprived (CD), receiving colostrum (COL), colostrum plus vaccination (VAC) and persistently infected with a pestivirus (PI) were compared. The PI calves were infected with a HoBi-...

  13. Circulating immune cell subpopulations in pestivirus persistently infected calves and non-infected calves varying in immune status [Abstract

    Science.gov (United States)

    The circulating immune cell subpopulations in cattle representing varying stages of immune status categorized as; colostrum deprived (CD), receiving colostrum (COL), colostrum plus vaccination (VAC) and persistently infected with a pestivirus (PI) were compared. The PI calves were infected with a H...

  14. Persistence and dynamics of DNA damage signal amplification determined by microcolony formation and live-cell imaging

    International Nuclear Information System (INIS)

    Oka, Yasuyoshi; Yamauchi, Motohiro; Suzuki, Masatoshi; Yamashita, Shunichi; Suzuki, Keiji

    2011-01-01

    Cell cycle checkpoints are essential cellular process protecting the integrity of the genome from DNA damaging agents. In the present study, we developed a microcolony assay, in which normal human diploid fibroblast-like cells exposed to ionizing radiation, were plated onto coverslips at very low density (3 cells/cm 2 ). Cells were grown for up to 3 days, and phosphorylated ataxia-telangiectasia mutated (ATM) at Ser1981 and 53BP1 foci were analyzed as the markers for an amplified DNA damage signal. We observed a dose-dependent increase in the fraction of non-dividing cells, whose increase was compromised by knocking down p53 expression. While large persistent foci were predominantly formed in non-dividing cells, we observed some growing colonies that contained cells with large foci. As each microcolony was derived from a single cell, it appeared that some cells could proliferate with large foci. A live-imaging analysis using hTERT-immortalized normal human diploid cells transfected with the EGFP-tagged 53BP1 gene revealed that the formation of persistent large foci was highly dynamic. Delayed appearance and disappearance of large foci were frequently observed in exposed cells visualized 12-72 hours after X-irradiation. Thus, our results indicate that amplified DNA damage signal could be ignored, which may be explained in part by the dynamic nature of the amplification process. (author)

  15. In vivo persistence of sister chromatid exchanges (SCE) induced by gamma rays in mouse bone marrow cells

    International Nuclear Information System (INIS)

    Morales-Ramirez, P.; Vallarino-Kelly, T.; Rodriguez-Reyes, R.

    1984-01-01

    The sister chromatid exchange (SCE) frequencies induced in bone marrow cells by in vivo irradiation with gamma rays before or after bromodeoxyuridine (BrdUrd) incorporation were compared. The frequency of SCE at different postirradiation times was also measured in bone marrow cells in vivo, irradiated before BrdUrd incorporation. Increased sensitivity to SCE induction by radiation was found in cells after BrdUrd incorporation for one cycle when compared with cells irradiated before BrdUrd incorporation. The increased SCE frequency persisted for at least 72 hr after the initial irradiation, implying that the gamma ray-induced lesion(s) capable of eliciting an SCE are persistent and cannot be easily repaired

  16. Persistence of sister chromatid exchanges and in vitro morphological transformation of Syrian hamster fetal cells by chemical and physical carcinogens

    International Nuclear Information System (INIS)

    Popescu, N.C.; Amsbaugh, S.C.; DiPaolo, J.A.

    1985-01-01

    The induction of neoplastic cell transformation is closely associated with DNA alterations which occur shortly after carcinogen exposure. Sister chromatid exchange (SCE) formation is a sensitive indicator of carcinogen-DNA interaction and correlates with the induction of morphological cell transformation. The persistence of lesions generating SCE produced by chemical and physical carcinogens and its relevance to the induction of morphologic transformation was evaluated in coordinated experiments with cultured Syrian hamster fetal cells (HFC). Exponentially growing HFC were exposed for 1 h to benzo[a]pyrene (BP), methyl-methanesulfonate (MMS), cis-platinum (II) diaminedichloride (cis Pt II), N-methyl-N'-nitrosourea (MNU), mitomycin C (MMC), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), N-acetoxy-2-fluorenyl-acetamide (AcAAF) or u.v. light irradiated. SCE analysis demonstrates that for a period of 48 h after carcinogen exposure, during which time the cells undergo at least four replicative cycles, DNA damage generating SCE induced by all chemical carcinogens either persisted or was partially removed, whereas u.v.-induced lesions were completely removed. An elevated SCE frequency persisted after two additional cell cycles after treatment with BP, AcAAF or MMC without increased cell lethality as compared to other carcinogens whose lesions were completely eliminated during the same period

  17. A new model of Hantaan virus persistence in mice: the balance between HTNV infection and CD8+ T-cell responses

    International Nuclear Information System (INIS)

    Araki, Koichi; Yoshimatsu, Kumiko; Lee, Byoung-Hee; Kariwa, Hiroaki; Takashima, Ikuo; Arikawa, Jiro

    2004-01-01

    We established a viral persistence model that involves the adoptive transfer of spleen cells from immunocompetent mice (H-2 d ) into Hantaan virus (HTNV)-infected severe combined immunodeficient (SCID, H-2 d ) mice. The infection is maintained despite the presence of neutralizing antibodies, without apparent signs of disease, and there is a correlation between HTNV persistence and the lack of HTNV-specific CD8 + T cells. In addition, disseminated HTNV infection before the initiation of immune responses appears to be important for virus persistence. The suppression of HTNV-specific CD8 + T cells in the present model appears to occur at the periphery. The present study also demonstrates that CD8 + T cells contribute to the clearance of HTNV. Thus, it seems that HTNV-specific CD8 + T cells play a key role in HTNV persistence in mice. This model of viral persistence is useful for studies of immune responses and immunocytotherapy against viral infection

  18. Curing of foot-and-mouth disease virus from persistently infected cells by ribavirin involves enhanced mutagenesis

    International Nuclear Information System (INIS)

    Airaksinen, Antero; Pariente, Nonia; Menendez-Arias, Luis; Domingo, Esteban

    2003-01-01

    BHK-21 cells persistently infected with foot-and-mouth disease virus (FMDV) can be cured of virus by treatment with the antiviral nucleoside analogue ribavirin. To study whether the process involved an increase in the number of mutations in the mutant spectrum of the viral population, viral genomes were cloned from persistently infected cells treated or untreated with ribavirin. An increase of up to 10-fold in mutation frequencies associated with ribavirin treatment was observed in the viral genomes from the treated cultures as compared with parallel, untreated cultures. To address the possible mechanisms of enhanced mutagenesis, we investigated the mutagenic effects of ribavirin together with guanosine, and mycophenolic acid in the presence or absence of guanosine. Changes in the intracellular nucleotide concentrations were determined for all treatments. The results suggest that the increased mutation frequencies were not dependent on nucleotide pool imbalances or due to selection of preexisting genomes but they were produced by a mutagenic action of ribavirin

  19. Nanohybrids with Magnetic and Persistent Luminescence Properties for Cell Labeling, Tracking, In Vivo Real-Time Imaging, and Magnetic Vectorization.

    Science.gov (United States)

    Teston, Eliott; Maldiney, Thomas; Marangon, Iris; Volatron, Jeanne; Lalatonne, Yoann; Motte, Laurence; Boisson-Vidal, Catherine; Autret, Gwennhael; Clément, Olivier; Scherman, Daniel; Gazeau, Florence; Richard, Cyrille

    2018-04-01

    Once injected into a living organism, cells diffuse or migrate around the initial injection point and become impossible to be visualized and tracked in vivo. The present work concerns the development of a new technique for therapeutic cell labeling and subsequent in vivo visualization and magnetic retention. It is hypothesized and subsequently demonstrated that nanohybrids made of persistent luminescence nanoparticles and ultrasmall superparamagnetic iron oxide nanoparticles incorporated into a silica matrix can be used as an effective nanoplatform to label therapeutic cells in a nontoxic way in order to dynamically track them in real-time in vitro and in living mice. As a proof-of-concept, it is shown that once injected, these labeled cells can be visualized and attracted in vivo using a magnet. This first step suggests that these nanohybrids represent efficient multifunctional nanoprobes for further imaging guided cell therapies development. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Reverting antibiotic tolerance of Pseudomonas aeruginosa PAO1 persister cells by (Z-4-bromo-5-(bromomethylene-3-methylfuran-2(5H-one.

    Directory of Open Access Journals (Sweden)

    Jiachuan Pan

    Full Text Available BACKGROUND: Bacteria are well known to form dormant persister cells that are tolerant to most antibiotics. Such intrinsic tolerance also facilitates the development of multidrug resistance through acquired mechanisms. Thus persister cells are a promising target for developing more effective methods to control chronic infections and help prevent the development of multidrug-resistant bacteria. However, control of persister cells is still an unmet challenge. METHODOLOGY/PRINCIPAL FINDINGS: We show in this report that (Z-4-bromo-5-(bromomethylene-3-methylfuran-2(5H-one (BF8 can restore the antibiotic susceptibility of Pseudomonas aeruginosa PAO1 persister cells at growth non-inhibitory concentrations. Persister control by BF8 was found to be effective against both planktonic and biofilm cells of P. aeruginosa PAO1. Interestingly, although BF8 is an inhibitor of quorum sensing (QS in Gram-negative bacteria, the data in this study suggest that the activities of BF8 to revert antibiotic tolerance of P. aeruginosa PAO1 persister cells is not through QS inhibition and may involve other targets. CONCLUSION: BF8 can sensitize P. aeruginosa persister cells to antibiotics.

  1. Induction and Maintenance of CX3CR1-Intermediate Peripheral Memory CD8+ T Cells by Persistent Viruses and Vaccines

    Directory of Open Access Journals (Sweden)

    Claire Louse Gordon

    2018-04-01

    Full Text Available Summary: The induction and maintenance of T cell memory is critical to the success of vaccines. A recently described subset of memory CD8+ T cells defined by intermediate expression of the chemokine receptor CX3CR1 was shown to have self-renewal, proliferative, and tissue-surveillance properties relevant to vaccine-induced memory. We tracked these cells when memory is sustained at high levels: memory inflation induced by cytomegalovirus (CMV and adenovirus-vectored vaccines. In mice, both CMV and vaccine-induced inflationary T cells showed sustained high levels of CX3R1int cells exhibiting an effector-memory phenotype, characteristic of inflationary pools, in early memory. In humans, CX3CR1int CD8+ T cells were strongly induced following adenovirus-vectored vaccination for hepatitis C virus (HCV (ChAd3-NSmut and during natural CMV infection and were associated with a memory phenotype similar to that in mice. These data indicate that CX3CR1int cells form an important component of the memory pool in response to persistent viruses and vaccines in both mice and humans. : Gordon et al. demonstrate that CX3CR1int peripheral memory T cells are a substantial component of memory inflation induced by persistent CMVs and adenoviral vaccination. They are characterized by sustained proliferation and an effector-memory phenotype linked to these expanded CD8+ T cell memory responses. Core phenotypic features are shared by humans and mice. Keywords: cytomegalovirus, T cells, memory, adenovirus, vaccination, CX3CR1, memory inflation, mouse, human

  2. The Immunomodulator VacA Promotes Immune Tolerance and Persistent Helicobacter pylori Infection through Its Activities on T-Cells and Antigen-Presenting Cells

    OpenAIRE

    Djekic, Aleksandra; M?ller, Anne

    2016-01-01

    VacA is a pore-forming toxin that has long been known to induce vacuolization in gastric epithelial cells and to be linked to gastric disorders caused by H. pylori infection. Its role as a major colonization and persistence determinant of H. pylori is less well-understood. The purpose of this review is to discuss the various target cell types of VacA and its mechanism of action; specifically, we focus on the evidence showing that VacA targets myeloid cells and T-cells to directly and indirect...

  3. Demographics of antibiotic persistence

    DEFF Research Database (Denmark)

    Kollerova, Silvia; Jouvet, Lionel; Steiner, Ulrich

    Persister cells, cells that can survive antibiotic exposure but lack heritable antibiotic resistance, are assumed to play a crucial role for the evolution of antibiotic resistance. Persistence is a stage associated with reduced metabolic activity. Most previous studies have been done on batch...... even play a more prominent role for the evolution of resistance and failures of medical treatment by antibiotics as currently assumed....

  4. Persistence of Activated and Adaptive-Like NK Cells in HIV+ Individuals despite 2 Years of Suppressive Combination Antiretroviral Therapy

    Directory of Open Access Journals (Sweden)

    Anna C. Hearps

    2017-06-01

    Full Text Available Innate immune dysfunction persists in HIV+ individuals despite effective combination antiretroviral therapy (cART. We recently demonstrated that an adaptive-like CD56dim NK cell population lacking the signal transducing protein FcRγ is expanded in HIV+ individuals. Here, we analyzed a cohort of HIV+ men who have sex with men (MSM, n = 20 at baseline and following 6, 12, and 24 months of cART and compared them with uninfected MSM (n = 15 to investigate the impact of cART on NK cell dysfunction. Proportions of NK cells expressing markers of early (CD69+ and late (HLA-DR+/CD38+ activation were elevated in cART-naïve HIV+ MSM (p = 0.004 and 0.015, respectively, as were FcRγ− NK cells (p = 0.003. Using latent growth curve modeling, we show that cART did not reduce levels of FcRγ− NK cells (p = 0.115 or activated HLA-DR+/CD38+ NK cells (p = 0.129 but did reduce T cell and monocyte activation (p < 0.001 for all. Proportions of FcRγ− NK cells were not associated with NK cell, T cell, or monocyte activation, suggesting different factors drive CD56dim FcRγ− NK cell expansion and immune activation in HIV+ individuals. While proportions of activated CD69+ NK cells declined significantly on cART (p = 0.003, the rate was significantly slower than the decline of T cell and monocyte activation, indicating a reduced potency of cART against NK cell activation. Our findings indicate that 2 years of suppressive cART have no impact on CD56dim FcRγ− NK cell expansion and that NK cell activation persists after normalization of other immune parameters. This may have implications for the development of malignancies and co-morbidities in HIV+ individuals on cART.

  5. Wnt family genes and their modulation in the ovary-independent and persistent vaginal epithelial cell proliferation and keratinization induced by neonatal diethylstilbestrol exposure in mice

    International Nuclear Information System (INIS)

    Nakamura, Takeshi; Miyagawa, Shinichi; Katsu, Yoshinao; Watanabe, Hajime; Mizutani, Takeshi

    2012-01-01

    Proliferation and differentiation of cells in female reproductive organs, the oviduct, uterus and vagina, are regulated by endogenous estrogen. In utero exposure to a synthetic estrogen, diethylstilbestrol (DES), induces vaginal clear-cell adenocarcinoma in humans. In mice, perinatal exposure to DES results in abnormalities such as polyovular follicles, uterine circular muscle disorganization and persistent vaginal epithelial cell proliferation. We reported the persistent gene expression change such as interleukin-1 (IL-1) related genes, insulin-like growth factor-I (IGF-I) and its downstream signaling in the mouse vagina exposed neonatally to DES. In this study, we found persistent up-regulation of Wnt4 and persistent down-regulation of Wnt11 in the vagina of mice exposed neonatally to DES and estrogen receptor α specific ligand. Also Wnt4 expression in vagina is correlated to the stratification of epithelial cells with the superficial keratinization of vagina, but not epithelial cell stratification only.

  6. Cell-Specific PKM Isoforms Contribute to the Maintenance of Different Forms of Persistent Long-Term Synaptic Plasticity.

    Science.gov (United States)

    Hu, Jiangyuan; Adler, Kerry; Farah, Carole Abi; Hastings, Margaret H; Sossin, Wayne S; Schacher, Samuel

    2017-03-08

    -term plasticity. This study provides evidence that the cell-specific activities of different PKM isoforms generated from PKCs by calpain-mediated cleavage maintain two forms of persistent synaptic plasticity, which are the cellular analogs of two forms of long-term memory. Moreover, we found that the activation of specific calpains depends on the features of the stimuli evoking the different forms of synaptic plasticity. Given the recent controversy over the role of PKMζ maintaining memory, these findings are significant in identifying roles of multiple PKMs in the retention of memory. Copyright © 2017 the authors 0270-6474/17/372746-18$15.00/0.

  7. Persistence of mucosal T-cell responses to herpes simplex virus type 2 in the female genital tract.

    Science.gov (United States)

    Posavad, C M; Zhao, L; Mueller, D E; Stevens, C E; Huang, M L; Wald, A; Corey, L

    2015-01-01

    Relatively little is known about the human T-cell response to herpes simplex virus type 2 (HSV-2) in the female genital tract, a major site of heterosexual HSV-2 acquisition, transmission, and reactivation. In order to understand the role of local mucosal immunity in HSV-2 infection, T-cell lines were expanded from serial cervical cytobrush samples from 30 HSV-2-infected women and examined for reactivity to HSV-2. Approximately 3% of the CD3+ T cells isolated from the cervix were HSV-2 specific and of these, a median of 91.3% were CD4+, whereas a median of 3.9% were CD8+. HSV-2-specific CD4+ T cells expanded from the cervix were not only more frequent than CD8+ T cells but also exhibited greater breadth in terms of antigenic reactivity. T cells directed at the same HSV-2 protein were often detected in serial cervical cytobrush samples and in blood. Thus, broad and persistent mucosal T-cell responses to HSV-2 were detected in the female genital tract of HSV-2+ women suggesting that these cells are resident at the site of HSV-2 infection. Understanding the role of these T cells at this biologically relevant site will be central to the elucidation of adaptive immune mechanisms involved in controlling HSV-2 disease.

  8. Curcumin targets breast cancer stem-like cells with microtentacles that persist in mammospheres and promote reattachment.

    Science.gov (United States)

    Charpentier, Monica S; Whipple, Rebecca A; Vitolo, Michele I; Boggs, Amanda E; Slovic, Jana; Thompson, Keyata N; Bhandary, Lekhana; Martin, Stuart S

    2014-02-15

    Cancer stem-like cells (CSC) and circulating tumor cells (CTC) have related properties associated with distant metastasis, but the mechanisms through which CSCs promote metastasis are unclear. In this study, we report that breast cancer cell lines with more stem-like properties display higher levels of microtentacles (McTN), a type of tubulin-based protrusion of the plasma cell membrane that forms on detached or suspended cells and aid in cell reattachment. We hypothesized that CSCs with large numbers of McTNs would more efficiently attach to distant tissues, promoting metastatic efficiency. The naturally occurring stem-like subpopulation of the human mammary epithelial (HMLE) cell line presents increased McTNs compared with its isogenic non-stem-like subpopulation. This increase was supported by elevated α-tubulin detyrosination and vimentin protein levels and organization. Increased McTNs in stem-like HMLEs promoted a faster initial reattachment of suspended cells that was inhibited by the tubulin-directed drug, colchicine, confirming a functional role for McTNs in stem cell reattachment. Moreover, live-cell confocal microscopy showed that McTNs persist in breast stem cell mammospheres as flexible, motile protrusions on the surface of the mammosphere. Although exposed to the environment, they also function as extensions between adjacent cells along cell-cell junctions. We found that treatment with the breast CSC-targeting compound curcumin rapidly extinguished McTN in breast CSC, preventing reattachment from suspension. Together, our results support a model in which breast CSCs with cytoskeletal alterations that promote McTNs can mediate attachment and metastasis but might be targeted by curcumin as an antimetastatic strategy. ©2013 AACR.

  9. Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS.

    Directory of Open Access Journals (Sweden)

    Anjie Zhen

    2017-12-01

    Full Text Available Chimeric Antigen Receptor (CAR T-cells have emerged as a powerful immunotherapy for various forms of cancer and show promise in treating HIV-1 infection. However, significant limitations are persistence and whether peripheral T cell-based products can respond to malignant or infected cells that may reappear months or years after treatment remains unclear. Hematopoietic Stem/Progenitor Cells (HSPCs are capable of long-term engraftment and have the potential to overcome these limitations. Here, we report the use of a protective CD4 chimeric antigen receptor (C46CD4CAR to redirect HSPC-derived T-cells against simian/human immunodeficiency virus (SHIV infection in pigtail macaques. CAR-containing cells persisted for more than 2 years without any measurable toxicity and were capable of multilineage engraftment. Combination antiretroviral therapy (cART treatment followed by cART withdrawal resulted in lower viral rebound in CAR animals relative to controls, and demonstrated an immune memory-like response. We found CAR-expressing cells in multiple lymphoid tissues, decreased tissue-associated SHIV RNA levels, and substantially higher CD4/CD8 ratios in the gut as compared to controls. These results show that HSPC-derived CAR T-cells are capable of long-term engraftment and immune surveillance. This study demonstrates for the first time the safety and feasibility of HSPC-based CAR therapy in a large animal preclinical model.

  10. Altered growth, differentiation, and responsiveness to epidermal growth factor of human embryonic mesenchymal cells of palate by persistent rubella virus infection

    International Nuclear Information System (INIS)

    Yoneda, T.; Urade, M.; Sakuda, M.; Miyazaki, T.

    1986-01-01

    We previously demonstrated that human embryonic mesenchymal cells derived from the palate (HEMP cells) retain alkaline phosphatase (ALP) content and capacity for collagen synthesis after long-term culture, and their growth is markedly stimulated by epidermal growth factor (EGF). There was a dramatic decrease in ALP content and capacity to synthesize collagen in HEMP cells (HEMP-RV cells) persistently infected with rubella virus (RV). EGF increased ALP activity and decreased collagen synthesis in HEMP cells, whereas EGF showed no effect on these activities in HEMP-RV cells. Growth of HEMP-RV cells was slightly reduced compared with that of HEMP cells. EGF stimulated growth of HEMP cells and to a lesser extent of HEMP-RV cells. Binding of 125 I-EGF to cell-surface receptors in HEMP-RV cells was, to our surprise, twice as much as that in HEMP cells. However, internalization of bound 125 I-EGF in HEMP-RV cells was profoundly diminished. Thus, persistent RV infection causes not only changes in HEMP cell growth and differentiation but a decrease in or loss of HEMP cell responsiveness to EGF. The effects of persistent RV infection on palatal cell differentiation as well as growth may be responsible for the pathogenesis of congenital rubella. Furthermore, since HEMP cells appear to be closely related to osteoblasts, these results suggest a mechanism for RV-induced osseous abnormalities manifested in congenital rubella patients

  11. Lack of CD4+ T cell percent decrease in alemtuzumab-treated multiple sclerosis patients with persistent relapses.

    Science.gov (United States)

    Rolla, Simona; De Mercanti, Stefania Federica; Bardina, Valentina; Horakova, Dana; Habek, Mario; Adamec, Ivan; Cocco, Eleonora; Annovazzi, Pietro; Vladic, Anton; Novelli, Francesco; Durelli, Luca; Clerico, Marinella

    2017-12-15

    Alemtuzumab, a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), induces lymphopenia especially of CD4+ T cells. Here, we report the atypical CD4+ T population behaviour of two patients with persistent disease activity despite repeated alemtuzumab treatments. Whereas lymphocytes count decreased and fluctuated accordingly to alemtuzumab administration, their CD4+ cell percentage was not or just mildly affected and was slightly below the lowest normal limit already before alemtuzumab. These cases anticipate further studies aimed to investigate whether the evaluation of the CD4+ cell percentage could represent a helpful tool to address the individual clinical response to alemtuzumab. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  12. Polarized and persistent Ca²⁺ plumes define loci for formation of wall ingrowth papillae in transfer cells.

    Science.gov (United States)

    Zhang, Hui-Ming; Imtiaz, Mohammad S; Laver, Derek R; McCurdy, David W; Offler, Christina E; van Helden, Dirk F; Patrick, John W

    2015-03-01

    Transfer cell morphology is characterized by a polarized ingrowth wall comprising a uniform wall upon which wall ingrowth papillae develop at right angles into the cytoplasm. The hypothesis that positional information directing construction of wall ingrowth papillae is mediated by Ca(2+) signals generated by spatiotemporal alterations in cytosolic Ca(2+) ([Ca(2+)]cyt) of cells trans-differentiating to a transfer cell morphology was tested. This hypothesis was examined using Vicia faba cotyledons. On transferring cotyledons to culture, their adaxial epidermal cells synchronously trans-differentiate to epidermal transfer cells. A polarized and persistent Ca(2+) signal, generated during epidermal cell trans-differentiation, was found to co-localize with the site of ingrowth wall formation. Dampening Ca(2+) signal intensity, by withdrawing extracellular Ca(2+) or blocking Ca(2+) channel activity, inhibited formation of wall ingrowth papillae. Maintenance of Ca(2+) signal polarity and persistence depended upon a rapid turnover (minutes) of cytosolic Ca(2+) by co-operative functioning of plasma membrane Ca(2+)-permeable channels and Ca(2+)-ATPases. Viewed paradermally, and proximal to the cytosol-plasma membrane interface, the Ca(2+) signal was organized into discrete patches that aligned spatially with clusters of Ca(2+)-permeable channels. Mathematical modelling demonstrated that these patches of cytosolic Ca(2+) were consistent with inward-directed plumes of elevated [Ca(2+)]cyt. Plume formation depended upon an alternating distribution of Ca(2+)-permeable channels and Ca(2+)-ATPase clusters. On further inward diffusion, the Ca(2+) plumes coalesced into a uniform Ca(2+) signal. Blocking or dispersing the Ca(2+) plumes inhibited deposition of wall ingrowth papillae, while uniform wall formation remained unaltered. A working model envisages that cytosolic Ca(2+) plumes define the loci at which wall ingrowth papillae are deposited. © The Author 2014. Published by Oxford

  13. Near Infrared-Emitting Cr3+/Eu3+ Co-doped Zinc Gallogermanate Persistence Luminescent Nanoparticles for Cell Imaging

    Science.gov (United States)

    Wang, Qiaoqiao; Zhang, Shuyun; Li, Zhiwei; Zhu, Qi

    2018-02-01

    Near infrared (NIR)-emitting persistent luminescent nanoparticles have been developed as potential agents for bioimaging. However, synthesizing uniform nanoparticles with long afterglow for long-term imaging is lacking. Here, we demonstrated the synthesis of spinel structured Zn3Ga2Ge2O10:Cr3+ (ZGGO:Cr3+) and Zn3Ga2Ge2O10:Cr3+,Eu3+ (ZGGO:Cr3+,Eu3+) nanoparticles by a sol-gel method in combination with a subsequent reducing atmosphere-free calcination. The samples were investigated via detailed characterizations by combined techniques of XRD, TEM, STEM, selected area electron diffraction, photoluminescence excitation (PLE)/photoluminescence (PL) spectroscopy, and temperature-dependent PL analysis. The single-crystalline nanoparticles are homogeneous solid solution, possessing uniform cubic shape and lateral size of 80-100 nm. Upon UV excitation at 273 nm, ZGGO:Cr3+,Eu3+ exhibited a NIR emission band at 697 nm (2E → 4A2 transition of distorted Cr3+ ions in gallogermanate), in the absence of Eu3+ emission. NIR persistent luminescence of the sample can last longer than 7200 s and still hold intense intensity. Eu3+ incorporation increased the persistent luminescence intensity and the afterglow time of ZGGO:Cr3+, but it did not significantly affect the thermal stability. The obtained ZGGO:Cr3+,Eu3+-NH2 nanoparticles possessed an excellent imaging capacity for cells in vitro.

  14. Persistent human Borna disease virus infection modifies the acetylome of human oligodendroglia cells towards higher energy and transporter levels

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Xia [Shanghai Key Laboratory of Forensic Medicine, Institute of Forensic Science, Ministry of Justice, Shanghai 200063 (China); Liu, Siwen [Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing 400016 (China); Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing 400016 (China); Bode, Liv [Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing 400016 (China); Liu, Chengyu [Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing 400016 (China); Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing 400016 (China); Zhang, Liang [Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing 400016 (China); Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing 400016 (China); Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016 (China); Wang, Xiao [Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing 400016 (China); Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing 400016 (China); Li, Dan [Department of Pathology, Faculty of Basic Medicine, Chongqing Medical University, Chongqing 400016 (China); Lei, Yang [Department of Internal Medicine, University-Town Hospital of Chongqing Medical University, Chongqing 400016 (China); Peng, Xiaojun [Jingjie PTM BioLab (Hangzhou) Co. Ltd, Hangzhou 310018 (China); Cheng, Zhongyi [Advanced Institute of Translational Medicine, Tongji University, Shanghai 200092 (China); and others

    2015-11-15

    Background: Borna disease virus (BDV) is a neurotropic RNA virus persistently infecting mammalian hosts including humans. Lysine acetylation (Kac) is a key protein post-translational modification (PTM). The unexpectedly broad regulatory scope of Kac let us to profile the entire acetylome upon BDV infection. Methods: The acetylome was profiled through stable isotope labeling for cell culture (SILAC)-based quantitative proteomics. The quantifiable proteome was annotated using bioinformatics. Results: We identified and quantified 791 Kac sites in 473 Kac proteins in human BDV Hu-H1-infected and non-infected oligodendroglial (OL) cells. Bioinformatic analysis revealed that BDV infection alters the acetylation of metabolic proteins, membrane-associated proteins and transmembrane transporter activity, and affects the acetylation of several lysine acetyltransferases (KAT). Conclusions: Upon BDV persistence the OL acetylome is manipulated towards higher energy and transporter levels necessary for shuttling BDV proteins to and from nuclear replication sites. - Highlights: • We used SILAC-based proteomics to analyze the acetylome of BDV infected OL cells. • We quantified 791Kac sites in 473 proteins. • Bioinformatic analysis revealed altered acetylation of metabolic proteins et al. • BDV manipulates the OL acetylome towards higher energy and transporter levels. • BDV infection is associated with enriched phosphate-associated metabolic processes.

  15. CD4+ T Cell-derived IL-10 Promotes Brucella abortus Persistence via Modulation of Macrophage Function

    Science.gov (United States)

    Xavier, Mariana N.; Winter, Maria G.; Spees, Alanna M.; Nguyen, Kim; Atluri, Vidya L.; Silva, Teane M. A.; Bäumler, Andreas J.; Müller, Werner; Santos, Renato L.; Tsolis, Renée M.

    2013-01-01

    Evasion of host immune responses is a prerequisite for chronic bacterial diseases; however, the underlying mechanisms are not fully understood. Here, we show that the persistent intracellular pathogen Brucella abortus prevents immune activation of macrophages by inducing CD4+CD25+ T cells to produce the anti-inflammatory cytokine interleukin-10 (IL-10) early during infection. IL-10 receptor (IL-10R) blockage in macrophages resulted in significantly higher NF-kB activation as well as decreased bacterial intracellular survival associated with an inability of B. abortus to escape the late endosome compartment in vitro. Moreover, either a lack of IL-10 production by T cells or a lack of macrophage responsiveness to this cytokine resulted in an increased ability of mice to control B. abortus infection, while inducing elevated production of pro-inflammatory cytokines, which led to severe pathology in liver and spleen of infected mice. Collectively, our results suggest that early IL-10 production by CD25+CD4+ T cells modulates macrophage function and contributes to an initial balance between pro-inflammatory and anti-inflammatory cytokines that is beneficial to the pathogen, thereby promoting enhanced bacterial survival and persistent infection. PMID:23818855

  16. Persistent human Borna disease virus infection modifies the acetylome of human oligodendroglia cells towards higher energy and transporter levels

    International Nuclear Information System (INIS)

    Liu, Xia; Liu, Siwen; Bode, Liv; Liu, Chengyu; Zhang, Liang; Wang, Xiao; Li, Dan; Lei, Yang; Peng, Xiaojun; Cheng, Zhongyi

    2015-01-01

    Background: Borna disease virus (BDV) is a neurotropic RNA virus persistently infecting mammalian hosts including humans. Lysine acetylation (Kac) is a key protein post-translational modification (PTM). The unexpectedly broad regulatory scope of Kac let us to profile the entire acetylome upon BDV infection. Methods: The acetylome was profiled through stable isotope labeling for cell culture (SILAC)-based quantitative proteomics. The quantifiable proteome was annotated using bioinformatics. Results: We identified and quantified 791 Kac sites in 473 Kac proteins in human BDV Hu-H1-infected and non-infected oligodendroglial (OL) cells. Bioinformatic analysis revealed that BDV infection alters the acetylation of metabolic proteins, membrane-associated proteins and transmembrane transporter activity, and affects the acetylation of several lysine acetyltransferases (KAT). Conclusions: Upon BDV persistence the OL acetylome is manipulated towards higher energy and transporter levels necessary for shuttling BDV proteins to and from nuclear replication sites. - Highlights: • We used SILAC-based proteomics to analyze the acetylome of BDV infected OL cells. • We quantified 791Kac sites in 473 proteins. • Bioinformatic analysis revealed altered acetylation of metabolic proteins et al. • BDV manipulates the OL acetylome towards higher energy and transporter levels. • BDV infection is associated with enriched phosphate-associated metabolic processes.

  17. Combined effects of PEG hydrogel elasticity and cell-adhesive coating on fibroblast adhesion and persistent migration.

    Science.gov (United States)

    Missirlis, Dimitris; Spatz, Joachim P

    2014-01-13

    The development and use of synthetic, cross-linked, macromolecular substrates with tunable elasticity has been instrumental in revealing the mechanisms by which cells sense and respond to their mechanical microenvironment. We here describe a hydrogel based on radical-free, cross-linked poly(ethylene glycol) to study the effects of both substrate elasticity and type of adhesive coating on fibroblast adhesion and migration. Hydrogel elasticity was controlled through the structure and concentration of branched precursors, which efficiently react via Michael-type addition to produce the polymer network. We found that cell spreading and focal adhesion characteristics are dependent on elasticity for all types of coatings (RGD peptide, fibronectin, vitronectin), albeit with significant differences in magnitude. Importantly, fibroblasts migrated slower but more persistently on stiffer hydrogels, with the effects being more pronounced on fibronectin-coated substrates. Therefore, our results validate the hydrogels presented in this study as suitable for future mechanosensing studies and indicate that cell adhesion, polarity, and associated migration persistence are tuned by substrate elasticity and biochemical properties.

  18. Persistence of memory B-cell and T-cell responses to the quadrivalent HPV vaccine in HIV-infected children.

    Science.gov (United States)

    Weinberg, Adriana; Huang, Sharon; Moscicki, Anna-Barbara; Saah, Afred; Levin, Myron J

    2018-04-24

    To determine the magnitude and persistence of quadrivalent human papillomavirus (HPV)16 and HPV18 B-cell and T-cell memory after three or four doses of quadrivalent HPV vaccine (QHPV) in HIV-infected children. Seventy-four HIV-infected children immunized with four doses and 23 with three doses of QHPV had HPV16 and HPV18 IgG B-cell and IFNγ and IL2 T-cell ELISPOT performed at 2, 3.5 and 4-5 years after the last dose. HPV16 and HPV18 T-cell responses were similar in both treatment groups, with higher responses to HPV16 vs. HPV18. These HPV T-cell responses correlated with HIV disease characteristics at the study visits. Global T-cell function declined over time as measured by nonspecific mitogenic stimulation. B-cell memory was similar across treatment groups and HPV genotypes. There was a decline in HPV-specific B-cell memory over time that reached statistical significance for HPV16 in the four-dose group. B-cell and T-cell memory did not significantly differ after either three or four doses of QHPV in HIV-infected children. The clinical consequences of decreasing global T-cell function and HPV B-cell memory over time in HIV-infected children requires further investigation.

  19. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer.

    Science.gov (United States)

    Priceman, Saul J; Gerdts, Ethan A; Tilakawardane, Dileshni; Kennewick, Kelly T; Murad, John P; Park, Anthony K; Jeang, Brook; Yamaguchi, Yukiko; Yang, Xin; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E; Wu, Anna M; Brown, Christine E; Forman, Stephen J

    2018-01-01

    Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies.

  20. Mutant human FUS Is ubiquitously mislocalized and generates persistent stress granules in primary cultured transgenic zebrafish cells.

    Directory of Open Access Journals (Sweden)

    Jamie Rae Acosta

    Full Text Available FUS mutations can occur in familial amyotrophic lateral sclerosis (fALS, a neurodegenerative disease with cytoplasmic FUS inclusion bodies in motor neurons. To investigate FUS pathology, we generated transgenic zebrafish expressing GFP-tagged wild-type or fALS (R521C human FUS. Cell cultures were made from these zebrafish and the subcellular localization of human FUS and the generation of stress granule (SG inclusions examined in different cell types, including differentiated motor neurons. We demonstrate that mutant FUS is mislocalized from the nucleus to the cytosol to a similar extent in motor neurons and all other cell types. Both wild-type and R521C FUS localized to SGs in zebrafish cells, demonstrating an intrinsic ability of human FUS to accumulate in SGs irrespective of the presence of disease-associated mutations or specific cell type. However, elevation in relative cytosolic to nuclear FUS by the R521C mutation led to a significant increase in SG assembly and persistence within a sub population of vulnerable cells, although these cells were not selectively motor neurons.

  1. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer

    Science.gov (United States)

    Priceman, Saul J.; Gerdts, Ethan A.; Tilakawardane, Dileshni; Kennewick, Kelly T.; Murad, John P.; Park, Anthony K.; Jeang, Brook; Yamaguchi, Yukiko; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E.; Brown, Christine E.; Forman, Stephen J.

    2018-01-01

    ABSTRACT Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies. PMID:29308300

  2. Rapid Elimination of the Persistent Synergid through a Cell Fusion Mechanism

    KAUST Repository

    Maruyama, Daisuke; Volz, Ronny; Takeuchi, Hidenori; Mori, Toshiyuki; Igawa, Tomoko; Kurihara, Daisuke; Kawashima, Tomokazu; Ueda, Minako; Ito, Masaki; Umeda, Masaaki; Nishikawa, Shuhichi; Groß -Hardt, Rita; Higashiyama, Tetsuya

    2015-01-01

    the endosperm proliferation, preventing attractions of excess number of pollen tubes (polytubey). The synergid-endosperm fusion is induced by fertilization of the central cell, while the egg cell fertilization predominantly activates ethylene signaling

  3. The MqsRA Toxin-Antitoxin System from Xylella fastidiosa Plays a Key Role in Bacterial Fitness, Pathogenicity, and Persister Cell Formation

    Science.gov (United States)

    Merfa, Marcus V.; Niza, Bárbara; Takita, Marco A.; De Souza, Alessandra A.

    2016-01-01

    Through the formation of persister cells, bacteria exhibit tolerance to multidrug and other environmental stresses without undergoing genetic changes. The toxin-antitoxin (TA) systems are involved in the formation of persister cells because they are able to induce cell dormancy. Among the TA systems, the MqsRA system has been observed to be highly induced in persister cells of Xylella fastidiosa (causal agent of citrus variegated chlorosis—CVC) activated by copper stress, and has been described in Escherichia coli as related to the formation of persister cells and biofilms. Thus, we evaluated the role of this TA system in X. fastidiosa by overexpressing the MqsR toxin, and verified that the toxin positively regulated biofilm formation and negatively cell movement, resulting in reduced pathogenicity in citrus plants. The overexpression of MqsR also increased the formation of persister cells under copper stress. Analysis of the gene and protein expression showed that this system likely has an autoregulation mechanism to express the toxin and antitoxin in the most beneficial ratio for the cell to oppose stress. Our results suggest that this TA system plays a key role in the adaptation and survival of X. fastidiosa and reveal new insights into the physiology of phytopathogen-host interactions. PMID:27375608

  4. Systemic BCG immunization induces persistent lung mucosal multifunctional CD4 T(EM cells which expand following virulent mycobacterial challenge.

    Directory of Open Access Journals (Sweden)

    Daryan A Kaveh

    Full Text Available To more closely understand the mechanisms of how BCG vaccination confers immunity would help to rationally design improved tuberculosis vaccines that are urgently required. Given the established central role of CD4 T cells in BCG induced immunity, we sought to characterise the generation of memory CD4 T cell responses to BCG vaccination and M. bovis infection in a murine challenge model. We demonstrate that a single systemic BCG vaccination induces distinct systemic and mucosal populations of T effector memory (T(EM cells in vaccinated mice. These CD4+CD44(hiCD62L(loCD27⁻ T cells concomitantly produce IFN-γ and TNF-α, or IFN-γ, IL-2 and TNF-α and have a higher cytokine median fluorescence intensity MFI or 'quality of response' than single cytokine producing cells. These cells are maintained for long periods (>16 months in BCG protected mice, maintaining a vaccine-specific functionality. Following virulent mycobacterial challenge, these cells underwent significant expansion in the lungs and are, therefore, strongly associated with protection against M. bovis challenge. Our data demonstrate that a persistent mucosal population of T(EM cells can be induced by parenteral immunization, a feature only previously associated with mucosal immunization routes; and that these multifunctional T(EM cells are strongly associated with protection. We propose that these cells mediate protective immunity, and that vaccines designed to increase the number of relevant antigen-specific T(EM in the lung may represent a new generation of TB vaccines.

  5. Melipona quadrifasciata (Hymenoptera: Apidae) fat body persists through metamorphosis with a few apoptotic cells and an increased autophagy.

    Science.gov (United States)

    Santos, Douglas Elias; Azevedo, Dihego Oliveira; Campos, Lúcio Antônio Oliveira; Zanuncio, José Cola; Serrão, José Eduardo

    2015-03-01

    Fat body, typically comprising trophocytes, provides energy during metamorphosis. The fat body can be renewed once the larval phase is complete or recycled and relocated to form the fat body of the adult insect. This study aims to identify the class of programmed cell death that occurs within the fat body cells during the metamorphosis of the stingless bee Melipona quadrifasciata. Using immunodetection techniques, the fat body of the post-defecating larvae and the white-, pink-, brown-, and black-eyed pupae were tested for cleaved caspase-3 and DNA integrity, followed by ultrastructural analysis and identification of autophagy using RT-PCR for the Atg1 gene. The fat body of M. quadrifasciata showed some apoptotic cells positive for cleaved caspase-3, although without DNA fragmentation. During development, the fat body cells revealed an increased number of mitochondria and free ribosomes, in addition to higher amounts of autophagy Atg1 mRNA, than that of the pupae. The fat body of M. quadrifasciata showed few cells which underwent apoptosis, but there was evidence of increased autophagy at the completion of the larval stage. All together, these data show that some fat body cells persist during metamorphosis in the stingless bee M. quadrifasciata.

  6. Whole thorax irradiation of non-human primates induces persistent nuclear damage and gene expression changes in peripheral blood cells.

    Directory of Open Access Journals (Sweden)

    Shanaz A Ghandhi

    Full Text Available We investigated the cytogenetic and gene expression responses of peripheral blood cells of non-human primates (NHP, Macaca mulatta that were whole-thorax irradiated with a single dose of 10 Gy. In this model, partial irradiation of NHPs in the thoracic region (Whole Thorax Lung Irradiation, WTLI allows the study of late radiation-induced lung injury, while avoiding acute radiation syndromes related to hematopoietic and gastrointestinal injury. A transient drop in circulating lymphocytes and platelets was seen by 9 days, followed by elevations in respiratory rate, circulating neutrophils, lymphocytes, and monocytes at 60-100 days, corresponding to computed tomography (CT and histologic evidence of pneumonitis, and elective euthanasia of four animals. To evaluate long-term DNA damage in NHP peripheral blood lymphocytes after 10 Gy WTLI, we used the cytokinesis-block micronucleus (CBMN assay to measure chromosomal aberrations as post-mitotic micronuclei in blood samples collected up to 8 months after irradiation. Regression analysis showed significant induction of micronuclei in NHP blood cells that persisted with a gradual decline over the 8-month study period, suggesting long-term DNA damage in blood lymphocytes after WTLI. We also report transcriptomic changes in blood up to 30 days after WTLI. We isolated total RNA from peripheral blood at 3 days before and then at 2, 5 and 30 days after irradiation. We identified 1187 transcripts that were significantly changed across the 30-day time course. From changes in gene expression, we identified biological processes related to immune responses, which persisted across the 30-day study. Response to oxygen-containing compounds and bacteria were implicated by gene-expression changes at the earliest day 2 and latest, day 30 time-points. Gene expression changes suggest a persistent altered state of the immune system, specifically response to infection, for at least a month after WTLI.

  7. Whole thorax irradiation of non-human primates induces persistent nuclear damage and gene expression changes in peripheral blood cells.

    Science.gov (United States)

    Ghandhi, Shanaz A; Turner, Helen C; Shuryak, Igor; Dugan, Gregory O; Bourland, J Daniel; Olson, John D; Tooze, Janet A; Morton, Shad R; Batinic-Haberle, Ines; Cline, J Mark; Amundson, Sally A

    2018-01-01

    We investigated the cytogenetic and gene expression responses of peripheral blood cells of non-human primates (NHP, Macaca mulatta) that were whole-thorax irradiated with a single dose of 10 Gy. In this model, partial irradiation of NHPs in the thoracic region (Whole Thorax Lung Irradiation, WTLI) allows the study of late radiation-induced lung injury, while avoiding acute radiation syndromes related to hematopoietic and gastrointestinal injury. A transient drop in circulating lymphocytes and platelets was seen by 9 days, followed by elevations in respiratory rate, circulating neutrophils, lymphocytes, and monocytes at 60-100 days, corresponding to computed tomography (CT) and histologic evidence of pneumonitis, and elective euthanasia of four animals. To evaluate long-term DNA damage in NHP peripheral blood lymphocytes after 10 Gy WTLI, we used the cytokinesis-block micronucleus (CBMN) assay to measure chromosomal aberrations as post-mitotic micronuclei in blood samples collected up to 8 months after irradiation. Regression analysis showed significant induction of micronuclei in NHP blood cells that persisted with a gradual decline over the 8-month study period, suggesting long-term DNA damage in blood lymphocytes after WTLI. We also report transcriptomic changes in blood up to 30 days after WTLI. We isolated total RNA from peripheral blood at 3 days before and then at 2, 5 and 30 days after irradiation. We identified 1187 transcripts that were significantly changed across the 30-day time course. From changes in gene expression, we identified biological processes related to immune responses, which persisted across the 30-day study. Response to oxygen-containing compounds and bacteria were implicated by gene-expression changes at the earliest day 2 and latest, day 30 time-points. Gene expression changes suggest a persistent altered state of the immune system, specifically response to infection, for at least a month after WTLI.

  8. Translocation of the B cell receptor to lipid rafts is inhibited in B cells from BLV-infected, persistent lymphocytosis cattle

    International Nuclear Information System (INIS)

    Hamilton, Valerie T.; Stone, Diana M.; Cantor, Glenn H.

    2003-01-01

    Bovine leukemia virus (BLV) infection causes a significant polyclonal expansion of CD5 + , IgM+ B lymphocytes known as persistent lymphocytosis (PL) in approximately 30% of infected cattle. There is evidence that this expanded B cell population has altered signaling, and resistance to apoptosis has been proposed as one mechanism of B cell expansion. In human and murine B cells, antigen binding initiates movement of the B cell receptor (BCR) into membrane microdomains enriched in sphingolipids and cholesterol, termed lipid rafts. Lipid rafts include members of the Src-family kinases and exclude certain phosphatases. Inclusion of the BCR into lipid rafts plays an important role in regulation of early signaling events and subsequent antigen internalization. Viral proteins may also influence signaling events in lipid rafts. Here we demonstrate that the largely CD5 + B cell population in PL cattle has different mobilization and internalization of the BCR when compared to the largely CD5-negative B cells in BLV-negative cattle. Unlike B cells from BLV-negative cattle, the BCR in B cells of BLV-infected, PL cattle resists movement into lipid rafts upon stimulation and is only weakly internalized. Expression of viral proteins as determined by detection of the BLV transmembrane (TM) envelope glycoprotein gp30 did not alter these events in cells from PL cattle. This exclusion of the BCR from lipid rafts may, in part, explain signaling differences seen between B cells of BLV-infected, PL, and BLV-negative cattle and the resistance to apoptosis speculated to contribute to persistent lymphocytosis

  9. Human prosthetic joint infections are associated with myeloid-derived suppressor cells (MDSCs): Implications for infection persistence.

    Science.gov (United States)

    Heim, Cortney E; Vidlak, Debbie; Odvody, Jessica; Hartman, Curtis W; Garvin, Kevin L; Kielian, Tammy

    2017-11-15

    Prosthetic joint infection (PJI) is a devastating complication of joint arthroplasty surgery typified by biofilm formation. Currently, mechanisms whereby biofilms persist and evade immune-mediated clearance in immune competent patients remain largely ill-defined. Therefore, the current study characterized leukocyte infiltrates and inflammatory mediator expression in tissues from patients with PJI compared to aseptic loosening. CD33 + HLA-DR - CD66b + CD14 -/low granulocytic myeloid-derived suppressor cells (G-MDSCs) were the predominant leukocyte population at sites of human PJI compared to aseptic tissues. MDSCs inhibit T cell proliferation, which coincided with reduced T cells in PJIs compared to aseptic tissues. IL-10, IL-6, and CXCL1 were significantly elevated in PJI tissues and have been implicated in MDSC inhibitory activity, expansion, and recruitment, respectively, which may account for their preferential increase in PJIs. This bias towards G-MDSC accumulation during human PJI could account for the chronicity of these infections by preventing the pro-inflammatory, antimicrobial actions of immune effector cells. Animal models of PJI have revealed a critical role for MDSCs and IL-10 in promoting infection persistence; however, whether this population is prevalent during human PJI and across distinct bacterial pathogens remains unknown. This study has identified that granulocytic-MDSC infiltrates are unique to human PJIs caused by distinct bacteria, which are not associated with aseptic loosening of prosthetic joints. Better defining the immune status of human PJIs could lead to novel immune-mediated approaches to facilitate PJI clearance in combination with conventional antibiotics. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  10. Quantitative analysis of the acute and long-term CD4(+) T-cell response to a persistent gammaherpesvirus

    DEFF Research Database (Denmark)

    Christensen, Jan Pravsgaard; Doherty, P C

    1999-01-01

    The murine gammaherpesvirus 68 (MHV-68) replicates in respiratory epithelial cells, where it establishes a persistent, latent infection limited predominantly to B lymphocytes. The virus-specific CD4(+) T-cell response in C57BL/6 mice challenged intranasally with MHV-68 is detected first...... in the mediastinal lymph nodes and then in the cervical lymph nodes and the spleen. The numbers of MHV-68-specific CD4(+) T cells generated in congenic mice homozygous for disruption of the beta2-microglobulin gene tended to be higher, indicating that the absence of the CD8(+) set in this group resulted...... in a compensatory response. The peak frequency within the splenic CD4(+) T-cell population may reach 1:50 in the acute response; it then drops to 1:400 to 1:500 within 4 months and stays at that level in the very long term. Sorting for L-selectin (CD62L) expression established that all virus-specific CD4(+) T cells...

  11. Persistent seropositivity for yellow fever in a previously vaccinated autologous hematopoietic stem cell transplantation recipient.

    Science.gov (United States)

    Hayakawa, Kayoko; Takasaki, Tomohiko; Tsunemine, Hiroko; Kanagawa, Shuzo; Kutsuna, Satoshi; Takeshita, Nozomi; Mawatari, Momoko; Fujiya, Yoshihiro; Yamamoto, Kei; Ohmagari, Norio; Kato, Yasuyuki

    2015-08-01

    The duration of a protective level of yellow fever antibodies after autologous hematopoietic stem cell transplantation in a previously vaccinated person is unclear. The case of a patient who had previously been vaccinated for yellow fever and who remained seropositive for 22 months after autologous peripheral blood stem cell transplantation for malignant lymphoma is described herein. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. Generation of a persistently infected MDBK cell line with natural bovine spongiform encephalopathy (BSE.

    Directory of Open Access Journals (Sweden)

    Dongseob Tark

    Full Text Available Bovine spongiform encephalopathy (BSE is a zoonotic transmissible spongiform encephalopathy (TSE thought to be caused by the same prion strain as variant Creutzfeldt-Jakob disease (vCJD. Unlike scrapie and chronic wasting disease there is no cell culture model allowing the replication of proteinase K resistant BSE (PrPBSE and the further in vitro study of this disease. We have generated a cell line based on the Madin-Darby Bovine Kidney (MDBK cell line over-expressing the bovine prion protein. After exposure to naturally BSE-infected bovine brain homogenate this cell line has shown to replicate and accumulate PrPBSE and maintain infection up to passage 83 after initial challenge. Collectively, we demonstrate, for the first time, that the BSE agent can infect cell lines over-expressing the bovine prion protein similar to other prion diseases. These BSE infected cells will provide a useful tool to facilitate the study of potential therapeutic agents and the diagnosis of BSE.

  13. TCR stimulation strength is inversely associated with establishment of functional brain-resident memory CD8 T cells during persistent viral infection.

    Science.gov (United States)

    Maru, Saumya; Jin, Ge; Schell, Todd D; Lukacher, Aron E

    2017-04-01

    Establishing functional tissue-resident memory (TRM) cells at sites of infection is a newfound objective of T cell vaccine design. To directly assess the impact of antigen stimulation strength on memory CD8 T cell formation and function during a persistent viral infection, we created a library of mouse polyomavirus (MuPyV) variants with substitutions in a subdominant CD8 T cell epitope that exhibit a broad range of efficiency in stimulating TCR transgenic CD8 T cells. By altering a subdominant epitope in a nonstructural viral protein and monitoring memory differentiation of donor monoclonal CD8 T cells in immunocompetent mice, we circumvented potentially confounding changes in viral infection levels, virus-associated inflammation, size of the immunodominant virus-specific CD8 T cell response, and shifts in TCR affinity that may accompany temporal recruitment of endogenous polyclonal cells. Using this strategy, we found that antigen stimulation strength was inversely associated with the function of memory CD8 T cells during a persistent viral infection. We further show that CD8 TRM cells recruited to the brain following systemic infection with viruses expressing epitopes with suboptimal stimulation strength respond more efficiently to challenge CNS infection with virus expressing cognate antigen. These data demonstrate that the strength of antigenic stimulation during recruitment of CD8 T cells influences the functional integrity of TRM cells in a persistent viral infection.

  14. TCR stimulation strength is inversely associated with establishment of functional brain-resident memory CD8 T cells during persistent viral infection.

    Directory of Open Access Journals (Sweden)

    Saumya Maru

    2017-04-01

    Full Text Available Establishing functional tissue-resident memory (TRM cells at sites of infection is a newfound objective of T cell vaccine design. To directly assess the impact of antigen stimulation strength on memory CD8 T cell formation and function during a persistent viral infection, we created a library of mouse polyomavirus (MuPyV variants with substitutions in a subdominant CD8 T cell epitope that exhibit a broad range of efficiency in stimulating TCR transgenic CD8 T cells. By altering a subdominant epitope in a nonstructural viral protein and monitoring memory differentiation of donor monoclonal CD8 T cells in immunocompetent mice, we circumvented potentially confounding changes in viral infection levels, virus-associated inflammation, size of the immunodominant virus-specific CD8 T cell response, and shifts in TCR affinity that may accompany temporal recruitment of endogenous polyclonal cells. Using this strategy, we found that antigen stimulation strength was inversely associated with the function of memory CD8 T cells during a persistent viral infection. We further show that CD8 TRM cells recruited to the brain following systemic infection with viruses expressing epitopes with suboptimal stimulation strength respond more efficiently to challenge CNS infection with virus expressing cognate antigen. These data demonstrate that the strength of antigenic stimulation during recruitment of CD8 T cells influences the functional integrity of TRM cells in a persistent viral infection.

  15. Hydrocephalus in mice following X-irradiation at early gestational stage. Possibly due to persistent deceleration of cell proliferation

    International Nuclear Information System (INIS)

    Aolad, H.M.; Inouye, Minoru; Darmanto, W.; Hayasaka, Shizu; Murata, Yoshiharu

    2000-01-01

    The pathogenesis of X-ray-induced congenital hydrocephalus was studied. Pregnant mice were irradiated at 1.4 Gy on gestational day 7 (G7). Four hours after irradiation, extensive cell death was evident in the neuroepithelium and underlying mesoderm of the head region, and proliferating cell nuclear antigen (PCNA)-immunoreactive cells almost disappeared. Embryos with thinner lamina terminalis of the telecephalon, when compared with that of the control, were found in the irradiated group on G9. As early as G11 in some irradiated embryos the telencephalic wall was thinner and lateral ventricles were larger than those of the control. The choroid invagination from the lamina terminalis began on G11 in the control brain, but not in the affected brain. During the following development, fetuses with readily apparent hydrocephalus were consistently found among irradiated fetuses. In these brains the brain mantle was thinner, the corpus striatum and thalamic regions were smaller, and lateral ventricles were larger than those of the control. Even on G11 and G13 the frequencies of PCNA-positive cells in the brain mantle and other brain regions were lower in the hydrocephalic brain than those of the control, suggesting a decelerated proliferation of successive cell generations following exposure to X-rays. The cerebral aqueduct was open in the hydrocephalic brain during the fetal period when the lateral ventricles were dilated. The head was vaulted after birth but the cerebral aqueduct was not completely occluded even in these animals. These findings suggested that cell death in the neuroepithelium followed by a persistent deceleration of neural cell proliferation, resulting in the hypoplasia of brain parenchyma with compensatory ventricular dilatation, is important for the establishment of hydrocephalus. (author)

  16. Hydrocephalus in mice following X-irradiation at early gestational stage. Possibly due to persistent deceleration of cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Aolad, H.M.; Inouye, Minoru; Darmanto, W.; Hayasaka, Shizu; Murata, Yoshiharu [Nagoya Univ. (Japan). Research Inst. of Environmental Medicine

    2000-09-01

    The pathogenesis of X-ray-induced congenital hydrocephalus was studied. Pregnant mice were irradiated at 1.4 Gy on gestational day 7 (G7). Four hours after irradiation, extensive cell death was evident in the neuroepithelium and underlying mesoderm of the head region, and proliferating cell nuclear antigen (PCNA)-immunoreactive cells almost disappeared. Embryos with thinner lamina terminalis of the telecephalon, when compared with that of the control, were found in the irradiated group on G9. As early as G11 in some irradiated embryos the telencephalic wall was thinner and lateral ventricles were larger than those of the control. The choroid invagination from the lamina terminalis began on G11 in the control brain, but not in the affected brain. During the following development, fetuses with readily apparent hydrocephalus were consistently found among irradiated fetuses. In these brains the brain mantle was thinner, the corpus striatum and thalamic regions were smaller, and lateral ventricles were larger than those of the control. Even on G11 and G13 the frequencies of PCNA-positive cells in the brain mantle and other brain regions were lower in the hydrocephalic brain than those of the control, suggesting a decelerated proliferation of successive cell generations following exposure to X-rays. The cerebral aqueduct was open in the hydrocephalic brain during the fetal period when the lateral ventricles were dilated. The head was vaulted after birth but the cerebral aqueduct was not completely occluded even in these animals. These findings suggested that cell death in the neuroepithelium followed by a persistent deceleration of neural cell proliferation, resulting in the hypoplasia of brain parenchyma with compensatory ventricular dilatation, is important for the establishment of hydrocephalus. (author)

  17. Characterization of Sendai virus persistently infected L929 cells and Sendai virus pi strain: recombinant Sendai viruses having Mpi protein shows lower cytotoxicity and are incapable of establishing persistent infection

    International Nuclear Information System (INIS)

    Nishio, Machiko; Tsurudome, Masato; Ito, Morihiro; Kawano, Mitsuo; Komada, Hiroshi; Ito, Yasuhiko

    2003-01-01

    It is commonly accepted that the temperature-sensitive phenotype of Sendai virus (SeV) persistently infected cells is caused by the M and/or HN proteins. Expression level of the L, M, HN, and V proteins is extremely low in L929 cells persistently infected with SeVpi (L929/SeVpi cells) incubated at 38 deg. C. The HN protein quickly disappears in L929/SeVpi cells following a temperature shift up to 38 deg. C, and pulse-chase experiments show that the Lpi, HNpi, and Mpi proteins are unstable at 38 deg. C. Following a temperature shift either upward or downward, M protein is translocated into the nucleus and then localizes to the perinuclear region. None of virus-specific polypeptides are detected in the cells primarily infected with SeVpi and incubated at 38 deg. C and virus proteins are not pulse-labeled at 38 deg. C, indicating that temperature-sensitive step is at an early stage of infection. The Mpi protein is transiently located in the nucleus of the SeVpi primarily infected cells. Recombinant SeVs possessing the HNpi or/and Mpi proteins are not temperature-sensitive. The HN protein is expressed at very low levels and the F protein localizes to the perinuclear region in rSeV(Mpi)-infected cells incubated at 38 deg. C for 18 h. rSeVs having the Mpi protein exhibit lower cytotoxicity and are incapable of establishing persistent infection. Amino acid 116 of the Mpi protein is related to the nuclear translocation and lower cytopathogenesis, whereas aa183 is involved in the interaction between M protein and viral glycoproteins

  18. Children's white blood cell counts in relation to developmental exposures to methylmercury and persistent organic pollutants

    DEFF Research Database (Denmark)

    Oulhote, Youssef; Shamim, Z; Kielsen, Katrine

    2017-01-01

    ), and total mercury (Hg) were measured in maternal (n = 56) and children's blood at 18 months (n = 42) and 5 years (n = 54). We constructed latent functions for exposures at three different ages using factor analyses and applied structural equation models adjusted for covariates. Results Prenatal mercury....... In contrast, the 5-year PFASs concentrations were associated with higher basophil counts (B = 46% SD, 95% CI: 13, 79). Significantly reduced subpopulations of lymphocytes such as B cells, CD4-positive T helper cells and CD4 positive recent thymic emigrants may suggest cellular immunity effects...... and dysregulation of T-cell mediated immunity. Conclusion Developmental exposure to environmental immunotoxicants appears to have different impacts on WBC counts in childhood....

  19. Evolution of a Cell Culture-Derived Genotype 1a Hepatitis C Virus (H77S.2) during Persistent Infection with Chronic Hepatitis in a Chimpanzee

    Science.gov (United States)

    Yi, MinKyung; Hu, Fengyu; Joyce, Michael; Saxena, Vikas; Welsch, Christoph; Chavez, Deborah; Guerra, Bernadette; Yamane, Daisuke; Veselenak, Ronald; Pyles, Rick; Walker, Christopher M.; Tyrrell, Lorne; Bourne, Nigel; Lanford, Robert E.

    2014-01-01

    ABSTRACT Persistent infection is a key feature of hepatitis C virus (HCV). However, chimpanzee infections with cell culture-derived viruses (JFH1 or related chimeric viruses that replicate efficiently in cell culture) have been limited to acute-transient infections with no pathogenicity. Here, we report persistent infection with chronic hepatitis in a chimpanzee challenged with cell culture-derived genotype 1a virus (H77S.2) containing 6 cell culture-adaptive mutations. Following acute-transient infection with a chimeric H77/JFH1 virus (HJ3-5), intravenous (i.v.) challenge with 106 FFU H77S.2 virus resulted in immediate seroconversion and, following an unusual 4- to 6-week delay, persistent viremia accompanied by alanine aminotransferase (ALT) elevation, intrahepatic innate immune responses, and diffuse hepatopathy. This first persistent infection with cell culture-produced HCV provided a unique opportunity to assess evolution of cell culture-adapted virus in vivo. Synonymous and nonsynonymous nucleotide substitution rates were greatest during the first 8 weeks of infection. Of 6 cell culture-adaptive mutations in H77S.2, Q1067R (NS3) had reverted to Q1067 and S2204I (NS5A) was replaced by T2204 within 8 weeks of infection. By 62 weeks, 4 of 6 mutations had reverted to the wild-type sequence, and all reverted to the wild-type sequence by 194 weeks. The data suggest H77S.2 virus has greater potential for persistence and pathogenicity than JFH1 and demonstrate both the capacity of a nonfit virus to persist for weeks in the liver in the absence of detectable viremia as well as strong selective pressure against cell culture-adaptive mutations in vivo. IMPORTANCE This study shows that mutations promoting the production of infectious genotype 1a HCV in cell culture have the opposite effect and attenuate replication in the liver of the only fully permissive animal species other than humans. It provides the only example to date of persistent infection in a chimpanzee

  20. Evolution of a cell culture-derived genotype 1a hepatitis C virus (H77S.2) during persistent infection with chronic hepatitis in a chimpanzee.

    Science.gov (United States)

    Yi, MinKyung; Hu, Fengyu; Joyce, Michael; Saxena, Vikas; Welsch, Christoph; Chavez, Deborah; Guerra, Bernadette; Yamane, Daisuke; Veselenak, Ronald; Pyles, Rick; Walker, Christopher M; Tyrrell, Lorne; Bourne, Nigel; Lanford, Robert E; Lemon, Stanley M

    2014-04-01

    Persistent infection is a key feature of hepatitis C virus (HCV). However, chimpanzee infections with cell culture-derived viruses (JFH1 or related chimeric viruses that replicate efficiently in cell culture) have been limited to acute-transient infections with no pathogenicity. Here, we report persistent infection with chronic hepatitis in a chimpanzee challenged with cell culture-derived genotype 1a virus (H77S.2) containing 6 cell culture-adaptive mutations. Following acute-transient infection with a chimeric H77/JFH1 virus (HJ3-5), intravenous (i.v.) challenge with 10(6) FFU H77S.2 virus resulted in immediate seroconversion and, following an unusual 4- to 6-week delay, persistent viremia accompanied by alanine aminotransferase (ALT) elevation, intrahepatic innate immune responses, and diffuse hepatopathy. This first persistent infection with cell culture-produced HCV provided a unique opportunity to assess evolution of cell culture-adapted virus in vivo. Synonymous and nonsynonymous nucleotide substitution rates were greatest during the first 8 weeks of infection. Of 6 cell culture-adaptive mutations in H77S.2, Q1067R (NS3) had reverted to Q1067 and S2204I (NS5A) was replaced by T2204 within 8 weeks of infection. By 62 weeks, 4 of 6 mutations had reverted to the wild-type sequence, and all reverted to the wild-type sequence by 194 weeks. The data suggest H77S.2 virus has greater potential for persistence and pathogenicity than JFH1 and demonstrate both the capacity of a nonfit virus to persist for weeks in the liver in the absence of detectable viremia as well as strong selective pressure against cell culture-adaptive mutations in vivo. This study shows that mutations promoting the production of infectious genotype 1a HCV in cell culture have the opposite effect and attenuate replication in the liver of the only fully permissive animal species other than humans. It provides the only example to date of persistent infection in a chimpanzee challenged with cell

  1. Persistent Mullerian duct syndrome in a Miniature Schnauzer dog with signs of feminization and a Sertoli cell tumour.

    Science.gov (United States)

    Vegter, A R; Kooistra, H S; van Sluijs, F J; van Bruggen, L W L; Ijzer, J; Zijlstra, C; Okkens, A C

    2010-06-01

    A 5-year-old male Miniature Schnauzer was presented with unilateral cryptorchidism and signs of feminization. Abdominal ultrasonography revealed an enlarged right testis and a large, fluid-filled cavity that appeared to arise from the prostate. Computed tomography revealed the cavity to be consistent with an enlarged uterine body, arising from the prostate, and showed two structures resembling uterine horns that terminated close to the adjacent testes. The dog had a normal male karyotype, 78 XY. Gonadohysterectomy was performed and both the surgical and the histological findings confirmed the presence of a uterus in this male animal, resulting in a diagnosis of persistent Mullerian duct syndrome (PMDS). The enlarged intra-abdominal testis contained a Sertoli cell tumour. Computed tomography proved to be an excellent diagnostic tool for PMDS.

  2. A case of persistent Müllerian duct syndrome with sertoli cell tumor and hydrometra in a dog.

    Science.gov (United States)

    Matsuu, Aya; Hashizume, Takuya; Kanda, Teppei; Nagano, Masashi; Sugiyama, Akihiko; Okamoto, Yoshiharu; Hikasa, Yoshiaki

    2009-03-01

    A 10-year-old Miniature Schnauzer with bilateral cryptorchidism and male external genitalia was referred with a history of abdominal enlargement. Upon exploratory laparotomy, two tumors and a connecting structure similar to fluid-filled uterus were recognized. After cytological and bacterial examinations of the fluid and histological examination, this dog was diagnosed with bilateral Sertoli cell tumor with hydrometra. The karyotype of this dog was 78, XY and the sry gene was detected positive by PCR. We diagnosed this dog as a case of persistent Müllerian duct syndrome (PMDS), which is male pseudohermaphroditism. This is the first report regarding the incidence of PMDS in Miniature Schnauzers in Japan, and it suggests the involvement of a gene carrier.

  3. Long-term persistence of functional thymic epithelial progenitor cells in vivo under conditions of low FOXN1 expression

    DEFF Research Database (Denmark)

    Jin, Xin; Nowell, Craig S; Ulyanchenko, Svetlana

    2014-01-01

    does not require FOXN1. Here, we have used a revertible severely hypomorphic allele of Foxn1, Foxn1R, to test the stability of the common TEPC in vivo. By reactivating Foxn1 expression postnatally in Foxn1R/- mice we demonstrate that functional TEPCs can persist in the thymic rudiment until at least 6...... months of age, and retain the potential to give rise to both cortical and medullary thymic epithelial cells (cTECs and mTECs). These data demonstrate that the TEPC-state is remarkably stable in vivo under conditions of low Foxn1 expression, suggesting that manipulation of FOXN1 activity may prove...... a valuable method for long term maintenance of TEPC in vitro....

  4. Persistence Increases in the Absence of the Alarmone Guanosine Tetraphosphate by Reducing Cell Growth

    Science.gov (United States)

    2016-08-16

    Pennsylvania, Pennsylvania State University, University Park, 16802- 4400, USA. 2Department of Biochemistry and Molecular Biology, Pennsylvania State...of Toxin- Antitoxin Activity. Cell 154, 1140–1150 (2013). 26. Osbourne, D. O., Soo, V. W. C., Konieczny, I. & Wood, T. K. Polyphosphate, cyclic AMP

  5. Persistent expansion of CD4(+) effector memory T cells in Wegener's granulomatosis

    NARCIS (Netherlands)

    Abdulahad, W. H.; van der Geld, Y. M.; Stegeman, C. A.; Kallenberg, C. G. M.

    In order to test the hypothesis that Wegener's granulomatosis (WG) is associated with an ongoing immune effector response, even in remission, we examined the distribution of peripheral naive and memory T-lymphocytes in this disease, and analyzed the function-related phenotypes of the memory T-cell

  6. Altered characteristics of cancer stem/initiating cells in a breast cancer cell line treated with persistent 5-FU chemotherapy

    OpenAIRE

    LÜ, XINQUAN; DENG, QING; LI, HUIXIANG; SUO, ZHENHE

    2011-01-01

    Drug resistance of cancer stem/initiating cells has been considered to be one of the main reasons for tumor relapse. However, knowledge concerning the changes in stem/ initiating cells during chemotherapy is limited. In the present study, the breast cancer cell line MDA-MB-468 was cultured with 5-fluorouracil and serially passaged. Six cell generations were collected. Semi-quantitative RT-PCR and flow cytometric techniques were used to evaluate the protein and mRNA expression of stem/initiati...

  7. Autoradiographical in-vitro examination of the cell proliferation of persisting psoriatic plaques in preferred areas under therapy with ultraviolet light: Photochemotherapy (PUVA) and selective ultraviolet phototherapy (SUP)

    International Nuclear Information System (INIS)

    Middendorf, M.

    1982-01-01

    The application of ultraviolet rays (PUVA, SUP) brought significant progress in the treatment of psoriasis. The goal of UV-irradiation is to normalise the epidermal growth conditions. The cell cycle of persisting psoriatic plaque in preferred areas was examined under therapy with PUVA and SUP using an autoradiographic in-vitro method, double labelling with 14 C- and 3 H-thymididin. The results were compared to the known cell-kinetic parameters of psoriasis. The values thus obtained confirm the characteristic changes in the cell cycle of psoriasis. Furthermore, there is a block within the DNA-synthesis phase in the plaques persisting under UV-therapy. The resistence of persisting psoriatic plaques in preferred regions against UV-therapy is regarded as an indication of an extreme disturbance in the proliferation behaviour of the psoriatic skin. (orig./MG) [de

  8. Cetuximab insufficiently inhibits glioma cell growth due to persistent EGFR downstream signaling

    DEFF Research Database (Denmark)

    Hasselbalch, Benedikte; Lassen, Ulrik; Poulsen, Hans S

    2010-01-01

    Overexpression and/or amplification of the epidermal growth factor receptor (EGFR) is present in 35-45% of primary glioblastoma multiforme tumors and has been correlated with a poor prognosis. In this study, we investigated the effect of cetuximab and intracellular signaling pathways downstream...... of EGFR, important for cell survival and proliferation. We show insufficient EGFR downregulation and competition with endogenous EGFR ligands upon cetuximab treatment. Dose-response experiments showed inhibition of EGFR phosphorylation without affecting two of the prominent downstream signaling pathways....... Our results indicate that amplification and/or overexpression of EGFR is an unsatisfactory predictor for response to cetuximab....

  9. Stereotactic Body Radiation Therapy for Re-irradiation of Persistent or Recurrent Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Trovo, Marco, E-mail: marcotrovo33@hotmail.com [Department of Radiation Oncology, Centro di Riferimento Oncologico of Aviano, Pordenone (Italy); Minatel, Emilio; Durofil, Elena [Department of Radiation Oncology, Centro di Riferimento Oncologico of Aviano, Pordenone (Italy); Polesel, Jerry [Department of Epidemiology and Biostatistics, Centro di Riferimento Oncologico of Aviano, Pordenone (Italy); Avanzo, Michele [Department of Medical Physics, Centro di Riferimento Oncologico of Aviano, Pordenone (Italy); Baresic, Tania [Department of Nuclear Medicine, Centro di Riferimento Oncologico of Aviano, Pordenone (Italy); Bearz, Alessandra [Department of Medical Oncology, Centro di Riferimento Oncologico of Aviano, Pordenone (Italy); Del Conte, Alessandro [Department of Medical Oncology, Pordenone General Hospital, Aviano, Pordenone (Italy); Franchin, Giovanni; Gobitti, Carlo; Rumeileh, Imad Abu; Trovo, Mauro G. [Department of Radiation Oncology, Centro di Riferimento Oncologico of Aviano, Pordenone (Italy)

    2014-04-01

    Purpose: To retrospectively assess toxicity and outcome of re-irradiation with stereotactic body radiation therapy (SBRT) in patients with recurrent or persistent non-small cell lung cancer (NSCLC), who were previously treated with radical radiation therapy (50-60 Gy). The secondary endpoint was to investigate whether there are dosimetric parameter predictors of severe radiation toxicity. Methods and Materials: The analysis was conducted in 17 patients with “in-field” recurrent/persistent centrally located NSCLC, who underwent re-irradiation with SBRT. SBRT consisted of 30 Gy in 5 to 6 fractions; these prescriptions would be equivalent for the tumor to 37.5 to 40 Gy, bringing the total 2-Gy-per-fraction cumulative dose to 87 to 100 Gy, considering the primary radiation therapy treatment. Actuarial analyses and survival were calculated by the Kaplan-Meier method, and P values were estimated by the log-rank test, starting from the date of completion of SBRT. Dosimetric parameters from the subgroups with and without grade ≥3 pulmonary toxicity were compared using a 2-tailed Student t test. Results: The median follow-up was 18 months (range, 4-57 months). Only 2 patients had local failure, corresponding to a local control rate of 86% at 1 year. The Kaplan-Meier estimates of overall survival (OS) rates at 1 and 2 years were 59% and 29%, respectively; the median OS was 19 months. Four patients (23%) experienced grade 3 radiation pneumonitis, and 1 patient developed fatal pneumonitis. One patient died of fatal hemoptysis 2 months after the completion of SBRT. Unexpectedly, heart maximum dose, D5 (minimum dose to at least 5% of the heart volume), and D10 were correlated with risk of radiation pneumonitis (P<.05). Conclusions: Re-irradiation with SBRT for recurrent/persistent centrally located NSCLC achieves excellent results in terms of local control. However, the high rate of severe toxicity reported in our study is of concern.

  10. Stereotactic Body Radiation Therapy for Re-irradiation of Persistent or Recurrent Non-Small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Trovo, Marco; Minatel, Emilio; Durofil, Elena; Polesel, Jerry; Avanzo, Michele; Baresic, Tania; Bearz, Alessandra; Del Conte, Alessandro; Franchin, Giovanni; Gobitti, Carlo; Rumeileh, Imad Abu; Trovo, Mauro G.

    2014-01-01

    Purpose: To retrospectively assess toxicity and outcome of re-irradiation with stereotactic body radiation therapy (SBRT) in patients with recurrent or persistent non-small cell lung cancer (NSCLC), who were previously treated with radical radiation therapy (50-60 Gy). The secondary endpoint was to investigate whether there are dosimetric parameter predictors of severe radiation toxicity. Methods and Materials: The analysis was conducted in 17 patients with “in-field” recurrent/persistent centrally located NSCLC, who underwent re-irradiation with SBRT. SBRT consisted of 30 Gy in 5 to 6 fractions; these prescriptions would be equivalent for the tumor to 37.5 to 40 Gy, bringing the total 2-Gy-per-fraction cumulative dose to 87 to 100 Gy, considering the primary radiation therapy treatment. Actuarial analyses and survival were calculated by the Kaplan-Meier method, and P values were estimated by the log-rank test, starting from the date of completion of SBRT. Dosimetric parameters from the subgroups with and without grade ≥3 pulmonary toxicity were compared using a 2-tailed Student t test. Results: The median follow-up was 18 months (range, 4-57 months). Only 2 patients had local failure, corresponding to a local control rate of 86% at 1 year. The Kaplan-Meier estimates of overall survival (OS) rates at 1 and 2 years were 59% and 29%, respectively; the median OS was 19 months. Four patients (23%) experienced grade 3 radiation pneumonitis, and 1 patient developed fatal pneumonitis. One patient died of fatal hemoptysis 2 months after the completion of SBRT. Unexpectedly, heart maximum dose, D5 (minimum dose to at least 5% of the heart volume), and D10 were correlated with risk of radiation pneumonitis (P<.05). Conclusions: Re-irradiation with SBRT for recurrent/persistent centrally located NSCLC achieves excellent results in terms of local control. However, the high rate of severe toxicity reported in our study is of concern

  11. A Resource for the Transcriptional Signature of Bona Fide Trophoblast Stem Cells and Analysis of Their Embryonic Persistence

    Directory of Open Access Journals (Sweden)

    Georg Kuales

    2015-01-01

    Full Text Available Trophoblast stem cells (TSCs represent the multipotent progenitors that give rise to the different cells of the embryonic portion of the placenta. Here, we analysed the expression of key TSC transcription factors Cdx2, Eomes, and Elf5 in the early developing placenta of mouse embryos and in cultured TSCs and reveal surprising heterogeneity in protein levels. We analysed persistence of TSCs in the early placenta and find that TSCs remain in the chorionic hinge until E9.5 and are lost shortly afterwards. To define the transcriptional signature of bona fide TSCs, we used inducible gain- and loss-of-function alleles of Eomes or Cdx2, and EomesGFP, to manipulate and monitor the core maintenance factors of TSCs, followed by genome-wide expression profiling. Combinatorial analysis of resulting expression profiles allowed for defining novel TSC marker genes that might functionally contribute to the maintenance of the TSC state. Analyses by qRT-PCR and in situ hybridisation validated novel TSC- and chorion-specific marker genes, such as Bok/Mtd, Cldn26, Duox2, Duoxa2, Nr0b1, and Sox21. Thus, these expression data provide a valuable resource for the transcriptional signature of bona fide and early differentiating TSCs and may contribute to an increased understanding of the transcriptional circuitries that maintain and/or establish stemness of TSCs.

  12. Persistent inhibition of pore-based cell migration by sub-toxic doses of miuraenamide, an actin filament stabilizer.

    Science.gov (United States)

    Moser, Christina; Rüdiger, Daniel; Förster, Florian; von Blume, Julia; Yu, Peng; Kuster, Bernhard; Kazmaier, Uli; Vollmar, Angelika M; Zahler, Stefan

    2017-11-27

    Opposed to tubulin-binding agents, actin-binding small molecules have not yet become part of clinical tumor treatment, most likely due to the fear of general cytotoxicity. Addressing this problem, we investigated the long-term efficacy of sub-toxic doses of miuraenamide, an actin filament stabilizing natural compound, on tumor cell (SKOV3) migration. No cytotoxic effects or persistent morphological changes occurred at a concentration of miuraenamide of 20 nM. After 72 h treatment with this concentration, nuclear stiffness was increased, causing reduced migration through pores in a Boyden chamber, while cell migration and chemotaxis per se were unaltered. A concomitant time-resolved proteomic approach showed down regulation of a protein cluster after 56 h treatment. This cluster correlated best with the Wnt signaling pathway. A further analysis of the actin associated MRTF/SRF signaling showed a surprising reduction of SRF-regulated proteins. In contrast to acute effects of actin-binding compounds on actin at high concentrations, long-term low-dose treatment elicits much more subtle but still functionally relevant changes beyond simple destruction of the cytoskeleton. These range from biophysical parameters to regulation of protein expression, and may help to better understand the complex biology of actin, as well as to initiate alternative regimes for the testing of actin-targeting drugs.

  13. Host Cell Responses to Persistent Mycoplasmas - Different Stages in Infection of HeLa Cells with Mycoplasma hominis

    Science.gov (United States)

    Hopfe, Miriam; Deenen, René; Degrandi, Daniel; Köhrer, Karl; Henrich, Birgit

    2013-01-01

    Mycoplasma hominis is a facultative human pathogen primarily associated with bacterial vaginosis and pelvic inflammatory disease, but it is also able to spread to other sites, leading to arthritis or, in neonates, meningitis. With a minimal set of 537 annotated genes, M. hominis is the second smallest self-replicating mycoplasma and thus an ideal model organism for studying the effects of an infectious agent on its host more closely. M. hominis adherence, colonisation and invasion of HeLa cells were characterised in a time-course study using scanning electron microscopy, confocal microscopy and microarray-based analysis of the HeLa cell transcriptome. At 4 h post infection, cytoadherence of M. hominis to the HeLa cell surface was accompanied by differential regulation of 723 host genes (>2 fold change in expression). Genes associated with immune responses and signal transduction pathways were mainly affected and components involved in cell-cycle regulation, growth and death were highly upregulated. At 48 h post infection, when mycoplasma invasion started, 1588 host genes were differentially expressed and expression of genes for lysosome-specific proteins associated with bacterial lysis was detected. In a chronically infected HeLa cell line (2 weeks), the proportion of intracellular mycoplasmas reached a maximum of 10% and M. hominis-filled protrusions of the host cell membrane were seen by confocal microscopy, suggesting exocytotic dissemination. Of the 1972 regulated host genes, components of the ECM-receptor interaction pathway and phagosome-related integrins were markedly increased. The immune response was quite different to that at the beginning of infection, with a prominent induction of IL1B gene expression, affecting pathways of MAPK signalling, and genes connected with cytokine-cytokine interactions and apoptosis. These data show for the first time the complex, time-dependent reaction of the host directed at mycoplasmal clearance and the counter measures of

  14. High proportion of PD-1-expressing CD4+ T cells in adipose tissue constitutes an immunomodulatory microenvironment that may support HIV persistence.

    Science.gov (United States)

    Damouche, Abderaouf; Pourcher, Guillaume; Pourcher, Valérie; Benoist, Stéphane; Busson, Elodie; Lataillade, Jean-Jacques; Le Van, Mélanie; Lazure, Thierry; Adam, Julien; Favier, Benoit; Vaslin, Bruno; Müller-Trutwin, Michaela; Lambotte, Olivier; Bourgeois, Christine

    2017-12-01

    We and others have demonstrated that adipose tissue is a reservoir for HIV. Evaluation of the mechanisms responsible for viral persistence may lead to ways of reducing these reservoirs. Here, we evaluated the immune characteristics of adipose tissue in HIV-infected patients receiving antiretroviral therapy (ART) and in non-HIV-infected patients. We notably sought to determine whether adipose tissue's intrinsic properties and/or HIV induced alteration of the tissue environment may favour viral persistence. ART-controlled HIV infection was associated with a difference in the CD4/CD8 T-cell ratio and an elevated proportion of Treg cells in subcutaneous adipose tissue. No changes in Th1, Th2 and Th17 cell proportions or activation markers expression on T cell (Ki-67, HLA-DR) could be detected, and the percentage of CD69-expressing resident memory CD4 + T cells was not affected. Overall, our results indicate that adipose-tissue-resident CD4 + T cells are not extensively activated during HIV infection. PD-1 was expressed by a high proportion of tissue-resident memory CD4 + T cells in both HIV-infected patients and non-HIV-infected patients. Our findings suggest that adipose tissue's intrinsic immunomodulatory properties may limit immune activation and thus may strongly contribute to viral persistence. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Bacterial persistence

    Indian Academy of Sciences (India)

    PRAKASH KUMAR

    Drug indifference versus persistence. Studies on the mode of ... is a special case of drug indifference, restricted to a small ... to his model (outlined in detail in Lewis 2008), treatment .... belong to the heat and cold shock response family; many.

  16. T-Cell Therapy Using Interleukin-21-Primed Cytotoxic T-Cell Lymphocytes Combined With Cytotoxic T-Cell Lymphocyte Antigen-4 Blockade Results in Long-Term Cell Persistence and Durable Tumor Regression.

    Science.gov (United States)

    Chapuis, Aude G; Roberts, Ilana M; Thompson, John A; Margolin, Kim A; Bhatia, Shailender; Lee, Sylvia M; Sloan, Heather L; Lai, Ivy P; Farrar, Erik A; Wagener, Felecia; Shibuya, Kendall C; Cao, Jianhong; Wolchok, Jedd D; Greenberg, Philip D; Yee, Cassian

    2016-11-01

    Purpose Peripheral blood-derived antigen-specific cytotoxic T cells (CTLs) provide a readily available source of effector cells that can be administered with minimal toxicity in an outpatient setting. In metastatic melanoma, this approach results in measurable albeit modest clinical responses in patients resistant to conventional therapy. We reasoned that concurrent cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) checkpoint blockade might enhance the antitumor activity of adoptively transferred CTLs. Patients and Methods Autologous MART1-specific CTLs were generated by priming with peptide-pulsed dendritic cells in the presence of interleukin-21 and enriched by peptide-major histocompatibility complex multimer-guided cell sorting. This expeditiously yielded polyclonal CTL lines uniformly expressing markers associated with an enhanced survival potential. In this first-in-human strategy, 10 patients with stage IV melanoma received the MART1-specific CTLs followed by a standard course of anti-CTLA-4 (ipilimumab). Results The toxicity profile of the combined treatment was comparable to that of ipilimumab monotherapy. Evaluation of best responses at 12 weeks yielded two continuous complete remissions, one partial response (PR) using RECIST criteria (two PRs using immune-related response criteria), and three instances of stable disease. Infused CTLs persisted with frequencies up to 2.9% of CD8 + T cells for as long as the patients were monitored (up to 40 weeks). In patients who experienced complete remissions, PRs, or stable disease, the persisting CTLs acquired phenotypic and functional characteristics of long-lived memory cells. Moreover, these patients also developed responses to nontargeted tumor antigens (epitope spreading). Conclusion We demonstrate that combining antigen-specific CTLs with CTLA-4 blockade is safe and produces durable clinical responses, likely reflecting both enhanced activity of transferred cells and improved recruitment of new responses

  17. T-Cell Therapy Using Interleukin-21–Primed Cytotoxic T-Cell Lymphocytes Combined With Cytotoxic T-Cell Lymphocyte Antigen-4 Blockade Results in Long-Term Cell Persistence and Durable Tumor Regression

    Science.gov (United States)

    Chapuis, Aude G.; Roberts, Ilana M.; Thompson, John A.; Margolin, Kim A.; Bhatia, Shailender; Lee, Sylvia M.; Sloan, Heather L.; Lai, Ivy P.; Farrar, Erik A.; Wagener, Felecia; Shibuya, Kendall C.; Cao, Jianhong; Wolchok, Jedd D.; Greenberg, Philip D.

    2016-01-01

    Purpose Peripheral blood–derived antigen-specific cytotoxic T cells (CTLs) provide a readily available source of effector cells that can be administered with minimal toxicity in an outpatient setting. In metastatic melanoma, this approach results in measurable albeit modest clinical responses in patients resistant to conventional therapy. We reasoned that concurrent cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) checkpoint blockade might enhance the antitumor activity of adoptively transferred CTLs. Patients and Methods Autologous MART1-specific CTLs were generated by priming with peptide-pulsed dendritic cells in the presence of interleukin-21 and enriched by peptide-major histocompatibility complex multimer-guided cell sorting. This expeditiously yielded polyclonal CTL lines uniformly expressing markers associated with an enhanced survival potential. In this first-in-human strategy, 10 patients with stage IV melanoma received the MART1-specific CTLs followed by a standard course of anti–CTLA-4 (ipilimumab). Results The toxicity profile of the combined treatment was comparable to that of ipilimumab monotherapy. Evaluation of best responses at 12 weeks yielded two continuous complete remissions, one partial response (PR) using RECIST criteria (two PRs using immune-related response criteria), and three instances of stable disease. Infused CTLs persisted with frequencies up to 2.9% of CD8+ T cells for as long as the patients were monitored (up to 40 weeks). In patients who experienced complete remissions, PRs, or stable disease, the persisting CTLs acquired phenotypic and functional characteristics of long-lived memory cells. Moreover, these patients also developed responses to nontargeted tumor antigens (epitope spreading). Conclusion We demonstrate that combining antigen-specific CTLs with CTLA-4 blockade is safe and produces durable clinical responses, likely reflecting both enhanced activity of transferred cells and improved recruitment of new responses

  18. [Persistent diarrhea

    Science.gov (United States)

    Andrade, J A; Moreira, C; Fagundes Neto, U

    2000-07-01

    INTRODUCTION: Persistent diarrhea has high impact on infantile morbidity and mortality rates in developing countries. Several studies have shown that 3 to 20% of acute diarrheal episodes in children under 5 years of age become persistent. DEFINITION: Persistent diarrhea is defined as an episode that lasts more than 14 days. ETIOLOGY: The most important agents isolated in persistent diarrhea are: Enteropathogenic E. coli (EPEC), Salmonella, Enteroaggregative E. coli (EAEC), Klebisiella and Cryptosporidium. CLINICAL ASPECTS: In general, the clinical characteristics of patients with persistent diarrhea do not change with the pathogenic agent. Persistent diarrhea seems to represent the final result of a several insults a infant suffers that predisposes to a more severe episode of diarrhea due to a combination of host factors and high rates of enviromental contamination. Therefore, efforts should be made to promptly treat all episodes of diarrhea with apropriate follow-up. THERAPY: The aim of the treatment is to restore hydroelectrolytic deficits and to replace losses until the diarrheal ceases. It is possible in the majority of the cases, using oral rehydration therapy and erly an appropriate type of diet. PREVENTION: It is imperative that management strategies also focus on preventive aspects. The most effective diarrheal prevention strategy in young infants worldwide is promotion of exclusive breast feeding.

  19. WIP regulates persistence of cell migration and ruffle formation in both mesenchymal and amoeboid modes of motility.

    Directory of Open Access Journals (Sweden)

    Inmaculada Banon-Rodriguez

    Full Text Available The spatial distribution of signals downstream from receptor tyrosine kinases (RTKs or G-protein coupled receptors (GPCR regulates fundamental cellular processes that control cell migration and growth. Both pathways rely significantly on actin cytoskeleton reorganization mediated by nucleation-promoting factors such as the WASP-(Wiskott-Aldrich Syndrome Protein family. WIP (WASP Interacting Protein is essential for the formation of a class of polarised actin microdomain, namely dorsal ruffles, downstream of the RTK for PDGF (platelet-derived growth factor but the underlying mechanism is poorly understood. Using lentivirally-reconstituted WIP-deficient murine fibroblasts we define the requirement for WIP interaction with N-WASP (neural WASP and Nck for efficient dorsal ruffle formation and of WIP-Nck binding for fibroblast chemotaxis towards PDGF-AA. The formation of both circular dorsal ruffles in PDGF-AA-stimulated primary fibroblasts and lamellipodia in CXCL13-treated B lymphocytes are also compromised by WIP-deficiency. We provide data to show that a WIP-Nck signalling complex interacts with RTK to promote polarised actin remodelling in fibroblasts and provide the first evidence for WIP involvement in the control of migratory persistence in both mesenchymal (fibroblast and amoeboid (B lymphocytes motility.

  20. Long-term persistence of robust antibody and cytotoxic T cell responses in recovered patients infected with SARS coronavirus.

    Directory of Open Access Journals (Sweden)

    Taisheng Li

    2006-12-01

    Full Text Available Most of the individuals infected with SARS coronavirus (SARS-CoV spontaneously recovered without clinical intervention. However, the immunological correlates associated with patients' recovery are currently unknown. In this report, we have sequentially monitored 30 recovered patients over a two-year period to characterize temporal changes in SARS-CoV-specific antibody responses as well as cytotoxic T cell (CTL responses. We have found persistence of robust antibody and CTL responses in all of the study subjects throughout the study period, with a moderate decline one year after the onset of symptoms. We have also identified two potential major CTL epitopes in N proteins based on ELISPOT analysis of pooled peptides. However, despite the potent immune responses and clinical recovery, peripheral lymphocyte counts in the recovered patients have not yet been restored to normal levels. In summary, our study has, for the first time, characterized the temporal and dynamic changes of humoral and CTL responses in the natural history of SARS-recovered individuals, and strongly supports the notion that high and sustainable levels of immune responses correlate strongly with the disease outcome. Our findings have direct implications for future design and development of effective therapeutic agents and vaccines against SARS-CoV infection.

  1. Linking Cellular Mechanisms to Behavior: Entorhinal Persistent Spiking and Membrane Potential Oscillations May Underlie Path Integration, Grid Cell Firing, and Episodic Memory

    Directory of Open Access Journals (Sweden)

    Michael E. Hasselmo

    2008-01-01

    Full Text Available The entorhinal cortex plays an important role in spatial memory and episodic memory functions. These functions may result from cellular mechanisms for integration of the afferent input to entorhinal cortex. This article reviews physiological data on persistent spiking and membrane potential oscillations in entorhinal cortex then presents models showing how both these cellular mechanisms could contribute to properties observed during unit recording, including grid cell firing, and how they could underlie behavioural functions including path integration. The interaction of oscillations and persistent firing could contribute to encoding and retrieval of trajectories through space and time as a mechanism relevant to episodic memory.

  2. Persistent angina

    DEFF Research Database (Denmark)

    Jespersen, L.; Abildstrom, S. Z.; Hvelplund, Anders

    2013-01-01

    To evaluate persistent angina in stable angina pectoris with no obstructive coronary artery disease (CAD) compared to obstructive CAD and its relation to long-term anxiety, depression, quality of life (QOL), and physical functioning. We invited 357 patients (men = 191; women = 166; response rate 83......-obstructive CAD or normal coronary arteries than in patients with obstructive CAD. Persistent angina symptoms were associated with long-term anxiety, depression, impaired physical functioning, and QOL irrespective of the degree of CAD. Contrary to common perception, excluding obstructive CAD in stable angina does...... %) with no prior cardiovascular disease who had a first-time coronary angiography (CAG) in 2008-2009 due to suspected stable angina to participate in a questionnaire survey in 2011 with the Seattle Angina Questionnaire and the Hospital Anxiety and Depression Scale as key elements. Long-term persistent angina (i...

  3. Deficient incorporation of spike protein into virions contributes to the lack of infectivity following establishment of a persistent, non-productive infection in oligodendroglial cell culture by murine coronavirus

    International Nuclear Information System (INIS)

    Liu Yin; Herbst, Werner; Cao Jianzhong; Zhang Xuming

    2011-01-01

    Infection of mouse oligodendrocytes with a recombinant mouse hepatitis virus (MHV) expressing a green fluorescence protein facilitated specific selection of virus-infected cells and subsequent establishment of persistence. Interestingly, while viral genomic RNAs persisted in infected cells over 14 subsequent passages with concomitant synthesis of viral subgenomic mRNAs and structural proteins, no infectious virus was isolated beyond passage 2. Further biochemical and electron microscopic analyses revealed that virions, while assembled, contained little spike in the envelope, indicating that lack of infectivity during persistence was likely due to deficiency in spike incorporation. This type of non-lytic, non-productive persistence in oligodendrocytes is unique among animal viruses and resembles MHV persistence previously observed in the mouse central nervous system. Thus, establishment of such a culture system that can recapitulate the in vivo phenomenon will provide a powerful approach for elucidating the mechanisms of coronavirus persistence in glial cells at the cellular and molecular levels.

  4. Habit persistence

    DEFF Research Database (Denmark)

    Vinther Møller, Stig

    2009-01-01

    This paper uses an iterated GMM approach to estimate and test the consumption based habit persistence model of Campbell and Cochrane (1999) on the US stock market. The empirical evidence shows that the model is able to explain the size premium, but fails to explain the value premium. Further...

  5. Persistent ER stress induces the spliced leader RNA silencing pathway (SLS, leading to programmed cell death in Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Hanoch Goldshmidt

    2010-01-01

    Full Text Available Trypanosomes are parasites that cycle between the insect host (procyclic form and mammalian host (bloodstream form. These parasites lack conventional transcription regulation, including factors that induce the unfolded protein response (UPR. However, they possess a stress response mechanism, the spliced leader RNA silencing (SLS pathway. SLS elicits shut-off of spliced leader RNA (SL RNA transcription by perturbing the binding of the transcription factor tSNAP42 to its cognate promoter, thus eliminating trans-splicing of all mRNAs. Induction of endoplasmic reticulum (ER stress in procyclic trypanosomes elicits changes in the transcriptome similar to those induced by conventional UPR found in other eukaryotes. The mechanism of up-regulation under ER stress is dependent on differential stabilization of mRNAs. The transcriptome changes are accompanied by ER dilation and elevation in the ER chaperone, BiP. Prolonged ER stress induces SLS pathway. RNAi silencing of SEC63, a factor that participates in protein translocation across the ER membrane, or SEC61, the translocation channel, also induces SLS. Silencing of these genes or prolonged ER stress led to programmed cell death (PCD, evident by exposure of phosphatidyl serine, DNA laddering, increase in reactive oxygen species (ROS production, increase in cytoplasmic Ca(2+, and decrease in mitochondrial membrane potential, as well as typical morphological changes observed by transmission electron microscopy (TEM. ER stress response is also induced in the bloodstream form and if the stress persists it leads to SLS. We propose that prolonged ER stress induces SLS, which serves as a unique death pathway, replacing the conventional caspase-mediated PCD observed in higher eukaryotes.

  6. Survival following salvage abdominoperineal resection for persistent and recurrent squamous cell carcinoma of the anus: do these disease categories affect survival?

    Science.gov (United States)

    Severino, N P; Chadi, S A; Rosen, L; Coiro, S; Choman, E; Berho, M; Wexner, S D

    2016-10-01

    This study aimed to investigate the results of salvage abdominoperineal excision (APR) in patients with persistent or recurrent squamous cell carcinoma of the anus (SCCA). Patients with anal neoplasia were identified from a prospective database. Patients with invasive SCCA with demonstrated failure of chemoradiation therapy (CRT) who underwent salvage APR for one of three disease categories (persistent,  24 months post-CRT) were included. The primary outcome was overall survival after salvage APR. Tumour size, metastatic lymph nodes (LN), circumferential resection margin positivity (CRM) and neurolymphovascular invasion (NLVI) were correlated with the outcome. Thirty-six patients with a median 3-year overall survival of 46% (median follow-up 24 months) underwent salvage APR due to persistent or recurrent SCCA (14 men, mean age 59 years). Eleven (31%) patients were diagnosed with persistent disease, 17 (47%) with early and 8 (22%) with late recurrence. Two-year overall survival of Stage 0/I/II and III/IV disease was 81.5% and 33.74%, respectively (P = 0.022). Overall disease stage was associated with disease categorization (P = 0.009): patients with persistent disease or early recurrence had a significantly higher disease stage than patients with late recurrence (OR = 20.9 and 17.2). Despite apparently improved survival in patients with late disease recurrence on live table analysis, no significant difference was identified in overall survival when stratified by disease category on log-rank test analysis. Persistent and recurrent disease does not show any significant difference in survival, but patients with late recurrence may have a better prognosis. Colorectal Disease © 2016 The Association of Coloproctology of Great Britain and Ireland.

  7. EBV induces persistent NF-κB activation and contributes to survival of EBV-positive neoplastic T- or NK-cells.

    Directory of Open Access Journals (Sweden)

    Honami Takada

    Full Text Available Epstein-Barr virus (EBV has been detected in several T- and NK-cell neoplasms such as extranodal NK/T-cell lymphoma nasal type, aggressive NK-cell leukemia, EBV-positive peripheral T-cell lymphoma, systemic EBV-positive T-cell lymphoma of childhood, and chronic active EBV infection (CAEBV. However, how this virus contributes to lymphomagenesis in T or NK cells remains largely unknown. Here, we examined NF-κB activation in EBV-positive T or NK cell lines, SNT8, SNT15, SNT16, SNK6, and primary EBV-positive and clonally proliferating T/NK cells obtained from the peripheral blood of patients with CAEBV. Western blotting, electrophoretic mobility shift assays, and immunofluorescent staining revealed persistent NF-κB activation in EBV-infected cell lines and primary cells from patients. Furthermore, we investigated the role of EBV in infected T cells. We performed an in vitro infection assay using MOLT4 cells infected with EBV. The infection directly induced NF-κB activation, promoted survival, and inhibited etoposide-induced apoptosis in MOLT4 cells. The luciferase assay suggested that LMP1 mediated NF-κB activation in MOLT4 cells. IMD-0354, a specific inhibitor of NF-κB that suppresses NF-κB activation in cell lines, inhibited cell survival and induced apoptosis. These results indicate that EBV induces NF-κB-mediated survival signals in T and NK cells, and therefore, may contribute to the lymphomagenesis of these cells.

  8. IL-17A and serum amyloid A are elevated in a cigarette smoke cessation model associated with the persistence of pigmented macrophages, neutrophils and activated NK cells.

    Directory of Open Access Journals (Sweden)

    Michelle J Hansen

    Full Text Available While global success in cessation advocacy has seen smoking rates fall in many developed countries, persistent lung inflammation in ex-smokers is an increasingly important clinical problem whose mechanistic basis remains poorly understood. In this study, candidate effector mechanisms were assessed in mice exposed to cigarette smoke (CS for 4 months following cessation from long term CS exposure. BALF neutrophils, CD4+ and CD8+ T cells and lung innate NK cells remained significantly elevated following smoking cessation. Analysis of neutrophil mobilization markers showed a transition from acute mediators (MIP-2α, KC and G-CSF to sustained drivers of neutrophil and macrophage recruitment and activation (IL-17A and Serum Amyoid A (SAA. Follicle-like lymphoid aggregates formed with CS exposure and persisted with cessation, where they were in close anatomical proximity to pigmented macrophages, whose number actually increased 3-fold following CS cessation. This was associated with the elastolytic protease, MMP-12 (macrophage metallo-elastase which remained significantly elevated post-cessation. Both GM-CSF and CSF-1 were significantly increased in the CS cessation group relative to the control group. In conclusion, we show that smoking cessation mediates a transition to accumulation of pigmented macrophages, which may contribute to the expanded macrophage population observed in COPD. These macrophages together with IL-17A, SAA and innate NK cells are identified here as candidate persistence determinants and, we suggest, may represent specific targets for therapies directed towards the amelioration of chronic airway inflammation.

  9. Persistence and selection of an expanded B-cell clone in the setting of rituximab therapy for Sjögren’s syndrome

    Science.gov (United States)

    2014-01-01

    Introduction Subjects with primary Sjögren’s syndrome (SjS) have an increased risk of developing B-cell lymphoma and may harbor monoclonal B-cell expansions in the peripheral blood. Expanded B-cell clones could be pathogenic, and their persistence could exacerbate disease or predispose toward the development of lymphoma. Therapy with anti-CD20 (rituximab) has the potential to eliminate expanded B-cell clones and thereby potentially ameliorate disease. This study was undertaken to identify and track expanded B-cell clones in the blood of subjects with primary SjS who were treated with rituximab. Methods To determine whether circulating B-cell clones in subjects with primary SjS emerge or remain after B cell-depleting therapy with rituximab, we studied the antibody heavy-chain repertoire. We performed single-memory B-cell and plasmablast sorting and antibody heavy-chain sequencing in six rituximab-treated SjS subjects over the course of a 1-year follow-up period. Results Expanded B-cell clones were identified in four out of the six rituximab-treated SjS subjects, based upon the independent amplification of sequences with identical or highly similar VH, DH, and JH gene segments. We identified one SjS subject with a large expanded B-cell clone that was present prior to therapy and persisted after therapy. Somatic mutations in the clone were numerous but did not increase in frequency over the course of the 1-year follow-up, suggesting that the clone had been present for a long period of time. Intriguingly, a majority of the somatic mutations in the clone were silent, suggesting that the clone was under chronic negative selection. Conclusions For some subjects with primary SjS, these data show that (a) expanded B-cell clones are readily identified in the peripheral blood, (b) some clones are not eliminated by rituximab, and (c) persistent clones may be under chronic negative selection or may not be antigen-driven. The analysis of sequence variation among members of an

  10. Persistence and selection of an expanded B-cell clone in the setting of rituximab therapy for Sjögren's syndrome.

    Science.gov (United States)

    Hershberg, Uri; Meng, Wenzhao; Zhang, Bochao; Haff, Nancy; St Clair, E William; Cohen, Philip L; McNair, Patrice D; Li, Ling; Levesque, Marc C; Luning Prak, Eline T

    2014-02-11

    Subjects with primary Sjögren's syndrome (SjS) have an increased risk of developing B-cell lymphoma and may harbor monoclonal B-cell expansions in the peripheral blood. Expanded B-cell clones could be pathogenic, and their persistence could exacerbate disease or predispose toward the development of lymphoma. Therapy with anti-CD20 (rituximab) has the potential to eliminate expanded B-cell clones and thereby potentially ameliorate disease. This study was undertaken to identify and track expanded B-cell clones in the blood of subjects with primary SjS who were treated with rituximab. To determine whether circulating B-cell clones in subjects with primary SjS emerge or remain after B cell-depleting therapy with rituximab, we studied the antibody heavy-chain repertoire. We performed single-memory B-cell and plasmablast sorting and antibody heavy-chain sequencing in six rituximab-treated SjS subjects over the course of a 1-year follow-up period. Expanded B-cell clones were identified in four out of the six rituximab-treated SjS subjects, based upon the independent amplification of sequences with identical or highly similar VH, DH, and JH gene segments. We identified one SjS subject with a large expanded B-cell clone that was present prior to therapy and persisted after therapy. Somatic mutations in the clone were numerous but did not increase in frequency over the course of the 1-year follow-up, suggesting that the clone had been present for a long period of time. Intriguingly, a majority of the somatic mutations in the clone were silent, suggesting that the clone was under chronic negative selection. For some subjects with primary SjS, these data show that (a) expanded B-cell clones are readily identified in the peripheral blood, (b) some clones are not eliminated by rituximab, and (c) persistent clones may be under chronic negative selection or may not be antigen-driven. The analysis of sequence variation among members of an expanded clone may provide a novel means

  11. Impact of clonal competition for peptide-MHC complexes on the CD8[superscript +] T-cell repertoire selection in a persistent viral infection

    Energy Technology Data Exchange (ETDEWEB)

    Wynn, Katherine K.; Fulton, Zara; Cooper, Leanne; Silins, Sharon L.; Gras, Stephanie; Archbold, Julia K.; Tynan, Fleur E.; Miles, John J.; McCluskey, James; Burrows, Scott R.; Rossjohn, Jamie; Khanna, Rajiv (Monash); (Queensland Inst. of Med. Rsrch.); (Melbourne)

    2008-04-29

    CD8{sup +} T-cell responses to persistent viral infections are characterized by the accumulation of an oligoclonal T-cell repertoire and a reduction in the naive T-cell pool. However, the precise mechanism for this phenomenon remains elusive. Here we show that human cytomegalovirus (HCMV)-specific CD8{sup +} T cells recognizing distinct epitopes from the pp65 protein and restricted through an identical HLA class I allele (HLA B*3508) exhibited either a highly conserved public T-cell repertoire or a private, diverse T-cell response, which was uniquely altered in each donor following in vitro antigen exposure. Selection of a public T-cell receptor (TCR) was coincident with an atypical major histocompatibility complex (MHC)-peptide structure, in that the epitope adopted a helical conformation that bulged from the peptide-binding groove, while a diverse TCR profile was observed in response to the epitope that formed a flatter, more 'featureless' landscape. Clonotypes with biased TCR usage demonstrated more efficient recognition of virus-infected cells, a greater CD8 dependency, and were more terminally differentiated in their phenotype when compared with the T cells expressing diverse TCR. These findings provide new insights into our understanding on how the biology of antigen presentation in addition to the structural features of the pMHC-I might shape the T-cell repertoire and its phenotype.

  12. Persistence and drug tolerance in pathogenic yeast

    DEFF Research Database (Denmark)

    Bojsen, Rasmus Kenneth; Regenberg, Birgitte; Folkesson, Sven Anders

    2017-01-01

    In this review, we briefly summarize the current understanding of how fungal pathogens can persist antifungal treatment without heritable resistance mutations by forming tolerant persister cells. Fungal infections tolerant to antifungal treatment have become a major medical problem. One mechanism...

  13. Curcumin targets breast cancer stem-like cells with microtentacles that persist in mammospheres and promote reattachment

    OpenAIRE

    Charpentier, Monica S.; Whipple, Rebecca A.; Vitolo, Michele I.; Boggs, Amanda E.; Slovic, Jana; Thompson, Keyata N.; Bhandary, Lekhana; Martin, Stuart S.

    2013-01-01

    Cancer stem-like cells (CSC) and circulating tumor cells (CTCs) have related properties associated with distant metastasis, but the mechanisms through which CSCs promote metastasis are unclear. In this study, we report that breast cancer cell lines with more stem-like properties display higher levels of microtentacles (McTNs), a type of tubulin-based protrusion of the plasma cell membrane which forms on detached or suspended cells and aid in cell reattachment. We hypothesized that CSCs with l...

  14. PDZ binding motif of HTLV-1 Tax promotes virus-mediated T-cell proliferation in vitro and persistence in vivo.

    Science.gov (United States)

    Xie, Li; Yamamoto, Brenda; Haoudi, Abdelali; Semmes, O John; Green, Patrick L

    2006-03-01

    HTLV-1 cellular transformation and disease induction is dependent on expression of the viral Tax oncoprotein. PDZ is a modular protein interaction domain used in organizing signaling complexes in eukaryotic cells through recognition of a specific binding motif in partner proteins. Tax-1, but not Tax-2, contains a PDZ-binding domain motif (PBM) that promotes the interaction with several cellular PDZ proteins. Herein, we investigate the contribution of the Tax-1 PBM in HTLV-induced proliferation and immortalization of primary T cells in vitro and viral survival in an infectious rabbit animal model. We generated several HTLV-1 and HTLV-2 Tax viral mutants, including HTLV-1deltaPBM, HTLV-2+C22(+PBM), and HTLV-2+ C18(deltaPBM). All Tax mutants maintained the ability to significantly activate the CREB/ATF or NFkappaB signaling pathways. Microtiter proliferation assays revealed that the Tax-1 PBM significantly increases both HTLV-1- and HTLV-2-induced primary T-cell proliferation. In addition, Tax-1 PBM was responsible for the micronuclei induction activity of Tax-1 relative to that of Tax-2. Viral infection and persistence were severely attenuated in rabbits inoculated with HTLV-1deltaPBM. Our results provide the first direct evidence suggesting that PBM-mediated associations between Tax-1 and cellular proteins play a key role in HTLV-induced cell proliferation and genetic instability in vitro and facilitate viral persistence in vivo.

  15. Persistent Transmissible Gastroenteritis Virus Infection Enhances Enterotoxigenic Escherichia coli K88 Adhesion by Promoting Epithelial-Mesenchymal Transition in Intestinal Epithelial Cells.

    Science.gov (United States)

    Xia, Lu; Dai, Lei; Yu, Qinghua; Yang, Qian

    2017-11-01

    Transmissible gastroenteritis virus (TGEV) is a coronavirus characterized by diarrhea and high morbidity rates, and the mortality rate is 100% in piglets less than 2 weeks old. Pigs infected with TGEV often suffer secondary infection by other pathogens, which aggravates the severity of diarrhea, but the mechanisms remain unknown. Here, we hypothesized that persistent TGEV infection stimulates the epithelial-mesenchymal transition (EMT), and thus enterotoxigenic Escherichia coli (ETEC) can more easily adhere to generating cells. Intestinal epithelial cells are the primary targets of TGEV and ETEC infections. We found that TGEV can persistently infect porcine intestinal columnar epithelial cells (IPEC-J2) and cause EMT, consistent with multiple changes in key cell characteristics. Infected cells display fibroblast-like shapes; exhibit increases in levels of mesenchymal markers with a corresponding loss of epithelial markers; have enhanced expression levels of interleukin-1β (IL-1β), IL-6, IL-8, transforming growth factor β (TGF-β), and tumor necrosis factor alpha (TNF-α) mRNAs; and demonstrate increases in migratory and invasive behaviors. Additional experiments showed that the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) signaling pathways via TGF-β is critical for the TGEV-mediated EMT process. Cellular uptake is also modified in cells that have undergone EMT. TGEV-infected cells have higher levels of integrin α5 and fibronectin and exhibit enhanced ETEC K88 adhesion. Reversal of EMT reduces ETEC K88 adhesion and inhibits the expression of integrin α5 and fibronectin. Overall, these results suggest that TGEV infection induces EMT in IPEC-J2 cells, increasing the adhesion of ETEC K88 in the intestine and facilitating dual infection. IMPORTANCE Transmissible gastroenteritis virus (TGEV) causes pig diarrhea and is often followed by secondary infection by other pathogens. In this study, we showed

  16. Transcriptomic Analysis of Persistent Infection with Foot-and-Mouth Disease Virus in Cattle Suggests Impairment of Apoptosis and Cell-Mediated Immunity in the Nasopharynx.

    Directory of Open Access Journals (Sweden)

    Michael Eschbaumer

    Full Text Available In order to investigate the mechanisms of persistent foot-and-mouth disease virus (FMDV infection in cattle, transcriptome alterations associated with the FMDV carrier state were characterized using a bovine whole-transcriptome microarray. Eighteen cattle (8 vaccinated with a recombinant FMDV A vaccine, 10 non-vaccinated were challenged with FMDV A24 Cruzeiro, and the gene expression profiles of nasopharyngeal tissues collected between 21 and 35 days after challenge were compared between 11 persistently infected carriers and 7 non-carriers. Carriers and non-carriers were further compared to 2 naïve animals that had been neither vaccinated nor challenged. At a controlled false-discovery rate of 10% and a minimum difference in expression of 50%, 648 genes were differentially expressed between FMDV carriers and non-carriers, and most (467 had higher expression in carriers. Among these, genes associated with cellular proliferation and the immune response-such as chemokines, cytokines and genes regulating T and B cells-were significantly overrepresented. Differential gene expression was significantly correlated between non-vaccinated and vaccinated animals (biological correlation +0.97, indicating a similar transcriptome profile across these groups. Genes related to prostaglandin E2 production and the induction of regulatory T cells were overexpressed in carriers. In contrast, tissues from non-carrier animals expressed higher levels of complement regulators and pro-apoptotic genes that could promote virus clearance. Based on these findings, we propose a working hypothesis for FMDV persistence in nasopharyngeal tissues of cattle, in which the virus may be maintained by an impairment of apoptosis and the local suppression of cell-mediated antiviral immunity by inducible regulatory T cells.

  17. Persistent Modelling

    DEFF Research Database (Denmark)

    2012-01-01

    The relationship between representation and the represented is examined here through the notion of persistent modelling. This notion is not novel to the activity of architectural design if it is considered as describing a continued active and iterative engagement with design concerns – an evident....... It also provides critical insight into the use of contemporary modelling tools and methods, together with an examination of the implications their use has within the territories of architectural design, realisation and experience....... on this subject, this book makes essential reading for anyone considering new ways of thinking about architecture. In drawing upon both historical and contemporary perspectives this book provides evidence of the ways in which relations between representation and the represented continue to be reconsidered...

  18. Persistent Modelling

    DEFF Research Database (Denmark)

    The relationship between representation and the represented is examined here through the notion of persistent modelling. This notion is not novel to the activity of architectural design if it is considered as describing a continued active and iterative engagement with design concerns – an evident....... It also provides critical insight into the use of contemporary modelling tools and methods, together with an examination of the implications their use has within the territories of architectural design, realisation and experience....... on this subject, this book makes essential reading for anyone considering new ways of thinking about architecture. In drawing upon both historical and contemporary perspectives this book provides evidence of the ways in which relations between representation and the represented continue to be reconsidered...

  19. Perturbation of B Cell Gene Expression Persists in HIV-Infected Children Despite Effective Antiretroviral Therapy and Predicts H1N1 Response.

    Science.gov (United States)

    Cotugno, Nicola; De Armas, Lesley; Pallikkuth, Suresh; Rinaldi, Stefano; Issac, Biju; Cagigi, Alberto; Rossi, Paolo; Palma, Paolo; Pahwa, Savita

    2017-01-01

    Despite effective antiretroviral therapy (ART), HIV-infected individuals with apparently similar clinical and immunological characteristics can vary in responsiveness to vaccinations. However, molecular mechanisms responsible for such impairment, as well as biomarkers able to predict vaccine responsiveness in HIV-infected children, remain unknown. Following the hypothesis that a B cell qualitative impairment persists in HIV-infected children (HIV) despite effective ART and phenotypic B cell immune reconstitution, the aim of the current study was to investigate B cell gene expression of HIV compared to age-matched healthy controls (HCs) and to determine whether distinct gene expression patterns could predict the ability to respond to influenza vaccine. To do so, we analyzed prevaccination transcriptional levels of a 96-gene panel in equal numbers of sort-purified B cell subsets (SPBS) isolated from peripheral blood mononuclear cells using multiplexed RT-PCR. Immune responses to H1N1 antigen were determined by hemaglutination inhibition and memory B cell ELISpot assays following trivalent-inactivated influenza vaccination (TIV) for all study participants. Although there were no differences in terms of cell frequencies of SPBS between HIV and HC, the groups were distinguishable based upon gene expression analyses. Indeed, a 28-gene signature, characterized by higher expression of genes involved in the inflammatory response and immune activation was observed in activated memory B cells (CD27 + CD21 - ) from HIV when compared to HC despite long-term viral control (>24 months). Further analysis, taking into account H1N1 responses after TIV in HIV participants, revealed that a 25-gene signature in resting memory (RM) B cells (CD27 + CD21 + ) was able to distinguish vaccine responders from non-responders (NR). In fact, prevaccination RM B cells of responders showed a higher expression of gene sets involved in B cell adaptive immune responses ( APRIL, BTK, BLIMP1 ) and

  20. Interaction between Galectin-9/TIM-3 pathway and follicular helper CD4+ T cells contributes to viral persistence in chronic hepatitis C.

    Science.gov (United States)

    Zhuo, Ya; Zhang, Yi-Fu; Wu, Hong-Jie; Qin, Lei; Wang, Yan-Ping; Liu, A-Min; Wang, Xin-Hong

    2017-10-01

    Both Galectin 9 (Gal-9)/T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) pathway and follicular helper CD4 + T (Tfh) cells play important roles in persistent hepatitis C virus (HCV) infection. Thus, we aimed to investigate the regulatory role of interaction between Gal-9/TIM-3 pathway and Tfh cells in chronic hepatitis C. A total of 44 chronic hepatitis C patients and 19 normal controls (NCs) were enrolled in this study. Purified CD4 + T cells were cultured by TIM-3 Fc protein, recombinant Gal-9, or IL-21 for 48h. TIM-3 expression, Tfh proportion, and IL-21 production was measured, respectively. The immunomodulatory role of Gal-9/TIM-3 and IL-21 was also investigated in HCV cell culture system in vitro. We found that the percentage corresponding to both TIM-3-positive and CXCR5 + ICOS + Tfh cells within CD4 + T cells, which correlated with HCV RNA replication, was significantly elevated in patients with chronic hepatitis C in comparison with those in NCs. Moreover, blockade of Gal-9/TIM-3 pathway by TIM-3 Fc protein increased Tfh cells proportion, IL-21 mRNA and protein expression within purified CD4 + T cells, while activation of Gal-9/TIM-3 signaling by Gal-9 stimulation decreased IL-21 production in both patients with chronic HCV infection and healthy individuals. Meanwhile, high concentrations (100 and 200ng/mL) of IL-21 stimulation also elevated TIM-3 expression on CD4 + T cells in chronic hepatitis C. Furthermore, TIM-3 blockage and IL-21 stimulation suppressed mRNA expressions of HCV-induced antiviral proteins (myxovirus resistance A and oligoadenylate synthetase) in Huh7.5 cells without affecting viral replication in HCV cell culture system. The interaction between Gal-9/TIM-3 pathway and Tfh cells contributed to viral persistent in chronic HCV infection, which might be pivotal for development of new therapeutic approaches for chronic hepatitis C. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  1. Persistence of collagen type II-specific T-cell clones in the synovial membrane of a patient with rheumatoid arthritis

    International Nuclear Information System (INIS)

    Londei, M.; Savill, C.M.; Verhoef, A.; Brennan, F.; Leech, Z.A.; Feldmann, M.; Duance, V.; Maini, R.N.

    1989-01-01

    Rheumatoid arthritis is an autoimmune disease characterized by T-cell infiltration of the synovium of joints. Analysis of the phenotype and antigen specificity of the infiltrating cells may thus provide insight into the pathogenesis of rheumatoid arthritis. T cells were cloned with interleukin 2, a procedure that selects for in vivo-activated cells. All clones had the CD4 CDW29 phenotype. Their antigen specificity was tested by using a panel of candidate joint autoantigens. Four of 17 reacted against autologous blood mononuclear cells. Two clones proliferated in response to collagen type II. After 21 months, another set of clones was derived from synovial tissue of the same joint. One of eight clones tested showed a strong proliferative response against collagen type II. The uncloned synovial T cells of a third operation from another joint also responded to collagen type II. The persistence of collagen type II-specific T cells in active rheumatoid joints over a period of 3 years suggests that collagen type II could be one of the autoantigens involved in perpetuating the inflammatory process in rheumatoid arthritis

  2. Persistent changes in circulating and intestinal γδ T cell subsets, invariant natural killer T cells and mucosal-associated invariant T cells in children and adults with coeliac disease.

    Science.gov (United States)

    Dunne, Margaret R; Elliott, Louise; Hussey, Seamus; Mahmud, Nasir; Kelly, Jacinta; Doherty, Derek G; Feighery, Conleth F

    2013-01-01

    Coeliac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals. The only current therapy is a lifelong gluten free diet. While much work has focused on the gliadin-specific adaptive immune response in coeliac disease, little is understood about the involvement of the innate immune system. Here we used multi-colour flow cytometry to determine the number and frequency of γδ T cells (Vδ1, Vδ2 and Vδ3 subsets), natural killer cells, CD56(+) T cells, invariant NKT cells, and mucosal associated invariant T cells, in blood and duodenum from adults and children with coeliac disease and healthy matched controls. All circulating innate lymphocyte populations were significantly decreased in adult, but not paediatric coeliac donors, when compared with healthy controls. Within the normal small intestine, we noted that Vδ3 cells were the most abundant γδ T cell type in the adult epithelium and lamina propria, and in the paediatric lamina propria. In contrast, patients with coeliac disease showed skewing toward a predominant Vδ1 profile, observed for both adult and paediatric coeliac disease cohorts, particularly within the gut epithelium. This was concurrent with decreases in all other gut lymphocyte subsets, suggesting a specific involvement of Vδ1 cells in coeliac disease pathogenesis. Further analysis showed that γδ T cells isolated from the coeliac gut display an activated, effector memory phenotype, and retain the ability to rapidly respond to in vitro stimulation. A profound loss of CD56 expression in all lymphocyte populations was noted in the coeliac gut. These findings demonstrate a sustained aberrant innate lymphocyte profile in coeliac disease patients of all ages, persisting even after elimination of gluten from the diet. This may lead to impaired immunity, and could potentially account for the increased incidence of autoimmune co-morbidity.

  3. Persistent changes in circulating and intestinal γδ T cell subsets, invariant natural killer T cells and mucosal-associated invariant T cells in children and adults with coeliac disease.

    Directory of Open Access Journals (Sweden)

    Margaret R Dunne

    Full Text Available Coeliac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals. The only current therapy is a lifelong gluten free diet. While much work has focused on the gliadin-specific adaptive immune response in coeliac disease, little is understood about the involvement of the innate immune system. Here we used multi-colour flow cytometry to determine the number and frequency of γδ T cells (Vδ1, Vδ2 and Vδ3 subsets, natural killer cells, CD56(+ T cells, invariant NKT cells, and mucosal associated invariant T cells, in blood and duodenum from adults and children with coeliac disease and healthy matched controls. All circulating innate lymphocyte populations were significantly decreased in adult, but not paediatric coeliac donors, when compared with healthy controls. Within the normal small intestine, we noted that Vδ3 cells were the most abundant γδ T cell type in the adult epithelium and lamina propria, and in the paediatric lamina propria. In contrast, patients with coeliac disease showed skewing toward a predominant Vδ1 profile, observed for both adult and paediatric coeliac disease cohorts, particularly within the gut epithelium. This was concurrent with decreases in all other gut lymphocyte subsets, suggesting a specific involvement of Vδ1 cells in coeliac disease pathogenesis. Further analysis showed that γδ T cells isolated from the coeliac gut display an activated, effector memory phenotype, and retain the ability to rapidly respond to in vitro stimulation. A profound loss of CD56 expression in all lymphocyte populations was noted in the coeliac gut. These findings demonstrate a sustained aberrant innate lymphocyte profile in coeliac disease patients of all ages, persisting even after elimination of gluten from the diet. This may lead to impaired immunity, and could potentially account for the increased incidence of autoimmune co-morbidity.

  4. The role of metabolism in bacterial persistence

    Directory of Open Access Journals (Sweden)

    Stephanie M. Amato

    2014-03-01

    Full Text Available Bacterial persisters are phenotypic variants with extraordinary tolerances toward antibiotics. Persister survival has been attributed to inhibition of essential cell functions during antibiotic stress, followed by reversal of the process and resumption of growth upon removal of the antibiotic. Metabolism plays a critical role in this process, since it participates in the entry, maintenance, and exit from the persister phenotype. Here, we review the experimental evidence that demonstrates the importance of metabolism to persistence, highlight the successes and potential for targeting metabolism in the search for anti-persister therapies, and discuss the current methods and challenges to understand persister physiology.

  5. Clinical isolates of GB virus type C vary in their ability to persist and replicate in peripheral blood mononuclear cell cultures

    International Nuclear Information System (INIS)

    George, Sarah L.; Xiang Jinhua; Stapleton, Jack T.

    2003-01-01

    GB virus C/hepatitis G virus (GBV-C) replication in vitro is inefficient and inconsistent. In this study, clinical isolates of GBV-C were evaluated using peripheral blood mononuclear cell (PBMC) based culture methods. Isolates varied consistently in their ability to persistently replicate, and yield increased in cells grown without PHA/IL-2 stimulation. The deduced polyprotein sequence of an isolate that replicated well was determined (GenBank AY196904) and compared to 20 full-length GBV-C sequences. Fourteen of the 16 unique amino acid polymorphisms identified were in the coding regions for nonstructural proteins associated with interferon resistance and RNA replication. These data indicate that clinical GBV-C isolates vary in their ability to persist in culture, do not require PHA/IL-2 stimulation, and that sequence variability in key regulatory regions may affect growth in PBMC cultures. Since GBV-C appears to inhibit HIV replication in a coinfection model, these studies should facilitate determination of the mechanism of this interaction

  6. The Attenuated Brucella abortus Strain 19 Invades, Persists in, and Activates Human Dendritic Cells, and Induces the Secretion of IL-12p70 but Not IL-23

    Science.gov (United States)

    Weinhold, Mario; Eisenblätter, Martin; Jasny, Edith; Fehlings, Michael; Finke, Antje; Gayum, Hermine; Rüschendorf, Ursula; Renner Viveros, Pablo; Moos, Verena; Allers, Kristina; Schneider, Thomas; Schaible, Ulrich E.; Schumann, Ralf R.; Mielke, Martin E.; Ignatius, Ralf

    2013-01-01

    Background Bacterial vectors have been proposed as novel vaccine strategies to induce strong cellular immunity. Attenuated strains of Brucella abortus comprise promising vector candidates since they have the potential to induce strong CD4+ and CD8+ T-cell mediated immune responses in the absence of excessive inflammation as observed with other Gram-negative bacteria. However, some Brucella strains interfere with the maturation of dendritic cells (DCs), which is essential for antigen-specific T-cell priming. In the present study, we investigated the interaction of human monocyte-derived DCs with the smooth attenuated B. abortus strain (S) 19, which has previously been employed successfully to vaccinate cattle. Methodology/Principal findings We first looked into the potential of S19 to hamper the cytokine-induced maturation of DCs; however, infected cells expressed CD25, CD40, CD80, and CD86 to a comparable extent as uninfected, cytokine-matured DCs. Furthermore, S19 activated DCs in the absence of exogeneous stimuli, enhanced the expression of HLA-ABC and HLA-DR, and was able to persist intracellularly without causing cytotoxicity. Thus, DCs provide a cellular niche for persisting brucellae in vivo as a permanent source of antigen. S19-infected DCs produced IL-12/23p40, IL-12p70, and IL-10, but not IL-23. While heat-killed bacteria also activated DCs, soluble mediators were not involved in S19-induced activation of human DCs. HEK 293 transfectants revealed cellular activation by S19 primarily through engagement of Toll-like receptor (TLR)2. Conclusions/Significance Thus, as an immunological prerequisite for vaccine efficacy, B. abortus S19 potently infects and potently activates (most likely via TLR2) human DCs to produce Th1-promoting cytokines. PMID:23805193

  7. The Attenuated Brucella abortus Strain 19 Invades, Persists in, and Activates Human Dendritic Cells, and Induces the Secretion of IL-12p70 but Not IL-23.

    Directory of Open Access Journals (Sweden)

    Mario Weinhold

    Full Text Available Bacterial vectors have been proposed as novel vaccine strategies to induce strong cellular immunity. Attenuated strains of Brucella abortus comprise promising vector candidates since they have the potential to induce strong CD4(+ and CD8(+ T-cell mediated immune responses in the absence of excessive inflammation as observed with other Gram-negative bacteria. However, some Brucella strains interfere with the maturation of dendritic cells (DCs, which is essential for antigen-specific T-cell priming. In the present study, we investigated the interaction of human monocyte-derived DCs with the smooth attenuated B. abortus strain (S 19, which has previously been employed successfully to vaccinate cattle.We first looked into the potential of S19 to hamper the cytokine-induced maturation of DCs; however, infected cells expressed CD25, CD40, CD80, and CD86 to a comparable extent as uninfected, cytokine-matured DCs. Furthermore, S19 activated DCs in the absence of exogeneous stimuli, enhanced the expression of HLA-ABC and HLA-DR, and was able to persist intracellularly without causing cytotoxicity. Thus, DCs provide a cellular niche for persisting brucellae in vivo as a permanent source of antigen. S19-infected DCs produced IL-12/23p40, IL-12p70, and IL-10, but not IL-23. While heat-killed bacteria also activated DCs, soluble mediators were not involved in S19-induced activation of human DCs. HEK 293 transfectants revealed cellular activation by S19 primarily through engagement of Toll-like receptor (TLR2.Thus, as an immunological prerequisite for vaccine efficacy, B. abortus S19 potently infects and potently activates (most likely via TLR2 human DCs to produce Th1-promoting cytokines.

  8. Association of Dioxin and Other Persistent Organic Pollutants (POPs) with Diabetes: Epidemiological Evidence and New Mechanisms of Beta Cell Dysfunction

    Science.gov (United States)

    De Tata, Vincenzo

    2014-01-01

    The worldwide explosion of the rates of diabetes and other metabolic diseases in the last few decades cannot be fully explained only by changes in the prevalence of classical lifestyle-related risk factors, such as physical inactivity and poor diet. For this reason, it has been recently proposed that other “nontraditional” risk factors could contribute to the diabetes epidemics. In particular, an increasing number of reports indicate that chronic exposure to and accumulation of a low concentration of environmental pollutants (especially the so-called persistent organic pollutants (POPs)) within the body might be associated with diabetogenesis. In this review, the epidemiological evidence suggesting a relationship between dioxin and other POPs exposure and diabetes incidence will be summarized, and some recent developments on the possible underlying mechanisms, with particular reference to dioxin, will be presented and discussed. PMID:24802877

  9. Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia subclones from diagnosis to relapse

    Science.gov (United States)

    Bashford-Rogers, R J M; Nicolaou, K A; Bartram, J; Goulden, N J; Loizou, L; Koumas, L; Chi, J; Hubank, M; Kellam, P; Costeas, P A; Vassiliou, G S

    2016-01-01

    The strongest predictor of relapse in B-cell acute lymphoblastic leukemia (B-ALL) is the level of persistence of tumor cells after initial therapy. The high mutation rate of the B-cell receptor (BCR) locus allows high-resolution tracking of the architecture, evolution and clonal dynamics of B-ALL. Using longitudinal BCR repertoire sequencing, we find that the BCR undergoes an unexpectedly high level of clonal diversification in B-ALL cells through both somatic hypermutation and secondary rearrangements, which can be used for tracking the subclonal composition of the disease and detect minimal residual disease with unprecedented sensitivity. We go on to investigate clonal dynamics of B-ALL using BCR phylogenetic analyses of paired diagnosis-relapse samples and find that large numbers of small leukemic subclones present at diagnosis re-emerge at relapse alongside a dominant clone. Our findings suggest that in all informative relapsed patients, the survival of large numbers of clonogenic cells beyond initial chemotherapy is a surrogate for inherent partial chemoresistance or inadequate therapy, providing an increased opportunity for subsequent emergence of fully resistant clones. These results frame early cytoreduction as an important determinant of long-term outcome. PMID:27211266

  10. New-found fundamentals of bacterial persistence.

    Science.gov (United States)

    Kint, Cyrielle I; Verstraeten, Natalie; Fauvart, Maarten; Michiels, Jan

    2012-12-01

    Persister cells display tolerance to high doses of bactericidal antibiotics and typically comprise a small fraction of a bacterial population. Recently, evidence was provided for a causal link between therapy failure and the presence of persister cells in chronic infections, underscoring the need for research on bacterial persistence. A series of recent breakthroughs have shed light on the multiplicity of persister genes, the contribution of gene expression noise to persister formation, the importance of active responses to antibiotic tolerance and heterogeneity among persister cells. Moreover, the development of in vivo model systems has highlighted the clinical relevance of persistence. This review discusses these recent advances and how this knowledge fundamentally changes the way in which we will perceive the problem of antibiotic tolerance in years to come. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. Prenatal cadmium exposure produces persistent changes to thymus and spleen cell phenotypic repertoire as well as the acquired immune response

    International Nuclear Information System (INIS)

    Holásková, Ida; Elliott, Meenal; Hanson, Miranda L.; Schafer, Rosana; Barnett, John B.

    2012-01-01

    Cadmium (Cd) is a common environmental contaminant. Adult exposure to Cd alters the immune system, however, there are limited studies on the effects of prenatal exposure to Cd. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl 2 (10 ppm) and the effects on the immune system of the offspring were assessed at 20 weeks of age. Prenatal Cd exposure caused an increase in the percent of CD4 − CD8 − CD44 + CD25 − (DN1) thymocytes in both sexes and a decrease in the percent of CD4 − CD8 − CD44 − CD25 + (DN3) thymocytes in females. Females had an increase in the percent of splenic CD4 + T cells, CD8 + T cells, and CD45R/B220 + B cells and a decrease in the percent of NK cells and granulocytes (Gr-1 + ). Males had an increase in the percent of splenic CD4 + T cells and CD45R/B220 + B cells and a decrease in the percent of CD8 + T cells, NK cells, and granulocytes. The percentage of neutrophils and myeloid-derived suppressor cells were reduced in both sexes. The percent of splenic nTreg cells was decreased in all Cd-exposed offspring. Cd-exposed offspring were immunized with a streptococcal vaccine and the antibody response was determined. PC-specific serum antibody titers were decreased in Cd exposed female offspring but increased in the males. PspA-specific serum IgG titers were increased in both females and males compared to control animals. Females had a decrease in PspA-specific serum IgM antibody titers. Females and males had a decrease in the number of splenic anti-PspA antibody-secreting cells when standardized to the number of B cells. These findings demonstrate that very low levels of Cd exposure during gestation can result in long term sex-specific alterations on the immune system of the offspring. -- Highlights: ► Prenatal exposure to cadmium alters the immune system of 20 week old offspring. ► The percentage of DN1 and DN3 thymocytes was changed. ► Males and females had changed percentages of numerous splenic cell

  12. Prenatal cadmium exposure produces persistent changes to thymus and spleen cell phenotypic repertoire as well as the acquired immune response

    Energy Technology Data Exchange (ETDEWEB)

    Holásková, Ida; Elliott, Meenal; Hanson, Miranda L.; Schafer, Rosana [Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26506 (United States); Barnett, John B., E-mail: jbarnett@hsc.wvu.edu [Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26506 (United States); Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, WV 26506 (United States)

    2012-12-01

    Cadmium (Cd) is a common environmental contaminant. Adult exposure to Cd alters the immune system, however, there are limited studies on the effects of prenatal exposure to Cd. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl{sub 2} (10 ppm) and the effects on the immune system of the offspring were assessed at 20 weeks of age. Prenatal Cd exposure caused an increase in the percent of CD4{sup −}CD8{sup −}CD44{sup +}CD25{sup −} (DN1) thymocytes in both sexes and a decrease in the percent of CD4{sup −}CD8{sup −}CD44{sup −}CD25{sup +} (DN3) thymocytes in females. Females had an increase in the percent of splenic CD4{sup +} T cells, CD8{sup +} T cells, and CD45R/B220{sup +} B cells and a decrease in the percent of NK cells and granulocytes (Gr-1{sup +}). Males had an increase in the percent of splenic CD4{sup +} T cells and CD45R/B220{sup +} B cells and a decrease in the percent of CD8{sup +} T cells, NK cells, and granulocytes. The percentage of neutrophils and myeloid-derived suppressor cells were reduced in both sexes. The percent of splenic nTreg cells was decreased in all Cd-exposed offspring. Cd-exposed offspring were immunized with a streptococcal vaccine and the antibody response was determined. PC-specific serum antibody titers were decreased in Cd exposed female offspring but increased in the males. PspA-specific serum IgG titers were increased in both females and males compared to control animals. Females had a decrease in PspA-specific serum IgM antibody titers. Females and males had a decrease in the number of splenic anti-PspA antibody-secreting cells when standardized to the number of B cells. These findings demonstrate that very low levels of Cd exposure during gestation can result in long term sex-specific alterations on the immune system of the offspring. -- Highlights: ► Prenatal exposure to cadmium alters the immune system of 20 week old offspring. ► The percentage of DN1 and DN3 thymocytes was changed

  13. Development and characteristics of a subline of Ehrlich ascites carcinoma cells persistently resistant to 5-fluoro-2'-deoxyuridine.

    Science.gov (United States)

    Jastreboff, M M; Zielińska, Z M

    1983-01-01

    A subline of Ehrlich ascites carcinoma (EAC) cells resistant to 5-fluoro-2'-deoxy-uridine (FdUrd) was developed by continuous exposure to progressively increasing concentrations of the drug (35-75 mg/kg per day) during 15 passages through mice. Since then, the EAC cells have been retransplanted more than 80 times through drug-untreated mice and continue to be resistant. After adaptation to growth in suspension culture the drug-adapted cells were 1000 times more resistant to FdUrd in comparison with parental ones, and remained near-tetraploid with doubling time longer than in parental line. The activity of thymidine kinase was deeply depressed (100-fold) whereas that of thymidylate synthetase several-fold increased in the resistant EAC cells, both grown in vivo and in vitro.

  14. The persistent inhibitory properties of saxagliptin on renal dipeptidyl peptidase-4: Studies with HK-2 cells in vitro and normal rats in vivo

    Directory of Open Access Journals (Sweden)

    Masako Uchii

    2017-11-01

    Full Text Available Saxagliptin, a potent and selective DPP-4 inhibitor, exhibits a slow dissociation from DPP-4. We investigated the sustained effects of saxagliptin on renal DPP-4 activity in a washout study using renal tubular (HK-2 cells, and in a pharmacodynamic study using normal rats. In HK-2 cells, the inhibitory potency of saxagliptin on DPP-4 activity persisted after washout, while that of sitagliptin was clearly reduced. In normal rats, a single treatment of saxagliptin or sitagliptin inhibited the plasma DPP-4 activity to similar levels. The inhibitory action of saxagliptin on the renal DPP-4 activity was retained, even when its inhibitory effect on the plasma DPP-4 activity disappeared. However, the inhibitory action of sitagliptin on the renal DPP-4 activity was abolished in correlation with the inhibition of the plasma DPP-4 activity. In situ staining showed that saxagliptin suppressed the DPP-4 activity in both glomerular and tubular cells and its inhibitory effects were significantly higher than those of sitagliptin. Saxagliptin exerted a sustained inhibitory effect on the renal DPP-4 activity in vitro and in vivo. The long binding action of saxagliptin in renal tubular cells might involve the sustained inhibition of renal DPP-4.

  15. Remodeling of the Host Cell Plasma Membrane by HIV-1 Nef and Vpu: A Strategy to Ensure Viral Fitness and Persistence.

    Science.gov (United States)

    Sugden, Scott M; Bego, Mariana G; Pham, Tram N Q; Cohen, Éric A

    2016-03-03

    The plasma membrane protects the cell from its surroundings and regulates cellular communication, homing, and metabolism. Not surprisingly, the composition of this membrane is highly controlled through the vesicular trafficking of proteins to and from the cell surface. As intracellular pathogens, most viruses exploit the host plasma membrane to promote viral replication while avoiding immune detection. This is particularly true for the enveloped human immunodeficiency virus (HIV), which assembles and obtains its lipid shell directly at the plasma membrane. HIV-1 encodes two proteins, negative factor (Nef) and viral protein U (Vpu), which function primarily by altering the quantity and localization of cell surface molecules to increase virus fitness despite host antiviral immune responses. These proteins are expressed at different stages in the HIV-1 life cycle and employ a variety of mechanisms to target both unique and redundant surface proteins, including the viral receptor CD4, host restriction factors, immunoreceptors, homing molecules, tetraspanins and membrane transporters. In this review, we discuss recent progress in the study of the Nef and Vpu targeting of host membrane proteins with an emphasis on how remodeling of the cell membrane allows HIV-1 to avoid host antiviral immune responses leading to the establishment of systemic and persistent infection.

  16. Hereditary Persistence of Fetal Hemoglobin Caused by Single Nucleotide Promoter Mutations in Sickle Cell Trait and Hb SC Disease.

    Science.gov (United States)

    Akinbami, Anthony O; Campbell, Andrew D; Han, Zeqiu J; Luo, Hong-Yuan; Chui, David H K; Steinberg, Martin H

    2016-01-01

    Hereditary persistence of fetal hemoglobin (HPFH) can be caused by point mutations in the γ-globin gene promoters. We report three rare cases: a child compound heterozygous for Hb S (HBB: c.20A > T) and HPFH with a novel point mutation in the (A)γ-globin gene promoter who had 42.0% Hb S, 17.0% Hb A and 38.0% Hb F; a man with Hb SC (HBB: c.19G > A) disease and a point mutation in the (G)γ-globin gene promoter who had 54.0% Hb S, 18.0% Hb C and 25.0% Hb F; a child heterozygous for Hb S and HPFH due to mutations in both the (A)γ- and (G)γ-globin gene promoters in cis [(G)γ(A)γ(β(+)) HPFH], with 67.0% Hb A, 6.5% Hb S and 25.0% Hb F.

  17. Long-term persistence of acquired resistance to 5-fluorouracil in the colon cancer cell line SW620

    Energy Technology Data Exchange (ETDEWEB)

    Tentes, I.K., E-mail: itentes@med.duth.gr [Department of Biochemistry, Medical School, Democritus University of Thrace, 6th km Alexandroupolis-Komotini (Dragana), 68100 Alexandroupolis (Greece); Schmidt, W.M. [Center for Anatomy and Cell Biology, Waehringer Strasse 13, 1090 Vienna (Austria); Krupitza, G. [Institute of Clinical Pathology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna (Austria); Steger, G.G.; Mikulits, W. [Department of Medicine I, Medical University of Vienna, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna (Austria); Kortsaris, A. [Department of Biochemistry, Medical School, Democritus University of Thrace, 6th km Alexandroupolis-Komotini (Dragana), 68100 Alexandroupolis (Greece); Mader, R.M. [Department of Medicine I, Medical University of Vienna, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna (Austria)

    2010-11-15

    Treatment resistance to antineoplastic drugs represents a major clinical problem. Here, we investigated the long-term stability of acquired resistance to 5-fluorouracil (FU) in an in vitro colon cancer model, using four sub-clones characterised by increasing FU-resistance derived from the cell line SW620. The resistance phenotype was preserved after FU withdrawal for 15 weeks ({approx} 100 cell divisions) independent of the established level of drug resistance and of epigenetic silencing. Remarkably, resistant clones tolerated serum deprivation, adopted a CD133{sup +} CD44{sup -} phenotype, and further exhibited loss of membrane-bound E-cadherin together with predominant nuclear {beta}-catenin localisation. Thus, we provide evidence for a long-term memory of acquired drug resistance, driven by multiple cellular strategies (epithelial-mesenchymal transition and selective propagation of CD133{sup +} cells). These resistance phenomena, in turn, accentuate the malignant phenotype.

  18. Human SGT interacts with Bag-6/Bat-3/Scythe and cells with reduced levels of either protein display persistence of few misaligned chromosomes and mitotic arrest

    International Nuclear Information System (INIS)

    Winnefeld, Marc; Grewenig, Annabel; Schnoelzer, Martina; Spring, Herbert; Knoch, Tobias A.; Gan, Eugene C.; Rommelaere, Jean; Cziepluch, Celina

    2006-01-01

    The human small glutamine-rich TPR-containing protein (hSGT) is essential for cell division since RNA-interference-mediated strong reduction of hSGT protein levels causes mitotic arrest (M. Winnefeld, J. Rommelaere, and C. Cziepluch, The human small glutamine-rich TPR-containing protein is required for progress through cell division, Exp. Cell Res. 293 (2004), 43-57). Analysis of HeLa cells expressing a histone 2A-YFP fusion protein revealed the continuous presence of few mislocalized chromosomes close to the spindle poles as possible cause for hSGT depletion-dependent prometaphase arrest. Cells unable to rescue these mislocalized chromosomes into the metaphase plate died at this stage through apoptosis. In order to address hSGT function at the molecular level, mass spectrometry analysis of proteins which co-immunoprecipitated with Flag-tagged hSGT was performed. Thereby, Hsp70 and Bag-6/Bat-3/Scythe were identified as novel hSGT interaction partners while interaction with Hsc70 was confirmed. Results obtained with truncated versions of the hSGT protein revealed that Bag-6/Bat-3/Scythe and Hsp70 or Hsc70 were independently able to form complexes with hSGT. Interaction of hSGT with Hsc70, Hsp70 or Bag-6/Bat-3/Scythe was demonstrated in prometaphase, thereby suggesting a possible role for complexes containing hSGT and distinct (co)-chaperones during mitosis. Finally, cells from populations with reduced levels of Bag-6/Bat-3/Scythe also displayed persistence of mislocalized chromosomes and mitotic arrest, which strongly indicated that hSGT-Bag-6/Bat-3/Scythe complexes could be directly or indirectly required for complete chromosome congression

  19. Effects of defined mixtures of persistent organic pollutants (POPs) on multiple cellular responses in the human hepatocarcinoma cell line, HepG2, using high content analysis screening

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, Jodie [Institute for Global Food Security, School of Biological Sciences, Queen' s University Belfast, Northern Ireland (United Kingdom); Berntsen, Hanne Friis; Zimmer, Karin Elisabeth [Norwegian University of Life Sciences, Oslo (Norway); Frizzell, Caroline [Institute for Global Food Security, School of Biological Sciences, Queen' s University Belfast, Northern Ireland (United Kingdom); Verhaegen, Steven; Ropstad, Erik [Norwegian University of Life Sciences, Oslo (Norway); Connolly, Lisa, E-mail: l.connolly@qub.ac.uk [Institute for Global Food Security, School of Biological Sciences, Queen' s University Belfast, Northern Ireland (United Kingdom)

    2016-03-01

    Persistent organic pollutants (POPs) are toxic substances, highly resistant to environmental degradation, which can bio-accumulate and have long-range atmospheric transport potential. Most studies focus on single compound effects, however as humans are exposed to several POPs simultaneously, investigating exposure effects of real life POP mixtures on human health is necessary. A defined mixture of POPs was used, where the compound concentration reflected its contribution to the levels seen in Scandinavian human serum (total mix). Several sub mixtures representing different classes of POPs were also constructed. The perfluorinated (PFC) mixture contained six perfluorinated compounds, brominated (Br) mixture contained seven brominated compounds, chlorinated (Cl) mixture contained polychlorinated biphenyls and also p,p’-dichlorodiphenyldichloroethylene, hexachlorobenzene, three chlordanes, three hexachlorocyclohexanes and dieldrin. Human hepatocarcinoma (HepG2) cells were used for 2 h and 48 h exposures to the seven mixtures and analysis on a CellInsight™ NXT High Content Screening platform. Multiple cytotoxic endpoints were investigated: cell number, nuclear intensity and area, mitochondrial mass and membrane potential (MMP) and reactive oxygen species (ROS). Both the Br and Cl mixtures induced ROS production but did not lead to apoptosis. The PFC mixture induced ROS production and likely induced cell apoptosis accompanied by the dissipation of MMP. Synergistic effects were evident for ROS induction when cells were exposed to the PFC + Br mixture in comparison to the effects of the individual mixtures. No significant effects were detected in the Br + Cl, PFC + Cl or total mixtures, which contain the same concentrations of chlorinated compounds as the Cl mixture plus additional compounds; highlighting the need for further exploration of POP mixtures in risk assessment. - Highlights: • High content analysis (HCA) is a novel approach for determining toxicity of

  20. Effects of defined mixtures of persistent organic pollutants (POPs) on multiple cellular responses in the human hepatocarcinoma cell line, HepG2, using high content analysis screening

    International Nuclear Information System (INIS)

    Wilson, Jodie; Berntsen, Hanne Friis; Zimmer, Karin Elisabeth; Frizzell, Caroline; Verhaegen, Steven; Ropstad, Erik; Connolly, Lisa

    2016-01-01

    Persistent organic pollutants (POPs) are toxic substances, highly resistant to environmental degradation, which can bio-accumulate and have long-range atmospheric transport potential. Most studies focus on single compound effects, however as humans are exposed to several POPs simultaneously, investigating exposure effects of real life POP mixtures on human health is necessary. A defined mixture of POPs was used, where the compound concentration reflected its contribution to the levels seen in Scandinavian human serum (total mix). Several sub mixtures representing different classes of POPs were also constructed. The perfluorinated (PFC) mixture contained six perfluorinated compounds, brominated (Br) mixture contained seven brominated compounds, chlorinated (Cl) mixture contained polychlorinated biphenyls and also p,p’-dichlorodiphenyldichloroethylene, hexachlorobenzene, three chlordanes, three hexachlorocyclohexanes and dieldrin. Human hepatocarcinoma (HepG2) cells were used for 2 h and 48 h exposures to the seven mixtures and analysis on a CellInsight™ NXT High Content Screening platform. Multiple cytotoxic endpoints were investigated: cell number, nuclear intensity and area, mitochondrial mass and membrane potential (MMP) and reactive oxygen species (ROS). Both the Br and Cl mixtures induced ROS production but did not lead to apoptosis. The PFC mixture induced ROS production and likely induced cell apoptosis accompanied by the dissipation of MMP. Synergistic effects were evident for ROS induction when cells were exposed to the PFC + Br mixture in comparison to the effects of the individual mixtures. No significant effects were detected in the Br + Cl, PFC + Cl or total mixtures, which contain the same concentrations of chlorinated compounds as the Cl mixture plus additional compounds; highlighting the need for further exploration of POP mixtures in risk assessment. - Highlights: • High content analysis (HCA) is a novel approach for determining toxicity of

  1. Fast intracellular dissolution and persistent cellular uptake of silver nanoparticles in CHO-K1 cells: implication for cytotoxicity

    DEFF Research Database (Denmark)

    Jiang, Xiumei; Miclaus, Teodora; Wang, Liming

    2015-01-01

    . Subsequent cytotoxicity studies show that Ag NPs decrease cell viability and increase ROS production. Pre-incubation with N-acetyl-l-cysteine, an efficient antioxidant and Ag+ chelator, diminished the cytotoxicity caused by Ag NPs or Ag+ exposure. Our study suggests that the cytotoxicity mechanism of Ag NPs...

  2. Persistence of antigen is required to maintain transplantation tolerance induced by genetic modification of bone marrow stem cells.

    Science.gov (United States)

    Tian, C; Bagley, J; Iacomini, J

    2006-09-01

    Genetic modification of hematopoietic stem cells (HSCs) resulting in a state of molecular chimerism can be used to induce donor-specific tolerance to allografts. However, the requirements for maintaining tolerance in molecular chimeras remain unknown. Here, we examined whether long-term expression of a retrovirally encoded alloantigen in hematopoietic cells is required to maintain donor-specific tolerance in molecular chimeras. To this end, mice were reconstituted with syngeneic bone marrow transduced with retroviruses carrying the gene encoding the allogeneic MHC class I molecule Kb. Following induction of molecular chimerism, mice were depleted of cells expressing Kb by administration of the anti-Kb monoclonal antibody Y-3. Mice that were effectively depleted of cells expressing the retrovirally encoded MHC class I antigen rejected Kb disparate skin allografts. In contrast, control molecular chimeras accepted Kb disparate skin allografts indefinitely. These data suggest maintenance of tolerance in molecular chimeras requires long-term expression of retrovirally transduced alloantigen on the progeny of retrovirally transduced HSCs.

  3. HIV-1 Subtype C Mosaic Gag Expressed by BCG and MVA Elicits Persistent Effector T Cell Responses in a Prime-Boost Regimen in Mice.

    Directory of Open Access Journals (Sweden)

    Tsungai Ivai Jongwe

    Full Text Available Over 90% of HIV/AIDS positive individuals in sub-Saharan Africa are infected with highly heterogeneous HIV-1 subtype C (HIV-1C viruses. One of the best ways to reduce the burden of this disease is the development of an affordable and effective prophylactic vaccine. Mosaic immunogens are computationally designed to overcome the hurdle of HIV diversity by maximizing the expression of potential T cell epitopes. Mycobacterium bovis BCG ΔpanCD auxotroph and modified vaccinia Ankara (MVA vaccines expressing HIV-1C mosaic Gag (GagM were tested in a prime-boost regimen to demonstrate immunogenicity in a mouse study. The BCG-GagM vaccine was stable and persisted 11.5 weeks post vaccination in BALB/c mice. Priming with BCG-GagM and boosting with MVA-GagM elicited higher Gag-specific IFN-γ ELISPOT responses than the BCG-GagM only and MVA-GagM only homologous vaccination regimens. The heterologous vaccination also generated a more balanced and persistent CD4+ and CD8+ T cell Gag-specific IFN-γ ELISPOT response with a predominant effector memory phenotype. A Th1 bias was induced by the vaccines as determined by the predominant secretion of IFN-γ, TNF-α, and IL-2. This study shows that a low dose of MVA (104 pfu can effectively boost a BCG prime expressing the same mosaic immunogen, generating strong, cellular immune responses against Gag in mice. Our data warrants further evaluation in non-human primates. A low dose vaccine would be an advantage in the resource limited countries of sub-Saharan Africa and India (where the predominating virus is HIV-1 subtype C.

  4. Highly differentiated, resting gn-specific memory CD8+ T cells persist years after infection by andes hantavirus.

    Directory of Open Access Journals (Sweden)

    Tobias Manigold

    2010-02-01

    Full Text Available In man, infection with South American Andes virus (ANDV causes hantavirus cardiopulmonary syndrome (HCPS. HCPS due to ANDV is endemic in Southern Chile and much of Argentina and increasing numbers of cases are reported all over South America. A case-fatality rate of about 36% together with the absence of successful antiviral therapies urge the development of a vaccine. Although T-cell responses were shown to be critically involved in immunity to hantaviruses in mouse models, no data are available on the magnitude, specificity and longevity of ANDV-specific memory T-cell responses in patients. Using sets of overlapping peptides in IFN-gamma ELISPOT assays, we herein show in 78 Chilean convalescent patients that Gn-derived epitopes were immunodominant as compared to those from the N- and Gc-proteins. Furthermore, while the relative contribution of the N-specific response significantly declined over time, Gn-specific responses remained readily detectable ex vivo up to 13 years after the acute infection. Tetramer analysis further showed that up to 16.8% of all circulating CD3(+CD8(+ T cells were specific for the single HLA-B*3501-restricted epitope Gn(465-473 years after the acute infection. Remarkably, Gn(465-473-specific cells readily secreted IFN-gamma, granzyme B and TNF-alpha but not IL-2 upon stimulation and showed a 'revertant' CD45RA(+CD27(-CD28(-CCR7(-CD127(- effector memory phenotype, thereby resembling a phenotype seen in other latent virus infections. Most intriguingly, titers of neutralizing antibodies increased over time in 10/17 individuals months to years after the acute infection and independently of whether they were residents of endemic areas or not. Thus, our data suggest intrinsic, latent antigenic stimulation of Gn-specific T-cells. However, it remains a major task for future studies to proof this hypothesis by determination of viral antigen in convalescent patients. Furthermore, it remains to be seen whether Gn-specific T

  5. Global expression profile of biofilm resistance to antimicrobial compounds in the plant-pathogenic bacterium Xylella fastidiosa reveals evidence of persister cells.

    Science.gov (United States)

    Muranaka, Lígia S; Takita, Marco A; Olivato, Jacqueline C; Kishi, Luciano T; de Souza, Alessandra A

    2012-09-01

    Investigations of biofilm resistance response rarely focus on plant-pathogenic bacteria. Since Xylella fastidiosa is a multihost plant-pathogenic bacterium that forms biofilm in the xylem, the behavior of its biofilm in response to antimicrobial compounds needs to be better investigated. We analyzed here the transcriptional profile of X. fastidiosa subsp. pauca in response to inhibitory and subinhibitory concentrations of copper and tetracycline. Copper-based products are routinely used to control citrus diseases in the field, while antibiotics are more widely used for bacterial control in mammals. The use of antimicrobial compounds triggers specific responses to each compound, such as biofilm formation and phage activity for copper. Common changes in expression responses comprise the repression of genes associated with metabolic functions and movement and the induction of toxin-antitoxin systems, which have been associated with the formation of persister cells. Our results also show that these cells were found in the population at a ca. 0.05% density under inhibitory conditions for both antimicrobial compounds and that pretreatment with subinhibitory concentration of copper increases this number. No previous report has detected the presence of these cells in X. fastidiosa population, suggesting that this could lead to a multidrug tolerance response in the biofilm under a stressed environment. This is a mechanism that has recently become the focus of studies on resistance of human-pathogenic bacteria to antibiotics and, based on our data, it seems to be more broadly applicable.

  6. Diagnostic performance of whole-body MRI for the detection of persistent or relapsing disease in multiple myeloma after stem cell transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Bannas, Peter; Hentschel, Hannah B.; Bley, Thorsten A.; Derlin, Thorsten; Yamamura, Jin; Adam, Gerhard; Weber, Christoph [University Medical Center Hamburg-Eppendorf, Department of Diagnostic and Interventional Radiology, Hamburg (Germany); Treszl, Andras; Eulenburg, Christine [University Medical Center Hamburg-Eppendorf, Department of Medical Biometry and Epidemiology, Hamburg (Germany); Stuebig, Thomas; Kroeger, Nicolaus [University Medical Center Hamburg-Eppendorf, Department of Stem Cell Transplantation, Hamburg (Germany)

    2012-09-15

    To compare the diagnostic performance of whole-body MRI (WBMRI) with haematological parameters for detecting persistent or relapsing disease in patients with multiple myeloma after stem cell transplantation. Sixty-six WBMRI acquisitions were performed in 33 patients with multiple myeloma at two time points after stem cell transplantation. Extent of disease and inter-test dynamics of intra- and extramedullary myeloma manifestations were compared (kappa statistics) with Uniform Response Criteria, comprising haematological parameters. Using data from 66 sequential WBMRI acquisitions in 33 patients, 10 patients (30.3 %) were classified as having progressive disease and 23 (69.7 %) as being in remission. Eight (80 %) of the ten patients with progressive disease revealed intramedullary lesions, and two patients (20 %) had intra- and extramedullary lesions. WBMRI and laboratory tests were concordant in 26/33 (78.8 %) patients. We found an agreement of 51.2 %, 95 % confidence interval 19.8 %-82.6 %, between results from WBMRI and haematological parameters. WBMRI had a sensitivity of 63.6 %, specificity of 86.4 %, PPV of 70.0 %, NPV of 82.6 % and accuracy of 78.8 % for detection of remission. WBMRI allows the detection and exact localisation of intra- and extramedullary myeloma manifestations after stem cell transplantation, but shows only moderate agreement with routinely performed laboratory tests for determination of remission. (orig.)

  7. Induction and Persistence of Large γH2AX Foci by High Linear Energy Transfer Radiation in DNA-Dependent protein kinase–Deficient Cells

    International Nuclear Information System (INIS)

    Bracalente, Candelaria; Ibañez, Irene L.; Molinari, Beatriz; Palmieri, Mónica; Kreiner, Andrés; Valda, Alejandro

    2013-01-01

    Purpose: To evaluate the cell response to DNA double-strand breaks induced by low and high linear energy transfer (LET) radiations when the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), an essential protein of the nonhomologous end-joining repair pathway, lacks kinase activity. Methods and Materials: CHO10B2, a Chinese hamster ovary cell line, and its derived radiosensitive mutant cell line, irs-20, lacking DNA-PKcs activity, were evaluated after 0 to 3 Gy of γ-rays, plateau and Bragg peak protons, and lithium beams by clonogenic assay, and as a measurement of double-strand breaks, phosphorylated H2AX (γH2AX) foci number and size were quantified by immunocytofluorescence. Results: Irs-20 exhibited greater radiosensitivity and a higher amount of γH2AX foci than CHO10B2 at 6 hours after irradiation for all types of radiations. Remarkably, CHO10B2 and irs-20 maintained their difference in radiosensitivity after high-LET radiation. Six hours after low-LET radiations, irs-20 did not reach basal levels of γH2AX at high doses, whereas CHO10B2 recovered basal levels for all doses. After high-LET radiation, only CHO10B2 exhibited a reduction in γH2AX foci, but it never reached basal levels. Persistent foci in irs-20 confirmed a repair deficiency. Interestingly, after 30 minutes of high-LET radiation both cell lines exhibited large foci (size >0.9 μm 2 ) related to the damage nature, whereas at 6 hours irs-20 showed a higher amount of large foci than CHO10B2, with a 7-fold increase at 3 Gy, that could also be associated to radiosensitivity. Conclusions: We demonstrated, for the first time, an association between deficient DNA-PKcs activity and not only high levels of H2AX phosphorylation but also persistence and size increase of γH2AX foci after high-LET irradiation

  8. Induction and Persistence of Large γH2AX Foci by High Linear Energy Transfer Radiation in DNA-Dependent protein kinase–Deficient Cells

    Energy Technology Data Exchange (ETDEWEB)

    Bracalente, Candelaria; Ibañez, Irene L. [Departamento de Micro y Nanotecnología, Comisión Nacional de Energía Atómica, San Martín, Buenos Aires (Argentina); Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires (Argentina); Molinari, Beatriz [Departamento de Radiobiología, Comisión Nacional de Energía Atómica, San Martín, Buenos Aires (Argentina); Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires (Argentina); Palmieri, Mónica [Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires (Argentina); Kreiner, Andrés [Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires (Argentina); Gerencia de Investigación y Aplicaciones, Comisión Nacional de Energía Atómica, San Martín, Buenos Aires (Argentina); Escuela de Ciencia y Tecnología, Universidad Nacional de San Martín, San Martín, Buenos Aires (Argentina); Valda, Alejandro [Escuela de Ciencia y Tecnología, Universidad Nacional de San Martín, San Martín, Buenos Aires (Argentina); and others

    2013-11-15

    Purpose: To evaluate the cell response to DNA double-strand breaks induced by low and high linear energy transfer (LET) radiations when the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), an essential protein of the nonhomologous end-joining repair pathway, lacks kinase activity. Methods and Materials: CHO10B2, a Chinese hamster ovary cell line, and its derived radiosensitive mutant cell line, irs-20, lacking DNA-PKcs activity, were evaluated after 0 to 3 Gy of γ-rays, plateau and Bragg peak protons, and lithium beams by clonogenic assay, and as a measurement of double-strand breaks, phosphorylated H2AX (γH2AX) foci number and size were quantified by immunocytofluorescence. Results: Irs-20 exhibited greater radiosensitivity and a higher amount of γH2AX foci than CHO10B2 at 6 hours after irradiation for all types of radiations. Remarkably, CHO10B2 and irs-20 maintained their difference in radiosensitivity after high-LET radiation. Six hours after low-LET radiations, irs-20 did not reach basal levels of γH2AX at high doses, whereas CHO10B2 recovered basal levels for all doses. After high-LET radiation, only CHO10B2 exhibited a reduction in γH2AX foci, but it never reached basal levels. Persistent foci in irs-20 confirmed a repair deficiency. Interestingly, after 30 minutes of high-LET radiation both cell lines exhibited large foci (size >0.9 μm{sup 2}) related to the damage nature, whereas at 6 hours irs-20 showed a higher amount of large foci than CHO10B2, with a 7-fold increase at 3 Gy, that could also be associated to radiosensitivity. Conclusions: We demonstrated, for the first time, an association between deficient DNA-PKcs activity and not only high levels of H2AX phosphorylation but also persistence and size increase of γH2AX foci after high-LET irradiation.

  9. Significant Depletion of CD4+ T Cells Occurs in the Oral Mucosa during Simian Immunodeficiency Virus Infection with the Infected CD4+ T Cell Reservoir Continuing to Persist in the Oral Mucosa during Antiretroviral Therapy

    Directory of Open Access Journals (Sweden)

    Jeffy George

    2015-01-01

    Full Text Available Human and simian immunodeficiency virus (HIV and SIV infections are characterized by manifestation of numerous opportunistic infections and inflammatory conditions in the oral mucosa. The loss of CD4+ T cells that play a critical role in maintaining mucosal immunity likely contributes to this process. Here we show that CD4+ T cells constitute a minor population of T cells in the oral mucosa and display a predominantly central memory phenotype mirroring other mucosal sites such as the rectal mucosa. Chronic SIV infection was associated with a near total depletion of CD4+ T cells in the oral mucosa that appear to repopulate during antiretroviral therapy (ART. Repopulating CD4+ T cells harbored a large fraction of Th17 cells suggesting that ART potentially reconstitutes oral mucosal immunity. However, a minor fraction of repopulating CD4+ T cells harbored SIV DNA suggesting that the viral reservoir continues to persist in the oral mucosa during ART. Therapeutic approaches aimed at obtaining sustainable CD4+ T cell repopulation in combination with strategies that can eradicate the latent viral reservoir in the oral mucosa are essential for better oral health and long-term outcome in HIV infected patients.

  10. Induction and persistence of abnormal testicular germ cells following gestational exposure to di-(n-butyl) phthalate in p53-null mice.

    Science.gov (United States)

    Saffarini, Camelia M; Heger, Nicholas E; Yamasaki, Hideki; Liu, Tao; Hall, Susan J; Boekelheide, Kim

    2012-01-01

    Phthalate esters are commonly used plasticizers found in many household items, personal care products, and medical devices. Animal studies have shown that in utero exposure to di-(n-butyl) phthalate (DBP) within a critical window during gestation causes male reproductive tract abnormalities resembling testicular dysgenesis syndrome. Our studies utilized p53-deficient mice for their ability to display greater resistance to apoptosis during development. This model was chosen to determine whether multinucleated germ cells (MNG) induced by gestational DBP exposure could survive postnatally and evolve into testicular germ cell cancer. Pregnant dams were exposed to DBP (500 mg/kg/day) by oral gavage from gestational day 12 until birth. Perinatal effects were assessed on gestational day 19 and postnatal days 1, 4, 7, and 10 for the number of MNGs present in control and DBP-treated p53-heterozygous and null animals. As expected, DBP exposure induced MNGs, with greater numbers found in p53-null mice. Additionally, there was a time-dependent decrease in the incidence of MNGs during the early postnatal period. Histologic examination of adult mice exposed in utero to DBP revealed persistence of abnormal germ cells only in DBP-treated p53-null mice, not in p53-heterozygous or wild-type mice. Immunohistochemical staining of perinatal MNGs and adult abnormal germ cells was negative for both octamer-binding protein 3/4 and placental alkaline phosphatase. This unique model identified a role for p53 in the perinatal apoptosis of DBP-induced MNGs and provided insight into the long-term effects of gestational DBP exposure within a p53-null environment.

  11. Clinical progress of human papillomavirus genotypes and their persistent infection in subjects with atypical squamous cells of undetermined significance cytology: Statistical and latent Dirichlet allocation analysis

    Science.gov (United States)

    Kim, Yee Suk; Lee, Sungin; Zong, Nansu; Kahng, Jimin

    2017-01-01

    The present study aimed to investigate differences in prognosis based on human papillomavirus (HPV) infection, persistent infection and genotype variations for patients exhibiting atypical squamous cells of undetermined significance (ASCUS) in their initial Papanicolaou (PAP) test results. A latent Dirichlet allocation (LDA)-based tool was developed that may offer a facilitated means of communication to be employed during patient-doctor consultations. The present study assessed 491 patients (139 HPV-positive and 352 HPV-negative cases) with a PAP test result of ASCUS with a follow-up period ≥2 years. Patients underwent PAP and HPV DNA chip tests between January 2006 and January 2009. The HPV-positive subjects were followed up with at least 2 instances of PAP and HPV DNA chip tests. The most common genotypes observed were HPV-16 (25.9%, 36/139), HPV-52 (14.4%, 20/139), HPV-58 (13.7%, 19/139), HPV-56 (11.5%, 16/139), HPV-51 (9.4%, 13/139) and HPV-18 (8.6%, 12/139). A total of 33.3% (12/36) patients positive for HPV-16 had cervical intraepithelial neoplasia (CIN)2 or a worse result, which was significantly higher than the prevalence of CIN2 of 1.8% (8/455) in patients negative for HPV-16 (Paged ≥51 years (38.7%) than in those aged ≤50 years (20.4%; P=0.036). Progression from persistent infection to CIN2 or worse (19/34, 55.9%) was higher than clearance (0/105, 0.0%; Page and long infection period with a clinical progression of CIN2 or worse. Therefore, LDA results may be presented as explanatory evidence during time-constrained patient-doctor consultations in order to deliver information regarding the patient's status. PMID:28587376

  12. Persistence of the cell-cycle checkpoint kinase Wee1 in SadA- and SadB-deficient neurons disrupts neuronal polarity.

    Science.gov (United States)

    Müller, Myriam; Lutter, Daniela; Püschel, Andreas W

    2010-01-15

    Wee1 is well characterized as a cell-cycle checkpoint kinase that regulates the entry into mitosis in dividing cells. Here we identify a novel function of Wee1 in postmitotic neurons during the establishment of distinct axonal and dendritic compartments, which is an essential step during neuronal development. Wee1 is expressed in unpolarized neurons but is downregulated after neurons have extended an axon. Suppression of Wee1 impairs the formation of minor neurites but does not interfere with axon formation. However, neuronal polarity is disrupted when neurons fail to downregulate Wee1. The kinases SadA and SadB (Sad kinases) phosphorylate Wee1 and are required to initiate its downregulation in polarized neurons. Wee1 expression persists in neurons that are deficient in SadA and SadB and disrupts neuronal polarity. Knockdown of Wee1 rescues the Sada(-/-);Sadb(-/-) mutant phenotype and restores normal polarity in these neurons. Our results demonstrate that the regulation of Wee1 by SadA and SadB kinases is essential for the differentiation of polarized neurons.

  13. Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo.

    Science.gov (United States)

    Song, Yanjing; Tong, Chuan; Wang, Yao; Gao, Yunhe; Dai, Hanren; Guo, Yelei; Zhao, Xudong; Wang, Yi; Wang, Zizheng; Han, Weidong; Chen, Lin

    2017-03-10

    Human epidermal growth factor receptor 2 (HER2) proteins are overexpressed in a high proportion of gastric cancer (GC) cases and affect the maintenance of cancer stem cell (CSC) subpopulations, which are used as targets for the clinical treatment of patients with HER2-positive GC. Despite improvements in survival, numerous HER2-positive patients fail treatment with trastuzumab, highlighting the need for more effective therapies. In this study, we generated a novel type of genetically modified human T cells, expressing a chimeric antigen receptor (CAR), and targeting the GC cell antigen HER2, which harbors the CD137 and CD3ζ moieties. Our findings show that the expanded CAR-T cells, expressing an increased central memory phenotype, were activated by the specific recognition of HER2 antigens in an MHC-independent manner, and effectively killed patient-derived HER2-positive GC cells. In HER2-positive xenograft tumors, CAR-T cells exhibited considerably enhanced tumor inhibition ability, long-term survival, and homing to targets, compared with those of non-transduced T cells. The sphere-forming ability and in vivo tumorigenicity of patient-derived gastric cancer stem-like cells, expressing HER2 and the CD44 protein, were also inhibited. Our results support the future development and clinical application of this adoptive immunotherapy in patients with HER2-positive advanced GC.

  14. Persistence Mechanisms of Conjugative Plasmids

    DEFF Research Database (Denmark)

    Bahl, Martin Iain; Hansen, Lars H.; Sørensen, Søren Johannes

    2009-01-01

    Are plasmids selfish parasitic DNA molecules or an integrated part of the bacterial genome? This chapter reviews the current understanding of the persistence mechanisms of conjugative plasmids harbored by bacterial cells and populations. The diversity and intricacy of mechanisms affecting the suc...

  15. Low doses of X-rays induce prolonged and ATM-independent persistence of γH2AX foci in human gingival mesenchymal stem cells.

    Science.gov (United States)

    Osipov, Andreyan N; Pustovalova, Margarita; Grekhova, Anna; Eremin, Petr; Vorobyova, Natalia; Pulin, Andrey; Zhavoronkov, Alex; Roumiantsev, Sergey; Klokov, Dmitry Y; Eremin, Ilya

    2015-09-29

    Diagnostic imaging delivering low doses of radiation often accompany human mesenchymal stem cells (MSCs)-based therapies. However, effects of low dose radiation on MSCs are poorly characterized. Here we examine patterns of phosphorylated histone H2AX (γH2AX) and phospho-S1981 ATM (pATM) foci formation in human gingiva-derived MSCs exposed to X-rays in time-course and dose-response experiments. Both γH2AX and pATM foci accumulated linearly with dose early after irradiation (5-60 min), with a maximum induction observed at 30-60 min (37 ± 3 and 32 ± 3 foci/cell/Gy for γH2AX and pATM, respectively). The number of γH2AX foci produced by intermediate doses (160 and 250 mGy) significantly decreased (40-60%) between 60 and 240 min post-irradiation, indicating rejoining of DNA double-strand breaks. In contrast, γH2AX foci produced by low doses (20-80 mGy) did not change after 60 min. The number of pATM foci between 60 and 240 min decreased down to control values in a dose-independent manner. Similar kinetics was observed for pATM foci co-localized with γH2AX foci. Collectively, our results suggest differential DNA double-strand break signaling and processing in response to low vs. intermediate doses of X-rays in human MSCs. Furthermore, mechanisms governing the prolonged persistence of γH2AX foci in these cells appear to be ATM-independent.

  16. Persistent Low-Level Replication of SIVΔnef Drives Maturation of Antibody and CD8 T Cell Responses to Induce Protective Immunity against Vaginal SIV Infection.

    Directory of Open Access Journals (Sweden)

    Sama Adnan

    2016-12-01

    Full Text Available Defining the correlates of immune protection conferred by SIVΔnef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV infection. Here we provide a comprehensive assessment of immune responses that protect against SIV infection through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIVΔnef and then vaginally challenged with wild-type SIV. Despite the presence of robust cellular immune responses, animals at 5 weeks after vaccination displayed only transient viral suppression of challenge virus, whereas all macaques challenged at weeks 20 and 40 post-SIVΔnef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters of CD8 T cell function temporally correlated with maturation of protection, including polyfunctionality, phenotypic differentiation, and redistribution to gut and lymphoid tissues. Importantly, we also demonstrate the induction of a tissue-resident memory population of SIV-specific CD8 T cells in the vaginal mucosa, which was dependent on ongoing low-level antigenic stimulation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral load, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIVΔnef antigenic load. In conclusion, maturation of SIVΔnef-induced CD8 T cell and antibody responses, both propelled by viral persistence in the gut mucosa and secondary lymphoid tissues, results in protective immune responses that are able to interrupt viral transmission at mucosal portals of entry as well as potential sites of viral dissemination.

  17. Persistent Low-Level Replication of SIVΔnef Drives Maturation of Antibody and CD8 T Cell Responses to Induce Protective Immunity against Vaginal SIV Infection.

    Science.gov (United States)

    Adnan, Sama; Reeves, R Keith; Gillis, Jacqueline; Wong, Fay E; Yu, Yi; Camp, Jeremy V; Li, Qingsheng; Connole, Michelle; Li, Yuan; Piatak, Michael; Lifson, Jeffrey D; Li, Wenjun; Keele, Brandon F; Kozlowski, Pamela A; Desrosiers, Ronald C; Haase, Ashley T; Johnson, R Paul

    2016-12-01

    Defining the correlates of immune protection conferred by SIVΔnef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV infection. Here we provide a comprehensive assessment of immune responses that protect against SIV infection through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIVΔnef and then vaginally challenged with wild-type SIV. Despite the presence of robust cellular immune responses, animals at 5 weeks after vaccination displayed only transient viral suppression of challenge virus, whereas all macaques challenged at weeks 20 and 40 post-SIVΔnef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters of CD8 T cell function temporally correlated with maturation of protection, including polyfunctionality, phenotypic differentiation, and redistribution to gut and lymphoid tissues. Importantly, we also demonstrate the induction of a tissue-resident memory population of SIV-specific CD8 T cells in the vaginal mucosa, which was dependent on ongoing low-level antigenic stimulation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral load, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIVΔnef antigenic load. In conclusion, maturation of SIVΔnef-induced CD8 T cell and antibody responses, both propelled by viral persistence in the gut mucosa and secondary lymphoid tissues, results in protective immune responses that are able to interrupt viral transmission at mucosal portals of entry as well as potential sites of viral dissemination.

  18. Dualities in persistent (co)homology

    International Nuclear Information System (INIS)

    De Silva, Vin; Morozov, Dmitriy; Vejdemo-Johansson, Mikael

    2011-01-01

    We consider sequences of absolute and relative homology and cohomology groups that arise naturally for a filtered cell complex. We establish algebraic relationships between their persistence modules, and show that they contain equivalent information. We explain how one can use the existing algorithm for persistent homology to process any of the four modules, and relate it to a recently introduced persistent cohomology algorithm. We present experimental evidence for the practical efficiency of the latter algorithm

  19. Human T-cell leukemia virus type 2 post-transcriptional control protein p28 is required for viral infectivity and persistence in vivo.

    Science.gov (United States)

    Yamamoto, Brenda; Li, Min; Kesic, Matthew; Younis, Ihab; Lairmore, Michael D; Green, Patrick L

    2008-05-12

    Human T-cell leukemia virus (HTLV) type 1 and type 2 are related but distinct pathogenic complex retroviruses. HTLV-1 is associated with adult T-cell leukemia and a variety of immune-mediated disorders including the chronic neurological disease termed HTLV-1-associated myelopathy/tropical spastic paraparesis. In contrast, HTLV-2 displays distinct biological differences and is much less pathogenic, with only a few reported cases of leukemia and neurological disease associated with infection. In addition to the structural and enzymatic proteins, HTLV encodes regulatory (Tax and Rex) and accessory proteins. Tax and Rex positively regulate virus production and are critical for efficient viral replication and pathogenesis. Using an over-expression system approach, we recently reported that the accessory gene product of the HTLV-1 and HTLV-2 open reading frame (ORF) II (p30 and p28, respectively) acts as a negative regulator of both Tax and Rex by binding to and retaining their mRNA in the nucleus, leading to reduced protein expression and virion production. Further characterization revealed that p28 was distinct from p30 in that it was devoid of major transcriptional modulating activity, suggesting potentially divergent functions that may be responsible for the distinct pathobiologies of HTLV-1 and HTLV-2. In this study, we investigated the functional significance of p28 in HTLV-2 infection, proliferation, and immortaliztion of primary T-cells in culture, and viral survival in an infectious rabbit animal model. An HTLV-2 p28 knockout virus (HTLV-2Deltap28) was generated and evaluated. Infectivity and immortalization capacity of HTLV-2Deltap28 in vitro was indistinguishable from wild type HTLV-2. In contrast, we showed that viral replication was severely attenuated in rabbits inoculated with HTLV-2Deltap28 and the mutant virus failed to establish persistent infection. We provide direct evidence that p28 is dispensable for viral replication and cellular immortalization of

  20. Human T-cell leukemia virus type 2 post-transcriptional control protein p28 is required for viral infectivity and persistence in vivo

    Directory of Open Access Journals (Sweden)

    Kesic Matthew

    2008-05-01

    Full Text Available Abstract Background Human T-cell leukemia virus (HTLV type 1 and type 2 are related but distinct pathogenic complex retroviruses. HTLV-1 is associated with adult T-cell leukemia and a variety of immune-mediated disorders including the chronic neurological disease termed HTLV-1-associated myelopathy/tropical spastic paraparesis. In contrast, HTLV-2 displays distinct biological differences and is much less pathogenic, with only a few reported cases of leukemia and neurological disease associated with infection. In addition to the structural and enzymatic proteins, HTLV encodes regulatory (Tax and Rex and accessory proteins. Tax and Rex positively regulate virus production and are critical for efficient viral replication and pathogenesis. Using an over-expression system approach, we recently reported that the accessory gene product of the HTLV-1 and HTLV-2 open reading frame (ORF II (p30 and p28, respectively acts as a negative regulator of both Tax and Rex by binding to and retaining their mRNA in the nucleus, leading to reduced protein expression and virion production. Further characterization revealed that p28 was distinct from p30 in that it was devoid of major transcriptional modulating activity, suggesting potentially divergent functions that may be responsible for the distinct pathobiologies of HTLV-1 and HTLV-2. Results In this study, we investigated the functional significance of p28 in HTLV-2 infection, proliferation, and immortaliztion of primary T-cells in culture, and viral survival in an infectious rabbit animal model. An HTLV-2 p28 knockout virus (HTLV-2Δp28 was generated and evaluated. Infectivity and immortalization capacity of HTLV-2Δp28 in vitro was indistinguishable from wild type HTLV-2. In contrast, we showed that viral replication was severely attenuated in rabbits inoculated with HTLV-2Δp28 and the mutant virus failed to establish persistent infection. Conclusion We provide direct evidence that p28 is dispensable for

  1. Persistence of Gamma-H2AX Foci in Irradiated Bronchial Cells Correlates with Susceptibility to Radiation Associated Lung Cancer in Mice

    Science.gov (United States)

    Ochola, Donasian O.; Sharif, Rabab; Bedford, Joel S.; Keefe, Thomas J.; Kato, Takamitsu A.; Fallgren, Christina M.; Demant, Peter; Costes, Sylvain V.; Weil, Michael M.

    2018-01-01

    The risk of developing radiation-induced lung cancer differs between different strains of mice, but the underlying cause of the strain differences is unknown. Strains of mice also differ in their ability to efficiently repair DNA double strand breaks resulting from radiation exposure. We phenotyped mouse strains from the CcS/Dem recombinant congenic strain set for their efficacy in repairing DNA double strand breaks during protracted radiation exposures. We monitored persistent gamma-H2AX radiation induced foci (RIF) 24 hours after exposure to chronic gamma-rays as a surrogate marker for repair deficiency in bronchial epithelial cells for 17 of the CcS/Dem strains and the BALB/cHeN founder strain. We observed a very strong correlation R2 = 79.18%, P cancer percent incidence measured in the same strains. Interestingly, spontaneous levels of foci in non-irradiated strains also showed good correlation with lung cancer incidence (R2=32.74%, P =0.013). These results suggest that genetic differences in DNA repair capacity largely account for differing susceptibilities to radiation-induced lung cancer among CcS/Dem mouse strains and that high levels of spontaneous DNA damage is also a relatively good marker of cancer predisposition. In a smaller pilot study, we found that the repair capacity measured in peripheral blood leucocytes also correlated well with radiogenic lung cancer susceptibility, raising the possibility that such phenotyping assay could be used to detect radiogenic lung cancer susceptibility in humans.

  2. Persistent Aerial Tracking

    KAUST Repository

    Mueller, Matthias

    2016-01-01

    persistent, robust and autonomous object tracking system for unmanned aerial vehicles (UAVs) called Persistent Aerial Tracking (PAT). A computer vision and control strategy is applied to a diverse set of moving objects (e.g. humans, animals, cars, boats, etc

  3. Is bacterial persistence a social trait?

    Directory of Open Access Journals (Sweden)

    Andy Gardner

    Full Text Available The ability of bacteria to evolve resistance to antibiotics has been much reported in recent years. It is less well-known that within populations of bacteria there are cells which are resistant due to a non-inherited phenotypic switch to a slow-growing state. Although such 'persister' cells are receiving increasing attention, the evolutionary forces involved have been relatively ignored. Persistence has a direct benefit to cells because it allows survival during catastrophes-a form of bet-hedging. However, persistence can also provide an indirect benefit to other individuals, because the reduced growth rate can reduce competition for limiting resources. This raises the possibility that persistence is a social trait, which can be influenced by kin selection. We develop a theoretical model to investigate the social consequences of persistence. We predict that selection for persistence is increased when: (a cells are related (e.g. a single, clonal lineage; and (b resources are scarce. Our model allows us to predict how the level of persistence should vary with time, across populations, in response to intervention strategies and the level of competition. More generally, our results clarify the links between persistence and other bet-hedging or social behaviours.

  4. Long-term persistence of immunity and B-cell memory following Haemophilus influenzae type B conjugate vaccination in early childhood and response to booster.

    Science.gov (United States)

    Perrett, K P; John, T M; Jin, C; Kibwana, E; Yu, L-M; Curtis, N; Pollard, A J

    2014-04-01

    Protection against Haemophilus influenzae type b (Hib), a rapidly invading encapsulated bacteria, is dependent on maintenance of an adequate level of serum antibody through early childhood. In many countries, Hib vaccine booster doses have been implemented after infant immunization to sustain immunity. We investigated the long-term persistence of antibody and immunological memory in primary-school children following infant (with or without booster) Hib vaccination. Anti-polyribosylribitol phosphate (PRP) immunoglobulin G (IgG) concentration and the frequency of circulating Hib-specific memory B cells were measured before a booster of a Hib-serogroup C meningococcal (MenC) conjugate vaccine and again 1 week, 1 month, and 1 year after the booster in 250 healthy children aged 6-12 years in an open-label phase 4 clinical study. Six to 12 years following infant priming with 3 doses of Hib conjugate vaccine, anti-PRP IgG geometric mean concentrations were 3.11 µg/mL and 0.71 µg/mL and proportions with anti-PRP IgG ≥1.0 µg/mL were 79% and 43% in children who had or had not, respectively, received a fourth Hib conjugate vaccine dose (mean age, 3.9 years). Higher baseline and post-Hib-MenC booster responses (anti-PRP IgG and memory B cells) were found in younger children and in those who had received a fourth Hib dose. Sustained Hib conjugate vaccine-induced immunity in children is dependent on time since infant priming and receipt of a booster. Understanding the relationship between humoral and cellular immunity following immunization with conjugate vaccines may direct vaccine design and boosting strategies to sustain individual and population immunity against encapsulated bacteria in early childhood. Clinical Trials Registration ISRCTN728588998.

  5. Phenotypes and functions of persistent Sendai virus-induced antibody forming cells and CD8+ T cells in diffuse nasal-associated lymphoid tissue typify lymphocyte responses of the gut.

    Science.gov (United States)

    Rudraraju, Rajeev; Surman, Sherri; Jones, Bart; Sealy, Robert; Woodland, David L; Hurwitz, Julia L

    2011-02-20

    Lymphocytes of the diffuse nasal-associated lymphoid tissue (d-NALT) are uniquely positioned to tackle respiratory pathogens at their point-of-entry, yet are rarely examined after intranasal (i.n.) vaccinations or infections. Here we evaluate an i.n. inoculation with Sendai virus (SeV) for elicitation of virus-specific antibody forming cells (AFCs) and CD8(+) T cells in the d-NALT. Virus-specific AFCs and CD8(+) T cells each appeared by day 7 after SeV inoculation and persisted for 8 months, explaining the long-sustained protection against respiratory virus challenge conferred by this vaccine. AFCs produced IgM, IgG1, IgG2a, IgG2b and IgA, while CD8+ T cells were cytolytic and produced low levels of cytokines. Phenotypic analyses of virus-specific T cells revealed striking similarities with pathogen-specific immune responses in the intestine, highlighting some key features of adaptive immunity at a mucosal site. Copyright © 2010 Elsevier Inc. All rights reserved.

  6. Retinoic acid reduces human neuroblastoma cell migration and invasiveness: effects on DCX, LIS1, neurofilaments-68 and vimentin expression

    International Nuclear Information System (INIS)

    Messi, Elio; Florian, Maria C; Caccia, Claudio; Zanisi, Mariarosa; Maggi, Roberto

    2008-01-01

    ) Retinoic acid treatment reduces migration and invasiveness of the more aggressive cell components of SK-N-SH cells; c) The cells that after retinoic acid exposure show migration and invasive capability may be identified on the basis of doublecortin expression

  7. Time Course of Spinal Doublecortin Expression in Developing Rat and Porcine Spinal Cord: Implication in In Vivo Neural Precursor Grafting Studies

    Czech Academy of Sciences Publication Activity Database

    Juhásová, Jana; Juhás, Štefan; Hruška-Plocháň, M.; Doležalová, D.; Holubová, Monika; Strnádel, Ján; Marsala, S.; Motlík, Jan; Marsala, M.

    2015-01-01

    Roč. 35, č. 1 (2015), s. 57-70 ISSN 0272-4340 R&D Projects: GA TA ČR(CZ) TA01011466; GA MŠk ED2.1.00/03.0124 Institutional support: RVO:67985904 Keywords : doublecortin * spinal cord development * spinal neural precursor grafting * minipig * rat * GFAP Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.328, year: 2015

  8. Neuronal differentiation of hair-follicle-bulge-derived stem cells co-cultured with mouse cochlear modiolus explants.

    Directory of Open Access Journals (Sweden)

    Timo Schomann

    Full Text Available Stem-cell-based repair of auditory neurons may represent an attractive therapeutic option to restore sensorineural hearing loss. Hair-follicle-bulge-derived stem cells (HFBSCs are promising candidates for this type of therapy, because they (1 have migratory properties, enabling migration after transplantation, (2 can differentiate into sensory neurons and glial cells, and (3 can easily be harvested in relatively high numbers. However, HFBSCs have never been used for this purpose. We hypothesized that HFBSCs can be used for cell-based repair of the auditory nerve and we have examined their migration and incorporation into cochlear modiolus explants and their subsequent differentiation. Modiolus explants obtained from adult wild-type mice were cultured in the presence of EF1α-copGFP-transduced HFBSCs, constitutively expressing copepod green fluorescent protein (copGFP. Also, modiolus explants without hair cells were co-cultured with DCX-copGFP-transduced HFBSCs, which demonstrate copGFP upon doublecortin expression during neuronal differentiation. Velocity of HFBSC migration towards modiolus explants was calculated, and after two weeks, co-cultures were fixed and processed for immunohistochemical staining. EF1α-copGFP HFBSC migration velocity was fast: 80.5 ± 6.1 μm/h. After arrival in the explant, the cells formed a fascicular pattern and changed their phenotype into an ATOH1-positive neuronal cell type. DCX-copGFP HFBSCs became green-fluorescent after integration into the explants, confirming neuronal differentiation of the cells. These results show that HFBSC-derived neuronal progenitors are migratory and can integrate into cochlear modiolus explants, while adapting their phenotype depending on this micro-environment. Thus, HFBSCs show potential to be employed in cell-based therapies for auditory nerve repair.

  9. Unexpected dramatic increase in CD4+ cell count in a patient with AIDS after enfuvirtide treatment despite persistent viremia and resistance mutations.

    Science.gov (United States)

    Soria, Alessandro; Cavarelli, Mariangela; Sala, Stefania; Alessandrini, Anna Ida; Scarlatti, Gabriella; Lazzarin, Adriano; Castagna, Antonella

    2008-06-01

    An unexpected dramatic immune recovery was observed in a patient with full-blown AIDS receiving enfuvirtide-based antiretroviral therapy after multiple treatment failures. A complex interplay of viral and host factors, including the control of X4 viruses and proviral burden, may favor immune restoration with HIV neutralizing activity, despite persistent viremia.

  10. Search along persistent random walks

    International Nuclear Information System (INIS)

    Friedrich, Benjamin M

    2008-01-01

    Optimal search strategies and their implementations in biological systems are a subject of active research. Here we study a search problem which is motivated by the hunt of sperm cells for the egg. We ask for the probability for an active swimmer to find a target under the condition that the swimmer starts at a certain distance from the target. We find that success probability is maximal for a certain level of fluctuations characterized by the persistence length of the swimming path of the swimmer. We derive a scaling law for the optimal persistence length as a function of the initial target distance and search time by mapping the search on a polymer physics problem

  11. Persistent myalgia following whiplash.

    Science.gov (United States)

    Dommerholt, Jan

    2005-10-01

    Persistent myalgia following whiplash is commonly considered the result of poor psychosocial status, illness behavior, or failing coping skills. However, there is much evidence that persistent myalgia may be due to neurophysiologic mechanisms involving peripheral and central sensitization. Myofascial trigger points may play a crucial role in maintaining sensitization. Recent research suggests that the chemical environment of myofascial trigger points is an important factor. Several consequences are reviewed when central pain mechanisms and myofascial trigger points are included in the differential diagnosis and in the management of patients with persistent pain following whiplash.

  12. Persistent Mullerian Duct Syndrome with Transverse Testicular ...

    African Journals Online (AJOL)

    Eastham JA, McEvoy K, Sullivan R, Chandrasoma P. A case of simultaneous bilateral nonseminomatous testicular tumors in persistent müllerian duct syndrome. J Urol 1992;148:407-8. 8. Shinmura Y, Yokoi T, Tsutsui Y. A case of clear cell adenocarcinoma of the müllerian duct in persistent müllerian duct syndrome: The first ...

  13. Introduction: Persistent Modelling

    DEFF Research Database (Denmark)

    Ayres, Phil

    2012-01-01

    This introduction to 'Persistent Modelling – an extended role for architectural representation' identifies how the book probes the relationship between representation and the represented, in an architectural context. It discusses how the book presents an examination and discussion of historical......, familiar contemporary and, perhaps, not so familiar emerging manifestations of this relation. What persists from this probing, fully intact, is that representation and the represented remain inextricably related in our contemporary and emerging practices. What comes into focus is that the nature...

  14. Dentate gyrus progenitor cell proliferation after the onset of spontaneous seizures in the tetanus toxin model of temporal lobe epilepsy.

    Science.gov (United States)

    Jiruska, Premysl; Shtaya, Anan B Y; Bodansky, David M S; Chang, Wei-Chih; Gray, William P; Jefferys, John G R

    2013-06-01

    Temporal lobe epilepsy alters adult neurogenesis. Existing experimental evidence is mainly from chronic models induced by an initial prolonged status epilepticus associated with substantial cell death. In these models, neurogenesis increases after status epilepticus. To test whether status epilepticus is necessary for this increase, we examined precursor cell proliferation and neurogenesis after the onset of spontaneous seizures in a model of temporal lobe epilepsy induced by unilateral intrahippocampal injection of tetanus toxin, which does not cause status or, in most cases, detectable neuronal loss. We found a 4.5 times increase in BrdU labeling (estimating precursor cells proliferating during the 2nd week after injection of toxin and surviving at least up to 7days) in dentate gyri of both injected and contralateral hippocampi of epileptic rats. Radiotelemetry revealed that the rats experienced 112±24 seizures, lasting 88±11s each, over a period of 8.6±1.3days from the first electrographic seizure. On the first day of seizures, their duration was a median of 103s, and the median interictal period was 23min, confirming the absence of experimentally defined status epilepticus. The total increase in cell proliferation/survival was due to significant population expansions of: radial glial-like precursor cells (type I; 7.2×), non-radial type II/III neural precursors in the dentate gyrus stem cell niche (5.6×), and doublecortin-expressing neuroblasts (5.1×). We conclude that repeated spontaneous brief temporal lobe seizures are sufficient to promote increased hippocampal neurogenesis in the absence of status epilepticus. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Persistent and recurrent hyperparathyroidism.

    Science.gov (United States)

    Guerin, Carole; Paladino, Nunzia Cinzia; Lowery, Aoife; Castinetti, Fréderic; Taieb, David; Sebag, Fréderic

    2017-06-01

    Despite remarkable progress in imaging modalities and surgical management, persistence or recurrence of primary hyperparathyroidism (PHPT) still occurs in 2.5-5% of cases of PHPT. The aim of this review is to expose the management of persistent and recurrent hyperparathyroidism. A literature search was performed on MEDLINE using the search terms "recurrent" or "persistent" and "hyperparathyroidism" within the past 10 years. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant. Before considering reoperation, the surgeon must confirm the diagnosis of PHPT. Then, the patient must be evaluated with new imaging modalities. A single adenoma is found in 68% of cases, multiglandular disease in 28%, and parathyroid carcinoma in 3%. Others causes (<1%) include parathyromatosis and graft recurrence. The surgeon must balance the benefits against the risks of a reoperation (permanent hypocalcemia and recurrent laryngeal nerve palsy). If surgery is necessary, a focused approach can be considered in cases of significant imaging foci, but in the case of multiglandular disease, a bilateral neck exploration could be necessary. Patients with multiple endocrine neoplasia syndromes are at high risk of recurrence and should be managed regarding their hereditary pathology. The cure rate of persistent-PHPT or recurrent-PHPT in expert centers is estimated from 93 to 97%. After confirming the diagnosis of PHPT, patients with persistent-PHPT and recurrent-PHPT should be managed in an expert center with all dedicated competencies.

  16. Persistent luminescence nanothermometers

    Science.gov (United States)

    Martín Rodríguez, Emma; López-Peña, Gabriel; Montes, Eduardo; Lifante, Ginés; García Solé, José; Jaque, Daniel; Diaz-Torres, Luis Armando; Salas, Pedro

    2017-08-01

    Persistent phosphorescence nanoparticles emitting in the red and near-infrared spectral regions are strongly demanded as contrast nanoprobes for autofluorescence free bioimaging and biosensing. In this work, we have developed Sr4Al14O25:Eu2+, Cr3+, Nd3+ nanopowders that produce persistent red phosphorescence peaking at 694 nm generated by Cr3+ ions. This emission displays temperature sensitivity in the physiological temperature range (20-60 °C), which makes these nanoparticles potentially useful as fluorescence (contactless) nanothermometers operating without requiring optical excitation. Nd3+ ions, which act as shallow electron traps for the red Cr3+ persistent emission, also display infrared emission bands, extending the fluorescence imaging capability to the second biological window. This unique combination of properties makes these nanoparticles multifunctional luminescent probes with great potential applications in nanomedicine.

  17. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity.

    Science.gov (United States)

    Liu, E; Tong, Y; Dotti, G; Shaim, H; Savoldo, B; Mukherjee, M; Orange, J; Wan, X; Lu, X; Reynolds, A; Gagea, M; Banerjee, P; Cai, R; Bdaiwi, M H; Basar, R; Muftuoglu, M; Li, L; Marin, D; Wierda, W; Keating, M; Champlin, R; Shpall, E; Rezvani, K

    2018-02-01

    Chimeric antigen receptors (CARs) have been used to redirect the specificity of autologous T cells against leukemia and lymphoma with promising clinical results. Extending this approach to allogeneic T cells is problematic as they carry a significant risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are highly cytotoxic effectors, killing their targets in a non-antigen-specific manner without causing GVHD. Cord blood (CB) offers an attractive, allogeneic, off-the-self source of NK cells for immunotherapy. We transduced CB-derived NK cells with a retroviral vector incorporating the genes for CAR-CD19, IL-15 and inducible caspase-9-based suicide gene (iC9), and demonstrated efficient killing of CD19-expressing cell lines and primary leukemia cells in vitro, with marked prolongation of survival in a xenograft Raji lymphoma murine model. Interleukin-15 (IL-15) production by the transduced CB-NK cells critically improved their function. Moreover, iC9/CAR.19/IL-15 CB-NK cells were readily eliminated upon pharmacologic activation of the iC9 suicide gene. In conclusion, we have developed a novel approach to immunotherapy using engineered CB-derived NK cells, which are easy to produce, exhibit striking efficacy and incorporate safety measures to limit toxicity. This approach should greatly improve the logistics of delivering this therapy to large numbers of patients, a major limitation to current CAR-T-cell therapies.

  18. Persistent genital arousal disorder

    DEFF Research Database (Denmark)

    Eibye, Simone; Jensen, Hans Mørch

    2014-01-01

    We report a case of a woman suffering from persistent genital arousal disorder (PGAD) after paroxetine cessation. She was admitted to a psychiatric department and diagnosed with agitated depression. Physical investigation showed no gynaecological or neurological explanation; however, a pelvic MRI...

  19. Persistent organic pollutants

    NARCIS (Netherlands)

    Dungen, van den M.W.

    2016-01-01

    Wild caught fish, especially marine fish, can contain high levels of persistent organic pollutants (POPs). In the Netherlands, especially eel from the main rivers have high POP levels. This led to a ban in 2011 on eel fishing due to health concerns. Many of the marine POPs have been related to

  20. Contributions to Persistence Theory

    Directory of Open Access Journals (Sweden)

    Du Dong

    2014-12-01

    Full Text Available Persistence theory discussed in this paper is an application of algebraic topology (Morse Theory [29] to Data Analysis, precisely to qualitative understanding of point cloud data, or PCD for short. PCD can be geometrized as a filtration of simplicial complexes (Vietoris-Rips complex [25] [36] and the homology changes of these complexes provide qualitative information about the data. Bar codes describe the changes in homology with coefficients in a fixed field. When the coefficient field is ℤ2, the calculation of bar codes is done by ELZ algorithm (named after H. Edelsbrunner, D. Letscher, and A. Zomorodian [20]. When the coefficient field is ℝ, we propose an algorithm based on the Hodge decomposition [17]. With Dan Burghelea and Tamal K. Dey we developed a persistence theory which involves level sets discussed in Section 4. We introduce and discuss new computable invariants, the “relevant level persistence numbers” and the “positive and negative bar codes”, and explain how they are related to the bar codes for level persistence. We provide enhancements and modifications of ELZ algorithm to calculate such invariants and illustrate them by examples.

  1. Is corruption really persistent?

    NARCIS (Netherlands)

    Seldadyo, H.; de Haan, J.

    Theoretical and empirical research on corruption generally concludes that corruption is persistent. However, using International Country Risk Guide data for the period 1984-2008 for 101 countries, we find strong evidence that corruption changes over time. In the present study, corruption levels of

  2. Persistence of gamma-H2AX and 53BP1 foci in proliferating and nonproliferating human mammary epithelial cells after exposure to gamma-rays or iron ions

    Energy Technology Data Exchange (ETDEWEB)

    Groesser, Torsten; Chang, Hang; Fontenay, Gerald; Chen, James; Costes, Sylvain V.; Barcellos-Hoff, Mary Helen; Parvin, Bahram; Rydberg, Bjorn

    2010-12-22

    To investigate {gamma}-H2AX (phosphorylated histone H2AX) and 53BP1 (tumour protein 53 binding protein No. 1) foci formation and removal in proliferating and non-proliferating human mammary epithelial cells (HMEC) after exposure to sparsely and densely ionizing radiation under different cell culture conditions. HMEC cells were grown either as monolayers (2D) or in extracellular matrix to allow the formation of acinar structures in vitro (3D). Foci numbers were quantified by image analysis at various time points after exposure. Our results reveal that in non-proliferating cells under 2D and 3D cell culture conditions, iron-ion induced {gamma}-H2AX foci were still present at 72 h after exposure, although 53BP1 foci returned to control levels at 48 h. In contrast in proliferating HMEC, both {gamma}-H2AX and 53BP1 foci decreased to control levels during the 24-48 h time interval after irradiation under 2D conditions. Foci numbers decreased faster after {gamma}-ray irradiation and returned to control levels by 12 h regardless of marker, cell proliferation status, and cell culture condition. Conclusions: The disappearance of radiation induced {gamma}-H2AX and 53BP1 foci in HMEC have different dynamics that depend on radiation quality and proliferation status. Notably, the general patterns do not depend on the cell culture condition (2D versus 3D). We speculate that the persistent {gamma}-H2AX foci in iron-ion irradiated non-proliferating cells could be due to limited availability of double strand break (DSB) repair pathways in G0/G1-phase, or that repair of complex DSB requires replication or chromatin remodeling.

  3. Intravaginal infection with herpes simplex virus type-2 (HSV-2) generates a functional effector memory T cell population that persists in the murine genital tract.

    Science.gov (United States)

    Tang, Vera A; Rosenthal, Kenneth L

    2010-12-01

    Although the female genital tract is the main portal of entry for sexually transmitted infections in women, we still have limited understanding of the generation, maintenance and characteristics of memory T cells in the local tissue. Here, we utilized a mouse model of intravaginal HSV-2 infection and tetramers against the immunodominant HSV glycoprotein B epitope recognized by CD8+ T cells to examine the generation, maintenance and characteristics of anti-HSV memory T cells in the genital tract following acute infection. Our results show that the highest percentage of HSVgB-specific CD8+ T cells was found in the genital tract compared to the spleen or iliac lymphnode. Indeed, although the actual number of CD8+ T cells contracted following viral clearance, approximately one quarter of the CD8+ population that remained in the genital tissue was HSVgB-specific. Memory gB-tetramer+CD8 T cells in the genital tract were positive for CD127 and KLRG1 and negative for CD62L and CCR7, thus confirming that HSV-specific CD8 cells were effector memory T cells that lack the capacity for homing to lymphoid tissues. Functionally, both memory CD8+ and CD4+ HSV-specific populations in the genital tract produced IFNγ when stimulated in vitro and CD4+ cells also produced TNFα. Genital HSVgB-specific memory T cells expressed tissue-homing integrins CD103 (αE integrin) and CD49a (VLA-1 or α1 integrin). Our findings suggest that HSV-specific memory T cells are retained in the genital tract, poised to act as an early line of defense against future virus encounter. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  4. TCR's genetically linked to CD28 and CD3e do not mispair with endogous TCR chains and mediate enhanced T cell persistance and anti-melanoma activity

    NARCIS (Netherlands)

    Govers, C.C.F.M.; Sebestyen, Z.; Roszik, J.; Brakel, van M.; Berrevoets, C.; Szoor, A.; Panoutsopoulou, K.; Broertjes, M.; Van, T.; Vereb, G.; Szollosi, J.; Debets, R.

    2014-01-01

    Adoptive transfer of T cells that are gene engineered to express a defined TCR represents a feasible and promising therapy for patients with tumors. However, TCR gene therapy is hindered by the transient presence and effectiveness of transferred T cells, which are anticipated to be improved by

  5. Persistence of STAT-1 inhibition and induction of cytokine resistance in pancreatic β cells treated with St John's wort and its component hyperforin.

    Science.gov (United States)

    Novelli, Michela; Beffy, Pascale; Gregorelli, Alex; Porozov, Svetlana; Mascia, Fabrizio; Vantaggiato, Chiara; Masiello, Pellegrino; Menegazzi, Marta

    2017-10-09

    St John's wort extract (SJW) and its component hyperforin (HPF) were shown to potently inhibit cytokine-induced STAT-1 and NF-κB activation in pancreatic β cells and protect them against injury. This study aimed at exploring the time course of STAT-1 inhibition afforded by these natural compounds in the β-cell line INS-1E. INS-1E cells were pre-incubated with SJW extract (2-5 μg/ml) or HPF (0.5-2 μm) and then exposed to a cytokine mixture. In some experiments, these compounds were added after or removed before cytokine exposure. STAT-1 activation was assessed by electrophoretic mobility shift assay, apoptosis by caspase-3 activity assay, mRNA gene expression by RT-qPCR. Pre-incubation with SJW/HPF for 1-2 h exerted a remarkable STAT-1 downregulation, which was maintained upon removal of the compounds before early or delayed cytokine addition. When the protective compounds were added after cell exposure to cytokines, between 15 and 90 min, STAT-1 inhibition also occurred at a progressively decreasing extent. Upon 24-h incubation, SJW and HPF counteracted cytokine-induced β-cell dysfunction, apoptosis and target gene expression. SJW and HPF confer to β cells a state of 'cytokine resistance', which can be elicited both before and after cytokine exposure and safeguards these cells from deleterious cytokine effects. © 2017 Royal Pharmaceutical Society.

  6. Persistent Hiccups Following Stapedectomy

    Directory of Open Access Journals (Sweden)

    Aidonis I

    2010-10-01

    Full Text Available Objective: We report a case of a 37 year-old man who developed persistent hiccups after elective stapedectomy. Method and Results: The diagnostic approach is discussed as well as the non-pharmacologic and pharmacologic treatments and overall management. The aim is to stress that there is a variety of potential factors that can induce hiccups perioperatively and in cases like this a step by step approach must be taken. Conclusion: Persistent hiccups are very rare following stapedectomy, control of them is crucial for the successful outcome. The trigger may be more than one factors and the good response to treatment may be due to dealing successfully with more than one thing.

  7. Persistent facial pain conditions

    DEFF Research Database (Denmark)

    Forssell, Heli; Alstergren, Per; Bakke, Merete

    2016-01-01

    Persistent facial pains, especially temporomandibular disorders (TMD), are common conditions. As dentists are responsible for the treatment of most of these disorders, up-to date knowledge on the latest advances in the field is essential for successful diagnosis and management. The review covers...... TMD, and different neuropathic or putative neuropathic facial pains such as persistent idiopathic facial pain and atypical odontalgia, trigeminal neuralgia and painful posttraumatic trigeminal neuropathy. The article presents an overview of TMD pain as a biopsychosocial condition, its prevalence......, clinical features, consequences, central and peripheral mechanisms, diagnostic criteria (DC/TMD), and principles of management. For each of the neuropathic facial pain entities, the definitions, prevalence, clinical features, and diagnostics are described. The current understanding of the pathophysiology...

  8. Persistent Model #2

    DEFF Research Database (Denmark)

    2013-01-01

    Tensegrity structures and Inflatable membranes can be considered analogous. They can both be described as pressure based systems in which a coherent envelope is tensioned through compressive force in order to achieve a state of self-equilibrium. Persistent Model #2 is a full-scale speculative pro...... Modelling and a sustained critical investigation of the roles digital tools can play in extending the ways in which we think, design, realise and experience architecture....

  9. Intergenerational Top Income Persistence

    DEFF Research Database (Denmark)

    Munk, Martin D.; Bonke, Jens; Hussain, M. Azhar

    2016-01-01

    In this paper, we investigate intergenerational top earnings and top income mobility in Denmark. Access to administrative registers allowed us to look at very small fractions of the population. We find that intergenerational mobility is lower in the top when including capital income in the income...... measure— for the rich top 0.1% fathers and sons the elasticity is 0.466. Compared with Sweden, however, the intergenerational top income persistence is about half the size in Denmark....

  10. Numeric invariants from multidimensional persistence

    Energy Technology Data Exchange (ETDEWEB)

    Skryzalin, Jacek [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Carlsson, Gunnar [Stanford Univ., Stanford, CA (United States)

    2017-05-19

    In this paper, we analyze the space of multidimensional persistence modules from the perspectives of algebraic geometry. We first build a moduli space of a certain subclass of easily analyzed multidimensional persistence modules, which we construct specifically to capture much of the information which can be gained by using multidimensional persistence over one-dimensional persistence. We argue that the global sections of this space provide interesting numeric invariants when evaluated against our subclass of multidimensional persistence modules. Lastly, we extend these global sections to the space of all multidimensional persistence modules and discuss how the resulting numeric invariants might be used to study data.

  11. Systematic Epstein-Barr virus-positive T-cell lymphoproliferative disease presenting as a persistent fever and cough: a case report.

    Science.gov (United States)

    Ameli, Fereshteh; Ghafourian, Firouzeh; Masir, Noraidah

    2014-08-27

    Systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease is an extremely rare disorder and classically arises following primary acute or chronic active Epstein-Barr virus infection. It is characterized by clonal proliferation of Epstein-Barr virus-infected T-cells with an activated cytotoxic phenotype. This disease has a rapid clinical course and is more frequent in Asia and South America, with relatively few cases being reported in Western countries. The clinical and pathological features of the disease overlap with other conditions including infectious mononucleosis, chronic active Epstein-Barr virus infection, hemophagocytic lymphohistiocytosis and natural killer cell malignancies. We describe the rare case of systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease in a 16-year-old Malay boy. He presented with a six-month history of fever and cough, with pulmonary and mediastinal lymphadenopathy and severe pancytopenia. Medium- to large-sized, CD8+ and Epstein-Barr virus-encoded RNA-positive atypical lymphoid cells were present in the bone marrow aspirate. He subsequently developed fatal virus-associated hemophagocytic syndrome and died due to sepsis and multiorgan failure. Although systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease is a disorder which is rarely encountered in clinical practice, our case report underlines the importance of a comprehensive diagnostic approach in the management of this disease. A high level of awareness of the disease throughout the diagnosis process for young patients who present with systemic illness and hemophagocytic syndrome may be of great help for the clinical diagnosis of this disease.

  12. Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells

    International Nuclear Information System (INIS)

    Spink, Barbara C.; Bennett, James A.; Pentecost, Brian T.; Lostritto, Nicole; Englert, Neal A.; Benn, Geoffrey K.; Goodenough, Angela K.; Turesky, Robert J.; Spink, David C.

    2009-01-01

    The cumulative exposure to estrogens is an important determinant in the risk of breast cancer, yet the full range of mechanisms involving estrogens in the genesis and progression of breast cancer remains a subject of debate. Interactions of estrogens and environmental toxicants have received attention as putative factors contributing to carcinogenesis. Mechanistic studies have demonstrated interactions between estrogen receptor α (ERα) and the aryl hydrocarbon receptor (AhR), with consequences on the genes that they regulate. Many studies of ERα and AhR-mediated effects and crosstalk between them have focused on the initial molecular events. In this study, we investigated ERα- and AhR-mediated effects in long-term estrogen exposed (LTEE) MCF-7 human breast cancer cells, which were obtained by continuous culturing for at least 12 weeks in medium supplemented with 1 nM of 17β-estradiol (E 2 ). With these LTEE cells and with parallel control cells cultured without E 2 supplementation, we performed an extensive study of cytochrome P450 (CYP) induction, carcinogen bioactivation, global gene expression, and tumorigenicity in immunocompromised mice. We found that LTEE cells, in comparison with control cells, had higher levels of AhR mRNA and protein, greater responsiveness for AhR-regulated CYP1A1 and CYP1B1 induction, a 6-fold higher initial level of benzo(a)pyrene-DNA adducts as determined by liquid chromatography tandem mass spectrometry, marked differences in the expression of numerous genes, and a higher rate of E 2 -dependent tumor growth as xenografts. These studies indicate that LTEE causes adaptive responses in MCF-7 cells, which may reflect processes that contribute to the overall carcinogenic effect of E 2 .

  13. Exposure to 4-tert-octylphenol, an environmentally persistent alkylphenol, enhances interleukin-4 production in T cells via NF-AT activation

    International Nuclear Information System (INIS)

    Lee, Mi H.; Kim, Eugene; Kim, Tae S.

    2004-01-01

    4-tert-Octylphenol (OP) is a representative endocrine disruptor that may have adverse effects on human health. The influence of this compound on allergic immune responses remains unclear. In this study, we have examined the effects of OP on production of interleukin-4 (IL-4), a pro-inflammatory cytokine closely associated with allergic immune responses. OP significantly enhanced IL-4 production in antigen-primed T cells in a dose-dependent manner. Treatment with OP in vivo resulted in significant increase of IL-4 production in T cells and of IgE levels in sera of antigen-primed mice. Furthermore, OP enhanced the activation of IL-4 gene promoter in EL4 T cells transiently transfected with IL-4 promoter/reporter constructs, and the enhancing effect mapped to a region in the IL-4 promoter containing binding sites for nuclear factor of activated T cell (NF-AT). Activation of T cells by phorbol-12-myristate-13-acetate (PMA) resulted in markedly enhanced binding activities to the NF-AT site, which significantly increased upon addition of OP, indicating that the transcription factor NF-AT was involved in the enhancing effect of OP on IL-4 production. The enhancement of IL-4 production by OP was blocked by FK506, a calcineurin inhibitor, but not by the estrogen receptor (ER) antagonist ICI 182 780. FK506 inhibited the NF-AT-DNA binding activity and IL-4 gene promoter activity enhanced by OP in a dose-dependent manner. These findings demonstrate that OP enhances IL-4 production in T cells via the stimulation of calcineurin-dependent NF-AT activation

  14. Inflation persistence and flexible prices

    OpenAIRE

    Robert Dittmar; William T. Gavin; Finn E. Kydland

    2004-01-01

    If the central bank follows an interest rate rule, then inflation is likely to be persistence, even when prices are fully flexible. Any shock, whether persistent or not, may lead to inflation persistence. In equilibrium, the dynamics of inflation are determined by the evolution of the spread between the real interest rate and the central bank’s target. Inflation persistence in U.S. data can be characterized by a vector autocorrelation function relating inflation and deviations of output from ...

  15. Changes in action potentials and intracellular ionic homeostasis in a ventricular cell model related to a persistent sodium current in SCN5A mutations underlying LQT3

    Czech Academy of Sciences Publication Activity Database

    Christé, G.; Chahine, M.; Chevalier, P.; Pásek, Michal

    2008-01-01

    Roč. 96, - (2008), s. 281-293 ISSN 0079-6107 Institutional research plan: CEZ:AV0Z20760514 Keywords : cardiac cell * SCN5A mutation * Long QT syndrome * quantitative modelling Subject RIV: BO - Biophysics Impact factor: 6.388, year: 2008

  16. HMGB1-dependent triggering of HIV-1 replication and persistence in dendritic cells as a consequence of NK-DC cross-talk.

    Directory of Open Access Journals (Sweden)

    Héla Saïdi

    Full Text Available HIV-1 has evolved ways to exploit DCs, thereby facilitating viral dissemination and allowing evasion of antiviral immunity. Recently, the fate of DCs has been found to be extremely dependent on the interaction with autologous NK cells, but the mechanisms by which NK-DC interaction controls viral infections remain unclear. Here, we investigate the impact of NK-DC cross-talk on maturation and functions of HIV-infected immature DCs.Immature DCs were derived from primary monocytes, cultured in the presence of IL-4 and GM-CSF. In some experiments, DCs were infected with R5-HIV-1(BaL or X4-HIV-1(NDK, and viral replication, proviral HIV-DNA and the frequency of infected DCs were measured. Autologous NK cells were sorted and either kept unstimulated in the presence of suboptimal concentration of IL-2, or activated by a combination of PHA and IL-2. The impact of 24 h NK-DC cross-talk on the fate of HIV-1-infected DCs was analyzed. We report that activated NK cells were required for the induction of maturation of DCs, whether uninfected or HIV-1-infected, and this process involved HMGB1. However, the cross-talk between HIV-1-infected DCs and activated NK cells was functionally defective, as demonstrated by the strong impairment of DCs to induce Th1 polarization of naïve CD4 T cells. This was associated with the defective production of IL-12 and IL-18 by infected DCs. Moreover, the crosstalk between activated NK cells and HIV-infected DCs resulted in a dramatic increase in viral replication and proviral DNA expression in DCs. HMGB1, produced both by NK cells and DCs, was found to play a pivotal role in this process, and inhibition of HMGB1 activity by glycyrrhizin, known to bind specifically to HMGB1, or blocking anti-HMGB1 antibodies, abrogated NK-dependent HIV-1 replication in DCs.These observations provide evidence for the crucial role of NK-DC cross-talk in promoting viral dissemination, and challenge the question of the in vivo involvement of HMGB1

  17. Reflections on Student Persistence

    Directory of Open Access Journals (Sweden)

    Vincent Tinto

    2017-07-01

    Full Text Available The Feature for this issue Reflections on Student Persistence has been prepared by Professor Vincent Tinto, Distinguished University Professor Emeritus at Syracuse University, United States of America (USA and a longtime friend and supporter of STARS. Vincent explores the case for motivation to be considered as a significant aspect of the tertiary student psyche by drawing on theoretical frameworks, research and practical experiences related to the issue. He synthesises this extensive, detailed, rich but often somewhat impenetrable data into a trilogy of clear and credible key dimensions of the motivation construct student self efficacy, sense of belonging and perceived value of the curriculum. This interpretation of the literature is a personal but informed reflection and is a timely piece which highlights the breadth and profundity of the presentations at this year's conference in Adelaide, Australia where students in all their diversity are central to our focus on enhancing the student experience. In this opening article, Vincent refers directly to the STARS papers selected for this Conference issue of the Journal which also address the importance of student persistence, self-efficacy and building the sense of belonging within their own institutional communities (Fernandes, Ford, Rayner & Pretorius; Kahu, Nelson, & Picton; McFarlane, Spes-Skrbis & Taib; Naylor; Smallhorn. Echoing his position on social justice and his advocacy for underserved students, Vincent reminds us that educational equity gaps still exist, and he encourages us to see the issue of persistence through the eyes of the students to support their perseverance and completion and thereby help reduce educational disadvantage.

  18. Persistent marine debris

    International Nuclear Information System (INIS)

    Levy, E.M.

    1992-01-01

    In this paper the distribution of persistent marine debris, adrift on world oceans and stranded on beaches globally, is reviewed and related to the known inputs and transport by the major surface currents. Since naturally occurring processes eventually degrade petroleum in the environment, international measures to reduce the inputs have been largely successful in alleviating oil pollution on a global, if not on a local, scale. Many plastics, however, are so resistant to natural degradation that merely controlling inputs will be insufficient, and more drastic and costly measures will be needed to cope with the emerging global problem posed by these materials

  19. Persistent postsurgical pain

    DEFF Research Database (Denmark)

    Werner, Mads Utke; Bischoff, Joakim Mutahi

    2014-01-01

    The prevalences of severe persistent postsurgical pain (PPP) following breast cancer surgery (BCS), groin hernia repair (GHR), and lung cancer surgery (LCS) are 13, 2, and 4-12 %, respectively. Estimates indicate that 80,000 patients each year in the U.S.A. are affected by severe pain...... duration of surgery, repeat surgery, more invasive surgical techniques, and intraoperative nerve lesion have been associated with PPP. One of the most consistent predictive factors for PPP is high intensity acute postsurgical pain, but also psychological factors including anxiety, catastrophizing trait...

  20. Term Structure Persistence

    OpenAIRE

    Abbritti, M. (Mirko); Gil-Alana, L.A. (Luis A.); Lovcha, Y. (Yuliya); Moreno, A. (Antonio)

    2012-01-01

    Stationary I(0) models employed in yield curve analysis typically imply an unrealistically low degree of volatility in long-run short-rate expectations due to fast mean reversion. In this paper we propose a novel multivariate affine term structure model with a two-fold source of persistence in the yield curve: Long-memory and short-memory. Our model, based on an I(d) specification, nests the I(0) and I(1) models as special cases and the I(0) model is decisively rejected by the data. Our model...

  1. Persistence of Salmonid Redds

    Science.gov (United States)

    Buffington, J. M.; Buxton, T.; Fremier, A. K.; Hassan, M. A.; Yager, E.

    2013-12-01

    The construction of redds by spawning salmonids modifies fluvial processes in ways that are beneficial to egg and embryo survival. Redd topography induces hyporheic flow that oxygenates embryos incubating within the streambed and creates form drag that reduces bed mobility and scour of salmonid eggs. Winnowing of fine material during redd construction also coarsens the streambed, increasing bed porosity and hyporheic flow and reducing bed mobility. In addition to the biological benefits, redds may influence channel morphology by altering channel hydraulics and bed load transport rates depending on the size and extent of redds relative to the size of the channel. A key question is how long do the physical and biological effects of redds last? Field observations indicate that in some basins redds are ephemeral, with redd topography rapidly erased by subsequent floods, while in other basins, redds can persist for years. We hypothesize that redd persistence is a function of basin hydrology, sediment supply, and characteristics of the spawning fish. Hydrology controls the frequency and magnitude of bed mobilizing flows following spawning, while bed load supply (volume and caliber) controls the degree of textural fining and consequent bed mobility after spawning, as well as the potential for burial of redd features. The effectiveness of flows in terms of their magnitude and duration depend on hydroclimate (i.e., snowmelt, rainfall, or transitional hydrographs), while bed load supply depends on basin geology, land use, and natural disturbance regimes (e.g., wildfire). Location within the stream network may also influence redd persistence. In particular, lakes effectively trap sediment and regulate downstream flow, which may promote long-lived redds in stream reaches below lakes. These geomorphic controls are modulated by biological factors: fish species (size of fish controls size of redds and magnitude of streambed coarsening); life history (timing of spawning and

  2. Intraventricular Transplantation of Autologous Bone Marrow Mesenchymal Stem Cells via Ommaya Reservoir in Persistent Vegetative State Patients after Haemorrhagic Stroke: Report of Two Cases & Review of the Literature

    Directory of Open Access Journals (Sweden)

    Fauzi AA

    2016-11-01

    Full Text Available Background: One of the most devastating diseases, stroke, is a leading cause of death and disability worldwide with severe emotional and economic consequences. The purpose of this article is mainly to report the effect of intraventricular transplantation via an Ommaya reservoir using autologous bone marrow mesenchymal stem cells (BM-MSCs in haemorrhagic stroke patients. Case Presentations: Two patients, aged 51 and 52, bearing sequels of haemorrhagic stroke were managed by intraventricular transplantation of BM-MSCs obtained from their own bone marrow. Before the procedure, both patients were bedridden, tracheostomised, on nasogastric (NG tube feeding and in hemiparesis. The cells were transplanted intraventricularly (20 x 106 cells/2.5 ml using an Ommaya reservoir, and then repeated transplantations were done after 1 and 2 months consecutively. The safety and efficacy of the procedures were evaluated 3, 6 and 12 months after treatment. The National Institute of Health Stroke Scale (NIHSS was used to evaluate the patients' neurological status before and after treatment. No adverse events derived from the procedures or transplants were observed in the one-year follow-up period, and the neurological status of both patients improved after treatment. Conclusions: Our report demonstrates that the intraventricular transplantation of BM-MSCs via an Ommaya reservoir is safe and it improves the neurological status of post-haemorrhagic stroke patients. The repeated transplantation procedure is easier and safer to perform via a subcutaneously implanted Ommaya reservoir.

  3. Persistence extends reciprocity.

    Science.gov (United States)

    Kurokawa, Shun

    2017-04-01

    One key potential explanation for the evolution of cooperation is conditional cooperation. This allows cooperation to evolve for cooperators who switch their behavior on the basis of information about the opponent's behavior or reputation. However, information about the opponent's behavior or reputation is sometimes unavailable, and previous studies have assumed that a player cooperates with some default probability when no information about the opponent's previous behavior or reputation is available. This default probability has been interpreted as the player's "optimism". Here, we make use of the fact that even if a player cannot observe the opponent's previous behavior or reputation, he may still condition his future behavior based on his own past behavior and in such a case, he can behave persistently. In this paper, we especially consider the case where information about the opponent's "behavior" is sometimes absent and the iterated prisoner's dilemma game between the same two individuals is played. Here, we examine the evolution of strategies that can refer to the own behavior in the previous round. Using evolutionarily stable strategy (ESS) analysis and analyzing replicator dynamics, we find that conditioning his future behavior based on his own past behavior is beneficial for the evolution. Persistence facilitates the evolution of cooperation. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Persistence of airline accidents.

    Science.gov (United States)

    Barros, Carlos Pestana; Faria, Joao Ricardo; Gil-Alana, Luis Alberiko

    2010-10-01

    This paper expands on air travel accident research by examining the relationship between air travel accidents and airline traffic or volume in the period from 1927-2006. The theoretical model is based on a representative airline company that aims to maximise its profits, and it utilises a fractional integration approach in order to determine whether there is a persistent pattern over time with respect to air accidents and air traffic. Furthermore, the paper analyses how airline accidents are related to traffic using a fractional cointegration approach. It finds that airline accidents are persistent and that a (non-stationary) fractional cointegration relationship exists between total airline accidents and airline passengers, airline miles and airline revenues, with shocks that affect the long-run equilibrium disappearing in the very long term. Moreover, this relation is negative, which might be due to the fact that air travel is becoming safer and there is greater competition in the airline industry. Policy implications are derived for countering accident events, based on competition and regulation. © 2010 The Author(s). Journal compilation © Overseas Development Institute, 2010.

  5. Stem cell Transplantation for Eradication of Minimal PAncreatic Cancer persisting after surgical Excision (STEM PACE Trial, ISRCTN47877138): study protocol for a phase II study

    International Nuclear Information System (INIS)

    Schmitz-Winnenthal, Friedrich H; Schmidt, Thomas; Lehmann, Monika; Beckhove, Philipp; Kieser, Meinhard; Ho, Anthony D; Dreger, Peter; Büchler, Markus W

    2014-01-01

    Pancreatic cancer is the third most common cancer related cause of death. Even in the 15% of patients who are eligible for surgical resection the outlook is dismal with less than 10% of patients surviving after 5 years. Allogeneic hematopoietic (allo-HSCT) stem cell transplantation is an established treatment capable of to providing cure in a variety of hematopoietic malignancies. Best results are achieved when the underlying neoplasm has been turned into a stage of minimal disease by chemotherapy. Allo-HSCT in advanced solid tumors including pancreatic cancer have been of limited success, however studies of allo-HSCT in solid tumors in minimal disease situations have never been performed. The aim of this trial is to provide evidence for the clinical value of allo-HSCT in pancreatic cancer put into a minimal disease status by effective surgical resection and standard adjuvant chemotherapy. The STEM PACE trial is a single center, phase II study to evaluate adjuvant allogeneic hematopoietic stem cell transplantation in pancreatic cancer after surgical resection. The study will evaluate as primary endpoint 2 year progression free survival and will generate first time state-of-the-art scientific clinical evidence if allo-HSCT is feasible and if it can provide long term disease control in patients with effectively resected pancreatic cancer. Screened eligible patients after surgical resection and standard adjuvant chemotherapy with HLA matched related stem cell donor can participate. Patients without a matched donor will be used as a historical control. Study patients will undergo standard conditioning for allo-HSCT followed by transplantation of allogeneic unmanipulated peripheral blood stem cells. The follow up of the patients will continue for 2 years. Secondary endpoints will be evaluated on 7 postintervention visits. The principal question addressed in this trial is whether allo-HSCT can change the unfavourable natural course of this disease. The underlying

  6. Caliber-Persistent Artery

    Directory of Open Access Journals (Sweden)

    Sabrina Araújo Pinho Costa

    2015-01-01

    Full Text Available Caliber-persistent artery (CPLA of the lip is a common vascular anomaly in which a main arterial branch extends to the surface of the mucous tissue with no reduction in its diameter. It usually manifests as pulsatile papule, is easily misdiagnosed, and is observed more frequently among older people, suggesting that its development may involve a degenerative process associated with aging; CPLA is also characterized by the loss of tone of the adjacent supporting connective tissue. Although the diagnosis is clinical, high-resolution Doppler ultrasound is a useful noninvasive tool for evaluating the lesion. This report describes the case of a 58-year-old male patient who complained of a lesion of the lower lip with bleeding and recurrent ulceration. The patient was successfully treated in our hospital after a diagnosis of CPLA and is currently undergoing a clinical outpatient follow-up with no complaints.

  7. An annoying persistent cough

    Directory of Open Access Journals (Sweden)

    Francesco Cipollini

    2007-03-01

    Full Text Available Chronic cough is a stressful condition and can lead to extensive investigations. We report a case of a 48-year-old woman who had suffered from persistent chronic cough for more than 3 months. She had been treated with cough suppressant. However, her cough was not alleviated by these treatments, and the patient was referred to our hospital. She did not exhibit typical gastroesophageal reflux disease (GERD symptoms heartburn and regurgitation. Esophagoscopy did not disclose reflux esophagitis. The patient was treated with a proton-pump inhibitor, which markedly alleviated her cough. Chronic cough due to GERD was diagnosed. Although the diagnosis of chronic cough due to GERD is not easy when traditionally symptoms are not present, our case report underscores the importance of this association to the differential diagnosis of chronic cough. In these cases a relatively simple test as high dose proton pump-inhibitors trial may be useful to confirm GERD related cough.

  8. New daily persistent headache

    Directory of Open Access Journals (Sweden)

    Alok Tyagi

    2012-01-01

    Full Text Available New daily persistent headache (NDPH is a chronic headache developing in a person who does not have a past history of headaches. The headache begins acutely and reaches its peak within 3 days. It is important to exclude secondary causes, particularly headaches due to alterations in cerebrospinal fluid (CSF pressure and volume. A significant proportion of NDPH sufferers may have intractable headaches that are refractory to treatment. The condition is best viewed as a syndrome rather than a diagnosis. The headache can mimic chronic migraine and chronic tension-type headache, and it is also important to exclude secondary causes, particularly headaches due to alterations in CSF pressure and volume. A large proportion of NDPH sufferers have migrainous features to their headache and should be managed with treatments used for treating migraine. A small group of NDPH sufferers may have intractable headaches that are refractory to treatment.

  9. Persistent idiopathic facial pain

    DEFF Research Database (Denmark)

    Maarbjerg, Stine; Wolfram, Frauke; Heinskou, Tone Bruvik

    2017-01-01

    Introduction: Persistent idiopathic facial pain (PIFP) is a poorly understood chronic orofacial pain disorder and a differential diagnosis to trigeminal neuralgia. To address the lack of systematic studies in PIFP we here report clinical characteristics and neuroimaging findings in PIFP. Methods...... pain 7 (13%), hypoesthesia 23 (48%), depression 16 (30%) and other chronic pain conditions 17 (32%) and a low prevalence of stabbing pain 21 (40%), touch-evoked pain 14 (26%) and remission periods 10 (19%). The odds ratio between neurovascular contact and the painful side was 1.4 (95% Cl 0.4–4.4, p = 0.......565) and the odds ratio between neurovascular contact with displacement of the trigeminal nerve and the painful side was 0.2 (95% Cl 0.0–2.1, p = 0.195). Conclusion: PIFP is separated from trigeminal neuralgia both with respect to the clinical characteristics and neuroimaging findings, as NVC was not associated...

  10. Persistent Aerial Tracking

    KAUST Repository

    Mueller, Matthias

    2016-04-13

    In this thesis, we propose a new aerial video dataset and benchmark for low altitude UAV target tracking, as well as, a photo-realistic UAV simulator that can be coupled with tracking methods. Our benchmark provides the rst evaluation of many state of-the-art and popular trackers on 123 new and fully annotated HD video sequences captured from a low-altitude aerial perspective. Among the compared trackers, we determine which ones are the most suitable for UAV tracking both in terms of tracking accuracy and run-time. We also present a simulator that can be used to evaluate tracking algorithms in real-time scenarios before they are deployed on a UAV "in the field", as well as, generate synthetic but photo-realistic tracking datasets with free ground truth annotations to easily extend existing real-world datasets. Both the benchmark and simulator will be made publicly available to the vision community to further research in the area of object tracking from UAVs. Additionally, we propose a persistent, robust and autonomous object tracking system for unmanned aerial vehicles (UAVs) called Persistent Aerial Tracking (PAT). A computer vision and control strategy is applied to a diverse set of moving objects (e.g. humans, animals, cars, boats, etc.) integrating multiple UAVs with a stabilized RGB camera. A novel strategy is employed to successfully track objects over a long period, by \\'handing over the camera\\' from one UAV to another. We integrate the complete system into an off-the-shelf UAV, and obtain promising results showing the robustness of our solution in real-world aerial scenarios.

  11. Persister formation in Staphylococcus aureus is associated with ATP depletion

    Energy Technology Data Exchange (ETDEWEB)

    Conlon, Brian P.; Rowe, Sarah E.; Gandt, Autumn Brown; Nuxoll, Austin S.; Donegan, Niles P.; Zalis, Eliza A.; Clair, Geremy; Adkins, Joshua N.; Cheung, Ambrose L.; Lewis, Kim

    2016-04-18

    Persisters are dormant phenotypic variants of bacterial cells that are tolerant to killing by antibiotics1. Persisters are associated with chronic bacterial infection and antibiotic treatment failure. In Escherichia coli, toxin/antitoxin (TA) modules are responsible for persister formation. The mechanism of persister formation in Gram positive bacteria is unknown. Staphylococcus aureus is a major human pathogen, responsible for a variety of chronic and relapsing infections such as osteomyelitis, endocarditis and infections of implanted devices. Deleting TA modules in S. aureus did not affect the level of persisters. Here we show that S. aureus persisters are produced due to a stochastic entrance to stationary phase accompanied by a drop in intracellular ATP. Cells expressing stationary state markers are present throughout the growth phase, increasing in frequency with cell density. Cell sorting revealed that expression of stationary markers was associated with a 100-1000 fold increased likelihood of survival to antibiotic challenge. We find that the antibiotic tolerance of these cells is due to a drop in intracellular ATP. The ATP level of the cell is predictive of bactericidal antibiotic efficacy and explains bacterial tolerance to antibiotic treatment.

  12. Demethylation by 5-aza-2'-deoxycytidine in colorectal cancer cells targets genomic DNA whilst promoter CpG island methylation persists

    International Nuclear Information System (INIS)

    Mossman, David; Kim, Kyu-Tae; Scott, Rodney J

    2010-01-01

    DNA methylation and histone acetylation are epigenetic modifications that act as regulators of gene expression. Aberrant epigenetic gene silencing in tumours is a frequent event, yet the factors which dictate which genes are targeted for inactivation are unknown. DNA methylation and histone acetylation can be modified with the chemical agents 5-aza-2'-deoxycytidine (5-aza-dC) and Trichostatin A (TSA) respectively. The aim of this study was to analyse de-methylation and re-methylation and its affect on gene expression in colorectal cancer cell lines treated with 5-aza-dC alone and in combination with TSA. We also sought to identify methylation patterns associated with long term reactivation of previously silenced genes. Colorectal cancer cell lines were treated with 5-aza-dC, with and without TSA, to analyse global methylation decreases by High Performance Liquid Chromatography (HPLC). Re-methylation was observed with removal of drug treatments. Expression arrays identified silenced genes with differing patterns of expression after treatment, such as short term reactivation or long term reactivation. Sodium bisulfite sequencing was performed on the CpG island associated with these genes and expression was verified with real time PCR. Treatment with 5-aza-dC was found to affect genomic methylation and to a lesser extent gene specific methylation. Reactivated genes which remained expressed 10 days post 5-aza-dC treatment featured hypomethylated CpG sites adjacent to the transcription start site (TSS). In contrast, genes with uniformly hypermethylated CpG islands were only temporarily reactivated. These results imply that 5-aza-dC induces strong de-methylation of the genome and initiates reactivation of transcriptionally inactive genes, but this does not require gene associated CpG island de-methylation to occur. In addition, for three of our selected genes, hypomethylation at the TSS of an epigenetically silenced gene is associated with the long term reversion of

  13. Immunogenicity, safety and antibody persistence of a purified vero cell cultured rabies vaccine (Speeda) administered by the Zagreb regimen or Essen regimen in post-exposure subjects.

    Science.gov (United States)

    Shi, Nianmin; Zhang, Yibin; Zheng, Huizhen; Zhu, Zhenggang; Wang, Dingming; Li, Sihai; Li, Yuhua; Yang, Liqing; Zhang, Junnan; Bai, Yunhua; Lu, Qiang; Zhang, Zheng; Luo, Fengji; Yu, Chun; Li, Li

    2017-06-03

    To compare the safety, immunogenicity and long-term effect of a purified vero cell cultured rabies vaccine in post-exposure subjects following 2 intramuscular regimens, Zagreb or Essen regimen. Serum samples were collected before vaccination and on days 7, 14, 42, 180 and 365 post vaccination. Solicited adverse events were recorded for 7 d following each vaccine dose, and unsolicited adverse events throughout the entire study period. This study was registered with ClinicalTrials.gov (NCT01821911 and NCT01827917). No serious adverse events were reported. Although Zagreb regimen had a higher incidence of adverse reactions than Essen regimen at the first and second injection, the incidence was similar at the third and fourth injection between these 2 groups as well. At day 42, 100% subjects developed adequate rabies virus neutralizing antibody concentrations (≥ 0.5IU/ml) for both regimens. At days 180 and 365, the antibody level decreased dramatically, however, the percentage of subjects with adequate antibody concentrations still remained high (above 75% and 50% respectively). None of confirmed rabies virus exposured subjects had rabies one year later, and percentage of subjects with adequate antibody concentrations reached 100% at days 14 and 42. Rabies post-exposure prophylaxis vaccination with PVRV following a Zagreb regimen had a similar safety, immunogenicity and long-term effect to the Essen regimen in China.

  14. Comparative 2D-DIGE proteomic analysis of bovine mammary epithelial cells during lactation reveals protein signatures for lactation persistency and milk yield.

    Directory of Open Access Journals (Sweden)

    Jagadeesh Janjanam

    Full Text Available Mammary gland is made up of a branching network of ducts that end with alveoli which surrounds the lumen. These alveolar mammary epithelial cells (MEC reflect the milk producing ability of farm animals. In this study, we have used 2D-DIGE and mass spectrometry to identify the protein changes in MEC during immediate early, peak and late stages of lactation and also compared differentially expressed proteins in MEC isolated from milk of high and low milk producing cows. We have identified 41 differentially expressed proteins during lactation stages and 22 proteins in high and low milk yielding cows. Bioinformatics analysis showed that a majority of the differentially expressed proteins are associated in metabolic process, catalytic and binding activity. The differentially expressed proteins were mapped to the available biological pathways and networks involved in lactation. The proteins up-regulated during late stage of lactation are associated with NF-κB stress induced signaling pathways and whereas Akt, PI3K and p38/MAPK signaling pathways are associated with high milk production mediated through insulin hormone signaling.

  15. Persistent viral infections and immune aging.

    Science.gov (United States)

    Brunner, Stefan; Herndler-Brandstetter, Dietmar; Weinberger, Birgit; Grubeck-Loebenstein, Beatrix

    2011-07-01

    Immunosenescence comprises a set of dynamic changes occurring to both, the innate as well as the adaptive immune system that accompany human aging and result in complex manifestations of still poorly defined deficiencies in the elderly population. One of the most prominent alterations during aging is the continuous involution of the thymus gland which is almost complete by the age of 50. Consequently, the output of naïve T cells is greatly diminished in elderly individuals which puts pressure on homeostatic forces to maintain a steady T cell pool for most of adulthood. In a great proportion of the human population, this fragile balance is challenged by persistent viral infections, especially Cytomegalovirus (CMV), that oblige certain T cell clones to monoclonally expand repeatedly over a lifetime which then occupy space within the T cell pool. Eventually, these inflated memory T cell clones become exhausted and their extensive accumulation accelerates the age-dependent decline of the diversity of the T cell pool. As a consequence, infectious diseases are more frequent and severe in elderly persons and immunological protection following vaccination is reduced. This review therefore aims to shed light on how various types of persistent viral infections, especially CMV, influence the aging of the immune system and highlight potential measures to prevent the age-related decline in immune function. Copyright © 2010 Elsevier B.V. All rights reserved.

  16. Persistent homology of complex networks

    International Nuclear Information System (INIS)

    Horak, Danijela; Maletić, Slobodan; Rajković, Milan

    2009-01-01

    Long-lived topological features are distinguished from short-lived ones (considered as topological noise) in simplicial complexes constructed from complex networks. A new topological invariant, persistent homology, is determined and presented as a parameterized version of a Betti number. Complex networks with distinct degree distributions exhibit distinct persistent topological features. Persistent topological attributes, shown to be related to the robust quality of networks, also reflect the deficiency in certain connectivity properties of networks. Random networks, networks with exponential connectivity distribution and scale-free networks were considered for homological persistency analysis

  17. The partitioning and copy number control systems of the selfish yeast plasmid: an optimized molecular design for stable persistence in host cells.

    Science.gov (United States)

    Yen-Ting-Liu; Sau, Saumitra; Ma, Chien-Hui; Kachroo, Aashiq H; Rowley, Paul A; Chang, Keng-Ming; Fan, Hsiu-Fang; Jayaram, Makkuni

    2014-10-01

    The multi-copy 2 micron plasmid of Saccharomyces cerevisiae, a resident of the nucleus, is remarkable for its high chromosome-like stability. The plasmid does not appear to contribute to the fitness of the host, nor does it impose a significant metabolic burden on the host at its steady state copy number. The plasmid may be viewed as a highly optimized selfish DNA element whose genome design is devoted entirely towards efficient replication, equal segregation and copy number maintenance. A partitioning system comprised of two plasmid coded proteins, Rep1 and Rep2, and a partitioning locus STB is responsible for equal or nearly equal segregation of plasmid molecules to mother and daughter cells. Current evidence supports a model in which the Rep-STB system promotes the physical association of the plasmid with chromosomes and thus plasmid segregation by a hitchhiking mechanism. The Flp site-specific recombination system housed by the plasmid plays a critical role in maintaining steady state plasmid copy number. A decrease in plasmid population due to rare missegregation events is rectified by plasmid amplification via a recombination induced rolling circle replication mechanism. Appropriate plasmid amplification, without runaway increase in copy number, is ensured by positive and negative regulation of FLP gene expression by plasmid coded proteins and by the control of Flp level/activity through host mediated post-translational modification(s) of Flp. The Flp system has been successfully utilized to understand mechanisms of site-specific recombination, to bring about directed genetic alterations for addressing fundamental problems in biology, and as a tool in biotechnological applications.

  18. Rarity and persistence.

    Science.gov (United States)

    Vermeij, Geerat J; Grosberg, Richard K

    2018-01-01

    Rarity is a population characteristic that is usually associated with a high risk of extinction. We argue here, however, that chronically rare species (those with low population densities over many generations across their entire ranges) may have individual-level traits that make populations more resistant to extinction. The major obstacle to persistence at low density is successful fertilisation (union between egg and sperm), and chronically rare species are more likely to survive when (1) fertilisation occurs inside or close to an adult, (2) mate choice involves long-distance signals, (3) adults or their surrogate gamete dispersers are highly mobile, or (4) the two sexes are combined in a single individual. In contrast, external fertilisation and wind- or water-driven passive dispersal of gametes, or sluggish or sedentary adult life habits in the absence of gamete vectors, appear to be incompatible with sustained rarity. We suggest that the documented increase in frequency of these traits among marine genera over geological time could explain observed secular decreases in rates of background extinction. Unanswered questions remain about how common chronic rarity actually is, which traits are consistently associated with chronic rarity, and how chronically rare species are distributed among taxa, and among the world's ecosystems and regions. © 2017 John Wiley & Sons Ltd/CNRS.

  19. The persistence of depression score

    NARCIS (Netherlands)

    Spijker, J.; de Graaf, R.; Ormel, J.; Nolen, W. A.; Grobbee, D. E.; Burger, H.

    2006-01-01

    Objective: To construct a score that allows prediction of major depressive episode (MDE) persistence in individuals with MDE using determinants of persistence identified in previous research. Method: Data were derived from 250 subjects from the general population with new MDE according to DSM-III-R.

  20. Variable Persister Gene Interactions with (pppGpp for Persister Formation in Escherichia coli

    Directory of Open Access Journals (Sweden)

    Shuang Liu

    2017-09-01

    Full Text Available Persisters comprise a group of phenotypically heterogeneous metabolically quiescent bacteria with multidrug tolerance and contribute to the recalcitrance of chronic infections. Although recent work has shown that toxin-antitoxin (TA system HipAB depends on stringent response effector (pppGppin persister formation, whether other persister pathways are also dependent on stringent response has not been explored. Here we examined the relationship of (pppGpp with 15 common persister genes (dnaK, clpB, rpoS, pspF, tnaA, sucB, ssrA, smpB, recA, umuD, uvrA, hipA, mqsR, relE, dinJ using Escherichia coli as a model. By comparing the persister levels of wild type with their single gene knockout and double knockout mutants with relA, we divided their interactions into five types, namely A “dependent” (dnaK, recA, B “positive reinforcement” (rpoS, pspF, ssrA, recA, C “antagonistic” (clpB, sucB, umuD, uvrA, hipA, mqsR, relE, dinJ, D “epistasis” (clpB, rpoS, tnaA, ssrA, smpB, hipA, and E “irrelevant” (dnaK, clpB, rpoS, tnaA, sucB, smpB, umuD, uvrA, hipA, mqsR, relE, dinJ. We found that the persister gene interactions are intimately dependent on bacterial culture age, cell concentrations (diluted versus undiluted culture, and drug classifications, where the same gene may belong to different groups with varying antibiotics, culture age or cell concentrations. Together, this study represents the first attempt to systematically characterize the intricate relationships among the different mechanisms of persistence and as such provide new insights into the complexity of the persistence phenomenon at the level of persister gene network interactions.

  1. HIV Persistence in Adipose Tissue Reservoirs.

    Science.gov (United States)

    Couturier, Jacob; Lewis, Dorothy E

    2018-02-01

    The purpose of this review is to examine the evidence describing adipose tissue as a reservoir for HIV-1 and how this often expansive anatomic compartment contributes to HIV persistence. Memory CD4 T cells and macrophages, the major host cells for HIV, accumulate in adipose tissue during HIV/SIV infection of humans and rhesus macaques. Whereas HIV and SIV proviral DNA is detectable in CD4 T cells of multiple fat depots in virtually all infected humans and monkeys examined, viral RNA is less frequently detected, and infected macrophages may be less prevalent in adipose tissue. However, based on viral outgrowth assays, adipose-resident CD4 T cells are latently infected with virus that is replication-competent and infectious. Additionally, adipocytes interact with CD4 T cells and macrophages to promote immune cell activation and inflammation which may be supportive for HIV persistence. Antiviral effector cells, such as CD8 T cells and NK/NKT cells, are abundant in adipose tissue during HIV/SIV infection and typically exceed CD4 T cells, whereas B cells are largely absent from adipose tissue of humans and monkeys. Additionally, CD8 T cells in adipose tissue of HIV patients are activated and have a late differentiated phenotype, with unique TCR clonotypes of less diversity relative to blood CD8 T cells. With respect to the distribution of antiretroviral drugs in adipose tissue, data is limited, but there may be class-specific penetration of fat depots. The trafficking of infected immune cells within adipose tissues is a common event during HIV/SIV infection of humans and monkeys, but the virus may be mostly transcriptionally dormant. Viral replication may occur less in adipose tissue compared to other major reservoirs, such as lymphoid tissue, but replication competence and infectiousness of adipose latent virus are comparable to other tissues. Due to the ubiquitous nature of adipose tissue, inflammatory interactions among adipocytes and CD4 T cells and macrophages, and

  2. Potential of Escherichia coli 0157:H7 to persist and form viable but non-culturable cells on a food-contact surface subjected to cycles of soiling and chemical treatment

    DEFF Research Database (Denmark)

    Marouani-Gadri, Nesrine; Firmesse, Olivier; Chassaing, Danielle

    2010-01-01

    Our aim was to assess the potential of Escherichia coli O157:H7 to persist in a processing environment. We studied E. coli behaviour under conditions modelling those of meat plants to establish one initial bacterial load that allows persistence and another that does not. Polyurethane coupons (3...

  3. Plasma Membrane Ca2+-Permeable Channels are Differentially Regulated by Ethylene and Hydrogen Peroxide to Generate Persistent Plumes of Elevated Cytosolic Ca2+ During Transfer Cell Trans-Differentiation.

    Science.gov (United States)

    Zhang, Hui-ming; van Helden, Dirk F; McCurdy, David W; Offler, Christina E; Patrick, John W

    2015-09-01

    The enhanced transport capability of transfer cells (TCs) arises from their ingrowth wall architecture comprised of a uniform wall on which wall ingrowths are deposited. The wall ingrowth papillae provide scaffolds to amplify plasma membranes that are enriched in nutrient transporters. Using Vicia faba cotyledons, whose adaxial epidermal cells spontaneously and rapidly (hours) undergo a synchronous TC trans-differentiation upon transfer to culture, has led to the discovery of a cascade of inductive signals orchestrating deposition of ingrowth wall papillae. Auxin-induced ethylene biosynthesis initiates the cascade. This in turn drives a burst in extracellular H2O2 production that triggers uniform wall deposition. Thereafter, a persistent and elevated cytosolic Ca(2+) concentration, resulting from Ca(2+) influx through plasma membrane Ca(2+)-permeable channels, generates a Ca(2+) signal that directs formation of wall ingrowth papillae to specific loci. We now report how these Ca(2+)-permeable channels are regulated using the proportionate responses in cytosolic Ca(2+) concentration as a proxy measure of their transport activity. Culturing cotyledons on various combinations of pharmacological agents allowed the regulatory influence of each upstream signal on Ca(2+) channel activity to be evaluated. The findings demonstrated that Ca(2+)-permeable channel activity was insensitive to auxin, but up-regulated by ethylene through two independent routes. In one route ethylene acts directly on Ca(2+)-permeable channel activity at the transcriptional and post-translational levels, through an ethylene receptor-dependent pathway. The other route is mediated by an ethylene-induced production of extracellular H2O2 which then acts translationally and post-translationally to up-regulate Ca(2+)-permeable channel activity. A model describing the differential regulation of Ca(2+)-permeable channel activity is presented. © The Author 2015. Published by Oxford University Press on

  4. Persistence, resistance, resonance

    Science.gov (United States)

    Tsadka, Maayan

    form of musical consumption and experience. The three pieces draw lines connecting different aspects of persistence, resistance, and resonance.

  5. Microbial Biofilms: Persisters, Tolerance and Dosing

    Science.gov (United States)

    Cogan, N. G.

    2005-03-01

    Almost all moist surfaces are colonized by microbial biofilms. Biofilms are implicated in cross-contamination of food products, biofouling, medical implants and various human infections such as dental cavities, ulcerative colitis and chronic respiratory infections. Much of current research is focused on the recalcitrance of biofilms to typical antibiotic and antimicrobial treatments. Although the polymer component of biofilms impedes the penetration of antimicrobials through reaction-diffusion limitation, this does not explain the observed tolerance, it merely delays the action of the agent. Heterogeneities in growth-rate also slow the eradication of the bacteria since most antimicrobials are far less effective for non-growing, or slowly growing bacteria. This also does not fully describe biofilm tolerance, since heterogeneities arr primairly a result of nutrient consumption. In this investigation, we describe the formation of `persister' cells which neither grow nor die in the presence of antibiotics. We propose that the cells are of a different phenotype than typical bacterial cells and the expression of the phenotype is regulated by the growth rate and the antibiotic concentration. We describe several experiments which describe the dynamics of persister cells and which motivate a dosing protocol that calls for periodic dosing of the population. We then introduce a mathematical model, which describes the effect of such a dosing regiment and indicates that the relative dose/withdrawal times are important in determining the effectiveness of such a treatment. A reduced model is introduced and the similar behavior is demonstrated analytically.

  6. Teriparatide Induced Delayed Persistent Hypercalcemia

    Directory of Open Access Journals (Sweden)

    Nirosshan Thiruchelvam

    2014-01-01

    Full Text Available Teriparatide, a recombinant PTH, is an anabolic treatment for osteoporosis that increases bone density. Transient hypercalcemia is a reported side effect of teriparatide that is seen few hours following administration of teriparatide and resolves usually within 16 hours of drug administration. Persistent hypercalcemia, although not observed in clinical trials, is rarely reported. The current case describes a rare complication of teriparatide induced delayed persistent hypercalcemia.

  7. Persistence in the Cryptocurrency Market

    OpenAIRE

    Caporale, Guglielmo Maria; Gil-Alaña, Luis A.; Plastun, Alex

    2017-01-01

    This paper examines persistence in the cryptocurrency market. Two different long-memory methods (R/S analysis and fractional integration) are used to analyse it in the case of the four main cryptocurrencies (BitCoin, LiteCoin, Ripple, Dash) over the sample period 2013-2017. The findings indicate that this market exhibits persistence (there is a positive correlation between its past and future values), and that its degree changes over time. Such predictability represents evidence of market ine...

  8. Persistence-Driven Durotaxis: Generic, Directed Motility in Rigidity Gradients

    Science.gov (United States)

    Novikova, Elizaveta A.; Raab, Matthew; Discher, Dennis E.; Storm, Cornelis

    2017-02-01

    Cells move differently on substrates with different rigidities: the persistence time of their motion is higher on stiffer substrates. We show that this behavior—in and of itself—results in a net flux of cells directed up a soft-to-stiff gradient. Using simple random walk models with varying persistence and stochastic simulations, we characterize the propensity to move in terms of the durotactic index also measured in experiments. A one-dimensional model captures the essential features and highlights the competition between diffusive spreading and linear, wavelike propagation. Persistence-driven durokinesis is generic and may be of use in the design of instructive environments for cells and other motile, mechanosensitive objects.

  9. Missed diagnosis-persistent delirium

    Directory of Open Access Journals (Sweden)

    Aseem Mehra

    2014-01-01

    Full Text Available Delirium is in general considered as an acute short lasting reversible neuropsychiatric syndrome. However, there is some evidence to suggest that in a small proportion of cases delirium may be a chronic or persistent condition. However, making this diagnosis requires clinical suspicion and ruling other differential diagnosis. In this report, we present a case of a 55-year-old man who had cognitive symptoms, psychotic symptoms and depressive symptoms along with persistent hypokalemia and glucose intolerance. He was seen by 3 psychiatrists with these symptoms and was initially diagnosed as having depressive disorder and later diagnosis of bipolar affective disorder (current episode mania, and psychosis were considered by the third psychiatrist. However, despite the presence of persistent neurocognitive deficits, evening worsening of symptoms, hypokalemia and glucose intolerance diagnosis of delirium was not suspected.

  10. The inhibition of activated hepatic stellate cells proliferation by arctigenin through G0/G1 phase cell cycle arrest: persistent p27(Kip1) induction by interfering with PI3K/Akt/FOXO3a signaling pathway.

    Science.gov (United States)

    Li, Ao; Wang, Jun; Wu, Mingjun; Zhang, Xiaoxun; Zhang, Hongzhi

    2015-01-15

    Proliferation of hepatic stellate cells (HSCs) is vital for the development of fibrosis during liver injury. In this study, we describe that arctigenin (ATG), a major bioactive component of Fructus Arctii, exhibited selective cytotoxic activity via inhibiting platelet-derived growth factor-BB (PDGF-BB)-activated HSCs proliferation and arrested cell cycle at G0/G1 phase, which could not be observed in normal human hepatocytes in vitro. The cyclin-dependent kinase (CDK) 4/6 activities could be strongly inhibited by ATG through down-regulation of cyclin D1 and CDK4/6 expression in early G1 phase arrest. In the ATG-treated HSCs, the expression level of p27(Kip1) and the formation of CDK2-p27(Kip1) complex were also increased. p27(Kip1) silencing significantly attenuated the effect of ATG, including cell cycle arrest and suppression of proliferation in activated HSCs. We also found that ATG suppressed PDGF-BB-induced phosphorylation of Akt and its downstream transcription factor Forkhead box O 3a (FOXO3a), decreased binding of FOXO3a to 14-3-3 protein, and stimulated nuclear translocation of FOXO3a in activated HSCs. Furthermore, knockdown of FOXO3a expression by FOXO3a siRNA attenuated ATG-induced up-regulation of p27(Kip1) in activated HSCs. All the above findings suggested that ATG could increase the levels of p27(Kip1) protein through inhibition of Akt and improvement of FOXO3a activity, in turn inhibited the CDK2 kinase activity, and eventually caused an overall inhibition of HSCs proliferation. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Energy Savings Lifetimes and Persistence

    Energy Technology Data Exchange (ETDEWEB)

    Hoffman, Ian M. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Schiller, Steven R. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Todd, Annika [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Billingsley, Megan A. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Goldman, Charles A. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Schwartz, Lisa C. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2016-02-01

    This technical brief explains the concepts of energy savings lifetimes and savings persistence and discusses how program administrators use these factors to calculate savings for efficiency measures, programs and portfolios. Savings lifetime is the length of time that one or more energy efficiency measures or activities save energy, and savings persistence is the change in savings throughout the functional life of a given efficiency measure or activity. Savings lifetimes are essential for assessing the lifecycle benefits and cost effectiveness of efficiency activities and for forecasting loads in resource planning. The brief also provides estimates of savings lifetimes derived from a national collection of costs and savings for electric efficiency programs and portfolios.

  12. On persistently positively expansive maps

    Directory of Open Access Journals (Sweden)

    Alexander Arbieto

    2010-06-01

    Full Text Available In this paper, we prove that any C¹-persistently positively expansive map is expanding. This improves a result due to Sakai (Sakai 2004.Neste artigo, mostramos que todo mapa C¹-persistentemente positivamente expansivo e expansor. Isto melhora um resultado devido a Sakai (Sakai 2004.

  13. Persistence

    DEFF Research Database (Denmark)

    Hansen, Kis Boisen

    2012-01-01

    The note shows an example of an architure for buildin g stand-alone program, where the programming language is object oriented and the databas system is a relational database system. Together with the notes is an example program.......The note shows an example of an architure for buildin g stand-alone program, where the programming language is object oriented and the databas system is a relational database system. Together with the notes is an example program....

  14. Immunological aspects of persistent hepatitis B in children

    Directory of Open Access Journals (Sweden)

    Harsoyo Notoatmojo

    2006-08-01

    Full Text Available We studied the immunological status of 203 children having persistence Hepatitis B (positive HBsAg ranging in age from 6 to 14 years in Semarang Municipality. The results of humoral immunity examination (IgM Anti-HBc showed that all were negative, indicating that they are not in acute phase of hepatitis B infection. Cellular immunity examination, i.e., CMI skin test has shown positive result in 64.9% on persistent and 65.2% in non persistent hepatitis B (p>0.05. T cell examination showed statistically significant difference (p<0.01 between persistenct and non persistent hepatitis B patients, there was is also significant difference (p<0.01 on CD4 cell examination. These findings indicated that there was difference in immunoregulation function and response repression of antivirus between both groups of patients. On the other hand CD4/ CD8 ratio and T cell function showed no significant difference between the two gorups of patients; similarly the specific function of cytotoxic T cell was not significantly difference.

  15. Persistence of enteric viruses within oysters (Crassostrea virginica)

    Science.gov (United States)

    It is well known that water-borne enteric viruses are concentrated by bivalves. Why these viruses are selectively retained and remain infectious within shellfish tissues for extended periods is unknown. Our current hypothesis is that phagocytic hemocytes (blood cells) are a site of virus persiste...

  16. Postnatal persistent infection with classical Swine Fever virus and its immunological implications.

    Directory of Open Access Journals (Sweden)

    Sara Muñoz-González

    Full Text Available It is well established that trans-placental transmission of classical swine fever virus (CSFV during mid-gestation can lead to persistently infected offspring. The aim of the present study was to evaluate the ability of CSFV to induce viral persistence upon early postnatal infection. Two litters of 10 piglets each were infected intranasally on the day of birth with low and moderate virulence CSFV isolates, respectively. During six weeks after postnatal infection, most of the piglets remained clinically healthy, despite persistent high virus titres in the serum. Importantly, these animals were unable to mount any detectable humoral and cellular immune response. At necropsy, the most prominent gross pathological lesion was a severe thymus atrophy. Four weeks after infection, PBMCs from the persistently infected seronegative piglets were unresponsive to both, specific CSFV and non-specific PHA stimulation in terms of IFN-γ-producing cells. These results suggested the development of a state of immunosuppression in these postnatally persistently infected pigs. However, IL-10 was undetectable in the sera of the persistently infected animals. Interestingly, CSFV-stimulated PBMCs from the persistently infected piglets produced IL-10. Nevertheless, despite the addition of the anti-IL-10 antibody in the PBMC culture from persistently infected piglets, the response of the IFN-γ producing cells was not restored. Therefore, other factors than IL-10 may be involved in the general suppression of the T-cell responses upon CSFV and mitogen activation. Interestingly, bone marrow immature granulocytes were increased and targeted by the virus in persistently infected piglets. Taken together, we provided the first data demonstrating the feasibility of CSFV in generating a postnatal persistent disease, which has not been shown for other members of the Pestivirus genus yet. Since serological methods are routinely used in CSFV surveillance, persistently infected pigs

  17. Is Farm Management Skill Persistent?

    OpenAIRE

    Li, Xin; Paulson, Nicholas

    2014-01-01

    Farm management skills can affect farm managers' performance. In this article, farm management performance is analyzed based on yearly Illinois Farm Business Farm Management (FBFM) panel data across 6,760 farms from 1996 through 2011. Two out-of-sample measures of skill are used to analyze the ability of farm managers that consistently perform well over yearly and longer time horizons. Persistence tests show management skills are consistent and predictable. Results also suggest that the most ...

  18. Persistent Authentication in Smart Environments

    DEFF Research Database (Denmark)

    Hansen, Mads Syska; Kirschmeyer, Martin; Jensen, Christian D.

    2008-01-01

    present a proof-of-concept implementation of the proposed mechanism, which employs camera based tracking with a single stationary 3D camera that uses the "time of flight" principle. A preliminary evaluation of the proposed mechanism indicates that persistent authentication is technically possible...... with the proposed hardware. The proposed model is sufficiently general to allow the addition of more cameras or supplemental tracking technologies, which will improve the robustness and scalability of the proposed mechanism....

  19. Long memory and changing persistence

    DEFF Research Database (Denmark)

    Kruse, Robinson; Sibbertsen, Philipp

    We study the empirical behaviour of semi-parametric log-periodogram estimation for long memory models when the true process exhibits a change in persistence. Simulation results confirm theoretical arguments which suggest that evidence for long memory is likely to be found. A recently proposed test...... by Sibbertsen and Kruse (2009) is shown to exhibit noticeable power to discriminate between long memory and a structural change in autoregressive parameters....

  20. How persistent is civilization growth?

    OpenAIRE

    Garrett, Timothy J.

    2011-01-01

    In a recent study (Garrett, 2011), I described theoretical arguments and empirical evidence showing how civilization evolution might be considered from a purely physical basis. One implication is that civilization exhibits the property of persistence in its growth. Here, this argument is elaborated further, and specific near-term forecasts are provided for key economic variables and anthropogenic CO2 emission rates at global scales. Absent some external shock, civilization wealth, energy cons...

  1. MOOCs and Persistence: Definitions and Predictors

    Science.gov (United States)

    Evans, Brent J.; Baker, Rachel B.

    2016-01-01

    The chapter argues for redefining the term "persistence" as it relates to MOOCs and considers how different measures produce different results in the research; it closes with a review of research on persistence in MOOCs.

  2. Intracellular survival of Staphylococcus aureus during persistent infection in the insect Tenebrio molitor.

    Science.gov (United States)

    McGonigle, John E; Purves, Joanne; Rolff, Jens

    2016-06-01

    Survival of bacteria within host cells and tissues presents a challenge to the immune systems of higher organisms. Escape from phagocytic immune cells compounds this issue, as immune cells become potential vehicles for pathogen dissemination. However, the duration of persistence within phagocytes and its contribution to pathogen load has yet to be determined. We investigate the immunological significance of intracellular persistence within the insect model Tenebrio molitor, assessing the extent, duration and location of bacterial recovery during a persistent infection. Relative abundance of Staphylococcus aureus in both intracellular and extracellular fractions was determined over 21 days, and live S. aureus were successfully recovered from both the hemolymph and within phagocytic immune cells across the entire time course. The proportion of bacteria recovered from within phagocytes also increased over time. Our results show that to accurately estimate pathogen load it is vital to account for bacteria persisting within immune cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli.

    Directory of Open Access Journals (Sweden)

    Tobias Dörr

    2010-02-01

    Full Text Available Bacteria induce stress responses that protect the cell from lethal factors such as DNA-damaging agents. Bacterial populations also form persisters, dormant cells that are highly tolerant to antibiotics and play an important role in recalcitrance of biofilm infections. Stress response and dormancy appear to represent alternative strategies of cell survival. The mechanism of persister formation is unknown, but isolated persisters show increased levels of toxin/antitoxin (TA transcripts. We have found previously that one or more components of the SOS response induce persister formation after exposure to a DNA-damaging antibiotic. The SOS response induces several TA genes in Escherichia coli. Here, we show that a knockout of a particular SOS-TA locus, tisAB/istR, had a sharply decreased level of persisters tolerant to ciprofloxacin, an antibiotic that causes DNA damage. Step-wise administration of ciprofloxacin induced persister formation in a tisAB-dependent manner, and cells producing TisB toxin were tolerant to multiple antibiotics. TisB is a membrane peptide that was shown to decrease proton motive force and ATP levels, consistent with its role in forming dormant cells. These results suggest that a DNA damage-induced toxin controls production of multidrug tolerant cells and thus provide a model of persister formation.

  4. Predictive features of persistent activity emergence in regular spiking and intrinsic bursting model neurons.

    Directory of Open Access Journals (Sweden)

    Kyriaki Sidiropoulou

    Full Text Available Proper functioning of working memory involves the expression of stimulus-selective persistent activity in pyramidal neurons of the prefrontal cortex (PFC, which refers to neural activity that persists for seconds beyond the end of the stimulus. The mechanisms which PFC pyramidal neurons use to discriminate between preferred vs. neutral inputs at the cellular level are largely unknown. Moreover, the presence of pyramidal cell subtypes with different firing patterns, such as regular spiking and intrinsic bursting, raises the question as to what their distinct role might be in persistent firing in the PFC. Here, we use a compartmental modeling approach to search for discriminatory features in the properties of incoming stimuli to a PFC pyramidal neuron and/or its response that signal which of these stimuli will result in persistent activity emergence. Furthermore, we use our modeling approach to study cell-type specific differences in persistent activity properties, via implementing a regular spiking (RS and an intrinsic bursting (IB model neuron. We identify synaptic location within the basal dendrites as a feature of stimulus selectivity. Specifically, persistent activity-inducing stimuli consist of activated synapses that are located more distally from the soma compared to non-inducing stimuli, in both model cells. In addition, the action potential (AP latency and the first few inter-spike-intervals of the neuronal response can be used to reliably detect inducing vs. non-inducing inputs, suggesting a potential mechanism by which downstream neurons can rapidly decode the upcoming emergence of persistent activity. While the two model neurons did not differ in the coding features of persistent activity emergence, the properties of persistent activity, such as the firing pattern and the duration of temporally-restricted persistent activity were distinct. Collectively, our results pinpoint to specific features of the neuronal response to a given

  5. Persistent currents in three-dimensional shell-doped nanorings

    International Nuclear Information System (INIS)

    Ning, Xu; Jian-Wen, Ding; Hong-Bo, Chen; Ming-Ming, Ma

    2009-01-01

    The persistent current in three-dimensional (P × N 2 ) nanorings as a function of the unit cell number (P), the channel number (M = N 2 ), surface disorder (ξ), and temperature (T) is theoretically investigated in terms of rotational symmetry. On the whole, the typical current increases linearly with √M but decreases exponentially with P, while wide fluctuations exist therein. In the presence of surface disorder, the persistent current decreases with ξ in the regime of weak disorder but increases in the regime of strong disorder. In addition, it is found that the persistent current in perfect rings decreases exponentially with temperature even at T * , while in most disorder rings, the typical current decreases slightly with temperature at T *

  6. Persistence of foot-and mouth disease virus in ruminants

    DEFF Research Database (Denmark)

    Stenfeldt, Carolina; Belsham, Graham; Tjørnehøj, Kirsten

    squamous epithelia of the coronary bands and oral cavity within a few days of infection. Viremia occurs within 2-3 days of infection, but is rapidly cleared through the effect of circulating antibodies of the adaptive immune response. The host response involves initial activation of the innate immune...... response, with activation and recruitment of effector-cells, and subsequent activation of T- and B-cells, leading to the production of circulating antibodies, as well as activation of cytotoxic T-cells. In ruminants, approximately 50% of animals infected with FMDV develop into persistently infected carrier...... animals, with intermittent excretion of live virus, whilst remaining animals clear the infection effectively. Previous experiments have indicated that the site of persistent viral replication is located in pharyngeal lymphoid tissue, as well as the basal epithelia of the dorsal soft palate...

  7. Physical trust-based persistent authentication

    DEFF Research Database (Denmark)

    Fujita, Masahiro; Jensen, Christian D.; Arimura, Shiori

    2015-01-01

    propose a new type of persistent authentication, called Persistent Authentication Based On physical Trust (PABOT). PABOT uses a context of “physical trust relationship” that is built by visual contact between users, and thus can offer a persistent authentication mechanism with better usability and higher...

  8. Distributed Persistent Identifiers System Design

    Directory of Open Access Journals (Sweden)

    Pavel Golodoniuc

    2017-06-01

    Full Text Available The need to identify both digital and physical objects is ubiquitous in our society. Past and present persistent identifier (PID systems, of which there is a great variety in terms of technical and social implementation, have evolved with the advent of the Internet, which has allowed for globally unique and globally resolvable identifiers. PID systems have, by in large, catered for identifier uniqueness, integrity, and persistence, regardless of the identifier’s application domain. Trustworthiness of these systems has been measured by the criteria first defined by Bütikofer (2009 and further elaborated by Golodoniuc 'et al'. (2016 and Car 'et al'. (2017. Since many PID systems have been largely conceived and developed by a single organisation they faced challenges for widespread adoption and, most importantly, the ability to survive change of technology. We believe that a cause of PID systems that were once successful fading away is the centralisation of support infrastructure – both organisational and computing and data storage systems. In this paper, we propose a PID system design that implements the pillars of a trustworthy system – ensuring identifiers’ independence of any particular technology or organisation, implementation of core PID system functions, separation from data delivery, and enabling the system to adapt for future change. We propose decentralisation at all levels — persistent identifiers and information objects registration, resolution, and data delivery — using Distributed Hash Tables and traditional peer-to-peer networks with information replication and caching mechanisms, thus eliminating the need for a central PID data store. This will increase overall system fault tolerance thus ensuring its trustworthiness. We also discuss important aspects of the distributed system’s governance, such as the notion of the authoritative source and data integrity

  9. Nutrient transitions are a source of persisters in Escherichia coli biofilms.

    Directory of Open Access Journals (Sweden)

    Stephanie M Amato

    Full Text Available Chronic and recurrent infections have been attributed to persisters in biofilms, and despite this importance, the mechanisms of persister formation in biofilms remain unclear. The plethora of biofilm characteristics that could give rise to persisters, including slower growth, quorum signaling, oxidative stress, and nutrient heterogeneity, have complicated efforts to delineate formation pathways that generate persisters during biofilm development. Here we sought to specifically determine whether nutrient transitions, which are a common metabolic stress encountered within surface-attached communities, stimulate persister formation in biofilms and if so, to then identify the pathway. To accomplish this, we established an experimental methodology where nutrient availability to biofilm cells could be controlled exogenously, and then used that method to discover that diauxic carbon source transitions stimulated persister formation in Escherichia coli biofilms. Previously, we found that carbon source transitions stimulate persister formation in planktonic E. coli cultures, through a pathway that involved ppGpp and nucleoid-associated proteins, and therefore, tested the functionality of that pathway in biofilms. Biofilm persister formation was also found to be dependent on ppGpp and nucleoid-associated proteins, but the importance of specific proteins and enzymes between biofilm and planktonic lifestyles was significantly different. Data presented here support the increasingly appreciated role of ppGpp as a central mediator of bacterial persistence and demonstrate that nutrient transitions can be a source of persisters in biofilms.

  10. Nutrient transitions are a source of persisters in Escherichia coli biofilms.

    Science.gov (United States)

    Amato, Stephanie M; Brynildsen, Mark P

    2014-01-01

    Chronic and recurrent infections have been attributed to persisters in biofilms, and despite this importance, the mechanisms of persister formation in biofilms remain unclear. The plethora of biofilm characteristics that could give rise to persisters, including slower growth, quorum signaling, oxidative stress, and nutrient heterogeneity, have complicated efforts to delineate formation pathways that generate persisters during biofilm development. Here we sought to specifically determine whether nutrient transitions, which are a common metabolic stress encountered within surface-attached communities, stimulate persister formation in biofilms and if so, to then identify the pathway. To accomplish this, we established an experimental methodology where nutrient availability to biofilm cells could be controlled exogenously, and then used that method to discover that diauxic carbon source transitions stimulated persister formation in Escherichia coli biofilms. Previously, we found that carbon source transitions stimulate persister formation in planktonic E. coli cultures, through a pathway that involved ppGpp and nucleoid-associated proteins, and therefore, tested the functionality of that pathway in biofilms. Biofilm persister formation was also found to be dependent on ppGpp and nucleoid-associated proteins, but the importance of specific proteins and enzymes between biofilm and planktonic lifestyles was significantly different. Data presented here support the increasingly appreciated role of ppGpp as a central mediator of bacterial persistence and demonstrate that nutrient transitions can be a source of persisters in biofilms.

  11. Immune Evasion Strategies and Persistence of Helicobacter pylori.

    Science.gov (United States)

    Mejías-Luque, Raquel; Gerhard, Markus

    Helicobacter pylori infection is commonly acquired during childhood, can persist lifelong if not treated, and can cause different gastric pathologies, including chronic gastritis, peptic ulcer disease, and eventually gastric cancer. H. pylori has developed a number of strategies in order to cope with the hostile conditions found in the human stomach as well as successful mechanisms to evade the strong innate and adaptive immune responses elicited upon infection. Thus, by manipulating innate immune receptors and related signaling pathways, inducing tolerogenic dendritic cells and inhibiting effector T cell responses, H. pylori ensures low recognition by the host immune system as well as its persistence in the gastric epithelium. Bacterial virulence factors such as cytotoxin-associated gene A, vacuolating cytotoxin A, or gamma-glutamyltranspeptidase have been extensively studied in the context of bacterial immune escape and persistence. Further, the bacterium possesses other factors that contribute to immune evasion. In this chapter, we discuss in detail the main evasion and persistence strategies evolved by the bacterium as well as the specific bacterial virulence factors involved.

  12. Occurrence and persistence of magnetic elements in the quiet Sun

    Science.gov (United States)

    Giannattasio, F.; Berrilli, F.; Consolini, G.; Del Moro, D.; Gošić, M.; Bellot Rubio, L.

    2018-03-01

    Context. Turbulent convection efficiently transports energy up to the solar photosphere, but its multi-scale nature and dynamic properties are still not fully understood. Several works in the literature have investigated the emergence of patterns of convective and magnetic nature in the quiet Sun at spatial and temporal scales from granular to global. Aims: To shed light on the scales of organisation at which turbulent convection operates, and its relationship with the magnetic flux therein, we studied characteristic spatial and temporal scales of magnetic features in the quiet Sun. Methods: Thanks to an unprecedented data set entirely enclosing a supergranule, occurrence and persistence analysis of magnetogram time series were used to detect spatial and long-lived temporal correlations in the quiet Sun and to investigate their nature. Results: A relation between occurrence and persistence representative for the quiet Sun was found. In particular, highly recurrent and persistent patterns were detected especially in the boundary of the supergranular cell. These are due to moving magnetic elements undergoing motion that behaves like a random walk together with longer decorrelations ( 2 h) with respect to regions inside the supergranule. In the vertices of the supegranular cell the maximum observed occurrence is not associated with the maximum persistence, suggesting that there are different dynamic regimes affecting the magnetic elements.

  13. Persistent infection with ebola virus under conditions of partial immunity.

    Science.gov (United States)

    Gupta, Manisha; Mahanty, Siddhartha; Greer, Patricia; Towner, Jonathan S; Shieh, Wun-Ju; Zaki, Sherif R; Ahmed, Rafi; Rollin, Pierre E

    2004-01-01

    Ebola hemorrhagic fever in humans is associated with high mortality; however, some infected hosts clear the virus and recover. The mechanisms by which this occurs and the correlates of protective immunity are not well defined. Using a mouse model, we determined the role of the immune system in clearance of and protection against Ebola virus. All CD8 T-cell-deficient mice succumbed to subcutaneous infection and had high viral antigen titers in tissues, whereas mice deficient in B cells or CD4 T cells cleared infection and survived, suggesting that CD8 T cells, independent of CD4 T cells and antibodies, are critical to protection against subcutaneous Ebola virus infection. B-cell-deficient mice that survived the primary subcutaneous infection (vaccinated mice) transiently depleted or not depleted of CD4 T cells also survived lethal intraperitoneal rechallenge for >/==" BORDER="0">25 days. However, all vaccinated B-cell-deficient mice depleted of CD8 T cells had high viral antigen titers in tissues following intraperitoneal rechallenge and died within 6 days, suggesting that memory CD8 T cells by themselves can protect mice from early death. Surprisingly, vaccinated B-cell-deficient mice, after initially clearing the infection, were found to have viral antigens in tissues later (day 120 to 150 post-intraperitoneal infection). Furthermore, following intraperitoneal rechallenge, vaccinated B-cell-deficient mice that were transiently depleted of CD4 T cells had high levels of viral antigen in tissues earlier (days 50 to 70) than vaccinated undepleted mice. This demonstrates that under certain immunodeficiency conditions, Ebola virus can persist and that loss of primed CD4 T cells accelerates the course of persistent infections. These data show that CD8 T cells play an important role in protection against acute disease, while both CD4 T cells and antibodies are required for long-term protection, and they provide evidence of persistent infection by Ebola virus suggesting

  14. Alterations in adaptive immunity persist during long-duration spaceflight

    Science.gov (United States)

    Crucian, Brian; Stowe, Raymond P; Mehta, Satish; Quiriarte, Heather; Pierson, Duane; Sams, Clarence

    2015-01-01

    Background: It is currently unknown whether immune system alterations persist during long-duration spaceflight. In this study various adaptive immune parameters were assessed in astronauts at three intervals during 6-month spaceflight on board the International Space Station (ISS). AIMS: To assess phenotypic and functional immune system alterations in astronauts participating in 6-month orbital spaceflight. Methods: Blood was collected before, during, and after flight from 23 astronauts participating in 6-month ISS expeditions. In-flight samples were returned to Earth within 48 h of collection for immediate analysis. Assays included peripheral leukocyte distribution, T-cell function, virus-specific immunity, and mitogen-stimulated cytokine production profiles. Results: Redistribution of leukocyte subsets occurred during flight, including an elevated white blood cell (WBC) count and alterations in CD8+ T-cell maturation. A reduction in general T-cell function (both CD4+ and CD8+) persisted for the duration of the 6-month spaceflights, with differential responses between mitogens suggesting an activation threshold shift. The percentage of CD4+ T cells capable of producing IL-2 was depressed after landing. Significant reductions in mitogen-stimulated production of IFNγ, IL-10, IL-5, TNFα, and IL-6 persisted during spaceflight. Following lipopolysaccharide (LPS) stimulation, production of IL-10 was reduced, whereas IL-8 production was increased during flight. Conclusions: The data indicated that immune alterations persist during long-duration spaceflight. This phenomenon, in the absence of appropriate countermeasures, has the potential to increase specific clinical risks for crewmembers during exploration-class deep space missions. PMID:28725716

  15. Host factors influencing viral persistence

    DEFF Research Database (Denmark)

    Thomsen, Allan Randrup; Nansen, A; Ørding Andreasen, Susanne

    2000-01-01

    host were used. Our results reveal that very different outcomes may be observed depending on virus strain and immunocompetence of the host. Thus while CD4+ cells are not critical during the initial phase of virus control, infectious virus reappear in mice lacking CD4+ cells, B cells or CD40 ligand...... replication, mice lacking the ability to produce interferon-gamma may develop either a severe, mostly fatal, T-cell mediated wasting syndrome or a chronic infection characterized by long-term coexistence of antiviral cytotoxic T lymphocytes and infectious virus. Mathematical modelling indicates...

  16. Persistent cough in an adolescent.

    Science.gov (United States)

    Stein, M T; Harper, G; Chen, J

    1999-12-01

    Jessica, a 14-year-old girl with a history of asthma, went to her pediatrician's office because of a persistent cough. She had been coughing for at least 3 months with occasional cough-free periods of less than a few days. The cough was nonproductive and was not accompanied by fever, rhinorrhea, or facial or chest pain. Jessica and her mother observed that the cough increased with exercise and typically was not present during sleep. She has used two metered-dose inhalers--albuterol and cromolyn--without any change in the cough pattern. For the past 5 years, Jessica has had mild asthma responsive to albuterol. She enjoys running on the cross-country team, soccer, and dancing. She is an average student and denies any change in academic performance. She has never been hospitalized or had an emergency department visit for asthma or pneumonia. There has been no recent travel or exposure to a person with a chronic productive cough, tobacco smoke, or a live-in pet. Jessica lives with her mother and younger sister in a 10-year-old, carpeted apartment without any evidence of mold or recent renovation. In the process of taking the history, the pediatrician noticed that Jessica coughed intermittently, with two or three coughs during each episode. At times, the cough was harsh; at other times, it was a quiet cough, as if she were clearing her throat. She was cooperative, without overt anxiety or respiratory distress. After a complete physical examination with normal findings, the pediatrician interviewed Jessica and her mother alone. Jessica's parents had been divorced for the past 6 years. She lived with her mother but visited her father, and his new family with two young children, every weekend. She spoke about this arrangement comfortably and said that she loved her father and mother but didn't like the tension she experienced at her father's home. "I don't like adults arguing when kids are around." When asked why she thought the cough persisted so long, she commented in a

  17. Persistent homology and string vacua

    Energy Technology Data Exchange (ETDEWEB)

    Cirafici, Michele [Center for Mathematical Analysis, Geometry and Dynamical Systems,Instituto Superior Técnico, Universidade de Lisboa,Av. Rovisco Pais, 1049-001 Lisboa (Portugal); Institut des Hautes Études Scientifiques,Le Bois-Marie, 35 route de Chartres, F-91440 Bures-sur-Yvette (France)

    2016-03-08

    We use methods from topological data analysis to study the topological features of certain distributions of string vacua. Topological data analysis is a multi-scale approach used to analyze the topological features of a dataset by identifying which homological characteristics persist over a long range of scales. We apply these techniques in several contexts. We analyze N=2 vacua by focusing on certain distributions of Calabi-Yau varieties and Landau-Ginzburg models. We then turn to flux compactifications and discuss how we can use topological data analysis to extract physical information. Finally we apply these techniques to certain phenomenologically realistic heterotic models. We discuss the possibility of characterizing string vacua using the topological properties of their distributions.

  18. Coping with persistent environmental problems

    DEFF Research Database (Denmark)

    Varjopuro, Riku; Andrulewicz, Eugeniusz; Brandt, Urs Steiner

    2014-01-01

    to a decision to taking action and several years further for actual implementation. Ecosystem responses to measures illustrate that feedback can keep the ecosystem in a certain state and cause a delay in ecosystem response. These delays can operate on decadal scales. Our aim in this paper...... involved in the implementation are keys to improve understanding of the systemic delays. The improved understanding is necessary for the adaptive management of a persistent environmental problem. In addition to the state of the environment, the monitoring and analysis should be targeted also......; (2) implementation delay: the time from the launch of a policy to the actual implementation; (3) ecosystem delay: the time difference between the implementation and an actual measurable effects. A policy process is one characterized by delays. It may take years from problem identification...

  19. Bilateral persistent hyperplastic primary vitreous

    Directory of Open Access Journals (Sweden)

    Jain Tarun

    2009-01-01

    Full Text Available A case of bilateral persistent hyperplastic primary vitreous (PHPV in a 3-month-old male infant, who had bilateral leukokoria, is presented. The child was referred for imaging with a clinical suspicion of retinoblastoma. Gray-scale ultrasound evaluation revealed an echogenic band in the posterior segment of both globes, extending from the posterior surface of the lens capsule to the optic disc. Doppler examination revealed the presence of arterial flow in the band in both globes. Associated echogenic hemorrhage was also seen, which was confirmed by computed tomography. Most cases of PHPV are sporadic and unilateral, and bilateral PHPV is rare. The imaging features in this case suggest the diagnosis of bilateral PHPV and differentiate it from retinoblastoma. This entity, although infrequent, should be considered in the differential diagnosis while evaluating bilateral leukokoria.

  20. Persistence of antimuscarinic drug use

    DEFF Research Database (Denmark)

    Brostrøm, Søren; Hallas, Jesper

    2009-01-01

    PURPOSE: Evidence suggests antimuscarinic drugs for the overactive-bladder syndrome only confer modest improvements in quality of life. We wanted to describe the persistence of therapy, including an extended analysis beyond the 1-year follow-up employed in other studies. METHODS: All prescriptions...... for drugs in ATC category G04BD were retrieved for the period 1999-2006 from a regional database with complete capture of all reimbursed prescriptions. Kaplan-Meyer curves were generated for duration of treatment for each substance and analyzed for determinants of termination. RESULTS: With the exception...... of trospium chloride, all drugs had continuation rates of less than 50% at 6 months, less than 25% at 1 year, and less than 10% at 2 years and longer. Trospium chloride, however, exhibited continuation rates of 46% at 6 months, 36% at 1 year, 22% at 2 years, and 16% at 3 years. CONCLUSIONS: In a setting...

  1. Dematerialization: Variety, caution, and persistence.

    Science.gov (United States)

    Ausubel, Jesse H; Waggoner, Paul E

    2008-09-02

    Dematerialization, represented by declining consumption per GDP of energy or of goods, offers some hope for rising environmental quality with development. The declining proportion of income spent on staples as affluence grows, which income elasticity <1.0 measures, makes dematerialization widespread. Further, as learning improves efficiency of resource use, the intensity of environmental impact per production of staples often declines. We observe that combinations of low income elasticity for staples and of learning by producers cause a variety of dematerializations and declining intensities of impact, from energy use and carbon emission to food consumption and fertilizer use, globally and in countries ranging from the United States and France to China, India, Brazil, and Indonesia. Because dematerialization and intensity of impact are ratios of parameters that may be variously defined and are sometimes difficult to estimate, their fluctuations must be interpreted cautiously. Nevertheless, substantial declining intensity of impact, and especially, dematerialization persisted between 1980 and 2006.

  2. Persistence of stapedial artery: a case report

    International Nuclear Information System (INIS)

    Carvalho, Bruna Vilaca de; Gaiotti, Juliana Oggioni; Diniz, Renata Lopes Furletti Caldeira; Ribeiro, Marcelo Almeida; Motta, Emilia Guerra Pinto Coelho; Moreira, Wanderval

    2013-01-01

    Persistent stapedial artery is a rare congenital anomaly that occurs by a failure in the involution of such artery. Most patients with persistent stapedial artery are asymptomatic. The imaging diagnosis is made principally by means of multidetector computed tomography. In the present case, persistent stapedial artery was an incidental computed tomography finding. The authors discuss the embryogenesis, computed tomography findings and the importance of an early diagnosis of such anomaly. (author)

  3. Drought Persistence Errors in Global Climate Models

    Science.gov (United States)

    Moon, H.; Gudmundsson, L.; Seneviratne, S. I.

    2018-04-01

    The persistence of drought events largely determines the severity of socioeconomic and ecological impacts, but the capability of current global climate models (GCMs) to simulate such events is subject to large uncertainties. In this study, the representation of drought persistence in GCMs is assessed by comparing state-of-the-art GCM model simulations to observation-based data sets. For doing so, we consider dry-to-dry transition probabilities at monthly and annual scales as estimates for drought persistence, where a dry status is defined as negative precipitation anomaly. Though there is a substantial spread in the drought persistence bias, most of the simulations show systematic underestimation of drought persistence at global scale. Subsequently, we analyzed to which degree (i) inaccurate observations, (ii) differences among models, (iii) internal climate variability, and (iv) uncertainty of the employed statistical methods contribute to the spread in drought persistence errors using an analysis of variance approach. The results show that at monthly scale, model uncertainty and observational uncertainty dominate, while the contribution from internal variability is small in most cases. At annual scale, the spread of the drought persistence error is dominated by the statistical estimation error of drought persistence, indicating that the partitioning of the error is impaired by the limited number of considered time steps. These findings reveal systematic errors in the representation of drought persistence in current GCMs and suggest directions for further model improvement.

  4. Modelling the role of Tax expression in HTLV-I persistence in vivo.

    Science.gov (United States)

    Li, Michael Y; Lim, Aaron G

    2011-12-01

    Human T-lymphotropic virus type I (HTLV-I) is a persistent human retrovirus characterized by life-long infection and risk of developing HAM/TSP, a progressive neurological and inflammatory disease, and adult T-cell leukemia (ATL). Chronically infected individuals often harbor high proviral loads despite maintaining a persistently activated immune response. Based on a new hypothesis for the persistence of HTLV-I infection, a three-dimensional compartmental model is constructed that describes the dynamic interactions among latently infected target cells, target-cell activation, and immune responses to HTLV-I, with an emphasis on understanding the role of Tax expression in the persistence of HTLV-I.

  5. Phenotypic and genetic heterogeneity within biofilms with particular emphasis on persistence and antimicrobial tolerance.

    Science.gov (United States)

    Sadiq, Faizan A; Flint, Steve; Li, YanJun; Ou, Kai; Yuan, Lei; He, Guo Qing

    2017-09-01

    Phenotypic changes or phase variation within biofilms is an important feature of bacterial dormant life. Enhanced resistance to antimicrobials is one of the distinct features displayed by a fraction of cells within biofilms. It is believed that persisters are mainly responsible for this phenotypic heterogeneity. However, there is still an unresolved debate on the formation of persisters. In this short review, we highlight all known genomic and proteomic changes encountered by bacterial cells within biofilms. We have also described all phenotypic changes displayed by bacterial cells within biofilms with particular emphasis on enhanced antimicrobial tolerance of biofilms with particular reference to persisters. In addition, all currently known models of persistence have been succinctly discussed.

  6. Translating Romans: some persistent headaches

    Directory of Open Access Journals (Sweden)

    A.B. du Toit

    2010-07-01

    Full Text Available Translating Romans: some persistent headaches Gone are the days when it was axiomatic that expertise in biblical languages automatically qualified one as a Bible translator. In 1949, Ronald Knox, who for nine years conscientiously struggled with translating the Bible for his generation, published a booklet under the title The trials of a translator. At that stage Bible translation as the subject of scientific study was still in its infancy. Since then, research into the intricacies of communicating the biblical message in an authentic but understandable manner, has made significant progress (cf. Roberts, 2009. However, the frustrations of Bible translators, first of all to really understand what the biblical authors wanted to convey to their original addressees, and then to commu-nicate that message to their own targeted readers in a meaningful way, have not disappeared. In fact, the challenge to meet the vary-ing requirements of the multiple kinds of translation that are present-ly in vogue, has only increased.

  7. Energy savings: persuasion and persistence

    Energy Technology Data Exchange (ETDEWEB)

    Eijadi, David; McDougall, Tom; Leaf, Kris; Douglas, Jim; Steinbock, Jason; Reimer, Paul [The Weidt Group, Minnetonka, MN (United States); Gauthier, Julia [Xcel Energy, Minneapolis, MN (United States); Wild, Doug; Richards McDaniel, Stephanie [BWBR Architects, Inc., Saint Paul, MN (United States)

    2005-07-01

    In this study, the architects, sponsoring utility and energy simulation specialist joined together to investigate the persistence of energy savings in three completed projects: a college library; a municipal transportation facility; and a hospital. The primary question being 'How well did the design decisions made with the help of simulation analysis translate into building operations over several years?' Design simulation and metered performance data are compared for specific energy-saving strategies. The paper provides a brief overview of the basis of selection of the three projects, the energy design assistance methods employed and the decisions made, along with their savings expectations. For each case, design characteristics, modelling assumptions, selected strategies and actual metered performance are outlined. We find evidence of appropriate levels of energy conservation, but they are not the absolute values predicted. In each case, the discrepancies between modelling assumptions and final construction or operating procedures are identified, examined and rectified. The paper illustrates that while owners are saving energy, they are not always getting the full savings potential for what they install. The paper concludes with a re-examination of the overall process. It evaluates the potential for additional savings of individual technologies and related larger utility incentives to design teams and building owners.

  8. Transposon mutagenesis identifies novel genes associated with Staphylococcus aureus persister formation

    Directory of Open Access Journals (Sweden)

    Wang ewenjie

    2015-12-01

    Full Text Available Pathogenic bacterial persisters are responsible for the recalcitrance of chronic and persistent infections to antimicrobial therapy. Although the mechanisms of persister formation and survival have been widely studied in Escherichia coli, persistence mechanisms in S. aureus remain largely unknown. Here, we screened a transposon mutant library of a clinical methicillin-resistant Staphylococcus aureus(MRSA)strain, USA500 (ST8, under antibiotic pressure and identified 13 genes whose insertion mutations resulted in a defect in persistence. These candidate genes were further confirmed by evaluating the survival of the mutants upon exposure to levofloxacin and several other stress conditions. We found 13 insertion mutants with significantly lower persister numbers under several stress conditions, including sdhA, sdhB, ureG, mnhG1, fbaA, ctaB, clpX, parE, HOU_0223, HOU_0587, HOU_2091, HOU_2315 and HOU_2346, which mapped into pathways of oxidative phosphorylation, TCA cycle, glycolysis, cell cycle and ABC transporters, suggesting that these genes and pathways may play an important role in persister formation and survival. The newly constructed knockout strains of ureG, sdhA and sdhB and their complemented strains were also tested for defect in persisters following exposure to levofloxacin and several other stress conditions. The results from these experiments were consistent with the screening results, which indicated that deletion of these genes in MRSA USA500 leads to persister defect. These findings provide novel insights into the mechanisms of persister formation and survival in S. aureus and offer new targets for the development of persister-directed antibiotics for the improved treatment of chronic and persistent infections.

  9. Pathogenic characteristics of persistent feline enteric coronavirus infection in cats

    Science.gov (United States)

    Vogel, Liesbeth; Van der Lubben, Mariken; Te Lintelo, Eddie G.; Bekker, Cornelis P.J.; Geerts, Tamara; Schuijff, Leontine S.; Grinwis, Guy C.M.; Egberink, Herman F.; Rottier, Peter J.M.

    2010-01-01

    Feline coronaviruses (FCoV) comprise two biotypes: feline enteric coronaviruses (FECV) and feline infectious peritonitis viruses (FIPV). FECV is associated with asymptomatic persistent enteric infections, while FIPV causes feline infectious peritonitis (FIP), a usually fatal systemic disease in domestic cats and some wild Felidae. FIPV arises from FECV by mutation. FCoV also occur in two serotypes, I and II, of which the serotype I viruses are by far the most prevalent in the field. Yet, most of our knowledge about FCoV infections relates to serotype II viruses, particularly about the FIPV, mainly because type I viruses grow poorly in cell culture. Hence, the aim of the present work was the detailed study of the epidemiologically most relevant viruses, the avirulent serotype I viruses. Kittens were inoculated oronasally with different doses of two independent FECV field strains, UCD and RM. Persistent infection could be reproducibly established. The patterns of clinical symptoms, faecal virus shedding and seroconversion were monitored for up to 10 weeks revealing subtle but reproducible differences between the two viruses. Faecal virus, i.e. genomic RNA, was detected during persistent FECV infection only in the large intestine, downstream of the appendix, and could occasionally be observed also in the blood. The implications of our results, particularly our insights into the persistently infected state, are discussed. PMID:20663472

  10. Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway.

    Science.gov (United States)

    Fineran, Paul; Lloyd-Evans, Emyr; Lack, Nathan A; Platt, Nick; Davis, Lianne C; Morgan, Anthony J; Höglinger, Doris; Tatituri, Raju Venkata V; Clark, Simon; Williams, Ian M; Tynan, Patricia; Al Eisa, Nada; Nazarova, Evgeniya; Williams, Ann; Galione, Antony; Ory, Daniel S; Besra, Gurdyal S; Russell, David G; Brenner, Michael B; Sim, Edith; Platt, Frances M

    2016-11-18

    Tuberculosis remains a major global health concern. The ability to prevent phagosome-lysosome fusion is a key mechanism by which intracellular mycobacteria, including Mycobacterium tuberculosis , achieve long-term persistence within host cells. The mechanisms underpinning this key intracellular pro-survival strategy remain incompletely understood. Host macrophages infected with persistent mycobacteria share phenotypic similarities with cells taken from patients suffering from Niemann-Pick Disease Type C (NPC), a rare lysosomal storage disease in which endocytic trafficking defects and lipid accumulation within the lysosome lead to cell dysfunction and cell death. We investigated whether these shared phenotypes reflected an underlying mechanistic connection between mycobacterial intracellular persistence and the host cell pathway dysfunctional in NPC. The induction of NPC phenotypes in macrophages from wild-type mice or obtained from healthy human donors was assessed via infection with mycobacteria and subsequent measurement of lipid levels and intracellular calcium homeostasis. The effect of NPC therapeutics on intracellular mycobacterial load was also assessed. Macrophages infected with persistent intracellular mycobacteria phenocopied NPC cells, exhibiting accumulation of multiple lipid types, reduced lysosomal Ca 2+ levels, and defects in intracellular trafficking. These NPC phenotypes could also be induced using only lipids/glycomycolates from the mycobacterial cell wall. These data suggest that persistent intracellular mycobacteria inhibit the NPC pathway, likely via inhibition of the NPC1 protein, and subsequently induce altered acidic store Ca 2+ homeostasis. Reduced lysosomal calcium levels may provide a mechanistic explanation for the reduced levels of phagosome-lysosome fusion in mycobacterial infection. Treatments capable of correcting defects in NPC mutant cells via modulation of host cell calcium were of benefit in promoting clearance of mycobacteria

  11. Persistence of Orientia tsutsugamushi in humans.

    Science.gov (United States)

    Chung, Moon-Hyun; Lee, Jin-Soo; Baek, Ji-hyeon; Kim, Mijeong; Kang, Jae-Seung

    2012-03-01

    We investigated the persistence of viable Orientia tsutsugamushi in patients who had recovered from scrub typhus. Blood specimens were available from six patients with scrub typhus who were at 1 to 18 months after the onset of the illness. The EDTA-treated blood specimens were inoculated into ECV304 cells, and cultures were maintained for 7 months. Sequencing of the 56-kDa type-specific antigen gene of O. tsutsugamushi was performed to ascertain the homology of isolates. O. tsutsugamushi was isolated from all six patients, and nucleotide sequences of isolates serially collected from each patient were identical in all five patients in whom nucleotide sequences were compared. One patient relapsed 2 days after completion of antibiotic therapy; two patients complained of weakness for 1 to 2.5 months after the illness; one patient underwent coronary angioplasty 6 months later; and one patient suffered from a transient ischemic attack 8 months later. This finding suggests that O. tsutsugamushi causes chronic latent infection, which may be associated with certain clinical illnesses, preceded by scrub typhus. Antibiotic therapy abates the symptoms of scrub typhus, but does not eradicate O. tsutsugamushi from the human body.

  12. Mastering NServiceBus and persistence

    CERN Document Server

    Helton, Rich

    2014-01-01

    This book is intended for developers, designers, and architects alike who wish to build C# NServiceBus enterprise architectures and learn how ESB persists data and messages to help them attain their goals. No prior knowledge of persistence in NServiceBus is required.

  13. The Persistence of Mutual Fund Performance.

    OpenAIRE

    Grinblatt, Mark; Titman, Sheridan

    1992-01-01

    This paper analyzes how mutual fund performance relates to past performance. These tests are based on a multiple portfolio benchmark that was formed on the basis of securities characteristics. The authors find evidence that differences in performance between funds persist over time and that this persistence is consistent with the ability of fund managers to earn abnormal returns. Copyright 1992 by American Finance Association.

  14. Modelling asymmetric persistence over the business cycle

    NARCIS (Netherlands)

    Ph.H.B.F. Franses (Philip Hans); R. Paap (Richard)

    1998-01-01

    textabstractWe address the issue of time varying persistence of shocks to macroeconomic time series variables by proposing a new and parsimonious time series model. Our model assumes that this time varying persistence depends on a linear combination of lagged explanatory variables, where this

  15. A model for persistency of egg production

    NARCIS (Netherlands)

    Grossman, M.; Gossman, T.N.; Koops, W.J.

    2000-01-01

    The objectives of our study were to propose a new definition for persistency of egg production and to develop a mathematical model to describe the egg production curve, one that includes a new measure for persistency, based on the proposed definition, for use as a selection criterion to improve

  16. Lymphogranuloma venereum causing a persistent genital ulcer.

    Science.gov (United States)

    Marcotte, Terrence; Lee, Yer; Pandori, Mark; Jain, Vivek; Cohen, Stephanie Elise

    2014-04-01

    Lymphogranuloma venereum (LGV) is a sexually transmitted cause of inguinal lymphadenopathy and proctocolitis. We report a patient with a persistent genital ulcer due to LGV (serovar L2b), an unusual presentation among US men who have sex with men. Lymphogranuloma venereum should be considered when evaluating persistent genital ulcers, and LGV-specific testing should be sought.

  17. Persistent Identifiers as Boundary Objects

    Science.gov (United States)

    Parsons, M. A.; Fox, P. A.

    2017-12-01

    In 1989, Leigh Star and Jim Griesemer defined the seminal concept of `boundary objects'. These `objects' are what Latour calls `immutable mobiles' that enable communication and collaboration across difference by helping meaning to be understood in different contexts. As Star notes, they are a sort of arrangement that allow different groups to work together without (a priori) consensus. Part of the idea is to recognize and allow for the `interpretive flexibility' that is central to much of the `constructivist' approach in the sociology of science. Persistent Identifiers (PIDs) can clearly act as boundary objects, but people do not usually assume that they enable interpretive flexibility. After all, they are meant to be unambiguous, machine-interpretable identifiers of defined artifacts. In this paper, we argue that PIDs can fill at least two roles: 1) That of the standardized form, where there is strong agreement on what is being represented and how and 2) that of the idealized type, a more conceptual concept that allows many different representations. We further argue that these seemingly abstract conceptions actually help us implement PIDs more effectively to link data, publications, various other artifacts, and especially people. Considering PIDs as boundary objects can help us address issues such as what level of granularity is necessary for PIDs, what metadata should be directly associated with PIDs, and what purpose is the PID serving (reference, provenance, credit, etc.). In short, sociological theory can improve data sharing standards and their implementation in a way that enables broad interdisciplinary data sharing and reuse. We will illustrate this with several specific examples of Earth science data.

  18. Biomorphic Multi-Agent Architecture for Persistent Computing

    Science.gov (United States)

    Lodding, Kenneth N.; Brewster, Paul

    2009-01-01

    A multi-agent software/hardware architecture, inspired by the multicellular nature of living organisms, has been proposed as the basis of design of a robust, reliable, persistent computing system. Just as a multicellular organism can adapt to changing environmental conditions and can survive despite the failure of individual cells, a multi-agent computing system, as envisioned, could adapt to changing hardware, software, and environmental conditions. In particular, the computing system could continue to function (perhaps at a reduced but still reasonable level of performance) if one or more component( s) of the system were to fail. One of the defining characteristics of a multicellular organism is unity of purpose. In biology, the purpose is survival of the organism. The purpose of the proposed multi-agent architecture is to provide a persistent computing environment in harsh conditions in which repair is difficult or impossible. A multi-agent, organism-like computing system would be a single entity built from agents or cells. Each agent or cell would be a discrete hardware processing unit that would include a data processor with local memory, an internal clock, and a suite of communication equipment capable of both local line-of-sight communications and global broadcast communications. Some cells, denoted specialist cells, could contain such additional hardware as sensors and emitters. Each cell would be independent in the sense that there would be no global clock, no global (shared) memory, no pre-assigned cell identifiers, no pre-defined network topology, and no centralized brain or control structure. Like each cell in a living organism, each agent or cell of the computing system would contain a full description of the system encoded as genes, but in this case, the genes would be components of a software genome.

  19. Stochastic convergence of persistence landscapes and silhouettes

    Directory of Open Access Journals (Sweden)

    Frédéric Chazal

    2015-03-01

    Full Text Available Persistent homology is a widely used tool in Topological Data Analysis that encodes multi-scale topological information as a multiset of points in the plane called a persistence diagram. It is difficult to apply statistical theory directly to a random sample of diagrams. Instead, we summarize persistent homology with a persistence landscape, introduced by Bubenik, which converts a diagram into a well-behaved real-valued function. We investigate the statistical properties of landscapes, such as weak convergence of the average landscapes and convergence of the bootstrap. In addition, we introduce an alternate functional summary of persistent homology, which we call the silhouette, and derive an analogous statistical theory.

  20. On persistence interfaces for scientific data stores

    International Nuclear Information System (INIS)

    Malon, D.M.; May, E.N.

    1996-01-01

    A common dilemma among builders of large scientific data stores is whether to use a lightweight object persistence manager or a genuine object-oriented database. There are often good reasons to consider each of these strategies; a few are described in this paper. Too often, however, electing to use a lightweight approach has meant programming to an interface that is entirely different than that expected by commercial object-oriented databases. With the emergence of object database standards, it is possible to provide an interface to persistence managers that does not needlessly inhibit coexistence with (and, perhaps, eventual migration to) object-oriented databases. This paper describes an implementation of a substantial subset of the ODMG-93[1]C++ specification that allows clients to use many of today's lightweight object persistence managers through an interface that conforms to the ODMG standard. We also describe a minimal interface that persistence software should support in order to provide persistence services for ODMG implementations

  1. Mycobacterium Lysine ε-aminotransferase is a novel alarmone metabolism related persister gene via dysregulating the intracellular amino acid level.

    Science.gov (United States)

    Duan, Xiangke; Li, Yunsong; Du, Qinglin; Huang, Qinqin; Guo, Siyao; Xu, Mengmeng; Lin, Yanping; Liu, Zhidong; Xie, Jianping

    2016-01-25

    Bacterial persisters, usually slow-growing, non-replicating cells highly tolerant to antibiotics, play a crucial role contributing to the recalcitrance of chronic infections and treatment failure. Understanding the molecular mechanism of persister cells formation and maintenance would obviously inspire the discovery of new antibiotics. The significant upregulation of Mycobacterium tuberculosis Rv3290c, a highly conserved mycobacterial lysine ε-aminotransferase (LAT) during hypoxia persistent model, suggested a role of LAT in persistence. To test this, a lat deleted Mycobacterium smegmatis was constructed. The expression of transcriptional regulator leucine-responsive regulatory protein (LrpA) and the amino acids abundance in M. smegmatis lat deletion mutants were lowered. Thus, the persistence capacity of the deletion mutant was impaired upon norfloxacin exposure under nutrient starvation. In summary, our study firstly reported the involvement of mycobacterium LAT in persister formation, and possibly through altering the intracellular amino acid metabolism balance.

  2. NH125 kills methicillin-resistant Staphylococcus aureus persisters by lipid bilayer disruption.

    Science.gov (United States)

    Kim, Wooseong; Fricke, Nico; Conery, Annie L; Fuchs, Beth Burgwyn; Rajamuthiah, Rajmohan; Jayamani, Elamparithi; Vlahovska, Petia M; Ausubel, Frederick M; Mylonakis, Eleftherios

    2016-01-01

    NH125, a known WalK inhibitor kills MRSA persisters. However, its precise mode of action is still unknown. The mode of action of NH125 was investigated by comparing its spectrum of antimicrobial activity and its effects on membrane permeability and giant unilamellar vesicles (GUVs) with walrycin B, a WalR inhibitor and benzyldimethylhexadecylammonium chloride (16-BAC), a cationic surfactant. NH125 killed persister cells of a variety of Staphylococcus aureus strains. Similar to 16-BAC, NH125 killed MRSA persisters by inducing rapid membrane permeabilization and caused the rupture of GUVs, whereas walrycin B did not kill MRSA persisters or induce membrane permeabilization and did not affect GUVs. NH125 kills MRSA persisters by interacting with and disrupting membranes in a detergent-like manner.

  3. Persistence Characteristics of Australian Rainfall Anomalies

    Science.gov (United States)

    Simmonds, Ian; Hope, Pandora

    1997-05-01

    Using 79 years (1913-1991) of Australian monthly precipitation data we examined the nature of the persistence of rainfall anomalies. Analyses were performed for four climate regions covering the country, as well as for the entire Australian continent. We show that rainfall over these regions has high temporal variability and that annual rainfall amounts over all five sectors vary in phase and are, with the exception of the north-west region, significantly correlated with the Southern Oscillation Index (SOI). These relationships were particularly strong during the spring season.It is demonstrated that Australian rainfall exhibits statistically significant persistence on monthly, seasonal, and (to a limited extent) annual time-scales, up to lags of 3 months and one season and 1 year. The persistence showed strong seasonal dependence, with each of the five regions showing memory out to 4 or 5 months from winter and spring. Many aspects of climate in the Australasian region are known to have undergone considerable changes about 1950. We show this to be true for persistence also; its characteristics identified for the entire record were present during the 1951--1980 period, but virtually disappeared in the previous 30-year period.Much of the seasonal distribution of rainfall persistence on monthly time-scales, particularly in the east, is due to the influence of the SOI. However, most of the persistence identified in winter and spring in the north-west is independent of the ENSO phenomenon.Rainfall anomalies following extreme dry and wet months, seasons and years (lowest and highest two deciles) persisted more than would be expected by chance. For monthly extreme events this was more marked in the winter semester for the wet events, except in the south-east region. In general, less persistence was found for the extreme seasons. Although the persistence of dry years was less than would have been expected by chance, the wet years appear to display persistence.

  4. Persistence of urinary excretion products of benzo(a)pyrene

    International Nuclear Information System (INIS)

    Uziel, M.; Haglund, R.; White, D.A.

    1988-01-01

    Persistence of DNA-adducts has been observed in a variety of experimental circumstances and has been suggested as one potential mechanism for explaining the long-term delay before expression of proliferative disease. In this concept, a stable DNA-adduct, which is a remnant of a prior exposure in a nondividing cell, would not express the genotoxic effect until the cells were stimulated to divide, and thus explain the long-term delay in expression of cancer. An alternative view of the observation of persistent DNA-adducts, described in this communication, is the continuing replenishment of DNA adducts by formation and turnover of these adducts from exposure to a constant supply of the ultimate carcinogenic species derived from a prior exposure. It is of interest to note that virtually all experiments where ''persistent'' adducts have been observed have been high dose exposures. During the course of experiments designed to develop improved methods for detection of DNA adducts and related derivatives derived from polynuclear aromatic hydrocarbons (PAH), we observed that there was a continuous excretion of urinary derivatives of the injected benzo(a)pyrene (BaP) beyond the initial burst of detoxification. This report describes the time dependent distribution of those derivatives in blood, urine, feces, and at the site of injection. 11 refs., 5 figs., 4 tabs

  5. Early life innate immune signatures of persistent food allergy.

    Science.gov (United States)

    Neeland, Melanie R; Koplin, Jennifer J; Dang, Thanh D; Dharmage, Shyamali C; Tang, Mimi L; Prescott, Susan L; Saffery, Richard; Martino, David J; Allen, Katrina J

    2017-11-14

    Food allergy naturally resolves in a proportion of food-allergic children without intervention; however the underlying mechanisms governing the persistence or resolution of food allergy in childhood are not understood. This study aimed to define the innate immune profiles associated with egg allergy at age 1 year, determine the phenotypic changes that occur with the development of natural tolerance in childhood, and explore the relationship between early life innate immune function and serum vitamin D. This study used longitudinally collected PBMC samples from a population-based cohort of challenge-confirmed egg-allergic infants with either persistent or transient egg allergy outcomes in childhood to phenotype and quantify the functional innate immune response associated with clinical phenotypes of egg allergy. We show that infants with persistent egg allergy exhibit a unique innate immune signature, characterized by increased numbers of circulating monocytes and dendritic cells that produce more inflammatory cytokines both at baseline and following endotoxin exposure when compared with infants with transient egg allergy. Follow-up analysis revealed that this unique innate immune signature continues into childhood in those with persistent egg allergy and that increased serum vitamin D levels correlate with changes in innate immune profiles observed in children who developed natural tolerance to egg. Early life innate immune dysfunction may represent a key immunological driver and predictor of persistent food allergy in childhood. Serum vitamin D may play an immune-modulatory role in the development of natural tolerance. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  6. Laboratory diagnosis of persistent human chlamydial infection

    Directory of Open Access Journals (Sweden)

    Mirja ePuolakkainen

    2013-12-01

    Full Text Available Diagnostic assays for persistent chlamydial infection are much needed to conduct high-quality, large-scale studies investigating the persistent state in vivo, its disease associations and the response to therapy. Yet in most studies the distinction between acute and persistent infection is based on the interpretation of the data obtained by the assays developed to diagnose acute infections or on complex assays available for research only and/or difficult to establish for clinical use. Novel biomarkers for detection of persistent chlamydial infection are urgently needed. Chlamydial whole genome proteome arrays are now available and they can identify chlamydial antigens that are differentially expressed between acute infection and persistent infection. Utilizing these data will lead to the development of novel diagnostic assays. Carefully selected specimens from well-studied patient populations are clearly needed in the process of translating the proteomic data into assays useful for clinical practice. Before such antigens are identified and validated assays become available, we face a challenge of deciding whether the persistent infection truly induced appearance of the proposed marker or do we just base our diagnosis of persistent infection on the presence of the suggested markers. Consequently, we must bear this in mind when interpreting the available data.

  7. Photocarcinogenesis and persistent hyperplasia in UV-irradiated SENCAR mouse skin

    International Nuclear Information System (INIS)

    Strickland, P.T.

    1986-01-01

    Susceptibility to photocarcinogenesis has been examined in several mouse strains and stocks including SENCAR, CD-1, BALB/c, C3H, C57Bl, and NZB. SENCAR mice are hypersusceptible to tumorigenesis caused by single high dose exposures to ultraviolet (UV) radiation but not by chronic low-dose exposures. SENCAR mice also exhibit an exaggerated and persistent epidermal hyperplasia in response to UV-induced tissue damage. The persistent hyperplasia is apparently due to a sustained proliferation of the epithelial basal cells, rather than to delayed cell differentiation. SENCAR mice did not exhibit persistent hyperplasia following other forms of tissue damage (surgical or thermal). In related studies, the levels of thymine dimers induced in SENCAR epidermis by UV radiation were comparable to those observed in BALB/c epidermis. In addition, no differences were found in the tissue distribution or persistence of thymine dimers in SENCAR and BALB/c skin

  8. Pathophysiology of Corneal Scarring in Persistent Epithelial Defects After PRK and Other Corneal Injuries.

    Science.gov (United States)

    Wilson, Steven E; Medeiros, Carla S; Santhiago, Marcony R

    2018-01-01

    To analyze corneal persistent epithelial defects that occurred at 3 to 4 weeks after -4.50 diopter (D) photorefractive keratectomy (PRK) in rabbits and apply this pathophysiology to the treatment of persistent epithelial defects that occur after any corneal manipulations or diseases. Two of 168 corneas that had -4.50 D PRK to study epithelial basement membrane regeneration developed spontaneous persistent epithelial defects that did not heal at 3 weeks after PRK. These were studied with slit-lamp photographs, immunohistochemistry for the myofibroblast marker alpha-smooth muscle actin (α-SMA), and transmission electron microscopy. Myofibroblasts developed at the stromal surface within the persistent epithelial defect and for a short distance peripheral to the leading edge of the epithelium. No normal epithelial basement membrane was detectable within the persistent epithelial defect or for up to 0.3 mm behind the leading edge of the epithelium, although epithelial basement membrane had normally regenerated in other areas of the zone ablated by an excimer laser where the epithelium healed promptly. A persistent epithelial defect in the cornea results in the development of myofibroblasts and disordered extracellular matrix produced by these cells that together cause opacity within, and a short distance beyond, the persistent epithelial defect. Clinicians should treat persistent epithelial defects within 10 days of non-closure of the epithelium to facilitate epithelial healing to prevent long-term stromal scarring (fibrosis). [J Refract Surg. 2018;34(1):59-64.]. Copyright 2018, SLACK Incorporated.

  9. Is adipose tissue a place for Mycobacterium tuberculosis persistence?

    Directory of Open Access Journals (Sweden)

    Olivier Neyrolles

    Full Text Available BACKGROUND: Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB, has the ability to persist in its human host for exceptionally long periods of time. However, little is known about the location of the bacilli in latently infected individuals. Long-term mycobacterial persistence in the lungs has been reported, but this may not sufficiently account for strictly extra-pulmonary TB, which represents 10-15% of the reactivation cases. METHODOLOGY/PRINCIPAL FINDINGS: We applied in situ and conventional PCR to sections of adipose tissue samples of various anatomical origins from 19 individuals from Mexico and 20 from France who had died from causes other than TB. M. tuberculosis DNA could be detected by either or both techniques in fat tissue surrounding the kidneys, the stomach, the lymph nodes, the heart and the skin in 9/57 Mexican samples (6/19 individuals, and in 8/26 French samples (6/20 individuals. In addition, mycobacteria could be immuno-detected in perinodal adipose tissue of 1 out of 3 biopsy samples from individuals with active TB. In vitro, using a combination of adipose cell models, including the widely used murine adipose cell line 3T3-L1, as well as primary human adipocytes, we show that after binding to scavenger receptors, M. tuberculosis can enter within adipocytes, where it accumulates intracytoplasmic lipid inclusions and survives in a non-replicating state that is insensitive to the major anti-mycobacterial drug isoniazid. CONCLUSIONS/SIGNIFICANCE: Given the abundance and the wide distribution of the adipose tissue throughout the body, our results suggest that this tissue, among others, might constitute a vast reservoir where the tubercle bacillus could persist for long periods of time, and avoid both killing by antimicrobials and recognition by the host immune system. In addition, M. tuberculosis-infected adipocytes might provide a new model to investigate dormancy and to evaluate new drugs for the treatment of

  10. Persistent insomnia is associated with mortality risk.

    Science.gov (United States)

    Parthasarathy, Sairam; Vasquez, Monica M; Halonen, Marilyn; Bootzin, Richard; Quan, Stuart F; Martinez, Fernando D; Guerra, Stefano

    2015-03-01

    Insomnia has been associated with mortality risk, but whether this association is different in subjects with persistent vs intermittent insomnia is unclear. Additionally, the role of systemic inflammation in such an association is unknown. We used data from a community-based cohort to determine whether persistent or intermittent insomnia, defined based on persistence of symptoms over a 6-year period, was associated with death during the following 20 years of follow-up. We also determined whether changes in serum C-reactive protein (CRP) levels measured over 2 decades between study initiation and insomnia determination were different for the persistent, intermittent, and never insomnia groups. The results were adjusted for confounders such as age, sex, body mass index, smoking, physical activity, alcohol, and sedatives. Of the 1409 adult participants, 249 (18%) had intermittent and 128 (9%) had persistent insomnia. During a 20-year follow-up period, 318 participants died (118 due to cardiopulmonary disease). In adjusted Cox proportional-hazards models, participants with persistent insomnia (adjusted hazards ratio [HR] 1.58; 95% confidence interval [CI], 1.02-2.45) but not intermittent insomnia (HR 1.22; 95% CI, 0.86-1.74) were more likely to die than participants without insomnia. Serum CRP levels were higher and increased at a steeper rate in subjects with persistent insomnia as compared with intermittent (P = .04) or never (P = .004) insomnia. Although CRP levels were themselves associated with increased mortality (adjusted HR 1.36; 95% CI, 1.01-1.82; P = .04), adjustment for CRP levels did not notably change the association between persistent insomnia and mortality. In a population-based cohort, persistent, and not intermittent, insomnia was associated with increased risk for all-cause and cardiopulmonary mortality and was associated with a steeper increase in inflammation. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Salt stress-induced transcription of σB- and CtsR-regulated genes in persistent and non-persistent Listeria monocytogenes strains from food processing plants.

    Science.gov (United States)

    Ringus, Daina L; Ivy, Reid A; Wiedmann, Martin; Boor, Kathryn J

    2012-03-01

    Listeria monocytogenes is a foodborne pathogen that can persist in food processing environments. Six persistent and six non-persistent strains from fish processing plants and one persistent strain from a meat plant were selected to determine if expression of genes in the regulons of two stress response regulators, σ(B) and CtsR, under salt stress conditions is associated with the ability of L. monocytogenes to persist in food processing environments. Subtype data were also used to categorize the strains into genetic lineages I or II. Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was used to measure transcript levels for two σ(B)-regulated genes, inlA and gadD3, and two CtsR-regulated genes, lmo1138 and clpB, before and after (t=10 min) salt shock (i.e., exposure of exponential phase cells to BHI+6% NaCl for 10 min at 37°C). Exposure to salt stress induced higher transcript levels relative to levels under non-stress conditions for all four stress and virulence genes across all wildtype strains tested. Analysis of variance (ANOVA) of induction data revealed that transcript levels for one gene (clpB) were induced at significantly higher levels in non-persistent strains compared to persistent strains (p=0.020; two-way ANOVA). Significantly higher transcript levels of gadD3 (p=0.024; two-way ANOVA) and clpB (p=0.053; two-way ANOVA) were observed after salt shock in lineage I strains compared to lineage II strains. No clear association between stress gene transcript levels and persistence was detected. Our data are consistent with an emerging model that proposes that establishment of L. monocytogenes persistence in a specific environment occurs as a random, stochastic event, rather than as a consequence of specific bacterial strain characteristics.

  12. The Major Histocompatibility Complex Class II Transactivator CIITA Inhibits the Persistent Activation of NF-κB by the Human T Cell Lymphotropic Virus Type 1 Tax-1 Oncoprotein.

    Science.gov (United States)

    Forlani, Greta; Abdallah, Rawan; Accolla, Roberto S; Tosi, Giovanna

    2016-01-20

    Human T cell lymphotropic virus type 1 (HTLV-1) Tax-1, a key protein in HTLV-1-induced T cell transformation, deregulates diverse cell signaling pathways. Among them, the NF-κB pathway is constitutively activated by Tax-1, which binds to NF-κB proteins and activates the IκB kinase (IKK). Upon phosphorylation-dependent IκB degradation, NF-κB migrates into the nucleus, mediating Tax-1-stimulated gene expression. We show that the transcriptional regulator of major histocompatibility complex class II genes CIITA (class II transactivator), endogenously or ectopically expressed in different cells, inhibits the activation of the canonical NF-κB pathway by Tax-1 and map the region that mediates this effect. CIITA affects the subcellular localization of Tax-1, which is mostly retained in the cytoplasm, and this correlates with impaired migration of RelA into the nucleus. Cytoplasmic and nuclear mutant forms of CIITA reveal that CIITA exploits different strategies to suppress Tax-1-mediated NF-κB activation in both subcellular compartments. CIITA interacts with Tax-1 without preventing Tax-1 binding to both IKKγ and RelA. Nevertheless, CIITA affects Tax-1-induced IKK activity, causing retention of the inactive p50/RelA/IκB complex in the cytoplasm. Nuclear CIITA associates with Tax-1/RelA in nuclear bodies, blocking Tax-1-dependent activation of NF-κB-responsive genes. Thus, CIITA inhibits cytoplasmic and nuclear steps of Tax-1-mediated NF-κB activation. These results, together with our previous finding that CIITA acts as a restriction factor inhibiting Tax-1-promoted HTLV-1 gene expression and replication, indicate that CIITA is a versatile molecule that might also counteract Tax-1 transforming activity. Unveiling the molecular basis of CIITA-mediated inhibition of Tax-1 functions may be important in defining new strategies to control HTLV-1 spreading and oncogenic potential. HTLV-1 is the causative agent of human adult T cell leukemia-lymphoma (ATLL). The viral

  13. Immunology: Exhausted T cells perk up

    Science.gov (United States)

    Williams, Matthew A.; Bevan, Michael J.

    2006-02-01

    During persistent infections, the immune cells responsible for killing infected cells and maintaining inflammation gradually stop functioning, allowing the pathogen to thrive. But can this process be reversed?

  14. Successful closure of persistent oro-cutaneous fistulas by injection of autologous adipose-derived stem cells: a case report [Erfolgreiche Behandlung persistierender oro-kutaner Fisteln durch Injektion mit autologen Fettstammzellen: ein Fallbericht

    Directory of Open Access Journals (Sweden)

    Föll, D. A.

    2013-07-01

    Full Text Available [english] Introduction: Oro-cutaneous fistulas are a possible complication of oro-facial surgery. If recurrent they are difficult to treat and greatly affect the patient's functional and aesthetic integrity besides carrying the risk of infection. Usage of concentrated adipose-derived stem cells for chronic wounds is a new and experimental treatment strategy, so far only applied in a few selected studies. We report the case of two oro-cutaneous fistulas in one patient treated with adipose-derived stem cells leading to closure of the fistulas.Case description: The patient was a 57-year old female immunosuppressed liver and kidney recipient who presented with a large mandibular and soft tissue defect after resection and irradiation of a squamous-cell carcinoma of the tongue base. After radical debridement, hardware removal and soft tissue reconstruction using a second free flap two oro-cutaneous fistulas reoccurred. Conventional surgical methods failed to consolidate the fistulas due to the severe radiation of the oral mucosa. Therefore autologous adipose-derived stem cells were extracted from lipoaspirate and applied in the surrounding fistula tissue in one session using the Cytori Celution system. The fistulas closed spontaneously during the postoperative course within 4 weeks and remain closed after 6 months.Conclusion: To our knowledge this is the first report of successful application of adipose-derived stem cells to two oro-cutaneous fistulas. Innovative stem cell therapy in combination with well established surgical methods can be a useful treatment strategy in certain cases.[german] Einleitung: Oro-kutane Fisteln sind eine mögliche Komplikation eines oro-fazialen Eingriffs. Bei Therapieresistenz können solche Fisteln zu hohem Leidensdruck führen und stellen eine ständige Infektionsgefahr dar. Die Applikation von konzentrierten Stammzellen aus Fettgewebe zur Behandlung chronischer Wunden ist eine neue und experimentelle Therapiestrategie

  15. Performance Persistence of Equity Funds in Hungary

    Directory of Open Access Journals (Sweden)

    Dariusz Filip

    2011-03-01

    Full Text Available This study examines the phenomenon of performance persistence of equity funds in Hungary in two time perspectives: 1-year and 6-month perspectives. The empirical results confirm the occurrence of performance dependence in consecutive periods. There is also a strong evidence of short-term persistence in the total horizon of the study (from the beginning of 2000 to the end of 2009, and in several sub-periods. The 1-year persistence was also found in the tested sample and, in general, depended on the measure applied. Furthermore, I observed performance reversal, which can be partly explained by trend changes in the financial markets. The persistence of equity funds performance in Hungary is shaped by market factors rather than the diversity of managerial characteristics.

  16. Near-total pancreatectomy for persistent hyperinsulinemic ...

    African Journals Online (AJOL)

    of persistent hypoglycemia in infancy with consequences ... (PHHI) is the most common cause of recurrent and per- sistent hypoglycemia in infancy and childhood. Causes .... a high rate of pancreatic surgery in the neonatal-onset group.

  17. The persistent stereotype: children's images of scientists

    Science.gov (United States)

    Emens McAdam, Janice

    1990-03-01

    Through their reading children learn to regard scientists as eccentrics. It is shown that this stereotype has persisted for over thirty years and affects many adult attitudes. Some methods of breaking the author-reader cycle are suggested.

  18. Persisting nutritional neuropathy amongst former war prisoners.

    OpenAIRE

    Gill, G V; Bell, D R

    1982-01-01

    Of 898 former Far East prisoners of war, assessed between 1968 and 1981, 49 (5.5%) had evidence of persisting symptomatic neurological disease dating back to their periods of malnutrition in captivity. The commonest syndromes were peripheral neuropathy (often of "burning foot" type), optic atrophy, and sensori-neural deafness. Though nutritional neuropathies disappeared soon after release in most ex-Far East prisoners of war, in some they have persisted up to 36 years since exposure to the nu...

  19. Long - Memory Persistence in African Stock Markets

    Directory of Open Access Journals (Sweden)

    Emmanuel Numapau Gyamfi

    2016-05-01

    Full Text Available Emerging stock markets are said to become efficient with time. This study seeks to investigate this assertion by analyzing long - memory persistence in 8 African stock markets covering the period from 28 August 2000 to 28 August 2015. The Hurst exponent is used as our efficiency measure which is evaluated by the Detrended Fluctuation Analysis (DFA. Our findings show strong evidence of long - memory persistence in the markets studied therefore violating the weak - form Efficient Market Hypothesis (EMH.

  20. Hyperthyroidism as a cause of persistent vomiting.

    Science.gov (United States)

    Hoogendoorn, E H; Cools, B M

    2004-09-01

    A 32-year-old woman presented with persistent vomiting, epigastric pain and weight loss. A sinus tachycardia was the clue to the diagnosis of hyperthyroidism due to Graves' disease. On treatment with propylthiouracil and a beta-blocking agent, her symptoms resolved within one day, even though her free thyroxine level was still high. Hyperthyroidism is an uncommon, but previously reported cause of persistent vomiting.

  1. Hyperthyroidism as a cause of persistent vomiting.

    OpenAIRE

    Hoogendoorn, E.H.; Cools, B.M.

    2004-01-01

    A 32-year-old woman presented with persistent vomiting, epigastric pain and weight loss. A sinus tachycardia was the clue to the diagnosis of hyperthyroidism due to Graves' disease. On treatment with propylthiouracil and a beta-blocking agent, her symptoms resolved within one day, even though her free thyroxine level was still high. Hyperthyroidism is an uncommon, but previously reported cause of persistent vomiting.

  2. Miocarditis de células gigantes con bloqueo AV completo persistente: respuesta al tratamiento con resincronizador cardiaco Giant cell myocarditis with complete persistent A-V block: treatment response with cardiac resynchronization

    Directory of Open Access Journals (Sweden)

    Julián Aristizábal

    2009-08-01

    Full Text Available La miocarditis de células gigantes es una enfermedad grave y poco frecuente, cuya etiología, posiblemente autoinmune, se caracteriza por la presencia de células gigantes multinucleadas con infiltrado inflamatorio y necrosis extensa en la biopsia endomiocárdica. Es común su asociación con taquicardias ventriculares y con alteraciones de la conducción aurículo-ventricular, lo cual se resuelve algunas veces con tratamiento inmunosupresor. Dada la complejidad del pronóstico de esta entidad, el papel de los dispositivos de resincronización después de la estabilización de la falla cardíaca, no está claro. Aquí se reporta un caso en el cual el implante de uno de estos dispositivos fue parte fundamental de la terapia y recuperación del paciente.Giant cell myocarditis is an infrequent and serious illness, possibly of autoimmune etiology, characterized by the presence of multinucleated giant cells with inflammatory infiltrate and extensive necrosis in the endomyocardial biopsy. Its association with ventricular tachycardia is common and alterations in atrioventricular conduction are frequently solved through immunosuppressive treatment. Given the generally complex prognosis of this entity, the role of the resynchronization devices after the heart failure stabilization, is unclear. We reported a case in which the implant of one of these devices was a fundamental part of the therapy and patient recovery.

  3. Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse.

    Science.gov (United States)

    Korpi, Esa R; den Hollander, Bjørnar; Farooq, Usman; Vashchinkina, Elena; Rajkumar, Ramamoorthy; Nutt, David J; Hyytiä, Petri; Dawe, Gavin S

    2015-10-01

    Adaptation of the nervous system to different chemical and physiologic conditions is important for the homeostasis of brain processes and for learning and remembering appropriate responses to challenges. Although processes such as tolerance and dependence to various drugs of abuse have been known for a long time, it was recently discovered that even a single pharmacologically relevant dose of various drugs of abuse induces neuroplasticity in selected neuronal populations, such as the dopamine neurons of the ventral tegmental area, which persist long after the drug has been excreted. Prolonged (self-) administration of drugs induces gene expression, neurochemical, neurophysiological, and structural changes in many brain cell populations. These region-specific changes correlate with addiction, drug intake, and conditioned drugs effects, such as cue- or stress-induced reinstatement of drug seeking. In rodents, adolescent drug exposure often causes significantly more behavioral changes later in adulthood than a corresponding exposure in adults. Clinically the most impairing and devastating effects on the brain are produced by alcohol during fetal development. In adult recreational drug users or in medicated patients, it has been difficult to find persistent functional or behavioral changes, suggesting that heavy exposure to drugs of abuse is needed for neurotoxicity and for persistent emotional and cognitive alterations. This review describes recent advances in this important area of research, which harbors the aim of translating this knowledge to better treatments for addictions and related neuropsychiatric illnesses. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  4. Activated ClpP kills persisters and eradicates a chronic biofilm infection.

    Energy Technology Data Exchange (ETDEWEB)

    Conlon, Brian P.; Nakayasu, Ernesto S.; Fleck, Laura E.; LaFleur, Michael D.; Isabella, Vincent M.; Coleman, K.; Leonard, Steve N.; Smith, Richard D.; Adkins, Joshua N.; Lewis, Kim

    2013-11-21

    The current antibiotic crisis stems from two distinct phenomena-drug resistance, and drug tolerance. Resistance mechanisms such as drug efflux or modification prevent antibiotics from binding to their targets 1, allowing pathogens to grow. Antibiotic tolerance is the property of persister cells, phenotypic variants of regular bacteria 2. Antibiotics kill by corrupting targets, but these are inactive in dormant persisters, leading to tolerance. Persisters were first identified by Joseph Bigger in 1944, when he discovered a surviving sub-population of Staphylococcus following treatment with penicillin3. Persisters are largely responsible for recalcitrance of chronic diseases such as tuberculosis, and various infections associated with biofilms - endocarditis, osteomyelitis, infections of catheters and indwelling devices, and deep-seated infections of soft tissues 4. There are a number of redundant pathways involved in persister formation5,6 precluding development of drugs inhibiting their formation. The acyldepsipeptide antibiotic (ADEP 4) has been shown to activate the ClpP protease resulting in death of growing cells 7. Here we show that ADEP4 activated ClpP becomes a fairly non-specific protease and kills persister cells by degradation of over 400 intracellular targets. clpP mutants are resistant to ADEP4 7, but we find that they display increased susceptibility to killing by a range of conventional antibiotics. Combining ADEP4 with rifampicin leads to eradication of persisters, stationary and biofilm populations of Staphylococcus aureus in vitro and in a deep-seated murine infection. Target corruption/activation provides an approach to killing persisters and eradicating chronic infections.

  5. Persistent Hyperprolactinemia and Bilateral Galactocele in a Male Infant

    Directory of Open Access Journals (Sweden)

    Casti Tiziana

    2009-02-01

    Full Text Available Galactocele is a benign breast lesion, usually occurring in nursing women. This lesion is a rare cause of breast enlargement in children. In this paper we describe the case of an infant with hyperprolactinemia (which persisted throughout 15 years of clinical observation and bilateral galactocele. We speculate that a congenital midline defect in our patient might have impaired the normal dopaminergic inhibitory tone on pituitary lactotroph cells, thus leading to an increased prolactin secretion by the pituitary gland; this, in turn, might have favored the development of the galactocele.

  6. Meningococcal serogroup C immunogenicity, antibody persistence and memory B-cells induced by the monovalent meningococcal serogroup C versus quadrivalent meningococcal serogroup ACWY conjugate booster vaccine: A randomized controlled trial.

    Science.gov (United States)

    van Ravenhorst, Mariëtte B; van der Klis, Fiona R M; van Rooijen, Debbie M; Knol, Mirjam J; Stoof, Susanne P; Sanders, Elisabeth A M; Berbers, Guy A M

    2017-08-24

    Adolescents are considered the key transmitters of meningococci in the population. Meningococcal serogroup C (MenC) antibody levels wane rapidly after MenC conjugate vaccination in young children, leaving adolescents with low antibody levels. In this study, we compared MenC immune responses after booster vaccination in adolescence with either tetanus toxoid conjugated MenC (MenC-TT) or MenACWY (MenACWY-TT) vaccine, and aimed to establish an optimal age for this booster. Healthy 10-, 12-, and 15-year-olds, who received a single dose of MenC-TT vaccine in early childhood, were randomized to receive MenC-TT or MenACWY-TT vaccine. MenC serum bactericidal antibody (rSBA) titers, MenC polysaccharide (PS) specific IgG, IgG1 and IgG2 and MenC-specific IgG and IgA memory B-cells were determined before, one month and one year after the booster. Non-inferiority was tested by comparing geometric mean titers (GMTs) between vaccinees at one year. Of 501 participants, 464 (92.6%) were included in the 'according to protocol' cohort analysis. At one month, all participants developed high MenC rSBA titers (>24,000 in all groups) and MenC-PS-specific IgG levels. Non-inferiority was not demonstrated one year after the booster with higher MenC GMTs after the monovalent vaccine, but 462/464 (99.6%) participants maintained protective MenC rSBA titers. IgG levels mainly consisted of IgG1, but similar levels of increase were observed for IgG1 and IgG2. Both vaccines induced a clear increase in the number of circulating MenC-PS specific IgG and IgA memory B-cells. Between one month and one year, the highest antibody decay rate was observed in the 10-year-olds. Both MenC-TT and MenACWY-TT vaccines induced robust protective MenC immune responses after the booster vaccination, although non-inferiority could not be demonstrated for the MenACWY-TT vaccine after one year. Our results underline the importance of optimal timing of a meningococcal booster vaccination to protect against MenC disease

  7. Herbicide Persistence in Seawater Simulation Experiments.

    Directory of Open Access Journals (Sweden)

    Philip Mercurio

    Full Text Available Herbicides are detected year-round in marine waters, including those of the World Heritage listed Great Barrier Reef (GBR. The few previous studies that have investigated herbicide persistence in seawater generally reported half-lives in the order of months, and several studies were too short to detect significant degradation. Here we investigated the persistence of eight herbicides commonly detected in the GBR or its catchments in standard OECD simulation flask experiments, but with the aim to mimic natural conditions similar to those found on the GBR (i.e., relatively low herbicide concentrations, typical temperatures, light and microbial communities. Very little degradation was recorded over the standard 60 d period (Experiment 1 so a second experiment was extended to 365 d. Half-lives of PSII herbicides ametryn, atrazine, diuron, hexazinone and tebuthiuron were consistently greater than a year, indicating high persistence. The detection of atrazine and diuron metabolites and longer persistence in mercuric chloride-treated seawater confirmed that biodegradation contributed to the breakdown of herbicides. The shortest half-life recorded was 88 d for growth-regulating herbicide 2,4-D at 31°C in the dark, while the fatty acid-inhibitor metolachlor exhibited a minimum half-life of 281 d. The presence of moderate light and elevated temperatures affected the persistence of most of the herbicides; however, the scale and direction of the differences were not predictable and were likely due to changes in microbial community composition. The persistence estimates here represent some of the first appropriate data for application in risk assessments for herbicide exposure in tropical marine systems. The long persistence of herbicides identified in the present study helps explain detection of herbicides in nearshore waters of the GBR year round. Little degradation of these herbicides would be expected during the wet season with runoff and associated

  8. Herbicide Persistence in Seawater Simulation Experiments

    Science.gov (United States)

    Mercurio, Philip; Mueller, Jochen F.; Eaglesham, Geoff; Flores, Florita; Negri, Andrew P.

    2015-01-01

    Herbicides are detected year-round in marine waters, including those of the World Heritage listed Great Barrier Reef (GBR). The few previous studies that have investigated herbicide persistence in seawater generally reported half-lives in the order of months, and several studies were too short to detect significant degradation. Here we investigated the persistence of eight herbicides commonly detected in the GBR or its catchments in standard OECD simulation flask experiments, but with the aim to mimic natural conditions similar to those found on the GBR (i.e., relatively low herbicide concentrations, typical temperatures, light and microbial communities). Very little degradation was recorded over the standard 60 d period (Experiment 1) so a second experiment was extended to 365 d. Half-lives of PSII herbicides ametryn, atrazine, diuron, hexazinone and tebuthiuron were consistently greater than a year, indicating high persistence. The detection of atrazine and diuron metabolites and longer persistence in mercuric chloride-treated seawater confirmed that biodegradation contributed to the breakdown of herbicides. The shortest half-life recorded was 88 d for growth-regulating herbicide 2,4-D at 31°C in the dark, while the fatty acid-inhibitor metolachlor exhibited a minimum half-life of 281 d. The presence of moderate light and elevated temperatures affected the persistence of most of the herbicides; however, the scale and direction of the differences were not predictable and were likely due to changes in microbial community composition. The persistence estimates here represent some of the first appropriate data for application in risk assessments for herbicide exposure in tropical marine systems. The long persistence of herbicides identified in the present study helps explain detection of herbicides in nearshore waters of the GBR year round. Little degradation of these herbicides would be expected during the wet season with runoff and associated flood plumes

  9. "Life-bearing molecules" versus "life-embodying systems": Two contrasting views on the what-is-life (WIL) problem persisting from the early days of molecular biology to the post-genomic cell- and organism-level biology.

    Science.gov (United States)

    Sato, Naoki

    2018-05-01

    "What is life?" is an ultimate biological quest for the principle that makes organisms alive. This 'WIL problem' is not, however, a simple one that we have a straightforward strategy to attack. From the beginning, molecular biology tried to identify molecules that bear the essence of life: the double helical DNA represented replication, and enzymes were micro-actuators of biological activities. A dominating idea behind these mainstream biological studies relies on the identification of life-bearing molecules, which themselves are models of life. Another, prevalent idea emphasizes that life resides in the whole system of an organism, but not in some particular molecules. The behavior of a complex system may be considered to embody the essence of life. The thermodynamic view of life system in the early 20th century was remodeled as physics of complex systems and systems biology. The two views contrast with each other, but they are no longer heritage of the historical dualism in biology, such as mechanism/materialism versus vitalism, or reductionism versus holism. These two views are both materialistic and mechanistic, and act as driving forces of modern biology. In reality, molecules function in a context of systems, whereas systems presuppose functional molecules. A key notion to reconcile this conflict is that subjects of biological studies are given before we start to study them. Cell- or organism-level biology is destined to the dialectic of molecules and systems, but this antagonism can be resolved by dynamic thinking involving biological evolution. Copyright © 2018 Elsevier B.V. All rights reserved.

  10. Generating Dynamic Persistence in the Time Domain

    Science.gov (United States)

    Guerrero, A.; Smith, L. A.; Smith, L. A.; Kaplan, D. T.

    2001-12-01

    Many dynamical systems present long-range correlations. Physically, these systems vary from biological to economical, including geological or urban systems. Important geophysical candidates for this type of behaviour include weather (or climate) and earthquake sequences. Persistence is characterised by slowly decaying correlation function; that, in theory, never dies out. The Persistence exponent reflects the degree of memory in the system and much effort has been expended creating and analysing methods that successfully estimate this parameter and model data that exhibits persistence. The most widely used methods for generating long correlated time series are not dynamical systems in the time domain, but instead are derived from a given spectral density. Little attention has been drawn to modelling persistence in the time domain. The time domain approach has the advantage that an observation at certain time can be calculated using previous observations which is particularly suitable when investigating the predictability of a long memory process. We will describe two of these methods in the time domain. One is a traditional approach using fractional ARIMA (autoregressive and moving average) models; the second uses a novel approach to extending a given series using random Fourier basis functions. The statistical quality of the two methods is compared, and they are contrasted with weather data which shows, reportedly, persistence. The suitability of this approach both for estimating predictability and for making predictions is discussed.

  11. Persistent agents in Axelrod's social dynamics model

    Science.gov (United States)

    Reia, Sandro M.; Neves, Ubiraci P. C.

    2016-01-01

    Axelrod's model of social dynamics has been studied under the effect of external media. Here we study the formation of cultural domains in the model by introducing persistent agents. These are agents whose cultural traits are not allowed to change but may be spread through local neighborhood. In the absence of persistent agents, the system is known to present a transition from a monocultural to a multicultural regime at some critical Q (number of traits). Our results reveal a dependence of critical Q on the occupation probability p of persistent agents and we obtain the phase diagram of the model in the (p,Q) -plane. The critical locus is explained by the competition of two opposite forces named here barrier and bonding effects. Such forces are verified to be caused by non-persistent agents which adhere (adherent agents) to the set of traits of persistent ones. The adherence (concentration of adherent agents) as a function of p is found to decay for constant Q. Furthermore, adherence as a function of Q is found to decay as a power law with constant p.

  12. The Economy of Persistence: Mario the Tailor

    Directory of Open Access Journals (Sweden)

    Prudence Black

    2016-03-01

    Full Text Available Mario Conte has had a tailor shop in King Street, Newtown since the mid 1960s. Taking an interview with Mario as its point of departure, this article describes the persistence of a skilled worker whose practices and techniques remain the same in a world that has long changed. While inattentive to what rules might be used to decorate a shop window, Mario continues to make and sew in the way that he learnt in post-war Italy. Mario’s persistence could be described as all the skills and other elements that need to be in place to keep him working, in particular the tradition of tailoring techniques he has remained true to over the last fifty years. The hand stitching of his tailoring is like a metronome of that persistence.

  13. Understanding mild persistent asthma in children

    DEFF Research Database (Denmark)

    Bisgaard, Hans; Szefler, Stanley J

    2005-01-01

    Limitations in asthma prevalence studies and difficulties in diagnosing pediatric asthma lead to uncertainty over the full extent of mild persistent asthma in children and adolescents. Although recent surveys have reported that the majority of pediatric patients with asthma in the United States...... and Europe have symptoms consistent with mild disease, these surveys have limitations in design. Thus, the true prevalence of mild asthma remains unknown. It is unclear whether children with mild persistent asthma progress to more severe asthma, but the risk of severe asthma exacerbations seems...... to be unrelated to the symptom severity. Clinical studies restricted to pediatric patients with mild asthma are limited, but available data do suggest substantial morbidity of mild persistent asthma in this population and support inhaled corticosteroid intervention. There is a need for further investigation...

  14. International perspectives on retention and persistence

    Directory of Open Access Journals (Sweden)

    Gary Burkholder

    2014-06-01

    Full Text Available Access to higher education globally is increasing dramatically; attainment of tertiary degrees is a high priority, as educational attainment is associated with increased personal incomes as well as growth of the middle class in developing countries. The purpose of this essay is to briefly examine retention and persistence issues from a global perspective, review some retention strategies that have been employed at schools outside the United States, and to identify several key factors that related to retention and persistence globally, including access, infrastructure, financial consideration, and readiness for tertiary education.  There exists an opportunity to utilize knowledge gained in the evolution of the higher education system in the United States to help address the problems associated with retention and persistence.   DOI: 10.18870/hlrc.v4i2.208

  15. Persistent toxic substances: sources, fates and effects.

    Science.gov (United States)

    Wong, Ming H; Armour, Margaret-Ann; Naidu, Ravi; Man, Ming

    2012-01-01

    Persistent toxic substances (PTS) include the Stockholm persistent organic pollutants, like dichlorodiphenyltrichloroethane, polychlorinated biphenyls, dioxin/furan, etc., and organometallic compounds, like organomercury, organotin, and organolead, which all share the same characteristics of being persistent, toxic, bioaccumulative, and able to travel long distances through different media. The adverse health effects of some of the emerging chemicals like pentabromodiphenyl ether, bisphenol A, and di(2-ethylhexyl)phthalate, which are widely used in daily appliances (e.g., TVs, computers, mobile phones, plastic baby bottles), have become a public health concern due to more evidence now available showing their adverse effects like disturbance of the endocrine system and cancer. This article is an attempt to review the current status of PTS in our environment, citing case studies in China and North America, and whether our existing drinking water treatment and wastewater treatment processes are adequate in removing them from water. Some management issues of these emerging chemicals of concern are also discussed.

  16. Modeling Real Exchange Rate Persistence in Chile

    Directory of Open Access Journals (Sweden)

    Leonardo Salazar

    2017-07-01

    Full Text Available The long and persistent swings in the real exchange rate have for a long time puzzled economists. Recent models built on imperfect knowledge economics seem to provide a theoretical explanation for this persistence. Empirical results, based on a cointegrated vector autoregressive (CVAR model, provide evidence of error-increasing behavior in prices and interest rates, which is consistent with the persistence observed in the data. The movements in the real exchange rate are compensated by movements in the interest rate spread, which restores the equilibrium in the product market when the real exchange rate moves away from its long-run benchmark value. Fluctuations in the copper price also explain the deviations of the real exchange rate from its long-run equilibrium value.

  17. Chronic hepatitis caused by persistent parvovirus B19 infection

    Directory of Open Access Journals (Sweden)

    Mogensen Trine H

    2010-08-01

    Full Text Available Abstract Background Human infection with parvovirus B19 may lead to a diverse spectrum of clinical manifestations, including benign erythema infectiosum in children, transient aplastic crisis in patients with haemolytic anaemia, and congenital hydrops foetalis. These different diseases represent direct consequences of the ability of parvovirus B19 to target the erythroid cell lineage. However, accumulating evidence suggests that this virus can also infect other cell types resulting in diverse clinical manifestations, of which the pathogenesis remains to be fully elucidated. This has prompted important questions regarding the tropism of the virus and its possible involvement in a broad range of infectious and autoimmune medical conditions. Case Presentation Here, we present an unusual case of persistent parvovirus B19 infection as a cause of chronic hepatitis. This patient had persistent parvovirus B19 viraemia over a period of more than four years and displayed signs of chronic hepatitis evidenced by fluctuating elevated levels of ALAT and a liver biopsy demonstrating chronic hepatitis. Other known causes of hepatitis and liver damage were excluded. In addition, the patient was evaluated for immunodeficiency, since she had lymphopenia both prior to and following clearance of parvovirus B19 infection. Conclusions In this case report, we describe the current knowledge on the natural history and pathogenesis of parvovirus B19 infection, and discuss the existing evidence of parvovirus B19 as a cause of acute and chronic hepatitis. We suggest that parvovirus B19 was the direct cause of this patient's chronic hepatitis, and that she had an idiopathic lymphopenia, which may have predisposed her to persistent infection, rather than bone marrow depression secondary to infection. In addition, we propose that her liver involvement may have represented a viral reservoir. Finally, we suggest that clinicians should be aware of parvovirus B19 as an unusual

  18. The origins of lactase persistence in Europe.

    Directory of Open Access Journals (Sweden)

    Yuval Itan

    2009-08-01

    Full Text Available Lactase persistence (LP is common among people of European ancestry, but with the exception of some African, Middle Eastern and southern Asian groups, is rare or absent elsewhere in the world. Lactase gene haplotype conservation around a polymorphism strongly associated with LP in Europeans (-13,910 C/T indicates that the derived allele is recent in origin and has been subject to strong positive selection. Furthermore, ancient DNA work has shown that the--13,910*T (derived allele was very rare or absent in early Neolithic central Europeans. It is unlikely that LP would provide a selective advantage without a supply of fresh milk, and this has lead to a gene-culture coevolutionary model where lactase persistence is only favoured in cultures practicing dairying, and dairying is more favoured in lactase persistent populations. We have developed a flexible demic computer simulation model to explore the spread of lactase persistence, dairying, other subsistence practices and unlinked genetic markers in Europe and western Asia's geographic space. Using data on--13,910*T allele frequency and farming arrival dates across Europe, and approximate Bayesian computation to estimate parameters of interest, we infer that the--13,910*T allele first underwent selection among dairying farmers around 7,500 years ago in a region between the central Balkans and central Europe, possibly in association with the dissemination of the Neolithic Linearbandkeramik culture over Central Europe. Furthermore, our results suggest that natural selection favouring a lactase persistence allele was not higher in northern latitudes through an increased requirement for dietary vitamin D. Our results provide a coherent and spatially explicit picture of the coevolution of lactase persistence and dairying in Europe.

  19. The origins of lactase persistence in Europe.

    Science.gov (United States)

    Itan, Yuval; Powell, Adam; Beaumont, Mark A; Burger, Joachim; Thomas, Mark G

    2009-08-01

    Lactase persistence (LP) is common among people of European ancestry, but with the exception of some African, Middle Eastern and southern Asian groups, is rare or absent elsewhere in the world. Lactase gene haplotype conservation around a polymorphism strongly associated with LP in Europeans (-13,910 C/T) indicates that the derived allele is recent in origin and has been subject to strong positive selection. Furthermore, ancient DNA work has shown that the--13,910*T (derived) allele was very rare or absent in early Neolithic central Europeans. It is unlikely that LP would provide a selective advantage without a supply of fresh milk, and this has lead to a gene-culture coevolutionary model where lactase persistence is only favoured in cultures practicing dairying, and dairying is more favoured in lactase persistent populations. We have developed a flexible demic computer simulation model to explore the spread of lactase persistence, dairying, other subsistence practices and unlinked genetic markers in Europe and western Asia's geographic space. Using data on--13,910*T allele frequency and farming arrival dates across Europe, and approximate Bayesian computation to estimate parameters of interest, we infer that the--13,910*T allele first underwent selection among dairying farmers around 7,500 years ago in a region between the central Balkans and central Europe, possibly in association with the dissemination of the Neolithic Linearbandkeramik culture over Central Europe. Furthermore, our results suggest that natural selection favouring a lactase persistence allele was not higher in northern latitudes through an increased requirement for dietary vitamin D. Our results provide a coherent and spatially explicit picture of the coevolution of lactase persistence and dairying in Europe.

  20. Persisting nutritional neuropathy amongst former war prisoners.

    Science.gov (United States)

    Gill, G V; Bell, D R

    1982-01-01

    Of 898 former Far East prisoners of war, assessed between 1968 and 1981, 49 (5.5%) had evidence of persisting symptomatic neurological disease dating back to their periods of malnutrition in captivity. The commonest syndromes were peripheral neuropathy (often of "burning foot" type), optic atrophy, and sensori-neural deafness. Though nutritional neuropathies disappeared soon after release in most ex-Far East prisoners of war, in some they have persisted up to 36 years since exposure to the nutritional insult. PMID:6292369

  1. PERSISTENCY ANALYSIS OF PARTICIPANTS OF PENSION PLANS

    OpenAIRE

    ROBERTA DE SOUZA CHUN

    2007-01-01

    O tema central deste trabalho é apresentar modelos de persistência. As probabilidades de persistência na carteira de um produto de determinada empresa de seguros e previdência serão estudadas de forma agregada, de tal forma que se torna possível a elaboração de outros estudos, como por exemplo, de análise de lucratividade, mesmo com poucos dados, o que inviabiliza a elaboração de tábuas de múltiplos decrementos. Serão avaliadas as possíveis causas de saí...

  2. Amnestically Induced Persistence in Random Walks

    Science.gov (United States)

    Cressoni, J. C.; da Silva, Marco Antonio Alves; Viswanathan, G. M.

    2007-02-01

    We study how the Hurst exponent α depends on the fraction f of the total time t remembered by non-Markovian random walkers that recall only the distant past. We find that otherwise nonpersistent random walkers switch to persistent behavior when inflicted with significant memory loss. Such memory losses induce the probability density function of the walker’s position to undergo a transition from Gaussian to non-Gaussian. We interpret these findings of persistence in terms of a breakdown of self-regulation mechanisms and discuss their possible relevance to some of the burdensome behavioral and psychological symptoms of Alzheimer’s disease and other dementias.

  3. The Persistence of Long Work Hours

    OpenAIRE

    Robert Drago; David Black; Mark Wooden

    2005-01-01

    Previous research hypothesizes that long working hours are related to consumerism, the ideal worker norm, high levels of human capital, and a high cost-of-job-loss. The authors test these hypotheses using panel data on working hours for an Australian sample of full-time employed workers. Analyses include a static cross-sectional model and a persistence model for long hours over time. The results suggest that long hours (50 or more hours in a usual week) are often persistent, and provide stron...

  4. Persistent G. lamblia impairs growth in a murine malnutrition model.

    Science.gov (United States)

    Bartelt, Luther A; Roche, James; Kolling, Glynis; Bolick, David; Noronha, Francisco; Naylor, Caitlin; Hoffman, Paul; Warren, Cirle; Singer, Steven; Guerrant, Richard

    2013-06-01

    Giardia lamblia infections are nearly universal among children in low-income countries and are syndemic with the triumvirate of malnutrition, diarrhea, and developmental growth delays. Amidst the morass of early childhood enteropathogen exposures in these populations, G. lamblia–specific associations with persistent diarrhea, cognitive deficits, stunting, and nutrient deficiencies have demonstrated conflicting results, placing endemic pediatric giardiasis in a state of equipoise. Many infections in endemic settings appear to be asymptomatic/ subclinical, further contributing to uncertainty regarding a causal link between G. lamblia infection and developmental delay. We used G. lamblia H3 cyst infection in a weaned mouse model of malnutrition to demonstrate that persistent giardiasis leads to epithelial cell apoptosis and crypt hyperplasia. Infection was associated with a Th2-biased inflammatory response and impaired growth. Malnutrition accentuated the severity of these growth decrements. Faltering malnourished mice exhibited impaired compensatory responses following infection and demonstrated an absence of crypt hyperplasia and subsequently blunted villus architecture. Concomitantly, severe malnutrition prevented increases in B220+ cells in the lamina propria as well as mucosal Il4 and Il5 mRNA in response to infection. These findings add insight into the potential role of G. lamblia as a "stunting" pathogen and suggest that, similarly, malnourished children may be at increased risk of G. lamblia– potentiated growth decrements.

  5. Identification of an Antimicrobial Agent Effective against Methicillin-Resistant Staphylococcus aureus Persisters Using a Fluorescence-Based Screening Strategy.

    Directory of Open Access Journals (Sweden)

    Wooseong Kim

    Full Text Available Persisters are a subpopulation of normal bacterial cells that show tolerance to conventional antibiotics. Persister cells are responsible for recalcitrant chronic infections and new antibiotics effective against persisters would be a major development in the treatment of these infections. Using the reporter dye SYTOX Green that only stains cells with permeabilized membranes, we developed a fluorescence-based screening assay in a 384-well format for identifying compounds that can kill methicillin-resistant Staphylococcus aureus (MRSA persisters. The assay proved robust and suitable for high throughput screening (Z`-factor: >0.7. In screening a library of hits from a previous screen, which identified compounds that had the ability to block killing of the nematode Caenorhabditis by MRSA, we discovered that the low molecular weight compound NH125, a bacterial histidine kinase inhibitor, kills MRSA persisters by causing cell membrane permeabilization, and that 5 μg/mL of the compound can kill all cells to the limit of detection in a 108 CFU/mL culture of MRSA persisters within 3h. Furthermore, NH125 disrupts 50% of established MRSA biofilms at 20 μg/mL and completely eradicates biofilms at 160 μg/mL. Our results suggest that the SYTOX Green screening assay is suitable for large-scale projects to identify small molecules effective against MRSA persisters and should be easily adaptable to a broad range of pathogens that form persisters. Since NH125 has strong bactericidal properties against MRSA persisters and high selectivity to bacteria, we believe NH125 is a good anti-MRSA candidate drug that should be further evaluated.

  6. Identification of an Antimicrobial Agent Effective against Methicillin-Resistant Staphylococcus aureus Persisters Using a Fluorescence-Based Screening Strategy.

    Science.gov (United States)

    Kim, Wooseong; Conery, Annie L; Rajamuthiah, Rajmohan; Fuchs, Beth Burgwyn; Ausubel, Frederick M; Mylonakis, Eleftherios

    2015-01-01

    Persisters are a subpopulation of normal bacterial cells that show tolerance to conventional antibiotics. Persister cells are responsible for recalcitrant chronic infections and new antibiotics effective against persisters would be a major development in the treatment of these infections. Using the reporter dye SYTOX Green that only stains cells with permeabilized membranes, we developed a fluorescence-based screening assay in a 384-well format for identifying compounds that can kill methicillin-resistant Staphylococcus aureus (MRSA) persisters. The assay proved robust and suitable for high throughput screening (Z`-factor: >0.7). In screening a library of hits from a previous screen, which identified compounds that had the ability to block killing of the nematode Caenorhabditis by MRSA, we discovered that the low molecular weight compound NH125, a bacterial histidine kinase inhibitor, kills MRSA persisters by causing cell membrane permeabilization, and that 5 μg/mL of the compound can kill all cells to the limit of detection in a 108 CFU/mL culture of MRSA persisters within 3h. Furthermore, NH125 disrupts 50% of established MRSA biofilms at 20 μg/mL and completely eradicates biofilms at 160 μg/mL. Our results suggest that the SYTOX Green screening assay is suitable for large-scale projects to identify small molecules effective against MRSA persisters and should be easily adaptable to a broad range of pathogens that form persisters. Since NH125 has strong bactericidal properties against MRSA persisters and high selectivity to bacteria, we believe NH125 is a good anti-MRSA candidate drug that should be further evaluated.

  7. Using Benchmarking To Strengthen the Assessment of Persistence.

    Science.gov (United States)

    McLachlan, Michael S; Zou, Hongyan; Gouin, Todd

    2017-01-03

    Chemical persistence is a key property for assessing chemical risk and chemical hazard. Current methods for evaluating persistence are based on laboratory tests. The relationship between the laboratory based estimates and persistence in the environment is often unclear, in which case the current methods for evaluating persistence can be questioned. Chemical benchmarking opens new possibilities to measure persistence in the field. In this paper we explore how the benchmarking approach can be applied in both the laboratory and the field to deepen our understanding of chemical persistence in the environment and create a firmer scientific basis for laboratory to field extrapolation of persistence test results.

  8. Exoproteome analysis reveals higher abundance of proteins linked to alkaline stress in persistent Listeria monocytogenes strains.

    Science.gov (United States)

    Rychli, Kathrin; Grunert, Tom; Ciolacu, Luminita; Zaiser, Andreas; Razzazi-Fazeli, Ebrahim; Schmitz-Esser, Stephan; Ehling-Schulz, Monika; Wagner, Martin

    2016-02-02

    The foodborne pathogen Listeria monocytogenes, responsible for listeriosis a rare but severe infection disease, can survive in the food processing environment for month or even years. So-called persistent L. monocytogenes strains greatly increase the risk of (re)contamination of food products, and are therefore a great challenge for food safety. However, our understanding of the mechanism underlying persistence is still fragmented. In this study we compared the exoproteome of three persistent strains with the reference strain EGDe under mild stress conditions using 2D differential gel electrophoresis. Principal component analysis including all differentially abundant protein spots showed that the exoproteome of strain EGDe (sequence type (ST) 35) is distinct from that of the persistent strain R479a (ST8) and the two closely related ST121 strains 4423 and 6179. Phylogenetic analyses based on multilocus ST genes showed similar grouping of the strains. Comparing the exoproteome of strain EGDe and the three persistent strains resulted in identification of 22 differentially expressed protein spots corresponding to 16 proteins. Six proteins were significantly increased in the persistent L. monocytogenes exoproteomes, among them proteins involved in alkaline stress response (e.g. the membrane anchored lipoprotein Lmo2637 and the NADPH dehydrogenase NamA). In parallel the persistent strains showed increased survival under alkaline stress, which is often provided during cleaning and disinfection in the food processing environments. In addition, gene expression of the proteins linked to stress response (Lmo2637, NamA, Fhs and QoxA) was higher in the persistent strain not only at 37 °C but also at 10 °C. Invasion efficiency of EGDe was higher in intestinal epithelial Caco2 and macrophage-like THP1 cells compared to the persistent strains. Concurrently we found higher expression of proteins involved in virulence in EGDe e.g. the actin-assembly-inducing protein ActA and the

  9. The Enigmatic Persistence of Anorexia Nervosa

    Science.gov (United States)

    Walsh, B. Timothy

    2014-01-01

    Objective In this review, based on recent advances in cognitive neuroscience, the author presents a formulation in which the marked persistence of anorexia nervosa can be usefully understood as a well-ingrained maladaptive habit. Method The author reviewed the relevant literature on the development and course of anorexia nervosa and interpreted critical features in light of developments in cognitive neuroscience. Results Anorexia nervosa is a well characterized disorder with remarkable persistence both across history and among affected individuals. Food restriction, the salient behavioral feature of the disorder, often begins innocently but gradually takes on a life of its own. Over time, it becomes highly entrenched and resistant to change through either psychological or pharmacological treatment. Cognitive neuroscience has described two related but distinct processes that underlie the acquisition of new patterns of behavior, namely, action-outcome and stimulus-response learning. It is likely that both processes are engaged in the development of anorexia nervosa and that stimulus-response learning (that is, habit formation) is critical to the persistence of the dieting behavior. Conclusions The formulation of the dieting behavior characteristic of anorexia nervosa as a well-entrenched habit provides a basis for understanding the striking persistence of this disorder. This model helps explain the resistance of anorexia nervosa to interventions that have established efficacy in related disorders and implies that addressing the dieting behavior is critical, especially early in the course of the illness, before it has become ingrained. PMID:23429750

  10. Nitrogen uptake dynamics of a persistent cyanobacterium ...

    African Journals Online (AJOL)

    Worldwide, persistent cyanobacterial blooms are becoming more frequent and are often associated with effects of global climate change. In June 2009, a widespread bloom of the unicellular cyanobacterium, Cyanothece sp., appeared in North Lake and False Bay of Lake St Lucia – a large (360 km2) estuarine lake system ...

  11. Persistent Functional Languages: Toward Functional Relational Databases

    NARCIS (Netherlands)

    Wevers, L.

    2014-01-01

    Functional languages provide new approaches to concurrency control, based on techniques such as lazy evaluation and memoization. We have designed and implemented a persistent functional language based on these ideas, which we plan to use for the implementation of a relational database system. With

  12. Persistent pain after mastectomy with reconstruction.

    LENUS (Irish Health Repository)

    Hickey, Oonagh T

    2011-09-01

    To determine the prevalence of persistent postsurgical pain (PPSP) and its influence on functional status, and to examine associations between PPSP and single nucleotide polymorphisms of the catechol-O-methyltransferase (COMT) gene and the guanosine triphosphate cyclohydrolase 1 (GCH1) gene following mastectomy and reconstruction.

  13. Persistent ovarian masses and pregnancy outcomes.

    Science.gov (United States)

    Goh, William A; Rincon, Monica; Bohrer, Justin; Tolosa, Jorge E; Sohaey, Roya; Riaño, Rene; Davis, James; Zalud, Ivica

    2013-07-01

    To determine if persistent ovarian masses in pregnancy are associated with increased adverse outcomes. This is a retrospective cohort of 126 pregnant women with a persistent ovarian mass measuring 5 cm or greater who delivered at two university hospitals between 2001 and 2009. Maternal outcomes included gestational age (GA) at diagnosis, delivery and surgery as well as miscarriage, preterm birth (PTB), ovarian torsion and hospital admission for pain. Neonatal outcomes included birth weight, respiratory distress syndrome (RDS), intra-ventricular hemorrhage (IVH), death and sepsis. A total of 1225 ovarian masses were identified (4.9%) in 24,868 patients. A persistent ovarian mass was found in 0.7%. Average GA at diagnosis was 17.8 weeks. Miscarriage rate was 3.3%. Average GA at delivery was 37.9 weeks. Of the patients, 8.5% had ovarian torsion, 10.3% had admission for pain and 9.3% had PTBs. The mean cesarean delivery rate was 46.3%. The average neonatal weight was 3273 g. There was one neonatal death in this cohort. The rate of RDS was 2.8%, IVH 0.9% and neonatal sepsis 1.9%. The most common surgical pathologic diagnosis was dermoids (37.6%). No overt malignancies were seen. A persistent ovarian mass in pregnancy does not confer an increased risk of adverse pregnancy outcomes.

  14. Persistence of Change: Fume Hood Campaign Lessons

    Science.gov (United States)

    Feder, Elah; Robinson, Jennifer; Wakefield, Sarah

    2012-01-01

    Purpose: Sustainability initiatives typically operate for a limited time period, but it is often unclear whether they have lasting effects. The purpose of this paper is to examine a laboratory fume hood campaign, in order to identify factors that might contribute or detract from long-term change persistence. Design/methodology/approach: The…

  15. Treatment of persistent pain from torture

    DEFF Research Database (Denmark)

    Williams, Amanda C de C; Amris, Kirstine

    2017-01-01

    the nature of persistent pain means that pain is largely overlooked and untreated in torture survivors. We carried out a systematic review on treatments for pain from torture, but found few studies and little use of current understanding and evidence. We discuss this in the context of treating pain...

  16. Reserve design to maximize species persistence

    Science.gov (United States)

    Robert G. Haight; Laurel E. Travis

    2008-01-01

    We develop a reserve design strategy to maximize the probability of species persistence predicted by a stochastic, individual-based, metapopulation model. Because the population model does not fit exact optimization procedures, our strategy involves deriving promising solutions from theory, obtaining promising solutions from a simulation optimization heuristic, and...

  17. Retrospective review of neonates with persistent pulmonary ...

    African Journals Online (AJOL)

    Persistent pulmonary hypertension of the newborn (PPHN) is a clinical condition characterised by severe respiratory failure and hypoxaemia.[1] Its incidence is estimated at around 2 per 1 000 live births worldwide and it is associated with a high morbidity and mortality.[2,3] Despite the progress in treating PPHN, it remains a.

  18. A Neonate with persistent hypoglycemia and seizures.

    African Journals Online (AJOL)

    MBY

    disorder was diagnosed and managed with limited success as the episodes hydroglycemic seizures persisted. ... the presence of hyperinsulinemia as the cause of the hypoglycemic dependent seizures. Case Presentation. A three day old girl was admitted to the neonatal .... the Prader-Willi syndrome, has been reported.

  19. Persistent Pain and Sensory Abnormalities after Abdominoplasty

    DEFF Research Database (Denmark)

    Presman, Benjamin; Finnerup, Kenneth; Andresen, Sven Robert

    2015-01-01

    and characteristics of persistent pain after abdominoplasty, which is one of the most frequent cosmetic surgical procedures. METHODS: In September 2014, a link to a web-based questionnaire was mailed to 217 patients who had undergone abdominoplasty between 2006 and 2014 at the Department of Plastic Surgery, Aalborg...

  20. The Myth of Persistence of Vision Revisited.

    Science.gov (United States)

    Anderson, Joseph; Anderson, Barbara

    1993-01-01

    Argues that "persistence of vision" myth (the succession of still images perceived as continuous motion) has a place in the history of film scholarship but can no longer be given currency in film theory. Suggests replacement of the concept of the passive viewer implied by the myth by an enlightened understanding of how viewers actually…

  1. Forecasting autoregressive time series under changing persistence

    DEFF Research Database (Denmark)

    Kruse, Robinson

    Changing persistence in time series models means that a structural change from nonstationarity to stationarity or vice versa occurs over time. Such a change has important implications for forecasting, as negligence may lead to inaccurate model predictions. This paper derives generally applicable...

  2. Persistence Modeling for Assessing Marketing Strategy Performance

    NARCIS (Netherlands)

    M.G. Dekimpe (Marnik); D.M. Hanssens (Dominique)

    2003-01-01

    textabstractThe question of long-run market response lies at the heart of any marketing strategy that tries to create a sustainable competitive advantage for the firm or brand. A key challenge, however, is that only short-run results of marketing actions are readily observable. Persistence modeling

  3. Persistent trophoblast disease following partial molar pregnancy.

    NARCIS (Netherlands)

    Wielsma, S.; Kerkmeijer, L.G.W.; Bekkers, R.L.M.; Pyman, J.; Tan, J.; Quinn, M.

    2006-01-01

    OBJECTIVE: Human chorionic gonadotrophin (hCG) follow-up data were analysed retrospectively in all patients registered in the Hydatidiform Mole Registry at the Royal Women's Hospital, Melbourne from January 1992 to January 2001 to determine the risk of persistent trophoblast disease following

  4. Intermediates, Catalysts, Persistence, and Boundary Steady States

    DEFF Research Database (Denmark)

    Marcondes de Freitas, Michael; Feliu, Elisenda; Wiuf, Carsten

    2017-01-01

    networks without breaking known necessary or sufficient conditions for persistence, by iteratively removing socalled intermediates and catalysts from the network. The procedures are easy to apply and, in many cases, lead to highly simplified network structures, such as monomolecular networks. For specific...

  5. Diversity of Lactase Persistence Alleles in Ethiopia

    DEFF Research Database (Denmark)

    Jones, BL; Raga, TO; Liebert, Anke

    2013-01-01

    The persistent expression of lactase into adulthood in humans is a recent genetic adaptation that allows the consumption of milk from other mammals after weaning. In Europe, a single allele (−13910∗T, rs4988235) in an upstream region that acts as an enhancer to the expression of the lactase gene ...

  6. Hyperthyroidism as a cause of persistent vomiting.

    NARCIS (Netherlands)

    Hoogendoorn, E.H.; Cools, B.M.

    2004-01-01

    A 32-year-old woman presented with persistent vomiting, epigastric pain and weight loss. A sinus tachycardia was the clue to the diagnosis of hyperthyroidism due to Graves' disease. On treatment with propylthiouracil and a beta-blocking agent, her symptoms resolved within one day, even though her

  7. Ethnic Differences in Persistence with COPD Medications

    DEFF Research Database (Denmark)

    Hu, Yusun; Cantarero-Arévalo, Lourdes; Frølich, Anne

    2017-01-01

    BACKGROUND: Long-acting bronchodilators (LABDs) are recommended as a first-line maintenance therapy in patients with moderate or severe chronic obstructive pulmonary disease (COPD). The aim of the study was to explore potential ethnic differences in persistence with LABD in COPD patients. METHODS...

  8. Persistence of Value-Driven Attentional Capture

    Science.gov (United States)

    Anderson, Brian A.; Yantis, Steven

    2013-01-01

    Stimuli that have previously been associated with the delivery of reward involuntarily capture attention when presented as unrewarded and task-irrelevant distractors in a subsequent visual search task. It is unknown how long such effects of reward learning on attention persist. One possibility is that value-driven attentional biases are plastic…

  9. Retrospective review of neonates with persistent pulmonary ...

    African Journals Online (AJOL)

    Background. Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome characterised by high pulmonary pressures, low systemic pressures and severe hypoxaemia due to circulation transition failure after birth. Objective. To determine the incidence of and describe the risk factors, infant ...

  10. Judgment of facial expressions and depression persistence

    NARCIS (Netherlands)

    Hale, WW

    1998-01-01

    In research it has been demonstrated that cognitive and interpersonal processes play significant roles in depression development and persistence. The judgment of emotions displayed in facial expressions by depressed patients allows for a better understanding of these processes. In this study, 48

  11. Persistence of environmental DNA in freshwater ecosystems.

    Directory of Open Access Journals (Sweden)

    Tony Dejean

    Full Text Available The precise knowledge of species distribution is a key step in conservation biology. However, species detection can be extremely difficult in many environments, specific life stages and in populations at very low density. The aim of this study was to improve the knowledge on DNA persistence in water in order to confirm the presence of the focus species in freshwater ecosystems. Aquatic vertebrates (fish: Siberian sturgeon and amphibian: Bullfrog tadpoles were used as target species. In control conditions (tanks and in the field (ponds, the DNA detectability decreases with time after the removal of the species source of DNA. DNA was detectable for less than one month in both conditions. The density of individuals also influences the dynamics of DNA detectability in water samples. The dynamics of detectability reflects the persistence of DNA fragments in freshwater ecosystems. The short time persistence of detectable amounts of DNA opens perspectives in conservation biology, by allowing access to the presence or absence of species e.g. rare, secretive, potentially invasive, or at low density. This knowledge of DNA persistence will greatly influence planning of biodiversity inventories and biosecurity surveys.

  12. Persistence of Mycoplasma genitalium following azithromycin therapy.

    Directory of Open Access Journals (Sweden)

    Catriona S Bradshaw

    Full Text Available BACKGROUND: To determine clinical outcomes and cure rates for M.genitalium genital infection in men and women following azithromycin 1 g. METHODOLOGY: Patients attending Melbourne Sexual Health Centre between March 2005 and November 2007 with urethritis/epididymitis, cervicitis/pelvic inflammatory disease and sexual contacts of M.genitalium were tested for M.genitalium by polymerase chain reaction (PCR. M.genitalium-infection was treated with 1 g of azithromycin and a test-of-cure (toc was performed one month post-azithromycin. Response to azithromycin, and response to moxifloxacin (400 mg daily for 10 days in individuals with persistent infection post-azithromycin, was determined. PRINCIPAL FINDINGS: Of 1538 males and 313 females tested, 161 males (11% and 30 females (10% were infected with M.genitalium. A toc was available on 131 (69% infected individuals (median = 36 days [range 12-373]. Of 120 individuals prescribed azithromycin only pre-toc, M.genitalium was eradicated in 101 (84%, 95% confidence intervals [CI]: 77-90% and persisted in 19 (16%, 95% CI: 10-23%. Eleven individuals with persistent infection (9%, 95% CI: 5-15% had no risk of reinfection from untreated-partners, while eight (7%, 95% CI: 3-12% may have been at risk of reinfection from doxycycline-treated or untreated-partners. Moxifloxacin was effective in eradicating persistent infection in all cases not responding to azithromycin. Patients with persistent-M.genitalium were more likely to experience persistent symptoms (91%, compared to patients in whom M.genitalium was eradicated (17%, p<0.0001. CONCLUSION: Use of azithromycin 1 g in M.genitalium-infected patients was associated with unacceptable rates of persistent infection, which was eradicated with moxifloxacin. These findings highlight the importance of follow-up in M.genitalium-infected patients prescribed azithromycin, and the need to monitor for the development of resistance. Research to determine optimal first and

  13. Multiscale Persistent Functions for Biomolecular Structure Characterization

    Energy Technology Data Exchange (ETDEWEB)

    Xia, Kelin [Nanyang Technological University (Singapore). Division of Mathematical Sciences, School of Physical, Mathematical Sciences and School of Biological Sciences; Li, Zhiming [Central China Normal University, Wuhan (China). Key Laboratory of Quark and Lepton Physics (MOE) and Institute of Particle Physics; Mu, Lin [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Computer Science and Mathematics Division

    2017-11-02

    Here in this paper, we introduce multiscale persistent functions for biomolecular structure characterization. The essential idea is to combine our multiscale rigidity functions (MRFs) with persistent homology analysis, so as to construct a series of multiscale persistent functions, particularly multiscale persistent entropies, for structure characterization. To clarify the fundamental idea of our method, the multiscale persistent entropy (MPE) model is discussed in great detail. Mathematically, unlike the previous persistent entropy (Chintakunta et al. in Pattern Recognit 48(2):391–401, 2015; Merelli et al. in Entropy 17(10):6872–6892, 2015; Rucco et al. in: Proceedings of ECCS 2014, Springer, pp 117–128, 2016), a special resolution parameter is incorporated into our model. Various scales can be achieved by tuning its value. Physically, our MPE can be used in conformational entropy evaluation. More specifically, it is found that our method incorporates in it a natural classification scheme. This is achieved through a density filtration of an MRF built from angular distributions. To further validate our model, a systematical comparison with the traditional entropy evaluation model is done. Additionally, it is found that our model is able to preserve the intrinsic topological features of biomolecular data much better than traditional approaches, particularly for resolutions in the intermediate range. Moreover, by comparing with traditional entropies from various grid sizes, bond angle-based methods and a persistent homology-based support vector machine method (Cang et al. in Mol Based Math Biol 3:140–162, 2015), we find that our MPE method gives the best results in terms of average true positive rate in a classic protein structure classification test. More interestingly, all-alpha and all-beta protein classes can be clearly separated from each other with zero error only in our model. Finally, a special protein structure index (PSI) is proposed, for the first

  14. Persistence of undergraduate women in STEM fields

    Science.gov (United States)

    Pedone, Maggie Helene

    The underrepresentation of women in science, technology, engineering, and mathematics (STEM) is a complex problem that continues to persist at the postsecondary level, particularly in computer science and engineering fields. This dissertation explored the pre-college and college level factors that influenced undergraduate women's persistence in STEM. This study also examined and compared the characteristics of undergraduate women who entered STEM fields and non-STEM fields in 2003-2004. The nationally representative Beginning Postsecondary Students Longitudinal Study (BPS:04/09) data set was used for analysis. BPS:04/09 study respondents were surveyed three times (NPSAS:04, BPS:04/06, BPS:04/09) over a six-year period, which enabled me to explore factors related to long-term persistence. Astin's Input-Environment-Output (I-E-O) model was used as the framework to examine student inputs and college environmental factors that predict female student persistence (output) in STEM. Chi-square tests revealed significant differences between undergraduate women who entered STEM and non-STEM fields in 2003-2004. Differences in student demographics, prior academic achievement, high school course-taking patterns, and student involvement in college such as participation in study groups and school clubs were found. Notably, inferential statistics showed that a significantly higher proportion of female minority students entered STEM fields than non-STEM fields. These findings challenge the myth that underrepresented female minorities are less inclined to enter STEM fields. Logistic regression analyses revealed thirteen significant predictors of persistence for undergraduate women in STEM. Findings showed that undergraduate women who were younger, more academically prepared, and academically and socially involved in college (e.g., lived on campus, interacted with faculty, participated in study groups, fine arts activities, and school sports) were more likely to persist in STEM

  15. Persistence drives gene clustering in bacterial genomes

    Directory of Open Access Journals (Sweden)

    Rocha Eduardo PC

    2008-01-01

    Full Text Available Abstract Background Gene clustering plays an important role in the organization of the bacterial chromosome and several mechanisms have been proposed to explain its extent. However, the controversies raised about the validity of each of these mechanisms remind us that the cause of this gene organization remains an open question. Models proposed to explain clustering did not take into account the function of the gene products nor the likely presence or absence of a given gene in a genome. However, genomes harbor two very different categories of genes: those genes present in a majority of organisms – persistent genes – and those present in very few organisms – rare genes. Results We show that two classes of genes are significantly clustered in bacterial genomes: the highly persistent and the rare genes. The clustering of rare genes is readily explained by the selfish operon theory. Yet, genes persistently present in bacterial genomes are also clustered and we try to understand why. We propose a model accounting specifically for such clustering, and show that indispensability in a genome with frequent gene deletion and insertion leads to the transient clustering of these genes. The model describes how clusters are created via the gene flux that continuously introduces new genes while deleting others. We then test if known selective processes, such as co-transcription, physical interaction or functional neighborhood, account for the stabilization of these clusters. Conclusion We show that the strong selective pressure acting on the function of persistent genes, in a permanent state of flux of genes in bacterial genomes, maintaining their size fairly constant, that drives persistent genes clustering. A further selective stabilization process might contribute to maintaining the clustering.

  16. Rotenone persistence model for montane streams

    Science.gov (United States)

    Brown, Peter J.; Zale, Alexander V.

    2012-01-01

    The efficient and effective use of rotenone is hindered by its unknown persistence in streams. Environmental conditions degrade rotenone, but current label instructions suggest fortifying the chemical along a stream based on linear distance or travel time rather than environmental conditions. Our objective was to develop models that use measurements of environmental conditions to predict rotenone persistence in streams. Detailed measurements of ultraviolet radiation, water temperature, dissolved oxygen, total dissolved solids (TDS), conductivity, pH, oxidation–reduction potential (ORP), substrate composition, amount of organic matter, channel slope, and travel time were made along stream segments located between rotenone treatment stations and cages containing bioassay fish in six streams. The amount of fine organic matter, biofilm, sand, gravel, cobble, rubble, small boulders, slope, pH, TDS, ORP, light reaching the stream, energy dissipated, discharge, and cumulative travel time were each significantly correlated with fish death. By using logistic regression, measurements of environmental conditions were paired with the responses of bioassay fish to develop a model that predicted the persistence of rotenone toxicity in streams. This model was validated with data from two additional stream treatment reaches. Rotenone persistence was predicted by a model that used travel time, rubble, and ORP. When this model predicts a probability of less than 0.95, those who apply rotenone can expect incomplete eradication and should plan on fortifying rotenone concentrations. The significance of travel time has been previously identified and is currently used to predict rotenone persistence. However, rubble substrate, which may be associated with the degradation of rotenone by adsorption and volatilization in turbulent environments, was not previously considered.

  17. Extending and implementing the Persistent ID pillars

    Science.gov (United States)

    Car, Nicholas; Golodoniuc, Pavel; Klump, Jens

    2017-04-01

    The recent double decade anniversary of scholarly persistent identifier use has triggered journal special editions such as "20 Years of Persistent Identifiers". For such a publication, it is apt to consider the longevity of some persistent identifier (PID) mechanisms (Digital Object Identifiers) and the partial disappearance of others (Life Sciences IDs). We have previously postulated a set of "PID Pillars" [1] which are design principles aimed at ensuring PIDs can survive technology and social change and thus persist for the long term that we have drawn from our observations of PIDs at work over many years. The principles: describe how to ensure identifiers' system and organisation independence; codify the delivery of essential PID system functions; mandate a separation of PID functions from data delivery mechanisms; and require generation of policies detailing how change is handled. In this presentation, first we extend on our previous work of introducing the pillars by refining their descriptions, giving specific suggestions for each and presenting some work that addresses them. Second, we propose a baseline data model for persistent identifiers that, if used, would assist the separation of PID metadata and PID system functioning. This would allow PID system function specifics to change over time (e.g. resolver services or even resolution protocols) and yet preserve the PIDs themselves. Third, we detail our existing PID system — the PID Service [2] — that partially implements the pillars and describe both its successes and shortcomings. Finally, we describe our planned next-generation system that will aim to use the baseline data model and fully implement the pillars.

  18. How to decode Unemployment Persistence: An econometric framework for identifying and comparing the sources of persistence

    DEFF Research Database (Denmark)

    Møller, Niels Framroze

    2016-01-01

    Most econometric analyses of persistence focus on the existence of non-stationary unemployment but not the origin of this. The present research contains a multivariate econometric framework for identifying and comparing different sources of unemployment persistence (e.g. hysteresis versus a slowly...... moving equilibrium rate). A small example, considering historical data (1988-2006) for the UK, demonstrates how the method can be applied in practice. Although this primarily serves as an illustration, the evidence clearly suggests that persistence was due to a slowly moving equilibrium (driven...

  19. Persistence of Bacillus thuringiensis bioinsecticides in the gut of human-flora-associated rats

    DEFF Research Database (Denmark)

    Wilcks, Andrea; Hansen, Bjarne Munk; Hendriksen, Niels Bohse

    2006-01-01

    The capability of two bioinsecticide strains of Bacillus thuringiensis (ssp. israelensis and ssp. kurstaki) to germinate and persist in vivo in the gastrointestinal tract of human-flora-associated rats was studied. Rats were dosed either with vegetative cells or spores of the bacteria for 4 conse...

  20. Hepatitis E virus persists in the presence of a type III interferon response.

    Science.gov (United States)

    Yin, Xin; Li, Xinlei; Ambardekar, Charuta; Hu, Zhimin; Lhomme, Sébastien; Feng, Zongdi

    2017-05-01

    The RIG-I-like RNA helicase (RLR)-mediated interferon (IFN) response plays a pivotal role in the hepatic antiviral immunity. The hepatitis A virus (HAV) and the hepatitis C virus (HCV) counter this response by encoding a viral protease that cleaves the mitochondria antiviral signaling protein (MAVS), a common signaling adaptor for RLRs. However, a third hepatotropic RNA virus, the hepatitis E virus (HEV), does not appear to encode a functional protease yet persists in infected cells. We investigated HEV-induced IFN responses in human hepatoma cells and primary human hepatocytes. HEV infection resulted in persistent virus replication despite poor spread. This was companied by a type III IFN response that upregulated multiple IFN-stimulated genes (ISGs), but type I IFNs were barely detected. Blocking type III IFN production or signaling resulted in reduced ISG expression and enhanced HEV replication. Unlike HAV and HCV, HEV did not cleave MAVS; MAVS protein size, mitochondrial localization, and function remained unaltered in HEV-replicating cells. Depletion of MAVS or MDA5, and to a less extent RIG-I, also diminished IFN production and increased HEV replication. Furthermore, persistent activation of the JAK/STAT signaling rendered infected cells refractory to exogenous IFN treatment, and depletion of MAVS or the receptor for type III IFNs restored the IFN responsiveness. Collectively, these results indicate that unlike other hepatotropic RNA viruses, HEV does not target MAVS and its persistence is associated with continuous production of type III IFNs.

  1. Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.

    Directory of Open Access Journals (Sweden)

    Melissa Starkey

    2014-08-01

    Full Text Available Etiological agents of acute, persistent, or relapsing clinical infections are often refractory to antibiotics due to multidrug resistance and/or antibiotic tolerance. Pseudomonas aeruginosa is an opportunistic Gram-negative bacterial pathogen that causes recalcitrant and severe acute chronic and persistent human infections. Here, we target the MvfR-regulated P. aeruginosa quorum sensing (QS virulence pathway to isolate robust molecules that specifically inhibit infection without affecting bacterial growth or viability to mitigate selective resistance. Using a whole-cell high-throughput screen (HTS and structure-activity relationship (SAR analysis, we identify compounds that block the synthesis of both pro-persistence and pro-acute MvfR-dependent signaling molecules. These compounds, which share a benzamide-benzimidazole backbone and are unrelated to previous MvfR-regulon inhibitors, bind the global virulence QS transcriptional regulator, MvfR (PqsR; inhibit the MvfR regulon in multi-drug resistant isolates; are active against P. aeruginosa acute and persistent murine infections; and do not perturb bacterial growth. In addition, they are the first compounds identified to reduce the formation of antibiotic-tolerant persister cells. As such, these molecules provide for the development of next-generation clinical therapeutics to more effectively treat refractory and deleterious bacterial-human infections.

  2. Persistence of interest in science, technology, engineering and mathematics: An analysis of persisting and non-persisting students

    Science.gov (United States)

    White, Jeffry L.

    While there has been an increase in enrollment, interest in science, technology, engineering, and mathematics (STEM) has been declining on college campuses since 1967. Higher enrollment does not transfer to an increase in the number of minorities in the STEM fields. The majority-minority enrollment ratio is nearly 2:1 but the gap widens to 4:1 when it comes to graduation. In fact, underrepresented minorities (URM) earned only 12% of the STEM degrees awarded in 1998. When the higher attrition and lower graduation rates of URM are scrutinized, upwards of 60% changed majors or dropped out of STEM. Further investigation reveals the most frequently cited reasons for departure were loss of initial interest, developed a greater interest in another field, or were turned off by the STEM disciplines. A primarily exploratory study was conducted into the conditions necessary for academic interest in the STEM fields to persist. A model based on student engagement (Astin, 1977) and interest operations (Prenzel, 1988a) theories was used with a random sample of URM at universities participating in the Ohio Science and Engineering Alliance. Survey research was employed to investigate interest development and the effect of student retention programs and activities on such interest. The latter part of the study could not be fully examined when 95% reported not utilizing retention services. For the section on interest, an online survey using a 5-point Likert scale was validated using principal components analysis. A binominal logistic regression was used to predict membership in one of two possible groups: persisters and students at-risk for not persisting. The major conclusions are: (1) While 3 variables (feelings, learning and difficulty) were statistically significant only one, feelings was substantively significant. (2) Persistence increased 80.9% for each 1-unit increase in feelings and 9.9% for learning. (3) Persistence decreased 19.8% for each one-unit increase in difficulty

  3. Emotional persistence in online chatting communities

    Science.gov (United States)

    Garas, Antonios; Garcia, David; Skowron, Marcin; Schweitzer, Frank

    2012-05-01

    How do users behave in online chatrooms, where they instantaneously read and write posts? We analyzed about 2.5 million posts covering various topics in Internet relay channels, and found that user activity patterns follow known power-law and stretched exponential distributions, indicating that online chat activity is not different from other forms of communication. Analysing the emotional expressions (positive, negative, neutral) of users, we revealed a remarkable persistence both for individual users and channels. I.e. despite their anonymity, users tend to follow social norms in repeated interactions in online chats, which results in a specific emotional ``tone'' of the channels. We provide an agent-based model of emotional interaction, which recovers qualitatively both the activity patterns in chatrooms and the emotional persistence of users and channels. While our assumptions about agent's emotional expressions are rooted in psychology, the model allows to test different hypothesis regarding their emotional impact in online communication.

  4. Persistent hyperlactacidaemia: about a clinical case.

    Science.gov (United States)

    Oliveira, Ana Rita Saraiva; Valente, Rosalina; Ramos, José; Ventura, Lurdes

    2013-05-22

    Lactate is the endogenous end product of the anaerobic glycolysis, whose production is favoured in situations of hypoperfusion or mitochondrial dysfunction. Leigh syndrome is a rare, progressive encephalomyopathy that represents a spectrum of mitochondrial genetic diseases phenotypically distinct, but with neuroradiological and pathological uniform presentation. We present the case of a 7-month-old infant, with a history of prematurity, psychomotor retardation and epilepsy, admitted to the paediatric intensive care unit (PICU) due to cardio-respiratory arrest because of respiratory infection. Hyperlactacidaemia was detected and was persistent. The study of redox potential was normal but MRI with spectroscopy identified bilateral and symmetrical lesions involving thalamic and basal ganglia, with small lactate peaks at T2 flair, findings that were suggestive of Leigh syndrome. Subsequent enzymatic study identified lack of pyruvate dehydrogenase. Persistent hyperlactacidaemia, in the appropriate clinical context, should lead to the screening of mitochondrial diseases.

  5. Persistent pulmonary hypertension of the newborn.

    Science.gov (United States)

    Nair, P M C; Bataclan, Maria Flordeliz A

    2004-06-01

    This article attempts to define a complicated, yet not rare disease of the neonate, which presents with extreme hypoxemia due to increased pulmonary vascular resistance, resulting in diversion of the pulmonary venous blood through persistent fetal channels, namely ductus arteriosus and foramen ovale. Pathophysiology, diagnostic approach and the various modalities of management are analyzed. Persistent pulmonary hypertension of the newborn is multi-factorial, which is reflected in the management as well. These babies are extremely labile to hypoxia and should be stabilized with minimum handling. One hundred percent oxygen and ventilation are the mainstay of treatment. The role of hyperventilation, alkalinization, various non-specific vasodilators such as tolazoline, magnesium sulphate, selective vasodilators such as inhaled nitric oxide, adenosine and the role of high frequency oscillatory ventilation and extra corporeal membrane oxygenation are discussed. With the newer modalities of management, the outlook has improved with mortality of less than 20% and fewer long-term deficits.

  6. Patients with persistent medically unexplained physical symptoms

    DEFF Research Database (Denmark)

    A, Aamland; Malterud, Kirsti; Werner, E.

    2014-01-01

    for all variables and split analysis on gender and age. RESULTS: The GPs registered 526 patients among their total of 17 688 consultations, giving a consultation prevalence of persistent MUPS of 3%. The mean age of patients was 46 years, and 399 (76%) were women. The most frequent group of symptoms...... was musculoskeletal problems, followed by asthenia/fatigue. There was no significant gender difference in symptom pattern. Almost half of the patients were currently working (45%), significantly more men. The major GP management strategy was supportive counseling. CONCLUSION: A consultation prevalence rate of 3......% implies that patients with persistent MUPS are common in general practice. Our study disclosed heterogeneity among the patients such as differences in employment status, which emphasizes the importance of personalized focus rather than unsubstantiated stereotyping of "MUPS patients" as a group....

  7. Persistent Identifiers for Dutch cultural heritage institutions

    Science.gov (United States)

    Ras, Marcel; Kruithof, Gijsbert

    2016-04-01

    Over the past years, more and more collections belonging to archives, libraries, media, museums, and knowledge institutes are being digitised and made available online. These are exciting times for ALM institutions. They are realising that, in the information society, their collections are goldmines. Unfortunately most heritage institutions in the Netherlands do not yet meet the basic preconditions for long-term availability of their collections. The digital objects often have no long lasting fixed reference yet. URL's and web addresses change. Some digital objects that were referenced in Europeana and other portals can no longer be found. References in scientific articles have a very short life span, which is damaging for scholarly research. In 2015, the Dutch Digital Heritage Network (NDE) has started a two-year work program to co-ordinate existing initiatives in order to improve the (long-term) accessibility of the Dutch digital heritage for a wide range of users, anytime, anyplace. The Digital Heritage Network is a partnership established on the initiative of the Ministry of Education, Culture and Science. The members of the NDE are large, national institutions that strive to professionally preserve and manage digital data, e.g. the National Library, The Netherlands Institute for Sound and Vision, the Netherlands Cultural Heritage Agency, the Royal Netherlands Academy of Arts and Sciences, the National Archive of the Netherlands and the DEN Foundation, and a growing number of associations and individuals both within and outside the heritage sector. By means of three work programmes the goals of the Network should be accomplished and improve the visibility, the usability and the sustainability of digital heritage. Each programme contains of a set of projects. Within the sustainability program a project on creating a model for persistent identifiers is taking place. The main goals of the project are (1) raise awareness among cultural heritage institutions on the

  8. Persistent Aerial Tracking system for UAVs

    KAUST Repository

    Mueller, Matthias

    2016-12-19

    In this paper, we propose a persistent, robust and autonomous object tracking system for unmanned aerial vehicles (UAVs) called Persistent Aerial Tracking (PAT). A computer vision and control strategy is applied to a diverse set of moving objects (e.g. humans, animals, cars, boats, etc.) integrating multiple UAVs with a stabilized RGB camera. A novel strategy is employed to successfully track objects over a long period, by ‘handing over the camera’ from one UAV to another. We evaluate several state-of-the-art trackers on the VIVID aerial video dataset and additional sequences that are specifically tailored to low altitude UAV target tracking. Based on the evaluation, we select the leading tracker and improve upon it by optimizing for both speed and performance, integrate the complete system into an off-the-shelf UAV, and obtain promising results showing the robustness of our solution in real-world aerial scenarios.

  9. Persistent Aerial Tracking system for UAVs

    KAUST Repository

    Mueller, Matthias; Sharma, Gopal; Smith, Neil; Ghanem, Bernard

    2016-01-01

    In this paper, we propose a persistent, robust and autonomous object tracking system for unmanned aerial vehicles (UAVs) called Persistent Aerial Tracking (PAT). A computer vision and control strategy is applied to a diverse set of moving objects (e.g. humans, animals, cars, boats, etc.) integrating multiple UAVs with a stabilized RGB camera. A novel strategy is employed to successfully track objects over a long period, by ‘handing over the camera’ from one UAV to another. We evaluate several state-of-the-art trackers on the VIVID aerial video dataset and additional sequences that are specifically tailored to low altitude UAV target tracking. Based on the evaluation, we select the leading tracker and improve upon it by optimizing for both speed and performance, integrate the complete system into an off-the-shelf UAV, and obtain promising results showing the robustness of our solution in real-world aerial scenarios.

  10. Geometry Helps to Compare Persistence Diagrams

    Energy Technology Data Exchange (ETDEWEB)

    Kerber, Michael; Morozov, Dmitriy; Nigmetov, Arnur

    2015-11-16

    Exploiting geometric structure to improve the asymptotic complexity of discrete assignment problems is a well-studied subject. In contrast, the practical advantages of using geometry for such problems have not been explored. We implement geometric variants of the Hopcroft--Karp algorithm for bottleneck matching (based on previous work by Efrat el al.), and of the auction algorithm by Bertsekas for Wasserstein distance computation. Both implementations use k-d trees to replace a linear scan with a geometric proximity query. Our interest in this problem stems from the desire to compute distances between persistence diagrams, a problem that comes up frequently in topological data analysis. We show that our geometric matching algorithms lead to a substantial performance gain, both in running time and in memory consumption, over their purely combinatorial counterparts. Moreover, our implementation significantly outperforms the only other implementation available for comparing persistence diagrams.

  11. Imaging approach to persistent neonatal jaundice

    International Nuclear Information System (INIS)

    Kirks, D.; Coleman, R.E.; Filston, H.C.; Rosenberg, E.R.; Merten, D.F.

    1984-01-01

    Fifteen patients with persistent neonatal jaundice were evaluated by sonography and radionuclide scintigraphy. The sonographic features of both neonatal hepatitis and biliary atresia are nonspecific. Hepatobiliary scintigraphy after phenobarbital pretreatment in patients with neonatal hepatitis demonstrates normal hepatic extraction and delayed tracer excretion into the gastrointestinal tract. If there is neonatal hepatitis with severe hepatocellular damage, the hepatic extraction of tracer activity is decreased and excretion may be delayed or absent. Patients under 3 months of age with biliary atresia have normal hepatic extraction of tracer with no excretion into the gastrointestinal tract. Sonography in patients with a choledochal cyst shows a cystic mass in the porta hepatis with associated bile-duct dilatation. Hepatobiliary scintigraphy confirms that the choledochal cyst communicates with the biliary system. Initial sonography demonstrates hepatobiliary anatomy; subsequent phenobarbital-enhanced radionuclide scintigraphy determines hepatobiliary function. An expedient diagnostic approach is recommended for the evaluation of persistent neonatal jaundice

  12. Quantifying the degree of persistence in random amoeboid motion based on the Hurst exponent of fractional Brownian motion.

    Science.gov (United States)

    Makarava, Natallia; Menz, Stephan; Theves, Matthias; Huisinga, Wilhelm; Beta, Carsten; Holschneider, Matthias

    2014-10-01

    Amoebae explore their environment in a random way, unless external cues like, e.g., nutrients, bias their motion. Even in the absence of cues, however, experimental cell tracks show some degree of persistence. In this paper, we analyzed individual cell tracks in the framework of a linear mixed effects model, where each track is modeled by a fractional Brownian motion, i.e., a Gaussian process exhibiting a long-term correlation structure superposed on a linear trend. The degree of persistence was quantified by the Hurst exponent of fractional Brownian motion. Our analysis of experimental cell tracks of the amoeba Dictyostelium discoideum showed a persistent movement for the majority of tracks. Employing a sliding window approach, we estimated the variations of the Hurst exponent over time, which allowed us to identify points in time, where the correlation structure was distorted ("outliers"). Coarse graining of track data via down-sampling allowed us to identify the dependence of persistence on the spatial scale. While one would expect the (mode of the) Hurst exponent to be constant on different temporal scales due to the self-similarity property of fractional Brownian motion, we observed a trend towards stronger persistence for the down-sampled cell tracks indicating stronger persistence on larger time scales.

  13. Cyclic AMP Regulates Bacterial Persistence through Repression of the Oxidative Stress Response and SOS-Dependent DNA Repair in Uropathogenic Escherichia coli.

    Science.gov (United States)

    Molina-Quiroz, Roberto C; Silva-Valenzuela, Cecilia; Brewster, Jennifer; Castro-Nallar, Eduardo; Levy, Stuart B; Camilli, Andrew

    2018-01-09

    Bacterial persistence is a transient, nonheritable physiological state that provides tolerance to bactericidal antibiotics. The stringent response, toxin-antitoxin modules, and stochastic processes, among other mechanisms, play roles in this phenomenon. How persistence is regulated is relatively ill defined. Here we show that cyclic AMP, a global regulator of carbon catabolism and other core processes, is a negative regulator of bacterial persistence in uropathogenic Escherichia coli , as measured by survival after exposure to a β-lactam antibiotic. This phenotype is regulated by a set of genes leading to an oxidative stress response and SOS-dependent DNA repair. Thus, persister cells tolerant to cell wall-acting antibiotics must cope with oxidative stress and DNA damage and these processes are regulated by cyclic AMP in uropathogenic E. coli IMPORTANCE Bacterial persister cells are important in relapsing infections in patients treated with antibiotics and also in the emergence of antibiotic resistance. Our results show that in uropathogenic E. coli , the second messenger cyclic AMP negatively regulates persister cell formation, since in its absence much more persister cells form that are tolerant to β-lactams antibiotics. We reveal the mechanism to be decreased levels of reactive oxygen species, specifically hydroxyl radicals, and SOS-dependent DNA repair. Our findings suggest that the oxidative stress response and DNA repair are relevant pathways to target in the design of persister-specific antibiotic compounds. Copyright © 2018 Molina-Quiroz et al.

  14. Persistent hepatitis virus infection and immune homeostasis

    OpenAIRE

    ZHOU Yun

    2014-01-01

    Homeostasis between the host and viruses is naturally maintained. On the one hand, the immune system activates the immune response to kill or eliminate viruses; on the other hand, the immune system controls the immune response to maintain immune homeostasis. The cause of persistent infections with hepatitis viruses such as HBV and HCV is that viral molecules damage the immune system of the host and their variants escape immune clearance. Long-term coexistence of the host and viruses is the pr...

  15. The persistence of marketing effects on sales

    OpenAIRE

    Dekimpe, Marnik; Hanssens, DM

    1993-01-01

    Are marketing efforts able to affect long-term trends in sales or other performance measures? Answering this question is essential for the creation of marketing strategies that deliver a sustainable competitive advantage. This paper introduces persistence modeling to derive long-term marketing effectiveness from time-series observations on sales and marketing expenditures. First, we use unit-root tests to determine whether sales are stable or evolving (trending) over time. If they are evolvin...

  16. Mobility-induced persistent chimera states

    Science.gov (United States)

    Petrungaro, Gabriela; Uriu, Koichiro; Morelli, Luis G.

    2017-12-01

    We study the dynamics of mobile, locally coupled identical oscillators in the presence of coupling delays. We find different kinds of chimera states in which coherent in-phase and antiphase domains coexist with incoherent domains. These chimera states are dynamic and can persist for long times for intermediate mobility values. We discuss the mechanisms leading to the formation of these chimera states in different mobility regimes. This finding could be relevant for natural and technological systems composed of mobile communicating agents.

  17. Understanding and Responding to Persistently High Unemployment

    Science.gov (United States)

    2012-02-01

    Persistent Effects of Job Displacement: The Importance of Multiple Job Losses,” Journal of Labor Economics , vol. 15, no. 1, part 1 (January 1997), pp...Capital: Evidence from Displaced Workers,” Journal of Labor Economics , vol. 13, no. 4 (October 1995), pp. 653–677.one-third had trouble meeting...Effects of Worker Displacement,” Journal of Labor Economics , vol. 26, no. 3 (July 2008), pp. 455–483. completed its most recent economic forecast), that

  18. Actinomyces associated with persistent vaginal granulation tissue.

    OpenAIRE

    Wai, Clifford Y; Nihira, Mikio A; Drewes, Peter G; Chang, Joe S; Siddiqui, Momin T; Hemsell, David L

    2005-01-01

    BACKGROUND: We report a case of symptomatic actinomycosis associated with vaginal suture erosion and granulation tissue refractory to conservative management, in an outpatient setting. CASE: Three months after total vaginal hysterectomy and uterosacral ligament vaginal vault suspension, a woman complained of painless, intermittent vaginal discharge and spotting. Despite cauterization of granulation tissue, vaginal spotting persisted for another month. On re-examination, braided polyester sutu...

  19. Persistent postsurgical pain: risk factors and prevention

    DEFF Research Database (Denmark)

    Kehlet, Henrik; Jensen, Troels Staehelin; Woolf, Clifford J.

    2006-01-01

    therapy for postoperative pain should be investigated, since the intensity of acute postoperative pain correlates with the risk of developing a persistent pain state. Finally, the role of genetic factors should be studied, since only a proportion of patients with intraoperative nerve damage develop...... chronic pain. Based on information about the molecular mechanisms that affect changes to the peripheral and central nervous system in neuropathic pain, several opportunities exist for multimodal pharmacological intervention. Here, we outline strategies for identification of patients at risk...

  20. Information persistence using XML database technology

    Science.gov (United States)

    Clark, Thomas A.; Lipa, Brian E. G.; Macera, Anthony R.; Staskevich, Gennady R.

    2005-05-01

    The Joint Battlespace Infosphere (JBI) Information Management (IM) services provide information exchange and persistence capabilities that support tailored, dynamic, and timely access to required information, enabling near real-time planning, control, and execution for DoD decision making. JBI IM services will be built on a substrate of network centric core enterprise services and when transitioned, will establish an interoperable information space that aggregates, integrates, fuses, and intelligently disseminates relevant information to support effective warfighter business processes. This virtual information space provides individual users with information tailored to their specific functional responsibilities and provides a highly tailored repository of, or access to, information that is designed to support a specific Community of Interest (COI), geographic area or mission. Critical to effective operation of JBI IM services is the implementation of repositories, where data, represented as information, is represented and persisted for quick and easy retrieval. This paper will address information representation, persistence and retrieval using existing database technologies to manage structured data in Extensible Markup Language (XML) format as well as unstructured data in an IM services-oriented environment. Three basic categories of database technologies will be compared and contrasted: Relational, XML-Enabled, and Native XML. These technologies have diverse properties such as maturity, performance, query language specifications, indexing, and retrieval methods. We will describe our application of these evolving technologies within the context of a JBI Reference Implementation (RI) by providing some hopefully insightful anecdotes and lessons learned along the way. This paper will also outline future directions, promising technologies and emerging COTS products that can offer more powerful information management representations, better persistence mechanisms and

  1. Anomaly equations and the persistent mass condition

    International Nuclear Information System (INIS)

    Cohen, E.; Frishman, Y.

    1982-01-01

    Vector SU(Nsub(c)) gauge theories with nsub(f) flavors in the fundamental representation are considered. We prove that if the persistent mass condition is assumed, the two anomaly equations are identical and flavor independent for nsub(f) >= 3. Integer solutions exist only for nsub(f) = 2. The necessity of a separate discussion for 2 <= nsub(f) <= Nsub(c) is explained. (orig.)

  2. [Persistent duodenal septum in an adult].

    Science.gov (United States)

    Helwing, E; Echtermeyer, V; Otten, G

    1977-02-01

    A case of duodenal obstruction by a congenital duodenal web in a 34-year-old woman is presented. A mucosal diaphragm obstructed the duodenum. It showed an excentric opening of 0.8 cm diameter, but the dilated diaphragm caused a total stop during the last months. Despite a typical history, exact X-ray, and endoscopic examination, the correct preoperative diagnosis was not found, because nobody thought it possible, that a mucosal diapharm of the duodenum could persist for 34 years.

  3. Irregular persistent activity induced by synaptic excitatory feedback

    Directory of Open Access Journals (Sweden)

    Francesca Barbieri

    2007-11-01

    Full Text Available Neurophysiological experiments on monkeys have reported highly irregular persistent activity during the performance of an oculomotor delayed-response task. These experiments show that during the delay period the coefficient of variation (CV of interspike intervals (ISI of prefrontal neurons is above 1, on average, and larger than during the fixation period. In the present paper, we show that this feature can be reproduced in a network in which persistent activity is induced by excitatory feedback, provided that (i the post-spike reset is close enough to threshold , (ii synaptic efficacies are a non-linear function of the pre-synaptic firing rate. Non-linearity between presynaptic rate and effective synaptic strength is implemented by a standard short-term depression mechanism (STD. First, we consider the simplest possible network with excitatory feedback: a fully connected homogeneous network of excitatory leaky integrate-and-fire neurons, using both numerical simulations and analytical techniques. The results are then confirmed in a network with selective excitatory neurons and inhibition. In both the cases there is a large range of values of the synaptic efficacies for which the statistics of firing of single cells is similar to experimental data.

  4. Endorectal magnetic resonance imaging in persistent hemospermia

    International Nuclear Information System (INIS)

    Prando, Adilson

    2008-01-01

    Objective: To present the spectrum of abnormalities found at endorectal magnetic resonance imaging (E-MRI), in patients with persistent hemospermia. Materials and methods: A review of E-MRI findings observed in 86 patients with persistent hemospermia was performed and results compared with those reported in the literature. Follow-up was possible in 37 of 86 (43%) patients with hemospermia. Results: E-MRI showed abnormal findings in 52 of 86 (60%) patients with hemospermia. These findings were: a) hemorrhagic seminal vesicle and ejaculatory duct, isolated (n = 11 or 21%) or associated with complicated midline prostatic cyst (n = 10 or 19.0%); b) hemorrhagic chronic seminal vesiculitis, isolated (n = 14 or 27%) or associated with calculi within dilated ejaculatory ducts (n = 2 or 4 %); c) hemorrhagic seminal vesicle associated with calculi within dilated ejaculatory duct (n = 4 or 7.7%) or within seminal vesicle (n = 4 or 7.7%); d) non-complicated midline prostatic cyst (n = 6 or 11.5%); and e) prostate cancer (n = 1 or 2%). Successful treatment was more frequent in patients with chronic inflammatory and/or obstructive abnormalities. Conclusion: E-MRI should be considered the modality of choice, for the evaluation of patients with persistent hemospermia. (author)

  5. Endorectal magnetic resonance imaging in persistent hemospermia

    Energy Technology Data Exchange (ETDEWEB)

    Prando, Adilson [Vera Cruz Hospital, Campinas, SP (Brazil). Dept. of Radiology and Diagnostic Imaging

    2008-03-15

    Objective: To present the spectrum of abnormalities found at endorectal magnetic resonance imaging (E-MRI), in patients with persistent hemospermia. Materials and methods: A review of E-MRI findings observed in 86 patients with persistent hemospermia was performed and results compared with those reported in the literature. Follow-up was possible in 37 of 86 (43%) patients with hemospermia. Results: E-MRI showed abnormal findings in 52 of 86 (60%) patients with hemospermia. These findings were: a) hemorrhagic seminal vesicle and ejaculatory duct, isolated (n = 11 or 21%) or associated with complicated midline prostatic cyst (n = 10 or 19.0%); b) hemorrhagic chronic seminal vesiculitis, isolated (n = 14 or 27%) or associated with calculi within dilated ejaculatory ducts (n = 2 or 4 %); c) hemorrhagic seminal vesicle associated with calculi within dilated ejaculatory duct (n = 4 or 7.7%) or within seminal vesicle (n = 4 or 7.7%); d) non-complicated midline prostatic cyst (n = 6 or 11.5%); and e) prostate cancer (n = 1 or 2%). Successful treatment was more frequent in patients with chronic inflammatory and/or obstructive abnormalities. Conclusion: E-MRI should be considered the modality of choice, for the evaluation of patients with persistent hemospermia. (author)

  6. Lactase Non-persistence and Lactose Intolerance.

    Science.gov (United States)

    Bayless, Theodore M; Brown, Elizabeth; Paige, David M

    2017-05-01

    To evaluate the clinical and nutritional significance of genetically determined lactase non-persistence and potential lactose and milk intolerance in 65-70% of the world's adult population. Milk consumption is decreasing in the USA and is the lowest in countries with a high prevalence of lactase non-persistence. The dairy industry and Minnesota investigators have made efforts to minimize the influence of lactose intolerance on milk consumption. Some lactose intolerant individuals, without co-existent irritable bowel syndrome, are able to consume a glass of milk with a meal with no or minor symptoms. The high frequency of lactase persistence in offspring of Northern European countries and in some nomadic African tribes is due to mutations in the promoter of the lactase gene in association with survival advantage of milk drinking. Educational and commercial efforts to improve calcium and Vitamin D intake have focused on urging consumption of tolerable amounts of milk with a meal, use of lowered lactose-content foods including hard cheeses, yogurt, and lactose-hydrolyzed milk products.

  7. Persistent physical symptoms as perceptual dysregulation

    DEFF Research Database (Denmark)

    Henningsen, Peter; Gündel, Harald; Kop, Willem J

    2018-01-01

    OBJECTIVE: The mechanisms underlying the perception and experience of persistent physical symptoms are not well understood, and in the models, the specific relevance of peripheral input versus central processing, or of neurobiological versus psychosocial factors in general, is not clear.In this a......OBJECTIVE: The mechanisms underlying the perception and experience of persistent physical symptoms are not well understood, and in the models, the specific relevance of peripheral input versus central processing, or of neurobiological versus psychosocial factors in general, is not clear.......In this article, we propose a model for this clinical phenomenon that is designed to be coherent with an underlying, relatively new model of the normal brain functions involved in the experience of bodily signals. METHODS: Based on a review of recent literature we describe central elements of this model and its...... of predictions and sensory input. Two possibilities exist: adaptation of the generative model underlying the predictions or alteration of the sensory input via autonomic nervous activation (in the case of interoception). Following this model, persistent physical symptoms can be described as "failures...

  8. Persistent producer-scrounger relationships in bats.

    Science.gov (United States)

    Harten, Lee; Matalon, Yasmin; Galli, Naama; Navon, Hagit; Dor, Roi; Yovel, Yossi

    2018-02-01

    Social foraging theory suggests that group-living animals gain from persistent social bonds, which lead to increased tolerance in competitive foraging and information sharing. Bats are among the most social mammals, often living in colonies of tens to thousands of individuals for dozens of years, yet little is known about their social foraging dynamics. We observed three captive bat colonies for over a year, quantifying >13,000 social foraging interactions. We found that individuals consistently used one of two foraging strategies, either producing (collecting) food themselves or scrounging it directly from the mouth of other individuals. Individual foraging types were consistent over at least 16 months except during the lactation period when females shifted toward producing. Scroungers intentionally selected whom to interact with when socially foraging, thus generating persistent nonrandom social relationships with two to three specific producers. These persistent producer-scrounger relationships seem to reduce aggression over time. Finally, scrounging was highly correlated with vigilance, and we hypothesize that vigilant-prone individuals turn to scrounging in the wild to mitigate the risk of landing on a potentially unsafe fruit tree. We find the bat colony to be a rich and dynamic social system, which can serve as a model to study the role that social foraging plays in the evolution of mammalian sociality. Our results highlight the importance of considering individual tendencies when exploring social behavior patterns of group-living animals. These tendencies further emphasize the necessity of studying social networks over time.

  9. Overview of persistent pain in older adults.

    Science.gov (United States)

    Molton, Ivan R; Terrill, Alexandra L

    2014-01-01

    With the shifting age demographics of the U.S. population, more psychologists will be asked to provide clinical services to older adults. Given the high prevalence of persistent pain in aging, in many cases this will mean providing empirically supported interventions for pain and the interference it creates. The purpose of this review is to provide a broad overview of the scope and impact of persistent pain in older people and to discuss mechanisms by which persistent geriatric pain can lead to suffering and disability. We consider the unique context of pain in older adulthood and review differences between older and younger people in terms of pain perception, the social network, beliefs about pain, pain-related coping, and adherence to pain medication. Finally, we discuss special issues affecting pain management in older adults, including dementia, polypharmacy, and barriers to accessing adequate pain care. This review also highlights a need for greater provider training in pain management to meet the needs of a changing U.S. population. PsycINFO Database Record (c) 2014 APA, all rights reserved.

  10. Sputum Neutrophilia in Severe Persistent Asthmatics

    International Nuclear Information System (INIS)

    Naseem, A.; Zaidi, S. B. H.; Liaqat, J.; Iftikhar, R.

    2014-01-01

    Objective: To determine the frequency of sputum neutrophilia in patients with severe persistent bronchial asthma. Study Design: A cross-sectional study. Place and Duration of Study: Department of Medicine, Military Hospital, Rawalpindi, from November 2009 to November 2010. Methodology: Cases of severe persistent bronchial asthma, aged between 12 and 40 years, were included. Sputum samples were collected by induction with hypertonic saline (4.5%). All samples were centrifuged and differential neutrophil count was calculated. Data was analyzed using SPSS 11. Results: Out of 195 patients, there were 129 (66.2%) males and 66 (33.8%) females. The mean age was 27.01 A +- 6.92 years. Mean sputum neutrophilic count was 126.47 A +- 16.52 x 106/ml and the mean neutrophilic percentage was 63.187 A +- 8.3363. Sputum neutrophilia was present in 84 patients (43.1%), out of whom, 56 were males and 28 females. In patients with sputum neutrophilia, mean neutrophilic count was 142.40 A +- 8.49 x 106/ml and the mean neutrophilic percentage was 71.2024 A +- 4.2441%. Conclusion: Sputum neutrophilia is a frequent finding in cases with severe persistent bronchial asthma. Presence of sputum neutrophilia in such cases can lessen the inappropriate use of corticosteroids with their associated long-term side effects. (author)

  11. University Experiences and Women Engineering Student Persistence

    Science.gov (United States)

    Ayers, LoAnn Debra Gienger

    Riverside University (a pseudonym), like many universities, has not significantly increased the number of women who graduate with bachelor's degrees in engineering. The purpose of the study is to understand how the university experiences of women students influence the decision to persist in an undergraduate engineering degree and to understand the role of self-perception in how the students perceive experiences as supporting or hindering their persistence in the major. Archival data, documents and artifacts, observations, individual interviews, and a focus group with women engineering students provide insights into students' perceived barriers and supports of student success. Analysis of the data results in two major themes. First, students' self-confidence and self-efficacy influence how women assimilate university experiences as either supportive or diminishing of academic success. Second, university policies and practices shape the campus environment within which student experiences are formed and influence a student's level of institutional, academic, and social integration. The results of the study indicate opportunities for university leadership to enhance strategies that positively shape students' institutional, academic and social integration as precursors toward increasing the number of women students who successfully complete undergraduate engineering degrees at Riverside University. Future research is indicated to better understand how gender and gender identity intersects with other demographic factors, such as socio-economic status, immigration status, and life stage (e.g., traditional versus non-traditional students), to support or deter the persistence of engineering students to degree completion.

  12. Reoperation for persistent or recurrent secondary hyperparathyroidism.

    Science.gov (United States)

    Abruzzo, Alida; Gioviale, Maria Concetta; Damiano, Giuseppe; Palumbo, Vincenzo Davide; Buscemi, Salvatore; Lo Monte, Giulia; Gulotta, Leonardo; Buscemi, Giuseppe; Lo Monte, Attilio Ignazio

    2017-10-23

    Secondary hyperparathyroidism is a common acquired disorder seen in chronic renal failure. Its pathophysiology is mainly due to hyperphosphatemia and vitamin D deficiency and resistance. When medical treatment fails, subtotal and total parathyroidectomy with autotransplantation are the standard procedures, although both are associated with high recurrence rates. 4 patients experienced persistence and 9 relapse. The first 4 were subjected to reoperation after 6 months for the persistence of symptoms due to the finding of a supernumerary adenomatous gland while the remaining patients at the reoperation showed in 5 cases 2 more glands in over thymic position, and 4 an hyperplasia of the residual glandular tissue. A classic cervicotomy was sufficient to remove the residual parathyroid in patients with persistent hyperparathyroidism. For cases of recurrent hyperparathyroidism it was enough a medial approach and sometimes lateral for the complete excision of the hyperplastic tissue. The advent of the intraoperative technique of parathyroid hormone dosage allowed a better performance of the surgical technique for the last 3 patients undergoing reoperation. After reoperation all patients had immediate regression of clinical symptoms with normalization of serum calcium and PTH levels. On the basis of these considerations, diagnostic imaging has a not negligible role because during the first intervention helps to have an idea of the possible location of the glands and thus to avoid the risk of recurrence and relapse due to ectopic or supernumerary tissue.

  13. Adolescents' experience of complex persistent pain.

    Science.gov (United States)

    Sørensen, Kari; Christiansen, Bjørg

    2017-04-01

    Persistent (chronic) pain is a common phenomenon in adolescents. When young people are referred to a pain clinic, they usually have amplified pain signals, with pain syndromes of unconfirmed ethology, such as fibromyalgia and complex regional pain syndrome (CRPS). Pain is complex and seems to be related to a combination of illness, injury, psychological distress, and environmental factors. These young people are found to have higher levels of distress, anxiety, sleep disturbance, and lower mood than their peers and may be in danger of entering adulthood with mental and physical problems. In order to understand the complexity of persistent pain in adolescents, there seems to be a need for further qualitative research into their lived experiences. The aim of this study was to explore adolescents' experiences of complex persistent pain and its impact on everyday life. The study has an exploratory design with individual in-depth interviews with six youths aged 12-19, recruited from a pain clinic at a main referral hospital in Norway. A narrative approach allowed the informants to give voice to their experiences concerning complex persistent pain. A hermeneutic analysis was used, where the research question was the basis for a reflective interpretation. Three main themes were identified: (1) a life with pain and unpleasant bodily expressions; (2) an altered emotional wellbeing; and (3) the struggle to keep up with everyday life. The pain was experienced as extremely strong, emerging from a minor injury or without any obvious causation, and not always being recognised by healthcare providers. The pain intensity increased as the suffering got worse, and the sensation was hard to describe with words. Parts of their body could change in appearance, and some described having pain-attacks or fainting. The feeling of anxiety was strongly connected to the pain. Despair and uncertainty contributed to physical disability, major sleep problems, school absence, and withdrawal from

  14. Trustworthy persistent identifier systems of the future

    Science.gov (United States)

    Golodoniuc, Pavel; Klump, Jens; Car, Nicholas

    2016-04-01

    Over the last two decades, persistent identifier (PID) systems have seen some significant changes in their governance policies, system capabilities, and technology. The development of most systems was driven by two main application areas, namely archives and libraries. Guidelines and criteria for trustworthy PID systems have been clearly devised (Bütikofer, 2009) and many PID system implementations for the identification of static digital objects have been built (e.g., PURL). However systems delivering persistent identifiers for dynamic datasets are not yet mature. There has been a rapid proliferation of different PID systems caused by the specific technical or organisational requirements of various communities that could not be met by existing systems such as DOI, ISBN, and EAN. Many of these different systems were limited by their inability to provide native means of persistent identifier resolution. This has prompted a decoupling of PID-associated data from the resolution service and this is where the Handle system has played a significant role. The Handle allowed to build a distributed system of independently managed resolver services. A trustworthy PID system must be designed to outlive the objects it provides persistent identifiers for, which may cease to exist or otherwise be deprecated, and the technology used to implement it, which will certainly need to change with time. We propose that such a system should rest on four pillars of agreements - (i) definitions, (ii) policies, (iii) services, and (iv) data services, to ensure longevity. While we believe all four pillars are equally important, we intentionally leave regulating aspects of issuing of identifiers and their registration out of the scope of this paper and focus on the agreements that have to be established between PID resolver services and the data sources indicated by the persistent identifiers. We propose an approach to development of PID systems that combines the use of (a) the Handle system

  15. A Subtype of Inhibitory Interneuron with Intrinsic Persistent Activity in Human and Monkey Neocortex

    Directory of Open Access Journals (Sweden)

    Bo Wang

    2015-03-01

    Full Text Available A critical step in understanding the neural basis of human cognitive functions is to identify neuronal types in the neocortex. In this study, we performed whole-cell recording from human cortical slices and found a distinct subpopulation of neurons with intrinsic persistent activity that could be triggered by single action potentials (APs but terminated by bursts of APs. This persistent activity was associated with a depolarizing plateau potential induced by the activation of a persistent Na+ current. Single-cell RT-PCR revealed that these neurons were inhibitory interneurons. This type of neuron was found in different cortical regions, including temporal, frontal, occipital, and parietal cortices in human and also in frontal and temporal lobes of nonhuman primate but not in rat cortical tissues, suggesting that it could be unique to primates. The characteristic persistent activity in these inhibitory interneurons may contribute to the regulation of pyramidal cell activity and participate in cortical processing.

  16. Lidocaine Patch (5%) in Treatment of Persistent Inguinal Postherniorrhaphy Pain

    DEFF Research Database (Denmark)

    Bischoff, Joakim M; Petersen, Marian; Uçeyler, Nurcan

    2013-01-01

    Evidence-based pharmacological treatment options for patients with persistent inguinal postherniorrhaphy pain are lacking.......Evidence-based pharmacological treatment options for patients with persistent inguinal postherniorrhaphy pain are lacking....

  17. Factors associated with persistent airflow limitation in severe asthma

    NARCIS (Netherlands)

    ten Brinke, A.; Zwinderman, A. H.; Sterk, P. J.; Rabe, K. F.; Bel, E. H.

    2001-01-01

    Persistent airflow limitation can develop in nonsmoking patients with asthma. However, the prevalence and risk factors for airways obstruction with incomplete reversibility in asthma are unknown. We assessed the prevalence of persistent airflow limitation (defined as postbronchodilator FEV(1) or

  18. A minimally invasive option for the treatment of persistent ...

    African Journals Online (AJOL)

    . Hospital, King Saud ... We present two patients with persistent esophageal leak after compli- .... easy, and quite effective in the management of persistent ... 6 Rakocz M, Mazar A, Varon D, Spierer S, Blinder D, Martinowitz U. Dental extractions ...

  19. A digital variable persistence oscilloscope for gamma cameras

    International Nuclear Information System (INIS)

    Fenwick, J.D.; Thompson, A.

    1981-01-01

    The system briefly described is intended as a direct replacement for the analogue persistence oscilloscope, particularly in systems without a computer processor. It uses digital and video techniques to produce an image quality suitable for use in positioning patients under the camera at a low cost (total cost of materials used, Pound500). The performance is superior to the analogue oscilloscope in that the image is displayed with 16 shades of grey. It incorporates an automatic brightness control which ensures that the image does not saturate at high count density, and the saturation can be changed manually allowing areas of low counts to be examined in the presence of high counts. The digital inability to store each single event as a dot which fades exponentially with time has been solved by adding each event into the appropriate cell of a digital display matrix, and then periodically dividing the contents of each image cell by two. The cells are addressed and divided in a pseudo-random pattern so that, to the observer, the whole image appears to fade smoothly and evenly. (U.K.)

  20. Human macrophages support persistent transcription from unintegrated HIV-1 DNA

    International Nuclear Information System (INIS)

    Kelly, Jeremy; Beddall, Margaret H.; Yu Dongyang; Iyer, Subashini R.; Marsh, Jon W.; Wu Yuntao

    2008-01-01

    Retroviruses require integration of their RNA genomes for both stability and productive viral replication. In HIV infection of non-dividing, resting CD4 T cells, where integration is greatly impeded, the reverse transcribed HIV DNA has limited biological activity and a short half-life. In metabolically active and proliferating T cells, unintegrated DNA rapidly diminishes with cell division. HIV also infects the non-dividing but metabolically active macrophage population. In an in vitro examination of HIV infection of macrophages, we find that unintegrated viral DNA not only has an unusual stability, but also maintains biological activity. The unintegrated linear DNA, 1-LTR, and 2-LTR circles are stable for at least 30 days. Additionally, there is persistent viral gene transcription, which is selective and skewed towards viral early genes such as nef and tat with highly diminished rev and vif. One viral early gene product Nef was measurably synthesized. We also find that independent of integration, the HIV infection process in macrophages leads to generation of numerous chemokines

  1. Prediction of antibody persistency from antibody titres to natalizumab

    DEFF Research Database (Denmark)

    Jensen, Poul Erik H; Koch-Henriksen, Nils; Sellebjerg, Finn

    2012-01-01

    In a subgroup of patients with multiple sclerosis natalizumab therapy causes generation of anti-natalizumab antibodies that may be transient or persistent. It is recommended to discontinue natalizumab therapy in persistently antibody-positive patients.......In a subgroup of patients with multiple sclerosis natalizumab therapy causes generation of anti-natalizumab antibodies that may be transient or persistent. It is recommended to discontinue natalizumab therapy in persistently antibody-positive patients....

  2. Mannitol enhances antibiotic sensitivity of persister bacteria in Pseudomonas aeruginosa biofilms.

    Directory of Open Access Journals (Sweden)

    Nicolas Barraud

    Full Text Available The failure of antibiotic therapies to clear Pseudomonas aeruginosa lung infection, the key mortality factor for cystic fibrosis (CF patients, is partly attributed to the high tolerance of P. aeruginosa biofilms. Mannitol has previously been found to restore aminoglycoside sensitivity in Escherichia coli by generating a proton-motive force (PMF, suggesting a potential new strategy to improve antibiotic therapy and reduce disease progression in CF. Here, we used the commonly prescribed aminoglycoside tobramycin to select for P. aeruginosa persister cells during biofilm growth. Incubation with mannitol (10-40 mM increased tobramycin sensitivity of persister cells up to 1,000-fold. Addition of mannitol to pre-grown biofilms was able to revert the persister phenotype and improve the efficacy of tobramycin. This effect was blocked by the addition of a PMF inhibitor or in a P. aeruginosa mutant strain unable to metabolise mannitol. Addition of glucose and NaCl at high osmolarity also improved the efficacy of tobramycin although to a lesser extent compared to mannitol. Therefore, the primary effect of mannitol in reverting biofilm associated persister cells appears to be an active, physiological response, associated with a minor contribution of osmotic stress. Mannitol was tested against clinically relevant strains, showing that biofilms containing a subpopulation of persister cells are better killed in the presence of mannitol, but a clinical strain with a high resistance to tobramycin was not affected by mannitol. Overall, these results suggest that in addition to improvements in lung function by facilitating mucus clearance in CF, mannitol also affects antibiotic sensitivity in biofilms and does so through an active, physiological response.

  3. Persistent discharges in dentate gyrus perisoma-inhibiting interneurons require hyperpolarization-activated cyclic nucleotide-gated channel activation.

    Science.gov (United States)

    Elgueta, Claudio; Köhler, Johannes; Bartos, Marlene

    2015-03-11

    Parvalbumin (PV)-expressing perisoma-inhibiting interneurons (PIIs) of the dentate gyrus integrate rapidly correlated synaptic inputs and generate short-duration action potentials that propagate along the axon to their output synapses, supporting fast inhibitory signaling onto their target cells. Here we show that PV-PIIs in rat and mouse dentate gyrus (DG) integrate their intrinsic activity over time and can turn into a persistent firing mode characterized by the ability to generate long-lasting trains of action potentials at ∼50 Hz in the absence of additional inputs. Persistent firing emerges in the axons remote from the axon initial segment and markedly depends on hyperpolarization-activated cyclic nucleotide-gated channel (HCNC) activation. Persistent firing properties are modulated by intracellular Ca(2+) levels and somatic membrane potential. Detailed computational single-cell PIIs models reveal that HCNC-mediated conductances can contribute to persistent firing during conditions of a shift in their voltage activation curve to more depolarized potentials. Paired recordings from PIIs and their target granule cells show that persistent firing supports strong inhibitory output signaling. Thus, persistent firing may emerge during conditions of intense activation of the network, thereby providing silencing to the circuitry and the maintenance of sparse activity in the dentate gyrus. Copyright © 2015 the authors 0270-6474/15/354131-09$15.00/0.

  4. Thoracoscopic pericardial fenestration for persistent pericardial effusion after radiotherapy for esophageal cancer. Report of a case

    Energy Technology Data Exchange (ETDEWEB)

    Sakamoto, Kazuhiro; Tsuchida, Kazuhito; Ariga, Takamitsu [Yokohama Rosai Hospital (Japan)

    2002-11-01

    We performed thoracoscopic pericardial fenestration for persistent pericardial effusion after radiotherapy for esophageal cancer. An 85-year-old man who had radiation therapy (70.2 Gy) for esophageal cancer was admitted for shortness of breath. Chest computed tomography showed a pericardial effusion. During the 6 months prior to this admission, the patient had undergone percutaneous pericardial drainage 3 times for cardiac tamponade. We performed thoracoscopic partial pericardiectomy with creation of a pleuropericardial window via one access port. Histopathologically, no malignant cells were found in either the resected pericardium or the pericardial effusion. Therefore, we believe the persistent pericardial effusion was secondary to radiotherapy. There was no recurrence of the pericardial effusion for 7 months postoperatively. In summary, thoracoscopic pericardial fenestration is useful in both the diagnosis and treatment of persistent pericardial effusion. (author)

  5. BEAM-BASED MEASUREMENTS OF PERSISTENT CURRENT DECAY IN RHIC

    International Nuclear Information System (INIS)

    FISCHER, W.; JAIN, A.; TEPIKIAN, S.

    2001-01-01

    The two RHIC rings are equipped with superconducting dipole magnets. At injection, induced persistent currents in these magnets lead to a sextupole component. As the persistent currents decay with time, the horizontal and vertical chromaticities change. From magnet measurements of persistent current decays, chromaticity changes in the machine are estimated and compared with chromaticity measurements

  6. Persistent Structural Priming from Language Comprehension to Language Production

    Science.gov (United States)

    Bock, Kathryn; Dell, Gary S.; Chang, Franklin; Onishi, Kristine H.

    2007-01-01

    To examine the relationship between syntactic processes in language comprehension and language production, we compared structural persistence from sentence primes that speakers heard to persistence from primes that speakers produced. [Bock, J. K., & Griffin, Z. M. (2000). The persistence of structural priming: transient activation or implicit…

  7. Bacterial persistence: some new insights into an old phenomenon

    Indian Academy of Sciences (India)

    PRAKASH KUMAR

    the involvement of the alarmone (p) ppGpp in the generation of persisters. However, the precise mechanisms are ... Bigger noticed that treatment of cultures of Staphylococcus aureus with high concentrations of ...... Li Y and Zhang Y 2007 pho U is a persister switch involved in persister formation and tolerance to multiple ...

  8. Volatility persistence in crude oil markets

    International Nuclear Information System (INIS)

    Charles, Amélie; Darné, Olivier

    2014-01-01

    Financial market participants and policy-makers can benefit from a better understanding of how shocks can affect volatility over time. This study assesses the impact of structural changes and outliers on volatility persistence of three crude oil markets – Brent, West Texas Intermediate (WTI) and Organization of Petroleum Exporting Countries (OPEC) – between January 2, 1985 and June 17, 2011. We identify outliers using a new semi-parametric test based on conditional heteroscedasticity models. These large shocks can be associated with particular event patterns, such as the invasion of Kuwait by Iraq, the Operation Desert Storm, the Operation Desert Fox, and the Global Financial Crisis as well as OPEC announcements on production reduction or US announcements on crude inventories. We show that outliers can bias (i) the estimates of the parameters of the equation governing volatility dynamics; (ii) the regularity and non-negativity conditions of GARCH-type models (GARCH, IGARCH, FIGARCH and HYGARCH); and (iii) the detection of structural breaks in volatility, and thus the estimation of the persistence of the volatility. Therefore, taking into account the outliers on the volatility modelling process may improve the understanding of volatility in crude oil markets. - Highlights: • We study the impact of outliers on volatility persistence of crude oil markets. • We identify outliers and patches of outliers due to specific events. • We show that outliers can bias (i) the estimates of the parameters of GARCH models, (ii) the regularity and non-negativity conditions of GARCH-type models, (iii) the detection of structural breaks in volatility of crude oil markets

  9. MR imaging of persistent primitive trigeminal artery

    International Nuclear Information System (INIS)

    Ashikaga, Ryuichiro; Araki, Yutaka; Ono, Yukihiko; Ishida, Osamu; Mabuchi, Nobuhisa.

    1997-01-01

    The persistent trigeminal artery is the most common anomaly of the primitive carotid-vertebrobasilar anastomoses. We reviewed MR images and MR angiographies of 11 patients with primitive trigeminal artery. In 8 of the 11 cases, PTA were identified with conventional long TR spin-echo images. In 8 of 11 cases, a hypoplastic basilar trunk associated with PTA was seen on both MR images and MR angiographies. In 7 of 11 cases, a hypoplasia or agenesis of the ipsilateral posterior communicating artery was seen on MR angiographies. (author)

  10. Calculation of persistent currents in superconducting magnets

    Directory of Open Access Journals (Sweden)

    C. Völlinger

    2000-12-01

    Full Text Available This paper describes a semianalytical hysteresis model for hard superconductors. The model is based on the critical state model considering the dependency of the critical current density on the varying local field in the superconducting filaments. By combining this hysteresis model with numerical field computation methods, it is possible to calculate the persistent current multipole errors in the magnet taking local saturation effects in the magnetic iron parts into consideration. As an application of the method, the use of soft magnetic iron sheets (coil protection sheets mounted between the coils and the collars for partial compensation of the multipole errors during the ramping of the magnets is investigated.

  11. Trust and persistence for Internet resources

    Directory of Open Access Journals (Sweden)

    Maurizio Lunghi

    2013-01-01

    Full Text Available Internet has changed our way of working, communicating, living, producing and accessing information, everything available on an open and flexible infrastructure accessible to all the users mainly free of cost. However in some cases, it’s not only important to find information but also having information about its authenticity, integrity, provenance and relations with other pieces of information. Systems for certification using URN technology like the persistent identifiers for digital objects, for authors and for bodies can extremely help in order to refine the quality of information retrievable from Internet and to increase largely its usability and potential development.

  12. Persistently increased intestinal fraction of alkaline phosphatase

    DEFF Research Database (Denmark)

    Nathan, E; Baatrup, G; Berg, H

    1984-01-01

    Persistent elevation of the intestinal fraction of the alkaline phosphatase (API) as an isolated finding has to our knowledge not been reported previously. It was found in a boy followed during a period of 5.5 years. The only symptom was transient periodic fatigue observed at home, but not apparent...... during hospitalization. His blood type was O, RH+, Le (a-, b+) and he was a secretor of H-substance, which may be associated with rising API activity after fat-loading. In this case API was unchanged after fat-loading. Neither intestinal nor liver diseases were found, and no other cause for the elevated...

  13. Distributed design approach in persistent identifiers systems

    Science.gov (United States)

    Golodoniuc, Pavel; Car, Nicholas; Klump, Jens

    2017-04-01

    The need to identify both digital and physical objects is ubiquitous in our society. Past and present persistent identifier (PID) systems, of which there is a great variety in terms of technical and social implementations, have evolved with the advent of the Internet, which has allowed for globally unique and globally resolvable identifiers. PID systems have catered for identifier uniqueness, integrity, persistence, and trustworthiness, regardless of the identifier's application domain, the scope of which has expanded significantly in the past two decades. Since many PID systems have been largely conceived and developed by small communities, or even a single organisation, they have faced challenges in gaining widespread adoption and, most importantly, the ability to survive change of technology. This has left a legacy of identifiers that still exist and are being used but which have lost their resolution service. We believe that one of the causes of once successful PID systems fading is their reliance on a centralised technical infrastructure or a governing authority. Golodoniuc et al. (2016) proposed an approach to the development of PID systems that combines the use of (a) the Handle system, as a distributed system for the registration and first-degree resolution of persistent identifiers, and (b) the PID Service (Golodoniuc et al., 2015), to enable fine-grained resolution to different information object representations. The proposed approach solved the problem of guaranteed first-degree resolution of identifiers, but left fine-grained resolution and information delivery under the control of a single authoritative source, posing risk to the long-term availability of information resources. Herein, we develop these approaches further and explore the potential of large-scale decentralisation at all levels: (i) persistent identifiers and information resources registration; (ii) identifier resolution; and (iii) data delivery. To achieve large-scale decentralisation

  14. Persistence of innovation in unstable environments

    DEFF Research Database (Denmark)

    Suarez, Diana Valeria

    2014-01-01

    of the environment impact on the type of profitable innovations, and past innovations might not be suitable for the new environment. As a result, firm's innovative behavior might change, which means that the firm's set of decisions about engaging in the seek for innovations or not and, if so, the set of investments...... during 1998-2006, which coincides with a period of macroeconomic instability. Results suggest that persistence has to be analyzed in terms of a dynamic firm's innovative behavior - regardless of its results - and how it allows the firm to accumulate competences and resources, which increases the odds...... of successfully responding to changes in the environment and continuing to innovate....

  15. Grails Persistence with GORM and GSQL

    CERN Document Server

    Fischer, Robert

    2009-01-01

    Unique to the popular Grails web framework is its architecture. While other frameworks are built from the ground up, Grails leverages existing and proven technologies that already have advanced functionality built in. One of the key technologies in this architecture is Hibernate, on top of which Grails builds its GORM (Grails Object Relational Mapping) model layer. This provides Grails a persistence solution. Published with the developer in mind, firstPress technical briefs explore emerging technologies that have the potential to be critical for tomorrow's industry. Apress keeps developers one

  16. Neonatal thyrotoxicosis presenting as persistent pulmonary hypertension

    Science.gov (United States)

    Obeid, Rawad; Kalra, Vaneet Kumar; Arora, Prem; Quist, Felix; Moltz, Kathleen C; Chouthai, Nitin Shashikant

    2012-01-01

    Neonatal hyperthyroidism is a rare condition caused either by transplacental passage of thyroid-stimulating immunoglobulins from a mother with Graves’ disease or by activating mutations of the thyrotropin receptors and α-subunit of G-protein. The clinical features may vary. We report a case of neonatal thyrotoxicosis in an infant born to a mother with Graves’ disease, who presented with cardiorespiratory failure and persistent pulmonary hypertension (PPHN). PPHN resolved with specific antithyroid treatment and extracorporeal membrane oxygenation was not required. PMID:22669869

  17. Gravity in one dimension - Persistence of correlation

    International Nuclear Information System (INIS)

    Miller, B.N.; Reidl, C.J. Jr.

    1990-01-01

    Central questions are concerning the thermalization time-scale in a one-dimensional, self-gravitating system are addressed in the present consideration of the persistent correlation between the positions and velocities of the mass-sheets. An algorithm developed for testing thermalization in the one-dimensional gravitating system was applied to the logistic map as a control; the parameter value associated with global chaos yields complete agreement with theoretical prediction. The implications of these results for gravitational interaction in higher dimension should be considered. 26 refs

  18. Explaining evolution via constrained persistent perfect phylogeny

    Science.gov (United States)

    2014-01-01

    Background The perfect phylogeny is an often used model in phylogenetics since it provides an efficient basic procedure for representing the evolution of genomic binary characters in several frameworks, such as for example in haplotype inference. The model, which is conceptually the simplest, is based on the infinite sites assumption, that is no character can mutate more than once in the whole tree. A main open problem regarding the model is finding generalizations that retain the computational tractability of the original model but are more flexible in modeling biological data when the infinite site assumption is violated because of e.g. back mutations. A special case of back mutations that has been considered in the study of the evolution of protein domains (where a domain is acquired and then lost) is persistency, that is the fact that a character is allowed to return back to the ancestral state. In this model characters can be gained and lost at most once. In this paper we consider the computational problem of explaining binary data by the Persistent Perfect Phylogeny model (referred as PPP) and for this purpose we investigate the problem of reconstructing an evolution where some constraints are imposed on the paths of the tree. Results We define a natural generalization of the PPP problem obtained by requiring that for some pairs (character, species), neither the species nor any of its ancestors can have the character. In other words, some characters cannot be persistent for some species. This new problem is called Constrained PPP (CPPP). Based on a graph formulation of the CPPP problem, we are able to provide a polynomial time solution for the CPPP problem for matrices whose conflict graph has no edges. Using this result, we develop a parameterized algorithm for solving the CPPP problem where the parameter is the number of characters. Conclusions A preliminary experimental analysis shows that the constrained persistent perfect phylogeny model allows to

  19. Gate-controlled switching between persistent and inverse persistent spin helix states

    International Nuclear Information System (INIS)

    Yoshizumi, K.; Sasaki, A.; Kohda, M.; Nitta, J.

    2016-01-01

    We demonstrate gate-controlled switching between persistent spin helix (PSH) state and inverse PSH state, which are detected by quantum interference effect on magneto-conductance. These special symmetric spin states showing weak localization effect give rise to a long spin coherence when the strength of Rashba spin-orbit interaction (SOI) is close to that of Dresselhaus SOI. Furthermore, in the middle of two persistent spin helix states, where the Rashba SOI can be negligible, the bulk Dresselhaus SOI parameter in a modulation doped InGaAs/InAlAs quantum well is determined.

  20. Gate-controlled switching between persistent and inverse persistent spin helix states

    Energy Technology Data Exchange (ETDEWEB)

    Yoshizumi, K.; Sasaki, A.; Kohda, M.; Nitta, J. [Department of Materials Science, Tohoku University, Sendai 980-8579 (Japan)

    2016-03-28

    We demonstrate gate-controlled switching between persistent spin helix (PSH) state and inverse PSH state, which are detected by quantum interference effect on magneto-conductance. These special symmetric spin states showing weak localization effect give rise to a long spin coherence when the strength of Rashba spin-orbit interaction (SOI) is close to that of Dresselhaus SOI. Furthermore, in the middle of two persistent spin helix states, where the Rashba SOI can be negligible, the bulk Dresselhaus SOI parameter in a modulation doped InGaAs/InAlAs quantum well is determined.

  1. Twitter web-service for soft agent reporting in persistent surveillance systems

    Science.gov (United States)

    Rababaah, Haroun; Shirkhodaie, Amir

    2010-04-01

    Persistent surveillance is an intricate process requiring monitoring, gathering, processing, tracking, and characterization of many spatiotemporal events occurring concurrently. Data associated with events can be readily attained by networking of hard (physical) sensors. Sensors may have homogeneous or heterogeneous (hybrid) sensing modalities with different communication bandwidth requirements. Complimentary to hard sensors are human observers or "soft sensors" that can report occurrences of evolving events via different communication devices (e.g., texting, cell phones, emails, instant messaging, etc.) to the command control center. However, networking of human observers in ad-hoc way is rather a difficult task. In this paper, we present a Twitter web-service for soft agent reporting in persistent surveillance systems (called Web-STARS). The objective of this web-service is to aggregate multi-source human observations in hybrid sensor networks rapidly. With availability of Twitter social network, such a human networking concept can not only be realized for large scale persistent surveillance systems (PSS), but also, it can be employed with proper interfaces to expedite rapid events reporting by human observers. The proposed technique is particularly suitable for large-scale persistent surveillance systems with distributed soft and hard sensor networks. The efficiency and effectiveness of the proposed technique is measured experimentally by conducting several simulated persistent surveillance scenarios. It is demonstrated that by fusion of information from hard and soft agents improves understanding of common operating picture and enhances situational awareness.

  2. Two regulatory RNA elements affect TisB-dependent depolarization and persister formation.

    Science.gov (United States)

    Berghoff, Bork A; Hoekzema, Mirthe; Aulbach, Lena; Wagner, E Gerhart H

    2017-03-01

    Bacterial survival strategies involve phenotypic diversity which is generated by regulatory factors and noisy expression of effector proteins. The question of how bacteria exploit regulatory RNAs to make decisions between phenotypes is central to a general understanding of these universal regulators. We investigated the TisB/IstR-1 toxin-antitoxin system of Escherichia coli to appreciate the role of the RNA antitoxin IstR-1 in TisB-dependent depolarization of the inner membrane and persister formation. Persisters are phenotypic variants that have become transiently drug-tolerant by arresting growth. The RNA antitoxin IstR-1 sets a threshold for TisB-dependent depolarization under DNA-damaging conditions, resulting in two sub-populations: polarized and depolarized cells. Furthermore, our data indicate that an inhibitory 5' UTR structure in the tisB mRNA serves as a regulatory RNA element that delays TisB translation to avoid inappropriate depolarization when DNA damage is low. Investigation of the persister sub-population further revealed that both regulatory RNA elements affect persister levels as well as persistence time. This work provides an intriguing example of how bacteria exploit regulatory RNAs to control phenotypic heterogeneity. © 2016 John Wiley & Sons Ltd.

  3. PERSISTENT ORGANIC POLLUTANS (POPS DAN KONVENSI STOCKHOLM

    Directory of Open Access Journals (Sweden)

    Lina Warlina

    2010-07-01

    Full Text Available Persistent organic pollutants (POPs are toxic chemicals that adversely affect human health and the environment around the world. Because they can be transported by wind and water, most POPs generated in one country can affect people and wildlife far from where they are used and released. They persist for long periods of time in the environment and can accumulate and pass from one species to the next through the food chain. To address this global concern, many countries in the world joined forces with 90 other countries and the European Community to sign a groundbreaking United Nations treaty in Stockholm, Sweden, in May 2001, known as the Stockholm Convention. One of important agreement is all countries agreed to reduce or eliminate the production, use, and/or release of 12 key POPs. The Convention specifies a scientific review process that could lead to the addition of other POPs chemicals of global concern. POPs include a range of substances that include intentionally produced chemicals currently or once used in agriculture, disease control, manufacturing, or industrial processes. Also it can be produced by unintentionally produced chemicals, such as dioxins, that result from some industrial processes and from combustion (for example, municipal and medical waste incineration and backyard burning of trash.

  4. Cosmic radiation exposure and persistent cognitive dysfunction

    Science.gov (United States)

    Parihar, Vipan K.; Allen, Barrett D.; Caressi, Chongshan; Kwok, Stephanie; Chu, Esther; Tran, Katherine K.; Chmielewski, Nicole N.; Giedzinski, Erich; Acharya, Munjal M.; Britten, Richard A.; Baulch, Janet E.; Limoli, Charles L.

    2016-01-01

    The Mars mission will result in an inevitable exposure to cosmic radiation that has been shown to cause cognitive impairments in rodent models, and possibly in astronauts engaged in deep space travel. Of particular concern is the potential for cosmic radiation exposure to compromise critical decision making during normal operations or under emergency conditions in deep space. Rodents exposed to cosmic radiation exhibit persistent hippocampal and cortical based performance decrements using six independent behavioral tasks administered between separate cohorts 12 and 24 weeks after irradiation. Radiation-induced impairments in spatial, episodic and recognition memory were temporally coincident with deficits in executive function and reduced rates of fear extinction and elevated anxiety. Irradiation caused significant reductions in dendritic complexity, spine density and altered spine morphology along medial prefrontal cortical neurons known to mediate neurotransmission interrogated by our behavioral tasks. Cosmic radiation also disrupted synaptic integrity and increased neuroinflammation that persisted more than 6 months after exposure. Behavioral deficits for individual animals correlated significantly with reduced spine density and increased synaptic puncta, providing quantitative measures of risk for developing cognitive impairment. Our data provide additional evidence that deep space travel poses a real and unique threat to the integrity of neural circuits in the brain. PMID:27721383

  5. PERSISTENCE MAPPING USING EUV SOLAR IMAGER DATA

    Energy Technology Data Exchange (ETDEWEB)

    Thompson, B. J. [NASA Goddard Space Flight Center, Code 671, Greenbelt, MD 20771 (United States); Young, C. A., E-mail: barbara.j.thompson@nasa.gov [NASA Goddard Space Flight Center, Code 670, Greenbelt, MD 20771 (United States)

    2016-07-01

    We describe a simple image processing technique that is useful for the visualization and depiction of gradually evolving or intermittent structures in solar physics extreme-ultraviolet imagery. The technique is an application of image segmentation, which we call “Persistence Mapping,” to isolate extreme values in a data set, and is particularly useful for the problem of capturing phenomena that are evolving in both space and time. While integration or “time-lapse” imaging uses the full sample (of size N ), Persistence Mapping rejects ( N − 1)/ N of the data set and identifies the most relevant 1/ N values using the following rule: if a pixel reaches an extreme value, it retains that value until that value is exceeded. The simplest examples isolate minima and maxima, but any quantile or statistic can be used. This paper demonstrates how the technique has been used to extract the dynamics in long-term evolution of comet tails, erupting material, and EUV dimming regions.

  6. Persistence of Women in Online Degree-Completion Programs

    Directory of Open Access Journals (Sweden)

    Terry Müller

    2008-06-01

    Full Text Available Although online courses at postsecondary institutions promise adults access, flexibility, and convenience, many barriers to online learning remain. This article presents findings from a qualitative case study, which explored the phenomenon of undergraduate and graduate women learners’ persistence in online degree-completion programs at a college in the Northeast of the United States. Research questions asked why women learners persisted or failed to persist, and how factors supporting or hindering persistence influenced learners. Interviews with a purposeful sample of 20 participants revealed the complexity of variables affecting learners’ persistence to graduation. Findings suggested that multiple responsibilities, insufficient interaction with faculty, technology, and coursework ranked highest as barriers to women’s persistence. Strong motivation to complete degrees, engagement in the learning community, and appreciation for the convenience of an online degree-completion option facilitated persistence.

  7. Spatial patterns of persistent neural activity vary with the behavioral context of short-term memory.

    Science.gov (United States)

    Daie, Kayvon; Goldman, Mark S; Aksay, Emre R F

    2015-02-18

    A short-term memory can be evoked by different inputs and control separate targets in different behavioral contexts. To address the circuit mechanisms underlying context-dependent memory function, we determined through optical imaging how memory is encoded at the whole-network level in two behavioral settings. Persistent neural activity maintaining a memory of desired eye position was imaged throughout the oculomotor integrator after saccadic or optokinetic stimulation. While eye position was encoded by the amplitude of network activity, the spatial patterns of firing were context dependent: cells located caudally generally were most persistent following saccadic input, whereas cells located rostrally were most persistent following optokinetic input. To explain these data, we computationally identified four independent modes of network activity and found these were differentially accessed by saccadic and optokinetic inputs. These results show how a circuit can simultaneously encode memory value and behavioral context, respectively, in its amplitude and spatial pattern of persistent firing. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Modeling the Mechanisms by Which HIV-Associated Immunosuppression Influences HPV Persistence at the Oral Mucosa.

    Science.gov (United States)

    Verma, Meghna; Erwin, Samantha; Abedi, Vida; Hontecillas, Raquel; Hoops, Stefan; Leber, Andrew; Bassaganya-Riera, Josep; Ciupe, Stanca M

    2017-01-01

    Human immunodeficiency virus (HIV)-infected patients are at an increased risk of co-infection with human papilloma virus (HPV), and subsequent malignancies such as oral cancer. To determine the role of HIV-associated immune suppression on HPV persistence and pathogenesis, and to investigate the mechanisms underlying the modulation of HPV infection and oral cancer by HIV, we developed a mathematical model of HIV/HPV co-infection. Our model captures known immunological and molecular features such as impaired HPV-specific effector T helper 1 (Th1) cell responses, and enhanced HPV infection due to HIV. We used the model to determine HPV prognosis in the presence of HIV infection, and identified conditions under which HIV infection alters HPV persistence in the oral mucosa system. The model predicts that conditions leading to HPV persistence during HIV/HPV co-infection are the permissive immune environment created by HIV and molecular interactions between the two viruses. The model also determines when HPV infection continues to persist in the short run in a co-infected patient undergoing antiretroviral therapy. Lastly, the model predicts that, under efficacious antiretroviral treatment, HPV infections will decrease in the long run due to the restoration of CD4+ T cell numbers and protective immune responses.

  9. Modeling the Mechanisms by Which HIV-Associated Immunosuppression Influences HPV Persistence at the Oral Mucosa.

    Directory of Open Access Journals (Sweden)

    Meghna Verma

    Full Text Available Human immunodeficiency virus (HIV-infected patients are at an increased risk of co-infection with human papilloma virus (HPV, and subsequent malignancies such as oral cancer. To determine the role of HIV-associated immune suppression on HPV persistence and pathogenesis, and to investigate the mechanisms underlying the modulation of HPV infection and oral cancer by HIV, we developed a mathematical model of HIV/HPV co-infection. Our model captures known immunological and molecular features such as impaired HPV-specific effector T helper 1 (Th1 cell responses, and enhanced HPV infection due to HIV. We used the model to determine HPV prognosis in the presence of HIV infection, and identified conditions under which HIV infection alters HPV persistence in the oral mucosa system. The model predicts that conditions leading to HPV persistence during HIV/HPV co-infection are the permissive immune environment created by HIV and molecular interactions between the two viruses. The model also determines when HPV infection continues to persist in the short run in a co-infected patient undergoing antiretroviral therapy. Lastly, the model predicts that, under efficacious antiretroviral treatment, HPV infections will decrease in the long run due to the restoration of CD4+ T cell numbers and protective immune responses.

  10. Severe Tryptophan Starvation Blocks Onset of Conventional Persistence and Reduces Reactivation of Chlamydia trachomatis▿

    Science.gov (United States)

    Leonhardt, Ralf M.; Lee, Seung-Joon; Kavathas, Paula B.; Cresswell, Peter

    2007-01-01

    The intracellular survival of the bacterial pathogen Chlamydia trachomatis depends on protein synthesis by the microbe soon after internalization. Pharmacologic inhibition of bacterial translation inhibits early trafficking of the parasitophorous vacuole (inclusion) to the microtubule-organizing center (MTOC) and promotes its fusion with lysosomes, which is normally blocked by Chlamydia. Depletion of cellular tryptophan pools by gamma interferon-inducible indoleamine-2,3-dioxygenase (IDO) is believed to be the major innate immune mechanism controlling C. trachomatis infection in human cells, an action to which the bacteria can respond by converting into a nonreplicating but highly reactivatable persistent state. However, whether severe IDO-mediated tryptophan starvation can be sufficient to fully arrest the chlamydial life cycle and thereby counteract the onset of persistence is unknown. Here we demonstrate that at low exogenous tryptophan concentrations a substantial fraction of C. trachomatis bacteria fail to traffic to the MTOC or to switch into the conventional persistent state in gamma interferon-induced human cells. The organisms stay scattered in the cell periphery, do not retain infectivity, and display only low transcriptional activity. Importantly, the rate at which these aberrant Chlamydia bacteria become reactivated upon replenishment of cellular tryptophan pools is substantially lower. Thus, severe tryptophan depletion in cells with high IDO activity affects chlamydial development more rigorously than previously described. PMID:17724071

  11. Persistent Thalamic Sound Processing Despite Profound Cochlear Denervation

    Directory of Open Access Journals (Sweden)

    Anna R. Chambers

    2016-08-01

    Full Text Available Neurons at higher stages of sensory processing can partially compensate for a sudden drop in input from the periphery through a homeostatic plasticity process that increases the gain on weak afferent inputs. Even after a profound unilateral auditory neuropathy where > 95% of synapses between auditory nerve fibers and inner hair cells have been eliminated with ouabain, central gain can restore the cortical processing and perceptual detection of basic sounds delivered to the denervated ear. In this model of profound auditory neuropathy, cortical processing and perception recover despite the absence of an auditory brainstem response (ABR or brainstem acoustic reflexes, and only a partial recovery of sound processing at the level of the inferior colliculus (IC, an auditory midbrain nucleus. In this study, we induced a profound cochlear neuropathy with ouabain and asked whether central gain enabled a compensatory plasticity in the auditory thalamus comparable to the full recovery of function previously observed in the auditory cortex (ACtx, the partial recovery observed in the IC, or something different entirely. Unilateral ouabain treatment in adult mice effectively eliminated the ABR, yet robust sound-evoked activity persisted in a minority of units recorded from the contralateral medial geniculate body (MGB of awake mice. Sound-driven MGB units could decode moderate and high-intensity sounds with accuracies comparable to sham-treated control mice, but low-intensity classification was near chance. Pure tone receptive fields and synchronization to broadband pulse trains also persisted, albeit with significantly reduced quality and precision, respectively. MGB decoding of temporally modulated pulse trains and speech tokens were both greatly impaired in ouabain-treated mice. Taken together, the absence of an ABR belied a persistent auditory processing at the level of the MGB that was likely enabled through increased central gain. Compensatory

  12. Swimming and Persons with Mild Persistant Asthma

    Directory of Open Access Journals (Sweden)

    Mirjana Arandelovic

    2007-01-01

    Full Text Available The aim of our study was to analyze the effect of recreational swimming on lung function and bronchial hyperresponsiveness (BHR in patients with mild persistent asthma. This study included 65 patients with mild persistent asthma, who were divided into two groups: experimental group A (n = 45 and control group B (n = 20. Patients from both groups were treated with low doses of inhaled corticosteroids (ICS and short-acting β2 agonists salbutamol as needed. Our program for patients in group A was combined asthma education with swimming (twice a week on a 1-h basis for the following 6 months. At the end of the study, in Group A, we found a statistically significant increase of lung function parameters FEV1 (forced expiratory volume in 1 sec (3.55 vs. 3.65 (p < 0.01, FVC (forced vital capacity (4.27 vs. 4.37 (p < 0.05, PEF (peak expiratory flow (7.08 vs. 7.46 (p < 0.01, and statistically significant decrease of BHR (PD20 0.58 vs. 2.01 (p < 0.001. In Group B, there was a statistically significant improvement of FEV1 3.29 vs. 3.33 (p < 0.05 and although FVC, FEV1/FVC, and PEF were improved, it was not significant. When Groups A and B were compared at the end of the study, there was a statistically significant difference of FVC (4.01 vs. 4.37, FEV1 (3.33 vs. 3.55, PEF (6.79 vs.7.46, and variability (p <0.001, and statistically significantly decreased BHR in Group A (2.01 vs. 1.75 (p < 0.001. Engagement of patients with mild persistent asthma in recreational swimming in nonchlorinated pools, combined with regular medical treatment and education, leads to better improvement of their parameters of lung function and also to more significant decrease of their airway hyperresponsiveness compared to patients treated with traditional medicine

  13. Persistent Identifiers, Discoverability and Open Science (Communication)

    Science.gov (United States)

    Murphy, Fiona; Lehnert, Kerstin; Hanson, Brooks

    2016-04-01

    Early in 2016, the American Geophysical Union announced it was incorporating ORCIDs into its submission workflows. This was accompanied by a strong statement supporting the use of other persistent identifiers - such as IGSNs, and the CrossRef open registry 'funding data'. This was partly in response to funders' desire to track and manage their outputs. However the more compelling argument, and the reason why the AGU has also signed up to the Center for Open Science's Transparency and Openness Promotion (TOP) Guidelines (http://cos.io/top), is that ultimately science and scientists will be the richer for these initiatives due to increased opportunities for interoperability, reproduceability and accreditation. The AGU has appealed to the wider community to engage with these initiatives, recognising that - unlike the introduction of Digital Object Identifiers (DOIs) for articles by CrossRef - full, enriched use of persistent identifiers throughout the scientific process requires buy-in from a range of scholarly communications stakeholders. At the same time, across the general research landscape, initiatives such as Project CRediT (contributor roles taxonomy), Publons (reviewer acknowledgements) and the forthcoming CrossRef DOI Event Tracker are contributing to our understanding and accreditation of contributions and impact. More specifically for earth science and scientists, the cross-functional Coalition for Publishing Data in the Earth and Space Sciences (COPDESS) was formed in October 2014 and is working to 'provide an organizational framework for Earth and space science publishers and data facilities to jointly implement and promote common policies and procedures for the publication and citation of data across Earth Science journals'. Clearly, the judicious integration of standards, registries and persistent identifiers such as ORCIDs and International Geo Sample Numbers (IGSNs) to the research and research output processes is key to the success of this venture

  14. Persistence of bacterial proteolytic enzymes in lake ecosystems.

    Science.gov (United States)

    Kiersztyn, Bartosz; Siuda, Waldemar; Chróst, Ryszard J

    2012-04-01

    This study analyzes proteolytic enzyme persistence and the role of dead (or metabolically inactive) aquatic bacteria in organic matter cycling. Samples from four lakes of different trophic status were used. Irrespective of the trophic status of the examined lakes, bacterial aminopeptidases remained active even 72 h after the death of the bacteria that produced them. The total pool of proteolytic enzymes in natural lake water samples was also stable. We found that the rates of amino acid enzymatic release from proteinaceous matter added to preserved lake water sample were constant for at least 96 h (r(2)  = 0.99, n = 17, P ≤ 0.0001, V(max)  = 84.6 nM h(-1) ). We also observed that proteases built into bacterial cell debris fragments remained active for a long time, even after the total destruction of cells. Moreover, during 24 h of incubation time, about 20% of these enzymatically active fragments adsorbed onto natural seston particles, becoming a part of the 'attached enzymes system' that is regarded as the 'hot-spot' of protein degradation in aquatic ecosystems. © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

  15. Shaping the CD4+ memory immune response against tuberculosis: the role of antigen persistence, location and multi-functionality.

    Science.gov (United States)

    Ancelet, Lindsay; Kirman, Joanna

    2012-02-01

    Abstract Effective vaccination against intracellular pathogens, such as tuberculosis (TB), relies on the generation and maintenance of CD4 memory T cells. An incomplete understanding of the memory immune response has hindered the rational design of a new, more effective TB vaccine. This review discusses how the persistence of antigen, the location of memory cells, and their multifunctional ability shape the CD4 memory T cell response against TB.

  16. Stability under persistent perturbation by white noise

    International Nuclear Information System (INIS)

    Kalyakin, L

    2014-01-01

    Deterministic dynamical system which has an asymptotical stable equilibrium is considered under persistent perturbation by white noise. It is well known that if the perturbation does not vanish in the equilibrium position then there is not Lyapunov's stability. The trajectories of the perturbed system diverge from the equilibrium to arbitrarily large distances with probability 1 in finite time. New concept of stability on a large time interval is discussed. The length of interval agrees the reciprocal quantity of the perturbation parameter. The measure of stability is the expectation of the square distance from the trajectory till the equilibrium position. The method of parabolic equation is applied to both estimate the expectation and prove such stability. The main breakthrough is the barrier function derived for the parabolic equation. The barrier is constructed by using the Lyapunov function of the unperturbed system

  17. Persistent Organic Pollutants and Type 2 Diabetes

    DEFF Research Database (Denmark)

    Wu, Hongyu; Bertrand, Kimberly A; Choi, Anna L

    2013-01-01

    and summarize existing evidence in a meta-analysis. METHODS: Plasma polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethylene (DDE), and hexachlorobenzene (HCB) concentrations were measured in 1,095 women who were free of diabetes at blood draw in 1989......BACKGROUND: Prospective data regarding persistent organic pollutants (POPs) and risk of type 2 diabetes (T2D) are limited, and the results for individual POPs are not entirely consistent across studies. OBJECTIVES: To prospectively examine plasma POP concentrations in relation to incident T2D......-1990 and participated in two case-control studies in the Nurses' Health Study. We identified 48 incident T2D cases through June 30, 2008. We conducted a literature search in MEDLINE and EMBASE through December 2011 to identify prospective studies on POPs in relation to diabetes. We used a fixed-effects model...

  18. Cognitive implications of facilitating echoic persistence.

    Science.gov (United States)

    Baldwin, Carryl L

    2007-06-01

    Seventeen participants performed a tone-pattern-matching task at different presentation levels while concurrently engaged in a simulated-driving task. Presentation levels of 60, 65, and 70 dBC (SPL) were combined factorially with tone-matching delays of 2, 3, and 4 sec. Intensity had no effect on performance in single-task conditions and short-delay conditions. However, when the participants were engaged concurrently in the driving task, a significant interaction between presentation level and delay was observed. In the longest delay condition, the participants performed the tone-pattern-matching task more efficiently (more quickly and without additional errors) as presentation intensity increased. These findings demonstrate the interaction between sensory and cognitive processes and point to a direct-intensity relationship where intensity affects the persistence of echoic memory. Implications for facilitating auditory processing and improving auditory interfaces in complex systems (i.e., transportation environments), particularly for older and hearing-impaired listeners, are discussed.

  19. Persistent organic pollutants in the Muda area

    International Nuclear Information System (INIS)

    Zuriati Zakaria; Md Pauzi Abdullah; Laily Din

    2002-01-01

    A screening for the presence of Persistent Organic Pollutants (POP) in Malaysia was undertaken by the Universiti Kebangsaan Malaysia as part of the Department of Environment's assessment process to study the extent of bioaccumulation or the transboundary effect of POPs in the country. Water, sediment and fish samples were tested for the presence of nine compounds which were aldrin, dieldrin, chlordane, DDT, hexachlordane, hexachlorobenzene, mirex, toxaphene and heptachlor. The Muda area was one of the areas investigated where samplings were conducted at Sungai Tajar, Sungai Tala and Sungai Fadang. Analyses of the samples showed that residues of DDT, aldrin, dieldrin, endrin and BHC were present in the sediment.The water samples also showed the presence of aldrin and dieldrin. (Author)

  20. Remote Biometrics for Robust Persistent Authentication

    DEFF Research Database (Denmark)

    Ingwar, Mads Ingerslew; Jensen, Christian D.

    2014-01-01

    This paper examines the problem of providing a robust non-invasive authentication service for mobile users in a smart environment. We base our work on the persistent authentication model (PAISE), which relies on available sensors to track principals from the location where they authenticate, e.......g., through a smart card based access control system, to the location where the authentication is required by a location-based service. The PAISE model is extended with remote biometrics to prevent the decay of authentication confidence when authenticated users encounter and interact with other users...... in the environment. The result is a calm approach to authentication, where mobile users are transparently authenticated towards the system, which allows the provision of location-based services. The output of the remote biometrics are fused using error-rate-based fusion to solve a common problem that occurs in score...

  1. Persistence of malathion residues in stored wheat

    International Nuclear Information System (INIS)

    Farghaly, M.; Zayed, S.M.A.D.

    1990-01-01

    The persistence of succinate- 14 C-malathion in stored wheat was investigated under local conditions during a storage period of 32 weeks. The insecticide penetrated readily into the seed and up to 16% of the applied dose was found to be bound after 32 weeks in storage. Total terminal residues declined to 9.3 and 21.0 mg/kg from initially applied doses of 12.2 and 24.4 mg/kg respectively. A small percentage of malaoxon was detected only during the early weeks after treatment (3-5%). Malathion was the major constituent of the extractable residues. In addition, seven degradation products were detected and identified. (author). 6 refs, 2 figs, 2 tabs

  2. Persisting effect of community approaches to resuscitation

    DEFF Research Database (Denmark)

    Nielsen, Anne Møller; Isbye, Dan Lou; Lippert, Freddy Knudsen

    2014-01-01

    BACKGROUND: On the Danish island of Bornholm an intervention was carried out during 2008-2010 aiming at increasing out-of-hospital cardiac arrest (OHCA) survival. The intervention included mass media focus on resuscitation and widespread educational activities. The aim of this study was to compare....... There was no significant change in all-rhythm 30-day survival for non-EMS witnessed OHCAs with presumed cardiac aetiology (6.7% [95% CI 3-13] in the follow-up period; vs. 4.6% [95% CI 1-12], p=0.76). CONCLUSION: In a 3-year follow-up period after an intervention engaging laypersons in resuscitation through mass education...... in BLS combined with a media focus on resuscitation, we observed a persistent significant increase in the bystander BLS rate for all OHCAs with presumed cardiac aetiology. There was no significant difference in 30-day survival....

  3. Predictive risk factors for persistent postherniotomy pain

    DEFF Research Database (Denmark)

    Aasvang, Eske K; Gmaehle, Eliza; Hansen, Jeanette B

    2010-01-01

    BACKGROUND: Persistent postherniotomy pain (PPP) affects everyday activities in 5-10% of patients. Identification of predisposing factors may help to identify the risk groups and guide anesthetic or surgical procedures in reducing risk for PPP. METHODS: A prospective study was conducted in 464...... patients undergoing open or laparoscopic transabdominal preperitoneal elective groin hernia repair. Primary outcome was identification of risk factors for substantial pain-related functional impairment at 6 months postoperatively assessed by the validated Activity Assessment Scale (AAS). Data on potential...... risk factors for PPP were collected preoperatively (pain from the groin hernia, preoperative AAS score, pain from other body regions, and psychometric assessment). Pain scores were collected on days 7 and 30 postoperatively. Sensory functions including pain response to tonic heat stimulation were...

  4. Determinants of persistent asthma in young adults

    DEFF Research Database (Denmark)

    Traulsen, Lisbet Krogh; Halling, Anders; Bælum, Jesper

    2018-01-01

    Objective: The aim of the study was to evaluate determinants for the prognosis of asthma in a population-based cohort of young adults. Design: The study was a nine-year clinical follow up of 239 asthmatic subjects from an enriched population-based sample of 1,191 young adults, aged 20-44 years, who...... participated in an interviewer-administered questionnaire and clinical examination at baseline in 2003-2006. From the interview, an asthma score was generated as the simple sum of affirmative answers to five main asthma-like symptoms in order to analyse symptoms of asthma as a continuum. The clinical...... examination comprised spirometry, bronchial challenge or bronchodilation, and skin prick test. Results: Among the 239 individuals with asthma at baseline 164 (69%) had persistent asthma at follow up, while 68 (28%) achieved remission of asthma and seven (3%) were diagnosed with COPD solely. Determinants...

  5. China's water pollution by persistent organic pollutants

    International Nuclear Information System (INIS)

    Bao Lianjun; Maruya, Keith A.; Snyder, Shane A.; Zeng, Eddy Y.

    2012-01-01

    Available data were reviewed to assess the status of contamination by persistent organic pollutants (POPs), including organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs), perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), in drinking water sources and coastal waters of China. The levels of POPs in China's waters were generally at the high end of the global range. A comparison of China's regulatory limits indicated that PCBs in rivers and coastal water may pose potential human health risk. Occurrence of DDTs in some rivers of China may also pose health risk to humans using the regulatory limits of DDTs recommended by the European Union. Future monitoring of POPs in China's waters should be directed towards analytes of concern (e.g. PCBs and PCDD/Fs) and to fill data gaps for analytes (e.g. PBDEs, PCDD/Fs, and chlordane) and in watersheds/regions (e.g. West China) where data are scarce. - Highlights: ► Levels of POPs in China's aquatic systems were generally at the high end of the global range. ► New inputs of DDTs, likely related to the use of dicofol and anti-fouling paints, were found. ► Occurrence of PCBs and DDTs in some water bodies pay pose potential human health risk. ► Long-term monitoring of POPs in China's waters is needed to fill data gaps. - Occurrence, potential sources and ecological and human health risk of persistent organic pollutants in China's waters are reviewed.

  6. Differential Persistence of Foot-and-Mouth Disease Virus in African Buffalo Is Related to Virus Virulence.

    Science.gov (United States)

    Maree, Francois; de Klerk-Lorist, Lin-Mari; Gubbins, Simon; Zhang, Fuquan; Seago, Julian; Pérez-Martín, Eva; Reid, Liz; Scott, Katherine; van Schalkwyk, Louis; Bengis, Roy; Charleston, Bryan; Juleff, Nicholas

    2016-05-15

    Foot-and-mouth disease (FMD) virus (FMDV) circulates as multiple serotypes and strains in many regions of endemicity. In particular, the three Southern African Territories (SAT) serotypes are maintained effectively in their wildlife reservoir, the African buffalo, and individuals may harbor multiple SAT serotypes for extended periods in the pharyngeal region. However, the exact site and mechanism for persistence remain unclear. FMD in buffaloes offers a unique opportunity to study FMDV persistence, as transmission from carrier ruminants has convincingly been demonstrated for only this species. Following coinfection of naive African buffaloes with isolates of three SAT serotypes from field buffaloes, palatine tonsil swabs were the sample of choice for recovering infectious FMDV up to 400 days postinfection (dpi). Postmortem examination identified infectious virus for up to 185 dpi and viral genomes for up to 400 dpi in lymphoid tissues of the head and neck, focused mainly in germinal centers. Interestingly, viral persistence in vivo was not homogenous, and the SAT-1 isolate persisted longer than the SAT-2 and SAT-3 isolates. Coinfection and passage of these SAT isolates in goat and buffalo cell lines demonstrated a direct correlation between persistence and cell-killing capacity. These data suggest that FMDV persistence occurs in the germinal centers of lymphoid tissue but that the duration of persistence is related to virus replication and cell-killing capacity. Foot-and-mouth disease virus (FMDV) causes a highly contagious acute vesicular disease in domestic livestock and wildlife species. African buffaloes (Syncerus caffer) are the primary carrier hosts of FMDV in African savannah ecosystems, where the disease is endemic. We have shown that the virus persists for up to 400 days in buffaloes and that there is competition between viruses during mixed infections. There was similar competition in cell culture: viruses that killed cells quickly persisted more

  7. Non-Monotonic Survival of Staphylococcus aureus with Respect to Ciprofloxacin Concentration Arises from Prophage-Dependent Killing of Persisters

    Directory of Open Access Journals (Sweden)

    Elizabeth L. Sandvik

    2015-11-01

    Full Text Available Staphylococcus aureus is a notorious pathogen with a propensity to cause chronic, non-healing wounds. Bacterial persisters have been implicated in the recalcitrance of S. aureus infections, and this motivated us to examine the persistence of S. aureus to ciprofloxacin, a quinolone antibiotic. Upon treatment of exponential phase S. aureus with ciprofloxacin, we observed that survival was a non-monotonic function of ciprofloxacin concentration. Maximal killing occurred at 1 µg/mL ciprofloxacin, which corresponded to survival that was up to ~40-fold lower than that obtained with concentrations ≥ 5 µg/mL. Investigation of this phenomenon revealed that the non-monotonic response was associated with prophage induction, which facilitated killing of S. aureus persisters. Elimination of prophage induction with tetracycline was found to prevent cell lysis and persister killing. We anticipate that these findings may be useful for the design of quinolone treatments.

  8. Persistence of Two Campylobacter jejuni Strains in Soil and on Spinach Plants

    International Nuclear Information System (INIS)

    Jaderlund, L.; Arthurson, V.; Sessitsch, A.

    2011-01-01

    There are indications that the more frequent use of untreated organic residues for fertilization results in increased risk of contamination with human pathogens. Here, we evaluate the ability of two different strains of Campylobacter jejuni to persist in manure and soil as well as spread to spinach plants. It was revealed that different strategies for inoculation of C. jejuni contribute to the persistence of the bacterium in soil, roots, and shoots. Upon inoculation of the bacteria into manure prior to soil application, the amount of C. jejuni subsequently recovered in soil was higher than that from treatments involving the addition of C. jejuni cells to the soil after plant emergence. Irrespective of the bacterial inoculation dose and strategy employed, the C. jejuni content in soil remained relatively constant, whereas the majority of C. jejuni cells applied to spinach leaves could be recovered during the whole evaluation period of 21 days.

  9. A Multifunctional Biomaterial with NIR Long Persistent Phosphorescence, Photothermal Response and Magnetism.

    Science.gov (United States)

    Wu, Yiling; Li, Yang; Qin, Xixi; Qiu, Jianrong

    2016-09-20

    There are many reports on long persistent phosphors (LPPs) applied in bioimaging. However, there are few reports on LPPs applied in photothermal therapy (PTT), and an integrated system with multiple functions of diagnosis and therapy. In this work, we fabricate effective multifunctional phosphors Zn3 Ga2 SnO8 : Cr(3+) , Nd(3+) , Gd(3+) with NIR persistent phosphorescence, photothermal response and magnetism. Such featured materials can act as NIR optical biolabels and magnetic resonance imaging (MRI) contrast agents for tracking the early cancer cells, but also as photothermal therapeutic agent for killing the cancer cells. This new multifunctional biomaterial is expected to open a new possibility of setting up an advanced imaging-guided therapy system featuring a high resolution for bioimaging and low side effects for the photothermal ablation of tumors. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Impact of Persistent Intracellular Infections on the Processes of Airway Remodeling in Children with Bronchial Asthma

    Directory of Open Access Journals (Sweden)

    O.Ye. Chernyshova

    2015-03-01

    Full Text Available The article presents information about the impact of persistent intracellular infections on the processes of airway remodeling in bronchial asthma in children. The influence of matrix metalloproteinases, tissue inhibitor of matrix metalloproteinase, transforming growth factor, antibodies to type III collagen, endothelin-1 on the processes of morphological reconstruction of the airway by way of smooth muscle hypertrophy, enhanced neovascularization, epithelial cell hyperplasia, collagen deposition, thickening of the basal membrane, observed in bronchial asthma in children, were described.

  11. Carboplatin enhances the production and persistence of radiation-induced DNA single-strand breaks

    International Nuclear Information System (INIS)

    Yang, L.; Douple, E.B.; O'Hara, J.A.; Wang, H.J.

    1995-01-01

    Fluorometric analysis of DNA unwinding and alkaline elution were used to investigate the production and persistence of DNA single-strand breaks (SSBs) in Chinese hamster V79 and xrs-5 cells treated with the chemotherapeutic agent carboplatin in combination with radiation. Carboplatin was administered to cells before irradiation in hypoxic conditions, or the drug was added immediately after irradiation during the postirradiation recovery period in air. The results of DNA unwinding studies suggest that carboplatin enhances the production of radiation-induced SSBs in hypoxic V79 cells and xrs-5 cells by a factor of 1.86 and 1.83, respectively, when combined with radiation compared to the SSBs produced by irradiation alone. Carboplatin alone did not produce a measureable number of SSBs. Alkaline elution profiles also indicated that the rate of elution of SSBs was higher in cells treated with the carboplatin is present after irradiation and during the postirradiation recovery period, the rejoining of radiation-induced SSBs by a factor of 1.46 in V79 cells with 20 Gy irradiation and by a factor of 2.02 in xrs-5 cells with 20 Gy irradiation. When carboplatin is present after irradiation and during the postirradiation recovery period, the rejoining of radiation-induced SSBs is inhibited during this postirradiation incubation period (radiopotentiation) with a relative inhibition factor at 1 h postirradiation of 1.25 in V79 cells and 1.15 in xrs-5 cells. An increased production and persistence of SSBs resulting from the interaction of carboplatin with radiation may be an important step in the mechanism responsible for the potentiated cell killing previously from studies in animal tumors and in cultured cells. 31 refs., 7 figs

  12. Diverse Secreted Effectors Are Required for Salmonella Persistence in a Mouse Infection Model

    Energy Technology Data Exchange (ETDEWEB)

    Kidwai, Afshan S.; Mushamiri, Ivy T.; Niemann, George; Brown, Roslyn N.; Adkins, Joshua N.; Heffron, Fred

    2013-08-12

    Salmonella enterica serovar Typhimurium causes typhoid-like disease in mice and is a model of typhoid fever in humans. One of the hallmarks of typhoid is persistence, the ability of the bacteria to survive in the host weeks after infection. Virulence factors called effectors facilitate this process by direct transfer to the cytoplasm of infected cells thereby subverting cellular processes. Secretion of effectors to the cell cytoplasm takes place through multiple routes, including two separate type III secretion (T3SS) apparati as well as outer membrane vesicles. The two T3SS are encoded on separate pathogenicity islands, SPI-1 and -2, with SPI-1 more strongly associated with the intestinal phase of infection, and SPI-2 with the systemic phase. Both T3SS are required for persistence, but the effectors required have not been systematically evaluated. In this study, mutations in 48 described effectors were tested for persistence. We replaced each effector with a specific DNA barcode sequence by allelic exchange and co-infected with a wild-type reference to calculate the ratio of wild-type parent to mutant at different times after infection. The competitive index (CI) was determined by quantitative PCR in which primers that correspond to the barcode were used for amplification. Mutations in all but seven effectors reduced persistence demonstrating that most effectors were required. One exception was CigR, a recently discovered effector that is widely conserved throughout enteric bacteria. Deletion of cigR increased lethality, suggesting that it may be an anti-virulence factor. The fact that almost all Salmonella effectors are required for persistence argues against redundant functions. This is different from effector repertoires in other intracellular pathogens such as Legionella.

  13. Inflation persistence in African countries: Does inflation targeting matter?

    OpenAIRE

    Phiri, Andrew

    2016-01-01

    This study investigates inflation persistence in annual CPI inflation collected between 1994 and 2014 for 46 African countries. We group these countries into panels according to whether they are inflation targeters or not and conduct estimations for pre and post inflation targeting periods. Interestingly enough, we find that inflation persistence was much higher for inflation targeters in periods before adopting their inflation targeting regimes and inflation persistence dropped by 40 percent...

  14. Biofilm Formation and Disinfectant Susceptibility of Persistent and Nonpersistent Listeria monocytogenes Isolates from Gorgonzola Cheese Processing Plants.

    Science.gov (United States)

    Costa, Annalisa; Bertolotti, Luigi; Brito, Luisa; Civera, Tiziana

    2016-11-01

    The aim of this study was to investigate whether the biofilm-forming ability and/or the disinfectant susceptibility accounted for the persistence of Listeria monocytogenes in Gorgonzola cheese processing plants. For this purpose, a set of 16 L. monocytogenes isolates collected in the 2004-2007 period was analyzed, including 11 persistent isolates collected in different years, within the collection period, and displaying identical or highly correlated pulsotypes. The evaluation of biofilm-forming ability was assessed using crystal violet (CV) staining and the enumeration of viable cells on stainless steel coupons (SSC). Absorbance values obtained with CV staining for persistent and nonpersistent isolates were not significantly different (rm-ANOVA p > 0.05) and the cell counts from nonpersistent isolates showed to be higher compared with persistent isolates (rm-ANOVA p biofilms on SSC, grown in nutrient-rich (dirty) and limiting (clean) conditions using acid acetic-hydrogen peroxide (P3) and acid citric-hydrogen peroxide (MS) commercial disinfectants. The treatment was considered effective when a 4 Log reduction in viable cell count was observed. The Log reductions of persistent and nonpersistent isolates, obtained with both the assays in clean and dirty conditions, were compared and no significant differences were detected (rm-ANOVA p > 0.05). A greater influence of organic matter on MS could explain why P3 was efficient in reducing to effective levels the majority of the isolates at the lowest concentration suggested by the manufacturer (0.2% [v/v]), while the same purpose required a higher concentration (1% [v/v]) of MS. In conclusion, our results demonstrate that the persistence of these isolates in Gorgonzola cheese processing plants was linked neither to the biofilm-forming ability nor to their susceptibility to hydrogen peroxide-based disinfe