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Sample records for og dyrking av

  1. OGS

    NASA Image and Video Library

    2009-06-22

    ISS020-E-012819 (22 June 2009) --- Japan Aerospace Exploration Agency (JAXA) astronaut Koichi Wakata, Expedition 20 flight engineer, performs in-flight maintenance on the Oxygen Generator System (OGS) in the Destiny laboratory of the International Space Station.

  2. Drosophila Dyrk2 plays a role in the development of the visual system.

    PubMed

    Luebbering, Nathan; Charlton-Perkins, Mark; Kumar, Justin P; Lochead, Pamela A; Rollmann, Stephanie M; Cook, Tiffany; Cleghon, Vaughn

    2013-01-01

    The DYRKs (dual-specificity tyrosine phosphorylation-regulated kinases) are a conserved family of protein kinases that are associated with a number of neurological disorders, but whose biological targets are poorly understood. Drosophila encodes three Dyrks: minibrain/Dyrk1A, DmDyrk2, and DmDyrk3. Here we describe the creation and characterization of a DmDyrk2 null allele, DmDyrk2(1w17) . We provide evidence that the smell impaired allele smi35A(1) , is likely to encode DmDyrk2. We also demonstrate that DmDyrk2 is expressed late in the developing third antennal segment, an anatomical structure associated with smell. In addition, we find that DmDyrk2 is expressed in the morphogenetic furrow of the developing eye, that loss of DmDyrk2 in the eye produced a subtle but measurable defect, and that ectopic DmDyrk2 expression in the eye produced a strong rough eye phenotype characterized by increased secondary, tertiary and bristle interommatidial cells. This phenotype was dependent on DmDyrk2 kinase activity and was only manifest when expressed in post-mitotic non-neuronal progenitors. Together, these data indicate that DmDyrk2 is expressed in developing sensory systems, that it is required for the development of the visual system, and that the eye is a good model to identify DmDyrk2 targets.

  3. Dyrk1 inhibition improves Alzheimer's disease-like pathology.

    PubMed

    Branca, Caterina; Shaw, Darren M; Belfiore, Ramona; Gokhale, Vijay; Shaw, Arthur Y; Foley, Christopher; Smith, Breland; Hulme, Christopher; Dunckley, Travis; Meechoovet, Bessie; Caccamo, Antonella; Oddo, Salvatore

    2017-10-01

    There is an urgent need for the development of new therapeutic strategies for Alzheimer's disease (AD). The dual-specificity tyrosine phosphorylation-regulated kinase-1A (Dyrk1a) is a protein kinase that phosphorylates the amyloid precursor protein (APP) and tau and thus represents a link between two key proteins involved in AD pathogenesis. Furthermore, Dyrk1a is upregulated in postmortem human brains, and high levels of Dyrk1a are associated with mental retardation. Here, we sought to determine the effects of Dyrk1 inhibition on AD-like pathology developed by 3xTg-AD mice, a widely used animal model of AD. We dosed 10-month-old 3xTg-AD and nontransgenic (NonTg) mice with a Dyrk1 inhibitor (Dyrk1-inh) or vehicle for eight weeks. During the last three weeks of treatment, we tested the mice in a battery of behavioral tests. The brains were then analyzed for the pathological markers of AD. We found that chronic Dyrk1 inhibition reversed cognitive deficits in 3xTg-AD mice. These effects were associated with a reduction in amyloid-β (Aβ) and tau pathology. Mechanistically, Dyrk1 inhibition reduced APP and insoluble tau phosphorylation. The reduction in APP phosphorylation increased its turnover and decreased Aβ levels. These results suggest that targeting Dyrk1 could represent a new viable therapeutic approach for AD. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  4. Targeting Dyrk1A with AAVshRNA Attenuates Motor Alterations in TgDyrk1A, a Mouse Model of Down Syndrome

    PubMed Central

    Ortiz-Abalia, Jon; Sahún, Ignasi; Altafaj, Xavier; Andreu, Núria; Estivill, Xavier; Dierssen, Mara; Fillat, Cristina

    2008-01-01

    Genetic-dissection studies carried out with Down syndrome (DS) murine models point to the critical contribution of Dyrk1A overexpression to the motor abnormalities and cognitive deficits displayed in DS individuals. In the present study we have used a murine model overexpressing Dyrk1A (TgDyrk1A mice) to evaluate whether functional CNS defects could be corrected with an inhibitory RNA against Dyrk1A, delivered by bilateral intrastriatal injections of adeno-associated virus type 2 (AAVshDyrk1A). We report that AAVshDyrk1A efficiently transduced HEK293 cells and primary neuronal cultures, triggering the specific inhibition of Dyrk1A expression. Injecting the vector into the striata of TgDyrk1A mice resulted in a restricted, long-term transduction of the striatum. This gene therapy was found to be devoid of toxicity and succeeded in normalizing Dyrk1A protein levels in TgDyrk1A mice. Importantly, the behavioral studies of the adult TgDyrk1A mice treated showed a reversal of corticostriatal-dependent phenotypes, as revealed by the attenuation of their hyperactive behavior, the restoration of motor-coordination defects, and an improvement in sensorimotor gating. Taken together, the data demonstrate that normalizing Dyrk1A gene expression in the striatum of adult TgDyrk1A mice, by means of AAVshRNA, clearly reverses motor impairment. Furthermore, these results identify Dyrk1A as a potential target for therapy in DS. PMID:18940310

  5. DYRK1A in neurodegeneration and cancer: Molecular basis and clinical implications.

    PubMed

    Abbassi, Ramzi; Johns, Terrance G; Kassiou, Michael; Munoz, Lenka

    2015-07-01

    Protein kinases are one of the most studied drug targets in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. Dual-specificity Tyrosine phosphorylation-Regulated Kinase 1A (DYRK1A) has been much less studied compared to many other kinases. DYRK1A primary function occurs during early development, where this protein regulates cellular processes related to proliferation and differentiation of neuronal progenitor cells. Although most extensively characterised for its role in brain development, DYRK1A is over-expressed in a variety of diseases including a number of human malignancies, such as haematological and brain cancers. Here we review the accumulating molecular studies that support our understanding of how DYRK1A signalling could underlie these pathological functions. The relevance of DYRK1A in a number of diseases is also substantiated with intensive drug discovery efforts to develop potent and selective inhibitors of DYRK1A. Several classes of DYRK1A inhibitors have recently been disclosed and some molecules are promising leads to develop DYRK1A inhibitors as drugs for DYRK1A-dependent diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. NFATc1 phosphorylation by DYRK1A increases its protein stability

    PubMed Central

    Chen, Shuai; Sun, Qian; Zhang, Yuankai; Chen, Long; Sun, Xiulian

    2017-01-01

    NFATs are transcription factors involved in immune activation and tumor progression. Previous reports showed that DYRK1A suppressed NFATc2 transcriptional activity through phosphorylation. Nonetheless, our results showed that DYRK1A increased NFATc1/αA protein level and subsequent transcriptional activity. DYRK1A phosphorylation of NFATc1/αA at S261, S278, S403 and S409 interfered with NFATc1 ubiquitination and ubiquitin-proteasome degradation. Our results imply that DYRK1A is a positive kinase in regulation of NFATc1. PMID:28235034

  7. Dyrk1A Haploinsufficiency Affects Viability and Causes Developmental Delay and Abnormal Brain Morphology in Mice

    PubMed Central

    Fotaki, Vassiliki; Dierssen, Mara; Alcántara, Soledad; Martínez, Salvador; Martí, Eulàlia; Casas, Caty; Visa, Joana; Soriano, Eduardo; Estivill, Xavier; Arbonés, Maria L.

    2002-01-01

    DYRK1A is the human orthologue of the Drosophila minibrain (mnb) gene, which is involved in postembryonic neurogenesis in flies. Because of its mapping position on chromosome 21 and the neurobehavioral alterations shown by mice overexpressing this gene, involvement of DYRK1A in some of the neurological defects of Down syndrome patients has been suggested. To gain insight into its physiological role, we have generated mice deficient in Dyrk1A function by gene targeting. Dyrk1A−/− null mutants presented a general growth delay and died during midgestation. Mice heterozygous for the mutation (Dyrk1A+/−) showed decreased neonatal viability and a significant body size reduction from birth to adulthood. General neurobehavioral analysis revealed preweaning developmental delay of Dyrk1A+/− mice and specific alterations in adults. Brains of Dyrk1A+/− mice were decreased in size in a region-specific manner, although the cytoarchitecture and neuronal components in most areas were not altered. Cell counts showed increased neuronal densities in some brain regions and a specific decrease in the number of neurons in the superior colliculus, which exhibited a significant size reduction. These data provide evidence about the nonredundant, vital role of Dyrk1A and suggest a conserved mode of action that determines normal growth and brain size in both mice and flies. PMID:12192061

  8. DYRK1A Controls HIV-1 Replication at a Transcriptional Level in an NFAT Dependent Manner

    PubMed Central

    Booiman, Thijs; Loukachov, Vladimir V.; van Dort, Karel A.; van ’t Wout, Angélique B.; Kootstra, Neeltje A.

    2015-01-01

    Background Transcription of the HIV-1 provirus is regulated by both viral and host proteins and is very important in the context of viral latency. In latently infected cells, viral gene expression is inhibited as a result of the sequestration of host transcription factors and epigenetic modifications. Results In our present study we analyzed the effect of host factor dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) on HIV-1 replication. We show that DYRK1A controls HIV-1 replication by regulating provirus transcription. Downregulation or inhibition of DYRK1A increased LTR-driven transcription and viral replication in cell lines and primary PBMC. Furthermore, inhibition of DYRK1A resulted in reactivation of latent HIV-1 provirus to a similar extent as two commonly used broad-spectrum HDAC inhibitors. We observed that DYRK1A regulates HIV-1 transcription via the Nuclear Factor of Activated T-cells (NFAT) by promoting its translocation from the nucleus to the cytoplasm. Therefore, inhibition of DYRK1A results in increased nuclear levels of NFAT and increased NFAT binding to the viral LTR and thus increasing viral transcription. Conclusions Our data indicate that host factor DYRK1A plays a role in the regulation of viral transcription and latency. Therefore, DYRK1A might be an attractive candidate for therapeutic strategies targeting the viral reservoir. PMID:26641855

  9. Truncation of the Down Syndrome Candidate Gene DYRK1A in Two Unrelated Patients with Microcephaly

    PubMed Central

    Møller, Rikke S.; Kübart, Sabine; Hoeltzenbein, Maria; Heye, Babett; Vogel, Ida; Hansen, Christian P.; Menzel, Corinna; Ullmann, Reinhard; Tommerup, Niels; Ropers, Hans-Hilger; Tümer, Zeynep; Kalscheuer, Vera M.

    2008-01-01

    We have identified and characterized two unrelated patients with prenatal onset of microcephaly, intrauterine growth retardation, feeding problems, developmental delay, and febrile seizures/epilepsy who both carry a de novo balanced translocation that truncates the DYRK1A gene at chromosome 21q22.2. DYRK1A belongs to the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family, which is highly conserved throughout evolution. Given its localization in both the Down syndrome critical region and in the minimal region for partial monosomy 21, the gene has been studied intensively in animals and in humans, and DYRK1A has been proposed to be involved in the neurodevelopmental alterations associated with these syndromes. In the present study, we show that truncating mutations of DYRK1A result in a clinical phenotype including microcephaly. PMID:18405873

  10. DYRK1A: a potential drug target for multiple Down syndrome neuropathologies.

    PubMed

    Becker, Walter; Soppa, Ulf; Tejedor, Francisco J

    2014-02-01

    Down syndrome (DS), the most common genetic cause of intellectual disability, is caused by the trisomy of chromosome 21. MNB/DYRK1A (Minibrain/dual specificity tyrosine phosphorylation-regulated kinase 1A) has possibly been the most extensively studied chromosome 21 gene during the last decade due to the remarkable correlation of its functions in the brain with important DS neuropathologies, such as neuronal deficits, dendrite atrophy, spine dysgenesis, precocious Alzheimer's-like neurodegeneration, and cognitive deficits. MNB/DYRK1A has become an attractive drug target because increasing evidence suggests that its overexpression may induce DS-like neurobiological alterations, and several small-molecule inhibitors of its protein kinase activity are available. Here, we summarize the functional complexity of MNB/DYRK1A from a DS-research perspective, paying particular attention to the capacity of different MNB/DYRK1A inhibitors to reverse the neurobiological alterations caused by the increased activity of MNB/DYRK1A in experimental models. Finally, we discuss the advantages and drawbacks of possible MNB/DYRK1A-based therapeutic strategies that result from the functional, molecular, and pharmacological complexity of MNB/DYRK1A.

  11. The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells

    PubMed Central

    Khor, Bernard; Gagnon, John D; Goel, Gautam; Roche, Marly I; Conway, Kara L; Tran, Khoa; Aldrich, Leslie N; Sundberg, Thomas B; Paterson, Alison M; Mordecai, Scott; Dombkowski, David; Schirmer, Melanie; Tan, Pauline H; Bhan, Atul K; Roychoudhuri, Rahul; Restifo, Nicholas P; O'Shea, John J; Medoff, Benjamin D; Shamji, Alykhan F; Schreiber, Stuart L; Sharpe, Arlene H; Shaw, Stanley Y; Xavier, Ramnik J

    2015-01-01

    The balance between Th17 and T regulatory (Treg) cells critically modulates immune homeostasis, with an inadequate Treg response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A in regulating this balance. Inhibition of DYRK1A enhances Treg differentiation and impairs Th17 differentiation without affecting known pathways of Treg/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either Treg or Th17 lineages. Importantly, both Treg cells generated using the DYRK1A inhibitor harmine and direct administration of harmine itself potently attenuate inflammation in multiple experimental models of systemic autoimmunity and mucosal inflammation. Our results identify DYRK1A as a physiologically relevant regulator of Treg cell differentiation and suggest a broader role for other DYRK family members in immune homeostasis. These results are discussed in the context of human diseases associated with dysregulated DYRK activity. DOI: http://dx.doi.org/10.7554/eLife.05920.001 PMID:25998054

  12. Low Expression of DYRK2 (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 2) Correlates with Poor Prognosis in Colorectal Cancer

    PubMed Central

    Wu, Wenjing; Li, Yu; Tian, Huan; Chu, Zhonghua; Koeffler, H. Phillip; Yin, Dong

    2016-01-01

    Dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) is a member of dual-specificity kinase family, which could phosphorylate both Ser/Thr and Tyr substrates. The role of DYRK2 in human cancer remains controversial. For example, overexpression of DYRK2 predicts a better survival in human non-small cell lung cancer. In contrast, amplification of DYRK2 gene occurs in esophageal/lung adenocarcinoma, implying the role of DYRK2 as a potential oncogene. However, its clinical role in colorectal cancer (CRC) has not been explored. In this study, we analyzed the expression of DYRK2 from Oncomine database and found that DYRK2 level is lower in primary or metastatic CRC compared to adjacent normal colon tissue or non-metastatic CRC, respectively, in 6 colorectal carcinoma data sets. The correlation between DYRK2 expression and clinical outcome in 181 CRC patients was also investigated by real-time PCR and IHC. DYRK2 expression was significantly down-regulated in colorectal cancer tissues compared with adjacent non-tumorous tissues. Functional studies confirmed that DYRK2 inhibited cell invasion and migration in both HCT116 and SW480 cells and functioned as a tumor suppressor in CRC cells. Furthermore, the lower DYRK2 levels were correlated with tumor sites (P = 0.023), advanced clinical stages (P = 0.006) and shorter survival in the advanced clinical stages. Univariate and multivariate analyses indicated that DYRK2 expression was an independent prognostic factor (P < 0.001). Taking all, we concluded that DYRK2 a novel prognostic biomarker of human colorectal cancer. PMID:27532268

  13. Identification of DYRK1B as a substrate of ERK1/2 and characterisation of the kinase activity of DYRK1B mutants from cancer and metabolic syndrome.

    PubMed

    Ashford, Anne L; Dunkley, Tom P J; Cockerill, Mark; Rowlinson, Rachel A; Baak, Lisa M; Gallo, Raffaella; Balmanno, Kathryn; Goodwin, Louise M; Ward, Richard A; Lochhead, Pamela A; Guichard, Sylvie; Hudson, Kevin; Cook, Simon J

    2016-02-01

    The dual-specificity tyrosine-phosphorylation-regulated kinase, DYRK1B, is expressed de novo during myogenesis, amplified or mutated in certain cancers and mutated in familial cases of metabolic syndrome. DYRK1B is activated by cis auto-phosphorylation on tyrosine-273 (Y273) within the activation loop during translation but few other DYRK1B phosphorylation sites have been characterised to date. Here, we demonstrate that DYRK1B also undergoes trans-autophosphorylation on serine-421 (S421) in vitro and in cells and that this site contributes to DYRK1B kinase activity. Whilst a DYRK1B(S421A) mutant was completely defective for p-S421 in cells, DYRK1B inhibitors caused only a partial loss of p-S421 suggesting the existence of an additional kinase that could also phosphorylate DYRK1B S421. Indeed, a catalytically inactive DYRK1B(D239A) mutant exhibited very low levels of p-S421 in cells but this was increased by KRAS(G12V). In addition, selective activation of the RAF-MEK1/2-ERK1/2 signalling pathway rapidly increased p-S421 in cells whereas activation of the stress kinases JNK or p38 could not. S421 resides within a Ser-Pro phosphoacceptor motif that is typical for ERK1/2 and recombinant ERK2 phosphorylated DYRK1B at S421 in vitro. Our results show that DYRK1B is a novel ERK2 substrate, uncovering new links between two kinases involved in cell fate decisions. Finally, we show that DYRK1B mutants that have recently been described in cancer and metabolic syndrome exhibit normal or reduced intrinsic kinase activity.

  14. Characterization of DYRK2 ( dual-specificity tyrosine-phosphorylation-regulated kinase 2) from Zebrafish ( Dario rerio)

    NASA Astrophysics Data System (ADS)

    Sun, Wei; Tan, Xungang; Zhang, Peijun; Zhang, Yuqing; Xu, Yongli

    2010-07-01

    Proteins of the DYRK (dual-specificity tyrosine-phosphorylation-regulated kinase) family are characterized by the presence of a conserved kinase domain and N-terminal DH box. DYRK2 is involved in regulating key developmental and cellular processes, such as neurogenesis, cell proliferation, cytokinesis, and cellular differentiation. Herein, we report that the ortholog of DYRK2 found in zebrafish shares about 70% identity with that of human, mouse, and chick. RT-PCR showed that DYRK2 is expressed maternally and zygotically. In-situ hybridization results show that DYRK2 is expressed in somite cells that will develop into muscles. Our results provide preliminary evidence for investigating the in-vivo function of DYRK2 in zebrafish muscle development.

  15. Haploinsufficiency of Dyrk1A in mice leads to specific alterations in the development and regulation of motor activity.

    PubMed

    Fotaki, V; Martínez De Lagrán, M; Estivill, X; Arbonés, M; Dierssen, M

    2004-08-01

    DYRK1A is a protein kinase proposed to be involved in neurogenesis. Gene-targeting disruption of Dyrk1A in mice leads to decreased body and brain size, with no severe disturbance of behavior. In this study, the authors focused on the motor profile of Dyrk1A(+/-) mice. These mice presented impairment of neuromotor development with decreased activity, suggesting a physiological role of Dyrk1A in the maturation of the neuromotor system. In the adult, a marked hypoactivity and alteration of specific motor parameters were detected. These results are in agreement with the significant expression of Dyrk1A in structures related to motor function and support a role of Dyrk1A in the control of motor function.

  16. Selective inhibition of the kinase DYRK1A by targeting its folding process

    PubMed Central

    Kii, Isao; Sumida, Yuto; Goto, Toshiyasu; Sonamoto, Rie; Okuno, Yukiko; Yoshida, Suguru; Kato-Sumida, Tomoe; Koike, Yuka; Abe, Minako; Nonaka, Yosuke; Ikura, Teikichi; Ito, Nobutoshi; Shibuya, Hiroshi; Hosoya, Takamitsu; Hagiwara, Masatoshi

    2016-01-01

    Autophosphorylation of amino-acid residues is part of the folding process of various protein kinases. Conventional chemical screening of mature kinases has missed inhibitors that selectively interfere with the folding process. Here we report a cell-based assay that evaluates inhibition of a kinase at a transitional state during the folding process and identify a folding intermediate-selective inhibitor of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), which we refer to as FINDY. FINDY suppresses intramolecular autophosphorylation of Ser97 in DYRK1A in cultured cells, leading to its degradation, but does not inhibit substrate phosphorylation catalysed by the mature kinase. FINDY also suppresses Ser97 autophosphorylation of recombinant DYRK1A, suggesting direct inhibition, and shows high selectivity for DYRK1A over other DYRK family members. In addition, FINDY rescues DYRK1A-induced developmental malformations in Xenopus laevis embryos. Our study demonstrates that transitional folding intermediates of protein kinases can be targeted by small molecules, and paves the way for developing novel types of kinase inhibitors. PMID:27102360

  17. Selective inhibition of the kinase DYRK1A by targeting its folding process.

    PubMed

    Kii, Isao; Sumida, Yuto; Goto, Toshiyasu; Sonamoto, Rie; Okuno, Yukiko; Yoshida, Suguru; Kato-Sumida, Tomoe; Koike, Yuka; Abe, Minako; Nonaka, Yosuke; Ikura, Teikichi; Ito, Nobutoshi; Shibuya, Hiroshi; Hosoya, Takamitsu; Hagiwara, Masatoshi

    2016-04-22

    Autophosphorylation of amino-acid residues is part of the folding process of various protein kinases. Conventional chemical screening of mature kinases has missed inhibitors that selectively interfere with the folding process. Here we report a cell-based assay that evaluates inhibition of a kinase at a transitional state during the folding process and identify a folding intermediate-selective inhibitor of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), which we refer to as FINDY. FINDY suppresses intramolecular autophosphorylation of Ser97 in DYRK1A in cultured cells, leading to its degradation, but does not inhibit substrate phosphorylation catalysed by the mature kinase. FINDY also suppresses Ser97 autophosphorylation of recombinant DYRK1A, suggesting direct inhibition, and shows high selectivity for DYRK1A over other DYRK family members. In addition, FINDY rescues DYRK1A-induced developmental malformations in Xenopus laevis embryos. Our study demonstrates that transitional folding intermediates of protein kinases can be targeted by small molecules, and paves the way for developing novel types of kinase inhibitors.

  18. Green Tea Polyphenols Rescue of Brain Defects Induced by Overexpression of DYRK1A

    PubMed Central

    Guedj, Fayçal; Sébrié, Catherine; Rivals, Isabelle; Ledru, Aurelie; Paly, Evelyne; Bizot, Jean C.; Smith, Desmond; Rubin, Edward; Gillet, Brigitte; Arbones, Mariona; Delabar, Jean M.

    2009-01-01

    Individuals with partial HSA21 trisomies and mice with partial MMU16 trisomies containing an extra copy of the DYRK1A gene present various alterations in brain morphogenesis. They present also learning impairments modeling those encountered in Down syndrome. Previous MRI and histological analyses of a transgenic mice generated using a human YAC construct that contains five genes including DYRK1A reveal that DYRK1A is involved, during development, in the control of brain volume and cell density of specific brain regions. Gene dosage correction induces a rescue of the brain volume alterations. DYRK1A is also involved in the control of synaptic plasticity and memory consolidation. Increased gene dosage results in brain morphogenesis defects, low BDNF levels and mnemonic deficits in these mice. Epigallocatechin gallate (EGCG) — a member of a natural polyphenols family, found in great amount in green tea leaves — is a specific and safe DYRK1A inhibitor. We maintained control and transgenic mice overexpressing DYRK1A on two different polyphenol-based diets, from gestation to adulthood. The major features of the transgenic phenotype were rescued in these mice. PMID:19242551

  19. DYRK1A: the double-edged kinase as a protagonist in cell growth and tumorigenesis

    PubMed Central

    Fernández-Martínez, P; Zahonero, C; Sánchez-Gómez, P

    2015-01-01

    DYRK1A (dual-specificity tyrosine-regulated kinase 1A) is a kinase with multiple implications for embryonic development, especially in the nervous system where it regulates the balance between proliferation and differentiation of neural progenitors. The DYRK1A gene is located in the Down syndrome critical region and may play a significant role in the developmental brain defects, early neurodegeneration, and cancer susceptibility of individuals with this syndrome. DYRK1A is also expressed in adults, where it might participate in the regulation of cell cycle, survival, and tumorigenesis, thus representing a potential therapeutic target for certain types of cancer. However, the final readout of DYRK1A overexpression or inhibition depends strongly on the cellular context, as it has both tumor suppressor and oncogenic activities. Here, we will discuss the functions and substrates of DYRK1A associated with the control of cell growth and tumorigenesis with a focus on the potential use of DYRK1A inhibitors in cancer therapy. PMID:27308401

  20. Identification of the autophosphorylation sites and characterization of their effects in the protein kinase DYRK1A.

    PubMed Central

    Himpel, S; Panzer, P; Eirmbter, K; Czajkowska, H; Sayed, M; Packman, L C; Blundell, T; Kentrup, H; Grötzinger, J; Joost, H G; Becker, W

    2001-01-01

    Protein kinases of the DYRK ('dual-specificity tyrosine-regulated kinase') family are characterized by a conserved Tyr-Xaa-Tyr motif (Tyr-319-Tyr-321) in a position exactly corresponding to the activation motif of the mitogen-activated protein kinase (MAP kinase) family (Thr-Xaa-Tyr). In a molecular model of the catalytic domain of DYRK1A, the orientation of phosphorylated Tyr-321 is strikingly similar to that of Tyr-185 in the known structure of the activated MAP kinase, extracellular-signal-regulated kinase 2. Consistent with our model, substitution of Tyr-321 but not of Tyr-319 by phenylalanine markedly reduced the enzymic activity of recombinant DYRK1A expressed in either Escherichia coli or mammalian cells. Direct identification of phosphorylated residues by tandem MS confirmed that Tyr-321, but not Tyr-319, was phosphorylated. When expressed in COS-7 cells, DYRK1A was found to be fully phosphorylated on Tyr-321. A catalytically inactive mutant of DYRK1A contained no detectable phosphotyrosine, indicating that Tyr-321 is autophosphorylated by DYRK1A. MS identified Tyr-111 and Ser-97 as additional autophosphorylation sites in the non-catalytic N-terminal domain of bacterially expressed DYRK1A. Enzymic activity was not affected in the DYRK1A-Y111F mutant. The present experimental data and the molecular model indicate that the activity of DYRK1A is dependent on the autophosphorylation of a conserved tyrosine residue in the activation loop. PMID:11672423

  1. A chemical with proven clinical safety rescues Down-syndrome-related phenotypes in through DYRK1A inhibition

    PubMed Central

    Kim, Hyeongki; Lee, Kyu-Sun; Kim, Ae-Kyeong; Choi, Miri; Choi, Kwangman; Kang, Mingu; Chi, Seung-Wook; Lee, Min-Sung; Lee, Jeong-Soo; Lee, So-Young; Song, Woo-Joo; Yu, Kweon

    2016-01-01

    ABSTRACT DYRK1A is important in neuronal development and function, and its excessive activity is considered a significant pathogenic factor in Down syndrome and Alzheimer's disease. Thus, inhibition of DYRK1A has been suggested to be a new strategy to modify the disease. Very few compounds, however, have been reported to act as inhibitors, and their potential clinical uses require further evaluation. Here, we newly identify CX-4945, the safety of which has been already proven in the clinical setting, as a potent inhibitor of DYRK1A that acts in an ATP-competitive manner. The inhibitory potency of CX-4945 on DYRK1A (IC50=6.8 nM) in vitro was higher than that of harmine, INDY or proINDY, which are well-known potent inhibitors of DYRK1A. CX-4945 effectively reverses the aberrant phosphorylation of Tau, amyloid precursor protein (APP) and presenilin 1 (PS1) in mammalian cells. To our surprise, feeding with CX-4945 significantly restored the neurological and phenotypic defects induced by the overexpression of minibrain, an ortholog of human DYRK1A, in the Drosophila model. Moreover, oral administration of CX-4945 acutely suppressed Tau hyperphosphorylation in the hippocampus of DYRK1A-overexpressing mice. Our research results demonstrate that CX-4945 is a potent DYRK1A inhibitor and also suggest that it has therapeutic potential for DYRK1A-associated diseases. PMID:27483355

  2. E3 Ligase SCFβTrCP-induced DYRK1A Protein Degradation Is Essential for Cell Cycle Progression in HEK293 Cells*

    PubMed Central

    Liu, Qiang; Tang, Yu; Chen, Long; Liu, Na; Lang, Fangfang; Liu, Heng; Wang, Pin; Sun, Xiulian

    2016-01-01

    DYRK1A, located on the Down syndrome (DS) critical region of chromosome 21, was found to be overexpressed in brains of DS and Alzheimer's disease individuals. DYRK1A was considered to play important roles in the pathogenesis of DS and Alzheimer's disease; however, the degradation mechanism of DYRK1A was still unclear. In this study, we found that DYRK1A was degraded through the ubiquitin-proteasome pathway in HEK293 cells. The N terminus of DYRK1A that was highly unstable in HEK293 cells contributed to proteolysis of DYRK1A. E3 ligase SCFβTrCP mediated ubiquitination and promoted degradation of DYRK1A through an unconserved binding motif (49SDQQVSALS57) lying in the N terminus. Any Ser-Ala substitution in this motif could decrease the binding between DYRK1A and β-transducin repeat containing protein (βTrCP), resulting in stabilization of DYRK1A. We also found DYRK1A protein was elevated in the G0/G1 phase and decreased in the S and G2/M phase, which was negatively correlated to βTrCP levels in the HEK293 cell cycle. Knockdown of βTrCP caused arrest of the G0/G1 phase, which could be partly rescued by down-regulation of DYRK1A. Our study uncovered a new regulatory mechanism of DYRK1A degradation by SCFβTrCP in HEK293 cell cycle progression. PMID:27807027

  3. An ELISA DYRK1A non-radioactive assay suitable for the characterization of inhibitors

    PubMed Central

    Liu, Yong; Adayev, Tatyana; Hwang, Yu-Wen

    2017-01-01

    The DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) gene encodes a proline-directed Ser/Thr kinase. Elevated expression and/or altered distribution of the kinase have been implicated in the neurological impairments associated with Down syndrome (DS) and Alzheimer’s disease (AD). Consequently, DYRK1A inhibition has been of significant interest as a potential strategy for therapeutic intervention of DS and AD. Many classes of novel inhibitors have been described in the past decade. Although non-radioactive methods for analyzing DYRK1A inhibition have been developed, methods employing radioactive tracers are still commonly used for quantitative characterization of DYRK1A inhibitors. Here, we present a non-radioactive ELISA assay based on the detection of DYRK1A-phosphorylated dynamin 1a fragment using a phosphorylation site-specific antibody. The assay was verified by the use of two well-characterized DYRK1A inhibitors, epigallocatechin gallate (EGCG) and harmine. The IC 50s for EGCG and harmine determined by the ELISA method were found to be comparable to those previously measured by radioactive tracing methods.  Furthermore, we determined the mode of inhibition for EGCG and harmine by a modification of the ELISA assay. This assay confirms the mode of inhibition of EGCG (non-ATP-competitive) and harmine (ATP-competitive), as previously determined. We conclude that the ELISA platform demonstrated here is a viable alternative to the traditional radioactive tracer assays for analyzing DYRK1A inhibitors. PMID:28163906

  4. Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A.

    PubMed

    Bronicki, Lucas M; Redin, Claire; Drunat, Severine; Piton, Amélie; Lyons, Michael; Passemard, Sandrine; Baumann, Clarisse; Faivre, Laurence; Thevenon, Julien; Rivière, Jean-Baptiste; Isidor, Bertrand; Gan, Grace; Francannet, Christine; Willems, Marjolaine; Gunel, Murat; Jones, Julie R; Gleeson, Joseph G; Mandel, Jean-Louis; Stevenson, Roger E; Friez, Michael J; Aylsworth, Arthur S

    2015-11-01

    The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.

  5. Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

    PubMed Central

    Bronicki, Lucas M; Redin, Claire; Drunat, Severine; Piton, Amélie; Lyons, Michael; Passemard, Sandrine; Baumann, Clarisse; Faivre, Laurence; Thevenon, Julien; Rivière, Jean-Baptiste; Isidor, Bertrand; Gan, Grace; Francannet, Christine; Willems, Marjolaine; Gunel, Murat; Jones, Julie R; Gleeson, Joseph G; Mandel, Jean-Louis; Stevenson, Roger E; Friez, Michael J; Aylsworth, Arthur S

    2015-01-01

    The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures. PMID:25920557

  6. Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth

    PubMed Central

    Pozo, Natividad; Zahonero, Cristina; Fernández, Paloma; Liñares, Jose M.; Ayuso, Angel; Hagiwara, Masatoshi; Pérez, Angel; Ricoy, Jose R.; Hernández-Laín, Aurelio; Sepúlveda, Juan M.; Sánchez-Gómez, Pilar

    2013-01-01

    Glioblastomas (GBMs) are very aggressive tumors that are resistant to conventional chemo- and radiotherapy. New molecular therapeutic strategies are required to effectively eliminate the subpopulation of GBM tumor–initiating cells that are responsible for relapse. Since EGFR is altered in 50% of GBMs, it represents one of the most promising targets; however, EGFR kinase inhibitors have produced poor results in clinical assays, with no clear explanation for the observed resistance. We uncovered a fundamental role for the dual-specificity tyrosine phosphorylation–regulated kinase, DYRK1A, in regulating EGFR in GBMs. We found that DYRK1A was highly expressed in these tumors and that its expression was correlated with that of EGFR. Moreover, DYRK1A inhibition promoted EGFR degradation in primary GBM cell lines and neural progenitor cells, sharply reducing the self-renewal capacity of normal and tumorigenic cells. Most importantly, our data suggest that a subset of GBMs depends on high surface EGFR levels, as DYRK1A inhibition compromised their survival and produced a profound decrease in tumor burden. We propose that the recovery of EGFR stability is a key oncogenic event in a large proportion of gliomas and that pharmacological inhibition of DYRK1A could represent a promising therapeutic intervention for EGFR-dependent GBMs. PMID:23635774

  7. Design and Synthesis of a Library of Lead-Like 2,4-Bisheterocyclic Substituted Thiophenes as Selective Dyrk/Clk Inhibitors

    PubMed Central

    Schmitt, Christian; Kail, Dagmar; Mariano, Marica; Empting, Martin; Weber, Nadja; Paul, Tamara; Hartmann, Rolf W.; Engel, Matthias

    2014-01-01

    The Dyrk family of protein kinases is implicated in the pathogenesis of several diseases, including cancer and neurodegeneration. Pharmacological inhibitors were mainly described for Dyrk1A so far, but in fewer cases for Dyrk1B, Dyrk2 or other isoforms. Herein, we report the development and optimization of 2,4-bisheterocyclic substituted thiophenes as a novel class of Dyrk inhibitors. The optimized hit compounds displayed favorable pharmacokinetic properties and high ligand efficiencies, and inhibited Dyrk1B in intact cells. In a larger selectivity screen, only Clk1 and Clk4 were identified as additional targets of compound 48, but no other kinases frequently reported as off-targets. Interestingly, Dyrk1A is implicated in the regulation of alternative splicing, a function shared with Clk1/Clk4; thus, some of the dual inhibitors might be useful as efficient splicing modulators. A further compound (29) inhibited Dyrk1A and 1B with an IC50 of 130 nM, showing a moderate selectivity over Dyrk2. Since penetration of the central nervous system (CNS) seems possible based on the physicochemical properties, this compound might serve as a lead for the development of potential therapeutic agents against glioblastoma. Furthermore, an inhibitor selective for Dyrk2 (24) was also identified, which might be are suitable as a pharmacological tool to dissect Dyrk2 isoform–mediated functions. PMID:24676346

  8. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitors: a survey of recent patent literature.

    PubMed

    Nguyen, Thu Lan; Fruit, Corinne; Hérault, Yann; Meijer, Laurent; Besson, Thierry

    2017-08-02

    Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a eukaryotic serine-threonine protein kinase belonging to the CMGC group. DYRK1A hyperactivity appears to contribute to the development of a number of human malignancies and to cognitive deficits observed in Down syndrome and Alzheimer's disease. As a result, the DYRK1A kinase represents an attractive target for the synthesis and optimization of pharmacological inhibitors of potential therapeutic interest. Like most tyrosine kinase inhibitors developed up to the market, DYRK1A inhibitors are essentially acting by competing with ATP for binding at the catalytic site of the kinase. Areas covered: This paper reviews patent activity associated with the discovery of synthetic novel heterocyclic molecules inhibiting the catalytic activity of DYRK1A. Expert opinion: Despite the important role of DYRK1A in biological processes and the growing interest in the design of new therapeutic drugs, there are only few patented synthetic DYRK1A inhibitors and most of them were and are still developed by academic research groups, sometimes with industrial partners.

  9. OGS Maintenance

    NASA Image and Video Library

    2010-07-21

    ISS024-E-009246 (21 July 2010) --- NASA astronaut Tracy Caldwell Dyson, Expedition 24 flight engineer, is pictured during troubleshooting operations of the Oxygen Generator System (OGS) hardware and replacement of an H2 (hydrogen) Dome Orbit Replaceable Unit (ORU) in the Destiny laboratory of the International Space Station.

  10. Probing the ATP-Binding Pocket of Protein Kinase DYRK1A with Benzothiazole Fragment Molecules.

    PubMed

    Rothweiler, Ulli; Stensen, Wenche; Brandsdal, Bjørn Olav; Isaksson, Johan; Leeson, Frederick Alan; Engh, Richard Alan; Svendsen, John S Mjøen

    2016-11-10

    DYRK1A has emerged as a potential target for therapies of Alzheimer's disease using small molecules. On the basis of the observation of selective DYRK1A inhibition by firefly d-luciferin, we have explored static and dynamic structural properties of fragment sized variants of the benzothiazole scaffold with respect to DYRK1A using X-ray crystallography and NMR techniques. The compounds have excellent ligand efficiencies and show a remarkable diversity of binding modes in dynamic equilibrium. Binding geometries are determined in part by interactions often considered "weak", including "orthogonal multipolar" types represented by, for example, F-CO, sulfur-aromatic, and halogen-aromatic interactions, together with hydrogen bonds that are modulated by variation of electron withdrawing groups. These studies show how the benzothiazole scaffold is highly promising for the development of therapeutic DYRK1A inhibitors. In addition, the subtleties of the binding interactions, including dynamics, show how full structural studies are required to fully interpret the essential physical determinants of binding.

  11. Characterization of the human DYRK1A promoter and its regulation by the transcription factor E2F1

    PubMed Central

    Maenz, Barbara; Hekerman, Paul; Vela, Eva M; Galceran, Juan; Becker, Walter

    2008-01-01

    Background Overexpression of the human DYRK1A gene due to the presence of a third gene copy in trisomy 21 is thought to play a role in the pathogenesis of Down syndrome. The observation of gene dosage effects in transgenic mouse models implies that subtle changes in expression levels can affect the correct function of the DYRK1A gene product. We have therefore characterized the promoter of the human DYRK1A gene in order to study its transcriptional regulation. Results Transcription start sites of the human DYRK1A gene are distributed over 800 bp within a region previously identified as an unmethylated CpG island. We have identified a new alternative noncoding 5'-exon of the DYRK1A gene which is located 772 bp upstream of the previously described transcription start site. Transcription of the two splicing variants is controlled by non-overlapping promoter regions that can independently drive reporter gene expression. We found no evidence of cell- or tissue-specific promoter usage, but the two promoter regions differed in their activity and their regulation. The sequence upstream of exon 1A (promoter region A) induced about 10-fold higher reporter gene activity than the sequence upstream of exon 1B (promoter region B). Overexpression of the transcription factor E2F1 increased DYRK1A mRNA levels in Saos2 and Phoenix cells and enhanced the activity of promoter region B three- to fourfold. Conclusion The identification of two alternatively spliced transcripts whose transcription is initiated from differentially regulated promoters regions indicates that the expression of the DYRK1A gene is subject to complex control mechanisms. The regulatory effect of E2F1 suggests that DYRK1A may play a role in cell cycle regulation or apoptosis. PMID:18366763

  12. Influence of prenatal EGCG treatment and Dyrk1a dosage reduction on craniofacial features associated with Down syndrome.

    PubMed

    McElyea, Samantha D; Starbuck, John M; Tumbleson-Brink, Danika M; Harrington, Emily; Blazek, Joshua D; Ghoneima, Ahmed; Kula, Katherine; Roper, Randall J

    2016-09-05

    Trisomy 21 (Ts21) affects craniofacial precursors in individuals with Down syndrome (DS). The resultant craniofacial features in all individuals with Ts21 may significantly affect breathing, eating and speaking. Using mouse models of DS, we have traced the origin of DS-associated craniofacial abnormalities to deficiencies in neural crest cell (NCC) craniofacial precursors early in development. Hypothetically, three copies of Dyrk1a (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), a trisomic gene found in most humans with DS and mouse models of DS, may significantly affect craniofacial structure. We hypothesized that we could improve DS-related craniofacial abnormalities in mouse models using a Dyrk1a inhibitor or by normalizing Dyrk1a gene dosage. In vitro and in vivo treatment with Epigallocatechin-3-gallate (EGCG), a Dyrk1a inhibitor, modulated trisomic NCC deficiencies at embryonic time points. Furthermore, prenatal EGCG treatment normalized some craniofacial phenotypes, including cranial vault in adult Ts65Dn mice. Normalization of Dyrk1a copy number in an otherwise trisomic Ts65Dn mice normalized many dimensions of the cranial vault, but did not correct all craniofacial anatomy. These data underscore the complexity of the gene-phenotype relationship in trisomy and suggest that changes in Dyrk1a expression play an important role in morphogenesis and growth of the cranial vault. These results suggest that a temporally specific prenatal therapy may be an effective way to ameliorate some craniofacial anatomical changes associated with DS.

  13. A dual specificity kinase, DYRK1A, as a potential therapeutic target for head and neck squamous cell carcinoma

    PubMed Central

    Radhakrishnan, Aneesha; Nanjappa, Vishalakshi; Raja, Remya; Sathe, Gajanan; Puttamallesh, Vinuth N.; Jain, Ankit P.; Pinto, Sneha M.; Balaji, Sai A.; Chavan, Sandip; Sahasrabuddhe, Nandini A.; Mathur, Premendu P.; Kumar, Mahesh M.; Prasad, T. S. Keshava; Santosh, Vani; Sukumar, Geethanjali; Califano, Joseph A.; Rangarajan, Annapoorni; Sidransky, David; Pandey, Akhilesh; Gowda, Harsha; Chatterjee, Aditi

    2016-01-01

    Despite advances in clinical management, 5-year survival rate in patients with late-stage head and neck squamous cell carcinoma (HNSCC) has not improved significantly over the past decade. Targeted therapies have emerged as one of the most promising approaches to treat several malignancies. Though tyrosine phosphorylation accounts for a minority of total phosphorylation, it is critical for activation of signaling pathways and plays a significant role in driving cancers. To identify activated tyrosine kinase signaling pathways in HNSCC, we compared the phosphotyrosine profiles of a panel of HNSCC cell lines to a normal oral keratinocyte cell line. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) was one of the kinases hyperphosphorylated at Tyr-321 in all HNSCC cell lines. Inhibition of DYRK1A resulted in an increased apoptosis and decrease in invasion and colony formation ability of HNSCC cell lines. Further, administration of the small molecular inhibitor against DYRK1A in mice bearing HNSCC xenograft tumors induced regression of tumor growth. Immunohistochemical labeling of DYRK1A in primary tumor tissues using tissue microarrays revealed strong to moderate staining of DYRK1A in 97.5% (39/40) of HNSCC tissues analyzed. Taken together our results suggest that DYRK1A could be a novel therapeutic target in HNSCC. PMID:27796319

  14. Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes.

    PubMed

    García-Cerro, Susana; Rueda, Noemí; Vidal, Verónica; Lantigua, Sara; Martínez-Cué, Carmen

    2017-10-01

    The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Aβ, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aβ load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of

  15. Luciferin and derivatives as a DYRK selective scaffold for the design of protein kinase inhibitors.

    PubMed

    Rothweiler, Ulli; Eriksson, Jonas; Stensen, Wenche; Leeson, Frederick; Engh, Richard A; Svendsen, John S

    2015-04-13

    D-Luciferin is widely used as a substrate in luciferase catalysed bioluminescence assays for in vitro studies. However, little is known about cross reactivity and potential interference of D-luciferin with other enzymes. We serendipitously found that firefly luciferin inhibited the CDK2/Cyclin A protein kinase. Inhibition profiling of D-luciferin over a 103-protein kinase panel showed significant inhibition of a small set of protein kinases, in particular the DYRK-family, but also other members of the CMGC-group, including ERK8 and CK2. Inhibition profiling on a 16-member focused library derived from D-luciferin confirms that D-luciferin represents a DYRK-selective chemotype of fragment-like molecular weight. Thus, observation of its inhibitory activity and the initial SAR information reported here promise to be useful for further design of protein kinase inhibitors with related scaffolds. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  16. Library-based discovery of DYRK1A/CLK1 inhibitors from natural product extracts.

    PubMed

    Grabher, Patrick; Durieu, Emilie; Kouloura, Eirini; Halabalaki, Maria; Skaltsounis, Leandros A; Meijer, Laurent; Hamburger, Matthias; Potterat, Olivier

    2012-06-01

    The dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A possesses diverse roles in neuronal development and adult brain physiology, and increased activity has been linked to neurodegenerative diseases. Very few inhibitors of this kinase have been reported up to now. Screening of a library of > 900 plant and fungal extracts afforded 25 extracts with IC₅₀s < 10 µg/mL against DYRK1A. To identify the active constituents, the extracts were submitted to a process integrating physicochemical data with biological information, referred to as HPLC-based activity profiling. Follow-up investigation of four extracts led to the targeted isolation of harmine (1, IC₅₀ 0.022 µM) from Peganum harmala, emodin (3, IC₅₀ 4.2 µM) from Cassia nigricans, kaempferol (4, IC₅₀ 0.91 µM) from Cuscuta chinensis, and 3,8-di-O-methylherbacetin (11, IC₅₀ 8.6 µM), 3,3',4'-tri-O-methylmyricetin (12, IC₅₀ 7.1 µM) and ombuin (15, IC₅₀ 1.7 µM) from Larrea tridentata as the active constituents. Active extracts and compounds were also tested on the closely related cdc2-like kinase CLK1. Finally, the selectivity profile of compounds was evaluated by including other members of the DYRKs and CLKs families. While the flavonoids and emodin did not show significant differences in the potency of their activities, harmine (1) was most active against DYRK1A, CLK1, and CLK4, and less potent against the other kinases, with selectivity ranging from 2- to 20-fold.

  17. Inhibition of DYRK1A Stimulates Human β-Cell Proliferation.

    PubMed

    Dirice, Ercument; Walpita, Deepika; Vetere, Amedeo; Meier, Bennett C; Kahraman, Sevim; Hu, Jiang; Dančík, Vlado; Burns, Sean M; Gilbert, Tamara J; Olson, David E; Clemons, Paul A; Kulkarni, Rohit N; Wagner, Bridget K

    2016-06-01

    Restoring functional β-cell mass is an important therapeutic goal for both type 1 and type 2 diabetes (1). While proliferation of existing β-cells is the primary means of β-cell replacement in rodents (2), it is unclear whether a similar principle applies to humans, as human β-cells are remarkably resistant to stimulation of division (3,4). Here, we show that 5-iodotubercidin (5-IT), an annotated adenosine kinase inhibitor previously reported to increase proliferation in rodent and porcine islets (5), strongly and selectively increases human β-cell proliferation in vitro and in vivo. Remarkably, 5-IT also increased glucose-dependent insulin secretion after prolonged treatment. Kinome profiling revealed 5-IT to be a potent and selective inhibitor of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) and cell division cycle-like kinase families. Induction of β-cell proliferation by either 5-IT or harmine, another natural product DYRK1A inhibitor, was suppressed by coincubation with the calcineurin inhibitor FK506, suggesting involvement of DYRK1A and nuclear factor of activated T cells signaling. Gene expression profiling in whole islets treated with 5-IT revealed induction of proliferation- and cell cycle-related genes, suggesting that true proliferation is induced by 5-IT. Furthermore, 5-IT promotes β-cell proliferation in human islets grafted under the kidney capsule of NOD-scid IL2Rg(null) mice. These results point to inhibition of DYRK1A as a therapeutic strategy to increase human β-cell proliferation.

  18. DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly.

    PubMed

    Litovchick, Larisa; Florens, Laurence A; Swanson, Selene K; Washburn, Michael P; DeCaprio, James A

    2011-04-15

    In the absence of growth signals, cells exit the cell cycle and enter into G0 or quiescence. Alternatively, cells enter senescence in response to inappropriate growth signals such as oncogene expression. The molecular mechanisms required for cell cycle exit into quiescence or senescence are poorly understood. The DREAM (DP, RB [retinoblastoma], E2F, and MuvB) complex represses cell cycle-dependent genes during quiescence. DREAM contains p130, E2F4, DP1, and a stable core complex of five MuvB-like proteins: LIN9, LIN37, LIN52, LIN54, and RBBP4. In mammalian cells, the MuvB core dissociates from p130 upon entry into the cell cycle and binds to BMYB during S phase to activate the transcription of genes expressed late in the cell cycle. We used mass spectroscopic analysis to identify phosphorylation sites that regulate the switch of the MuvB core from BMYB to DREAM. Here we report that DYRK1A can specifically phosphorylate LIN52 on serine residue 28, and that this phosphorylation is required for DREAM assembly. Inhibiting DYRK1A activity or point mutation of LIN52 disrupts DREAM assembly and reduces the ability of cells to enter quiescence or undergo Ras-induced senescence. These data reveal an important role for DYRK1A in the regulation of DREAM activity and entry into quiescence.

  19. 10-Iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A

    PubMed Central

    2015-01-01

    The protein kinase DYRK1A has been suggested to act as one of the intracellular regulators contributing to neurological alterations found in individuals with Down syndrome. For an assessment of the role of DYRK1A, selective synthetic inhibitors are valuable pharmacological tools. However, the DYRK1A inhibitors described in the literature so far either are not sufficiently selective or have not been tested against closely related kinases from the DYRK and the CLK protein kinase families. The aim of this study was the identification of DYRK1A inhibitors exhibiting selectivity versus the structurally and functionally closely related DYRK and CLK isoforms. Structure modification of the screening hit 11H-indolo[3,2-c]quinoline-6-carboxylic acid revealed structure–activity relationships for kinase inhibition and enabled the design of 10-iodo-substituted derivatives as very potent DYRK1A inhibitors with considerable selectivity against CLKs. X-ray structure determination of three 11H-indolo[3,2-c]quinoline-6-carboxylic acids cocrystallized with DYRK1A confirmed the predicted binding mode within the ATP binding site. PMID:25730262

  20. The adaptor protein DCAF7 mediates the interaction of the adenovirus E1A oncoprotein with the protein kinases DYRK1A and HIPK2

    PubMed Central

    Glenewinkel, Florian; Cohen, Michael J.; King, Cason R.; Kaspar, Sophie; Bamberg-Lemper, Simone; Mymryk, Joe S.; Becker, Walter

    2016-01-01

    DYRK1A is a constitutively active protein kinase that has a critical role in growth and development which functions by regulating cell proliferation, differentiation and survival. DCAF7 (also termed WDR68 or HAN11) is a cellular binding partner of DYRK1A and also regulates signalling by the protein kinase HIPK2. DCAF7 is an evolutionarily conserved protein with a single WD40 repeat domain and has no catalytic activity. We have defined a DCAF7 binding motif of 12 amino acids in the N-terminal domain of class 1 DYRKs that is functionally conserved in DYRK1 orthologs from Xenopus, Danio rerio and the slime mold Dictyostelium discoideum. A similar sequence was essential for DCAF7 binding to HIPK2, whereas the closely related HIPK1 family member did not bind DCAF7. Immunoprecipitation and pulldown experiments identified DCAF7 as an adaptor for the association of the adenovirus E1A protein with DYRK1A and HIPK2. Furthermore, DCAF7 was required for the hyperphosphorylation of E1A in DYRK1A or HIPK2 overexpressing cells. Our results characterize DCAF7 as a substrate recruiting subunit of DYRK1A and HIPK2 and suggest that it is required for the negative effect of DYRK1A on E1A-induced oncogenic transformation. PMID:27307198

  1. Potent and Selective Small Molecule Inhibitors of Specific Isoforms of Cdc2-like Kinases (Clk) and Dual Specificity Tyrosine-Phosphorylation-Regulated Kinases (Dyrk)

    PubMed Central

    Rosenthal, Andrew S.; Tanega, Cordelle; Shen, Min; Mott, Bryan T.; Bougie, James M.; Nguyen, Dac-Trung; Misteli, Tom; Auld, Douglas S.; Maloney, David J.; Thomas, Craig J.

    2011-01-01

    Continued examination of substituted 6-arylquinazolin-4-amines as Clk4 inhibitors resulted in selective inhibitors of Clk1, Clk4, Dyrk1A and Dyrk1B. Several of the most potent inhibitors were validated as being highly selective within a comprehensive kinome scan. PMID:21450467

  2. The Link Between DYRK1A Overexpression and Several-fold Enhancement of Neurofibrillary Degeneration with 3-Repeat Tau Protein in Down Syndrome

    PubMed Central

    Wegiel, Jerzy; Kaczmarski, Wojciech; Barua, Madhabi; Kuchna, Izabela; Nowicki, Krzysztof; Wang, Kuo-Chiang; Wegiel, Jarek; Ma, Shuang Yang; Frackowiak, Janusz; Mazur-Kolecka, Bozena; Silverman, Wayne P.; Reisberg, Barry; Monteiro, Isabel; Leon, Mony de; Wisniewski, Thomas; Dalton, Arthur; Lai, Florence; Hwang, Yu-Wen; Adayev, Tatyana; Liu, Fei; Iqbal, Khalid; Iqbal, Inge-Grundke; Gong, Cheng-Xin

    2011-01-01

    Triplication of chromosome 21 in Down syndrome (DS) results in overexpression of the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A gene (DYRK1A). DYRK1A phosphorylates cytoplasmic tau protein and appears in intraneuronal neurofibrillary tangles (NFTs). We have previously shown significantly more DYRK1A-positive NFTs in DS brains than in sporadic Alzheimer disease (AD) brains. This study demonstrates a gene dosage–proportional increase in the level of DYRK1A in DS in the cytoplasm and the cell nucleus and enhanced cytoplasmic and nuclear immunoreactivity of DYRK1A in DS. The results suggest that overexpressed DYRK1A may alter both phosphorylation of tau and alternative splicing factor (ASF). Two-dimensional electrophoresis revealed modification of ASF phosphorylation in DS/AD and AD in comparison to controls. Altered phosphorylation of ASF by overexpressed nuclear DYRK1A may contribute to the alternative splicing of the tau gene and an increase by 2.68× of the 3R/4R ratio in DS/AD, and a several-fold increase in the number of 3R-tau–positive NFTs in DS/AD subjects compared to in sporadic AD subjects. These data support the hypothesis that phosphorylation of ASF by overexpressed DYRK1A may contribute to alternative splicing of exon 10, increased expression of 3R tau, and early onset of neurofibrillary degeneration in DS. PMID:21157379

  3. AV dissociation, an inevitable response.

    PubMed

    Wang, Kyuhyun; Benditt, David G

    2011-07-01

    The independent activation of the atria and ventricles, AV dissociation, is a common phenomenon that occurs during a wide variety of electrophysiologic circumstances. The clinical significance of AV dissociation is often misunderstood. This article examines the basis and clinical implications of AV dissociation. AV dissociation is often an obligatory, secondary phenomenon, and should not be construed as the primary disorder; it may be due to either the AV conduction system being completely blocked (3° AV block) or the P wave and the QRS complex being generated from separate sources (usually, the AV junction or ventricle) but occurring close together during the physiologic refractory period of each other. The latter may happen in junctional or ventricular arrhythmias including escape or accelerated rhythm, tachycardia, or premature beats. The crucial clinical point is not the AV dissociation itself, but that an underlying triggering primary disorder is present and should be identified. ©2011, Wiley Periodicals, Inc.

  4. DYRK2 Negatively Regulates Cardiomyocyte Growth by Mediating Repressor Function of GSK-3β on eIF2Bε

    PubMed Central

    Hagenmueller, Marco; Streit, Marcus R.; Malekar, Pratima; Riffel, Johannes H.; Buss, Sebastian J.; Weiss, Karl H.; Sadoshima, Junichi; Katus, Hugo A.; Hardt, Stefan E.

    2013-01-01

    Background A prerequisite of hypertrophic response of the myocardium is an increase in protein synthesis. A central regulator of translation initiation is Eukaryotic initiation factor 2B (eIF2B). Here we assessed the hypothesis that regulation of protein synthesis via eIF2Bε is essential to cardiac hypertrophic response in vivo. Methods Two transgenic mouse lines were generated with cardiac restricted overexpression of eIF2Bε or its mutant eIF2Bε-eIFS535A, which cannot be inactivated by phosphorylation through GSK-3β. Results (1) Under baseline conditions eIF2Bε transgenic mice showed no difference in cardiac phenotype compared to wild type, whereas in the mutant eIF2Bε-S535A an increase in LV/tibia length (7.5±0.4 mg/mm vs. 6.2±0.2 mg/mm, p<0.001) and cardiomyocyte cross sectional area (13004±570 vs. 10843±347 RU, p<0.01) was observed. (2) Cardiac overexpression of eIF2Bε did not change the response of the heart to pathologic stress induced by chronic isoproterenol treatment. (3) Cardiac overexpression of the eIF2Bε transgene was followed by overexpression of DYRK2 which is known to prime the inhibitory action of GSK-3β on eIF2Bε, while DYRK1A and GSK-3β itself were not increased. (4) In C57BL/6 mice after 48 h of isoproterenol-stimulation or aortic banding, eIF2Bε was increased and DYRK2 was concomitantly decreased. (5) In line with these in vivo findings, siRNA knockdown of DYRK2 in cultured cardiomyocytes resulted in decreased levels of p(S535)- eIF2Bε, (6) whereas adenoviral induced overexpression of DYRK2 was accompanied by clearly increased phosphorylation of eIF2Bε, indicating a coordinated response pattern (7) Adenoviral induced overexpression of DYRK2 leads to significantly reduced cardiomyocyte size and diminishes hypertrophic response to adrenergic stimulation. Conclusions The interaction of GSK-3β and its priming kinase DYRK2 regulate the activity of eIF2Bε in cardiac myocytes. DYRK2 is a novel negative regulator of cardiomyocyte

  5. DYRK1B as therapeutic target in Hedgehog/GLI-dependent cancer cells with Smoothened inhibitor resistance.

    PubMed

    Gruber, Wolfgang; Hutzinger, Martin; Elmer, Dominik Patrick; Parigger, Thomas; Sternberg, Christina; Cegielkowski, Lukasz; Zaja, Mirko; Leban, Johann; Michel, Susanne; Hamm, Svetlana; Vitt, Daniel; Aberger, Fritz

    2016-02-09

    A wide range of human malignancies displays aberrant activation of Hedgehog (HH)/GLI signaling, including cancers of the skin, brain, gastrointestinal tract and hematopoietic system. Targeting oncogenic HH/GLI signaling with small molecule inhibitors of the essential pathway effector Smoothened (SMO) has shown remarkable therapeutic effects in patients with advanced and metastatic basal cell carcinoma. However, acquired and de novo resistance to SMO inhibitors poses severe limitations to the use of SMO antagonists and urgently calls for the identification of novel targets and compounds.Here we report on the identification of the Dual-Specificity-Tyrosine-Phosphorylation-Regulated Kinase 1B (DYRK1B) as critical positive regulator of HH/GLI signaling downstream of SMO. Genetic and chemical inhibition of DYRK1B in human and mouse cancer cells resulted in marked repression of HH signaling and GLI1 expression, respectively. Importantly, DYRK1B inhibition profoundly impaired GLI1 expression in both SMO-inhibitor sensitive and resistant settings. We further introduce a novel small molecule DYRK1B inhibitor, DYRKi, with suitable pharmacologic properties to impair SMO-dependent and SMO-independent oncogenic GLI activity. The results support the use of DYRK1B antagonists for the treatment of HH/GLI-associated cancers where SMO inhibitors fail to demonstrate therapeutic efficacy.

  6. Design and synthesis of thiazolo[5,4-f]quinazolines as DYRK1A inhibitors, part II.

    PubMed

    Foucourt, Alicia; Hédou, Damien; Dubouilh-Benard, Carole; Girard, Angélique; Taverne, Thierry; Casagrande, Anne-Sophie; Désiré, Laurent; Leblond, Bertrand; Besson, Thierry

    2014-09-26

    The convenient synthesis of a focused library (forty molecules) of novel 6,6,5-tricyclic thiazolo[5,4-f]quinazolines was realized mainly under microwave irradiation. A novel 6-aminobenzo[d]thiazole-2,7-dicarbonitrile (1) was used as a versatile molecular platform for the synthesis of various derivatives. Kinase inhibition, of the obtained final compounds, was evaluated on a panel of two kinases (DYRK1A/1B) together with some known reference DYRK1A and DYRK1B inhibitors (harmine, TG003, NCGC-00189310 and leucettine L41). Compound IC50 values were obtained and compared. Five of the novel thiazolo[5,4-f]quinazoline derivatives prepared, EHT 5372 (8c), EHT 6840 (8h), EHT 1610 (8i), EHT 9851 (8k) and EHT 3356 (9b) displayed single-digit nanomolar or subnanomolar IC50 values and are among the most potent DYRK1A/1B inhibitors disclosed to date. DYRK1A/1B kinases are known to be involved in the regulation of various molecular pathways associated with oncology, neurodegenerative diseases (such as Alzheimer disease, AD, or other tauopathies), genetic diseases (such as Down Syndrome, DS), as well as diseases involved in abnormal pre-mRNA splicing. The compounds described in this communication constitute a highly potent set of novel molecular probes to evaluate the biology/pharmacology of DYR1A/1B in such diseases.

  7. Developing DYRK inhibitors derived from the meridianins as a means of increasing levels of NFAT in the nucleus.

    PubMed

    Shaw, Simon J; Goff, Dane A; Lin, Nan; Singh, Rajinder; Li, Wei; McLaughlin, John; Baltgalvis, Kristen A; Payan, Donald G; Kinsella, Todd M

    2017-06-01

    A structure-activity relationship has been developed around the meridianin scaffold for inhibition of Dyrk1a. The compounds have been focussed on the inhibition of kinase Dyrk1a, as a means to retain the transcription factor NFAT in the nucleus. NFAT is responsible for up-regulation of genes responsible for the induction of a slow, oxidative skeletal muscle phenotype, which may be an effective treatment for diseases where exercise capacity is compromised. The SAR showed that while strong Dyrk1a binding was possible with the meridianin scaffold the compounds have no effect on NFAT localisation, however, by moving from the indole to a 6-azaindole scaffold both potent Dyrk1a binding and increased NFAT residence time in the nucleus were obtained - properties not observed with the reported Dyrk1a inhibitors. One compound was shown to be effective in an ex vivo muscle fiber assay. The increased biological activity is thought to arise from the added interaction between the azaindole nitrogen and the lysine residue in the back pocket. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID.

    PubMed

    van Bon, B W M; Coe, B P; Bernier, R; Green, C; Gerdts, J; Witherspoon, K; Kleefstra, T; Willemsen, M H; Kumar, R; Bosco, P; Fichera, M; Li, D; Amaral, D; Cristofoli, F; Peeters, H; Haan, E; Romano, C; Mefford, H C; Scheffer, I; Gecz, J; de Vries, B B A; Eichler, E E

    2016-01-01

    Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 × 10(-10)) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.

  9. DYRK1B as therapeutic target in Hedgehog/GLI-dependent cancer cells with Smoothened inhibitor resistance

    PubMed Central

    Gruber, Wolfgang; Hutzinger, Martin; Elmer, Dominik Patrick; Parigger, Thomas; Sternberg, Christina; Cegielkowski, Lukasz; Zaja, Mirko; Leban, Johann; Michel, Susanne; Hamm, Svetlana; Vitt, Daniel; Aberger, Fritz

    2016-01-01

    A wide range of human malignancies displays aberrant activation of Hedgehog (HH)/GLI signaling, including cancers of the skin, brain, gastrointestinal tract and hematopoietic system. Targeting oncogenic HH/GLI signaling with small molecule inhibitors of the essential pathway effector Smoothened (SMO) has shown remarkable therapeutic effects in patients with advanced and metastatic basal cell carcinoma. However, acquired and de novo resistance to SMO inhibitors poses severe limitations to the use of SMO antagonists and urgently calls for the identification of novel targets and compounds. Here we report on the identification of the Dual-Specificity-Tyrosine-Phosphorylation-Regulated Kinase 1B (DYRK1B) as critical positive regulator of HH/GLI signaling downstream of SMO. Genetic and chemical inhibition of DYRK1B in human and mouse cancer cells resulted in marked repression of HH signaling and GLI1 expression, respectively. Importantly, DYRK1B inhibition profoundly impaired GLI1 expression in both SMO-inhibitor sensitive and resistant settings. We further introduce a novel small molecule DYRK1B inhibitor, DYRKi, with suitable pharmacologic properties to impair SMO-dependent and SMO-independent oncogenic GLI activity. The results support the use of DYRK1B antagonists for the treatment of HH/GLI-associated cancers where SMO inhibitors fail to demonstrate therapeutic efficacy. PMID:26784250

  10. Generation of improved human cerebral organoids from single copy DYRK1A knockout induced pluripotent stem cells in trisomy 21: hypothetical solutions for neurodevelopmental models and therapeutic alternatives in down syndrome.

    PubMed

    Çağlayan, E Sacide

    2016-12-01

    Dual-specificity thyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a strong therapeutic target to ameliorate cognitive functions of Down Syndrome (DS). Genetic normalization of Dyrk1a is sufficient to normalize early cortical developmental phenotypes in DS mouse models. Gyrencephalic human neocortical development is more complex than that in lissencephalic mice; hence, cerebral organoids (COs) can be used to model early neurodevelopmental defects of DS. Single copy DYRK1A knockout COs (scDYRK1AKO-COs) can be generated from manipulated DS derived (DS-) induced pluripotent stem cells (iPSCs) and genetic normalization of DYRK1A is expected to result in corrected neurodevelopmental phenotypes that can be reminiscent of normal COs. DYRK1A knock-in (DYRK1AKI) COs can be derived after genetic manipulations of normal iPSCs and would be valuable to evaluate impaired neocortical development as can be seen in DS-COs. DYRK1A mutations cause severe human primary microcephaly; hence, dose optimization studies of DYRK1A inhibitors will be critical for prenatal therapeutic applications in DS. Several doses of DYRK1A inhibitors can be tested in the neurodevelopment process of DS-COs and DS-scDYRK1AKO-COs would be used as optimum models for evaluating phenotypic ameliorations. Overdose drug exposure in DS-COs can be explained by similar defects present in DS-baDYRK1AKO-COs and DYRK1AKO-COs. There are several limitations in the current CO technology, which can be reduced by the generation of vascularized brain-like organoids giving opportunities to mimic late-stage corticogenesis and complete hippocampal development. In the future, improved DS-DYRK1AKO-COs can be efficient in studies that aim to generate efficiently transplantable and implantable neurons for tissue regeneration alternatives in DS individuals. © 2016 International Federation for Cell Biology.

  11. Apparent AV junctional escape in Wenckebach AV block: markedly slow conduction through the slow AV pathway.

    PubMed

    Kinoshita, Shinji; Katoh, Takakazu; Hagisawa, Kohsuke; Fukushima, Tsutomu; Ikawa, Shinji

    2009-02-01

    We report here two cases of Wenckebach atrioventricular (AV) block in which apparent AV junctional escape was observed, but most likely resulted from markedly slow conduction through the slow pathway of dual AV junctional pathways. In these cases, it seems that a blocked P-wave was followed by an AV junctional escape beat. However, a blocked P-wave occasionally failed to be followed by an escape beat, and the RR interval containing the blocked P-wave was markedly longer than the above escape interval. In one case, apparent AV junctional escape beats with aberrant ventricular conduction were found, and QRS complexes of the same configuration were also found without the preceding ventricular pause. This strengthens the possibility that apparent AV junctional escape occurred because of markedly slow conduction through the slow AV pathway.

  12. Dyrk1A overexpression leads to increase of 3R-tau expression and cognitive deficits in Ts65Dn Down syndrome mice.

    PubMed

    Yin, Xiaomin; Jin, Nana; Shi, Jianhua; Zhang, Yanchong; Wu, Yue; Gong, Cheng-Xin; Iqbal, Khalid; Liu, Fei

    2017-04-04

    Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats, 3R-tau and 4R-tau, which is equally expressed in adult human brain. Imbalanced expression in 3R-tau and 4R-tau has been found in several sporadic and inherited tauopathies, suggesting that dysregulation of tau exon 10 is sufficient to cause neurodegenerative diseases. We previously reported that Dyrk1A, which is overexpressed in Down syndrome brains, regulates alternative splicing of exogenous tau exon 10. In the present study, we investigated the regulation of endogenous tau exon 10 splicing by Dyrk1A. We found that inhibition of Dyrk1A enhanced tau exon 10 inclusion, leading to an increase in 4R-tau/3R-tau ratio in differentiated-human neuronal progenitors and in the neonatal rat brains. Accompanied with overexpression of Dyrk1A, 3R-tau was increased and 4R-tau was decreased in the neonatal brains of Ts65Dn mice, a model of Down syndrome. Treatment with Dyrk1A inhibitor, green tea flavonol epigallocatechin-gallate (EGCG), from gestation to adulthood suppressed 3R-tau expression and rescued anxiety and memory deficits in Ts65Dn mouse brains. Thus, Dyrk1A might be an ideal therapeutic target for Alzheimer's disease, especially for Down syndrome and EGCG which inhibits Dyrk1A may have potential effect on the treatment or prevention of this disease.

  13. Decrease of miR-622 expression suppresses migration and invasion by targeting regulation of DYRK2 in colorectal cancer cells

    PubMed Central

    Wang, Yong; Sun, Jie; Wei, Xilin; Luan, Lan; Zeng, Xiandong; Wang, Cuifang; Zhao, Wei

    2017-01-01

    Background More and more evidence indicates that microRNAs are present and involved in many tumor-related diseases. The function of microRNA-622 (miR-622) in colorectal cancer (CRC) remains controversial. Dual specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) has been reported as a tumor suppressor gene in different cancers. The detailed regulation mechanism of DYRK2 in CRC remains unclear. Methods miR-622 and DYRK2 expression levels were detected at tissue and cellular level respectively by using real time polymerase chain reaction (PCR), Western blot, and immunohistochemical staining. Pearson’s correlation analysis was used to evaluate the correlation between miR-622 and DYRK2. Transwell assay was applied to measure the effect of miR-622 on migration and invasion of SW1116 and SW480. We used dual luciferase reporter assay to confirm the targeted binding effect of miR-622 and DYRK2 3′-untranslated region (3′UTR). An antisense experiment was executed to further confirm the role miR-622 had played with regard to migration and invasion by targeting regulation of DYRK2 pathway in CRC cells. Results In our research, we found that the expression of miR-622 was elevated in CRC tissues and cell lines compared to that of nonCRC tissues and the normal human colon epithelial cell line NCM460. Correspondingly, the expression of DYRK2 in CRC tissues and cell lines showed a contrary tendency. The different expression level of DYRK2 was closely correlated with clinicopathological characteristics of CRC patients. We demonstrated that down-regulation of miR-622 could inhibit the ability of migration and invasion of CRC cell lines SW1116 and SW480. Also, we confirmed that DYRK2 was negatively regulated by miR-622 via a specific targeted binding site within the 3′UTR. We finally verified that the migration and invasion ability of CRC cells in the conducted DYRK2 3′UTR defect plasmid transfection group were lower compared to miR-622 and cotransfection group

  14. Distinctive Phenotypic Abnormalities Associated with Submicroscopic 21q22 Deletion Including DYRK1A

    PubMed Central

    Oegema, R.; de Klein, A.; Verkerk, A.J.; Schot, R.; Dumee, B.; Douben, H.; Eussen, B.; Dubbel, L.; Poddighe, P.J.; van der Laar, I.; Dobyns, W.B.; van der Spek, P.J.; Lequin, M.H.; de Coo, I.F.M.; de Wit, M.-C.Y.; Wessels, M.W.; Mancini, G.M.S.

    2010-01-01

    Partial monosomy 21 has been reported, but the phenotypes described are variable with location and size of the deletion. We present 2 patients with a partially overlapping microdeletion of 21q22 and a striking phenotypic resemblance. They both presented with severe psychomotor delay, behavioral problems, no speech, microcephaly, feeding problems with frequent regurgitation, idiopathic thrombocytopenia, obesity, deep set eyes, down turned corners of the mouth, dysplastic ears, and small chin. Brain MRI showed cerebral atrophy mostly evident in frontal and temporal lobes, widened ventricles and thin corpus callosum in both cases, and in one patient evidence of a migration disorder. The first patient also presented with epilepsy and a ventricular septum defect. The second patient had a unilateral Peters anomaly. Microarray analysis showed a partially overlapping microdeletion spanning about 2.5 Mb in the 21q22.1–q22.2 region including the DYRK1A gene and excluding RUNX1. These patients present with a recognizable phenotype specific for this 21q22.1–q22.2 locus. We searched the literature for patients with overlapping deletions including the DYRK1A gene, in order to define other genes responsible for this presentation. PMID:21031080

  15. Restrained Phosphatidylcholine Synthesis in a Cellular Model of Down's Syndrome is Associated with the Overexpression of Dyrk1A.

    PubMed

    Hijazi, Maruan; Medina, José M; Velasco, Ana

    2017-03-01

    Aberrant formation of the cerebral cortex could be attributed to the lack of suitable substrates that direct the migration of neurons. Previous work carried out at our laboratory has shown that oleic acid is a neurotrophic factor. In order to characterize the effect of oleic acid in a cellular model of Down's syndrome (DS), here, we used immortalized cell lines derived from the cortex of trisomy Ts16 and euploid mice. We report that in the plasma membrane of euploid cells, an increase in phosphatidylcholine concentrations occurs in the presence of oleic acid. However, in trisomic cells, oleic acid failed to increase phosphatidylcholine incorporation into the plasma membrane. Gene expression analysis of trisomic cells revealed that the phosphatidylcholine biosynthetic pathway was deregulated. Taken together, these results suggest that the overdose of specific genes in trisomic lines delays differentiation in the presence of oleic acid. The dual-specificity tyrosine (Y) phosphorylation-regulated kinase 1A (DYRK1A) gene is located on human chromosome 21. DYRK1A contributes to intellectual disability and the early onset of Alzheimer's disease in DS patients. Here, we explored the potential role of Dyrk1A in the reduction of phosphatidylcholine concentrations in trisomic cells in the presence of oleic acid. The downregulation of Dyrk1A by small interfering RNA (siRNA) in trisomic cells returned phosphatidylcholine concentrations up to similar levels to those of euploid cells in the presence of oleic acid. Thus, our results highlight the role of Dyrk1A in brain development through the modulation of phosphatidylcholine location, levels and synthesis.

  16. Case report of novel DYRK1A mutations in 2 individuals with syndromic intellectual disability and a review of the literature.

    PubMed

    Luco, Stephanie M; Pohl, Daniela; Sell, Erick; Wagner, Justin D; Dyment, David A; Daoud, Hussein

    2016-02-27

    Chromosomal deletions encompassing DYRK1A have been associated with intellectual disability for several years. More recently, point mutations in DYRK1A have been shown to be responsible for a recognizable syndrome characterized by microcephaly, developmental delay and intellectual disability (ID) as well as characteristic facial features. Here we present 2 individuals with novel mutations in DYRK1A, and a review of the cases reported to date. Both individuals presented with the well-known characteristic features, as well as rarer anomalies seen in a minority of patients. Patient 1 presented shortly after birth with an enlarged cisterna magna, distal contractures, and distinctive facies that included bitemporal narrowing and deep set eyes. A de novo splice site mutation in DYRK1A [c.951 + 4_951 + 7delAGTA; p.Val222Aspfs*22] was identified by next generation sequencing. Patient 2 presented at 7 months of age with microcephaly and dysmorphic features. She went several years without a diagnosis until a de novo DYRK1A nonsense mutation [c.787C>T; p.(Arg263*)] was identified at age 12. These individuals, and the 52 cases reviewed from the literature, show the characteristic features of the DYRK1A-related syndrome including global developmental delay, ID, microcephaly, feeding difficulties, and the facial gestalt. Other common findings include seizures, vision defects, brain abnormalities and skeletal abnormalities of the hands and feet. Less common features include optic nerve defects, contractures, ataxia, and cardiac anomalies. DYRK1A testing should be considered in individuals with the facial features, intellectual disability and post-natal microcephaly. Once diagnosed with DYRK1A-related intellectual disability, a cardiac and ophthalmologic assessment would be recommended as would routine surveillance by a pediatrician for psychomotor development, growth, and feeding.

  17. A novel DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro.

    PubMed

    Coutadeur, Séverine; Benyamine, Hélène; Delalonde, Laurence; de Oliveira, Catherine; Leblond, Bertrand; Foucourt, Alicia; Besson, Thierry; Casagrande, Anne-Sophie; Taverne, Thierry; Girard, Angélique; Pando, Matthew P; Désiré, Laurent

    2015-05-01

    The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene is located within the Down Syndrome (DS) critical region on chromosome 21 and is implicated in the generation of Tau and amyloid pathologies that are associated with the early onset Alzheimer's Disease (AD) observed in DS. DYRK1A is also found associated with neurofibrillary tangles in sporadic AD and phosphorylates key AD players (Tau, amyloid precursor, protein, etc). Thus, DYRK1A may be an important therapeutic target to modify the course of Tau and amyloid beta (Aβ) pathologies. Here, we describe EHT 5372 (methyl 9-(2,4-dichlorophenylamino) thiazolo[5,4-f]quinazoline-2-carbimidate), a novel, highly potent (IC50 = 0.22 nM) DYRK1A inhibitor with a high degree of selectivity over 339 kinases. Models in which inhibition of DYRK1A by siRNA reduced and DYRK1A over-expression induced Tau phosphorylation or Aβ production were used. EHT 5372 inhibits DYRK1A-induced Tau phosphorylation at multiple AD-relevant sites in biochemical and cellular assays. EHT 5372 also normalizes both Aβ-induced Tau phosphorylation and DYRK1A-stimulated Aβ production. DYRK1A is thus as a key element of Aβ-mediated Tau hyperphosphorylation, which links Tau and amyloid pathologies. EHT 5372 and other compounds in its class warrant in vivo investigation as a novel, high-potential therapy for AD and other Tau opathies. Inhibition of the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a new high-potential therapeutic approach for Alzheimer disease. Here we describe EHT 5372, a novel potent and selective DYRK1A inhibitor. EHT 5372 inhibits DYRK1A-induced Tau phosphorylation, Aβ production and Aβ effects on phospho-Tau, including Tau aggregation.

  18. Dyrk1A Is Dynamically Expressed on Subsets of Motor Neurons and in the Neuromuscular Junction: Possible Role in Down Syndrome

    PubMed Central

    Arque, Gloria; Casanovas, Anna; Dierssen, Mara

    2013-01-01

    Individuals with Down syndrome (DS) present important motor deficits that derive from altered motor development of infants and young children. DYRK1A, a candidate gene for DS abnormalities has been implicated in motor function due to its expression in motor nuclei in the adult brain, and its overexpression in DS mouse models leads to hyperactivity and altered motor learning. However, its precise role in the adult motor system, or its possible involvement in postnatal locomotor development has not yet been clarified. During the postnatal period we observed time-specific expression of Dyrk1A in discrete subsets of brainstem nuclei and spinal cord motor neurons. Interestingly, we describe for the first time the presence of Dyrk1A in the presynaptic terminal of the neuromuscular junctions and its axonal transport from the facial nucleus, suggesting a function for Dyrk1A in these structures. Relevant to DS, Dyrk1A overexpression in transgenic mice (TgDyrk1A) produces motor developmental alterations possibly contributing to DS motor phenotypes and modifies the numbers of motor cholinergic neurons, suggesting that the kinase may have a role in the development of the brainstem and spinal cord motor system. PMID:23342120

  19. Direct Association of Sprouty-related Protein with an EVH1 Domain (SPRED) 1 or SPRED2 with DYRK1A Modifies Substrate/Kinase Interactions*

    PubMed Central

    Li, Dan; Jackson, Rebecca A.; Yusoff, Permeen; Guy, Graeme R.

    2010-01-01

    The mammalian SPRED (Sprouty-related protein with an EVH1 domain) proteins include a family of three members, SPRED1–3. Currently, little is known about their biochemistry. The best described, SPRED1, has been shown to inhibit the Ras/ERK pathway downstream of Ras. All three SPREDs have a cysteine-rich domain (CRD) that has high homology to the CRD of the Sprouty family of proteins, several of which are also Ras/ERK inhibitors. In the belief that binding partners would clarify SPRED function, we assayed for their associated proteins. Here, we describe the direct and endogenous interaction of SPRED1 and SPRED2 with the novel kinase, DYRK1A. DYRK1A has become the subject of recent research focus as it plays a central role in Caenorhabditis elegans oocyte maturation and egg activation, and there is strong evidence that it could be involved in Down syndrome in humans. Both SPRED1 and SPRED2 inhibit the ability of DYRK1A to phosphorylate its substrates, Tau and STAT3. This inhibition occurs via an interaction of the CRD of the SPREDs with the kinase domain of DYRK1A. DYRK1A substrates must bind to the kinase to enable phosphorylation, and SPRED proteins compete for the same binding site to modify this process. Our accumulated evidence indicates that the SPRED proteins are likely physiological modifiers of DYRK1A. PMID:20736167

  20. Insights into mechanism of pyrido[2,3-d]pyrimidines as DYRK1A inhibitors based on molecular dynamic simulations.

    PubMed

    Li, Jiao Jiao; Tian, Yue Li; Zhai, Hong Lin; Lv, Min; Zhang, Xiao Yun

    2016-08-01

    DYRK1A is characterized by the early development and regulation of neuronal proliferation, and its over expression gives rise to neurological abnormalities. As the promising DYRK1A inhibitors, the binding mechanism between DYRK1A and pyrido[2,3-d]pyrimidines derivatives at molecular level are still veiled. In this article, it was achieved to get the structural insights into pyrido[2,3-d]pyrimidines derivatives as DYRK1A inhibitors by means of comprehensive computational approaches involving molecular docking, molecular dynamics simulation, free energy calculation, and energy decomposition analysis. The calculated energy values were highly consistent with the experimental activities. Based on the individual energy terms analysis, the van der Waals interaction was the major leading force in the DYRK1A-ligand interaction. Lys188 was the important residue that formed the hydrogen bond, which improved the inhibitory activity. Furthermore, four novel inhibitors with higher predicted activity were designed based on the obtained findings and confirmed by molecular simulations. Our study is expected to provide significant drug design strategy for the development of more promising DYRK1A inhibitors. Proteins 2016; 84:1108-1123. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. Astrometry VLBI in Space (AVS)

    NASA Technical Reports Server (NTRS)

    Cheng, Li-Jen; Reyes, George

    1995-01-01

    This paper describes a proposal for a new space radio astronomy mission for astrometry using Very Long Baseline Interferometry (VLBI) called Astrometry VLBI in Space (AVS). The ultimate goals of AVS are improving the accuracy of radio astrometry measurements to the microarcsecond level in one epoch of measurements and improving the accuracy of the transformation between the inertial radio and optical coordinate reference frames. This study will also assess the impact of this mission on astrophysics astrometry and geophysics.

  2. DYRK1B blocks canonical and promotes non-canonical Hedgehog signaling through activation of the mTOR/AKT pathway

    PubMed Central

    Singh, Rajeev; Dhanyamraju, Pavan Kumar; Lauth, Matthias

    2017-01-01

    Hedgehog (Hh) signaling plays important roles in embryonic development and in tumor formation. Apart from the well-established stimulation of the GLI family of transcription factors, Hh ligands promote the phosphorylation and activation of mTOR and AKT kinases, yet the molecular mechanism underlying these processes are unknown. Here, we identify the DYRK1B kinase as a mediator between Hh signaling and mTOR/AKT activation. In fibroblasts, Hh signaling induces DYRK1B protein expression, resulting in activation of the mTOR/AKT kinase signaling arm. Furthermore, DYRK1B exerts positive and negative feedback regulation on the Hh pathway itself: It negatively interferes with SMO-elicited canonical Hh signaling, while at the same time it provides positive feed-forward functions by promoting AKT-mediated GLI stability. Due to the fact that the mTOR/AKT pathway is itself subject to strong negative feedback regulation, pharmacological inhibition of DYRK1B results in initial upregulation followed by downregulation of AKT phosphorylation and GLI stabilization. Addressing this issue therapeutically, we show that a pharmacological approach combining a DYRK1B antagonist with an mTOR/AKT inhibitor results in strong GLI1 targeting and in pronounced cytotoxicity in human pancreatic and ovarian cancer cells. PMID:27903983

  3. Recent advances in the design, synthesis, and biological evaluation of selective DYRK1A inhibitors: a new avenue for a disease modifying treatment of Alzheimer's?

    PubMed

    Smith, Breland; Medda, Federico; Gokhale, Vijay; Dunckley, Travis; Hulme, Christopher

    2012-11-21

    With 24.3 million people affected in 2005 and an estimated rise to 42.3 million in 2020, dementia is currently a leading unmet medical need and costly burden on public health. Seventy percent of these cases have been attributed to Alzheimer's disease (AD), a neurodegenerative pathology whose most evident symptom is a progressive decline in cognitive functions. Dual specificity tyrosine phosphorylation regulated kinase-1A (DYRK1A) is important in neuronal development and plays a variety of functional roles within the adult central nervous system. The DYRK1A gene is located within the Down syndrome critical region (DSCR) on human chromosome 21 and current research suggests that overexpression of DYRK1A may be a significant factor leading to cognitive deficits in people with Alzheimer's disease (AD) and Down syndrome (DS). Currently, treatment options for cognitive deficiencies associated with Down syndrome, as well as Alzheimer's disease, are extremely limited and represent a major unmet therapeutic need. Small molecule inhibition of DYRK1A activity in the brain may provide an avenue for pharmaceutical intervention of mental impairment associated with AD and other neurodegenerative diseases. We herein review the current state of the art in the development of DYRK1A inhibitors.

  4. Rescue of the abnormal skeletal phenotype in Ts65Dn Down syndrome mice using genetic and therapeutic modulation of trisomic Dyrk1a.

    PubMed

    Blazek, Joshua D; Abeysekera, Irushi; Li, Jiliang; Roper, Randall J

    2015-10-15

    Trisomy 21 causes skeletal alterations in individuals with Down syndrome (DS), but the causative trisomic gene and a therapeutic approach to rescue these abnormalities are unknown. Individuals with DS display skeletal alterations including reduced bone mineral density, modified bone structure and distinctive facial features. Due to peripheral skeletal anomalies and extended longevity, individuals with DS are increasingly more susceptible to bone fractures. Understanding the genetic and developmental origin of DS skeletal abnormalities would facilitate the development of therapies to rescue these and other deficiencies associated with DS. DYRK1A is found in three copies in individuals with DS and Ts65Dn DS mice and has been hypothesized to be involved in many Trisomy 21 phenotypes including skeletal abnormalities. Return of Dyrk1a copy number to normal levels in Ts65Dn mice rescued the appendicular bone abnormalities, suggesting that appropriate levels of DYRK1A expression are critical for the development and maintenance of the DS appendicular skeleton. Therapy using the DYRK1A inhibitor epigallocatechin-3-gallate improved Ts65Dn skeletal phenotypes. These outcomes suggest that the osteopenic phenotype associated with DS may be rescued postnatally by targeting trisomic Dyrk1a.

  5. Recent Advances in the Design, Synthesis, and Biological Evaluation of Selective DYRK1A Inhibitors: A New Avenue for a Disease Modifying Treatment of Alzheimer’s?

    PubMed Central

    2012-01-01

    With 24.3 million people affected in 2005 and an estimated rise to 42.3 million in 2020, dementia is currently a leading unmet medical need and costly burden on public health. Seventy percent of these cases have been attributed to Alzheimer’s disease (AD), a neurodegenerative pathology whose most evident symptom is a progressive decline in cognitive functions. Dual specificity tyrosine phosphorylation regulated kinase-1A (DYRK1A) is important in neuronal development and plays a variety of functional roles within the adult central nervous system. The DYRK1A gene is located within the Down syndrome critical region (DSCR) on human chromosome 21 and current research suggests that overexpression of DYRK1A may be a significant factor leading to cognitive deficits in people with Alzheimer’s disease (AD) and Down syndrome (DS). Currently, treatment options for cognitive deficiencies associated with Down syndrome, as well as Alzheimer’s disease, are extremely limited and represent a major unmet therapeutic need. Small molecule inhibition of DYRK1A activity in the brain may provide an avenue for pharmaceutical intervention of mental impairment associated with AD and other neurodegenerative diseases. We herein review the current state of the art in the development of DYRK1A inhibitors. PMID:23173067

  6. Impaired Spatial Learning Strategies and Novel Object Recognition in Mice Haploinsufficient for the Dual Specificity Tyrosine-Regulated Kinase-1A (Dyrk1A)

    PubMed Central

    Fernández, David; de Lagrán, María Martínez; Arbonés, Maria L.; Dierssen, Mara

    2008-01-01

    Background Pathogenic aneuploidies involve the concept of dosage-sensitive genes leading to over- and underexpression phenotypes. Monosomy 21 in human leads to mental retardation and skeletal, immune and respiratory function disturbances. Most of the human condition corresponds to partial monosomies suggesting that critical haploinsufficient genes may be responsible for the phenotypes. The DYRK1A gene is localized on the human chromosome 21q22.2 region, and has been proposed to participate in monosomy 21 phenotypes. It encodes a dual-specificity kinase involved in neuronal development and in adult brain physiology, but its possible role as critical haploinsufficient gene in cognitive function has not been explored. Methodology/Principal Findings We used mice heterozygous for a Dyrk1A targeted mutation (Dyrk1A+/−) to investigate the implication of this gene in the cognitive phenotypes of monosomy 21. Performance of Dyrk1A+/− mice was assayed 1/ in a navigational task using the standard hippocampally related version of the Morris water maze, 2/ in a swimming test designed to reveal potential kinesthetic and stress-related behavioral differences between control and heterozygous mice under two levels of aversiveness (25°C and 17°C) and 3/ in a long-term novel object recognition task, sensitive to hippocampal damage. Dyrk1A+/− mice showed impairment in the development of spatial learning strategies in a hippocampally-dependent memory task, they were impaired in their novel object recognition ability and were more sensitive to aversive conditions in the swimming test than euploid control animals. Conclusions/Significance The present results are clear examples where removal of a single gene has a profound effect on phenotype and indicate that haploinsufficiency of DYRK1A might contribute to an impairment of cognitive functions and stress coping behavior in human monosomy 21. PMID:18648535

  7. Identification of a DYRK1A Inhibitor that Induces Degradation of the Target Kinase using Co-chaperone CDC37 fused with Luciferase nanoKAZ

    PubMed Central

    Sonamoto, Rie; Kii, Isao; Koike, Yuka; Sumida, Yuto; Kato-Sumida, Tomoe; Okuno, Yukiko; Hosoya, Takamitsu; Hagiwara, Masatoshi

    2015-01-01

    The protein kinase family includes attractive targets for drug development. Methods for screening of kinase inhibitors remain largely limited to in vitro catalytic assays. It has been shown that ATP-competitive inhibitors antagonize interaction between the target kinase and kinase-specific co-chaperone CDC37 in living cells. Here we show a cell-based method to screen kinase inhibitors using fusion protein of CDC37 with a mutated catalytic 19-kDa component of Oplophorus luciferase, nanoKAZ (CDC37-nanoKAZ). A dual-specificity kinase DYRK1A, an importance of which has been highlighted in Alzheimer’s disease, was targeted in this study. We established 293T cells stably expressing CDC37-nanoKAZ, and analyzed interaction between CDC37-nanoKAZ and DYRK1A. We revealed that DYRK1A interacted with CDC37-nanoKAZ. Importantly, point mutations that affect autophosphorylation strengthened the interaction, thus improving signal/noise ratio of the interaction relative to non-specific binding of CDC37-nanoKAZ. This high signal/noise ratio enabled screening of chemical library that resulted in identification of a potent inhibitor of DYRK1A, named CaNDY. CaNDY induced selective degradation of DYRK1A, and inhibited catalytic activity of recombinant DYRK1A with IC50 value of 7.9 nM by competing with ATP. This method based on a mutant target kinase and a bioluminescence-eliciting co-chaperone CDC37 could be applicable to evaluation and development of inhibitors targeting other kinases. PMID:26234946

  8. Inactivation of Mirk/Dyrk1b Kinase Targets Quiescent Pancreatic Cancer Cells *

    PubMed Central

    Ewton, Daina Z.; Hu, Jing; Vilenchik, Maria; Deng, Xiaobing; Luk, Kin-chun; Polonskaia, Ann; Hoffman, Ann F.; Zipf, Karen; Boylan, John F.; Friedman, Eileen A.

    2011-01-01

    A major problem in the treatment of cancer arises from quiescent cancer cells that are relatively insensitive to most chemotherapeutic drugs and radiation. Such residual cancer cells can cause tumor regrowth or recurrence when they re-enter the cell cycle. Earlier studies demonstrated that levels of the serine/theronine kinase Mirk/dyrk1B are elevated up to 10-fold in quiescent G0 tumor cells, that Mirk uses several mechanisms to block cell cycling, and that Mirk increases expression of antioxidant genes which lower ROS levels and increase quiescent cell viability. We now show that a novel small molecule Mirk kinase inhibitor blocked tumor cells from undergoing reversible arrest in a quiescent G0 state and enabled some cells to exit quiescence. The inhibitor increased cycling in Panc1, AsPc1 and SW620 cells that expressed Mirk, but not in HCT116 cells that did not. Mirk kinase inhibition elevated ROS levels and DNA damage detected by increased phosphorylation of the histone protein H2AX and by S phase checkpoints. The Mirk kinase inhibitor increased cleavage of the apoptotic proteins PARP and caspase 3, and increased tumor cell kill several-fold by gemcitabine and cisplatin. A phenocopy of these effects occurred following Mirk depletion, showing drug specificity. In prior studies Mirk knockout or depletion had no detectable effect on normal tissue, suggesting that the Mirk kinase inhibitor could have a selective effect on cancer cells expressing elevated levels of Mirk kinase. PMID:21878655

  9. Regulated segregation of kinase Dyrk1A during asymmetric neural stem cell division is critical for EGFR-mediated biased signaling.

    PubMed

    Ferron, Sacri R; Pozo, Natividad; Laguna, Ariadna; Aranda, Sergi; Porlan, Eva; Moreno, Mireia; Fillat, Cristina; de la Luna, Susana; Sánchez, Pilar; Arbonés, María L; Fariñas, Isabel

    2010-09-03

    Stem cell division can result in two sibling cells exhibiting differential mitogenic and self-renewing potential. Here, we present evidence that the dual-specificity kinase Dyrk1A is part of a molecular pathway involved in the regulation of biased epidermal growth factor receptor (EGFR) signaling in the progeny of dividing neural stem cells (NSC) of the adult subependymal zone (SEZ). We show that EGFR asymmetry requires regulated sorting and that a normal Dyrk1a dosage is required to sustain EGFR in the two daughters of a symmetrically dividing progenitor. Dyrk1A is symmetrically or asymmetrically distributed during mitosis, and biochemical analyses indicate that it prevents endocytosis-mediated degradation of EGFR by a mechanism that requires phosphorylation of the EGFR signaling modulator Sprouty2. Finally, Dyrk1a heterozygous NSCs exhibit defects in self-renewal, EGF-dependent cell-fate decisions, and long-term persistence in vivo, suggesting that symmetrical divisions play a role in the maintenance of the SEZ reservoir.

  10. DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome.

    PubMed

    Duchon, Arnaud; Herault, Yann

    2016-01-01

    Down syndrome (DS) is one of the leading causes of intellectual disability, and patients with DS face various health issues, including learning and memory deficits, congenital heart disease, Alzheimer's disease (AD), leukemia, and cancer, leading to huge medical and social costs. Remarkable advances on DS research have been made in improving cognitive function in mouse models for future therapeutic approaches in patients. Among the different approaches, DYRK1A inhibitors have emerged as promising therapeutics to reduce DS cognitive deficits. DYRK1A is a dual-specificity kinase that is overexpressed in DS and plays a key role in neurogenesis, outgrowth of axons and dendrites, neuronal trafficking and aging. Its pivotal role in the DS phenotype makes it a prime target for the development of therapeutics. Recently, disruption of DYRK1A has been found in Autosomal Dominant Mental Retardation 7 (MRD7), resulting in severe mental deficiency. Recent advances in the development of kinase inhibitors are expected, in the near future, to remove DS from the list of incurable diseases, providing certain conditions such as drug dosage and correct timing for the optimum long-term treatment. In addition the exact molecular and cellular mechanisms that are targeted by the inhibition of DYRK1A are still to be discovered.

  11. DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome

    PubMed Central

    Duchon, Arnaud; Herault, Yann

    2016-01-01

    Down syndrome (DS) is one of the leading causes of intellectual disability, and patients with DS face various health issues, including learning and memory deficits, congenital heart disease, Alzheimer’s disease (AD), leukemia, and cancer, leading to huge medical and social costs. Remarkable advances on DS research have been made in improving cognitive function in mouse models for future therapeutic approaches in patients. Among the different approaches, DYRK1A inhibitors have emerged as promising therapeutics to reduce DS cognitive deficits. DYRK1A is a dual-specificity kinase that is overexpressed in DS and plays a key role in neurogenesis, outgrowth of axons and dendrites, neuronal trafficking and aging. Its pivotal role in the DS phenotype makes it a prime target for the development of therapeutics. Recently, disruption of DYRK1A has been found in Autosomal Dominant Mental Retardation 7 (MRD7), resulting in severe mental deficiency. Recent advances in the development of kinase inhibitors are expected, in the near future, to remove DS from the list of incurable diseases, providing certain conditions such as drug dosage and correct timing for the optimum long-term treatment. In addition the exact molecular and cellular mechanisms that are targeted by the inhibition of DYRK1A are still to be discovered. PMID:27375444

  12. HIV-1-Tat Protein Inhibits SC35-mediated Tau Exon 10 Inclusion through Up-regulation of DYRK1A Kinase.

    PubMed

    Kadri, Ferdous; Pacifici, Marco; Wilk, Anna; Parker-Struckhoff, Amanda; Del Valle, Luis; Hauser, Kurt F; Knapp, Pamela E; Parsons, Christopher; Jeansonne, Duane; Lassak, Adam; Peruzzi, Francesca

    2015-12-25

    The HIV-1 transactivator protein Tat is implicated in the neuronal damage that contributes to neurocognitive impairment affecting people living with HIV/AIDS. Aberrant splicing of TAU exon 10 results in tauopathies characterized by alterations in the proportion of TAU isoforms containing three (3R) or four (4R) microtubule-binding repeats. The splicing factor SC35/SRSF2 binds to nuclear RNA and facilitates the incorporation of exon 10 in the TAU molecule. Here, we utilized clinical samples, an animal model, and neuronal cell cultures and found that Tat promotes TAU 3R up-regulation through increased levels of phosphorylated SC35, which is retained in nuclear speckles. This mechanism involved Tat-mediated increased expression of DYRK1A and was prevented by DYRK1A silencing. In addition, we found that Tat associates with TAU RNA, further demonstrating that Tat interferes with host RNA metabolism in the absence of viral infection. Altogether, our data unravel a novel mechanism of Tat-mediated neuronal toxicity through dysregulation of the SC35-dependent alternative splicing of TAU exon 10. Furthermore, the increased immunostaining of DYRK1A in HIV+ brains without pathology points at dysregulation of DYRK1A as an early event in the neuronal complications of HIV infection.

  13. HIV-1-Tat Protein Inhibits SC35-mediated Tau Exon 10 Inclusion through Up-regulation of DYRK1A Kinase*

    PubMed Central

    Kadri, Ferdous; Pacifici, Marco; Wilk, Anna; Parker-Struckhoff, Amanda; Del Valle, Luis; Hauser, Kurt F.; Knapp, Pamela E.; Parsons, Christopher; Jeansonne, Duane; Lassak, Adam; Peruzzi, Francesca

    2015-01-01

    The HIV-1 transactivator protein Tat is implicated in the neuronal damage that contributes to neurocognitive impairment affecting people living with HIV/AIDS. Aberrant splicing of TAU exon 10 results in tauopathies characterized by alterations in the proportion of TAU isoforms containing three (3R) or four (4R) microtubule-binding repeats. The splicing factor SC35/SRSF2 binds to nuclear RNA and facilitates the incorporation of exon 10 in the TAU molecule. Here, we utilized clinical samples, an animal model, and neuronal cell cultures and found that Tat promotes TAU 3R up-regulation through increased levels of phosphorylated SC35, which is retained in nuclear speckles. This mechanism involved Tat-mediated increased expression of DYRK1A and was prevented by DYRK1A silencing. In addition, we found that Tat associates with TAU RNA, further demonstrating that Tat interferes with host RNA metabolism in the absence of viral infection. Altogether, our data unravel a novel mechanism of Tat-mediated neuronal toxicity through dysregulation of the SC35-dependent alternative splicing of TAU exon 10. Furthermore, the increased immunostaining of DYRK1A in HIV+ brains without pathology points at dysregulation of DYRK1A as an early event in the neuronal complications of HIV infection. PMID:26534959

  14. Domitia AV-L-05

    NASA Image and Video Library

    2013-09-28

    This image of Domitia AV-L-05, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19509

  15. Mamilia AV-L-06

    NASA Image and Video Library

    2013-09-28

    This image of Mamilia AV-L-06, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19510

  16. Sextilia AV-L-26

    NASA Image and Video Library

    2013-09-28

    This image of Sextilia AV-L-26, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19530

  17. Aricia AV-L-11

    NASA Image and Video Library

    2013-09-28

    This image of Aricia AV-L-11, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19515

  18. Arruntia AV-L-03

    NASA Image and Video Library

    2013-09-28

    This image of Arruntia AV-L-03, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19507

  19. Serena AV-L-18

    NASA Image and Video Library

    2013-09-28

    This image of Serena AV-L-18, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19522

  20. Justina AV-L-29

    NASA Image and Video Library

    2013-09-28

    This image of Justina AV-L-29, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19533

  1. Rheasilvia AV-L-30

    NASA Image and Video Library

    2013-09-28

    This image of Rheasilvia AV-L-30, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19534

  2. Numisia AV-L-21

    NASA Image and Video Library

    2013-09-28

    This image of Numisia AV-L-21, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19525

  3. Oppia AV-L-22

    NASA Image and Video Library

    2013-09-28

    This image of Oppia AV-L-22, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19526

  4. Licinia AV-L-08

    NASA Image and Video Library

    2013-09-28

    This image of Licinia AV-L-08, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19512

  5. Eusebia AV-L-27

    NASA Image and Video Library

    2013-09-28

    This image of Eusebia AV-L-27, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19531

  6. Claudia AV-L-23

    NASA Image and Video Library

    2013-09-28

    his image of Claudia AV-L-23, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19527

  7. Canuleia AV-L-28

    NASA Image and Video Library

    2013-09-28

    This image of Canuleia AV-L-28, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19532

  8. Fabia AV-L-13

    NASA Image and Video Library

    2013-09-28

    This image of Fabia AV-L-13, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19517

  9. Domna AV-L-17

    NASA Image and Video Library

    2013-09-28

    This image of Domna AV-L-17, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19521

  10. Lepida AV-L-14

    NASA Image and Video Library

    2013-09-28

    This image of Lepida AV-L-14, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19518

  11. Marcia AV-L-12

    NASA Image and Video Library

    2013-09-28

    This image of Marcia AV-L-12, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19516

  12. Caparronia AV-L-04

    NASA Image and Video Library

    2013-09-28

    This image of Caparronia AV-L-04, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19508

  13. Vibidia AV-L-20

    NASA Image and Video Library

    2013-09-28

    This image of Vibidia AV-L-20, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19524

  14. Rubria AV-L-16

    NASA Image and Video Library

    2013-09-28

    This image of Rubria AV-L-16, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19520

  15. Floronia AV-L-07

    NASA Image and Video Library

    2013-09-28

    This image of Floronia AV-L-07, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19511

  16. Octavia AV-L-19

    NASA Image and Video Library

    2013-09-28

    This image of Octavia AV-L-19, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19523

  17. Gegania AV-L-09

    NASA Image and Video Library

    2013-09-28

    This image of Gegania AV-L-09, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19513

  18. Paulina AV-L-15

    NASA Image and Video Library

    2013-09-28

    This image of Paulina AV-L-15, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19519

  19. Eutropia AV-L-10

    NASA Image and Video Library

    2013-09-28

    This image of Eutropia AV-L-10, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19514

  20. Aquilia AV-L-24

    NASA Image and Video Library

    2013-09-28

    This image of Aquilia AV-L-24, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19528

  1. Matronalia AV-L-25

    NASA Image and Video Library

    2013-09-28

    This image of Matronalia AV-L-25, from the atlas of the giant asteroid Vesta, was created from images taken as NASA Dawn mission flew around the object, also known as a protoplanet. The set of maps was created from mosaics of10,000 images from Dawn's framing camera instrument, taken at a low altitude of about 130 miles (210 kilometers). This map is mostly at a scale about that of regional road touring maps, where every inch of map is equivalent to a little more than 3 miles of asteroid (one centimeter equals 2 kilometers). http://photojournal.jpl.nasa.gov/catalog/PIA19529

  2. Syncope and Idiopathic (Paroxysmal) AV Block.

    PubMed

    Brignole, Michele; Deharo, Jean-Claude; Guieu, Regis

    2015-08-01

    Syncope due to idiopathic AV block is characterized by: 1) ECG documentation (usually by means of prolonged ECG monitoring) of paroxysmal complete AV block with one or multiple consecutive pauses, without P-P cycle lengthening or PR interval prolongation, not triggered by atrial or ventricular premature beats nor by rate variations; 2) long history of recurrent syncope without prodromes; 3) absence of cardiac and ECG abnormalities; 4) absence of progression to persistent forms of AV block; 5) efficacy of cardiac pacing therapy. The patients affected by idiopathic AV block have low baseline adenosine plasma level values and show an increased susceptibility to exogenous adenosine. The APL value of the patients with idiopathic AV block is much lower than patients affected by vasovagal syncope who have high adenosine values.

  3. Hyper-accumulation of starch and oil in a Chlamydomonas mutant affected in a plant-specific DYRK kinase.

    PubMed

    Schulz-Raffelt, Miriam; Chochois, Vincent; Auroy, Pascaline; Cuiné, Stéphan; Billon, Emmanuelle; Dauvillée, David; Li-Beisson, Yonghua; Peltier, Gilles

    2016-01-01

    Because of their high biomass productivity and their ability to accumulate high levels of energy-rich reserve compounds such as oils or starch, microalgae represent a promising feedstock for the production of biofuel. Accumulation of reserve compounds takes place when microalgae face adverse situations such as nutrient shortage, conditions which also provoke a stop in cell division, and down-regulation of photosynthesis. Despite growing interest in microalgal biofuels, little is known about molecular mechanisms controlling carbon reserve formation. In order to discover new regulatory mechanisms, and identify genes of interest to boost the potential of microalgae for biofuel production, we developed a forward genetic approach in the model microalga Chlamydomonas reinhardtii. By screening an insertional mutant library on the ability of mutants to accumulate and re-mobilize reserve compounds, we isolated a Chlamydomonas mutant (starch degradation 1, std1) deficient for a dual-specificity tyrosine-phosphorylation-regulated kinase (DYRK). The std1 mutant accumulates higher levels of starch and oil than wild-type and maintains a higher photosynthetic activity under nitrogen starvation. Phylogenetic analysis revealed that this kinase (named DYRKP) belongs to a plant-specific subgroup of the evolutionarily conserved DYRK kinase family. Furthermore, hyper-accumulation of storage compounds occurs in std1 mostly under low light in photoautotrophic condition, suggesting that the kinase normally acts under conditions of low energy status to limit reserve accumulation. The DYRKP kinase is proposed to act as a negative regulator of the sink capacity of photosynthetic cells that integrates nutrient and energy signals. Inactivation of the kinase strongly boosts accumulation of reserve compounds under photoautotrophic nitrogen deprivation and allows maintaining high photosynthetic activity. The DYRKP kinase therefore represents an attractive target for improving the energy density

  4. Arctic Visiting Speakers Series (AVS)

    NASA Astrophysics Data System (ADS)

    Fox, S. E.; Griswold, J.

    2011-12-01

    The Arctic Visiting Speakers (AVS) Series funds researchers and other arctic experts to travel and share their knowledge in communities where they might not otherwise connect. Speakers cover a wide range of arctic research topics and can address a variety of audiences including K-12 students, graduate and undergraduate students, and the general public. Host applications are accepted on an on-going basis, depending on funding availability. Applications need to be submitted at least 1 month prior to the expected tour dates. Interested hosts can choose speakers from an online Speakers Bureau or invite a speaker of their choice. Preference is given to individuals and organizations to host speakers that reach a broad audience and the general public. AVS tours are encouraged to span several days, allowing ample time for interactions with faculty, students, local media, and community members. Applications for both domestic and international visits will be considered. Applications for international visits should involve participation of more than one host organization and must include either a US-based speaker or a US-based organization. This is a small but important program that educates the public about Arctic issues. There have been 27 tours since 2007 that have impacted communities across the globe including: Gatineau, Quebec Canada; St. Petersburg, Russia; Piscataway, New Jersey; Cordova, Alaska; Nuuk, Greenland; Elizabethtown, Pennsylvania; Oslo, Norway; Inari, Finland; Borgarnes, Iceland; San Francisco, California and Wolcott, Vermont to name a few. Tours have included lectures to K-12 schools, college and university students, tribal organizations, Boy Scout troops, science center and museum patrons, and the general public. There are approximately 300 attendees enjoying each AVS tour, roughly 4100 people have been reached since 2007. The expectations for each tour are extremely manageable. Hosts must submit a schedule of events and a tour summary to be posted online

  5. Uptake of AV-1451 in meningiomas.

    PubMed

    Bruinsma, Tyler J; Johnson, Derek R; Fang, Ping; Senjem, Matthew; Josephs, Keith A; Whitwell, Jennifer L; Boeve, Bradley F; Pandey, Mukesh K; Kantarci, Kejal; Jones, David T; Vemuri, Prashanthi; Murray, Melissa; Graff-Radford, Jonathan; Schwarz, Christopher G; Knopman, David S; Petersen, Ronald C; Jack, Clifford R; Lowe, Val J

    2017-09-08

    AV-1451 is an imaging agent labeled with the positron-emitting radiolabel Fluorine-18. 18F-AV-1451 binds paired helical filament tau (PHF-tau), a pathology related to Alzheimer's disease. In our study of AV-1451 uptake in the brains of cognitively normal subjects, we noted a case of a meningioma with visually significant uptake of AV-1451. We initiated the present retrospective study to further examine cases of meningioma that underwent AV-1451 imaging. We searched the patient records of 650 patients who had undergone AV-1451 at our institution for the keyword "meningioma" to identify potential cases. PET/CT and MRI results were visually reviewed and semi-quantitative analysis of PET was performed. A paired student's t test was run between background and tumor standard uptake values. Fisher's exact test was used to examine the association between AV-1451 uptake and presence of calcifications on CT. We identified 12 cases of meningioma, 58% (7/12) of which demonstrated uptake greater than background using both visual analysis and tumor-to-normal cortex ratios (T/N + 1.90 ± 0.83). The paired student's t test revealed no statistically significant difference between background and tumor standard uptake values (p = 0.09); however, cases with a T/N ratio greater than one showed statistically higher uptake in tumor tissue (p = 0.01). A significant association was noted between AV-1451 uptake and presence of calcifications (p = 0.01). AV-1451 PET imaging should be reviewed concurrently with anatomic imaging to prevent misleading interpretations of PHF-tau distribution due to meningiomas.

  6. Phosphorylation of β-Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis

    PubMed Central

    Ori-McKenney, Kassandra M.; McKenney, Richard J.; Huang, Hector H.; Li, Tun; Meltzer, Shan; Jan, Lily Yeh; Vale, Ronald D.; Wiita, Arun P.; Jan, Yuh Nung

    2016-01-01

    SUMMARY Dendritic arborization patterns are consistent anatomical correlates of genetic disorders such as Down syndrome (DS) and autism spectrum disorders (ASD). In a screen for abnormal dendrite development, we identified Minibrain(MNB)/DYRK1a, a kinase implicated in DS and ASD, as a regulator of the microtubule cytoskeleton. We show that MNB is necessary to establish the length and cytoskeletal composition of terminal dendrites by controlling microtubule growth. Altering MNB levels disrupts dendrite morphology and perturbs neuronal electrophysiological activity, resulting in larval mechanosensation defects. Using in vivo and in vitro approaches, we uncover a molecular pathway whereby direct phosphorylation of β-tubulin by MNB inhibits tubulin polymerization, a function that is conserved for mammalian DYRK1a. Our results demonstrate that phospho-regulation of microtubule dynamics by MNB/DYRK1a is critical for dendritic patterning and neuronal function, revealing a previously unidentified mode of post-translational microtubule regulation in neurons and uncovering a conserved pathway for a DS- and ASD-associated kinase. PMID:27112495

  7. Outcomes of AV Fistulas and AV Grafts after Interventional Stent-Graft Deployment in Haemodialysis Patients

    SciTech Connect

    Schmelter, Christopher Raab, Udo; Lazarus, Friedrich; Ruppert, Volker; Vorwerk, Dierk

    2015-08-15

    PurposeThe study was designed to assess outcomes of arteriovenous (AV) accesses after interventional stent-graft deployment in haemodialysis patients.Materials and Methods63 haemodialysis patients with 66 AV fistulas and AV grafts were treated by interventional stent-graft deployment from 2006 to 2012 at our hospital. Data of these patients were retrospectively analysed for location of deployed stent-grafts, occurrence and location of (re-)stenosis and (re-)thrombosis. Complex stenosis was the most frequent indication for stent-graft deployment (45.5 %), followed by complications of angioplasty with vessel rupture or dissection (31.8 %).ResultsA high rate of procedural success was achieved (98.5 %). The most frequent location of the deployed stent-graft was the draining vein (66.7 %). Stent-graft deployment was more frequent in AV grafts than in AV fistulas. Primary patency was 45.5 % at 6 month, 31.3 % at 12 month and 19.2 % at 24 month. Primary patency was significantly better for AV fistulas than for AV grafts with deployed stent-grafts. Patency of the deployed stent-graft was much better than overall AV access primary patency with deployed stent-graft. Re-stenosis with thrombosis was the most frequent indication for re-intervention. Most frequent location of re-stenosis was the draining vein (37.1 %), followed by stenosis at the AV access (29.5 %) and the deployed stent-graft (23.5 %).ConclusionRe-stenosis and re-thrombosis remain frequent in AV fistulas and AV grafts in haemodialysis patients despite stent-graft deployment. Re-stenosis of the deployed stent-graft is, only in the minority of the cases, responsible for AV access dysfunction.

  8. Outcomes of AV Fistulas and AV Grafts after Interventional Stent-Graft Deployment in Haemodialysis Patients.

    PubMed

    Schmelter, Christopher; Raab, Udo; Lazarus, Friedrich; Ruppert, Volker; Vorwerk, Dierk

    2015-08-01

    The study was designed to assess outcomes of arteriovenous (AV) accesses after interventional stent-graft deployment in haemodialysis patients. 63 haemodialysis patients with 66 AV fistulas and AV grafts were treated by interventional stent-graft deployment from 2006 to 2012 at our hospital. Data of these patients were retrospectively analysed for location of deployed stent-grafts, occurrence and location of (re-)stenosis and (re-)thrombosis. Complex stenosis was the most frequent indication for stent-graft deployment (45.5%), followed by complications of angioplasty with vessel rupture or dissection (31.8%). A high rate of procedural success was achieved (98.5%). The most frequent location of the deployed stent-graft was the draining vein (66.7%). Stent-graft deployment was more frequent in AV grafts than in AV fistulas. Primary patency was 45.5% at 6 month, 31.3% at 12 month and 19.2% at 24 month. Primary patency was significantly better for AV fistulas than for AV grafts with deployed stent-grafts. Patency of the deployed stent-graft was much better than overall AV access primary patency with deployed stent-graft. Re-stenosis with thrombosis was the most frequent indication for re-intervention. Most frequent location of re-stenosis was the draining vein (37.1%), followed by stenosis at the AV access (29.5%) and the deployed stent-graft (23.5%). Re-stenosis and re-thrombosis remain frequent in AV fistulas and AV grafts in haemodialysis patients despite stent-graft deployment. Re-stenosis of the deployed stent-graft is, only in the minority of the cases, responsible for AV access dysfunction.

  9. Bradycardia: sinus and AV node dysfunction.

    PubMed

    Pellegrini, Cara N; Scheinman, Melvin M

    2015-09-01

    The surface electrocardiogram (ECG) holds many clues with regard to the etiology of bradycardia and site of atrioventricular (AV) block. Bedside maneuvers may prove helpful in cases of 2:1 AV block or situations where the data is not all concordant. Wenckebach conduction may occur in any region of the heart, and there are nonpathologic mimickers of Mobitz II AV block as well. The surface ECG may aid in the inference of etiology for better than expected or slowed rather than blocked AV conduction. Sinus node dysfunction may present in several forms and often accompanies other conduction system disease. On occasion invasive studies may be required to help elucidate the mechanism of bradycardia.

  10. Subcellular distribution of cyclin-dependent kinase-like 5 (CDKL5) is regulated through phosphorylation by dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).

    PubMed

    Oi, Ami; Katayama, Syouichi; Hatano, Naoya; Sugiyama, Yasunori; Kameshita, Isamu; Sueyoshi, Noriyuki

    2017-01-08

    Cyclin-dependent kinase-like 5 (CDKL5) is a Ser/Thr protein kinase primarily expressed in the central nervous system and is known to cause X-linked neurodevelopmental disorders such as Rett syndrome. However, the mechanisms regulating CDKL5 have not yet been fully clarified. Therefore, in this study, we investigated the protein kinase that directly phosphorylates CDKL5, identifying it as dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), an enzyme binding to and phosphorylating CDKL5. We showed that subcellular distribution of CDKL5 was regulated by its phosphorylation by DYRK1A. In mouse neuroblastoma Neuro2a cells, CDKL5 was localized in both the cytosol and nucleus, whereas DYRK1A showed a typical nuclear localization. When CDKL5 and DYRK1A were co-expressed, the cytosolic localization of CDKL5 was significantly increased. Results of site-directed mutagenesis revealed that the phosphorylation site was Ser-308, in the vicinity of the nuclear localization signal. A mutation mimicking the phosphorylated serine residue by aspartate substitution (S308D) changed CDKL5 localization to the cytosol, whereas the corresponding alanine-substituted analog, CDKL5(S308A), was primarily localized to the nucleus. Taken together, these results strongly suggested that DYRK1A bound to CDKL5 and phosphorylated it on Ser-308, thus interfering with its nuclear localization.

  11. Pharmacophore and 3D-QSAR Characterization of 6-Arylquinazolin-4-amines as Cdc2-like Kinase 4 (Clk4) and Dual Specificity Tyrosine-phosphorylation-regulated Kinase 1A (Dyrk1A) Inhibitors

    PubMed Central

    2013-01-01

    Cdc2-like kinase 4 (Clk4) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) are protein kinases that are promising targets for treatment of diseases caused by abnormal gene splicing. 6-Arylquinazolin-4-amines have been recently identified as potent Clk4 and Dyrk1A inhibitors. In order to understand the structure–activity correlation of these analogs, we have applied ligand-based pharmacophore and 3D-QSAR modeling combined with structure-based homology modeling and docking. The high R2 and Q2 (0.88 and 0.79 for Clk4, 0.85 and 0.82 for Dyrk1A, respectively) based on validation with training and test set compounds suggested that the generated 3D-QSAR models are reliable in predicting novel ligand activities against Clk4 and Dyrk1A. The binding mode identified through docking ligands to the ATP binding domain of Clk4 was consistent with the structural properties and energy field contour maps characterized by pharmacophore and 3D-QSAR models and gave valuable insights into the structure–activity profile of 6-arylquinazolin-4-amine analogs. The obtained 3D-QSAR and pharmacophore models in combination with the binding mode between inhibitor and residues of Clk4 will be helpful for future lead compound identification and optimization to design potent and selective Clk4 and Dyrk1A inhibitors. PMID:23496085

  12. Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome.

    PubMed

    Malinge, Sébastien; Bliss-Moreau, Meghan; Kirsammer, Gina; Diebold, Lauren; Chlon, Timothy; Gurbuxani, Sandeep; Crispino, John D

    2012-03-01

    Individuals with Down syndrome (DS; also known as trisomy 21) have a markedly increased risk of leukemia in childhood but a decreased risk of solid tumors in adulthood. Acquired mutations in the transcription factor-encoding GATA1 gene are observed in nearly all individuals with DS who are born with transient myeloproliferative disorder (TMD), a clonal preleukemia, and/or who develop acute megakaryoblastic leukemia (AMKL). Individuals who do not have DS but bear germline GATA1 mutations analogous to those detected in individuals with TMD and DS-AMKL are not predisposed to leukemia. To better understand the functional contribution of trisomy 21 to leukemogenesis, we used mouse and human cell models of DS to reproduce the multistep pathogenesis of DS-AMKL and to identify chromosome 21 genes that promote megakaryoblastic leukemia in children with DS. Our results revealed that trisomy for only 33 orthologs of human chromosome 21 (Hsa21) genes was sufficient to cooperate with GATA1 mutations to initiate megakaryoblastic leukemia in vivo. Furthermore, through a functional screening of the trisomic genes, we demonstrated that DYRK1A, which encodes dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A, was a potent megakaryoblastic tumor-promoting gene that contributed to leukemogenesis through dysregulation of nuclear factor of activated T cells (NFAT) activation. Given that calcineurin/NFAT pathway inhibition has been implicated in the decreased tumor incidence in adults with DS, our results show that the same pathway can be both proleukemic in children and antitumorigenic in adults.

  13. Mineralogical mapping of quadrangles AV-13 (Tuccia) and AV-14 (Urbinia)

    NASA Astrophysics Data System (ADS)

    Zambon, F.; Frigeri, A.; Combe, J.-Ph.; De Sanctis, M. C.; Ammannito, E.; Tosi, F.; Blewett, T. D.; Denevi, B. W.; Stephan, K.; Russell, C. T.; Raymond, C. A.

    2014-04-01

    The surface of Vesta, one of the largest bodies in the main asteroid belt, has been divided in 15 quadrangles (Fig. 1) [1]. Here we analyze the spectral properties of the quadrangles Av-13 Tuccia (270°-360°E; 21°- 66°S), and Av-14 Urbinia (270°-360°E; 21°-66°S) located in the southwest part of the asteroid (Fig. 1).

  14. Iron-induced oxidative stress activates AKT and ERK1/2 and decreases Dyrk1B and PRMT1 in neuroblastoma SH-SY5Y cells.

    PubMed

    Bautista, Elizabeth; Vergara, Paula; Segovia, José

    2016-03-01

    Iron is essential for proper neuronal functioning; however, excessive accumulation of brain iron is reported in Parkinson's, Alzheimer's, Huntington's diseases and amyotrophic lateral sclerosis. This indicates that dysregulated iron homeostasis is involved in the pathogenesis of these diseases. To determinate the effect of iron on oxidative stress and on cell survival pathways, such as AKT, ERK1/2 and DyrK1B, neuroblastoma SH-SY5Y cells were exposed to different concentration of FeCl2 (iron). We found that iron induced cell death in SH-SY5Y cells in a concentration-dependent manner. Detection of iNOS and 3-nitrotyrosine confirms the presence of increased nitrogen species. Furthermore, we found a decrease of catalase and protein arginine methyl-transferase 1 (PRMT1). Interestingly, iron increased the activity of ERK and AKT and reduced DyrK1B. Moreover, after FeCl2 treatment, the transcription factors c-Jun and pSmad1/5 were activated. These results indicate that the presence of high levels of iron increase the vulnerability of neurons to oxidative stress. Copyright © 2015 Elsevier GmbH. All rights reserved.

  15. AV nodal dual pathway electrophysiology and Wenckebach periodicity.

    PubMed

    Zhang, Youhua; Mazgalev, Todor N

    2011-11-01

    The precise mechanism(s) governing the phenomenon of AV nodal Wenckebach periodicity is not fully elucidated. Currently 2 hypotheses, the decremental conduction and the Rosenbluethian step-delay, are most frequently used. We have provided new evidence that, in addition, dual pathway (DPW) electrophysiology is directly involved in the manifestation of AV nodal Wenckebach phenomenon. AV nodal cellular action potentials (APs) were recorded from 6 rabbit AV node preparations during standard A1A2 and incremental pacing protocols. His electrogram alternans, a validated index of DPW electrophysiology, was used to monitor fast (FP) and slow (SP) pathway conduction. The data were collected in intact AV nodes, as well as after SP ablation. In all studied hearts the Wenckebach cycle started with FP propagation, followed by transition to SP until its ultimate block. During this process complex cellular APs were observed, with decremental foot formations reflecting the fading FP and second depolarizations produced by the SP. In addition, the AV node cells exhibited a progressive loss in maximal diastolic membrane potential (MDP) due to incomplete repolarization. The pause created with the blocked Wenckebach beat was associated with restoration of MDP and reinitiation of the conduction cycle via the FP wavefront. DPW electrophysiology is dynamically involved in the development of AV nodal Wenckebach periodicity. In the intact AV node, the cycle starts with FP that is progressively weakened and then replaced by SP propagation, until block occurs. AV nodal SP modification did not eliminate Wenckebach periodicity but strongly affected its paradigm. © 2011 Wiley Periodicals, Inc.

  16. Pollen transmission of asparagus virus 2 (AV-2) may facilitate mixed infection by two AV-2 isolates in asparagus plants.

    PubMed

    Kawamura, Ryusuke; Shimura, Hanako; Mochizuki, Tomofumi; Ohki, Satoshi T; Masuta, Chikara

    2014-09-01

    Asparagus virus 2 (AV-2) is a member of the genus Ilarvirus and thought to induce the asparagus decline syndrome. AV-2 is known to be transmitted by seed, and the possibility of pollen transmission was proposed 25 years ago but not verified. In AV-2 sequence analyses, we have unexpectedly found mixed infection by two distinct AV-2 isolates in two asparagus plants. Because mixed infections by two related viruses are normally prevented by cross protection, we suspected that pollen transmission of AV-2 is involved in mixed infection. Immunohistochemical analyses and in situ hybridization using AV-2-infected tobacco plants revealed that AV-2 was localized in the meristem and associated with pollen grains. To experimentally produce a mixed infection via pollen transmission, two Nicotiana benthamiana plants that were infected with each of two AV-2 isolates were crossed. Derived cleaved-amplified polymorphic sequence analysis identified each AV-2 isolate in the progeny seedlings, suggesting that pollen transmission could indeed result in a mixed infection, at least in N. benthamiana.

  17. Association of the Single Nucleotide Polymorphisms in RUNX1, DYRK1A, and KCNJ15 with Blood Related Traits in Pigs.

    PubMed

    Lee, Jae-Bong; Yoo, Chae-Kyoung; Park, Hee-Bok; Cho, In-Cheol; Lim, Hyun-Tae

    2016-12-01

    The aim of this study was to detect positional candidate genes located within the support interval (SI) regions based on the results of red blood cell, mean corpuscular volume (MCV), and mean corpuscular hemoglobin quantitative trait locus (QTL) in Sus scrofa chromosome 13, and to verify the correlation between specific single-nucleotide polymorphisms (SNPs) located in the exonic region of the positional candidate gene and the three genetic traits. The flanking markers of the three QTL SI regions are SW38 and S0215. Within the QTL SI regions, 44 genes were located, and runt-related transcription factor 1, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), and potassium inwardly-rectifying channel, subfamily J, member 15 KCNJ15-which are reported to be related to the hematological traits and clinical features of Down syndrome-were selected as positional candidate genes. The ten SNPs located in the exonic region of the three genes were detected by next generation sequencing. A total of 1,232 pigs of an F2 resource population between Landrace and Korean native pigs were genotyped. To investigate the effects of the three genes on each genotype, a mixed-effect model which is the considering family structure model was used to evaluate the associations between the SNPs and three genetic traits in the F2 intercross population. Among them, the MCV level was highly significant (nominal p = 9.8×10(-9)) in association with the DYRK1A-SNP1 (c.2989 G

  18. Association of the Single Nucleotide Polymorphisms in RUNX1, DYRK1A, and KCNJ15 with Blood Related Traits in Pigs

    PubMed Central

    Lee, Jae-Bong; Yoo, Chae-Kyoung; Park, Hee-Bok; Cho, In-Cheol; Lim, Hyun-Tae

    2016-01-01

    The aim of this study was to detect positional candidate genes located within the support interval (SI) regions based on the results of red blood cell, mean corpuscular volume (MCV), and mean corpuscular hemoglobin quantitative trait locus (QTL) in Sus scrofa chromosome 13, and to verify the correlation between specific single-nucleotide polymorphisms (SNPs) located in the exonic region of the positional candidate gene and the three genetic traits. The flanking markers of the three QTL SI regions are SW38 and S0215. Within the QTL SI regions, 44 genes were located, and runt-related transcription factor 1, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), and potassium inwardly-rectifying channel, subfamily J, member 15 KCNJ15–which are reported to be related to the hematological traits and clinical features of Down syndrome–were selected as positional candidate genes. The ten SNPs located in the exonic region of the three genes were detected by next generation sequencing. A total of 1,232 pigs of an F2 resource population between Landrace and Korean native pigs were genotyped. To investigate the effects of the three genes on each genotype, a mixed-effect model which is the considering family structure model was used to evaluate the associations between the SNPs and three genetic traits in the F2 intercross population. Among them, the MCV level was highly significant (nominal p = 9.8×10−9) in association with the DYRK1A-SNP1 (c.2989 G

  19. SmartDelay Determined AV Optimization: A Comparison of AV Delay Methods Used in Cardiac Resynchronization Therapy (SMART-AV): Rationale and Design

    PubMed Central

    STEIN, KENNETH M.; ELLENBOGEN, KENNETH A.; GOLD, MICHAEL R.; LEMKE, BERND; LOZANO, IGNACIO FERNÁNDEZ; MITTAL, SUNEET; SPINALE, FRANCIS G.; VAN EYK, JENNIFER E.; WAGGONER, ALAN D.; MEYER, TIMOTHY E.

    2010-01-01

    Background The clinical benefit of cardiac resynchronization therapy (CRT) for patients with moderate-to-severely symptomatic heart failure, left ventricular systolic dysfunction, and ventricular conduction delay is established. However, some patients do not demonstrate clinical improvement following CRT. It is unclear whether systematic optimization of the programmed atrioventricular (AV) delay improves the rate of clinical response. Methods SMART-AV is a randomized, multicenter, double-blinded, three-armed trial that will investigate the effects of optimizing AV delay timing in heart failure patients receiving CRT + defibrillator (CRT-D) therapy. A minimum of 950 patients will be randomized in a 1:1:1 ratio using randomly permuted blocks within each center programmed to either DDD or DDDR with a lower rate of 60. The study will include echocardiographic measurements of volumes and function [e.g., left ventricular end-systolic volume (LVESV)], biochemical measurements of plasma biomarker profiles, and functional measurements (e.g., 6-minute hall walk) in CRT-D patients who are enrolled and randomized to fixed AV delay (i.e., 120 ms), AV delay determined by electrogram-based SmartDelay, or an AV delay determined by echocardiography (i.e., mitral inflow). Patients will be evaluated prior to initiation of CRT, 3 and 6 months post-implant. The primary endpoint is the relative change in LVESV at 6 months between the groups. Patient enrollment commenced in May 2008 and the study is registered at clinicaltrials.gov. Conclusion SMART-AV is a randomized, clinical trial designed to evaluate three different methods of AV delay optimization to determine whether systematic AV optimization is beneficial for patients receiving CRT for 6 months post-implant. PMID:19821938

  20. 15 CFR 740.15 - Aircraft and vessels (AVS).

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 15 Commerce and Foreign Trade 2 2013-01-01 2013-01-01 false Aircraft and vessels (AVS). 740.15... EXCEPTIONS § 740.15 Aircraft and vessels (AVS). This License Exception authorizes departure from the United States of foreign registry civil aircraft on temporary sojourn in the United States and of U.S....

  1. 15 CFR 740.15 - Aircraft and vessels (AVS).

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 15 Commerce and Foreign Trade 2 2011-01-01 2011-01-01 false Aircraft and vessels (AVS). 740.15... EXCEPTIONS § 740.15 Aircraft and vessels (AVS). This License Exception authorizes departure from the United States of foreign registry civil aircraft on temporary sojourn in the United States and of U.S....

  2. 15 CFR 740.15 - Aircraft and vessels (AVS).

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 15 Commerce and Foreign Trade 2 2012-01-01 2012-01-01 false Aircraft and vessels (AVS). 740.15... EXCEPTIONS § 740.15 Aircraft and vessels (AVS). This License Exception authorizes departure from the United States of foreign registry civil aircraft on temporary sojourn in the United States and of U.S....

  3. 15 CFR 740.15 - Aircraft and vessels (AVS).

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Aircraft and vessels (AVS). 740.15... EXCEPTIONS § 740.15 Aircraft and vessels (AVS). This License Exception authorizes departure from the United States of foreign registry civil aircraft on temporary sojourn in the United States and of U.S. civil...

  4. An autoradiographic evaluation of AV-1451 Tau PET in dementia.

    PubMed

    Lowe, Val J; Curran, Geoffry; Fang, Ping; Liesinger, Amanda M; Josephs, Keith A; Parisi, Joseph E; Kantarci, Kejal; Boeve, Bradley F; Pandey, Mukesh K; Bruinsma, Tyler; Knopman, David S; Jones, David T; Petrucelli, Leonard; Cook, Casey N; Graff-Radford, Neill R; Dickson, Dennis W; Petersen, Ronald C; Jack, Clifford R; Murray, Melissa E

    2016-06-13

    It is essential to determine the specificity of AV-1451 PET for tau in brain imaging by using pathological comparisons. We performed autoradiography in autopsy-confirmed Alzheimer disease and other neurodegenerative disorders to evaluate the specificity of AV-1451 binding for tau aggregates. Tissue samples were selected that had a variety of dementia-related neuropathologies including Alzheimer disease, primary age-related tauopathy, tangle predominant dementia, non-Alzheimer disease tauopathies, frontotemporal dementia, parkinsonism, Lewy body disease and multiple system atrophy (n = 38). Brain tissue sections were stained for tau, TAR DNA-binding protein-43, and α-synuclein and compared to AV-1451 autoradiography on adjacent sections. AV-1451 preferentially localized to neurofibrillary tangles, with less binding to areas enriched in neuritic pathology and less mature tau. The strength of AV-1451 binding with respect to tau isoforms in various neurodegenerative disorders was: 3R + 4R tau (e.g., AD) > 3R tau (e.g., Pick disease) or 4R tau. Only minimal binding of AV-1451 to TAR DNA-binding protein-43 positive regions was detected. No binding of AV-1451 to α-synuclein was detected. "Off-target" binding was seen in vessels, iron-associated regions, substantia nigra, calcifications in the choroid plexus, and leptomeningeal melanin. Reduced AV-1451 binding in neuritic pathology compared to neurofibrillary tangles suggests that the maturity of tau pathology may affect AV-1451 binding and suggests complexity in AV-1451 binding. Poor association of AV-1451 with tauopathies that have preferential accumulation of either 4R tau or 3R tau suggests limited clinical utility in detecting these pathologies. In contrast, for disorders associated with 3R + 4R tau, such as Alzheimer disease, AV-1451 binds tau avidly but does not completely reflect the early stage tau progression suggested by Braak neurofibrillary tangle staging. AV-1451 binding to TAR DNA

  5. Cofactor Requirement of HpyAV Restriction Endonuclease

    PubMed Central

    Chan, Siu-Hong; Opitz, Lars; Higgins, Lauren; O'loane, Diana; Xu, Shuang-yong

    2010-01-01

    Background Helicobacter pylori is the etiologic agent of common gastritis and a risk factor for gastric cancer. It is also one of the richest sources of Type II restriction-modification (R-M) systems in microorganisms. Principal Findings We have cloned, expressed and purified a new restriction endonuclease HpyAV from H. pylori strain 26695. We determined the HpyAV DNA recognition sequence and cleavage site as CCTTC 6/5. In addition, we found that HpyAV has a unique metal ion requirement: its cleavage activity is higher with transition metal ions than in Mg++. The special metal ion requirement of HpyAV can be attributed to the presence of a HNH catalytic site similar to ColE9 nuclease instead of the canonical PD-X-D/EXK catalytic site found in many other REases. Site-directed mutagenesis was carried out to verify the catalytic residues of HpyAV. Mutation of the conserved metal-binding Asn311 and His320 to alanine eliminated cleavage activity. HpyAV variant H295A displayed approximately 1% of wt activity. Conclusions/Significance Some HNH-type endonucleases have unique metal ion cofactor requirement for optimal activities. Homology modeling and site-directed mutagenesis confirmed that HpyAV is a member of the HNH nuclease family. The identification of catalytic residues in HpyAV paved the way for further engineering of the metal binding site. A survey of sequenced microbial genomes uncovered 10 putative R-M systems that show high sequence similarity to the HpyAV system, suggesting lateral transfer of a prototypic HpyAV-like R-M system among these microorganisms. PMID:20140205

  6. Nanoscience and its relationship to the AVS

    NASA Astrophysics Data System (ADS)

    Murday, James S.

    2003-09-01

    Nanometer structures have played a role in technology for millennia, but empirically derived. The invention of surface analytical tools in the 1960s/70s enabled science with one dimension in the nanometer range; commercial products based on that science are significant and growing. The invention of the proximal probes (scanning tunneling microscopy, atomic force microscopy) has stimulated science with all dimensions-0 (dots, clusters, macromolecules), 1 (wires, tubes), 2 (vicinal surfaces), 3 (nanostructured composites)-in the nanometer range. The U.S. National Nanotechnology Initiative, and its equivalents in other countries, seek to accelerate progress in the scientific phase of discovery and invention, and to transition rapidly those innovations into technological opportunities. Building on its foundations in surface science, surface analysis, and electronics materials processing, the AVS has played a significant role in first creating and then promoting that progress.

  7. OGS Water ORU R&R

    NASA Image and Video Library

    2009-08-21

    ISS020-E-033496 (21 Aug. 2009) --- Canadian Space Agency astronaut Robert Thirsk, Expedition 20 flight engineer, is pictured with the oxygen generator system (OGS) rack cover in the Destiny laboratory of the International Space Station.

  8. Nyberg with OGS R&R

    NASA Image and Video Library

    2013-07-19

    ISS036-E-021797 (18 July 2013) --- NASA astronaut Karen Nyberg, Expedition 36 flight engineer, performs a remove and replace of the Oxygen Generation System (OGS) Hydrogen (H2) Sensor in the Tranquility node of the International Space Station.

  9. Functional mathematical model of dual pathway AV nodal conduction.

    PubMed

    Climent, A M; Guillem, M S; Zhang, Y; Millet, J; Mazgalev, T N

    2011-04-01

    Dual atrioventricular (AV) nodal pathway physiology is described as two different wave fronts that propagate from the atria to the His bundle: one with a longer effective refractory period [fast pathway (FP)] and a second with a shorter effective refractory period [slow pathway (SP)]. By using His electrogram alternance, we have developed a mathematical model of AV conduction that incorporates dual AV nodal pathway physiology. Experiments were performed on five rabbit atrial-AV nodal preparations to develop and test the presented model. His electrogram alternances from the inferior margin of the His bundle were used to identify fast and slow wave front propagations. The ability to predict AV conduction time and the interaction between FP and SP wave fronts have been analyzed during regular and irregular atrial rhythms (e.g., atrial fibrillation). In addition, the role of dual AV nodal pathway wave fronts in the generation of Wenckebach periodicities has been illustrated. Finally, AV node ablative modifications have been evaluated. The model accurately reproduced interactions between FP and SP during regular and irregular atrial pacing protocols. In all experiments, specificity and sensitivity higher than 85% were obtained in the prediction of the pathway responsible for conduction. It has been shown that, during atrial fibrillation, the SP ablation significantly increased the mean HH interval (204 ± 39 vs. 274 ± 50 ms, P < 0.05), whereas FP ablation did not produce significant slowing of ventricular rate. The presented mathematical model can help in understanding some of the intriguing AV node mechanisms and should be considered as a step forward in the studies of AV nodal conduction.

  10. OGS Hydrogen Sensor ORU R&R

    NASA Image and Video Library

    2012-04-18

    ISS030-E-236919 (18 April 2012) --- NASA astronaut Dan Burbank, Expedition 30 commander, works with the Oxygen Generator System (OGS) rack in the Tranquility node of the International Space Station. Burbank unpowered the OGS, purged the hydrogen sensor Orbital Replacement Unit (ORU) with the Hydrogen Sensor ORU Purge Adapter (HOPA) for return to Earth, and replaced the hydrogen sensor with a new spare, then cleaned the rack Avionics Air Assembly (AAA).

  11. Phase 4 paroxysmal AV block in a patient with scleroderma.

    PubMed

    Butschek, Ross; Powell, Brian D; Littmann, Laszlo

    2013-01-01

    A 72-year-old man with limited cutaneous systemic scleroderma was hospitalized for two episodes of witnessed syncope. The baseline 12-lead electrocardiogram was normal but on telemetry there were numerous episodes of paroxysmal AV block with asystolic periods of up to 7.5 s duration. Analysis of the rhythm strips revealed phase 4 intra-His bundle block characterized by critical P-P intervals that triggered the AV block, and a narrow range of junctional escape to subsequent P wave intervals that were required to release the AV block. A dual chamber pacemaker was implanted.

  12. AV-95 Sun Devil: High-Speed Military Rotorcraft

    NASA Technical Reports Server (NTRS)

    1996-01-01

    The AV-95 Sun Devil must combine helicopter capabilities, such as vertical takeoff and landings (VTOL) and rotor-powered flight, along with long-duration cruise and high-speed dash capabilities unobtainable by conventional helicopters. To be able to perform both tasks, and perform them well, the AV-95 Sun Devil design incorporates several unconventional devices; the AV-95 uses two convertible turbofan engines, able to provide both shaft power for the main rotor and tall fan as well as jet thrust either separately or simultaneously. Other devices used for the AV-95 include a variable diameter main rotor and a blown flap. In helicopter mode, the AV-95 Sun Devil performs like a winged helicopter. The addition of wings to an attack helicopter results in two significant advantages. First, the addition of wings makes a helicopter more maneuverable than a wingless, but otherwise similar helicopter. Second, since the wings produce lift, rotor stall and compressibility effects can be significantly delayed at high tip velocities. In fixed-wing mode, the main rotor is completely off-loaded but slightly powered, and the rotor diameter has been minimized. The AV-95 Sun Devil has many advantages over other VTOL aircraft. The conversion process is simple and fast; conversion does not make the AV-95 vulnerable to enemy attack during conversion such as a tilt-wing or a tilt-rotor. Stop-rotor aircraft and a stowed rotor aircraft require heavy breaking of the rotor for conversion; this adds time for conversion and weight to the aircraft. Because the AV-95 never stops the rotor in flight, much weight is spared, and conversion is much simpler and faster.

  13. Altered regulation of the Spry2/Dyrk1A/PP2A triad by homocysteine impairs neural progenitor cell proliferation.

    PubMed

    Rabaneda, Luis G; Geribaldi-Doldán, Noelia; Murillo-Carretero, Maribel; Carrasco, Manuel; Martínez-Salas, José M; Verástegui, Cristina; Castro, Carmen

    2016-12-01

    Hyperhomocysteinemia reduces neurogenesis in the adult mouse brain. Homocysteine (Hcy) inhibits postnatal neural progenitor cell (NPC) proliferation by specifically impairing the fibroblast growth factor receptor (FGFR)-Erk1/2-cyclin E signaling pathway. We demonstrate herein that the inhibition of FGFR-dependent NPC proliferation induced by Hcy is mediated by its capacity to alter the cellular methylation potential. Our results show that this alteration modified the expression pattern and activity of Sprouty2 (Spry2), a negative regulator of the above mentioned pathway. Both elevated concentrations of Hcy and methyltransferase activity inhibition induced Spry2 promoter demethylation in NPC cultures leading to a sustained upregulation of the expression of Spry2 mRNA and protein. In addition, protein levels of two kinases responsible for Spry2 activation/deactivation were altered by Hcy: Spry2 kinase Dyrk1A levels diminished while Spry2 phosphatase PP2A increased, leading to changes in the phosphorylation pattern, activity and stability of Spry2. In conclusion, Hcy inhibits NPC proliferation by indirect mechanisms involving alterations in DNA methylation, gene expression, and Spry2 function, causing FGFR signaling impairment. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Yak1p, a DYRK family kinase, translocates to the nucleus and phosphorylates yeast Pop2p in response to a glucose signal

    PubMed Central

    Moriya, Hisao; Shimizu-Yoshida, Yuki; Omori, Akira; Iwashita, Shintaro; Katoh, Mariko; Sakai, Akira

    2001-01-01

    POP2 protein of Saccharomyces cerevisiae is a component of a protein complex that regulates the transcription of many genes. We found that the 97th threonine residue (Thr 97) of Pop2p was phosphorylated upon glucose limitation. The Thr 97 phosphorylation occurred within 2 min after removing glucose and was reversed within 1 min after the readdition of glucose. The effects of hexokinase mutations and glucose analogs indicate that this phosphorylation is dependent on glucose phosphorylating activity. We purified a protein kinase that phosphorylates a peptide containing Thr 97 of Pop2p and identified it as Yak1p, a DYRK family kinase. Phosphorylation of Pop2p was barely detectable in a yak1Δ strain. We found that Yak1p interacted with Bmh1p and Bmh2p only in the presence of glucose. A GFP-Yak1p fusion protein shuttled rapidly between the nucleus and the cytoplasm in response to glucose. A strain with alanine substituted for Thr 97 in Pop2p showed overgrowth in the postdiauxic transition and failed to stop the cell cycle at G1 phase in response to glucose deprivation. Thus, Yak1p and Pop2p are part of a novel glucose-sensing system in yeast that is involved in growth control in response to glucose availability. PMID:11358866

  15. A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication.

    PubMed

    Wang, Peng; Alvarez-Perez, Juan-Carlos; Felsenfeld, Dan P; Liu, Hongtao; Sivendran, Sharmila; Bender, Aaron; Kumar, Anil; Sanchez, Roberto; Scott, Donald K; Garcia-Ocaña, Adolfo; Stewart, Andrew F

    2015-04-01

    Types 1 and 2 diabetes affect some 380 million people worldwide. Both ultimately result from a deficiency of functional pancreatic insulin-producing beta cells. Beta cells proliferate in humans during a brief temporal window beginning around the time of birth, with a peak percentage (∼2%) engaged in the cell cycle in the first year of life. In embryonic life and after early childhood, beta cell replication is barely detectable. Whereas beta cell expansion seems an obvious therapeutic approach to beta cell deficiency, adult human beta cells have proven recalcitrant to such efforts. Hence, there remains an urgent need for antidiabetic therapeutic agents that can induce regeneration and expansion of adult human beta cells in vivo or ex vivo. Here, using a high-throughput small-molecule screen (HTS), we find that analogs of the small molecule harmine function as a new class of human beta cell mitogenic compounds. We also define dual-specificity tyrosine-regulated kinase-1a (DYRK1A) as the likely target of harmine and the nuclear factors of activated T cells (NFAT) family of transcription factors as likely mediators of human beta cell proliferation and differentiation. Using three different mouse and human islet in vivo-based models, we show that harmine is able to induce beta cell proliferation, increase islet mass and improve glycemic control. These observations suggest that harmine analogs may have unique therapeutic promise for human diabetes therapy. Enhancing the potency and beta cell specificity of these compounds are important future challenges.

  16. Accessory pathway reciprocating tachycardia involving twin AV nodes in a patient with atrioventricular discordance and mitral atresia.

    PubMed

    Miyazaki, Aya; Sakaguchi, Heima; Uchiyama, Takamichi; Kurita, Takashi; Ohuchi, Hideo; Yamada, Osamu

    2010-05-01

    The atrioventricular (AV) conduction system in AV discordance remains unclear, especially in cases with complex cardiac anomaly. We report a case of accessory pathway reciprocating tachycardia in atrioventricular discordance (AVD) and mitral atresia with twin AV nodes. In this case, the anterior AV node was located along the atretic mitral valve. The anterior AV node was involved in tachycardia and the posterior AV node acted as a bystander during tachycardia. The anterior AV node in AVD can be located along the atretic mitral valve, and one of twin AV nodes might act as a bystander during AV reciprocating tachycardia.

  17. Enhanced A-V nodal conduction (Lown-Ganong-Levine syndrome) by congenitally hypoplastic A-V node.

    PubMed

    Ometto, R; Thiene, G; Corrado, D; Vincenzi, M; Rossi, L

    1992-11-01

    The basic anatomical substrate of enhanced A-V nodal conduction, manifesting or not as Lown-Ganong-Levine syndrome, is still a controversial issue. We describe the case of a 34-year-old man who presented episodes of ventricular fibrillation. Electrophysiological studies showed that the AH interval was 55 ms, and increased by only 20 ms at paced cycle lengths of 300 ms; atrial pacing induced atrial fibrillation, with a shortest RR interval of 240 ms. Despite verapamil therapy, this patient died suddenly at home. Histological study disclosed a severe A-V node hypoplasia that was evidently congenital in nature; the rest of the conduction system was normal, and no accessory A-V pathways were present. We suggest that enhanced A-V nodal conduction in this patient was due to the developmental defect in the A-V node; this abnormality caused a loss of specific impulse-delaying function, and thus allowed rapid, unfiltered atrial impulses to reach the lower A-V junction and ventricles.

  18. OGS Water ORU R&R

    NASA Image and Video Library

    2009-08-21

    ISS020-E-033472 (21 Aug. 2009) --- Canadian Space Agency astronaut Robert Thirsk, Expedition 20 flight engineer, prepares to perform in-flight maintenance (IFM) on the oxygen generator system (OGS) rack in the Destiny laboratory of the International Space Station.

  19. DYRK2 and GSK-3 phosphorylate and promote the timely degradation of OMA-1, a key regulator of the oocyte-to-embryo transition in C. elegans.

    PubMed

    Nishi, Yuichi; Lin, Rueyling

    2005-12-01

    Oocyte maturation and fertilization initiates a dynamic and tightly regulated process in which a non-dividing oocyte is transformed into a rapidly dividing embryo. We have shown previously that two C. elegans CCCH zinc finger proteins, OMA-1 and OMA-2, have an essential and redundant function in oocyte maturation. Both OMA-1 and OMA-2 are expressed only in oocytes and 1-cell embryos, and need to be degraded rapidly after the first mitotic division for embryogenesis to proceed normally. We report here a distinct redundant function for OMA-1 and OMA-2 in the 1-cell embryo. Depletion of both oma-1 and oma-2 in embryos leads to embryonic lethality. We also show that OMA-1 protein is directly phosphorylated at T239 by the DYRK kinase MBK-2, and that phosphorylation at T239 is required both for OMA-1 function in the 1-cell embryo and its degradation after the first mitosis. OMA-1 phosphorylated at T239 is only detected within a short developmental window of 1-cell embryos, beginning soon after the proposed activation of MBK-2. Phosphorylation at T239 facilitates subsequent phosphorylation of OMA-1 by another kinase, GSK-3, at T339 in vitro. Phosphorylation at both T239 and T339 are essential for correctly-timed OMA-1 degradation in vivo. We propose that a series of precisely-timed phosphorylation events regulates both the activity and the timing of degradation for OMA proteins, thereby allowing restricted and distinct functions of OMA-1 and OMA-2 in the maturing oocyte and 1-cell embryo, ensuring a normal oocyte-to-embryo transition in C. elegans.

  20. Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans

    PubMed Central

    Gonzales, Jon C.; Gordts, Philip L.S.M.; Foley, Erin M.; Esko, Jeffrey D.

    2013-01-01

    The heparan sulfate proteoglycan (HSPG) syndecan-1 (SDC1) acts as a major receptor for triglyceride-rich lipoprotein (TRL) clearance in the liver. We sought to identify the relevant apolipoproteins on TRLs that mediate binding to SDC1 and determine their clinical relevance. Evidence supporting ApoE as a major determinant arose from its enrichment in TRLs from mice defective in hepatic heparan sulfate (Ndst1f/fAlbCre+ mice), decreased binding of ApoE-deficient TRLs to HSPGs on human hepatoma cells, and decreased clearance of ApoE-deficient [3H]TRLs in vivo. Evidence for a second ligand was suggested by the faster clearance of ApoE-deficient TRLs after injection into WT Ndst1f/fAlbCre– versus mutant Ndst1f/fAlbCre+ mice and elevated fasting and postprandial plasma triglycerides in compound Apoe–/–Ndst1f/fAlbCre+ mice compared with either single mutant. ApoAV emerged as a candidate based on 6-fold enrichment of ApoAV in TRLs accumulating in Ndst1f/fAlbCre+ mice, decreased binding of TRLs to proteoglycans after depletion of ApoAV or addition of anti-ApoAV mAb, and decreased heparan sulfate–dependent binding of ApoAV-deficient particles to hepatocytes. Importantly, disruption of hepatic heparan sulfate–mediated clearance increased atherosclerosis. We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV. PMID:23676495

  1. Brachial artery aneurysms following brachio-cephalic AV fistula ligation.

    PubMed

    Khalid, Usman; Parkinson, Frances; Mohiuddin, Kamran; Davies, Paula; Woolgar, Justin

    2014-01-01

    Peripheral artery aneurysms proximal to a long-standing arteriovenous (AV) fistula can be a serious complication. It is important to be aware of this and manage it appropriately. Vascular access nurses input all data regarding patients undergoing dialysis access procedures into a securely held database prospectively. This was retrospectively reviewed to identify cases of brachial artery aneurysms over the last 3 years. In Morriston Hospital, around 200 forearm and arm AV fistulas are performed annually for vascular access in renal dialysis patients. Of these, approximately 15 (7.5%) are ligated. Three patients who had developed brachial artery aneurysms following AV fistula ligation were identified. All 3 patients had developed brachial artery aneurysms following ligation of a long-standing brachio-cephalic AV fistula. Two patients presented with pain and a pulsatile mass in the arm, and one presented with pins and needles and discoloration of fingertips. Two were managed with resection of the aneurysm and reconstruction with a reversed long saphenous vein interposition graft, the third simply required ligation of a feeding arterial branch. True aneurysm formation proximal to an AV fistula that has been ligated is a rare complication. There are several reasons for why these aneurysms develop in such patients, the most plausible one being the increase in blood flow and resistance following ligation of the AV fistula. Of note, all the patients in this study were on immunosuppressive therapy following successful renal transplantation. Vigilance by the vascular access team and nephrologists is paramount to identify those patients who may warrant further evaluation and investigation by the vascular surgeon.

  2. Assessment of the NASA AvSTAR Project Plan

    NASA Technical Reports Server (NTRS)

    Ulrey, Michael L.; Haraldsdottir, Aslaug; Berge, Matthew E.; Hopperstad, Craig A.; Schwab, Robert W.

    2004-01-01

    This report is a preliminary evaluation of NASA's proposed Aviation System Technology Advanced Research (AvSTAR) Program during the early stages of its definition, in the first half of the year 2001. This evaluation focuses on how well the program goals address the needs of the U.S. National Airspace System, the technical feasibility of the program goals, and the logistical feasibility of the program plan. This report also provides recommendations on how the AvSTAR program could be strengthened and improved. This document has two appendices.

  3. The C. elegans anaphase promoting complex and MBK-2/DYRK kinase act redundantly with CUL-3/MEL-26 ubiquitin ligase to degrade MEI-1 microtubule-severing activity after meiosis.

    PubMed

    Lu, Chenggang; Mains, Paul E

    2007-02-15

    The C. elegans embryo supports both meiotic and mitotic spindles, requiring careful regulation of components specific to each spindle type. The MEI-1/katanin microtubule-severing complex is required for meiosis but must be inactivated prior to mitosis. Downregulation of MEI-1 depends on MEL-26, which binds MEI-1, targeting it for degradation by the CUL-3 E3 ubiquitin ligase complex. Here we report that other protein degradation pathways, involving the anaphase promoting complex (APC) and the MBK-2/DYRK kinase, act in parallel to MEL-26 to inactivate MEI-1. At 25 degrees all mel-26(null) embryos die due to persistence of MEI-1 into mitosis, but at 15 degrees a significant portion of embryos hatch due to lower levels of ectopic MEI-1, suggesting that a redundant pathway also regulates MEI-1 degradation at 15 degrees. Previously the MBK-2/DYRK kinase was suggested to trigger MEL-26 mediated MEI-1 degradation. However, mbk-2 enhances the incomplete lethality of mel-26(null) at 15 degrees, arguing that MEL-26 acts in parallel to MBK-2. APC mutants behave similarly. In mel-26 embryos, ectopic MEI-1 remains until the onset of gastrulation, but in mbk-2; apc embryos, MEI-1 only persists through the first mitosis. We propose that mbk-2 and apc couple the initial phase of MEI-1 degradation to meiotic exit, after which MEL-26 completes MEI-1 degradation.

  4. A case of reversible third-degree AV block due to Lyme carditis.

    PubMed

    Timmer, Stefan A J; Boswijk, Dirk J; Kimman, Geert P; Germans, Tjeerd

    2016-01-01

    The most common manifestation of Lyme carditis is a varying degree of atrioventricular (AV) conduction block. This case describes a 45-year-old male with third-degree AV block due to Lyme carditis. Treatment with intravenous antibiotics resulted in complete normalization of AV conduction, thereby averting permanent pacemaker implantation.

  5. Prevention of AV Nodal Reentry Tachycardia by Oral Amiodarone: An Alternative Mechanism of Action

    PubMed Central

    Gold, Robert L.; Haffajee, Charles I.; Entes, Kenneth L.

    1987-01-01

    A 73-year-old man was noted to have atrioventricular (AV) nodal reentry tachycardia, which was induced during programmed electrical stimulation. After 1 month of oral amiodarone therapy, AV nodal reentry tachycardia was prevented by the prolongation of atrial refractoriness and not by direct action on the AV node itself. (Texas Heart Institute Journal 1987; 14:99-101) PMID:15227337

  6. Centralized Library Services for Audiovisual Media. AV in Action 4.

    ERIC Educational Resources Information Center

    Nederlands Bibliotheek en Lektuur Centrum, The Hague (Netherlands).

    Designed to provide assistance to countries in developing centralized services to their libraries for nonbook materials, this pamphlet contains examples from five countries that have succeeded in establishing such services. Those examples include: (1) "The Central Library Service for AV-Materials in Denmark" (Suzanne Hemmeth…

  7. Minimizing ventricular pacing by a novel atrioventricular (AV) delay hysteresis algorithm in patients with intact or compromised intrinsic AV conduction and different atrial and ventricular lead locations.

    PubMed

    Pakarinen, Sami; Toivonen, Lauri

    2013-09-01

    To investigate if an advanced AV search hysteresis (AVSH) algorithm, Ventricular Intrinsic Preference (VIP(™)), reduces the incidence of ventricular pacing (VP) in sinus node dysfunction (SND) with both intact and compromised AV conduction and with intermittent AV block regardless of the lead positions in the right atria and the ventricle. Patients were classified as having intact AV (AVi) conduction if the PR interval was ≤ 210 ms on ECG and 1:1 AV conduction during atrial pacing up to 120 bpm with PR interval ≤ 350 ms. Otherwise the AV conduction was classified as compromised (AVc). Both AVi and AVc patients were randomized to VIP ON or OFF. VIP performed an intrinsic AV conduction search every 30 s for three consecutive atrial cycles with the extension of the sensed and paced AV (SAV/PAV) delays from basic values of 150/200 ms to 300/350 ms. Extended AV intervals were allowed for three cycles when VP occurred before returning to basic AV delays. The primary end-point was %VP at 12 months. Among 389 patients, 30.1% had intact and 69.9% had compromised AV conduction. The mean %VP at 12 months was 9.6% by VIP compared to 51.8% with standard AV settings in patients with AVi (P < 0.0001) and 28.0% versus 78.9% (P < 0.0001) with AVc. With VIP, excessive %VP among most used lead positions was not seen. Conversely, when VIP was off %VP was low only in patients who had leads in the RA septal-RV septal position (23.0%). VIP feature reduces VP both in patients with SND and with intermittent heart block regardless of the lead positions in the right atria and the ventricle.

  8. Cloning and characterization of a novel apolipoprotein gene, apolipoprotein AV, in tree shrews.

    PubMed

    Li, Guoping; Luo, Huairong; Sun, Guotao; Wu, Guisheng; Wu, Gang; Wang, Yan; Man, Yong; Wang, Shu; Li, Jian; Chen, Baosheng

    2013-09-01

    Apolipoprotein AV (apoAV) modulates plasma triglyceride levels, which is an independent risk factor for cardiovascular disease. ApoAV is also involved in atherosclerosis lesion formation. In order to systematically evaluate the apolipoprotein-related gene profile in tree shrew, a model for its insusceptibility to atherosclerosis, we performed apoAV cloning and characterization. The full-length cDNA of apoAV was identified using SMART-RACE. ApoAV cDNA sequence revealed two transcripts, 1,948 and 1,397 base pairs, due to alternative polyadenylation. These two transcripts share the same open reading frame (ORF), which encodes a 369-amino acid protein with high identity to human apoAV (75 %), including a 23-amino acid N-terminal signal peptide. ApoAV is expressed exclusively in the liver. Mature apoAV was expressed in E. coli BL21(DE3) and purified by Ni-chelated resin. Lipoprotein lipase activity was significantly stimulated by this recombinant protein. The full-length ORF of apoAV was cloned into pDsRed-monomer-N1 vector with a red fluorescent protein tag and was primarily localized in cytoplasm of hepG2 cells. The successful cloning, expression and localization of apoAV in tree shrew has laid down the foundation for further investigation on its structure and functions.

  9. The molecular chaperone TRiC/CCT binds to the Trp-Asp 40 (WD40) repeat protein WDR68 and promotes its folding, protein kinase DYRK1A binding, and nuclear accumulation.

    PubMed

    Miyata, Yoshihiko; Shibata, Takeshi; Aoshima, Masato; Tsubata, Takuichi; Nishida, Eisuke

    2014-11-28

    Trp-Asp (WD) repeat protein 68 (WDR68) is an evolutionarily conserved WD40 repeat protein that binds to several proteins, including dual specificity tyrosine phosphorylation-regulated protein kinase (DYRK1A), MAPK/ERK kinase kinase 1 (MEKK1), and Cullin4-damage-specific DNA-binding protein 1 (CUL4-DDB1). WDR68 affects multiple and diverse physiological functions, such as controlling anthocyanin synthesis in plants, tissue growth in insects, and craniofacial development in vertebrates. However, the biochemical basis and the regulatory mechanism of WDR68 activity remain largely unknown. To better understand the cellular function of WDR68, here we have isolated and identified cellular WDR68 binding partners using a phosphoproteomic approach. More than 200 cellular proteins with wide varieties of biochemical functions were identified as WDR68-binding protein candidates. Eight T-complex protein 1 (TCP1) subunits comprising the molecular chaperone TCP1 ring complex/chaperonin-containing TCP1 (TRiC/CCT) were identified as major WDR68-binding proteins, and phosphorylation sites in both WDR68 and TRiC/CCT were identified. Co-immunoprecipitation experiments confirmed the binding between TRiC/CCT and WDR68. Computer-aided structural analysis suggested that WDR68 forms a seven-bladed β-propeller ring. Experiments with a series of deletion mutants in combination with the structural modeling showed that three of the seven β-propeller blades of WDR68 are essential and sufficient for TRiC/CCT binding. Knockdown of cellular TRiC/CCT by siRNA caused an abnormal WDR68 structure and led to reduction of its DYRK1A-binding activity. Concomitantly, nuclear accumulation of WDR68 was suppressed by the knockdown of TRiC/CCT, and WDR68 formed cellular aggregates when overexpressed in the TRiC/CCT-deficient cells. Altogether, our results demonstrate that the molecular chaperone TRiC/CCT is essential for correct protein folding, DYRK1A binding, and nuclear accumulation of WDR68.

  10. (24495) 2001 AV1 - A Suspected Very Wide Binary

    NASA Astrophysics Data System (ADS)

    Stephens, Robert D.; Warner, Brian D.; Aznar Macias, Amadeo; Benishek, Vladimir

    2017-10-01

    We report that asteroid (24495) 2001 AV1 is a binary asteroid. It is another candidate for the special case of very wide binaries. The primary lightcurve has a period of 24.083 ± 0.005 h and an amplitude 0.58 ± 0.05 mag. and the secondary lightcurve has a period of 2.7375 ± 0.0001 h.

  11. Toward robust AV conferencing on next-generation networks

    NASA Astrophysics Data System (ADS)

    Liu, Haining; Cheng, Liang; El Zarki, Magda

    2004-12-01

    In order to enable a truly pervasive computing environment, next generation networks (including B3G and 4G) will merge the broadband wireless and wireline networking infrastructure. However, due to the tremendous complexity in administration and the unreliability of the wireless channel, provision of hard-guarantees for services on such networks will not happen in the foreseeable future. This consequently makes it particularly challenging to offer viable AV conferencing services due to their stringent synchronization, delay and data fidelity requirements. We propose in this paper a robust application-level solution for wireless mobile AV conferencing on B3G/4G networks. Expecting no special treatment from the network, we apply a novel adaptive delay and synchronization control mechanism to maintain the synchronization and reduce the latency as much as possible. We also employ a robust video coding technique that has better error-resilience capability. We investigate the performance of the proposed solution through simulations using a three-state hidden Markov chain as the generic end-to-end transport channel model. The results show that our scheme yields tight synchronization performance, relatively low end-to-end latency and satisfactory presentation quality. The scheme successfully provides a fairly robust AV conferencing service.

  12. Toward robust AV conferencing on next-generation networks

    NASA Astrophysics Data System (ADS)

    Liu, Haining; Cheng, Liang; El Zarki, Magda

    2005-01-01

    In order to enable a truly pervasive computing environment, next generation networks (including B3G and 4G) will merge the broadband wireless and wireline networking infrastructure. However, due to the tremendous complexity in administration and the unreliability of the wireless channel, provision of hard-guarantees for services on such networks will not happen in the foreseeable future. This consequently makes it particularly challenging to offer viable AV conferencing services due to their stringent synchronization, delay and data fidelity requirements. We propose in this paper a robust application-level solution for wireless mobile AV conferencing on B3G/4G networks. Expecting no special treatment from the network, we apply a novel adaptive delay and synchronization control mechanism to maintain the synchronization and reduce the latency as much as possible. We also employ a robust video coding technique that has better error-resilience capability. We investigate the performance of the proposed solution through simulations using a three-state hidden Markov chain as the generic end-to-end transport channel model. The results show that our scheme yields tight synchronization performance, relatively low end-to-end latency and satisfactory presentation quality. The scheme successfully provides a fairly robust AV conferencing service.

  13. TIME VARIATION OF AV AND RV FOR TYPE Ia SUPERNOVAE BEHIND INTERSTELLAR DUST

    NASA Astrophysics Data System (ADS)

    Huang, Xiaosheng; Biederman, M.; Herger, B.; Aldering, G. S.

    2014-01-01

    TIME VARIATION OF AV AND RV FOR TYPE Ia SUPERNOVAE BEHIND NON-UNIFORM INTERSTELLAR DUST ABSTRACT We investigate the time variation of the visual extinction, AV, and the total-to-selective extinction ratio, RV, resulting from interstellar dust in front of an expanding photospheric disk of a type Ia supernova (SN Ia). We simulate interstellar dust clouds according to a power law power spectrum and produce extinction maps that either follow a pseudo-Gaussian distribution or a lognormal distribution. The RV maps are produced through a correlation between AV and RV. With maps of AV and RV generated in each case (pseudo-Gaussian and lognormal), we then compute the effective AV and RV for a SN as its photospheric disk expands behind the dust screen. We find for a small percentage of SNe the AV and RV values can vary by a large factor from day to day in the first 40 days after explosion.

  14. Synthesis and biological evaluation of N-aryl-7-methoxybenzo[b]furo[3,2-d]pyrimidin-4-amines and their N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amine analogues as dual inhibitors of CLK1 and DYRK1A kinases.

    PubMed

    Loidreau, Yvonnick; Marchand, Pascal; Dubouilh-Benard, Carole; Nourrisson, Marie-Renée; Duflos, Muriel; Loaëc, Nadège; Meijer, Laurent; Besson, Thierry

    2013-01-01

    Novel N-aryl-7-methoxybenzo[b]furo[3,2-d]pyrimidin-4-amines (1) and their N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amine analogues (2) were designed and prepared for the first time via microwave-accelerated multi-step synthesis. Various anilines were condensed with N'-(2-cyanaryl)-N,N-dimethylformimidamide intermediates obtained by reaction of 3-amino-6-methoxybenzofuran-2-carbonitrile (3) and 3-amino-6-methoxybenzothiophene-2-carbonitrile (4) precursors with dimethylformamide dimethylacetal. The inhibitory potency of the final products against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A and CLK1) was estimated. Compounds (2a-z) turned out to be particularly promising for the development of new pharmacological dual inhibitors of CLK1 and DYRK1A kinases.

  15. Development of a Serological Assay for the Sea Lion (Zalophus californianus) Anellovirus, ZcAV

    PubMed Central

    Fahsbender, Elizabeth; Rosario, Karyna; Cannon, John P.; Gulland, Frances; Dishaw, Larry J.; Breitbart, Mya

    2015-01-01

    New diseases in marine animals are emerging at an increasing rate, yet methodological limitations hinder characterization of viral infections. Viral metagenomics is an effective method for identifying novel viruses in diseased animals; however, determining virus pathogenesis remains a challenge. A novel anellovirus (Zalophus californianus anellovirus, ZcAV) was recently reported in the lungs of captive California sea lions involved in a mortality event. ZcAV was not detected by PCR in the blood of these animals, creating the inability to assess the prevalence of ZcAV in live sea lions. This study developed an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to ZcAV in sea lion serum. To assess ZcAV prevalence, paired serum and lung samples (n = 96) from wild sea lions that stranded along the California coast were tested through ELISA and PCR, respectively. Over 50% of the samples tested positive for ZcAV by ELISA (34%), PCR (29%), or both (11%) assays. ZcAV is prevalent in stranded wild sea lion populations and results suggest that PCR assays alone may grossly underestimate ZcAV exposure. This ELISA provides a tool for testing live sea lions for ZcAV exposure and is valuable for subsequent studies evaluating the potential pathogenicity of this anellovirus. PMID:25965294

  16. Development of a Serological Assay for the Sea Lion (Zalophus californianus) Anellovirus, ZcAV.

    PubMed

    Fahsbender, Elizabeth; Rosario, Karyna; Cannon, John P; Gulland, Frances; Dishaw, Larry J; Breitbart, Mya

    2015-05-12

    New diseases in marine animals are emerging at an increasing rate, yet methodological limitations hinder characterization of viral infections. Viral metagenomics is an effective method for identifying novel viruses in diseased animals; however, determining virus pathogenesis remains a challenge. A novel anellovirus (Zalophus californianus anellovirus, ZcAV) was recently reported in the lungs of captive California sea lions involved in a mortality event. ZcAV was not detected by PCR in the blood of these animals, creating the inability to assess the prevalence of ZcAV in live sea lions. This study developed an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to ZcAV in sea lion serum. To assess ZcAV prevalence, paired serum and lung samples (n = 96) from wild sea lions that stranded along the California coast were tested through ELISA and PCR, respectively. Over 50% of the samples tested positive for ZcAV by ELISA (34%), PCR (29%), or both (11%) assays. ZcAV is prevalent in stranded wild sea lion populations and results suggest that PCR assays alone may grossly underestimate ZcAV exposure. This ELISA provides a tool for testing live sea lions for ZcAV exposure and is valuable for subsequent studies evaluating the potential pathogenicity of this anellovirus.

  17. Prevalence of E/A wave fusion and A wave truncation in DDD pacemaker patients with complete AV block under nominal AV intervals.

    PubMed

    Poller, Wolfram C; Dreger, Henryk; Schwerg, Marius; Melzer, Christoph

    2015-01-01

    Optimization of the AV-interval (AVI) in DDD pacemakers improves cardiac hemodynamics and reduces pacemaker syndromes. Manual optimization is typically not performed in clinical routine. In the present study we analyze the prevalence of E/A wave fusion and A wave truncation under resting conditions in 160 patients with complete AV block (AVB) under the pre-programmed AVI. We manually optimized sub-optimal AVI. We analyzed 160 pacemaker patients with complete AVB, both in sinus rhythm (AV-sense; n = 129) and under atrial pacing (AV-pace; n = 31). Using Doppler analyses of the transmitral inflow we classified the nominal AVI as: a) normal, b) too long (E/A wave fusion) or c) too short (A wave truncation). In patients with a sub-optimal AVI, we performed manual optimization according to the recommendations of the American Society of Echocardiography. All AVB patients with atrial pacing exhibited a normal transmitral inflow under the nominal AV-pace intervals (100%). In contrast, 25 AVB patients in sinus rhythm showed E/A wave fusion under the pre-programmed AV-sense intervals (19.4%; 95% confidence interval (CI): 12.6-26.2%). A wave truncations were not observed in any patient. All patients with a complete E/A wave fusion achieved a normal transmitral inflow after AV-sense interval reduction (mean optimized AVI: 79.4 ± 13.6 ms). Given the rate of 19.4% (CI 12.6-26.2%) of patients with a too long nominal AV-sense interval, automatic algorithms may prove useful in improving cardiac hemodynamics, especially in the subgroup of atrially triggered pacemaker patients with AV node diseases.

  18. An uncommon case of spontaneous conversion from AV re-entry tachycardia to AV nodal re-entry tachycardia in a patient with dual tachycardia.

    PubMed

    Zeljković, Ivan; Benko, Ivica; Manola, Šime; Radeljić, Vjekoslav; Pavlović, Nikola

    2015-01-01

    We report the case of a 46-year old patient in whom an electrophysiology study (EP) was performed due to paroxysmal supraventricular tachycardia documented in 12-lead ECG. During the EP study, supraventricular tachycardia was induced easily and it corresponded to orthodromic AV reentry tachycardia (AVRT) using a concealed left free wall accessory pathway. However, during the study AVRT spontaneously and repeatedly converted to the typical slow-fast AV node reentry tachycardia (AVNRT). Both accessory and AV nodal slow pathways were ablated, due to the finding that both AVRT and AVNRT were independently inducible during the EP study.

  19. Artificial vision support system (AVS(2)) for improved prosthetic vision.

    PubMed

    Fink, Wolfgang; Tarbell, Mark A

    2014-11-01

    State-of-the-art and upcoming camera-driven, implanted artificial vision systems provide only tens to hundreds of electrodes, affording only limited visual perception for blind subjects. Therefore, real time image processing is crucial to enhance and optimize this limited perception. Since tens or hundreds of pixels/electrodes allow only for a very crude approximation of the typically megapixel optical resolution of the external camera image feed, the preservation and enhancement of contrast differences and transitions, such as edges, are especially important compared to picture details such as object texture. An Artificial Vision Support System (AVS(2)) is devised that displays the captured video stream in a pixelation conforming to the dimension of the epi-retinal implant electrode array. AVS(2), using efficient image processing modules, modifies the captured video stream in real time, enhancing 'present but hidden' objects to overcome inadequacies or extremes in the camera imagery. As a result, visual prosthesis carriers may now be able to discern such objects in their 'field-of-view', thus enabling mobility in environments that would otherwise be too hazardous to navigate. The image processing modules can be engaged repeatedly in a user-defined order, which is a unique capability. AVS(2) is directly applicable to any artificial vision system that is based on an imaging modality (video, infrared, sound, ultrasound, microwave, radar, etc.) as the first step in the stimulation/processing cascade, such as: retinal implants (i.e. epi-retinal, sub-retinal, suprachoroidal), optic nerve implants, cortical implants, electric tongue stimulators, or tactile stimulators.

  20. Effects of AV-delay optimization on hemodynamic parameters in patients with VDD pacemakers.

    PubMed

    Krychtiuk, Konstantin A; Nürnberg, Michael; Volker, Romana; Pachinger, Linda; Jarai, Rudolf; Freynhofer, Matthias K; Wojta, Johann; Huber, Kurt; Weiss, Thomas W

    2014-05-01

    Atrioventricular (AV) delay optimization improves hemodynamics and clinical parameters in patients treated with cardiac resynchronization therapy and dual-chamber-pacemakers (PM). However, data on optimizing AV delay in patients treated with VDD-PMs are scarce. We, therefore, investigated the acute and chronic effects of AV delay optimization on hemodynamics in patients treated with VDD-PMs due to AV-conduction disturbances. In this prospective, single-center interventional trial, we included 64 patients (38 men, 26 women, median age: 77 (70-82) years) with implanted VDD-PM. AV-delay optimization was performed using a formula based on the surface electrocardiogram (ECG). Hemodynamic parameters (stroke volume (SV), cardiac output (CO), heart rate (HR), and blood pressure (BP)) were measured at baseline and follow-up after 3 months using impedance cardiography. Using an ECG formula for AV-delay optimization, the AV interval was decreased from 180 (180-180) to 75 (75-100) ms. At baseline, AV-delay optimization led to a significant increase of both SV (71.3 ± 15.8 vs. 55.3 ± 12.7 ml, p < 0.001, for optimized AV delay vs. nominal AV interval, respectively) and CO (5.1 ± 1.4 vs. 3.9 ± 1.0 l/min, p < 0.001), while HR and BP remained unchanged. At follow-up, the improvement in CO remained stable (4.9 ± 1.3 l/min, p = 0.09), while SV slightly, but significantly, decreased (to 65.1 ± 17.6, p < 0.01). AV-delay optimization in patients treated with VDD-PMs exhibits immediate beneficial effects on hemodynamic parameters that are sustained for 3 months.

  1. First Aviation System Technology Advanced Research (AvSTAR) Workshop

    NASA Technical Reports Server (NTRS)

    Denery, Dallas G. (Editor); Weathers, Del W. (Editor); Rosen, Robert (Technical Monitor); Edwards, Tom (Technical Monitor)

    2001-01-01

    This Conference Proceedings documents the results of a two-day NASA/FAA/Industry workshop that was held at the NASA Ames Research Center, located at Moffett Field, CA, on September 21-22, 2000. The purpose of the workshop was to bring together a representative cross section of leaders in air traffic management, from industry. FAA, and academia, to assist in defining the requirements for a new research effort, referred to as AvSTAR Aviation Systems Technology Advanced Research). The Conference Proceedings includes the individual presentation, and summarizes the workshop discussions and recommendations.

  2. Pilot Implementation and Preliminary Evaluation of START:AV Assessments in Secure Juvenile Correctional Facilities

    PubMed Central

    Sellers, Brian G; Viljoen, Jodi L.; Cruise, Keith R.; Nicholls, Tonia L.; Dvoskin, Joel A.

    2012-01-01

    The Short-Term Assessment of Risk and Treatability: Adolescent Version (START:AV) is a new structured professional judgment guide for assessing short-term risks in adolescents. The scheme may be distinguished from other youth risk assessment and treatment planning instruments by its inclusion of 23 dynamic factors that are each rated for both vulnerability and strength. In addition, START:AV is also unique in that it focuses on multiple adverse outcomes—namely, violence, self-harm, suicide, unauthorized leave, substance abuse, self-neglect, victimization, and general offending—over the short-term (i.e., weeks to months) rather than long-term (i.e., years). This paper describes a pilot implementation and preliminary evaluation of START:AV in three secure juvenile correctional facilities in the southern United States. Specifically, we examined the descriptive characteristics and psychometric properties of START:AV assessments completed by 21 case managers on 291 adolescent offenders (250 boys and 41 girls) at the time of admission. Results provide preliminary support for the feasibility of completing START:AV assessments as part of routine practice. Findings also highlight differences in the characteristics of START:AV assessments for boys and girls and differential associations between the eight START:AV risk domains. Though results are promising, further research is needed to establish the reliability and validity of START:AV assessments completed in the field. PMID:23316116

  3. Pilot Implementation and Preliminary Evaluation of START:AV Assessments in Secure Juvenile Correctional Facilities.

    PubMed

    Desmarais, Sarah L; Sellers, Brian G; Viljoen, Jodi L; Cruise, Keith R; Nicholls, Tonia L; Dvoskin, Joel A

    2012-01-01

    The Short-Term Assessment of Risk and Treatability: Adolescent Version (START:AV) is a new structured professional judgment guide for assessing short-term risks in adolescents. The scheme may be distinguished from other youth risk assessment and treatment planning instruments by its inclusion of 23 dynamic factors that are each rated for both vulnerability and strength. In addition, START:AV is also unique in that it focuses on multiple adverse outcomes-namely, violence, self-harm, suicide, unauthorized leave, substance abuse, self-neglect, victimization, and general offending-over the short-term (i.e., weeks to months) rather than long-term (i.e., years). This paper describes a pilot implementation and preliminary evaluation of START:AV in three secure juvenile correctional facilities in the southern United States. Specifically, we examined the descriptive characteristics and psychometric properties of START:AV assessments completed by 21 case managers on 291 adolescent offenders (250 boys and 41 girls) at the time of admission. Results provide preliminary support for the feasibility of completing START:AV assessments as part of routine practice. Findings also highlight differences in the characteristics of START:AV assessments for boys and girls and differential associations between the eight START:AV risk domains. Though results are promising, further research is needed to establish the reliability and validity of START:AV assessments completed in the field.

  4. Third-degree AV block sensitive to prednisolone 72 hours post AVNRT ablation.

    PubMed

    Parwani, Abdul S; Schröder, Anna I; Blaschke, Daniela; Blaschke, Florian; Huemer, Martin; Attanasio, Philipp; Pieske, Burkert; Boldt, Leif-Hendrik; Haverkamp, Wilhelm

    2017-05-01

    A patient developed a transient first-degree AV block during a radiofrequency ablation of an atrioventricular nodal reentrant tachycardia. Three days later the patient presented with a third-degree AV block. It resolved within 24 h under antiphlogistic therapy. Patient was asymptomatic without necessity for pacemaker implantation at 12 months follow-up.

  5. Association of temporary complete AV block and junctional ectopic tachycardia after surgery for congenital heart disease.

    PubMed

    Paech, Christian; Dähnert, Ingo; Kostelka, Martin; Mende, Meinhardt; Gebauer, Roman

    2015-01-01

    Junctional ectopic tachycardia (JET) is a postoperative complication with a mortality rate of up to 14% after surgery for congenital heart disease. This study evaluated the risk factors of JET and explored the association of postoperative temporary third degree atrioventricular (AV) block and the occurrence of JET. Data were collected retrospectively from 1158 patients who underwent surgery for congenital heart disease. The overall incidence of JET was 2.8%. Temporary third degree AV block occurred in 1.6% of cases. Permanent third degree AV block requiring pacemaker implantation occurred in 1% of cases. In all, 56% of patients with JET had temporary AV block (P < 0.001), whereas no case of postoperative JET was reported in patients with permanent AV block (P = 0.56). temporary third degree AV block did not suffer from JET. A correlation between temporary third degree AV block and postoperative JET could be observed. The risk factors identified for JET include younger age groups at the time of surgery, longer aortic cross clamping time and surgical procedures in proximity to the AV node.

  6. Examination of Office Visit Patient Preferences for the After-Visit Summary (AVS)

    PubMed Central

    Neuberger, Marolee; Dontje, Katherine; Holzman, Greg; Corser, Bill; Keskimaki, Abigail; Chant, Ericka

    2014-01-01

    The federal government advocates the practice of routinely providing an after-visit summary (AVS) to patients after each office-based visit as an element of stage 1 meaningful use. A significant potential benefit of the AVS is improved patient engagement achieved by enabling patients and family members to better understand and retain key health information. The methodology for this study was a mixed-methods pilot study to examine, through the perspectives of adult primary care patients, how relevant and actionable data can be better formatted in the AVS. Results of this study suggest that the goal of the AVS to serve as a communication tool to engage and support patients is frequently not being met. Further study is needed to understand, from the viewpoints of patients and providers, what barriers are keeping them from optimally providing and using the information on the AVS. PMID:25593570

  7. Examination of office visit patient preferences for the after-visit summary (AVS).

    PubMed

    Neuberger, Marolee; Dontje, Katherine; Holzman, Greg; Corser, Bill; Keskimaki, Abigail; Chant, Ericka

    2014-01-01

    The federal government advocates the practice of routinely providing an after-visit summary (AVS) to patients after each office-based visit as an element of stage 1 meaningful use. A significant potential benefit of the AVS is improved patient engagement achieved by enabling patients and family members to better understand and retain key health information. The methodology for this study was a mixed-methods pilot study to examine, through the perspectives of adult primary care patients, how relevant and actionable data can be better formatted in the AVS. Results of this study suggest that the goal of the AVS to serve as a communication tool to engage and support patients is frequently not being met. Further study is needed to understand, from the viewpoints of patients and providers, what barriers are keeping them from optimally providing and using the information on the AVS.

  8. 78 FR 52872 - Airworthiness Directives; 328 Support Services GmbH (Type Certificate Previously Held by AvCraft...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-27

    ... Services GmbH (Type Certificate Previously Held by AvCraft Aerospace GmbH; Fairchild Dornier GmbH; Dornier... certain 328 Support Services GmbH (Type Certificate Previously Held by AvCraft Aerospace GmbH; Fairchild... GmbH (Type Certificate Previously Held by AvCraft Aerospace GmbH; Fairchild Dornier GmbH;...

  9. In vivo retention of 18F-AV-1451 in corticobasal syndrome

    PubMed Central

    Schöll, Michael; Widner, Håkan; van Westen, Danielle; Svenningsson, Per; Hägerström, Douglas; Ohlsson, Tomas; Jögi, Jonas; Nilsson, Christer

    2017-01-01

    Objective: To study the usefulness of 18F-AV-1451 PET in patients with corticobasal syndrome (CBS). Methods: We recruited 8 patients with CBS, 17 controls, 31 patients with Alzheimer disease (AD), and 11 patients with progressive supranuclear palsy (PSP) from the Swedish BioFINDER study. All patients underwent clinical assessment, 18F-AV-1451 PET, MRI, and quantification of β-amyloid pathology. A subset of participants also underwent 18F-FDG-PET. Results: In the 8 patients with CBS, 6 had imaging findings compatible with the corticobasal degeneration pathology and 2 with typical AD pathology. In the 6 patients with CBS without typical AD pathology, there were substantial retentions of 18F-AV-1451 in the motor cortex, corticospinal tract, and basal ganglia contralateral to the most affected body side. These patients could be clearly distinguished from patients with AD dementia or PSP using 18F-AV-1451. However, cortical atrophy was more widespread than the cortical retention of 18F-AV1451 in these CBS cases, and cortical AV-1451 uptake did not correlate with cortical thickness or glucose hypometabolism. These results are in sharp contrast to AD dementia, where 18F-AV-1451 retention was more widespread than cortical atrophy, and correlated well with cortical thickness and hypometabolism. Conclusions: Patients with CBS without typical AD pathology exhibited AV-1451 retention in the motor cortex, corticospinal tract, and basal ganglia contralateral to the affected body side, clearly different from controls and patients with AD dementia or PSP. However, cortical atrophy measured with MRI and decreased 18F-fluorodeoxyglucose uptake were more widespread than 18F-AV-1451 uptake and probably represent earlier, yet less specific, markers of CBS. Classification of evidence: This study provides Class III evidence that 18F-AV-1451 PET distinguishes between CBS and AD or PSP. PMID:28754841

  10. In vivo retention of (18)F-AV-1451 in corticobasal syndrome.

    PubMed

    Smith, Ruben; Schöll, Michael; Widner, Håkan; van Westen, Danielle; Svenningsson, Per; Hägerström, Douglas; Ohlsson, Tomas; Jögi, Jonas; Nilsson, Christer; Hansson, Oskar

    2017-08-22

    To study the usefulness of (18)F-AV-1451 PET in patients with corticobasal syndrome (CBS). We recruited 8 patients with CBS, 17 controls, 31 patients with Alzheimer disease (AD), and 11 patients with progressive supranuclear palsy (PSP) from the Swedish BioFINDER study. All patients underwent clinical assessment, (18)F-AV-1451 PET, MRI, and quantification of β-amyloid pathology. A subset of participants also underwent (18)F-FDG-PET. In the 8 patients with CBS, 6 had imaging findings compatible with the corticobasal degeneration pathology and 2 with typical AD pathology. In the 6 patients with CBS without typical AD pathology, there were substantial retentions of (18)F-AV-1451 in the motor cortex, corticospinal tract, and basal ganglia contralateral to the most affected body side. These patients could be clearly distinguished from patients with AD dementia or PSP using (18)F-AV-1451. However, cortical atrophy was more widespread than the cortical retention of (18)F-AV1451 in these CBS cases, and cortical AV-1451 uptake did not correlate with cortical thickness or glucose hypometabolism. These results are in sharp contrast to AD dementia, where (18)F-AV-1451 retention was more widespread than cortical atrophy, and correlated well with cortical thickness and hypometabolism. Patients with CBS without typical AD pathology exhibited AV-1451 retention in the motor cortex, corticospinal tract, and basal ganglia contralateral to the affected body side, clearly different from controls and patients with AD dementia or PSP. However, cortical atrophy measured with MRI and decreased (18)F-fluorodeoxyglucose uptake were more widespread than (18)F-AV-1451 uptake and probably represent earlier, yet less specific, markers of CBS. This study provides Class III evidence that (18)F-AV-1451 PET distinguishes between CBS and AD or PSP. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

  11. [(18) F]AV-1451 tau positron emission tomography in progressive supranuclear palsy.

    PubMed

    Whitwell, Jennifer L; Lowe, Val J; Tosakulwong, Nirubol; Weigand, Stephen D; Senjem, Matthew L; Schwarz, Christopher G; Spychalla, Anthony J; Petersen, Ronald C; Jack, Clifford R; Josephs, Keith A

    2017-01-01

    The [(18) F]AV-1451 positron emission tomography ligand allows the in vivo assessment of tau proteins in the brain. It shows strong binding in Alzheimer's dementia, but little is known about how it performs in progressive supranuclear palsy, a primary 4R tauopathy. The objectives of this study were to determine whether [(18) F]AV-1451 uptake can be observed in progressive supranuclear palsy and to characterize the regional distribution when compared with controls and Alzheimer's dementia. [(18) F]AV-1451 positron emission tomography was performed in 10 patients with probable progressive supranuclear palsy. These patients were age- and gender-matched to 50 controls and 10 Alzheimer's dementia patients who had undergone identical [(18) F]AV-1451 imaging. Regional comparisons of [(18) F]AV-1451 uptake were performed across the whole brain using region-of-interest and voxel-level analyses, and correlations between regional [(18) F]AV-1451 and the progressive supranuclear palsy rating scale were assessed. An elevated [(18) F]AV-1451 signal was observed in progressive supranuclear palsy when compared with controls in the pallidum, midbrain, dentate nucleus of the cerebellum, thalamus, caudate nucleus, and frontal regions. Signal in the cerebellar dentate and pallidum were also greater in progressive supranuclear palsy when compared with Alzheimer's dementia. Conversely, the [(18) F]AV-1451 signal across the cortex was higher in Alzheimer's dementia when compared with progressive supranuclear palsy. The [(18) F]AV-1451 signal in a number of regions correlated with the progressive supranuclear palsy rating scale. Progressive supranuclear palsy is associated with an elevated [(18) F]AV-1451 signal in a characteristic and distinct regional pattern that correlates with disease severity and differs from the patterns observed in Alzheimer's dementia. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

  12. BMP2 expression in the endocardial lineage is required for AV endocardial cushion maturation and remodeling.

    PubMed

    Saxon, Jacob G; Baer, Daniel R; Barton, Julie A; Hawkins, Travis; Wu, Bingruo; Trusk, Thomas C; Harris, Stephen E; Zhou, Bin; Mishina, Yuji; Sugi, Yukiko

    2017-10-01

    Distal outgrowth, maturation and remodeling of the endocardial cushion mesenchyme in the atrioventricular (AV) canal are the essential morphogenetic events during four-chambered heart formation. Mesenchymalized AV endocardial cushions give rise to the AV valves and the membranous ventricular septum (VS). Failure of these processes results in several human congenital heart defects. Despite this clinical relevance, the mechanisms governing how mesenchymalized AV endocardial cushions mature and remodel into the membranous VS and AV valves have only begun to be elucidated. The role of BMP signaling in the myocardial and secondary heart forming lineage has been well studied; however, little is known about the role of BMP2 expression in the endocardial lineage. To fill this knowledge gap, we generated Bmp2 endocardial lineage-specific conditional knockouts (referred to as Bmp2 cKO(Endo)) by crossing conditionally-targeted Bmp2(flox/flox) mice with a Cre-driver line, Nfatc1(Cre), wherein Cre-mediated recombination was restricted to the endocardial cells and their mesenchymal progeny. Bmp2 cKO(Endo) mouse embryos did not exhibit failure or delay in the initial AV endocardial cushion formation at embryonic day (ED) 9.5-11.5; however, significant reductions in AV cushion size were detected in Bmp2 cKO(Endo) mouse embryos when compared to control embryos at ED13.5 and ED16.5. Moreover, deletion of Bmp2 from the endocardial lineage consistently resulted in membranous ventricular septal defects (VSDs), and mitral valve deficiencies, as evidenced by the absence of stratification of mitral valves at birth. Muscular VSDs were not found in Bmp2 cKO(Endo) mouse hearts. To understand the underlying morphogenetic mechanisms leading to a decrease in cushion size, cell proliferation and cell death were examined for AV endocardial cushions. Phospho-histone H3 analyses for cell proliferation and TUNEL assays for apoptotic cell death did not reveal significant differences between control

  13. A 2:1 AV rhythm: an adverse effect of a long AV delay during DDI pacing and its prevention by the ventricular intrinsic preference algorithm in DDD mode.

    PubMed

    Minamiguchi, Hitoshi; Oginosawa, Yasushi; Kohno, Ritsuko; Tamura, Masahito; Takeuchi, Masaaki; Otsuji, Yutaka; Abe, Haruhiko

    2012-07-01

    A 91-year-old woman received a dual-chamber pacemaker for sick sinus syndrome and intermittently abnormal atrioventricular (AV) conduction. The pacemaker was set in DDI mode with a 350-ms AV delay to preserve intrinsic ventricular activity. She complained of palpitation during AV sequential pacing. The electrocardiogram showed a 2:1 AV rhythm from 1:1 ventriculoatrial (VA) conduction during ventricular pacing in DDI mode with a long AV interval. After reprogramming of the pacemaker in DDD mode with a 250-ms AV interval and additional 100-ms prolongation of the AV interval by the ventricular intrinsic preference function, VA conduction disappeared and the patient's symptom were alleviated without increasing unnecessary right ventricular pacing.

  14. Baseline HV-interval predicts complete AV-block secondary to transcatheter aortic valve implantation.

    PubMed

    Shin, Dong-In; Merx, Marc W; Meyer, Christian; Kirmanoglou, Kiriakos; Hellhammer, Katharina; Ohlig, Jan; Katsani, Dimitra; Zeus, Tobias; Westenfeld, Ralf; Eickholt, Christian; Linke, Axel; Kelm, Malte

    2015-10-01

    Development of AV-block is a frequent complication associated with transcatheter aortic valve implantation (TAVI). To date little is known about the predictive value of the HV-interval prior to TAVI with respect to the risk of AV-block development. HV-interval was determined in 25 consecutive elderly patients with severe aortic valve stenosis (AS) before and immediately after TAVI. All patients subsequently underwent TAVI and 8 of these 25 patients (32%) developed complete AV-block during the TAVI procedure requiring permanent pacemaker implantation. Six of these 8 patients (75%) had marked HV prolongation (>54 ms). Pre-procedural HV-interval was significantly prolonged in the subgroup developing complete AV-block (62.1 ms±13.0 vs 49.2 ms±12.9; P=0.029). Prolongation of the HV-interval above 54 ms was associated with a higher rate of complete AV-block (sensitivity 75.0%, specificity 77.8%, P=0.01). HV-interval was prolonged in approximately one third of our elderly patients with aortic valve stenosis and associated with a high rate of complete AV-block following TAVI. HV-interval is easily obtained during TAVI screening procedures, thus facilitating identification of patients at risk for complete AV-block due to TAVI and consequently enabling bespoke risk management.

  15. Developing a computational model of human hand kinetics using AVS

    SciTech Connect

    Abramowitz, Mark S.

    1996-05-01

    As part of an ongoing effort to develop a finite element model of the human hand at the Institute for Scientific Computing Research (ISCR), this project extended existing computational tools for analyzing and visualizing hand kinetics. These tools employ a commercial, scientific visualization package called AVS. FORTRAN and C code, originally written by David Giurintano of the Gillis W. Long Hansen`s Disease Center, was ported to a different computing platform, debugged, and documented. Usability features were added and the code was made more modular and readable. When the code is used to visualize bone movement and tendon paths for the thumb, graphical output is consistent with expected results. However, numerical values for forces and moments at the thumb joints do not yet appear to be accurate enough to be included in ISCR`s finite element model. Future work includes debugging the parts of the code that calculate forces and moments and verifying the correctness of these values.

  16. American AV: Edgar Dale and the Information Age Classroom.

    PubMed

    Acland, Charles R

    2017-01-01

    This article demonstrates how the influential scholar Edgar Dale, alongside a generation of educational technologists, helped build an essential place for AV materials and pedagogical methods in the American classroom. It also shows that, for decades, the Payne Fund philanthropy supported multimedia research agendas that shaped ideas about teaching and technology, far beyond involvement in their famed studies on motion pictures and children in the 1930s. With his writings and research programs, Dale advanced concepts of media experience and systematicity, which came to be understood as common sense to the information society. In so doing he was a leading contributor to the discursive and ideological structure of our age of technological and informational abundance.

  17. Validating novel tau PET tracer [F-18]-AV-1451 (T807) on postmortem brain tissue

    PubMed Central

    Marquie, Marta; Normandin, Marc D.; Vanderburg, Charles R.; Costantino, Isabel; Bien, Elizabeth A.; Rycyna, Lisa G.; Klunk, William E.; Mathis, Chester A.; Ikonomovic, Milos D.; Debnath, Manik L.; Vasdev, Neil; Dickerson, Bradford C.; Gomperts, Stephen N.; Growdon, John H.; Johnson, Keith A.; Frosch, Matthew P.; Hyman, Bradley T.; Gomez-Isla, Teresa

    2016-01-01

    Objective To examine region and substrate-specific autoradiographic and in vitro binding patterns of PET tracer [F-18]-AV-1451 (previously known as T807), tailored to allow in vivo detection of paired helical filament tau-containing lesions, and to determine whether there is off-target binding to other amyloid/non-amyloid proteins. Methods We applied [F-18]-AV-1451 phosphor screen autoradiography, [F-18]-AV-1451 nuclear emulsion autoradiography and [H-3]-AV-1451 in vitro binding assays to the study of postmortem samples from patients with a definite pathological diagnosis of Alzheimer’s disease, frontotemporal lobar degeneration-tau, frontotemporal lobar degeneration-TDP-43, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy, cerebral amyloid angiopathy and elderly controls free of pathology. Results Our data suggest that AV-1451 strongly binds to tau lesions primarily made of paired helical filaments in Alzheimer’s brains e.g. intra and extraneuronal tangles and dystrophic neurites, but does not seem to bind to a significant extent to neuronal and glial inclusions mainly composed of straight tau filaments in non-Alzheimer tauopathy brains or to β-amyloid, α-synuclein or TDP-43-containing lesions. AV-1451 off-target binding to neuromelanin- and melanin-containing cells and, to a lesser extent, to brain hemorrhagic lesions was identified. Interpretation Our data suggest that AV-1451 holds promise as surrogate marker for the detection of brain tau pathology in the form of tangles and paired helical filament-tau-containing neurites in Alzheimer’s brains but also point to its relatively lower affinity for lesions primarily made of straight tau filaments in non-Alzheimer tauopathy cases and to the existence of some AV-1451 off-target binding. These findings provide important insights for interpreting in vivo patterns of [F-18]-AV-1451 retention. PMID:26344059

  18. Pathological correlations of [F-18]-AV-1451 imaging in non-alzheimer tauopathies.

    PubMed

    Marquié, Marta; Normandin, Marc D; Meltzer, Avery C; Siao Tick Chong, Michael; Andrea, Nicolas V; Antón-Fernández, Alejandro; Klunk, William E; Mathis, Chester A; Ikonomovic, Milos D; Debnath, Manik; Bien, Elizabeth A; Vanderburg, Charles R; Costantino, Isabel; Makaretz, Sara; DeVos, Sarah L; Oakley, Derek H; Gomperts, Stephen N; Growdon, John H; Domoto-Reilly, Kimiko; Lucente, Diane; Dickerson, Bradford C; Frosch, Matthew P; Hyman, Bradley T; Johnson, Keith A; Gómez-Isla, Teresa

    2017-01-01

    Recent studies have shown that positron emission tomography (PET) tracer AV-1451 exhibits high binding affinity for paired helical filament (PHF)-tau pathology in Alzheimer's brains. However, the ability of this ligand to bind to tau lesions in other tauopathies remains controversial. Our goal was to examine the correlation of in vivo and postmortem AV-1451 binding patterns in three autopsy-confirmed non-Alzheimer tauopathy cases. We quantified in vivo retention of [F-18]-AV-1451 and performed autoradiography, [H-3]-AV-1451 binding assays, and quantitative tau measurements in postmortem brain samples from two progressive supranuclear palsy (PSP) cases and a MAPT P301L mutation carrier. They all underwent [F-18]-AV-1451 PET imaging before death. The three subjects exhibited [F-18]-AV-1451 in vivo retention predominantly in basal ganglia and midbrain. Neuropathological examination confirmed the PSP diagnosis in the first two subjects; the MAPT P301L mutation carrier had an atypical tauopathy characterized by grain-like tau-containing neurites in gray and white matter with heaviest burden in basal ganglia. In all three cases, autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined, with the exception of entorhinal cortex (reflecting incidental age-related neurofibrillary tangles) and neuromelanin-containing neurons in the substantia nigra (off-target binding). The lack of a consistent significant correlation between in vivo [F-18]-AV-1541 retention and postmortem in vitro binding and tau measures in these cases suggests that this ligand has low affinity for tau lesions primarily made of straight tau filaments. AV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in these non-Alzheimer tauopathies. ANN NEUROL 2017;81:117-128. © 2016 American Neurological Association.

  19. Subcortical (18) F-AV-1451 binding patterns in progressive supranuclear palsy.

    PubMed

    Cho, Hanna; Choi, Jae Yong; Hwang, Mi Song; Lee, Seung Ha; Ryu, Young Hoon; Lee, Myung Sik; Lyoo, Chul Hyoung

    2017-01-01

    Accumulation of cortical and subcortical tau pathology is the primary pathological substrate for progressive supranuclear palsy (PSP). (18) F-AV-1451, a radiotracer that binds to the pathological tau protein, may be helpful for in vivo visualization and quantitation of tau pathology in PSP. The objectives of this study were to investigate cortical and subcortical (18) F-AV-1451 binding patterns in patients with PSP. We recruited 14 PSP patients and compared their cortical and subcortical binding patterns in (18) F-AV-1451 positron emission tomography (PET) studies with those of 15 Parkinson's disease (PD) patients and 15 healthy controls. In both the PD and PSP groups, subcortical (18) F-AV-1451 binding did not correlate with the severity of motor dysfunctions, and cortical binding did not differ between the controls and each patient group. However, the PSP patients showed greater (18) F-AV-1451 binding in the putamen, globus pallidus, subthalamic nucleus, and dentate nucleus when compared with the controls, whereas the PD patients showed lower (18) F-AV-1451 binding in the substantia nigra than controls. The PSP and PD patients showed distinct subcortical (18) F-AV-1451 binding patterns reflecting subcortical tau pathology in PSP and reduced nigral neuromelanin in PD. However, there was no correlation with the severity of motor dysfunction, no cortical regions with increased binding in PSP patients, and variable degrees of subcortical binding even in the controls. Therefore, the (18) F-AV-1451 PET may be less than ideal for assessing tau pathology in PSP. Further studies will be required to validate the clinical correlation and to understand the clinical utility of (18) F-AV-1451 PET for PSP patients. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

  20. [The functional dissociation of conduction within the human AV-node (author's transl)].

    PubMed

    Runge, M; Narula, O S; Ehlers, E; Luckmann, E; Pantlen, H

    1980-07-15

    The functional dissociation (FD) of conduction within the AV-node is characterized by sudden prolongations and/or shortenings of the AH-time during stimulation. Examples for FD are presented during regular atrial stimulation and atrial extrastimulus technique. The appearance of FD is no proof for functional impairment of the AV-node. The blockade of the parasympathetic nervous system abolishes FD and leads to the well known continuous and regular adaptation of the AH-time with the various kinds of stimulation examined. It is recommended to replace the term "pathways" by the more comprehensive concept of functional dissociation with the AV-node.

  1. Reference Tissue-Based Kinetic Evaluation of 18F-AV-1451 for Tau Imaging.

    PubMed

    Baker, Suzanne L; Lockhart, Samuel N; Price, Julie C; He, Mark; Huesman, Ronald H; Schonhaut, Daniel; Faria, Jamie; Rabinovici, Gil; Jagust, William J

    2017-02-01

    The goal of this paper was to evaluate the in vivo kinetics of the novel tau-specific PET radioligand (18)F-AV-1451 in cognitively healthy control (HC) and Alzheimer disease (AD) subjects, using reference region analyses.

  2. Design Release Reliability Prediciton Test Set, Weapon Control, Aircraft, AN/ASM-184A(V).

    DTIC Science & Technology

    This report presents a design release reliability prediction for the Test Set, Weapon Control , Aircraft , AN/ASM-184A(V). The data and methods used to arrive at this prediction are included. (Author)

  3. Crystallization and preliminary structure determination of the plant food allergen Pru av 2

    SciTech Connect

    Dall’Antonia, Yuliya; Pavkov, Tea; Fuchs, Heidemarie; Breiteneder, Heimo; Keller, Walter

    2005-02-01

    Crystals of Pru av 2, the first allergenic thaumatin-like protein, have been obtained and diffracted to 1.6 Å at a synchrotron. Using an annealing protocol, the resolution limit was improved to 1.3 Å:.

  4. Dynamics of AV coupling during human atrial fibrillation: role of atrial rate.

    PubMed

    Masè, M; Marini, M; Disertori, M; Ravelli, F

    2015-07-01

    The causal relationship between atrial and ventricular activities during human atrial fibrillation (AF) is poorly understood. This study analyzed the effects of an increase in atrial rate on the link between atrial and ventricular activities during AF. Atrial and ventricular time series were determined in 14 patients during the spontaneous acceleration of the atrial rhythm at AF onset. The dynamic relationship between atrial and ventricular activities was quantified in terms of atrioventricular (AV) coupling by AV synchrogram analysis. The technique identified n:m coupling patterns (n atrial beats in m ventricular cycles), quantifying their percentage, maximal length, and conduction ratio (= m/n). Simulations with a difference-equation AV model were performed to correlate the observed dynamics to specific atrial/nodal properties. The atrial rate increase significantly affected AV coupling and ventricular response during AF. The shortening of atrial intervals from 185 ± 32 to 165 ± 24 ms (P < 0.001) determined transitions toward AV patterns with progressively decreasing m/n ratios (from conduction ratio = 0.34 ± 0.09 to 0.29 ± 0.08, P < 0.01), lower occurrence (from percentage of coupled beats = 27.1 ± 8.0 to 21.8 ± 6.9%, P < 0.05), and higher instability (from maximal length = 3.9 ± 1.5 to 2.8 ± 0.7 s, P < 0.01). Advanced levels of AV block and coupling instability at higher atrial rates were associated with increased ventricular interval variability (from 123 ± 52 to 133 ± 55 ms, P < 0.05). AV pattern transitions and coupling instability in patients were predicted, assuming the filtering of high-rate irregular atrial beats by the slow recovery of nodal excitability. These results support the role of atrial rate in determining AV coupling and ventricular response and may have implications for rate control in AF.

  5. [(18)F]AV-1451 binding to neuromelanin in the substantia nigra in PD and PSP.

    PubMed

    Coakeley, Sarah; Cho, Sang Soo; Koshimori, Yuko; Rusjan, Pablo; Ghadery, Christine; Kim, Jinhee; Lang, Anthony E; Houle, Sylvain; Strafella, Antonio P

    2017-09-07

    This study investigated binding of [(18)F]AV-1451 to neuromelanin in the substantia nigra of patients with Parkinson's disease (PD) and progressive supranuclear palsy (PSP). [(18)F]AV-1451 is a positron emission tomography radiotracer designed to bind pathological tau. A post-mortem study using [(18)F]AV-1451 discovered off-target binding properties to neuromelanin in the substantia nigra. A subsequent clinical study reported a 30% decrease in [(18)F]AV-1451 binding in the midbrain of PD patients. A total of 12 patients and 10 healthy age-matched controls were recruited. An anatomical MRI and a 90-min PET scan, using [(18)F]AV-1451, were acquired from all participants. The standardized uptake value ratio (SUVR) from 60 to 90 min post-injection was calculated for the substantia nigra, using the cerebellar cortex as the reference region. The substantia nigra was delineated using automated region of interest software. An independent samples ANOVA and LSD post hoc testing were used to test for differences in [(18)F]AV-1451 SUVR between groups. Substantia nigra SUVR from 60 to 90 min was significantly greater in HC compared to both PSP and PD groups. Although the PD group had the lowest SUVR, there was no significant difference in substantia nigra uptake between PD and PSP. [(18)F]AV-1451 may be the first PET radiotracer capable of imaging neurodegeneration of the substantia nigra in parkinsonisms. Further testing must be done in PD and atypical parkinsonian disorders to support this off-target use of [(18)F]AV-1451.

  6. Utilization of Electrocardiographic P-wave Duration for AV Interval Optimization in Dual-Chamber Pacemakers.

    PubMed

    Sorajja, Dan; Bhakta, Mayurkumar D; Scott, Luis Rp; Altemose, Gregory T; Srivathsan, Komandoor

    2010-09-05

    Empiric programming of the atrio-ventricular (AV) delay is commonly performed during pacemaker implantation. Transmitral flow assessment by Doppler echocardiography can be used to find the optimal AV delay by Ritter's method, but this cannot easily be performed during pacemaker implantation. We sought to determine a non-invasive surrogate for this assessment. Since electrocardiographic P-wave duration estimates atrial activation time, we hypothesized this measurement may provide a more appropriate basis for programming AV intervals. A total of 19 patients were examined at the time of dual chamber pacemaker implantation, 13 (68%) being male with a mean age of 77. Each patient had the optimal AV interval determined by Ritter's method. The P-wave duration was measured independently on electrocardiograms using MUSE® Cardiology Information System (version 7.1.1). The relationship between P-wave duration and the optimal AV interval was analyzed. The P-wave duration and optimal AV delay were related by a correlation coefficient of 0.815 and a correction factor of 1.26. The mean BMI was 27. The presence of hypertension, atrial fibrillation, and valvular heart disease was 13 (68%), 3 (16%), and 2 (11%) respectively. Mean echocardiographic parameters included an ejection fraction of 58%, left atrial index of 32 ml/m(2), and diastolic dysfunction grade 1 (out of 4). In patients with dual chamber pacemakers in AV sequentially paced mode and normal EF, electrocardiographic P-wave duration correlates to the optimal AV delay by Ritter's method by a factor of 1.26.

  7. [F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging.

    PubMed

    Marquié, Marta; Siao Tick Chong, Michael; Antón-Fernández, Alejandro; Verwer, Eline E; Sáez-Calveras, Nil; Meltzer, Avery C; Ramanan, Prianca; Amaral, Ana C; Gonzalez, Jose; Normandin, Marc D; Frosch, Matthew P; Gómez-Isla, Teresa

    2017-06-13

    [F-18]-AV-1451, a PET tracer specifically developed to detect brain neurofibrillary tau pathology, has the potential to facilitate accurate diagnosis of Alzheimer's disease (AD), staging of brain tau burden and monitoring disease progression. Recent PET studies show that patients with mild cognitive impairment and AD dementia exhibit significantly higher in vivo [F-18]-AV-1451 retention than cognitively normal controls. Importantly, PET patterns of [F-18]-AV-1451 correlate well with disease severity and seem to match the predicted topographic Braak staging of neurofibrillary tangles (NFTs) in AD, although this awaits confirmation. We studied the correlation of autoradiographic binding patterns of [F-18]-AV-1451 and the stereotypical spatiotemporal pattern of progression of NFTs using legacy postmortem brain samples representing different Braak NFT stages (I-VI). We performed [F-18]-AV-1451 phosphor-screen autoradiography and quantitative tau measurements (stereologically based NFT counts and biochemical analysis of tau pathology) in three brain regions (entorhinal cortex, superior temporal sulcus and visual cortex) in a total of 22 cases: low Braak (I-II, n = 6), intermediate Braak (III-IV, n = 7) and high Braak (V-VI, n = 9). Strong and selective [F-18]-AV-1451 binding was detected in all tangle-containing regions matching precisely the observed pattern of PHF-tau immunostaining across the different Braak stages. As expected, no signal was detected in the white matter or other non-tangle containing regions. Quantification of [F-18]-AV-1451 binding was very significantly correlated with the number of NFTs present in each brain region and with the total tau and phospho-tau content as reported by Western blot and ELISA. [F-18]-AV-1451 is a promising biomarker for in vivo quantification of brain tau burden in AD. Neuroimaging-pathologic studies conducted on postmortem material from individuals imaged while alive are now needed to confirm these observations.

  8. Update of the AN/AVS-7 Head-Up Display program

    NASA Astrophysics Data System (ADS)

    Nicholson, Robert K.; Troxel, David

    1996-06-01

    The AN/AVS-7 head up display (HUD) system is designed to enhance night vision goggle pilotage by superimposing aircraft, navigation and flight symbology on the aviator's night vision imaging system. The AN/AVS-7 system is produced by AEL Industries Inc., Cross Systems Division under a five year production contract with the Army's Communications and Electronics Command. The program is managed by the Army's Project Manager for Night Vision, Reconnaissance, Surveillance and Target Acquisition.

  9. First-degree AV block-an entirely benign finding or a potentially curable cause of cardiac disease?

    PubMed

    Holmqvist, Fredrik; Daubert, James P

    2013-05-01

    First-degree atrioventricular (AV) block is a delay within the AV conduction system and is defined as a prolongation of the PR interval beyond the upper limit of what is considered normal (generally 0.20 s). Up until recently, first-degree AV block was considered an entirely benign condition. In fact, some complain that it is a misnomer since there is only delay and no actual block in the AV conduction system (usually within the AV node). However, it has long been acknowledged that extreme forms of first-degree AV block (typically a PR interval exceeding 0.30 s) can cause symptoms due to inadequate timing of atrial and ventricular contractions, similar to the so-called pacemaker syndrome. Consequently, the current guidelines state that permanent pacemaker implantation is reasonable for first-degree AV block with symptoms similar to those of pacemaker syndrome or with hemodynamic compromise, but also stresses that there is little evidence to suggest that pacemakers improve survival in patients with isolated first-degree AV block. Recent reports suggest that it may be time to revisit the impact of first-degree AV block. Also, several findings in post hoc analyses of randomized device trials give important insights in possible treatment options. The present review aims to provide an update on the current knowledge concerning the impact of first-degree AV block and also to address the issue of pacing in patients with this condition.

  10. [Academician O.G. Gazenko and aviation medicine].

    PubMed

    Ushakov, I B; Bednenko, V S; Khomenko, M N; Stepanov, V K

    2008-01-01

    The paper analyzes the contribution of O.G. Gazenko to the theory and practice of aviation medicine in the period of his service at the State Test and Research Institute of Aviation and Space Medicine under the USSR Ministry of Defense (1947-1969). O.G. Gazenko took the leadership and participated in personally in the broad investigations of the altitude effects on human organism, medical care of the staff of AF units and troops based in the Arctic, improvement of life and duty conditions for pilots and technicians in hot climate, ejection seat testing, development of methods modeling erroneous pilot's actions in order to understand their triggers.

  11. Patients' and procedural characteristics of AV-block during slow pathway modulation for AVNRT-single center 10year experience.

    PubMed

    Wasmer, Kristina; Dechering, Dirk G; Köbe, Julia; Leitz, Patrick; Frommeyer, Gerrit; Lange, Phillip S; Kochhäuser, Simon; Reinke, Florian; Pott, Christian; Mönnig, Gerold; Breithardt, Günter; Eckardt, Lars

    2017-10-01

    Permanent AV-block is a recognized and feared complication of slow pathway modulation for AVNRT. We aimed to assess incidence of transient and permanent AV-block as well as consequences of transient AV-block in a large contemporary AVNRT ablation cohort. We searched our single center prospective ablation database for occurrence of transient and permanent AV-block during slow pathway modulation between January 2004 and October 2015. We analyzed patients' and procedural characteristics as well as outcome of patients in whom transient or permanent AV-block occurred. Of 9170 patients who underwent a catheter ablation at our institution between January 2004 and October 2015, 2101 patients (64% women, mean age 50±18years) underwent slow pathway modulation. In three patients, permanent AV-block occurred during RF application. Additional two patients had transient AV-block that recovered (after a few minutes and 25min), but recurred within two days of the procedure. All five patients underwent dual chamber pacemaker implantation (0.2%). Transient AV-block related to RF delivery occurred in 44 patients (2%). Transient mechanical AV-block occurred in additional 17 patients (0.8%). In 12 patients, ablation was continued despite transient AV-block. One of these patients developed permanent AV-block. Permanent AV-block following slow pathway modulation is a rare event, occurring in 0.2% of patients in a large contemporary single center cohort. Transient AV-block is more frequent (2%). Copyright © 2017 Elsevier B.V. All rights reserved.

  12. A histone variant, H2AvD, is essential in Drosophila melanogaster.

    PubMed Central

    van Daal, A; Elgin, S C

    1992-01-01

    H2AvD, a Drosophila melanogaster histone variant of the H2A.Z class, is encoded by a single copy gene in the 97CD region of the polytene chromosomes. Northern analysis shows that the transcript is expressed in adult females and is abundant throughout the first 12 h of embryogenesis but then decreases. The H2AvD protein is present at essentially constant levels in all developmental stages. Using D. melanogaster stocks with deletions in the 97CD region, we have localized the H2AvD gene to the 97D1-9 interval. A lethal mutation in this interval, l(3)810, exhibits a 311-base pair deletion in the H2AvD gene, which removes the second exon. P-element mediated transformation using a 4.1-kilobase fragment containing the H2AvD gene rescues the lethal phenotype. H2AvD is therefore both essential and continuously present, suggesting a requirement for its utilization, either to provide an alternative capability for nucleosome assembly or to generate an alternative nucleosome structure. Images PMID:1498368

  13. BMP-2 induces versican and hyaluronan that contribute to post-EMT AV cushion cell migration.

    PubMed

    Inai, Kei; Burnside, Jessica L; Hoffman, Stanley; Toole, Bryan P; Sugi, Yukiko

    2013-01-01

    Distal outgrowth and maturation of mesenchymalized endocardial cushions are critical morphogenetic events during post-EMT atrioventricular (AV) valvuloseptal morphogenesis. We explored the role of BMP-2 in the regulation of valvulogenic extracellular matrix (ECM) components, versican and hyaluronan (HA), and cell migration during post-EMT AV cushion distal outgrowth/expansion. We observed intense staining of versican and HA in AV cushion mesenchyme from the early cushion expansion stage, Hamburger and Hamilton (HH) stage-17 to the cushion maturation stage, HH stage-29 in the chick. Based on this expression pattern we examined the role of BMP-2 in regulating versican and HA using 3D AV cushion mesenchymal cell (CMC) aggregate cultures on hydrated collagen gels. BMP-2 induced versican expression and HA deposition as well as mRNA expression of versican and Has2 by CMCs in a dose dependent manner. Noggin, an antagonist of BMP, abolished BMP-2-induced versican and HA as well as mRNA expression of versican and Has2. We further examined whether BMP-2-promoted cell migration was associated with expression of versican and HA. BMP-2- promoted cell migration was significantly impaired by treatments with versican siRNA and HA oligomer. In conclusion, we provide evidence that BMP-2 induces expression of versican and HA by AV CMCs and that these ECM components contribute to BMP-2-induced CMC migration, indicating critical roles for BMP-2 in distal outgrowth/expansion of mesenchymalized AV cushions.

  14. Amyloid deposition after cerebral hypoperfusion: evidenced on [(18)F]AV-45 positron emission tomography.

    PubMed

    Huang, Kuo-Lun; Lin, Kun-Ju; Ho, Meng-Yang; Chang, Yeu-Jhy; Chang, Chien-Hung; Wey, Shiaw-Pyng; Hsieh, Chia-Ju; Yen, Tzu-Chen; Hsiao, Ing-Tsung; Lee, Tsong-Hai

    2012-08-15

    Animal studies have shown that cerebral hypoperfusion may be associated with amyloid plaque accumulation. Amyloid plaque is known to be associated with dementia and [(18)F]AV-45 is a positron emission tomography (PET) ligand that binds to extracelluar plaques. We hypothesized that demented patients with cerebral hypoperfusion may have increased [(18)F]AV-45 uptake. Five demented patients with cerebral hypoperfusion due to unilateral carotid artery stenosis (CAS) were examined with [(18)F]AV-45 PET, and the results were compared with six elderly controls. The standard uptake value ratio (SUVR) of each region of interest (ROI) was created using whole cerebellum as the reference region. All subjects underwent magnetic resonance imaging (MRI) for obtaining structural information. Patients with dementia and unilateral CAS had a higher global [(18)F]AV-45 SUVR (1.34 ± 0.06) as compared with controls (1.10 ± 0.04, p=0.0043), especially over the frontal, temporal, precuneus, anterior cingulate and occipital regions. The statistical distribution maps revealed a significantly increased [(18)F]AV-45 SUVR in the medial frontal, caudate, thalamus, posterior cingulate, occipital and middle and superior temporal regions ipsilateral to the side of CAS (p<0.01). The present study found that cerebral [(18)F]AV-45 binding is increased in demented patients with CAS, and its distribution is lateralized to the CAS side, suggesting that amyloid-related dementia may occur under cerebral hypoperfusion.

  15. Genome-Wide DNA Methylation Analysis and Epigenetic Variations Associated with Congenital Aortic Valve Stenosis (AVS)

    PubMed Central

    Radhakrishna, Uppala; Albayrak, Samet; Alpay-Savasan, Zeynep; Zeb, Amna; Turkoglu, Onur; Sobolewski, Paul; Bahado-Singh, Ray O.

    2016-01-01

    Congenital heart defect (CHD) is the most common cause of death from congenital anomaly. Among several candidate epigenetic mechanisms, DNA methylation may play an important role in the etiology of CHDs. We conducted a genome-wide DNA methylation analysis using an Illumina Infinium 450k human methylation assay in a cohort of 24 newborns who had aortic valve stenosis (AVS), with gestational-age matched controls. The study identified significantly-altered CpG methylation at 59 sites in 52 genes in AVS subjects as compared to controls (either hypermethylated or demethylated). Gene Ontology analysis identified biological processes and functions for these genes including positive regulation of receptor-mediated endocytosis. Consistent with prior clinical data, the molecular function categories as determined using DAVID identified low-density lipoprotein receptor binding, lipoprotein receptor binding and identical protein binding to be over-represented in the AVS group. A significant epigenetic change in the APOA5 and PCSK9 genes known to be involved in AVS was also observed. A large number CpG methylation sites individually demonstrated good to excellent diagnostic accuracy for the prediction of AVS status, thus raising possibility of molecular screening markers for this disorder. Using epigenetic analysis we were able to identify genes significantly involved in the pathogenesis of AVS. PMID:27152866

  16. BMP-2 Induces Versican and Hyaluronan That Contribute to Post-EMT AV Cushion Cell Migration

    PubMed Central

    Inai, Kei; Burnside, Jessica L.; Hoffman, Stanley; Toole, Bryan P.; Sugi, Yukiko

    2013-01-01

    Distal outgrowth and maturation of mesenchymalized endocardial cushions are critical morphogenetic events during post-EMT atrioventricular (AV) valvuloseptal morphogenesis. We explored the role of BMP-2 in the regulation of valvulogenic extracellular matrix (ECM) components, versican and hyaluronan (HA), and cell migration during post-EMT AV cushion distal outgrowth/expansion. We observed intense staining of versican and HA in AV cushion mesenchyme from the early cushion expansion stage, Hamburger and Hamilton (HH) stage-17 to the cushion maturation stage, HH stage-29 in the chick. Based on this expression pattern we examined the role of BMP-2 in regulating versican and HA using 3D AV cushion mesenchymal cell (CMC) aggregate cultures on hydrated collagen gels. BMP-2 induced versican expression and HA deposition as well as mRNA expression of versican and Has2 by CMCs in a dose dependent manner. Noggin, an antagonist of BMP, abolished BMP-2-induced versican and HA as well as mRNA expression of versican and Has2. We further examined whether BMP-2-promoted cell migration was associated with expression of versican and HA. BMP-2- promoted cell migration was significantly impaired by treatments with versican siRNA and HA oligomer. In conclusion, we provide evidence that BMP-2 induces expression of versican and HA by AV CMCs and that these ECM components contribute to BMP-2-induced CMC migration, indicating critical roles for BMP-2 in distal outgrowth/expansion of mesenchymalized AV cushions. PMID:24147033

  17. ADVANCED VITRIFICATION SYSTEM (RIC AVS) RESEARCH AND DEVELOPMENT PROJECT

    SciTech Connect

    J.R. Powell; M. Reich

    2003-06-30

    The objective of this AVS testing program is to use bench-scale test equipment to produce a vitrified product at maximum waste loading from the specified AZ-101 waste simulant and conduct a TTT analysis using laboratory scale melts to show compliance with the DOE Waste Acceptance Product Specifications for Vitrified High-Level Waste Forms (WAPS). The vitrified product complies with the following WAPS. A borosilicate glass with a waste loading of 60.9-wt% was produced from a slurry feed of AZ101 simulant. Glass durability testing, glass characterization testing, and testing methodology were performed in accordance with the Department of Energy approved Test Plan. The glass has two crystalline phases and good uniformity of composition. The Product Consistency Test on the 6 location-specific samples are at least 1 to 2 orders of magnitude below the mean PCT results for the EA glass. Standard deviations were less than 10% of measured values. The glass transition temperature averaged 658 {+-} 9 C. A TTT diagram was produced. There was measured cesium loss of about 2%, and compliance with the Universal Treatment Standards.

  18. Whether noninvasive optimization of AV and VV delays improves the response to cardiac resynchronization therapy.

    PubMed

    Urbanek, Bożena; Chudzik, Michał; Klimczak, Artur; Rosiak, Marcin; Lewek, Joanna; Wranicz, Jerzy Krzysztof

    2013-01-01

    Device optimization is not routinely performed in patients who underwent cardiac resynchronization therapy (CRT) device implantation. Noninvasive optimization of CRT devices by measurement of cardiac output (CO) can be used as a simple method to assess ventricular systolic performance. The aim of this study was to assess whether optimization of atrioventricular (AV) and interventricular (VV) delay can improve hemodynamic response to CRT and whether this optimization should be performed for each patient individually. Twenty patients with advanced heart failure New York Heart Association (NYHA) class III/IV, left ventricular ejection fraction ≤ 35% and left bundle branch block (QRS ≥ 120 ms) in sinus rhythm were evaluated from 24 h to 48 h after implantation of a CRT device by means of impedance cardiography (ICG). CO was first measured at each patient's intrinsic rhythm. Patients then underwent adjustments of AV and VV delay from 80 ms to 140 ms and from -60 ms to +60 ms, respectively in 20 ms increment steps and CO at each setting was measured by ICG. Both AV and VV delays were programmed according to the greatest improvement in CO compared to intrinsic rhythm. There was a statistically signifi cant increase in CO measured at the intrinsic rhythm compared to different AV delay by mean of 21% (3.8 ± 1.0 vs. 4.6 ± 0.1 L/min, p < 0.05). Optimal AV/VV delays with left ventricle-preexcitation or simultaneous biventricular pacing caused additional increased CO from intrinsic rhythm by mean of 32.6% (3.8 ± 1.0 vs. 5.04 ± ± 1.0 L/min, p < 0.05). Optimal AV/VV setting delays also resulted in improved hemodynamic responses compared to VV factory setting delay. Both AV and VV delay optimization should be performed in clinical practice. Optimal AV delay improved outcome. However, combination of optimized AV/VV delays provided the best hemodynamic response. Optimized AV/VV delays with left ventricle-preexcitation or simultaneous biventricular pacing increased

  19. Pinunuuchi Po'og'ani: Southern Ute Indian Academy.

    ERIC Educational Resources Information Center

    Oberly, Stacey Inez (Wachimamachi [Antelope Woman])

    2002-01-01

    Describes the Pinunuuchi Po'og'ani, the Southern Ute Indian Academy, providing Montessori education for Southern Ute tribal members ages 6 weeks through 10 years and reviving the use of the Southern Ute language and culture among young students and their families. Describes how the program supports families, students, and staff, and incorporates…

  20. Clinical AV nodal reentrant tachycardia in a patient with left sided accessory pathway and immediate occurrence of antidromic AV reentrant tachycardia after slow pathway ablation.

    PubMed

    Surber, Ralf; Kühnert, Helmut; Heinke, Matthias; Malur, Frank-Michael; Sigusch, Holger H; Figulla, Hans R

    2002-06-01

    The only inducible arrhythmia in a patient with exclusive antegrade conducting left anterolateral accessory pathway, consists of slow/fast atrioventricular nodal reentrant tachycardia. After radiofrequency catheter ablation of the slow pathway, true antidromic AV reentrant tachycardia was easily induced by atrial pacing. Following ablation of the accessory pathway no arrhythmia could be induced.

  1. 76 FR 54145 - Airworthiness Directives; 328 Support Services GmbH (Type Certificate Previously Held by AvCraft...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-31

    ... Services GmbH (Type Certificate Previously Held by AvCraft Aerospace GmbH; Fairchild Dornier GmbH; Dornier... AvCraft Aerospace GmbH; Fairchild Dornier GmbH; Dornier Luftfahrt GmbH): Docket No. FAA-2011-0912... previously held by AvCraft Aerospace GmbH; Fairchild Dornier GmbH; Dornier Luftfahrt GmbH) Model...

  2. 76 FR 19721 - Airworthiness Directives; 328 Support Services GmbH (Type Certificate Previously Held by AvCraft...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-08

    ... Services GmbH (Type Certificate Previously Held by AvCraft Aerospace GmbH; Fairchild Dornier GmbH; Dornier... AvCraft Aerospace GmbH; Fairchild Dornier GmbH; Dornier Luftfahrt GmbH): Docket No. FAA-2011-0308... previously held by AvCraft Aerospace GmbH; Fairchild Dornier GmbH; Dornier Luftfahrt GmbH) Model 328-100...

  3. A novel curve fitting method for AV optimisation of biventricular pacemakers.

    PubMed

    Dehbi, Hakim-Moulay; Jones, Siana; Sohaib, S M Afzal; Finegold, Judith A; Siggers, Jennifer H; Stegemann, Berthold; Whinnett, Zachary I; Francis, Darrel P

    2015-09-01

    In this study, we designed and tested a new algorithm, which we call the 'restricted parabola', to identify the optimum atrioventricular (AV) delay in patients with biventricular pacemakers. This algorithm automatically restricts the hemodynamic data used for curve fitting to the parabolic zone in order to avoid inadvertently selecting an AV optimum that is too long.We used R, a programming language and software environment for statistical computing, to create an algorithm which applies multiple different cut-offs to partition curve fitting of a dataset into a parabolic and a plateau region and then selects the best cut-off using a least squares method. In 82 patients, AV delay was adjusted and beat-to-beat systolic blood pressure (SBP) was measured non-invasively using our multiple-repetition protocol. The novel algorithm was compared to fitting a parabola across the whole dataset to identify how many patients had a plateau region, and whether a higher hemodynamic response was achieved with one method.In 9/82 patients, the restricted parabola algorithm detected that the pattern was not parabolic at longer AV delays. For these patients, the optimal AV delay predicted by the restricted parabola algorithm increased SBP by 1.36 mmHg above that predicted by the conventional parabolic algorithm (95% confidence interval: 0.65 to 2.07 mmHg, p-value = 0.002).AV optima selected using our novel restricted parabola algorithm give a greater improvement in acute hemodynamics than fitting a parabola across all tested AV delays. Such an algorithm may assist the development of automated methods for biventricular pacemaker optimisation.

  4. Nodal recovery, dual pathway physiology, and concealed conduction determine complex AV dynamics in human atrial tachyarrhythmias.

    PubMed

    Masè, Michela; Glass, Leon; Disertori, Marcello; Ravelli, Flavia

    2012-11-15

    The genesis of complex ventricular rhythms during atrial tachyarrhythmias in humans is not fully understood. To clarify the dynamics of atrioventricular (AV) conduction in response to a regular high-rate atrial activation, 29 episodes of spontaneous or pacing-induced atrial flutter (AFL), covering a wide range of atrial rates (cycle lengths from 145 to 270 ms), were analyzed in 10 patients. AV patterns were identified by applying firing sequence and surrogate data analysis to atrial and ventricular activation series, whereas modular simulation with a difference-equation AV node model was used to correlate the patterns with specific nodal properties. AV node response at high atrial rate was characterized by 1) AV patterns of decreasing conduction ratios at the shortening of atrial cycle length (from 236.3 ± 32.4 to 172.6 ± 17.8 ms) according to a Farey sequence ordering (conduction ratio from 0.34 ± 0.12 to 0.23 ± 0.06; P < 0.01); 2) the appearance of high-order alternating Wenckebach rhythms, such as 6:2, 10:2, and 12:2, associated with ventricular interval oscillations of large amplitude (407.7 ± 150.4 ms); and 3) the deterioration of pattern stability at advanced levels of block, with the percentage of stable patterns decreasing from 64.3 ± 35.2% to 28.3 ± 34.5% (P < 0.01). Simulations suggested these patterns to originate from the combined effect of nodal recovery, dual pathway physiology, and concealed conduction. These results indicate that intrinsic nodal properties may account for the wide spectrum of AV block patterns occurring during regular atrial tachyarrhythmias. The characterization of AV nodal function during different AFL forms constitutes an intermediate step toward the understanding of complex ventricular rhythms during atrial fibrillation.

  5. Integrated rate-dependent and dual pathway AV nodal functions: principles and assessment framework.

    PubMed

    Billette, Jacques; Tadros, Rafik

    2014-01-15

    The atrioventricular (AV) node conducts slowly and has a long refractory period. These features sustain the filtering of atrial impulses and hence are often modulated to optimize ventricular rate during supraventricular tachyarrhythmias. The AV node is also the site of a clinically common reentrant arrhythmia. Its function is assessed for a variety of purposes from its responses to a premature protocol (S1S2, test beats introduced at different cycle lengths) repeatedly performed at different basic rates and/or to an incremental pacing protocol (increasingly faster rates). Puzzlingly, resulting data and interpretation differ with protocols as well as with chosen recovery and refractory indexes, and are further complicated by the presence of built-in fast and slow pathways. This problem applies to endocavitary investigations of arrhythmias as well as to many experimental functional studies. This review supports an integrated framework of rate-dependent and dual pathway AV nodal function that can account for these puzzling characteristics. The framework was established from AV nodal responses to S1S2S3 protocols that, compared with standard S1S2 protocols, allow for an orderly quantitative dissociation of the different factors involved in changes in AV nodal conduction and refractory indexes under rate-dependent and dual pathway function. Although largely based on data from experimental studies, the proposed framework may well apply to the human AV node. In conclusion, the rate-dependent and dual pathway properties of the AV node can be integrated within a common functional framework the contribution of which to individual responses can be quantitatively determined with properly designed protocols and analytic tools.

  6. Increased basal ganglia binding of (18) F-AV-1451 in patients with progressive supranuclear palsy.

    PubMed

    Smith, Ruben; Schain, Martin; Nilsson, Christer; Strandberg, Olof; Olsson, Tomas; Hägerström, Douglas; Jögi, Jonas; Borroni, Edilio; Schöll, Michael; Honer, Michael; Hansson, Oskar

    2017-01-01

    Progressive supranuclear palsy (PSP) is difficult to diagnose accurately. The recently developed tau PET tracers may improve the diagnostic work-up of PSP. Regional tau accumulation was studied using (18) F-AV-1451 PET in 11 patients with PSP and 11 age-matched healthy controls in the Swedish BioFinder study. (18) F-AV-1451 standard uptake volume ratios were significantly higher in the basal ganglia in PSP patients when compared with controls (globus pallidus 1.75 vs 1.50; putamen 1.51 vs 1.35). Retention in the basal ganglia was correlated with age in both groups (r = .43-.78, P < .05). In PSP, we observed a significant correlation between clinical deterioration measured with the PSP rating scale and standard uptake volume ratios in the globus pallidus (r = .74, P < .05). However, no (18) F-AV-1451 retention was observed in the cerebral cortex or white matter of either PSP patients or controls, and autoradiography did not reveal any specific binding of AV-1451 to PSP tau aggregates. We found higher (18) F-AV-1451 retention in the basal ganglia of PSP patients when compared with healthy elderly controls, but also increases with age in both controls and patients. As a result of the overlap in retention between diagnostic groups and the age-dependent increase present also in controls, (18) F-AV-1451 PET might not reliably distinguish individual patients with PSP from controls. However, further studies are needed to evaluate whether (18) F-AV-1451 PET might be useful as a progression marker in clinical PSP trials. © The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

  7. 18F-AV-1451 positron emission tomography in Alzheimer's disease and progressive supranuclear palsy.

    PubMed

    Passamonti, Luca; Vázquez Rodríguez, Patricia; Hong, Young T; Allinson, Kieren S J; Williamson, David; Borchert, Robin J; Sami, Saber; Cope, Thomas E; Bevan-Jones, W Richard; Jones, P Simon; Arnold, Robert; Surendranathan, Ajenthan; Mak, Elijah; Su, Li; Fryer, Tim D; Aigbirhio, Franklin I; O'Brien, John T; Rowe, James B

    2017-03-01

    The ability to assess the distribution and extent of tau pathology in Alzheimer's disease and progressive supranuclear palsy in vivo would help to develop biomarkers for these tauopathies and clinical trials of disease-modifying therapies. New radioligands for positron emission tomography have generated considerable interest, and controversy, in their potential as tau biomarkers. We assessed the radiotracer 18F-AV-1451 with positron emission tomography imaging to compare the distribution and intensity of tau pathology in 15 patients with Alzheimer's pathology (including amyloid-positive mild cognitive impairment), 19 patients with progressive supranuclear palsy, and 13 age- and sex-matched controls. Regional analysis of variance and a support vector machine were used to compare and discriminate the clinical groups, respectively. We also examined the 18F-AV-1451 autoradiographic binding in post-mortem tissue from patients with Alzheimer's disease, progressive supranuclear palsy, and a control case to assess the 18F-AV-1451 binding specificity to Alzheimer's and non-Alzheimer's tau pathology. There was increased 18F-AV-1451 binding in multiple regions in living patients with Alzheimer's disease and progressive supranuclear palsy relative to controls [main effect of group, F(2,41) = 17.5, P < 0.0001; region of interest × group interaction, F(2,68) = 7.5, P < 0.00001]. More specifically, 18F-AV-1451 binding was significantly increased in patients with Alzheimer's disease, relative to patients with progressive supranuclear palsy and with control subjects, in the hippocampus and in occipital, parietal, temporal, and frontal cortices (t's > 2.2, P's < 0.04). Conversely, in patients with progressive supranuclear palsy, relative to patients with Alzheimer's disease, 18F-AV-1451 binding was elevated in the midbrain (t = 2.1, P < 0.04); while patients with progressive supranuclear palsy showed, relative to controls, increased 18F-AV-1451 uptake in the putamen, pallidum

  8. sugE: A gene involved in tributyltin (TBT) resistance of Aeromonas molluscorum Av27.

    PubMed

    Cruz, Andreia; Micaelo, Nuno; Félix, Vitor; Song, Jun-Young; Kitamura, Shin-Ichi; Suzuki, Satoru; Mendo, Sónia

    2013-01-01

    The mechanism of bacterial resistance to tributyltin (TBT) is still unclear. The results herein presented contribute to clarify that mechanism in the TBT-resistant bacterium Aeromonas molluscorum Av27. We have identified and cloned a new gene that is involved in TBT resistance in this strain. The gene is highly homologous (84%) to the Aeromonas hydrophila-sugE gene belonging to the small multidrug resistance gene family (SMR), which includes genes involved in the transport of lipophilic drugs. In Av27, expression of the Av27-sugE was observed at the early logarithmic growth phase in the presence of a high TBT concentration (500 μM), thus suggesting the contribution of this gene for TBT resistance. E. coli cells transformed with Av27-sugE become resistant to ethidium bromide (EtBr), chloramphenicol (CP) and tetracycline (TE), besides TBT. According to the Moriguchi logP (miLogP) values, EtBr, CP and TE have similar properties and are substrates for the sugE-efflux system. Despite the different miLogP of TBT, E. coli cells transformed with Av27-sugE become resistant to this compound. So it seems that TBT is also a substrate for the SugE protein. The modelling studies performed also support this hypothesis. The data herein presented clearly indicate that sugE is involved in TBT resistance of this bacterium.

  9. Electrocardiographic and chronobiological features of paroxysmal AV block recorded by ambulatory electrocardiography.

    PubMed

    Saito, Ken; Takeda, Shiho; Saito, Yuko; Kawamura, Mami; Yoshikawa, Yoko; Yano, Hayato; Sata, Masataka

    2014-01-01

    The goal of this study was to investigate the electrocardiographic and chronobio-logical features of paroxysmal atrioventricular (AV) block (PAVB) using data from ambulatory electrocardiography (AECG). The study population consisted of five men and six women aged from 47 to 82 years of age. Main presenting symptoms were pre-syncope in five patients (45.5%) and syncope in three patients (27.3%). Organic cardiovascular diseases were seen in eight patients (72.7%), and AV conduction disturbances were seen in six patients (54.5%), such as right bundle branch block, first to second degree AV block on standard 12-lead electrocardiography. Incidence of PAVB events were 1-329 (37.9 ± 98.0) episodes/patient/day, and the maximum pause during Holter recordings was 3.3-12.4 (6.39 ± 3.09) seconds. This maximum pause caused by intrinsic AV block was longer than that of vagally mediated AV block (8.4 ± 3.2 sec vs 4.7 ± 1.0 sec, p<0.05). In chronobiological analysis, episodes of PAVB exhibited a circadian rhythm characterized by a peak between 2:00 am and 4:00 am and a trough between 0:00 pm and 2:00 pm. AECG is a useful tool to detect the maximum pause occurring during sleep and provides critical data necessary to prevent the sudden cardiac death caused by PAVB.

  10. An av-RGD integrin inhibitor toolbox: drug discovery insight, challenges and opportunities.

    PubMed

    Hatley, Richard; Macdonald, Simon; Slack, Robert; Le, Joelle; Ludbrook, Steve; Lukey, Pauline

    2017-09-25

    There is a requirement for efficacious and safe medicines to treat diseases with high unmet need. The resurgence in av RGD integrin inhibitor drug discovery is poised to contribute to this requirement. However, drug discovery in the av integrin space is notoriously difficult due to the receptors being structurally very similar as well as the polar zwitterionic nature of the pharmacophore. This review aims to guide drug discovery research in this field through an av inhibitor toolbox, consisting of small molecules and antibodies. Small molecule av tool compounds with extended profiles in avb1, 3, 5, 6 and 8 cell adhesion assays, with key physicochemical properties, have been collated to assist in the selection of the right tool for the right experiment. This should also facilitate an understanding of partial selectivity profiles of compounds generated in different assays across research institutions. Prospects for further av integrin research and the critical importance of target validation are discussed, where increased knowledge of the selectivity for individual RGD v integrins is key. Insights into the design of small molecule RGD chemotypes for topical or oral administration are provided and clinical findings on advanced molecules are examined. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Antimicrobial efficacy of AvGard carcase wash under industrial processing conditions.

    PubMed

    Coppen, P; Fenner, S; Salvat, G

    1998-05-01

    1. The efficacy of the AvGard Trisodium Phosphate (TSP) immersion carcase wash process was evaluated during 5 industrial trials against Salmonella, Enterobacteriaceae, thermotolerant coliforms and total aerobic count. The effect against Pseudomonas was also studied in the first 3 trials. 2. Dramatic reductions in Salmonella incidence were seen using a whole carcase rinse method. In 4 of the 5 trial sites, only one positive sample was found after AvGard treatment (average 0.5% incidence), in spite of an average control incidence of 57.7%. In the 5th site, a water-chilled broiler plant, an average control incidence of 74.0% was reduced to 9.4% after AvGard treatment. 3. In the latter case, Most Probable Number (MPN) analyses were performed on some of the Salmonella positive samples taken from the control and post-treatment series; the average MPN count per carcase on controls was 115, whereas for AvGard treated birds the figure was only 0.6 per carcase, a greater than 2 log reduction. 4. In addition, AvGard treatment gave average log reductions for all trials of: Enterobacteriaceae; 2.5 log; Coliforms; 2.7 log, and Total Aerobic Count; 1.1 log, leading to carcases substantially free of Gram negative pathogens. 5. Pseudomonas was reduced by an average of 1.7 log in the first 3 trials, dramatically reducing the carcase loading of this important spoilage organism.

  12. Vorticity-divergence semi-Lagrangian global atmospheric model SL-AV20: dynamical core

    NASA Astrophysics Data System (ADS)

    Tolstykh, Mikhail; Shashkin, Vladimir; Fadeev, Rostislav; Goyman, Gordey

    2017-05-01

    SL-AV (semi-Lagrangian, based on the absolute vorticity equation) is a global hydrostatic atmospheric model. Its latest version, SL-AV20, provides global operational medium-range weather forecast with 20 km resolution over Russia. The lower-resolution configurations of SL-AV20 are being tested for seasonal prediction and climate modeling. The article presents the model dynamical core. Its main features are a vorticity-divergence formulation at the unstaggered grid, high-order finite-difference approximations, semi-Lagrangian semi-implicit discretization and the reduced latitude-longitude grid with variable resolution in latitude. The accuracy of SL-AV20 numerical solutions using a reduced lat-lon grid and the variable resolution in latitude is tested with two idealized test cases. Accuracy and stability of SL-AV20 in the presence of the orography forcing are tested using the mountain-induced Rossby wave test case. The results of all three tests are in good agreement with other published model solutions. It is shown that the use of the reduced grid does not significantly affect the accuracy up to the 25 % reduction in the number of grid points with respect to the regular grid. Variable resolution in latitude allows us to improve the accuracy of a solution in the region of interest.

  13. Heart Rate and AV delay modify left ventricular filling vortex properties

    NASA Astrophysics Data System (ADS)

    Del Alamo, Juan C.; Benito, Yolanda; Bermejo, Javier; Alhama, Marta; Yotti, Raquel; Perez Del Villar, Candelas; Martinez-Legazpi, Pablo; Gonzalez Mansilla, Ana; Fernandez-Aviles, Francisco

    2012-11-01

    Intraventricular flow generates a vortex ring during rapid filling that optimizes filling, couples inflow kinetic energy to ejection, improves blood mixing and avoids stasis. LV vorticity has been related to chamber geometrical properties, but the effects of electrical events have never been characterized, partly due to the difficulty of performing MRI in patients with implanted devices. We have recently developed a new method that allows measuring vortex properties by processing conventional transthoracic color-Doppler sequences. Using this modality, 27 patients carrying an implantable cardiac resynchronization device were studied after AV optimization at 100 beats per minute. Our results reveal that, compared to optimal AV, the main vortex component remained closer to the base during 100BPM (difference = -20% of Lax length, p <.05) and closer to the apex when AV is minimized (diff= +11% of Lax, p <.05). Radius, circulation and energy of the vortices were larger when AV is maximized (p <.05). In conclusion, the duration of diastole, as modulated by heart rate and AV-delay, significantly modifies intraventricular vortex dynamics. Funded by NIH Grant R21HL108268.

  14. Brain uptake of a non-radioactive pseudo-carrier and its effect on the biodistribution of [(18)F]AV-133 in mouse brain.

    PubMed

    Wu, Xianying; Zhou, Xue; Zhang, Shuxian; Zhang, Yan; Deng, Aifang; Han, Jie; Zhu, Lin; Kung, Hank F; Qiao, Jinping

    2015-07-01

    9-[(18)F]Fluoropropyl-(+)-dihydrotetrabenazine ([(18)F]AV-133) is a new PET imaging agent targeting vesicular monoamine transporter type II (VMAT2). To shorten the preparation of [(18)F]AV-133 and to make it more widely available, a simple and rapid purification method using solid-phase extraction (SPE) instead of high-pressure liquid chromatography (HPLC) was developed. The SPE method produced doses containing the non-radioactive pseudo-carrier 9-hydroxypropyl-(+)-dihydrotetrabenazine (AV-149). The objectives of this study were to evaluate the brain uptake of AV-149 by UPLC-MS/MS and its effect on the biodistribution of [(18)F]AV-133 in the brains of mice. The mice were injected with a bolus including [(18)F]AV-133 and different doses of AV-149. Brain tissue and blood samples were harvested. The effect of different amounts of AV-149 on [(18)F]AV-133 was evaluated by quantifying the brain distribution of radiolabelled tracer [(18)F]AV-133. The concentrations of AV-149 in the brain and plasma were analyzed using a UPLC-MS/MS method. The concentrations of AV-149 in the brain and plasma exhibited a good linear relationship with the doses. The receptor occupancy curve was fit, and the calculated ED50 value was 8.165mg/kg. The brain biodistribution and regional selectivity of [(18)F]AV-133 had no obvious differences at AV-149 doses lower than 0.1mg/kg. With increasing doses of AV-149, the brain biodistribution of [(18)F]AV-133 changed significantly. The results are important to further support that the improved radiolabelling procedure of [(18)F]AV-133 using an SPE method may be suitable for routine clinical application. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. AV interval optimization using pressure volume loops in dual chamber pacemaker patients with maintained systolic left ventricular function.

    PubMed

    Eberhardt, Frank; Hanke, Thorsten; Fitschen, Joern; Heringlake, Matthias; Bode, Frank; Schunkert, Heribert; Wiegand, Uwe K H

    2012-08-01

    Atrioventricular (AV) interval optimization is often deemed too time-consuming in dual-chamber pacemaker patients with maintained LV function. Thus the majority of patients are left at their default AV interval. To quantify the magnitude of hemodynamic improvement following AV interval optimization in chronically paced dual chamber pacemaker patients. A pressure volume catheter was placed in the left ventricle of 19 patients with chronic dual chamber pacing and an ejection fraction >45 % undergoing elective coronary angiography. AV interval was varied in 10 ms steps from 80 to 300 ms, and pressure volume loops were recorded during breath hold. The average optimal AV interval was 152 ± 39 ms compared to 155 ± 8 ms for the average default AV interval (range 100-240 ms). The average improvement in stroke work following AV interval optimization was 935 ± 760 mmHg/ml (range 0-2,908; p < 0.001), which translates into an average improvement of 14 ± 9 % (range 0-28). A 10 ms variation of the AV interval changes the average stroke work by 207 ± 162 mmHg/ml. AV interval optimization also leads to improved systolic dyssynchrony indices (17.7 ± 7.0 vs. 19.4 ± 7.1 %; p = 0.01). The overall hemodynamic effect of AV interval optimization in patients with maintained LV function is in the same range as for patients undergoing cardiac resynchronization therapy for several parameters. The positive effect of AV interval optimization also applies to patients who have been chronically paced for years.

  16. The Unusual Resistance of Avian Defensin AvBD7 to Proteolytic Enzymes Preserves Its Antibacterial Activity

    PubMed Central

    Bailleul, Geoffrey; Kravtzoff, Amanda; Joulin-Giet, Alix; Lecaille, Fabien; Labas, Valérie; Meudal, Hervé; Loth, Karine; Teixeira-Gomes, Ana-Paula; Gilbert, Florence B.; Coquet, Laurent; Jouenne, Thierry; Brömme, Dieter; Schouler, Catherine; Landon, Céline; Lalmanach, Gilles; Lalmanach, Anne-Christine

    2016-01-01

    Defensins are frontline peptides of mucosal immunity in the animal kingdom, including birds. Their resistance to proteolysis and their ensuing ability to maintain antimicrobial potential remains questionable and was therefore investigated. We have shown by bottom-up mass spectrometry analysis of protein extracts that both avian beta-defensins AvBD2 and AvBD7 were ubiquitously distributed along the chicken gut. Cathepsin B was found by immunoblotting in jejunum, ileum, caecum, and caecal tonsils, while cathepsins K, L, and S were merely identified in caecal tonsils. Hydrolysis product of AvBD2 and AvBD7 incubated with a panel of proteases was analysed by RP-HPLC, mass spectrometry and antimicrobial assays. AvBD2 and AvBD7 were resistant to serine proteases and to cathepsins D and H. Conversely cysteine cathepsins B, K, L, and S degraded AvBD2 and abolished its antibacterial activity. Only cathepsin K cleaved AvBD7 and released Ile4-AvBD7, a N-terminal truncated natural peptidoform of AvBD7 that displayed antibacterial activity. Besides the 3-stranded antiparallel beta-sheet typical of beta-defensins, structural analysis of AvBD7 by two-dimensional NMR spectroscopy highlighted the restricted accessibility of the C-terminus embedded by the N-terminal region and gave a formal evidence of a salt bridge (Asp9-Arg12) that could account for proteolysis resistance. The differential susceptibility of avian defensins to proteolysis opens intriguing questions about a distinctive role in the mucosal immunity against pathogen invasion. PMID:27561012

  17. Mobitz II AV block within the His bundle, with progression to complete heart block.

    PubMed Central

    Amuchástegui, L M; Moreyra, E; Alday, L E

    1976-01-01

    A case of a 48-year-old woman with frequent syncopal episodes is reported. The electrocardiogram showed high degree AV block with narrow QRS complexes. The His bundle electrogram displayed a split His deflection indicating impairment of conduction within the His bundle of the Mobitz II type. The AH interval was prolonged and Wenckebach phenomenon occurred at the same atrial pacing rate before and after atropine administration. During spontaneous or induced high grade AV block an escape rhythm originating in the distal His bundle was observed. A secondary study performed one year later showed progression to complete AV block. Both His potentials were present, one following the atrial and the other preceding the ventricular deflection. The H'V interval was prolonged and a further lengthening was seen after ajmaline. All these findings indicated proximal, mid, and distal disease of the His trunk. PMID:973908

  18. WE-G-213CD-07: Enhancing Respiratory Motion Prediction Accuracy Using Audiovisual (AV) Biofeedback.

    PubMed

    Pollock, S; Lee, D; Keall, P; Kim, T

    2012-06-01

    Prediction of respiratory-related tumor motion is hampered by irregularities present in the patient breathing patterns. Audiovisual (AV) biofeedback reduces irregularities, thereby producing a less complex breathing pattern. The aim of this project is to improve respiratory motion prediction accuracy using an AV biofeedback system. An AV biofeedback system combined with real-time MRI was implemented in this project (4 human subjects across 5 studies (one subject had both an initial and follow-up study)). The AV biofeedback system consists of external marker positioned on the abdomen of human subjects, being tracked using an RPM system (Real-time Position Management, Varian) to guide the subject's breathing. Acquired respiratory data has been used as input for motion prediction through a dynamic multi-leaf collimator (DMLC) simulator developed by Prof. Keall. The prediction algorithm utilized was a kernel density estimation-based real-time prediction algorithm. A variety of prediction parameters were tested to determine optimum prediction performance. Prediction parameters adjusted were the delay time (DT) and training examples (TE); the parameters tested here were: DT/TE = 2500/1500, 2500/100, 1000/250, 500/250; Given that the data sampling rate was kept at 30 Hz, the resultant prediction training window lengths were 49.5, 8.25, 3.3 and 3.3seconds respectively. The mean difference between measured and predicted data for free breathing was 1.98±2.32mm; and 0.65±0.65mm for when AV biofeedback was implemented (reduction of error of 67%). The most accurate prediction results were attained using the parameters: DT/TE = 500 ms/250. This study demonstrates the improvement of respiratory motion prediction accuracy when AV biofeedback is implemented to produce a more regular breathing pattern. © 2012 American Association of Physicists in Medicine.

  19. AV-1451 tau and β-amyloid positron emission tomography imaging in dementia with Lewy bodies.

    PubMed

    Kantarci, Kejal; Lowe, Val J; Boeve, Bradley F; Senjem, Matthew L; Tosakulwong, Nikki; Lesnick, Timothy G; Spychalla, Anthony J; Gunter, Jeffrey L; Fields, Julie A; Graff-Radford, Jonathan; Ferman, Tanis J; Jones, David T; Murray, Melissa E; Knopman, David S; Jack, Clifford R; Petersen, Ronald C

    2017-01-01

    Patients with probable dementia with Lewy bodies (DLB) often have Alzheimer's disease (AD)-related pathology. Our objective was to determine the pattern of positron emission tomography (PET) tau tracer AV-1451 uptake in patients with probable DLB, compared to AD, and its relationship to β-amyloid deposition on PET. Consecutive patients with clinically probable DLB (n = 19) from the Mayo Clinic Alzheimer's Disease Research Center underwent magnetic resonance imaging, AV-1451, and Pittsburgh compound-B (PiB) PET examinations. Age- and sex-matched groups of AD dementia (n = 19) patients and clinically normal controls (n = 95) from an epidemiological cohort served as a comparison groups. Atlas- and voxel-based analyses were performed. The AD dementia group had significantly higher AV-1451 uptake than the probable DLB group, and medial temporal uptake completely distinguished AD dementia from probable DLB. Patients with probable DLB had greater AV-1451 uptake in the posterior temporoparietal and occipital cortex compared to clinically normal controls, and in probable DLB, the uptake in these regions correlated with global cortical PiB uptake (Spearman rho = 0.63; p = 0.006). Medial temporal lobe AV-1451 uptake distinguishes AD dementia from probable DLB, which may be useful for differential diagnosis. Elevated posterior temporoparietal and occipital AV-1451 uptake in probable DLB and its association with global cortical PiB uptake suggest an atypical pattern of tau deposition in DLB. ANN NEUROL 2017;81:58-67. © 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

  20. Simplified Cardioneuroablation in the Treatment of Reflex Syncope, Functional AV Block, and Sinus Node Dysfunction.

    PubMed

    Aksu, Tolga; Golcuk, Ebru; Yalin, Kivanç; Guler, Tümer Erdem; Erden, Ismail

    2016-01-01

    Cardio neuroablation (CNA) is a lesser-known technique for management of patients with excessive vagal activation on the basis of radiofrequency catheter ablation (RFCA) of the areas related to the three main autonomic ganglia around the heart. We investigated the effectiveness of selective and/or stepwise RFCA of these areas via right atrium (RA) and/or left atrium (LA) in the patients with recurrent syncope due to excessive vagal activity. Twenty-two patients presenting symptomatic functional bradyarrhythmias, neurally mediated reflex syncope (NMS), symptomatic atrioventricular (AV) block, and symptomatic sinus node dysfunction (SND; number = 8, 7, 7, respectively) were enrolled. The three main paracardiac ganglia were targeted via RA and LA in the patients with NMS and SND. The procedure was performed via RA in the patients with AV block, followed by RFCA of all ganglia via LA, if AV conduction disorder persists. The sites showing fragmented potentials were identified by electrical mapping and verified by high-frequency stimulation and ablated until atrial electrical potential was completely eliminated (<0.1 mV). The patients with NMS and SND were free from new syncopal episode at a mean 12.3 ± 3.4 months and 9.5 ± 3.1 months follow-up, respectively. Ablation from RA was successful in six of seven patients with AV block. Despite the increased heart rate, the resolution of AV block after the RFCA could not be achieved in one patient who had partial resolution with atropine infusion on admission. CNA may be an alternative and safe strategy to reduce NMS episodes, and to treat functional AV block and symptomatic SND, especially in young patients. © 2015 Wiley Periodicals, Inc.

  1. Multinational evaluation of the interpretability of the iterative method of optimisation of AV delay for CRT.

    PubMed

    Raphael, Claire E; Kyriacou, Andreas; Jones, Siana; Pabari, Punam; Cole, Graham; Baruah, Resham; Hughes, Alun D; Francis, Darrel P

    2013-09-20

    AV delay optimisation of biventricular pacing devices (cardiac resynchronisation therapy, CRT) is performed in trials and recommended by current guidelines. The Doppler echocardiographic iterative method is the most commonly recommended. Yet whether it can be executed reliably has never been tested formally. 36 multinational specialists, familiar with using the echocardiographic iterative method of CRT optimisation, were shown 20-40 sets of transmitral Doppler traces at 6-8 AV settings and asked to select the optimal AV delay. Unknown to the specialists, some Doppler datasets appeared in duplicate, allowing assessment of both inter and intra-specialist interpretation. On the Kappa scale of agreement (1 = perfect agreement, 0 = chance alone), the agreement regarding optimal AV delay between specialists was poor (kappa=0.12 ± 0.08). More importantly, agreement of specialists with themselves (i.e. viewing identical sets of traces, twice) was also poor, with Kappa=0.23 ± 0.07 and mean absolute difference in optimum AV delay of 83 ms between first and second viewing of the same traces. Iterative AV optimisation is not executed reliably by experts, even in an artificially simplified context where biological variability and variation in image acquisition are eliminated by use of identical traces. This cannot be blamed on insufficient skills of some experts or discordant methods of selecting the optimum, because operators also showed poor agreement with themselves when assessing the same trace. Instead, guidelines should retract any recommendation for this algorithm. Guideline-development processes might usefully begin with a rudimentary check on proposed algorithms, to establish at least minimal credibility. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  2. Mineralogic mapping of the Av-9 Numisia quadrangle of Vesta

    NASA Astrophysics Data System (ADS)

    Frigeri, A.; De Sanctis, M. C.; Ammannito, E.; Buczkowski, D.; Combe, J. P.; Tosi, F.; Zambon, F.; Rocchini, D.; Jaumann, R.; Raymond, C. A.; Russell, C. T.

    2015-10-01

    In this manuscript we present the mineralogic mapping of the Av-9 Numisia quadrangle of Vesta using the most up-to-date data from the NASA-Dawn mission. This quadrangle is located in Vesta's equatorial zone (22° south to 22° north, 218° to 288° east, in Claudia coordinate system) and takes its name from the impact crater Numisia. The main feature, which dominates the quadrangle, is the Vestalia Terra plateau, a topographic high about 10 km above the surrounding areas. To the south, this region fades into the Rheasilvia basin, while to the north it is bounded by the steep scarp of Postumia basin. The Visible and Infrared mapping spectrometer (VIR) onboard NASA/Dawn provided the main data source for this work, at an unprecedented level of spatial and spectral resolution. In particular we are using spectral parameters to synthesize characteristics of the whole spectra into a single value. Pyroxene-related spectral parameters allow for the detection of lower crust or mantle material (diogenites) and upper crust material (eucrites) in the study area. The combined analysis of albedo from the Framing Camera, the geologic map and the spectroscopic data offer an interesting opportunity to understand better the surface features of this region of Vesta, and their evolution. Numisia, Cornelia, Fabia, Teia and Drusilla are the main craters in the study area, rich in bright and dark material outcrops, pitted terrains and OH-rich materials. Using the spectral parameters we demonstrate that the internal composition of Vestalia Terra is mainly diogenite-rich howardite, as shown by materials excavated by Cornelia and Fabia, and the composition of the slope north of Vestalia Terra. This agrees with the strong positive Bouguer Anomaly observed in the area, indicating a higher density of these features in relation to the surrounding areas. Besides the recently published works based on gravimetric modeling and geologic interpretation, the mineralogic mapping presented herein gives

  3. 76 FR 419 - Airworthiness Directives; 328 Support Services GmbH (Type Certificate Previously Held by AvCraft...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-05

    ... Certificate Previously Held by AvCraft Aerospace GmbH; Fairchild Dornier GmbH; Dornier Luftfahrt GmbH) Model... (Type Certificate Previously Held by AvCraft Aerospace GmbH; Fairchild Dornier GmbH; Dornier Luftfahrt.... Applicability (c) This AD applies to 328 Support Services GmbH (Type Certificate previously held by...

  4. 77 FR 41400 - AV Solar Ranch 1, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-13

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission AV Solar Ranch 1, LLC; Supplemental Notice That Initial Market- Based Rate...-referenced proceeding of AV Solar Ranch 1, LLC's application for market-based rate authority, with...

  5. The Helminth-Derived Immunomodulator AvCystatin Reduces Virus Enhanced Inflammation by Induction of Regulatory IL-10+ T Cells

    PubMed Central

    Schuijs, Martijn J.; Hartmann, Susanne; Selkirk, Murray E.; Roberts, Luke B.

    2016-01-01

    Respiratory Syncytial Virus (RSV) is a major pathogen causing low respiratory tract disease (bronchiolitis), primarily in infants. Helminthic infections may alter host immune responses to both helminths and to unrelated immune triggers. For example, we have previously shown that filarial cystatin (AvCystatin/Av17) ameliorates allergic airway inflammation. However, helminthic immunomodulators have so far not been tested in virus-induced disease. We now report that AvCystatin prevents Th2-based immunopathology in vaccine-enhanced RSV lung inflammation, a murine model for bronchiolitis. AvCystatin ablated eosinophil influx, reducing both weight loss and neutrophil recruitment without impairing anti-viral immune responses. AvCystatin also protected mice from excessive inflammation following primary RSV infection, significantly reducing neutrophil influx and cytokine production in the airways. Interestingly, we found that AvCystatin induced an influx of CD4+ FoxP3+ interleukin-10-producing T cells in the airway and lungs, correlating with immunoprotection, and the corresponding cells could also be induced by adoptive transfer of AvCystatin-primed F4/80+ macrophages. Thus, AvCystatin ameliorates enhanced RSV pathology without increasing susceptibility to, or persistence of, viral infection and warrants further investigation as a possible therapy for virus-induced airway disease. PMID:27560829

  6. The Helminth-Derived Immunomodulator AvCystatin Reduces Virus Enhanced Inflammation by Induction of Regulatory IL-10+ T Cells.

    PubMed

    Schuijs, Martijn J; Hartmann, Susanne; Selkirk, Murray E; Roberts, Luke B; Openshaw, Peter J M; Schnoeller, Corinna

    2016-01-01

    Respiratory Syncytial Virus (RSV) is a major pathogen causing low respiratory tract disease (bronchiolitis), primarily in infants. Helminthic infections may alter host immune responses to both helminths and to unrelated immune triggers. For example, we have previously shown that filarial cystatin (AvCystatin/Av17) ameliorates allergic airway inflammation. However, helminthic immunomodulators have so far not been tested in virus-induced disease. We now report that AvCystatin prevents Th2-based immunopathology in vaccine-enhanced RSV lung inflammation, a murine model for bronchiolitis. AvCystatin ablated eosinophil influx, reducing both weight loss and neutrophil recruitment without impairing anti-viral immune responses. AvCystatin also protected mice from excessive inflammation following primary RSV infection, significantly reducing neutrophil influx and cytokine production in the airways. Interestingly, we found that AvCystatin induced an influx of CD4+ FoxP3+ interleukin-10-producing T cells in the airway and lungs, correlating with immunoprotection, and the corresponding cells could also be induced by adoptive transfer of AvCystatin-primed F4/80+ macrophages. Thus, AvCystatin ameliorates enhanced RSV pathology without increasing susceptibility to, or persistence of, viral infection and warrants further investigation as a possible therapy for virus-induced airway disease.

  7. Improved insecticidal toxicity by fusing Cry1Ac of Bacillus thuringiensis with Av3 of Anemonia viridis.

    PubMed

    Yan, Fu; Cheng, Xing; Ding, Xuezhi; Yao, Ting; Chen, Hanna; Li, Wenping; Hu, Shengbiao; Yu, Ziquan; Sun, Yunjun; Zhang, Youming; Xia, Liqiu

    2014-05-01

    Av3, a neurotoxin of Anemonia viridis, is toxic to crustaceans and cockroaches but inactive in mammals. In the present study, Av3 was expressed in Escherichia coli Origami B (DE3) and purified by reversed-phase liquid chromatography. The purified Av3 was injected into the hemocoel of Helicoverpa armigera, rendering the worm paralyzed. Then, Av3 was expressed alone or fusion expressed with the Cry1Ac in acrystalliferous strain Cry(-)B of Bacillus thuringiensis. The shape of Cry1Ac was changed by fusion with Av3. The expressed fusion protein, Cry1AcAv3, formed irregular rhombus- or crescent-shaped crystalline inclusions, which is quite different from the shape of original Cry1Ac crystals. The toxicity of Cry1Ac was improved by fused expression. Compared with original Cry1Ac expressed in Cry(-)B, the oral toxicity of Cry1AcAv3 to H. armigera was elevated about 2.6-fold. No toxicity was detected when Av3 was expressed in Cry(-)B alone. The present study confirmed that marine toxins could be used in bio-control and implied that fused expression with other insecticidal proteins could be an efficient way for their application.

  8. LLCD operations using the Lunar Lasercom OGS Terminal

    NASA Astrophysics Data System (ADS)

    Sodnik, Zoran; Smit, Hans; Sans, Marc; Zayer, Igor; Lanucara, Marco; Montilla, Iciar; Alonso, Angel

    2014-03-01

    The paper describes the operations of ESA's Optical Ground Station (OGS) during the Lunar Laser Communications Demonstration (LLCD) experiment, performed in October and November 2013 with NASA's Lunar Atmospheric and Dust Environmental Explorer (LADEE) spacecraft. First the transmitter and receiver designs at the OGS telescope are described, which are geometrically separated to prevent cross-talk. Problems encountered and the lesson learned will be explained. As it turned the chosen arrangement was not sufficiently stable in terms of alignment and the paper will describe the solution found. A new industrial contract has been placed for improvement of the design of two solutions will be presented, which will both be tested in a follow-up laser communication campaign, scheduled for end March 2014.

  9. In vivo imaging of neuromelanin in Parkinson's disease using 18F-AV-1451 PET.

    PubMed

    Hansen, Allan K; Knudsen, Karoline; Lillethorup, Thea P; Landau, Anne M; Parbo, Peter; Fedorova, Tatyana; Audrain, Hélène; Bender, Dirk; Østergaard, Karen; Brooks, David J; Borghammer, Per

    2016-07-01

    The tau tangle ligand (18)F-AV-1451 ((18)F-T807) binds to neuromelanin in the midbrain, and may therefore be a measure of the pigmented dopaminergic neuronal count in the substantia nigra. Parkinson's disease is characterized by progressive loss of dopaminergic neurons. Extrapolation of post-mortem data predicts that a ∼30% decline of nigral dopamine neurons is necessary to cause motor symptoms in Parkinson's disease. Putamen dopamine terminal loss at disease onset most likely exceeds that of the nigral cell bodies and has been estimated to be of the order of 50-70%. We investigated the utility of (18)F-AV-1451 positron emission tomography to visualize the concentration of nigral neuromelanin in Parkinson's disease and correlated the findings to dopamine transporter density, measured by (123)I-FP-CIT single photon emission computed tomography. A total of 17 patients with idiopathic Parkinson's disease and 16 age- and sex-matched control subjects had (18)F-AV-1451 positron emission tomography using a Siemens high-resolution research tomograph. Twelve patients with Parkinson's disease also received a standardized (123)I-FP-CIT single photon emission computed tomography scan at our imaging facility. Many of the patients with Parkinson's disease displayed visually apparent decreased (18)F-AV-1451 signal in the midbrain. On quantitation, patients showed a 30% mean decrease in total nigral (18)F-AV-1451 volume of distribution compared with controls (P = 0.004), but there was an overlap of the individual ranges. We saw no significant correlation between symptom dominant side and contralateral nigral volume of distribution. There was no correlation between nigral (18)F-AV-1451 volume of distribution and age or time since diagnosis. In the subset of 12 patients, who also had a (123)I-FP-CIT scan, the mean total striatal dopamine transporter signal was decreased by 45% and the mean total (18)F-AV-1451 substantia nigra volume of distribution was decreased by 33% after

  10. Rate-adaptive AV delay and exercise performance following cardiac resynchronization therapy.

    PubMed

    Shanmugam, Nesan; Prada-Delgado, Oscar; Campos, Ana Garcia; Grimster, Alex; Valencia, Oswaldo; Baltabaeva, Aigul; Jones, Sue; Anderson, Lisa

    2012-11-01

    Physiological shortening of the atrioventricular (AV) interval with increasing heart rate is well documented in normal human beings and is an established component of dual-chamber pacing for bradycardia. To assess the effect of exercise on optimal AV delay and the impact of a patient-specific rate-adaptive AV delay (RAAVD) on exercise capacity in patients with heart failure following cardiac resynchronization therapy. Phase 1: We performed iterative AV optimization at rest and exercise in 52 cardiac resynchronization therapy patients in atrial-sensed mode (mean age 71.6 ± 9.2 years, 25% females). Phase 2: Subsequently, 20 consecutive volunteers from this group (mean age 69.2 ± 9.6 years, 15% females) underwent cardiopulmonary exercise testing with RAAVD individually programmed ON (RAAVD-ON) or OFF (RAAVD-OFF). Phase 1: In 94% of the patients, there was a marked reduction (mean 50%) in optimal AV delay with exercise. The optimal resting vs exercise AV delay was 114.2 ± 29 ms at a heart rate of 64.4 ± 7.1 beats/min vs 57 ± 31 ms at a heart rate of 103 ± 13 beats/min (P < .001). No patients required an increase in AV delay with exercise, and 3 (6%) showed no change. Phase 2: With RAAVD-ON, significantly better exercise times were achieved (8.7 ± 3.2 minutes) compared with RAAVD-OFF (7.9 ± 3.2 minutes; P = .003), and there was a significant improvement in Vo(2)max (RAAVD-ON 16.1 ± 4.0 vs RAAVD-OFF 14.9 ± 3.7 mL/(kg · min); P = .024). There was a dramatic reduction in optimal AV delay with physiological exercise in the majority of this heart failure cardiac resynchronization therapy cohort. Replicating this physiological response with a programmable RAAVD translated into a 10% improvement in exercise capacity. Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  11. Correlation of early-phase 18F-florbetapir (AV-45/Amyvid) PET images to FDG images: preliminary studies.

    PubMed

    Hsiao, Ing-Tsung; Huang, Chin-Chang; Hsieh, Chia-Ju; Hsu, Wen-Chun; Wey, Shiaw-Pyng; Yen, Tzu-Chen; Kung, Mei-Ping; Lin, Kun-Ju

    2012-04-01

    (18)F-Florbetapir (AV-45/Amyvid) is a novel positron emission tomography (PET) tracer for imaging plaque pathology in Alzheimer's disease (AD), while PET images of fluorodeoxyglucose (FDG) for cerebral glucose metabolism can provide complementary information to amyloid plaque images for diagnosis of AD. The goal of this preliminary study was to investigate the perfusion-like property of relative cerebral blood flow estimates (R(1)) and summed early-phase AV-45 images [perfusion AV-45 (pAV-45)] and optimize the early time frame for pAV-45. Dynamic AV-45 PET scans (0-180 min) were performed in seven subjects. pAV-45, late-phase AV-45, and FDG images were spatially normalized to the Montreal Neurological Institute template aided by individual MRI images, and the corresponding standardized uptake value ratio (SUVR) was computed. The R(1) images were derived from a simplified reference tissue model. Correlations between regional and voxelwise R(1) and the corresponding FDG images were calculated. An optimization of time frames of pAV-45 was conducted in terms of correlation to FDG images. The optimal early time frame was validated in a separate cohort. The regional distribution in the R(1) images correlated well (R = 0.91) to that of the FDG within subjects. Consistently high correlation was noted across a long range of time frames. The maximal correlation of pAV-45 to FDG SUVR of R = 0.95 was observed at the time frame of 1-6 min, while the peak correlation of R = 0.99 happened at 0-2 min between pAV-45 and R(1). A similar result was achieved in the validation cohort. Preliminary results showed that the distribution patterns of R(1) and pAV-45 images are highly correlated with normalized FDG images, and the initial 5-min early time frame of 1-6 min is potentially useful in providing complementary FDG-like information to the amyloid plaque density by late-phase AV-45 images.

  12. 45 CFR 156.135 - AV calculation for determining level of coverage.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 1 2013-10-01 2013-10-01 false AV calculation for determining level of coverage. 156.135 Section 156.135 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES REQUIREMENTS RELATING... after January 1, 2014; (3) Is large enough that: (i) The demographic and spending patterns are stable...

  13. Simulation of AV hysteresis pacing using an integrated dual chamber heart and pacer model.

    PubMed

    Lian, Jie; Garner, Garth; Kratschmer, Hannes; Mussig, Dirk

    2009-01-01

    Long term right ventricular apical pacing has been known to have adverse effects in cardiac function. The AV hysteresis (AVH) is a feature existing in many dual-chamber cardiac pacemakers that aims to minimize the right ventricular pacing, but its clinical efficacy remains inconclusive due to conflicting evidence from different studies. We have recently developed a novel integrated dual-chamber heart and pacer (IDHP) model, which can simulate various interactions between intrinsic heart activity and extrinsic cardiac pacing. In this study, we use the IDHP model to simulate various atrio-ventricular (AV) conduction pathologies, and to investigate the effects of an AVH algorithm on reducing right ventricular pacing. Our results show that the efficacy of AVH is dependent on the underlying cardiac conditions. While it can preserve intrinsic conduction during minor or moderate first degree AV block, its efficacy is reduced at higher degree AV block conditions. This pilot study further supports using the IDHP model to design and evaluate more advanced pacemaker algorithms for therapeutic interventions.

  14. The role of variant histone H2AV in Drosophila melanogaster larval hematopoiesis.

    PubMed

    Grigorian, Melina; DeBruhl, Heather; Lipsick, Joseph S

    2017-04-15

    Replication-independent histone variants can replace the canonical replication-dependent histones. Vertebrates have multiple H2A variant histones, including H2AZ and H2AX that are present in most eukaryotes. H2AZ regulates transcriptional activation as well as the maintenance of gene silencing, while H2AX is important in DNA damage repair. The fruit fly Drosophila melanogaster has only one histone H2A variant (H2AV), which is a chimera of H2AZ and H2AX. In this study we found that lack of H2AV led to the formation of black melanotic masses in Drosophila third instar larvae. The formation of these masses was found in conjunction with a loss of the majority of the primary lymph gland lobes. Interestingly, the cells of the posterior signaling center were preserved in these mutants. Reduction of H2AV levels by RNAi knockdown caused a milder phenotype that preserved the lymph gland structure but that included precocious differentiation of the prohemocytes located within the medullary zone and the secondary lobes of the lymph gland. Mutant rescue experiments suggest that the H2AZ-like rather than the H2AX-like function of H2AV is primarily required for normal hematopoiesis. © 2017. Published by The Company of Biologists Ltd.

  15. AV delay optimization and management of DDD paced patients with dilated cardiomyopathy.

    PubMed

    Guardigli, G; Ansani, L; Percoco, G F; Toselli, T; Spisani, P; Braggion, G; Antonioli, G E

    1994-11-01

    Ten DDD paced patients, suffering from dilated cardiomyopathy in the NYHA functional classes III or IV were studied by means of Doppler echocardiography at different programmed values of atrioventricular (AV) delay (200, 150, 120, 100, and 80 msec). The following variables were evaluated: LV diameter, ejection fraction, mitral and aortic flow velocity integrals, and stroke volume. During VDD pacing, a resting AV delay associated with the best diastolic filling and systolic function was identified and programmed individually. Shortening of the AV delay to about 100 msec was associated with a gradual and progressive improvement. Further decrease caused an impairment of systolic function. The patients were clinically and hemodynamically reevaluated after 2 months of follow-up. A reduction of NYHA class and an improvement of LV function were consistently found. The reported data suggest that programming of an optimal AV delay may improve myocardial function in DDD paced patients with congestive heart failure. This result may be the consequence of an optimization of left ventricular filling and a better use of the Frank-Starling law.

  16. 45 CFR 156.135 - AV calculation for determining level of coverage.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 1 2014-10-01 2014-10-01 false AV calculation for determining level of coverage. 156.135 Section 156.135 Public Welfare Department of Health and Human Services REQUIREMENTS RELATING..., where such adaptations can be based on actuarially sound principles and will not have a substantial...

  17. Utility of High-Output His Pacing during Difficult AV Node Ablation. An Underutilized Strategy.

    PubMed

    Kanjwal, Khalil; Grubb, Blair P

    2016-06-01

    Atrioventricular (AV) node ablation is a commonly performed procedure for patients with chronic drug refractory atrial fibrillation (AF) with episodes of rapid ventricular response. We report on a 72-year-old man who had difficulty managing chronic drug refractory AFs with frequent hospitalizations for rapid ventricular rate. The patient was taken to the electrophysiology laboratory for AV node ablation. Extensive mapping and localization techniques of the compact AV node and ablation in the region were unsuccessful. Subsequently, high-output His bundle pacing using 20 mA at 2 ms of output energy was performed in an attempt to localize the His bundle in areas where high-output pacing resulted in a narrower QRS complex. Further ablations in the areas where pacing produced a narrower QRS complex resulted in complete heart block. This case highlights the importance of using this simple pacing maneuver to achieve complete heart block in patients in whom standard strategies to localize and ablate the compact AV node are unsuccessful.

  18. Dramatic Response to Cardiac Resynchronization Therapy With AV Delay Optimization in Narrow QRS Heart Failure.

    PubMed

    Kogawa, Rikitake; Nakai, Toshiko; Ikeya, Yukitoshi; Mano, Hiroaki; Sonoda, Kazumasa; Sasaki, Naoko; Iso, Kazuki; Okumura, Yasuo; Ohkubo, Kimie; Kunimoto, Satoshi; Watanabe, Ichiro; Hirayama, Atsushi

    2015-01-01

    Cardiac resynchronization therapy (CRT) has been shown to be effective for heart failure. However, as outlined in the AHA/ACC/HRS Appropriate Use Criteria, CRT is not strongly recommended for patients with a narrow QRS complex. We describe a case of dilated cardiomyopathy and narrow QRS complex in which we obtained a dramatic response to CRT by optimizing the atrioventricular (AV) delay. The patient was a 61-year-old man with intractable heart failure. Echocardiography showed a low ejection fraction of 22% but no dyssynchrony. Because he had been hospitalized many times for congestive heart failure despite β-blocker and diuretic treatment, we decided to use CRT. However, after implantation of the CRT device, the QRS complex widened abnormally, and his symptoms worsened. He was re-admitted 2 months after CRT implantation. We examined the pacemaker status and optimized the AV delay to obtain a "narrow" QRS complex. The patient's condition improved dramatically after the AV delay optimization. His clinical status has been good, and there has been no subsequent hospitalization. Our case points to the effectiveness of CRT in patients with a narrow QRS complex and to the importance of AV optimization for successful CRT.

  19. Identification of the human ApoAV gene as a novel ROR{alpha} target gene

    SciTech Connect

    Lind, Ulrika; Nilsson, Tina; McPheat, Jane; Stroemstedt, Per-Erik; Bamberg, Krister; Balendran, Clare; Kang, Daiwu . E-mail: Daiwu.Kang@astrazeneca.com

    2005-04-29

    Retinoic acid receptor-related orphan receptor-{alpha} (ROR{alpha}) (NR1F1) is an orphan nuclear receptor with a potential role in metabolism. Previous studies have shown that ROR{alpha} regulates transcription of the murine Apolipoprotein AI gene and human Apolipoprotein CIII genes. In the present study, we present evidence that ROR{alpha} also induces transcription of the human Apolipoprotein AV gene, a recently identified apolipoprotein associated with triglyceride levels. Adenovirus-mediated overexpression of ROR{alpha} increased the endogenous expression of ApoAV in HepG2 cells and ROR{alpha} also enhanced the activity of an ApoAV promoter construct in transiently transfected HepG2 cells. Deletion and mutation studies identified three AGGTCA motifs in the ApoAV promoter that mediate ROR{alpha} transactivation, one of which overlaps with a previously identified binding site for PPAR{alpha}. Together, these results suggest a novel mechanism whereby ROR{alpha} modulates lipid metabolism and implies ROR{alpha} as a potential target for the treatment of dyslipidemia and atherosclerosis.

  20. Impact of e-AV Biology Website for Learning about Renewable Energy

    ERIC Educational Resources Information Center

    Nugraini, Siti Hadiati; Choo, Koo Ah; Hin, Hew Soon; Hoon, Teoh Sian

    2013-01-01

    This paper considers the design and development of a Website for Biology in senior high schools in Indonesia. The teaching media, namely e-AV Biology, was developed with the main features of video lessons and other features in supporting the students' learning process. Some video lessons describe the production process of Biofuel or Renewable…

  1. Human Radiation Dosimetry of [(18)F]AV-1451(T807) to Detect Tau Pathology.

    PubMed

    Choi, Jae Yong; Lyoo, Chul Hyoung; Lee, Jae Hoon; Cho, Hanna; Kim, Kyeong Min; Kim, Jin Su; Ryu, Young Hoon

    2016-08-01

    [(18)F]AV-1451 is a positron emission tomography (PET) radioligand for detecting paired helical filament tau. Our aim was to estimate the radiation dose of [(18)F]AV-1451 in humans. Whole-body PET scans were acquired for six healthy volunteers (three male, three female) for 128 min after injection of [(18)F]AV-1451 (268 ± 31 MBq). Radiation doses were estimated using the OLINDA/EXM software. The estimated organ doses ranged from 7.81 to 81.2 μSv/MBq. The critical organ for radiation burden was the liver. Radiation doses to the reproductive and blood-forming organs were 14.15, 8.43, and 18.35 μSv/MBq for the ovaries, testes, and red marrow, respectively. The mean effective dose was 22.47 ± 3.59 μSv/MBq. A standard single injection of 185 MBq (5 mCi) results in an effective dose of 4.7 mSv in a healthy subject. Therefore, [(18)F]AV-1451 could be used in multiple PET scans of the same subject per year.

  2. In Vivo cortical tau in Parkinson's disease using 18F-AV-1451 positron emission tomography.

    PubMed

    Hansen, Allan K; Damholdt, Malene Flensborg; Fedorova, Tatyana D; Knudsen, Karoline; Parbo, Peter; Ismail, Rola; Østergaard, Karen; Brooks, David J; Borghammer, Per

    2017-06-01

    Alzheimer's disease copathology is common in PD at autopsy. In non-PD subjects with mild cognitive impairment, tau depositions can be detected using 18F-AV-1451 PET. We hypothesized that 18F-AV-1451 PET would show tau aggregation in PD with mild cognitive impairment and correlate with cognitive dysfunction. To describe tau aggregation in PD patients. Twenty-six PD patients and 23 controls had 18F-AV-1451 PET and neuropsychological assessment to detect mild cognitive impairment. Nine PD patients (35%) were identified with mild cognitive impairment. Regional analyses showed no significant differences between groups. Voxel-wise analyses showed no correlation with cognitive domain z-scores within patients. One patient with mild cognitive impairment was estimated Braak tau stage 5; all other patients were stage 0. Our results indicate that tau pathology, as detected by 18F-AV-1451, is uncommon in PD with mild cognitive impairment and shows no significant correlation with cognitive dysfunction at this stage. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  3. [Promoting venous return in plaster cast by AV impulse system. A preclinical study].

    PubMed

    Bulitta, C; Kock, H J; Hanke, J; Sievers, K W; Schmit-Neuerburg, K P

    1996-08-01

    A new pneumatic compression pump--the AV-impulse system--causes increased return of venous blood from the lower limbs to the heart and increases total blood flow in the lower limbs by emptying the plantar venous plexus. Up to date there exist no experiences with using this system in plaster cast. We studied the maximum venous blood flow, the venous blood flow per minute and the venous diameters above the popliteal and femoral vein by duplexsonography in 12 lower limbs of 6 healthy persons before and after applying below-the-knee plaster casts. After applying the plaster cast we observed a slight increase in venous diameter (p = 0.02). By using the AV-impulse-system we observed a significant increase in maximum venous blood flow and venous blood flow per minute (p < 0.05). We demonstrated a significant increase of venous blood return in the deep veins of the lower limbs after applying a lower limb plaster cast by using the AV-impulse-system. These results indicate the possible benefit of using the AV-impulse-system as a physical method of thromboprophylaxis in orthopaedic and trauma patients with plaster cast immobilisation of the leg.

  4. Targeting the dengue β-OG with serotype-specific alkaloid virtual leads.

    PubMed

    Gangopadhyay, Aditi; Chakraborty, Hirak Jyoti; Datta, Abhijit

    2017-03-01

    The dengue envelope β-OG pocket is a crucial hinge for mediating virus-host fusion via conformational changes in the envelope to the fusion-competent form. The β-OG pocket is a small molecule target site for inhibition of virus-host fusion. As of date, the only structure of the β-OG pocket known is of serotype 2. Studies of β-OG inhibition by small molecules primarily target viral serotype 2. Envelope and β-OG sequence alignments, reveal dissimilarities across serotypes. In light of protein sequence-structure-function correlation, sequence variations suggest serotypic variations in β-OG druggability. This, together with the fact that dengue viral proteins do have serotype-specific variations of structure and function, lead to the study of the serotype-specificity of the dengue β-OG ligand binding behaviour. β-OG druggability was compared using comparative models of envelope proteins containing the β-OG pocket in four serotypes of the dengue virus. β-OG ligand binding was found to vary with respect to hydrophobicity, hydrophilicity, hydrogen bonding, van der Waals interactions with ligands and tightness of the binding site. The study also reports serotype-specific virtual leads identified from a library of 9175 alkaloids, using a consensus docking and scoring approach. The docking algorithms of Glide SP and XP, together with the Lamarckian genetic algorithm were employed for consensus docking. For consensus scoring, the Glide empirical score was employed along with the scoring function of AutoDock. A multi-dimensional lead optimisation approach was performed for optimising affinity, ligand efficiency, lipophilic ligand efficiency, ADMET and molecular torsional strains. The study proposes the serotype-specific inhibition of the β-OG for an effective inhibition of virus-host fusion, in contrast to a pan inhibitor.

  5. A Practical ECG Criterion to Unmask Left Accessory AV Connections in Patients With Subtle Preexcitation.

    PubMed

    Thompson, J Jenkins; Shah, Jignesh; Charnigo, Richard; Tackett, Andrea; Darrat, Yousef H; Bailey, Alison; Delisle, Brian; Kakavand, Bahram; DI Biase, Luigi; Natale, Andrea; Morales, Gustavo; Elayi, Claude S

    2015-05-20

    Accessory AV-connections capable of antegrade conduction need to be recognized because of the potential for life-threatening arrhythmias. However, the preexcited ECG pattern may be subtle, especially among left-sided AV-connections. We explored whether additional ECG criteria might help identify left-sided AV-connections. We analyzed 156 patients who underwent an electrophysiology study (EPS) and ablation for paroxysmal supraventricular tachycardias (PSVT). Patients were divided into 2 groups: those with left-sided AV-connections (Group 1) and all other PSVT (Group 2). Various ECG parameters were compared before and after ablation in both groups. The EPS identified left-sided AV-connections among 43 patients (Group 1) and excluded it among 113 (Group 2). Baseline ECG in Group 1 demonstrated obvious preexcitation among 24/43 patients (55.8%), the remaining 19/43 missing obvious preexcitation. R/S ratio > 0.5 in V1 was noted in 38/43 (88.4%) patients in Group 1 before ablation (median 1.00; IQR 0.58-2.20), including 16/19 (84.2%) patients lacking obvious left-sided AVconnections. Conversely, only 10/113 (8.8%) patients in Group 2 had R/S ratios in V1 ≥ 0.5 (0.20; 0.10-0.31), P < 0.0001. After ablation, the R/S ratio decreased significantly in Group 1 (0.29; 0.17-0.45), P < 0.0001. Thus, a combined criterion of classic preexcitation or R/S ratio ≥ 0.5 on ECG identified 40/43 left-sided AV-connections (sensitivity 93.0%). The negative predictive value of this combined criterion was 103/106 (97.2%). In symptomatic patients, combining the R/S ratio (≥ 0.5) in lead V1 with the classic preexcitation pattern on ECG markedly improved the sensitivity to diagnose left-sided AV-connections. This ratio may be particularly useful among patients lacking obvious preexcitation. © 2015 Wiley Periodicals, Inc.

  6. Longer Left Ventricular Electric Delay Reduces Mitral Regurgitation After Cardiac Resynchronization Therapy: Mechanistic Insights From the SMART-AV Study (SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy).

    PubMed

    Chatterjee, Neal A; Gold, Michael R; Waggoner, Alan D; Picard, Michael H; Stein, Kenneth M; Yu, Yinghong; Meyer, Timothy E; Wold, Nicholas; Ellenbogen, Kenneth A; Singh, Jagmeet P

    2016-11-01

    Mitral regurgitation (MR) is associated with worse survival in those undergoing cardiac resynchronization therapy (CRT). Left ventricular (LV) lead position in CRT may ameliorate mechanisms of MR. We examine the association between a longer LV electric delay (QLV) at the LV stimulation site and MR reduction after CRT. QLV was assessed retrospectively in 426 patients enrolled in the SMART-AV study (SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in CRT). QLV was defined as the time from QRS onset to the first large peak of the LV electrogram. Linear regression and logistic regression were used to assess the association between baseline QLV and MR reduction at 6 months (absolute change in vena contracta width and odds of ≥1 grade reduction in MR). At baseline, there was no difference in MR grade, LV dyssynchrony, or LV volumes in those with QLV above versus below the median (95 ms). After multivariable adjustment, increasing QLV was an independent predictor of MR reduction at 6 months as reflected by an increased odds of MR response (odds ratio: 1.13 [1.03-1.25]/10 ms increase QLV; P=0.02) and a decrease in vena contracta width (P<0.001). At 3 months, longer QLV (≥median) was associated with significant decrease in LV end-systolic volume (ΔLV end-systolic volume -28.2±38.9 versus -4.9±33.8 mL, P<0.001). Adjustment for 3-month ΔLV end-systolic volume attenuated the association between QLV and 6-month MR reduction. In patients undergoing CRT, longer QLV was an independent predictor of MR reduction at 6 months and associated with interval 3-month LV reverse remodeling. These findings provide a mechanistic basis for using an electric-targeting LV lead strategy at the time of CRT implant. © 2016 American Heart Association, Inc.

  7. A Heart too Drunk to Drive; AV Block following Acute Alcohol Intoxication.

    PubMed

    van Stigt, Arthur H; Overduin, Ruben J; Staats, Liza C; Loen, Vera; van der Heyden, Marcel A G

    2016-02-29

    Acute excessive alcohol consumption is associated with heart rhythm disorders like atrial fibrillation but also premature ventricular contractions, collectively known as the "holiday heart syndrome". More rarely but clinically significant are reports of atrioventricular (AV) conduction disturbances in binge drinkers with no underlying heart disease or chronic alcohol consumption. To obtain better insights into common denominators and the potential underlying mechanisms we collected and compared individual case reports of AV block following acute alcohol intoxication in otherwise healthy people. By screening PubMed, Google Scholar, Scopus and JSTOR, fifteen cases were found of which eight were sufficiently documented for full analysis. Blood alcohol levels ranged from 90 to 958 mg/dl (19 to 205 mM). Second and third degree AV block was observed most (6/8) albeit that in two of these patients a vagal stimulus led to deterioration from first into higher order AV block. In all cases, patients reverted to normal sinus rhythm upon becoming sober again. Mildly lowered body temperature (35.9 ± 0.5°C) was observed but can be excluded as a major cause of conduction blockade. We hypothesize that ethanol induced partial inhibition of calcium and potentially also sodium currents in conductive tissue structures may be one of the mechanisms of conduction slowing and block that may become exaggerated upon increased vagal tone. An impairment of gap junction function cannot be excluded as a contributing factor. In conclusion, cases of documented alcohol induced AV block are very rare but events can occur at relatively low serum alcohol levels which should prompt to awareness of this phenomenon in alcohol intoxicated patients.

  8. PHOTOMETRIC PROPERTIES FOR SELECTED ALGOL-TYPE BINARIES. IV. AV HYDRAE AND DZ CASSIOPEIAE

    SciTech Connect

    Yang, Y.-G.; Dai, H.-F.; Li, L.-H.

    2012-08-15

    We present BVR photometric observations and several eclipsing times for AV Hya and DZ Cas from 2004 to 2011. Using the Wilson-Devinney method, the photometric solutions with hot spots were deduced from their asymmetric light curves. The results indicate that both stars are Algol-type binaries, whose mass ratio, q{sub ph}, and fill-out factor of the primary, f{sub 1}, are q{sub ph} = 0.255({+-} 0.002) and f{sub 1} = 81.2({+-} 0.2)% for AV Hya, and q{sub ph} = 0.093({+-} 0.003) and f{sub 1} = 98.7({+-} 0.3)% for DZ Cas. Based on all available light minimum times, it is discovered that the O - C curve of each star could be described by a light-time orbit overlying on a downward parabola. Their periods and amplitudes are P{sub 3} = 37.2({+-} 0.7) yr and A = 0fd0095({+-}0fd0006) for AV Hya, and P{sub 3} = 62.5({+-} 1.0) yr and A = 0fd0183({+-}0fd0007) for DZ Cas. Cyclic variations may result from the light-time effect due to the third body. The secular period decrease rates are dP/dt = -1.47({+-} 0.04) Multiplication-Sign 10{sup -7} days yr{sup -1} for AV Hya and dP/dt = -0.92({+-} 0.04) Multiplication-Sign 10{sup -7} days yr{sup -1} for DZ Cas. This may be interpreted using mass and angular momentum loss from the system. With decreasing period, the fill-out factor of the primary increases and it may finally fill its inner Roche lobe. Therefore, AV Hya and DZ Cas with a secular period decrease will evolve from semi-detached configurations into contact ones.

  9. Effect of cardiac resynchronization therapy on left atrial reverse remodeling: role of echocardiographic AV delay optimization.

    PubMed

    Malagoli, Alessandro; Rossi, Luca; Franchi, Francesco; Piepoli, Massimo Francesco; Malavasi, Vincenzo; Casali, Edoardo; Modena, Maria Grazia; Villani, Giovanni Quinto

    2013-08-20

    Cardiac resynchronization therapy (CRT) improves left ventricular (LV) function in patients with advanced heart failure (HF) and there are some evidences about beneficial effects also on left atrial (LA) dimension and function. The contribution of atrioventricular delay (AVD) optimization on LA changes has not been evaluated. The purpose of the present study was to further investigate the effect of CRT on LA reverse remodelling and to evaluate the contribution of AVD optimization. From the Cardiology Department of Piacenza Hospital and Modena University Hospital fifty one patients with refractory systolic HF and left bundle branch block were prospectively enrolled before CRT implantation. Patients were 1:1 randomized to either an optimized AVD (AV Opt group) determined by continuous wave Doppler aortic velocity-time integral (VTI) or an empiric AVD of 110 ms (AV Fixed group). Optimal AVD was defined as the AVD that yielded the largest aortic VTI at one of eight tested AV intervals (between 60 and 200 ms). LA volumes and emptying fractions were assessed by two-dimensional echocardiography at baseline and 6 months after CRT. At 6-month follow-up, CRT induced LA reverse remodeling in the whole population (maximal LA volume: 55.8 ± 16.4 ml/m² vs 50.3 ± 18.9 ml/m², p=0.006; pre-systolic LA volume: 47.0 ± 15.2 ml/m² vs 41.4 ± 17.4 ml/m², p=0.003; post-systolic LA volume: 36.4 ± 15.0 ml/m² vs 30.3 ± 18.0 ml/m(2), p=0.001); nevertheless, no substantial difference was observed about LA structural and functional remodeling between both AV Opt group and AV Fixed group. CRT induces LA reverse remodeling that appears independent from AVD optimization. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  10. AV-1451 PET imaging of tau pathology in preclinical Alzheimer disease: Defining a summary measure.

    PubMed

    Mishra, Shruti; Gordon, Brian A; Su, Yi; Christensen, Jon; Friedrichsen, Karl; Jackson, Kelley; Hornbeck, Russ; Balota, David A; Cairns, Nigel J; Morris, John C; Ances, Beau M; Benzinger, Tammie L S

    2017-07-26

    Utilizing [18F]-AV-1451 tau positron emission tomography (PET) as an Alzheimer disease (AD) biomarker will require identification of brain regions that are most important in detecting elevated tau pathology in preclinical AD. Here, we utilized an unsupervised learning, data-driven approach to identify brain regions whose tau PET is most informative in discriminating low and high levels of [18F]-AV-1451 binding. 84 cognitively normal participants who had undergone AV-1451 PET imaging were used in a sparse k-means clustering with resampling analysis to identify the regions most informative in dividing a cognitively normal population into high tau and low tau groups. The highest-weighted FreeSurfer regions of interest (ROIs) separating these groups were the entorhinal cortex, amygdala, lateral occipital cortex, and inferior temporal cortex, and an average SUVR in these four ROIs was used as a summary metric for AV-1451 uptake. We propose an AV-1451 SUVR cut-off of 1.25 to define high tau as described by imaging. This spatial distribution of tau PET is a more widespread pattern than that predicted by pathological staging schemes. Our data-derived metric was validated first in this cognitively normal cohort by correlating with early measures of cognitive dysfunction, and with disease progression as measured by β-amyloid PET imaging. We additionally validated this summary metric in a cohort of 13 Alzheimer disease patients, and showed that this measure correlates with cognitive dysfunction and β-amyloid PET imaging in a diseased population. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. (18)F-AV-1451 binds to motor-related subcortical gray and white matter in corticobasal syndrome.

    PubMed

    Cho, Hanna; Baek, Min Seok; Choi, Jae Yong; Lee, Seung Ha; Kim, Joong Seok; Ryu, Young Hoon; Lee, Myung Sik; Lyoo, Chul Hyoung

    2017-09-12

    To investigate tau distribution in patients with corticobasal syndrome (CBS) using (18)F-AV-1451 PET. Six consecutively recruited patients with CBS and 20 age-matched healthy controls underwent 2 PET scans with (18)F-AV-1451 (for tau) and (18)F-florbetaben (for β-amyloid). We compared standardized uptake value ratio maps of the (18)F-AV-1451 PET images between the patients with CBS and controls. Compared to controls, patients with CBS exhibited asymmetrically increased (18)F-AV-1451 binding in the putamen, globus pallidus, and thalamus contralateral to the clinically more affected side and in the ipsilateral globus pallidus and dentate nucleus. Voxel-based comparison additionally showed asymmetrically increased (18)F-AV-1451 binding in the focal regions of the precentral gray and white matter and in the midbrain, predominantly in the contralateral side. (18)F-AV-1451 binding in the precentral white matter correlated with motor severity. (18)F-AV-1451 asymmetrically binds to motor-related subcortical gray and white matter structures in patients with CBS. This pattern corresponds to tau pathology distribution in postmortem studies, and motor deficit in patients with CBS may be associated with tau accumulation predominantly in the subcortical white matter underlying the motor cortex, leading to disruptions in motor-related networks. © 2017 American Academy of Neurology.

  12. Atorvastatin and fenofibrate increase apolipoprotein AV and decrease triglycerides by up-regulating peroxisome proliferator-activated receptor-α

    PubMed Central

    Huang, Xian-sheng; Zhao, Shui-ping; Bai, Lin; Hu, Min; Zhao, Wang; Zhang, Qian

    2009-01-01

    Background and purpose: Combining statin and fibrate in clinical practice provides a greater reduction of triglycerides than either drug given alone, but the mechanism for this effect is poorly understood. Apolipoprotein AV (apoAV) has been implicated in triglyceride metabolism. This study was designed to investigate the effect of the combination of statin and fibrate on apoAV and the underlying mechanism(s). Experimental approach: Hypertriglyceridaemia was induced in rats by giving them 10% fructose in drinking water for 2 weeks. They were then treated with atorvastatin, fenofibrate or the two agents combined for 4 weeks, and plasma triglyceride and apoAV measured. We also tested the effects of these two agents on triglycerides and apoAV in HepG2 cells in culture. Western blot and reverse transcription polymerase chain reaction was used to measure apoAV and peroxisome proliferator-activated receptor-α (PPARα) expression. Key results: The combination of atorvastatin and fenofibrate resulted in a greater decrease in plasma triglycerides and a greater increase in plasma and hepatic apoAV than either agent given alone. Hepatic expression of the PPARα was also more extensively up-regulated in rats treated with the combination. A similar, greater increase in apoAV and a greater decrease in triglycerides were observed following treatment of HepG2 cells pre-exposed to fructose), with the combination. Adding an inhibitor of PPARα (MK886) abolished the effects of atorvastatin on HepG2 cells. Conclusions and implications: A combination of atorvastatin and fenofibrate increased apoAV and decreased triglycerides through up-regulation of PPARα. PMID:19694729

  13. Clinical feasibility of exercise-based A-V interval optimization for cardiac resynchronization: a pilot study.

    PubMed

    Choudhuri, Indrajit; MacCarter, Dean; Shaw, Rachael; Anderson, Steve; St Cyr, John; Niazi, Imran

    2014-11-01

    One-third of eligible patients fail to respond to cardiac resynchronization therapy (CRT). Current methods to "optimize" the atrio-ventricular (A-V) interval are performed at rest, which may limit its efficacy during daily activities. We hypothesized that low-intensity cardiopulmonary exercise testing (CPX) could identify the most favorable physiologic combination of specific gas exchange parameters reflecting pulmonary blood flow or cardiac output, stroke volume, and left atrial pressure to guide determination of the optimal A-V interval. We assessed relative feasibility of determining the optimal A-V interval by three methods in 17 patients who underwent optimization of CRT: (1) resting echocardiographic optimization (the Ritter method), (2) resting electrical optimization (intrinsic A-V interval and QRS duration), and (3) during low-intensity, steady-state CPX. Five sequential, incremental A-V intervals were programmed in each method. Assessment of cardiopulmonary stability and potential influence on the CPX-based method were assessed. CPX and determination of a physiological optimal A-V interval was successfully completed in 94.1% of patients, slightly higher than the resting echo-based approach (88.2%). There was a wide variation in the optimal A-V delay determined by each method. There was no observed cardiopulmonary instability or impact of the implant procedure that affected determination of the CPX-based optimized A-V interval. Determining optimized A-V intervals by CPX is feasible. Proposed mechanisms explaining this finding and long-term impact require further study. ©2014 Wiley Periodicals, Inc.

  14. Cardiac resynchronization therapy and AV optimization increase myocardial oxygen consumption, but increase cardiac function more than proportionally.

    PubMed

    Kyriacou, Andreas; Pabari, Punam A; Mayet, Jamil; Peters, Nicholas S; Davies, D Wyn; Lim, P Boon; Lefroy, David; Hughes, Alun D; Kanagaratnam, Prapa; Francis, Darrel P; Whinnett, Zachary I

    2014-02-01

    The mechanoenergetic effects of atrioventricular delay optimization during biventricular pacing ("cardiac resynchronization therapy", CRT) are unknown. Eleven patients with heart failure and left bundle branch block (LBBB) underwent invasive measurements of left ventricular (LV) developed pressure, aortic flow velocity-time-integral (VTI) and myocardial oxygen consumption (MVO2) at 4 pacing states: biventricular pacing (with VV 0 ms) at AVD 40 ms (AV-40), AVD 120 ms (AV-120, a common nominal AV delay), at their pre-identified individualised haemodynamic optimum (AV-Opt); and intrinsic conduction (LBBB). AV-120, relative to LBBB, increased LV developed pressure by a mean of 11(SEM 2)%, p=0.001, and aortic VTI by 11(SEM 3)%, p=0.002, but also increased MVO2 by 11(SEM 5)%, p=0.04. AV-Opt further increased LV developed pressure by a mean of 2(SEM 1)%, p=0.035 and aortic VTI by 4(SEM 1)%, p=0.017. MVO2 trended further up by 7(SEM 5)%, p=0.22. Mechanoenergetics at AV-40 were no different from LBBB. The 4 states lay on a straight line for Δexternal work (ΔLV developed pressure × Δaortic VTI) against ΔMVO2, with slope 1.80, significantly >1 (p=0.02). Biventricular pacing and atrioventricular delay optimization increased external cardiac work done but also myocardial oxygen consumption. Nevertheless, the increase in cardiac work was ~80% greater than the increase in oxygen consumption, signifying an improvement in cardiac mechanoenergetics. Finally, the incremental effect of optimization on external work was approximately one-third beyond that of nominal AV pacing, along the same favourable efficiency trajectory, suggesting that AV delay dominates the biventricular pacing effect - which may therefore not be mainly "resynchronization". © 2013. Published by Elsevier Ireland Ltd. All rights reserved.

  15. Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue.

    PubMed

    Marquié, Marta; Normandin, Marc D; Vanderburg, Charles R; Costantino, Isabel M; Bien, Elizabeth A; Rycyna, Lisa G; Klunk, William E; Mathis, Chester A; Ikonomovic, Milos D; Debnath, Manik L; Vasdev, Neil; Dickerson, Bradford C; Gomperts, Stephen N; Growdon, John H; Johnson, Keith A; Frosch, Matthew P; Hyman, Bradley T; Gómez-Isla, Teresa

    2015-11-01

    To examine region- and substrate-specific autoradiographic and in vitro binding patterns of positron emission tomography tracer [F-18]-AV-1451 (previously known as T807), tailored to allow in vivo detection of paired helical filament-tau-containing lesions, and to determine whether there is off-target binding to other amyloid/non-amyloid proteins. We applied [F-18]-AV-1451 phosphor screen autoradiography, [F-18]-AV-1451 nuclear emulsion autoradiography, and [H-3]-AV-1451 in vitro binding assays to the study of postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau, frontotemporal lobar degeneration-transactive response DNA binding protein 43 (TDP-43), progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy, cerebral amyloid angiopathy and elderly controls free of pathology. Our data suggest that [F-18]-AV-1451 strongly binds to tau lesions primarily made of paired helical filaments in Alzheimer brains (eg, intraneuronal and extraneuronal tangles and dystrophic neurites), but does not seem to bind to a significant extent to neuronal and glial inclusions mainly composed of straight tau filaments in non-Alzheimer tauopathy brains or to lesions containing β-amyloid, α-synuclein, or TDP-43. [F-18]-AV-1451 off-target binding to neuromelanin- and melanin-containing cells and, to a lesser extent, to brain hemorrhagic lesions was identified. Our data suggest that [F-18]-AV-1451 holds promise as a surrogate marker for the detection of brain tau pathology in the form of tangles and paired helical filament-tau-containing neurites in Alzheimer brains but also point to its relatively lower affinity for lesions primarily made of straight tau filaments in non-Alzheimer tauopathy cases and to the existence of some [F-18]-AV-1451 off-target binding. These findings provide important insights for interpreting in vivo patterns of [F-18]-AV-1451 retention

  16. Non-physiological increase of AV conduction time in sinus disease patients programmed in AAIR-based pacing mode.

    PubMed

    Mabo, Philippe; Cebron, Jean-Pierre; Solnon, Aude; Tassin, Aude; Graindorge, Laurence; Gras, Daniel

    2012-11-01

    The EVOCAV(DS) trial aimed to quantify the paradoxal atrioventricular (AV) conduction time lengthening in sinus node (SD) patients (pts) paced in AAIR-based pacing mode. SD pts, implanted with dual-chamber pacemaker programmed in AAIR-based pacing mode, were randomized in two arms for a 1-month period: the low atrial pacing (LAP; basic rate at 60 bpm, dual sensor with minimal slope) and the high atrial pacing (HAP; basic rate at 70 bpm, dual sensor with optimized slope, overdrive pacing) arm. At 1 month, crossover was performed for an additional 1-month period. AV conduction time, AV block occurrence and AV conduction time adaptation during exercise were ascertained from device memories at each follow-up. Seventy-nine pts participated to the analysis (75 ± 8 years; 32 male; PR = 184 ± 38 ms; bundle branch block n = 12; AF history n = 36; antiarrhythmic treatment n = 53; beta-blockers n = 27; class III/Ic n = 18; both n = 8). The mean AV conduction time was significantly greater during the HAP (275 ± 51 ms) vs. LAP (263 ± 49 ms) period (p < 0.0001). Class III/Ic drugs were the only predictors of this abnormal behaviour. Degree II/III AV blocks occurred in 49 % of pts in the HAP vs. 19 % in the LAP period (p < 0.0001). Fifty-two patients (66 %) presented a lengthening of AV conduction time during exercise. AAIR-based pacing in SD pts may induce a significant lengthening of pts' AV conduction time, including frequent abnormal adaptation of AV conduction time during exercise.

  17. Novel method of predicting the optimal atrioventricular delay in patients with complete AV block, normal left ventricular function and an implanted DDD pacemaker.

    PubMed

    Miki, Yuko; Ishikawa, Toshiyuki; Matsushita, Kohei; Yamakawa, Youhei; Matsumoto, Katsumi; Sumita, Shinichi; Uchino, Kazuaki; Kimura, Kazuo; Umemura, Satoshi

    2009-04-01

    The optimal atrioventricular (AV) delay setting is important for achieving optimal AV synchrony in patients with an implanted DDD pacemaker. Using pulsed Doppler echocardiography is the most common method of predicting the optimal AV delay, but it is a complicated and time-consuming method. Therefore, an automatic optimizing function of the AV delay at different atrial rates is desirable for achieving a favorable hemodynamic state. This study aimed to predict the optimal AV delay using phonocardiography. The amplitude of the first heart sound (S1) recorded on the phonocardiogram was measured with different AV delays in 6 patents with complete AV block, normal left ventricular function and an implanted DDD pacemaker. The correlation between the amplitude of S1 and the length of the AV delay was a cubic curve (y=974.15x(3)-23.084x(2)-8.0074x+0.7495, R2=0.9511). The length of the AV delay at the inflection point of the curve showed a significant positive correlation with the optimal AV delay determined by pulsed Doppler echocardiography (R=0.9254, P<0.01). This study demonstrated a novel simple method of predicting the optimal AV delay using phono-cardiography.

  18. Incidence of Dual AV Node Physiology Following Termination of AV Nodal Reentrant Tachycardia by Adenosine-5'-Triphosphate: A Comparison with Drug Administration in Sinus Rhythm

    PubMed Central

    Belhassen, Bernard; Fish, Roman; Viskin, Sami; Glick, Aharon; Glikson, Michael; Eldar, Michael

    2003-01-01

    Administration of adenosine triphosphate (ATP) in sinus rhythm identifies dual atrioventricular node physiology (DAVNP) in 75% of patients with inducible slow / fast AV nodal reentrant tachycardia (AVNRT). The incidence of DAVNP following termination of AVNRT with ATP is unknown. Incremental doses of ATP (10-60mg) were administered, first in sinus rhythm and then during tachycardia induced at electrophysiologic study, to 84 patients with inducible AVNRT and to 18 control patients with inducible AV reentrant tachycardia (AVRT) and no electrophysiologic evidence of DAVNP. Study end-points were the occurrence of DAVNP or ≥ 2nd degree AV block following administration of ATP in sinus rhythm and tachycardia termination following administration of ATP during tachycardia. Of the 82 patients with AVNRT who completed the study, 62 (75.6%) exhibited DAVNP following administration of 17.1 ± 9.4 mg ATP in sinus rhythm, while 30 (36.5%) exhibited DAVNP at the termination of AVNRT following administration of 10.6 ± 2.4 mg ATP. The occurrence of DAVNP following the administration of 10 mg ATP in sinus rhythm.was a good predictor (62%) of its occurrence after termination of AVNRT with ATP. The dose of ATP had a strong correlation between the presence of DAVNP following AVNRT termination and the ATP doses needed for tachycardia termination. Of the 18 control patients, none had DAVNP at ATP test during sinus rhythm but 1 (5.5%) showed slight (60 msec) PR jump after termination of AVRT with ATP. In conclusion, DAVNP is present in a relatively high proportion (36.5%) of patients following termination of AVNRT with ATP but is much less frequent (5.5%) in control patients. Thus, findings at termination of tachycardia by ATP may be useful in the noninvasive diagnosis of the mechanism of a paroxysmal supraventricular tachycardia. PMID:16943985

  19. Performance evaluation and optimization of BM4D-AV denoising algorithm for cone-beam CT images

    NASA Astrophysics Data System (ADS)

    Huang, Kuidong; Tian, Xiaofei; Zhang, Dinghua; Zhang, Hua

    2015-12-01

    The broadening application of cone-beam Computed Tomography (CBCT) in medical diagnostics and nondestructive testing, necessitates advanced denoising algorithms for its 3D images. The block-matching and four dimensional filtering algorithm with adaptive variance (BM4D-AV) is applied to the 3D image denoising in this research. To optimize it, the key filtering parameters of the BM4D-AV algorithm are assessed firstly based on the simulated CBCT images and a table of optimized filtering parameters is obtained. Then, considering the complexity of the noise in realistic CBCT images, possible noise standard deviations in BM4D-AV are evaluated to attain the chosen principle for the realistic denoising. The results of corresponding experiments demonstrate that the BM4D-AV algorithm with optimized parameters presents excellent denosing effect on the realistic 3D CBCT images.

  20. Ixodes ricinus immunogenic saliva protein, homologue to Amblyomma americanum AV422: Determining its potential for use in tick bite confirmation.

    PubMed

    Mihaljica, Darko; Marković, Dragana; Radulović, Željko; Mulenga, Albert; Ćakić, Sanja; Sukara, Ratko; Samardžić, Jelena; Tomanović, Snežana

    2017-03-01

    Tick bites often go unnoticed, so specific reliable tests are needed to confirm them for prompt diagnosis and treatment of tick-borne diseases. One of the promising candidates for developing such a test is AV422, a tick saliva protein that has been conserved across tick genera. In this study, we demonstrate the potential of the AV422 homologue from Ixodes ricinus to be used for tick bite detection for both Prostriata and Metastriata. We expressed recombinant (r) I. ricinus (Ir) AV422 in E. coli and subjected it to Western blot analysis using rat antibodies to saliva proteins of both I. ricinus (Prostriata) and Dermacentor reticulatus (Metastriata) larvae. Our data demonstrate that rIrAV422 specifically bound to antibodies from sera of rats used for both I. ricinus and D. reticulatus larvae feeding, but not to antibodies from control serum, emphasizing its specificity since tick bites were the sole cause of sera reactivity.

  1. The relation between Acid Volatile Sulfides (AVS) and metal accumulation in aquatic invertebrates: implications of feeding behavior and ecology.

    PubMed

    De Jonge, Maarten; Blust, Ronny; Bervoets, Lieven

    2010-05-01

    The present study evaluates the relationship between Acid Volatile Sulfides (AVS) and metal accumulation in invertebrates with different feeding behavior and ecological preferences. Natural sediments, pore water and surface water, together with benthic and epibenthic invertebrates were sampled at 28 Flemish lowland rivers. Different metals as well as metal binding sediment characteristics including AVS were measured and multiple regression was used to study their relationship with accumulated metals in the invertebrates taxa. Bioaccumulation in the benthic taxa was primarily influenced by total metal concentrations in the sediment. Regarding the epibenthic taxa metal accumulation was mostly explained by the more bioavailable metal fractions in both the sediment and the water. AVS concentrations were generally better correlated with metal accumulation in the epibenthic invertebrates, rather than with the benthic taxa. Our results indicated that the relation between AVS and metal accumulation in aquatic invertebrates is highly dependent on feeding behavior and ecology.

  2. 2008 OG19: a highly elongated Trans-Neptunian object

    NASA Astrophysics Data System (ADS)

    Fernández-Valenzuela, E.; Ortiz, J. L.; Duffard, R.; Santos-Sanz, P.; Morales, N.

    2016-03-01

    From two observing runs during the 2014 summer at the Calar Alto Observatory in Almería (Spain) and at the Sierra Nevada Observatory in Granada (Spain), we were able to derive CCD photometry of the Trans-Neptunian object 2008 OG19. We analysed the time series and obtained a double-peaked light curve with a peak-to-valley amplitude of 0.437 ± 0.011 mag and a rotational period of 8.727 ± 0.003 h. This implies that this object is very elongated, closely resembling the case of Varuna. The photometry also allowed us to obtain an absolute magnitude in the R band of 4.39 ± 0.07 mag. From this result, we estimated an equivalent diameter of 2008 OG19 of 619^{+56}_{-113} km using an average albedo for scattered disc objects. Finally, we interpreted the results under the assumption of hydrostatic equilibrium and found a lower limit for the density of 544^{+42}_{-4} kg m-3. However, a more likely density is 609 ± 4 kg m-3 using an aspect angle of 60°, which corresponds to the most likely configuration for the spin axis with respect to the observer assuming random orientations.

  3. AV3V lesions attenuate the cardiovascular responses produced by blood-borne excitatory amino acid analogs

    NASA Technical Reports Server (NTRS)

    Whalen, E. J.; Beltz, T. G.; Lewis, S. J.; Johnson, A. K.

    1999-01-01

    Systemic injections of the excitatory amino acid (EAA) analogs, kainic acid (KA) and N-methyl-D-aspartate (NMDA), produce a pressor response in conscious rats that is caused by a centrally mediated activation of sympathetic drive and the release of arginine vasopressin (AVP). This study tested the hypothesis that the tissue surrounding the anteroventral part of the third ventricle (AV3V) plays a role in the expression of the pressor responses produced by systemically injected EAA analogs. Specifically, we examined whether prior electrolytic ablation of the AV3V region would affect the pressor responses to KA and NMDA (1 mg/kg iv) in conscious rats. The KA-induced pressor response was smaller in AV3V-lesioned than in sham-lesioned rats (11 +/- 2 vs. 29 +/- 2 mmHg; P < 0.05). After ganglion blockade, KA produced a pressor response in sham-lesioned but not AV3V-lesioned rats (+27 +/- 3 vs. +1 +/- 2 mmHg; P < 0.05). The KA-induced pressor response in ganglion-blocked sham-lesioned rats was abolished by a vasopressin V1-receptor antagonist. Similar results were obtained with NMDA. The pressor response to AVP (10 ng/kg iv) was slightly smaller in AV3V-lesioned than in sham-lesioned ganglion-blocked rats (45 +/- 3 vs. 57 +/- 4 mmHg; P < 0.05). This study demonstrates that the pressor responses to systemically injected EAA analogs are smaller in AV3V-lesioned rats. The EAA analogs may produce pressor responses by stimulation of EAA receptors in the AV3V region, or the AV3V region may play an important role in the expression of these responses.

  4. Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies.

    PubMed

    Ono, Maiko; Sahara, Naruhiko; Kumata, Katsushi; Ji, Bin; Ni, Ruiqing; Koga, Shunsuke; Dickson, Dennis W; Trojanowski, John Q; Lee, Virginia M-Y; Yoshida, Mari; Hozumi, Isao; Yoshiyama, Yasumasa; van Swieten, John C; Nordberg, Agneta; Suhara, Tetsuya; Zhang, Ming-Rong; Higuchi, Makoto

    2017-03-01

    Diverse neurodegenerative disorders are characterized by deposition of tau fibrils composed of conformers (i.e. strains) unique to each illness. The development of tau imaging agents has enabled visualization of tau lesions in tauopathy patients, but the modes of their binding to different tau strains remain elusive. Here we compared binding of tau positron emission tomography ligands, PBB3 and AV-1451, by fluorescence, autoradiography and homogenate binding assays with homologous and heterologous blockades using tauopathy brain samples. Fluorescence microscopy demonstrated intense labelling of non-ghost and ghost tangles with PBB3 and AV-1451, while dystrophic neurites were more clearly detected by PBB3 in brains of Alzheimer's disease and diffuse neurofibrillary tangles with calcification, characterized by accumulation of all six tau isoforms. Correspondingly, partially distinct distributions of autoradiographic labelling of Alzheimer's disease slices with 11C-PBB3 and 18F-AV-1451 were noted. Neuronal and glial tau lesions comprised of 4-repeat isoforms in brains of progressive supranuclear palsy, corticobasal degeneration and familial tauopathy due to N279K tau mutation and 3-repeat isoforms in brains of Pick's disease and familial tauopathy due to G272V tau mutation were sensitively detected by PBB3 fluorescence in contrast to very weak AV-1451 signals. This was in line with moderate 11C-PBB3 versus faint 18F-AV-1451 autoradiographic labelling of these tissues. Radioligand binding to brain homogenates revealed multiple binding components with differential affinities for 11C-PBB3 and 18F-AV-1451, and higher availability of binding sites on progressive supranuclear palsy tau deposits for 11C-PBB3 than 18F-AV-1451. Our data indicate distinct selectivity of PBB3 compared to AV-1451 for diverse tau fibril strains. This highlights the more robust ability of PBB3 to capture wide-range tau pathologies.

  5. Apolipoprotein AV accelerates plasma hydrolysis of triglyceride-rich lipoproteins by interaction with proteoglycan-bound lipoprotein lipase.

    PubMed

    Merkel, Martin; Loeffler, Britta; Kluger, Malte; Fabig, Nathalie; Geppert, Gesa; Pennacchio, Len A; Laatsch, Alexander; Heeren, Joerg

    2005-06-03

    Apolipoprotein A5 (APOA5) is associated with differences in triglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasma triglycerides. To elucidate the mechanism by which apoAV influences plasma triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In human APOA5 transgenic mice (hAPOA5tr), catabolism of chylomicrons and very low density lipoprotein (VLDL) was accelerated due to a faster plasma hydrolysis of triglycerides by lipoprotein lipase (LPL). Hepatic VLDL and intestinal chylomicron production were not affected. The functional interplay between apoAV and LPL was further investigated by cross-breeding a human LPL transgene with the apoa5 knock-out and the hAPOA5tr to an lpl-deficient background. Increased LPL activity completely normalized hypertriglyceridemia of apoa5-deficient mice; however, overexpression of human apoAV modulated triglyceride levels only slightly when LPL was reduced. To reflect the physiological situation in which LPL is bound to cell surface proteoglycans, we examined hydrolysis in the presence or absence of proteoglycans. Without proteoglycans, apoAV derived either from triglyceride-rich lipoproteins, hAPOA5tr high density lipoprotein, or a recombinant source did not alter the LPL hydrolysis rate. In the presence of proteoglycans, however, apoAV led to a significant and dose-dependent increase in LPL-mediated hydrolysis of VLDL triglycerides. These results were confirmed in cell culture using a proteoglycan-deficient cell line. A direct interaction between LPL and apoAV was found by ligand blotting. It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycan-bound LPL for lipolysis.

  6. Apolipoprotein AV Accelerates Plasma Hydrolysis OfTriglyceride-Rich Lipoproteins By Interaction With Proteoglycan BoundLipoprotein Lipase

    SciTech Connect

    Merkel, Martin; Loeffler, Britta; Kluger, Malte; Fabig, Nathalie; Geppert, Gesa; Pennacchio, Len A.; Laatsch, Alexander; Heeren, Joerg

    2005-02-22

    Apolipoprotein A5 (APOA5) is associated with differences intriglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasmatriglycerides. To elucidate the mechanism by which apoAV influences plasma triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In hAPOA5 transgenic mice(hAPOA5tr), catabolism of chylomicrons and VLDL was accelerated due to a faster plasma hydrolysis of triglycerides by lipoprotein lipase (LPL).Hepatic VLDL and intestinal chylomicron production were not affected. The functional interplay between apoAV and LPL was further investigated by crossbreeding a human LPL transgene with the apoa5 knockout, and the hAPOA5tr to an LPL deficient background. Increased LPL activity completely normalized hypertriglyceridemia of apoa5 deficient mice,however, over expression of human apoAV modulated triglyceride levels only slightly when LPL was reduced. To reflect the physiological situation in which LPL is bound to cell surface proteoglycans, we examined hydrolysis in the presence or absence of proteoglycans. Without proteoglycans, apoAV derived either from triglyceride-rich lipoproteins, hAPOA5tr HDL, or a recombinant source did not alter the LPL hydrolysis rate. In the presence of proteoglycans, however, apoAV led to a significant and dose-dependent increase in LPL mediated hydrolysis of VLDL triglycerides. These results were confirmed in cell culture using a proteoglycan-deficient cell line.A direct interaction between LPL and apoAV was found by ligand blotting.It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycans bound LPL for lipolysis.

  7. Molecular characterization of LvAV in response to white spot syndrome virus infection in the Pacific white shrimp (Litopenaeus vannamei).

    PubMed

    He, Shulin; Song, Lei; Qian, Zhaoying; Hou, Fujun; Liu, Yongjie; Wang, Xianzong; Peng, Zhangming; Sun, Chengbo; Liu, Xiaolin

    2015-07-01

    Litopenaeus vannamei is the most important farmed shrimp species globally, but its production is affected by several factors, including infectious disease. White spot syndrome virus (WSSV), in particular, causes significant shrimp losses. To understand the shrimp's immune response against WSSV, we cloned LvAV from L. vannamei and analyzed its expression pattern in different tissues, in addition to its expression following infection. We employed dsRNA and recombinant (r)LvAV to explore the potential role of LvAV in shrimp immunity when infected with WSSV. We find that LvAV is a C-type Lectin composed of 176 amino acids with a signal peptide and a specific C-type Lectin-type domain (CTLD). It shares 81% amino acid similarity with PmAV, an antiviral-like C-type Lectin from Penaeus monodom, and it is highly expressed in the hepatopancreas. Its expression is affected by infection with both WSSV and V. parahaemolyticus. Significantly, injection with rLvAV slowed WSSV replication, while injection with LvAV dsRNA initially led to enhanced virus propagation. Surprisingly, LvAV dsRNA subsequently led to a dramatic decrease in viral load in the later stages of infection, suggesting that LvAV may be subverted by WSSV to enhance viral replication or immune avoidance. Our results indicate that LvAV plays an important, but potentially complex role in the Pacific white shrimp's immune defense.

  8. Integrating computation and visualization for biomolecular analysis: an example using python and AVS.

    PubMed

    Sanner, M F; Duncan, B S; Carrillo, C J; Olson, A J

    1999-01-01

    One of the challenges in biocomputing is to enable the efficient use of a wide variety of fast-evolving computational methods to simulate, analyze, and understand the complex properties and interactions of molecular systems. Our laboratory investigates several areas including molecular visualization, protein-ligand docking, protein-protein docking, molecular surfaces, and the derivation of phenomenological potentials. In this paper we present an approach based on the Python programming language to achieve a high level of integration between these different computational methods and our primary visualization system AVS. This approach removes many limitations of AVS while increasing dramatically the inter-operability of our computational tools. Several examples are shown to illustrate how this approach enables a high level of integration and inter-operability between different tools, while retaining modularity and avoiding the creation of a large monolithic package that is difficult to extend and maintain.

  9. Patterns of spatial genetic structuring in a hydropsychid caddisfly (Cheumatopsyche sp. AV1) from southeastern Australia.

    PubMed

    Baker, A M; Williams, S A; Hughes, J M

    2003-12-01

    We assessed levels of mitochondrial genetic spatial structuring in the hydropsychid caddisfly Cheumatopsyche sp. AV1 in southeastern New South Wales, Australia. No significant spatial structuring was detected within or between catchments using analysis of molecular variance, and nested clade contingency analysis suggested no strong relationship between haplotypes and geographical location, at any clade level. However, tests for association among haplotypes incorporating geographical distance in the nested clade analysis, revealed patterns of historical range expansion and recent restricted gene flow. Most likely, population fragmentation preceded range expansion, although subsequent recontact and gene flow among the previously sundered populations has apparently obscured the geographical signature of the former fragmentation. Taken together, our analyses suggest that a number of populations fragmented during the Pleistocene evolved in isolation for a time and subsequently expanded into secondary contact. Since expansion, there has apparently been substantial (albeit somewhat restricted) dispersal and gene flow of adult female Cheumatopsyche sp. AV1, throughout the study area.

  10. 18F-AV-1451 PET Imaging in Three Patients with Probable Cerebral Amyloid Angiopathy.

    PubMed

    Kim, Hee Jin; Cho, Hanna; Werring, David J; Jang, Young Kyoung; Kim, Yeo Jin; Lee, Jin San; Lee, Juyoun; Jun, Soomin; Park, Seongbeom; Ryu, Young Hoon; Choi, Jae Yong; Cho, Young Seok; Moon, Seung Hwan; Na, Duk L; Lyoo, Chul Hyoung; Seo, Sang Won

    2017-03-06

    Cerebrovascular deposition of amyloid-β, known as cerebral amyloid angiopathy (CAA), is associated with MRI findings of lobar hemorrhage, cerebral microbleeds, and cortical superficial siderosis. Although pathological studies suggest that tau may co-localize with vascular amyloid, this has not yet been investigated in CAA in vivo. Three patients with probable CAA underwent 11C-Pittsburgh Compound B (PiB) PET or 18F-florbetaben PET to evaluate amyloid burden, and 18F-AV-1451 PET to evaluate paired helical filament tau burden. Regions that had cerebral microbleeds or cortical superficial siderosis largely overlapped with those showing increased 18F-AV-1451 and increased 11C-PiB uptake. Our preliminary study raised the possibility that lobar cerebral microbleeds, and cortical superficial siderosis, which are characteristic markers of vascular amyloid, may be associated with local production of paired helical filament tau.

  11. [AV-reentrant tachycardia and Wolff-Parkinson-White syndrome : Diagnosis and treatment].

    PubMed

    Voss, Frederik; Eckardt, Lars; Busch, Sonia; Estner, Heidi L; Steven, Daniel; Sommer, Philipp; von Bary, Christian; Neuberger, Hans-Ruprecht

    2016-12-01

    The AV-reentrant tachycardia (AVRT) is a supraventricular tachycardia with an incidence of 1-3/1000. The pathophysiological basis is an accessory atrioventricular pathway (AP). Patients with AVRT typically present with palpitations, an on-off characteristic, anxiety, dyspnea, and polyuria. This type of tachycardia may often be terminated by vagal maneuvers. Although the clinical presentation of AVRT is quite similar to AV-nodal reentrant tachycardias, the correct diagnosis is often facilitated by analyzing a standard 12-lead ECG at normal heart rate showing ventricular preexcitation. Curative catheter ablation of the AP represents the therapy of choice in symptomatic patients. This article is the fourth part of a series written to improve the professional education of young electrophysiologists. It explains pathophysiology, symptoms, and electrophysiological findings of an invasive EP study. It focusses on mapping and ablation of accessory pathways.

  12. Characterization of the Cryptic AV3 Promoter of Ageratum Yellow Vein Virus in Prokaryotic and Eukaryotic Systems

    PubMed Central

    Wang, Wei-Chen; Wu, Chia-Ying; Lai, Yi-Chin; Lin, Na-Sheng; Hsu, Yau-Heiu; Hu, Chung-Chi

    2014-01-01

    A cryptic prokaryotic promoter, designated AV3 promoter, has been previously identified in certain begomovirus genus, including ageratum yellow vein virus isolate NT (AYVV-NT). In this study, we demonstrated that the core nucleotides in the putative −10 and −35 boxes are necessary but not sufficient for promoter activity in Escherichia coli, and showed that AYVV-NT AV3 promoter could specifically interact with single-stranded DNA-binding protein and sigma 70 of E. coli involved in transcription. Several AYVV-NT-encoded proteins were found to increase the activity of AV3 promoter. The transcription start sites downstream to AV3 promoter were mapped to nucleotide positions 803 or 805 in E. coli, and 856 in Nicotiana benthamiana. The eukaryotic activity of AV3 promoter and the translatability of a short downstream open reading frame were further confirmed by using a green fluorescent protein reporter construct in yeast (Saccharomyces cerevisiae) cells. These results suggested that AV3 promoter might be a remnant of evolution that retained cryptic activity at present. PMID:25268755

  13. (18)F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer's disease.

    PubMed

    Mattsson, Niklas; Schöll, Michael; Strandberg, Olof; Smith, Ruben; Palmqvist, Sebastian; Insel, Philip S; Hägerström, Douglas; Ohlsson, Tomas; Zetterberg, Henrik; Jögi, Jonas; Blennow, Kaj; Hansson, Oskar

    2017-09-01

    To elucidate the relationship between cerebrospinal fluid (CSF) total-tau (T-tau) and phosphorylated tau (P-tau) with the tau PET ligand (18)F-AV-1451 in Alzheimer's disease (AD), we examined 30 cognitively healthy elderly (15 with preclinical AD), 14 prodromal AD, and 39 AD dementia patients. CSF T-tau and P-tau were highly correlated (R = 0.92, P < 0.001), but they were only moderately associated with retention of (18)F-AV-1451, and mainly in demented AD patients. (18)F-AV-1451, but not CSF T-tau or P-tau, was strongly associated with atrophy and cognitive impairment. CSF tau was increased in preclinical AD, despite normal (18)F-AV-1451 retention. However, not all dementia AD patients exhibited increased CSF tau, even though (18)F-AV-1451 retention was always increased at this disease stage. We conclude that CSF T-tau and P-tau mainly behave as biomarkers of "disease state", since they appear to be increased in many cases of AD at all disease stages, already before the emergence of tau aggregates. In contrast, (18)F-AV-1451 is a biomarker of "disease stage", since it is increased in clinical stages of the disease, and is associated with brain atrophy and cognitive decline. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

  14. "Off-Target" (18)F-AV-1451 Binding in the Basal Ganglia Correlates with Age-Related Iron Accumulation.

    PubMed

    Choi, Jae Yong; Cho, Hanna; Ahn, Sung Jun; Lee, Jae Hoon; Ryu, Young Hoon; Lee, Myung Sik; Lyoo, Chul Hyoung

    2017-08-03

    Backgrounds: "Off-target" binding in the basal ganglia is commonly observed in the (18)F-AV-1451 positron emission tomography (PET) studies of the elderly. We sought to investigate the relationship between this phenomenon in the basal ganglia and iron accumulation using iron-sensitive R2(*) magnetic resonance (MR) imaging. Methods: 59 healthy controls and 61 patients with Alzheimer's disease and mild cognitive impairment (AD/MCI) underwent (18)F-AV-1451 PET and R2(*) MR imaging studies. A correlation analysis was performed for age, (18)F-AV-1451 binding, and R2(*) values. Results: There was an age-related increase in both (18)F-AV-1451 binding in the basal ganglia and R2(*) values in the putamen in both the controls and AD/MCI patients. (18)F-AV-1451 binding in the basal ganglia increased with R2(*) values. Conclusion: "Off-target" (18)F-AV-1451 binding in the basal ganglia is associated with the age-related increases in iron accumulation. Postmortem studies are required to further investigate the nature of this association. Copyright © 2017 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  15. Tissue and cell tropism of Indian cassava mosaic virus (ICMV) and its AV2 (precoat) gene product

    SciTech Connect

    Rothenstein, Dirk; Krenz, Bjoern; Selchow, Olaf; Jeske, Holger . E-mail: holger.jeske@bio.uni-stuttgart.de

    2007-03-01

    In order to establish defined viruses for challenging plants in resistance breeding programmes, Indian cassava mosaic virus (ICMV; family Geminiviridae) DNA clones were modified to monitor viral spread in plants by replacing the coat protein gene with the green fluorescent protein (GFP) reporter gene. Comparative in situ hybridization experiments showed that ICMV was restricted to the phloem in cassava and tobacco. GFP-tagged virus spread similarly, resulting in homogeneous fluorescence within nuclei and cytoplasm of infected cells. To analyze viral intercellular transport in further detail, GFP was fused to AV2, a protein that has been implicated in viral movement. Expressed from replicating viruses or from plasmids, AV2:GFP became associated with the cell periphery in punctate spots, formed cytoplasmic as well as nuclear inclusion bodies, the latter as conspicuous paired globules. Upon particle bombardment of expression plasmids, AV2:GFP was transported into neighboring cells of epidermal tissues showing that the intercellular transport of the AV2 protein is not restricted to the phloem. The results are consistent with a redundant function of ICMV AV2 acting as a movement protein, presumably as an evolutionary relic of a monopartite geminivirus that may still increase virus fitness but is no longer necessary in a bipartite genome. The fusion of ICMV ORF AV2 to the GFP gene is the first example of a reporter construct that follows the whole track of viral DNA from inside the nucleus to the cell periphery and to the next cell.

  16. Investigation of Aeroelastic Flow Control of a Fluttering Wing with HPCMP CREATE(trademark)-AV Kestrel

    DTIC Science & Technology

    2015-01-05

    The aeroelastic behavior of a finite aspect ratio (AR=6) NACA0018 wing is computationally analyzed. HPCMP CREATE(trademark)-AV Kestrel, a fully... aeroelastically deforming wing. Externally controlled blowing slots distributed along the span of the wing are used to inject mass into the flow field to...coefficients. For the rigid wing, the lift is increased, as are the pitching and rolling moments. When aeroelastic deformation is considered, the

  17. Design of the Dialysis Access Consortium (DAC) Clopidogrel Prevention of Early AV Fistula Thrombosis Trial.

    PubMed

    Dember, Laura M; Kaufman, James S; Beck, Gerald J; Dixon, Bradley S; Gassman, Jennifer J; Greene, Tom; Himmelfarb, Jonathan; Hunsicker, Lawrence G; Kusek, John W; Lawson, Jeffrey H; Middleton, John P; Radeva, Milena; Schwab, Steve J; Whiting, James F; Feldman, Harold I

    2005-01-01

    The Dialysis Access Consortium (DAC) was developed to investigate interventions to improve hemodialysis vascular access outcomes. The autogenous arteriovenous fistula created by direct connection of native artery to vein is the recommended vascular access for hemodialysis. However, it fails frequently due to clotting after surgery. The DAC Early AV Fistula Thrombosis Trial tests the hypothesis that clopidogrel can prevent early fistula failure and increase the number of fistulas that ultimately become usable for hemodialysis access. This is one of two initial and concurrent trials being performed by the DAC. The companion trial investigates pharmacologic approaches to prevent venous stenosis leading to AV graft failure. This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1,284 patients over four years. Patients undergoing creation of a new native arteriovenous (AV) fistula are randomized to treatment with clopidogrel or placebo for six weeks following fistula creation surgery. The primary outcome is fistula patency at six weeks. The major secondary outcome is fistula suitability for dialysis. This paper examines key aspects of this study that have broad relevance to trial design including: 1) the selection of an intermediate event as the primary outcome, 2) timing of the intervention to balance efficacy and safety concerns, 3) ethical considerations arising from required modifications of concomitant drug therapy, and 4) choosing an efficacy or effectiveness evaluation of the intervention. This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent early AV fistula failure and promote more usable fistulas for hemodialysis. The methodologic challenges identified and addressed during the development of this trial should help to inform the design of future vascular access trials, and are relevant to clinical trials addressing a wide range of questions.

  18. A.V. Usova's Contribution to the Field of Concept Learning in Physics Classroom

    ERIC Educational Resources Information Center

    Yavoruk, Oleg

    2015-01-01

    A.V. Usova (1921-2014) has always been one of the leading figures in Russian physics education. Her theory of physics concept formation was formulated during the 1970s and the 1980s and directly influenced the process of physics education in the 20th and the 21st century. Over the years there have been a lot of theories of concept formation. Her…

  19. Prospective evaluation of parenteral magnesium sulfate in the treatment of patients with reentrant AV supraventricular tachycardia.

    PubMed

    Sager, P T; Widerhorn, J; Petersen, R; Leon, C; Ryzen, E; Rude, R; Rahimtoola, S H; Bhandari, A K

    1990-02-01

    This study prospectively assessed the electrophysiologic effects of parenteral magnesium sulfate administration on paroxysmal atrioventricular (AV) reentrant supraventricular tachycardia and the efficacy of magnesium to terminate these arrhythmias. Eleven normomagnesemic patients, seven with orthodromic reentrant supraventricular tachycardia that used an accessory AV pathway, and four with typical AV nodal reentry were examined. All patients had a history of sustained supraventricular tachycardia requiring pharmacologic therapy or electrical cardioversion for termination of tachycardia. After baseline electrophysiologic study, including documentation of sustained supraventricular tachycardia that was reproducibly induced, parenteral magnesium sulfate (a bolus of 0.3 mEq/kg of elemental magnesium infused over a 10-minute period followed by a maintenance infusion of 0.2 mEq/kg/hr) was administered during sustained supraventricular tachycardia. The serum magnesium concentration increased from (mean +/- standard deviation) 1.9 +/- 0.2 mg/dl to 4.0 +/- 0.6 mg/dl (p = 0.0001). Except for flushing and mild diaphoresis during infusion of the magnesium sulfate bolus, and dry heaves in one patient, there were no untoward effects or significant changes in systolic blood pressure. During administration of magnesium, the tachycardia cycle length increased from 319 +/- 39 msec to 348 +/- 43 msec (p = 0.0001). Slowing of the tachycardia occurred predominantly in the antegrade limb of the circuit at the level of the AV node with the AH interval increasing from 171 +/- 66 msec to 197 +/- 68 msec (p = 0.0001), whereas there was no significant change in the HV interval (43 +/- 3 msec to 43 +/- 4 msec, p = NS) or the VA interval (106 +/- 43 msec to 110 +/- 47 msec, p = NS) during tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. BPhyOG: an interactive server for genome-wide inference of bacterial phylogenies based on overlapping genes.

    PubMed

    Luo, Yingqin; Fu, Cong; Zhang, Da-Yong; Lin, Kui

    2007-07-25

    Overlapping genes (OGs) in bacterial genomes are pairs of adjacent genes of which the coding sequences overlap partly or entirely. With the rapid accumulation of sequence data, many OGs in bacterial genomes have now been identified. Indeed, these might prove a consistent feature across all microbial genomes. Our previous work suggests that OGs can be considered as robust markers at the whole genome level for the construction of phylogenies. An online, interactive web server for inferring phylogenies is needed for biologists to analyze phylogenetic relationships among a set of bacterial genomes of interest. BPhyOG is an online interactive server for reconstructing the phylogenies of completely sequenced bacterial genomes on the basis of their shared overlapping genes. It provides two tree-reconstruction methods: Neighbor Joining (NJ) and Unweighted Pair-Group Method using Arithmetic averages (UPGMA). Users can apply the desired method to generate phylogenetic trees, which are based on an evolutionary distance matrix for the selected genomes. The distance between two genomes is defined by the normalized number of their shared OG pairs. BPhyOG also allows users to browse the OGs that were used to infer the phylogenetic relationships. It provides detailed annotation for each OG pair and the features of the component genes through hyperlinks. Users can also retrieve each of the homologous OG pairs that have been determined among 177 genomes. It is a useful tool for analyzing the tree of life and overlapping genes from a genomic standpoint. BPhyOG is a useful interactive web server for genome-wide inference of any potential evolutionary relationship among the genomes selected by users. It currently includes 177 completely sequenced bacterial genomes containing 79,855 OG pairs, the annotation and homologous OG pairs of which are integrated comprehensively. The reliability of phylogenies complemented by annotations make BPhyOG a powerful web server for genomic and genetic

  1. Successful catheter ablation of a slow AV-nodal pathway from the left posteroseptal region.

    PubMed

    Wieczorek, M; Höltgen, R; Djajadisastra, I

    2005-08-01

    We present the case of a 44 year old woman with recurrent episodes of supraventricular tachycardia due to AV-nodal reentry (AVNRT). She was refractory to conventional medical treatment and referred to our hospital with the view to catheter ablation of the slow AV-nodal pathway. AVNRT of the common type was easily induced performing stimulation from the high right atrium and proximal coronary sinus. Other forms of supraventricular tachycardia were definitely ruled out during further electrophysiologic study. Repetitive RF applications around the right posteroseptal region failed to cure the tachycardia which remained inducible with a typical jump in the AH interval. Extensive RF applications from posteroinferior to the midseptum including the area of the proximal coronary sinus and its os were ineffective as well.AVNRT was transiently but reproducibly eliminated while burns were applied to the high midseptum but AVNRT reoccured within 20 minutes. Finally after retrograde passage of the aortic valve with a 4 mm tip ablation catheter, RF was applied to the left postero to midseptal region. An accelerated junctional rhythm was immediately observed and AVNRT remained non-inducible from that time onwards. It is concluded that an atypical posterior extension of the AV node with predominant leftatrial course might be responsible for this unusual success of slow pathway elimination from left posteroseptal.

  2. British randomised controlled trial of AV and VV optimization ("BRAVO") study: rationale, design, and endpoints.

    PubMed

    Whinnett, Zachary I; Sohaib, S M Afzal; Jones, Siana; Kyriacou, Andreas; March, Katherine; Coady, Emma; Mayet, Jamil; Hughes, Alun D; Frenneaux, Michael; Francis, Darrel P

    2014-04-03

    Echocardiographic optimization of pacemaker settings is the current standard of care for patients treated with cardiac resynchronization therapy. However, the process requires considerable time of expert staff. The BRAVO study is a non-inferiority trial comparing echocardiographic optimization of atrioventricular (AV) and interventricular (VV) delay with an alternative method using non-invasive blood pressure monitoring that can be automated to consume less staff resources. BRAVO is a multi-centre, randomized, cross-over, non-inferiority trial of 400 patients with a previously implanted cardiac resynchronization device. Patients are randomly allocated to six months in each arm. In the echocardiographic arm, AV delay is optimized using the iterative method and VV delay by maximizing LVOT VTI. In the haemodynamic arm AV and VV delay are optimized using non-invasive blood pressure measured using finger photoplethysmography. At the end of each six month arm, patients undergo the primary outcome measure of objective exercise capacity, quantified as peak oxygen uptake (VO2) on a cardiopulmonary exercise test. Secondary outcome measures are echocardiographic measurement of left ventricular remodelling, quality of life score and N-terminal pro B-type Natriuretic Peptide (NT-pro BNP). The study is scheduled to complete recruitment in December 2013 and to complete follow up in December 2014. If exercise capacity is non-inferior with haemodynamic optimization compared with echocardiographic optimization, it would be proof of concept that haemodynamic optimization is an acceptable alternative which has the potential to be more easily implemented. Clinicaltrials.gov NCT01258829.

  3. Characterisation of human AV-nodal properties using a network model.

    PubMed

    Wallman, Mikael; Sandberg, Frida

    2017-07-13

    Characterisation of the AV-node is an important step in determining the optimal form of treatment for supraventricular tachycardias. To integrate and analyse patient-specific measurements, mathematical modelling has emerged as a valuable tool. Here we present a model of the human AV-node, consisting of a series of interacting nodes, each with separate dynamics in refractory time and conduction delay. The model is evaluated in several scenarios, including atrial fibrillation (AF) and clinical pacing, using simulated and measured data. The model is able to replicate signals derived from clinical ECG data as well as from invasive measurements, both under AF and pacing. To quantify the uncertainty in parameter estimation, 1000 parameter sets were sampled, showing that model output similar to data corresponds to limited regions in the model parameter space. The model is the first human AV-node model to capture both spatial and temporal dynamics while being efficient enough to allow interactive use on clinical timescales, as well as parameter estimation and uncertainty quantification. As such, it fills a new niche in the current set of published models and forms a valuable tool for both understanding and clinical research.

  4. CORONAS-F/AVS-F Observations of Terrestrial Gamma-ray Flashes

    NASA Astrophysics Data System (ADS)

    Arkhangelskaja, I.

    2005-12-01

    Terrestrial gamma ray flashes (TGFs) were first detected by BATSE experiment onboard CGRO satellite. Whole BATSE database contains 78 TGF but it is possible to define duration only for 65 ones. We have analyze all BATSE TGF temporal profile and obtain that these duration is in region from 0.01 to 20 ms. TGFs are produced in a process of bremsstrahlung of the runaway electrons in the middle atmosphere which are accelerated upward by the thundercloud electric field and collide with the material constituting the atmosphere. These electrons are very energetic (E near 1 MeV) and the gamma radiation pattern is directed along the beam. The AVS-F (amplitude-time Sun spectrometry) apparatus is intended to study characteristics of fluxes of hard X-rays, gamma-rays and neutrons from the Sun and solar flares and to detect and record events like gamma-ray bursts. The experiment is carry out at the CORONAS-F special-purpose automatic station (NORAD catalog number 26873, International Designator 2001-032A) that had been launched from Russian kosmodrom Plesetsk at 11:00 UT of 31 July 2001 into a circular orbit oriented towards the Sun with inclination 82.5 degrees and altitude near 500 km. The AVS-F apparatus uses signals produced by the SONG-D detector (based on the CsI(Tl) crystal of 20 cm and height of 10 cm, energy deposition ranges of 0.1 to 17.0 MeV and and 4.0 to 94.0 MeV by up to date calibration data), XSS-1 detector (the semiconductor detector with 3-30 keV energy deposition range) and the anticoincidence signal generated by the plastic scintillation counter of SONG-D. The basic time resolution of AVS-F apparatus is 16 sec in the bands of X-ray and low-energy gamma-emission registration and 128 sec for high- energy gamma-band. But AVS-F apparatus also allow to obtain event temporal profile with 1 ms time resolution in the low energy gamma-band. Using data of this type we have separated several short events with duration 1 to 16 ms in AVS-F database. These short events

  5. Phase 1 Trial of Subcutaneous rAvPAL-PEG in Subjects with Phenylketonuria

    PubMed Central

    Longo, Nicola; Harding, Cary O.; Burton, Barbara K.; Grange, Dorothy K.; Vockley, Jerry; Wasserstein, Melissa; Rice, Gregory M.; Musson, Donald G.; Gu, Zhonghua; Sile, Saba

    2014-01-01

    Objective Phenylketonuria is an inherited disease caused by impaired activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, leading to accumulation of phenylalanine and subsequent neurocognitive dysfunction. A phenylalanine-restricted diet initiated early in life can ameliorate the toxic effects of phenylalanine. However, the diet is onerous and compliance is extremely difficult. Phenylalanine ammonia lyase (PAL) is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. This Phase 1, multicenter clinical trial evaluated the safety, tolerability, pharmacokinetics and efficacy of rAvPAL-PEG (recombinant Anabaena variabilis PAL produced in E. coli conjugated with polyethylene glycol [PEG] to reduce immunogenicity) in reducing phenylalanine levels in subjects with phenylketonuria. Methods Single subcutaneous injections of rAvPAL-PEG in escalating doses (0·001, 0·003, 0·01, 0·03, and 0·1 mg/kg) were administered to 25 adults with phenylketonuria recruited from those attending metabolic clinics in North America whose blood phenylalanine concentrations were ≥600 μmol/L. Results The most frequently reported adverse events were injection-site reactions and dizziness. Reactions were self-limited without sequelae. During the trial, two subjects had adverse reactions to intramuscular (IM) medroxyprogesterone acetate, a drug containing polyethylene glycol as an excipient. Three subjects developed a generalized skin rash at the highest rAvPAL-PEG dose (0·1 mg/kg). Drug levels peaked ∼5 days after the injection. Treatment was effective in reducing blood phenylalanine in all five subjects receiving the highest dose (0·1 mg/kg, mean percent change of -58 from baseline), with a nadir ∼6 days after injection and inverse correlation between drug and phenylalanine concentrations in plasma. Phenylalanine concentrations returned to near-baseline levels ∼20 days after the single injection. Conclusions

  6. DNA-binding studies of AV-153, an antimutagenic and DNA repair-stimulating derivative of 1,4-dihydropiridine.

    PubMed

    Buraka, E; Chen, C Yu-Chian; Gavare, M; Grube, M; Makarenkova, G; Nikolajeva, V; Bisenieks, I; Brūvere, I; Bisenieks, E; Duburs, G; Sjakste, N

    2014-09-05

    The ability to intercalate between DNA strands determines the cytotoxic activity of numerous anticancer drugs. Strikingly, intercalating activity was also reported for some compounds considered to be antimutagenic. The aim of this study was to determine the mode of interaction of DNA with the antimutagenic and DNA repair-stimulating dihydropyridine (DHP) AV-153. DNA and AV-153 interactions were studied by means of UV/VIS spectroscopy, fluorimetry and infrared spectroscopy. Compound AV-153 is a 1,4 dihydropyridine with ethoxycarbonyl groups in positions 3 and 5. Computer modeling of AV-153 and DNA interactions suggested an ability of the compound to dock between DNA strands at a single strand break site in the vicinity of two pyrimidines, which was confirmed in the present study. AV-153 evidently interacted with DNA, as addition of DNA to AV-153 solutions resulted in pronounced hyperchromic and bathochromic effects on the spectra. Base modification in a plasmid by peroxynitrite only minimally changed binding affinity of the compound; however, induction of single-strand breaks using Fenton's reaction greatly increased binding affinity. The affinity did not change when the ionic strength of the solution was changed from 5 to 150 mM NaCl, although it increased somewhat at 300 mM. Neither was it influenced by temperature changes from 25 to 40°C, however, it decreased when the pH of the solution was changed from 7.4 to 4.7. AV-153 competed with EBr for intercalation sites in DNA: 116 mM of the compound caused a two-fold decrease in fluorescence intensity. FT-IR spectral data analyses indicated formation of complexes between DNA and AV-153. The second derivative spectra analyses indicated interaction of AV-153 with guanine, cytosine and thymine bases, but no interaction with adenine was detected. The antimutagenic substance AV-153 appears to intercalate between the DNA strands at the site of a DNA nick in the vicinity of two pyrimidines. Copyright © 2014 Elsevier

  7. Construction of Recombinant Pichia pastoris Carrying a Constitutive AvBD9 Gene and Analysis of Its Activity.

    PubMed

    Tu, Jian; Qi, Kezong; Xue, Ting; Wei, Haiting; Zhang, Yongzheng; Wu, Yanli; Zhou, Xiuhong; Lv, Xiaolong

    2015-12-28

    Avian beta-defensin 9 (AvBD9) is a small cationic peptide consisting of 41 amino acids that plays a crucial rule in innate immunity and acquired immunity in chickens. Owing to its wide antibacterial spectrum, lack of a residue, and failure to induce bacterial drug resistance, AvBD9 is expected to become a substitute for conventional antibiotics in the livestock and poultry industries. Using the preferred codon of Pichia pastoris, the mature AvBD9 peptide was designed and synthesized, based on the sequence from GenBank. The P. pastoris constitutive expression vector pGHKα was used to construct a pGHKα-AvBD9 recombinant plasmid. Restriction enzyme digestion was performed using SacI and BglII to remove the ampicillin resistance gene, and the plasmid was electrotransformed into P. pastoris GS115. High-expression strains with G418 resistance were screened, and the culture supernatant was analyzed by Tricine-SDS-PAGE and western blot assay to identify target bands of about 6 kDa. A concentrate of the supernatant containing AvBD9 was used for determination of antimicrobial activity. The supernatant concentrate was effective against Escherichia coli, Salmonella paratyphi, Salmonella pullorum, Pseudomonas aeruginosa, Enterococcus faecalis, and Enterobacter cloacae. The fermentation product of P. pastoris carrying the recombinant AvBD9 plasmid was adjusted to 1.0 × 10(8) CFU/ml and added to the drinking water of white feather broilers at different concentrations. The daily average weight gain and immune organ indices in broilers older than 7 days were significantly improved by the AvBD9 treatment.

  8. Preclinical Properties of 18F-AV-45: A PET Agent for Aβ Plaques in the Brain

    PubMed Central

    Choi, Seok Rye; Golding, Geoff; Zhuang, Zhiping; Zhang, Wei; Lim, Nathaniel; Hefti, Franz; Benedum, Tyler E.; Kilbourn, Michael R.; Skovronsky, Daniel; Kung, Hank F.

    2011-01-01

    β-amyloid plaques (Aβ plaques) in the brain, containing predominantly fibrillary Aβ peptide aggregates, represent a defining pathologic feature of Alzheimer disease (AD). Imaging agents targeting the Aβ plaques in the living human brain are potentially valuable as biomarkers of pathogenesis processes in AD. (E)-4-(2-(6-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine (18F-AV-45) is such as an agent currently in phase III clinical studies for PET of Aβ plaques in the brain. Methods In vitro binding of 18F-AV-45 to Aβ plaques in the postmortem AD brain tissue was evaluated by in vitro binding assay and autoradiography. In vivo biodistribution of 18F-AV-45 in mice and ex vivo autoradiography of AD transgenic mice (APPswe/PSEN1) with Aβ aggregates in the brain were performed. Small-animal PET of a monkey brain after an intravenous injection of 18F-AV-45 was evaluated. Results 18F-AV-45 displayed a high binding affinity and specificity to Aβ plaques (Kd, 3.72 ± 0.30 nM). In vitro autoradiography of postmortem human brain sections showed substantial plaque labeling in AD brains and not in the control brains. Initial high brain uptake and rapid washout from the brain of healthy mice and monkey were observed. Metabolites produced in the blood of healthy mice after an intravenous injection were identified. 18F-AV-45 displayed excellent binding affinity to Aβ plaques in the AD brain by ex vivo autoradiography in transgenic AD model mice. The results lend support that 18F-AV-45 may be a useful PET agent for detecting Aβ plaques in the living human brain. PMID:19837759

  9. Flow Induced Microvascular Network Formation of Therapeutic Relevant Arteriovenous (AV) Loop-Based Constructs in Response to Ionizing Radiation

    PubMed Central

    Schmidt, Volker J.; Covi, Jennifer M.; Koepple, Christoph; Hilgert, Johannes G.; Polykandriotis, Elias; Bigdeli, Amir K.; Distel, Luitpold V.; Horch, Raymund E.; Kneser, Ulrich

    2017-01-01

    Background The arteriovenous (AV) loop model enables axial vascularization to gain a functional microcirculatory system in tissue engineering constructs in vivo. These constructs might replace surgical flaps for the treatment of complex wounds in the future. Today, free flaps are often exposed to high-dose radiation after defect coverage, according to guideline-oriented treatment plans. Vascular response of AV loop-based constructs has not been evaluated after radiation, although it is of particular importance. It is further unclear whether the interposed venous AV loop graft is crucial for the induction of angiogenesis. Material/Methods We exposed the grafted vein to a single radiation dose of 2 Gy prior to loop construction to alter intrinsic and angio-inductive properties specifically within the graft. Vessel loops were embedded in a fibrin-filled chamber for 15 days and radiation-induced effects on flow-mediated vascularization were assessed by micro-CT and two-dimensional histological analysis. Results Vessel amount was significantly impaired when an irradiated vein graft was used for AV loop construction. However, vessel growth and differentiation were still present. In contrast to vessel density, which was homogeneously diminished in constructs containing irradiated veins, vessel diameter was primarily decreased in the more peripheral regions. Conclusions Vascular luminal sprouts were significantly diminished in irradiated venous grafts, suggesting that the interposing vein constitutes a vital part of the AV loop model and is essential to initiate flow-mediate angiogenesis. These results add to the current understanding of AV loop-based neovascularization and suggest clinical implications for patients requiring combined AV loop-based tissue transfer and adjuvant radiotherapy. PMID:28199294

  10. The expression of intact and mutant human apoAI/CIII/AIV/AV gene cluster in transgenic mice.

    PubMed

    Gao, Jun; Wei, Yusheng; Huang, Yue; Liu, Depei; Liu, Guang; Wu, Min; Wu, Lin; Zhang, Qingjun; Zhang, Zhuqin; Zhang, Ran; Liang, Chihchuan

    2005-04-01

    The apoAI/CIII/AIV gene cluster is involved in lipid metabolism and has a complex pattern of gene expression modulated by a common regulatory element, the apoCIII enhancer. A new member of this cluster, apolipoprotein (apo) AV, has recently been discovered as a novel modifier in triglyceride metabolism. To determine the expression of all four apo genes in combination and, most importantly, whether the transcription of apoAV is coregulated by the apoCIII enhancer in the cluster, we generated an intact transgenic line carrying the 116-kb human apoAI/CIII/AIV/AV gene cluster and a mutant transgenic line in which the apoCIII enhancer was deleted from the 116-kb structure. We demonstrated that the apoCIII enhancer regulated hepatic and intestinal apoAI, apoCIII, and apoAIV expression; however, it did not direct the newly identified apoAV in the cluster. Furthermore, human apo genes displayed integrated position-independent expression and a closer approximation of copy number-dependent expression in the intact transgenic mice. Because apoCIII and apoAV play opposite roles in triglyceride homeostasis, we analyzed the lipid profiles in our transgenic mice to assess the effects of human apoAI gene cluster expression on lipid metabolism. The triglyceride level was elevated in intact transgenic mice but decreased in mutant ones compared with nontransgenic mice. In addition, the expression of human apoAI and apoAIV elevated high density lipoprotein cholesterol in transgenic mice fed an atherogenic diet. In conclusion, our studies with human apoAI/CIII/AIV/AV gene cluster transgenic models showed that the apoCIII enhancer regulated expression of apoAI, apo-CIII, and apoAIV but not apoAV in vivo and showed the influences of expression of the entire cluster on lipid metabolism.

  11. Flow Induced Microvascular Network Formation of Therapeutic Relevant Arteriovenous (AV) Loop-Based Constructs in Response to Ionizing Radiation.

    PubMed

    Schmidt, Volker J; Covi, Jennifer M; Koepple, Christoph; Hilgert, Johannes G; Polykandriotis, Elias; Bigdeli, Amir K; Distel, Luitpold V; Horch, Raymund E; Kneser, Ulrich

    2017-02-15

    BACKGROUND The arteriovenous (AV) loop model enables axial vascularization to gain a functional microcirculatory system in tissue engineering constructs in vivo. These constructs might replace surgical flaps for the treatment of complex wounds in the future. Today, free flaps are often exposed to high-dose radiation after defect coverage, according to guideline-oriented treatment plans. Vascular response of AV loop-based constructs has not been evaluated after radiation, although it is of particular importance. It is further unclear whether the interposed venous AV loop graft is crucial for the induction of angiogenesis. MATERIAL AND METHODS We exposed the grafted vein to a single radiation dose of 2 Gy prior to loop construction to alter intrinsic and angio-inductive properties specifically within the graft. Vessel loops were embedded in a fibrin-filled chamber for 15 days and radiation-induced effects on flow-mediated vascularization were assessed by micro-CT and two-dimensional histological analysis. RESULTS Vessel amount was significantly impaired when an irradiated vein graft was used for AV loop construction. However, vessel growth and differentiation were still present. In contrast to vessel density, which was homogeneously diminished in constructs containing irradiated veins, vessel diameter was primarily decreased in the more peripheral regions. CONCLUSIONS Vascular luminal sprouts were significantly diminished in irradiated venous grafts, suggesting that the interposing vein constitutes a vital part of the AV loop model and is essential to initiate flow-mediate angiogenesis. These results add to the current understanding of AV loop-based neovascularization and suggest clinical implications for patients requiring combined AV loop-based tissue transfer and adjuvant radiotherapy.

  12. Role of AV nodal ablation in cardiac resynchronization in patients with coexistent atrial fibrillation and heart failure a systematic review.

    PubMed

    Ganesan, Anand N; Brooks, Anthony G; Roberts-Thomson, Kurt C; Lau, Dennis H; Kalman, Jonathan M; Sanders, Prashanthan

    2012-02-21

    The aim of this study was to systematically review the medical literature to evaluate the impact of AV nodal ablation in patients with heart failure and coexistent atrial fibrillation (AF) receiving cardiac resynchronization therapy (CRT). CRT has a substantial evidence base in patients in sinus rhythm with significant systolic dysfunction, symptomatic heart failure, and prolonged QRS duration. The role of CRT is less well established in AF patients with coexistent heart failure. AV nodal ablation has recently been suggested to improve outcomes in this group. Electronic databases and reference lists through September 15, 2010, were searched. Two reviewers independently evaluated citation titles, abstracts, and articles. Studies reporting the outcomes after AV nodal ablation in patients with AF undergoing CRT for symptomatic heart failure and left ventricular dyssynchrony were selected. Data were extracted from 6 studies, including 768 CRT-AF patients, composed of 339 patients who underwent AV nodal ablation and 429 treated with medical therapy aimed at rate control alone. AV nodal ablation in CRT-AF patients was associated with significant reductions in all-cause mortality (risk ratio: 0.42 [95% confidence interval: 0.26 to 0.68]), cardiovascular mortality (risk ratio: 0.44 [95% confidence interval: 0.24 to 0.81]), and improvement in mean New York Heart Association functional class (risk ratio: -0.52 [95% confidence interval: -0.87 to -0.17]). AV nodal ablation was associated with a substantial reduction in all-cause mortality and cardiovascular mortality and with improvements in New York Heart Association functional class compared with medical therapy in CRT-AF patients. Randomized controlled trials are warranted to confirm the efficacy and safety of AV nodal ablation in this patient population. © 2012 American College of Cardiology Foundation.

  13. Frequency-dependent electrophysiological remodeling of the AV node by hydroalcohol extract of Crocus sativus L. (saffron) during experimental atrial fibrillation: the role of endogenous nitric oxide.

    PubMed

    Khori, Vahid; Alizadeh, Ali Mohammad; Yazdi, Hamidreza; Rakhshan, Elnaz; Mirabbasi, Abbas; Changizi, Shima; Mazandarani, Masumeh; Nayebpour, Mohsen

    2012-06-01

    The study assessed the hydroalcohol extract effects of Crocus sativus L. (saffron) on (i) the basic and rate-dependent electrophysiological properties of the AV node, (ii) remodeling of the AV node during experimental atrial fibrillation (AF) and (iii) the role of nitric oxide (NO) in the effects of saffron on the AV node. Stimulation protocols in isolated AV node were used to quantify AV nodal recovery, facilitation and fatigue in four groups of rabbits (n = 8-16 per group). In addition, the nodal response to AF was evaluated at multiple cycle lengths and during AF. Saffron had a depressant effect on AV nodal rate-dependent properties; further, it increased Wenckebach block cycle length, functional refractory period, facilitation and fatigue (p < 0.05). A NO-synthase inhibitor (L-NAME) prevented the depressant effects of saffron on the AV node (p < 0.05). Saffron increased the zone of concealment in experimental AF (p < 0.05). The present research showed, for the first time, established electrophysiological remodeling of the AV node during AF by saffron. Saffron increased the AV nodal refractoriness and zone of concealment. These depressant effects of saffron were mediated by endogenous NO.

  14. 18F-AV-1451 positron emission tomography in Alzheimer’s disease and progressive supranuclear palsy

    PubMed Central

    Vázquez Rodríguez, Patricia; Hong, Young T.; Allinson, Kieren S. J.; Williamson, David; Borchert, Robin J.; Sami, Saber; Cope, Thomas E.; Bevan-Jones, W. Richard; Jones, P. Simon; Arnold, Robert; Surendranathan, Ajenthan; Mak, Elijah; Su, Li; Fryer, Tim D.; Aigbirhio, Franklin I.; O’Brien, John T.; Rowe, James B.

    2017-01-01

    Abstract The ability to assess the distribution and extent of tau pathology in Alzheimer’s disease and progressive supranuclear palsy in vivo would help to develop biomarkers for these tauopathies and clinical trials of disease-modifying therapies. New radioligands for positron emission tomography have generated considerable interest, and controversy, in their potential as tau biomarkers. We assessed the radiotracer 18F-AV-1451 with positron emission tomography imaging to compare the distribution and intensity of tau pathology in 15 patients with Alzheimer’s pathology (including amyloid-positive mild cognitive impairment), 19 patients with progressive supranuclear palsy, and 13 age- and sex-matched controls. Regional analysis of variance and a support vector machine were used to compare and discriminate the clinical groups, respectively. We also examined the 18F-AV-1451 autoradiographic binding in post-mortem tissue from patients with Alzheimer’s disease, progressive supranuclear palsy, and a control case to assess the 18F-AV-1451 binding specificity to Alzheimer’s and non-Alzheimer’s tau pathology. There was increased 18F-AV-1451 binding in multiple regions in living patients with Alzheimer’s disease and progressive supranuclear palsy relative to controls [main effect of group, F(2,41) = 17.5, P < 0.0001; region of interest × group interaction, F(2,68) = 7.5, P < 0.00001]. More specifically, 18F-AV-1451 binding was significantly increased in patients with Alzheimer’s disease, relative to patients with progressive supranuclear palsy and with control subjects, in the hippocampus and in occipital, parietal, temporal, and frontal cortices (t’s > 2.2, P’s < 0.04). Conversely, in patients with progressive supranuclear palsy, relative to patients with Alzheimer’s disease, 18F-AV-1451 binding was elevated in the midbrain (t = 2.1, P < 0.04); while patients with progressive supranuclear palsy showed, relative to controls, increased 18F-AV-1451 uptake

  15. Cardiac resynchronization therapy and AV optimization increase myocardial oxygen consumption, but increase cardiac function more than proportionally☆

    PubMed Central

    Kyriacou, Andreas; Pabari, Punam A.; Mayet, Jamil; Peters, Nicholas S.; Davies, D. Wyn; Lim, P. Boon; Lefroy, David; Hughes, Alun D.; Kanagaratnam, Prapa; Francis, Darrel P.; I.Whinnett, Zachary

    2014-01-01

    Background The mechanoenergetic effects of atrioventricular delay optimization during biventricular pacing (“cardiac resynchronization therapy”, CRT) are unknown. Methods Eleven patients with heart failure and left bundle branch block (LBBB) underwent invasive measurements of left ventricular (LV) developed pressure, aortic flow velocity-time-integral (VTI) and myocardial oxygen consumption (MVO2) at 4 pacing states: biventricular pacing (with VV 0 ms) at AVD 40 ms (AV-40), AVD 120 ms (AV-120, a common nominal AV delay), at their pre-identified individualised haemodynamic optimum (AV-Opt); and intrinsic conduction (LBBB). Results AV-120, relative to LBBB, increased LV developed pressure by a mean of 11(SEM 2)%, p = 0.001, and aortic VTI by 11(SEM 3)%, p = 0.002, but also increased MVO2 by 11(SEM 5)%, p = 0.04. AV-Opt further increased LV developed pressure by a mean of 2(SEM 1)%, p = 0.035 and aortic VTI by 4(SEM 1)%, p = 0.017. MVO2 trended further up by 7(SEM 5)%, p = 0.22. Mechanoenergetics at AV-40 were no different from LBBB. The 4 states lay on a straight line for Δexternal work (ΔLV developed pressure × Δaortic VTI) against ΔMVO2, with slope 1.80, significantly > 1 (p = 0.02). Conclusions Biventricular pacing and atrioventricular delay optimization increased external cardiac work done but also myocardial oxygen consumption. Nevertheless, the increase in cardiac work was ~ 80% greater than the increase in oxygen consumption, signifying an improvement in cardiac mechanoenergetics. Finally, the incremental effect of optimization on external work was approximately one-third beyond that of nominal AV pacing, along the same favourable efficiency trajectory, suggesting that AV delay dominates the biventricular pacing effect — which may therefore not be mainly “resynchronization”. PMID:24332598

  16. Optimization of automated radiosynthesis of [18F]AV-45: a new PET imaging agent for Alzheimer's disease.

    PubMed

    Liu, Yajing; Zhu, Lin; Plössl, Karl; Choi, Seok Rye; Qiao, Hongwen; Sun, Xiaotao; Li, Song; Zha, Zhihao; Kung, Hank F

    2010-11-01

    Accumulation of β-amyloid (Aβ) aggregates in the brain is linked to the pathogenesis of Alzheimer's disease (AD). Imaging probes targeting these Aβ aggregates in the brain may provide a useful tool to facilitate the diagnosis of AD. Recently, [(18)F]AV-45 ([(18)F]5) demonstrated high binding to the Aβ aggregates in AD patients. To improve the availability of this agent for widespread clinical application, a rapid, fully automated, high-yield, cGMP-compliant radiosynthesis was necessary for production of this probe. We report herein an optimal [(18)F]fluorination, de-protection condition and fully automated radiosynthesis of [(18)F]AV-45 ([(18)F]5) on a radiosynthesis module (BNU F-A2). The preparation of [(18)F]AV-45 ([(18)F]5) was evaluated under different conditions, specifically by employing different precursors (-OTs and -Br as the leaving group), reagents (K222/K(2)CO(3) vs. tributylammonium bicarbonate) and deprotection in different acids. With optimized conditions from these experiments, the automated synthesis of [(18)F]AV-45 ([(18)F]5) was accomplished by using a computer-programmed, standard operating procedure, and was purified on an on-line solid-phase cartridge (Oasis HLB). The optimized reaction conditions were successfully implemented to an automated nucleophilic fluorination module. The radiochemical purity of [(18)F]AV-45 ([(18)F]5) was >95%, and the automated synthesis yield was 33.6 ± 5.2% (no decay corrected, n=4), 50.1 ± 7.9% (decay corrected) in 50 min at a quantity level of 10-100 mCi (370-3700 MBq). Autoradiography studies of [(18)F]AV-45 ([(18)F]5) using postmortem AD brain and Tg mouse brain sections in the presence of different concentration of "cold" AV-136 showed a relatively low inhibition of in vitro binding of [(18)F]AV-45 ([(18)F]5) to the Aβ plaques (IC50=1-4 μM, a concentration several order of magnitude higher than the expected pseudo carrier concentration in the brain). Solid-phase extraction purification and improved

  17. Optimal pacing for symptomatic AV block: a comparison of VDD and DDD pacing.

    PubMed

    Huang, Max; Krahn, Andrew D; Yee, Raymond; Klein, George J; Skanes, Allan C

    2004-01-01

    VDD pacing provides the physiological benefits of atrioventricular synchronous pacing with the convenience of a single lead system, but is hampered by uncertainty regarding long term atrial sensing and potential development of sinus node disease. To examine the long-term reliability and complication rates of VDD pacing, we compared the outcome of 112 consecutive patients (age 70 +/- 13 years, 59% men) with symptomatic AV block who received a single pass bipolar VDD system, to 80 patients (age 63 +/- 16 years, 70% men) who received DDD pacing for the same indication. All patients were judged to have intact sinus node function based on submitted ECGs and monitoring results at the time of implant. Implant time was reduced in VDD patients compared to DDD patients (63 +/- 20 vs 97 +/- 36 minutes, P < 0.0001). Implant complications occurred in 5 (6%) DDD patients compared to 3 (3%) VDD patients (P = 0.15). The implant P wave was lower with VDD pacing compared to DDD patients (2.91 +/- 1.48 vs 4.0 +/- 1.7 mv, P < 0.0001), but remained stable during long-term follow-up in both groups. During 17.7 +/- 10.0 months of follow-up in the VDD group, only two VDD patients were reprogrammed to VVIR mode, compared to three DDD patients. Physiological atrioventricular activation was maintained in 94%-99% of beats throughout the follow-up period in the VDD group. VDD pacing is an excellent strategy for treatment of patients with symptomatic AV block. The lower cost, high reliability, and abbreviated implantation time suggest that VDD pacing is a viable alternative to DDD pacing in patients with high degree AV block and normal sinus node function.

  18. Optimal pacing for symptomatic AV block: a comparison of VDD and DDD pacing.

    PubMed

    Huang, Max; Krahn, Andrew D; Yee, Raymond; Klein, George J; Skanes, Allan C

    2003-12-01

    VDD pacing provides the physiological benefits of atrioventricular synchronous pacing with the convenience of a single lead system, but is hampered by uncertainty regarding long-term atrial sensing and potential development of sinus node disease. To examine the long-term reliability and complication rates of VDD pacing, we compared the outcome of 112 consecutive patients (age 70 +/- 13 years, 59% male) with symptomatic AV block who received a single pass bipolar VDD system to 80 patients (age 63 +/- 16 years, 70% male) who received DDD pacing for the same indication. All patients were judged to have intact sinus node function based on submitted ECGs and monitoring results at the time of implant. Implant time was reduced in VDD patients compared to DDD patients (63 +/- 20 vs 97 +/- 36 minutes, P < 0.0001). Implant complications occurred in 5 (6%) DDD patients compared to 3 (3%) VDD patients (P = 0.15). The implant P wave was lower with VDD pacing compared to DDD patients (2.91 +/- 1.48 vs 4.0 +/- 1.7 mV, P < 0.0001), but remained stable during long-term follow-up in both groups. During 17.7 +/- 10.0 months of follow-up in the VDD group, only 2 VDD patients were reprogrammed to VVIR mode, compared to 3 DDD patients. Physiological atrioventricular activation was maintained in 94%-99% of beats throughout the follow-up period in the VDD group. VDD pacing is an excellent strategy for treatment of patients with symptomatic AV block. The lower cost, high reliability, and abbreviated implantation time suggest that VDD pacing is a viable alternative to DDD pacing in patients with high-degree AV block and normal sinus node function.

  19. ND2 AV: N-dimensional data analysis and visualization analysis for the National Ignition Campaign

    DOE PAGES

    Bremer, Peer -Timo; Maljovec, Dan; Saha, Avishek; ...

    2015-07-01

    Here, one of the biggest challenges in high-energy physics is to analyze a complex mix of experimental and simulation data to gain new insights into the underlying physics. Currently, this analysis relies primarily on the intuition of trained experts often using nothing more sophisticated than default scatter plots. Many advanced analysis techniques are not easily accessible to scientists and not flexible enough to explore the potentially interesting hypotheses in an intuitive manner. Furthermore, results from individual techniques are often difficult to integrate, leading to a confusing patchwork of analysis snippets too cumbersome for data exploration. This paper presents a case study on how a combination of techniques from statistics, machine learning, topology, and visualization can have a significant impact in the field of inertial confinement fusion. We present themore » $$\\mathrm{ND}^2\\mathrm{AV}$$: N-dimensional data analysis and visualization framework, a user-friendly tool aimed at exploiting the intuition and current workflow of the target users. The system integrates traditional analysis approaches such as dimension reduction and clustering with state-of-the-art techniques such as neighborhood graphs and topological analysis, and custom capabilities such as defining combined metrics on the fly. All components are linked into an interactive environment that enables an intuitive exploration of a wide variety of hypotheses while relating the results to concepts familiar to the users, such as scatter plots. $$\\mathrm{ND}^2\\mathrm{AV}$$ uses a modular design providing easy extensibility and customization for different applications. $$\\mathrm{ND}^2\\mathrm{AV}$$ is being actively used in the National Ignition Campaign and has already led to a number of unexpected discoveries.« less

  20. The Arteriovenous (AV) Loop in a Small Animal Model to Study Angiogenesis and Vascularized Tissue Engineering.

    PubMed

    Weigand, Annika; Beier, Justus P; Arkudas, Andreas; Al-Abboodi, Majida; Polykandriotis, Elias; Horch, Raymund E; Boos, Anja M

    2016-11-02

    A functional blood vessel network is a prerequisite for the survival and growth of almost all tissues and organs in the human body. Moreover, in pathological situations such as cancer, vascularization plays a leading role in disease progression. Consequently, there is a strong need for a standardized and well-characterized in vivo model in order to elucidate the mechanisms of neovascularization and develop different vascularization approaches for tissue engineering and regenerative medicine. We describe a microsurgical approach for a small animal model for induction of a vascular axis consisting of a vein and artery that are anastomosed to an arteriovenous (AV) loop. The AV loop is transferred to an enclosed implantation chamber to create an isolated microenvironment in vivo, which is connected to the living organism only by means of the vascular axis. Using 3D imaging (MRI, micro-CT) and immunohistology, the growing vasculature can be visualized over time. By implanting different cells, growth factors and matrices, their function in blood vessel network formation can be analyzed without any disturbing influences from the surroundings in a well controllable environment. In addition to angiogenesis and antiangiogenesis studies, the AV loop model is also perfectly suited for engineering vascularized tissues. After a certain prevascularization time, the generated tissues can be transplanted into the defect site and microsurgically connected to the local vessels, thereby ensuring immediate blood supply and integration of the engineered tissue. By varying the matrices, cells, growth factors and chamber architecture, it is possible to generate various tissues, which can then be tailored to the individual patient's needs.

  1. Catheter ablation of pediatric AV nodal reentrant tachycardia: results in small children.

    PubMed

    Krause, Ulrich; Backhoff, David; Klehs, Sophia; Kriebel, Thomas; Paul, Thomas; Schneider, Heike E

    2015-11-01

    AV nodal reentrant tachycardia (AVNRT) is commonly encountered in pediatric patients. Definite treatment can be achieved by catheter ablation. The purpose of the study was to evaluate the efficacy and safety of AVNRT ablation focusing on children with a body weight ≤25 kg. Catheter ablation of AVNRT was attempted in 253 patients. Median age was 12.5 years; median body weight was 48.7 kg. 25 (9.9 %) children had a body weight ≤25 kg. Congenital heart disease was present in 6 patients (2.4 %). Procedural success was achieved in 98 % using radiofrequency, in 100 % using cryoenergy alone, and in 94 % using both energy sources. In patients with a body weight ≤25 kg, success was achieved in 96 %. In patients ≤25 kg, fluoroscopy and procedure duration did not differ from those >25 kg. The rate of major complications was significantly higher in the patients ≤25 kg (12 vs. 2.2 %, p = 0.04). Permanent AV block after RF ablation occurred in 2 patients with congenital heart disease and one infant with a body weight of 8.7 kg. Catheter ablation of AVNRT in children and adolescents was safe and effective. Infants and small children with a body weight ≤25 kg had a higher prevalence of serious complications. This should alert physicians in decision making toward catheter ablation in these patients. In patients with congenital heart disease and different anatomy of the cardiac conduction system, operators must be aware of an increased risk for AV block.

  2. Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial: a randomized trial comparing empirical, echocardiography-guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy.

    PubMed

    Ellenbogen, Kenneth A; Gold, Michael R; Meyer, Timothy E; Fernndez Lozano, Ignacio; Mittal, Suneet; Waggoner, Alan D; Lemke, Bernd; Singh, Jagmeet P; Spinale, Francis G; Van Eyk, Jennifer E; Whitehill, Jeffrey; Weiner, Stanislav; Bedi, Maninder; Rapkin, Joshua; Stein, Kenneth M

    2010-12-21

    one variable that may influence cardiac resynchronization therapy response is the programmed atrioventricular (AV) delay. The SmartDelay determined av optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial prospectively randomized patients to a fixed empirical AV delay (120 milliseconds), echocardiographically optimized AV delay, or AV delay optimized with SmartDelay, an electrogram-based algorithm. a total of 1014 patients (68% men; mean age, 66 ± 11 years; mean left ventricular ejection fraction, 25 ± 7%) who met enrollment criteria received a cardiac resynchronization therapy defibrillator, and 980 patients were randomized in a 1:1:1 ratio. All patients were programmed (DDD-60 or DDDR-60) and evaluated after implantation and 3 and 6 months later. The primary end point was left ventricular end-systolic volume. Secondary end points included New York Heart Association class, quality-of-life score, 6-minute walk distance, left ventricular end-diastolic volume, and left ventricular ejection fraction. The medians (quartiles 1 and 3) for change in left ventricular end-systolic volume at 6 months for the SmartDelay, echocardiography, and fixed arms were -21 mL (-45 and 6 mL), -19 mL (-45 and 6 mL), and -15 mL (-41 and 6 mL), respectively. No difference in improvement in left ventricular end-systolic volume at 6 months was observed between the SmartDelay and echocardiography arms (P=0.52) or the SmartDelay and fixed arms (P=0.66). Secondary end points, including structural (left ventricular end-diastolic volume and left ventricular ejection fraction) and functional (6-minute walk, quality of life, and New York Heart Association classification) measures, were not significantly different between arms. neither SmartDelay nor echocardiography was superior to a fixed AV delay of 120 milliseconds. The routine use of AV optimization techniques assessed in this trial is not warranted. However, these data do not exclude

  3. Atmospheric Turbulence Measurements With the Automatic Mini UAV 'M2AV Carolo'

    NASA Astrophysics Data System (ADS)

    Bange, J.; van den Kroonenberg, A. C.; Spieß, T.; Buschmann, M.; Krüger, L.; Heindorf, A.; Vörsmann, P.

    2007-05-01

    The limitations of manned airborne meteorological measurements led to the development of an autonomously operating mini aircraft, the Meteorological Mini-UAV (M2AV), at the Institute of Aerospace Systems, Technical University of Braunschweig, Germany. The task was to develop, test and verify a meteorological sensor package as payload for an already available automatic carrier aircraft, the UAV 'Carolo T200', which operates autonomously i.e. without remote control. The M2AV is a self constructed model aircraft with two electrically powered engines and a wingspan of two meters. The maximum take-off weight is 4.5~kg (the M2AV is therefore classified as an model plane which simplifies authority issues), including 1.5~kg of payload. It is hand-launched which makes operation of the aircraft easy. With an endurance of approximately 50 minutes, the range accounts for 60 km at a cruising speed of 20~m/s. The M2AV is capable of performing turbulence measurements (wind vector, temperature and humidity) within the troposphere and offers an economic component during meteorological campaigns. The meteorological sensors are mounted on a noseboom to minimise the aircraft's influence on the measurements and to position the sensors closely to each other. Wind is measured via a small five-hole probe, an inertia measurement unit and GPS. The flight mission (waypoints, altitudes, airspeed) is planned and assigned to the aircraft before the semi- automatic launch. The flight is only controlled by the on-board autopilot system which only communicates with a ground station (laptop PC) for the exchange of measured data and command updates like new waypoints etc. The talk gives details on the technical items, calibration and first missions. Results from first field experiments like the LAUNCH-2005 campaign near Berlin are used for data quality assessment by comparison with simultaneous lidar and sodar measurements. An in situ comparison with the highly accurate helicopter-borne turbulence

  4. Complete A-V block: incidental or a part of cor triatriatum dexter.

    PubMed

    Guler, Y; Akgun, T; Toprak, C; Guler, A; Esen, A M

    2014-05-01

    Cor triatriatum dexter (CTD) is an extremely rare cardiac anomaly in which the right atrium is divided into two distinct chambers by a membrane. The persistence of the right valve of sinus venosus results in a complete septation of the right atrium. This anomaly is frequently associated with other right-sided cardiac abnormalities. Its clinical manifestation and the need for intervention are determined by the number and the size of the fenestrations on the membrane, associated cardiac anomalies and arrhythmias. We describe a case of CTD in a patient with complete atrioventricular (A-V) block.

  5. Parachute-deployment-parameter identification based on an analytical simulation of Viking BLDT AV-4

    NASA Technical Reports Server (NTRS)

    Talay, T. A.

    1974-01-01

    A six-degree-of-freedom analytical simulation of parachute deployment dynamics developed at the Langley Research Center is presented. A comparison study was made using flight results from the Viking Balloon Launched Decelerator Test (BLDT) AV-4. Since there are significant voids in the knowledge of vehicle and decelerator aerodynamics and suspension system physical properties, a set of deployment-parameter input has been defined which may be used as a basis for future studies of parachute deployment dynamics. The study indicates the analytical model is sufficiently sophisticated to investigate parachute deployment dynamics with reasonable accuracy.

  6. The Histone Variant His2Av is Required for Adult Stem Cell Maintenance in the Drosophila Testis

    PubMed Central

    Fuller, Margaret T.

    2013-01-01

    Many tissues are sustained by adult stem cells, which replace lost cells by differentiation and maintain their own population through self-renewal. The mechanisms through which adult stem cells maintain their identity are thus important for tissue homeostasis and repair throughout life. Here, we show that a histone variant, His2Av, is required cell autonomously for maintenance of germline and cyst stem cells in the Drosophila testis. The ATP-dependent chromatin-remodeling factor Domino is also required in this tissue for adult stem cell maintenance possibly by regulating the incorporation of His2Av into chromatin. Interestingly, although expression of His2Av was ubiquitous, its function was dispensable for germline and cyst cell differentiation, suggesting a specific role for this non-canonical histone in maintaining the stem cell state in these lineages. PMID:24244183

  7. Stability and activity of lactate dehydrogenase on biofunctional layers deposited by activated vapor silanization (AVS) and immersion silanization (IS)

    NASA Astrophysics Data System (ADS)

    Calvo, Jorge Nieto-Márquez; Elices, Manuel; Guinea, Gustavo V.; Pérez-Rigueiro, José; Arroyo-Hernández, María

    2017-09-01

    The interaction between surfaces and biological elements, in particular, proteins is critical for the performance of biomaterials and biosensors. This interaction can be controlled by modifying the surface in a process known as biofunctionalization. In this work, the enzyme lactate dehydrogenase (LDH) is used to study the stability of the interaction between a functional protein and amine-functionalized surfaces. Two different functionalization procedures were compared: Activated Vapor Silanization (AVS) and Immersion Silanization (IS). Adsorption kinetics is shown to follow the Langmuir model for AVS-functionalized samples, while IS-functionalized samples show a certain instability if immersed in an aqueous medium for several hours. In turn, the enzymatic activity of LDH is preserved for longer times by using glutaraldehyde as crosslinker between the AVS biofunctional surface and the enzyme.

  8. A Comparison of the AVS-9 and the Panoramic Night Vision Goggles During Rotorcraft Hover and Landing

    NASA Technical Reports Server (NTRS)

    Szoboszlay, Zoltan; Haworth, Loran; Simpson, Carol

    2000-01-01

    A flight test was conducted to assess any differences in pilot-vehicle performance and pilot opinion between the use of a current generation night vision goggle (the AVS-9) and one variant of the prototype panoramic night vision goggle (the PNVGII). The panoramic goggle has more than double the horizontal field-of-view of the AVS-9, but reduced image quality. Overall the panoramic goggles compared well to the AVS-9 goggles. However, pilot comment and data are consistent with the assertion that some of the benefits of additional field-of-view with the panoramic goggles were negated by the reduced image quality of the particular variant of the panoramic goggles tested.

  9. Chemometric formulation of bacterial consortium-AVS for improved decolorization of resonance-stabilized and heteropolyaromatic dyes.

    PubMed

    Kumar, Madhava Anil; Kumar, Vaidyanathan Vinoth; Premkumar, Manickam Periyaraman; Baskaralingam, Palanichamy; Thiruvengadaravi, Kadathur Varathachary; Dhanasekaran, Anuradha; Sivanesan, Subramanian

    2012-11-01

    A bacterial consortium-AVS, consisting of Pseudomonas desmolyticum NCIM 2112, Kocuria rosea MTCC 1532 and Micrococcus glutamicus NCIM 2168 was formulated chemometrically, using the mixture design matrix based on the design of experiments methodology. The formulated consortium-AVS decolorized acid blue 15 and methylene blue with a higher average decolorization rate, which is more rapid than that of the pure cultures. The UV-vis spectrophotometric, Fourier transform infra red spectrophotometric and high performance liquid chromatographic analysis confirm that the decolorization was due to biodegradation by oxido-reductive enzymes, produced by the consortium-AVS. The toxicological assessment of plant growth parameters and the chlorophyll pigment concentrations of Phaseolus mungo and Triticum aestivum seedlings revealed the reduced toxic nature of the biodegraded products.

  10. Maillard reaction and enzymatic browning affect the allergenicity of Pru av 1, the major allergen from cherry (Prunus avium).

    PubMed

    Gruber, Patrick; Vieths, Stefan; Wangorsch, Andrea; Nerkamp, Jörg; Hofmann, Thomas

    2004-06-16

    The influence of thermal processing and nonenymatic as well as polyphenoloxidase-catalyzed browning reaction on the allergenicity of the major cherry allergen Pru av 1 was investigated. After thermal treatment of the recombinant protein rPru av 1 in the absence or presence of carbohydrates, SDS-PAGE, enzyme allergosorbent tests, and inhibition assays revealed that thermal treatment of rPru av 1 alone did not show any influence on the IgE-binding activity of the protein at least for 30 min, thus correlating well with the refolding of the allergen in buffer solution as demonstrated by CD spectroscopic experiments. Incubation of the protein with starch and maltose also showed no effect on IgE-binding activity, whereas reaction with glucose and ribose and, even more pronounced, with the carbohydrate breakdown products glyceraldehyde and glyoxal induced a strong decrease of the IgE-binding capacity of rPru av 1. In the second part of the study, the effect of polyphenoloxidase-catalyzed oxidation of polyphenols on food allergen activity was investigated. Incubation of rPru av 1 with epicatechin in the presence of tyrosinase led to a drastic decrease in IgE-binding activity of the protein. Variations of the phenolic compound revealed caffeic acid and epicatechin as the most active inhibitors of the IgE-binding activity of rPru av 1, followed by catechin and gallic acid, and, finally, by quercetin and rutin, showing significantly lower activity. On the basis of these data, reactive intermediates formed during thermal carbohydrate degradation as well as during enzymatic polyphenol oxidation are suggested as the active chemical species responsible for modifying nucleophilic amino acid side chains of proteins, thus inducing an irreversible change in the tertiary structure of the protein and resulting in a loss of conformational epitopes of the allergen.

  11. Autophagy impairment by Helicobacter pylori-induced methylation silencing of MAP1LC3Av1 promotes gastric carcinogenesis.

    PubMed

    Muhammad, Jibran Sualeh; Nanjo, Sohachi; Ando, Takayuki; Yamashita, Satoshi; Maekita, Takao; Ushijima, Toshikazu; Tabuchi, Yoshiaki; Sugiyama, Toshiro

    2017-05-15

    Helicobacter pylori (H. pylori) infection induces methylation silencing of tumor suppressor genes causing gastric carcinogenesis. Impairment of autophagy induces DNA damage leading to genetic instability and carcinogenesis. We aimed to identify whether H. pylori infection induced methylation silencing of host autophagy-related (Atg) genes, impairing autophagy and enhancing gastric carcinogenesis. Gastric mucosae were obtained from 41 gastric cancer patients and 11 healthy volunteers (8 H. pylori-uninfected and 3 H. pylori-infected). Methylation status of Atg genes was analyzed by a methylation microarray and quantitative methylation-specific PCR (qMSP); mRNA expression was assessed by quantitative reverse transcription PCR (qRT-PCR). Cell proliferation, migration and invasion were assessed in normal rat gastric epithelial cells. Gene knock-down was performed by siRNA. Autophagy was assessed by western blotting. Of 34 Atg genes, MAP1LC3A variant 1 (MAP1LC3Av1) and ULK2 were identified by methylation microarray analysis as exhibiting specific methylation in H. pylori-infected mucosae and gastric cancer tissues. Methylation silencing of MAP1LC3Av1 was confirmed by qMSP, qRT-PCR and de-methylation treatment in two gastric cancer cell lines. Knock-down of map1lc3a, the rat homolog of the human MAP1LC3Av1, inhibited autophagy response and increased cell proliferation, migration and invasion in normal rat gastric epithelial cells, despite the presence of map1lc3b, the rat homolog of the human MAP1LC3B gene important for autophagy. Furthermore, MAP1LC3Av1 was methylation-silenced in 23.3% of gastric cancerous mucosae and 40% of non-cancerous mucosae with H. pylori infection. MAP1LC3Av1 is essential for autophagy and H. pylori-induced methylation silencing of MAP1LC3Av1 may impair autophagy, facilitating gastric carcinogenesis.

  12. Cognition and amyloid load in Alzheimer disease imaged with florbetapir F 18(AV-45) positron emission tomography.

    PubMed

    Rosenberg, Paul B; Wong, D F; Edell, S L; Ross, J S; Joshi, A D; Brašić, J R; Zhou, Y; Raymont, V; Kumar, A; Ravert, H T; Dannals, R F; Pontecorvo, M J; Skovronsky, D M; Lyketsos, C G

    2013-03-01

    To examine the association between regional brain uptake of a novel amyloid positron emission tomography (PET) tracer florbetapir F 18 ([(18)F]-AV-45) and cognitive performance in a pilot study. Cross-sectional comparison of [(18)F]-AV-45 in AD patients versus controls. Three specialty memory clinics. Eleven participants with probable Alzheimer disease (AD) by NINDS/ADRDA criteria and 15 healthy comparison (HC) participants. Participants underwent PET imaging following a 370 MBq (10 mCi) intravenous administration of [(18)F]-AV-45. Regional/cerebellar standardized uptake value ratios (SUVRs) were calculated. Cognition was assessed using Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Wechsler Logical Memory IA (immediate recall) test (LMIA), and verbal category fluency. Greater [(18)F]-AV-45 SUVR was associated with poorer performance on all cognitive tests. In the HC group, occipital, parietal, precuneus, temporal, and cortical average SUVR was associated with greater ADAS-Cog, and greater anterior cingulate SUVR was associated with lower LMIA. Two HC participants had [(18)F]-AV-45 cortical/cerebellar SUVR greater than 1.5, one of whom had deficits in episodic recall and on follow-up met criteria for amnestic mild cognitive impairment. [(18)F]-AV-45 SUVR in several brain regions was associated with worse global cognitive performance particularly in HC, suggesting its potential as a marker of preclinical AD. Copyright © 2013 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

  13. 77 FR 1667 - Nelson S. Galgoul, Av. Edison Passess 909, Rio De Janeiro, R.J., Brazil 20531-070, Respondent...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF COMMERCE Bureau of Industry and Security Nelson S. Galgoul, Av. Edison Passess 909, Rio De Janeiro, R.J., Brazil... a last known address of Av. Edison Passess 909, Rio De Janeiro, R.J., Brazil 20531-070, and...

  14. First Case of Automatic His Potential Detection With a Novel Ultra High-density Electroanatomical Mapping System for AV Nodal Ablation

    PubMed Central

    Hilbert, Sebastian; Kosiuk, Jedrzej; John, Silke; Hindricks, Gerhard; Bollmann, Andreas

    2016-01-01

    A 74-year old was considered for atrioventricular (AV) nodal ablation in view of atrial fibrillation (AF) with poorly controlled ventricular rate despite being on amiodarone. Targeted AV nodal ablation was successfully performed after identifying the target site for ablation by reviewing an ultra high-density map of the His region produced by automatic electrogram annotation. PMID:25852249

  15. Overexpression of an Apocynum venetum DEAD-Box Helicase Gene (AvDH1) in Cotton Confers Salinity Tolerance and Increases Yield in a Saline Field

    PubMed Central

    Chen, Jie; Wan, Sibao; Liu, Huaihua; Fan, Shuli; Zhang, Yujuan; Wang, Wei; Xia, Minxuan; Yuan, Rui; Deng, Fenni; Shen, Fafu

    2016-01-01

    Soil salinity is a major environmental stress limiting plant growth and productivity. We have reported previously the isolation of an Apocynum venetum DEAD-box helicase 1 (AvDH1) that is expressed in response to salt exposure. Here, we report that the overexpression of AvDH1 driven by a constitutive cauliflower mosaic virus-35S promoter in cotton plants confers salinity tolerance. Southern and Northern blotting analyses showed that the AvDH1 gene was integrated into the cotton genome and expressed. In this study, the growth of transgenic cotton expressing AvDH1 was evaluated under saline conditions in a growth chamber and in a saline field trial. Transgenic cotton overexpressing AvDH1 was much more resistant to salt than the wild-type plants when grown in a growth chamber. The lower membrane ion leakage, along with increased activity of superoxide dismutase, in AvDH1 transgenic lines suggested that these characteristics may prevent membrane damage, which increases plant survival rates. In a saline field, the transgenic cotton lines expressing AvDH1 showed increased boll numbers, boll weights and seed cotton yields compared with wild-type plants, especially at high soil salinity levels. This study indicates that transgenic cotton expressing AvDH1 is a promising option for increasing crop productivity in saline fields. PMID:26779246

  16. Relationship of Serum Apolipoprotein A-V Levels, Oxidative Stress and Inflammatory Biomarkers with Hypertriglyceridemia in Type 2 Diabetes Mellitus.

    PubMed

    Sharma, Devesh; Garg, Seema; Mehndiratta, Mohit; V Madhu, S; Puri, Dinesh

    2017-04-01

    Serum levels of triglycerides (TGs) are often found to be raised in type 2 diabetes mellitus (T2DM). TG levels ≥ 2.2 mM, systemic inflammation and oxidative stress (OS) are known to increase the risk of incident cardiovascular disease (CVD) substantially. In recent years, apolipoprotein A-V (Apo A-V protein) has attracted considerably as a modulator of circulating TG levels. The study was conducted in order to evaluate the levels of Apo A - V proteins and markers of inflammation and OS in patients of T2DM with and without hypertriglyceridemia (HTG) and also to assess correlation between them. T2DM patients were categorized into two groups of 40 participants, according to criteria for risk of CVD: group 1/ controls (TG ≤ 1.65 mM, n = 40) and group 2/ cases (TG ≥ 2.2 mM, n = 40). Despite the routine investigations, serum levels of Apo A-V, interleukin-6 (IL-6) and Insulin were estimated using ELISA, free fatty acids (FFA) with fluorometric assay and malondialdehyde (MDA) was measured using a spectrophotometer. Comparison of levels and correlation between variables was carried out with appropriate statistical tools. Serum Apo A-V protein levels were found significantly lower (P = 0.04) and MDA was significantly higher (P = 0.049) in cases. MDA correlated with TG levels positively (P = 0.000) and negatively with high density lipoproteins (HDL) (P = 0.000). However Apo A-V protein levels did not correlate with TG levels (P = 0.819, r = -0.027), IL-6 (r = 0.135, P = 0.269), FFA (r = 0.128, P = 0.277) and MDA (r = -0.217, P = 0.073). IL-6 levels significantly and positively correlated with HOMA-IR (r = 0.327, P = 0.004) in the all patients. In patients of T2DM, low levels of Apo A-V are associated with HTG, indicating that Apo A-V is linked with TG metabolism. Burden of oxidative stress is greater in HTG of T2DM as is evident from MDA levels and its correlation with TG levels. Since oxidative stress is an important patho-physiological basis which increases the risk

  17. Identification of the neoplastically transformed cells in Marek's disease herpesvirus-induced lymphomas: recognition by the monoclonal antibody AV37.

    PubMed

    Burgess, Shane C; Davison, T Fred

    2002-07-01

    Understanding the interactions between herpesviruses and their host cells and also the interactions between neoplastically transformed cells and the host immune system is fundamental to understanding the mechanisms of herpesvirus oncology. However, this has been difficult as no animal models of herpesvirus-induced oncogenesis in the natural host exist in which neoplastically transformed cells are also definitively identified and may be studied in vivo. Marek's disease (MD) herpesvirus (MDV) of poultry, although a recognized natural oncogenic virus causing T-cell lymphomas, is no exception. In this work, we identify for the first time the neoplastically transformed cells in MD as the CD4(+) major histocompatibility complex (MHC) class I(hi), MHC class II(hi), interleukin-2 receptor alpha-chain-positive, CD28(lo/-), phosphoprotein 38-negative (pp38(-)), glycoprotein B-negative (gB(-)), alphabeta T-cell-receptor-positive (TCR(+)) cells which uniquely overexpress a novel host-encoded extracellular antigen that is also expressed by MDV-transformed cell lines and recognized by the monoclonal antibody (MAb) AV37. Normal uninfected leukocytes and MD lymphoma cells were isolated directly ex vivo and examined by flow cytometry with MAb recognizing AV37, known leukocyte antigens, and MDV antigens pp38 and gB. CD28 mRNA was examined by PCR. Cell cycle distribution and in vitro survival were compared for each lymphoma cell population. We demonstrate for the first time that the antigen recognized by AV37 is expressed at very low levels by small minorities of uninfected leukocytes, whereas particular MD lymphoma cells uniquely express extremely high levels of the AV37 antigen; the AV37(hi) MD lymphoma cells fulfill the accepted criteria for neoplastic transformation in vivo (protection from cell death despite hyperproliferation, presence in all MD lymphomas, and not supportive of MDV production); the lymphoma environment is essential for AV37(+) MD lymphoma cell survival; pp38 is

  18. Wenckebach second-degree A-V block in top-ranking athletes: an old problem revisited.

    PubMed

    Zeppilli, P; Fenici, R; Sassara, M; Pirrami, M M; Caselli, G

    1980-09-01

    The occurrence of Wenckebach second-degree (Mobitz I) A-V block in apparently normal persons still provides a puzzle for the cardiologist, as the benign nature of this event has been recently questioned. This problem becomes more intriguing when Wenckebach A-V block is encountered in asymptomatic top-ranking athletes, because of medico-legal implications. We report 10 cases of highly-trained athletes, including three with mitral valve prolapse (MVP) features, with a spontaneous or induced Wenckebach second-degree A-V block. Previous ECGs of six subjects, dating from a maximum of 6 years to a minimum of 18 months, were available. Deterioration of A-V conduction has never been documented and all six cases have remained asymptomatic for the whole follow-up period. Athletes have been submitted to a protocol study consisting of ECG recording at rest, during, and after vagal and sympathetic reflex maneuvers, drug administration (isoproterenol and atropine), submaximal and maximal exercise. Nine subjects have been considered to have "normal" responses of the A-V node to provocative tests, since conduction disturbances were improved or normalized by reflex sympathetic stimulations and were completely normalized by autonomic drug administration and exercise. One athlete showed "abnormal" responses to tests. In order to give a conclusive prognostic and medico-legal assessment, we advised him to submit to an invasive electrophysiological investigation. Wenckebach second-degree A-V block in athletes may be a more common finding than so far described, especially when a systematic search is made. In our opinion, this event can still be considered a vagally-induced benign feature of athlete's heart, provided that an immediate improvement of A-V conduction is obtained in response to reflex sympathetic maneuvers, and that a complete normalization after sympathomimetic and vagolytic drug administration and physical exercise is observed. The clinical histories of our athletes and the

  19. Can acid volatile sulfides (AVS) influence metal concentrations in the macrophyte Myriophyllum aquaticum?

    PubMed

    Teuchies, Johannes; De Jonge, Maarten; Meire, Patrick; Blust, Ronny; Bervoets, Lieven

    2012-08-21

    The difference between the molar concentrations of simultaneously extracted metals (SEM) and acid volatile sulfides (AVS) is widely used to predict metal availability toward invertebrates in hypoxic sediments. However, this model is poorly investigated for macrophytes. The present study evaluates metal accumulation in roots and stems of the macrophyte Myriophyllum aquaticum during a 54 day lab experiment. The macrophytes, rooting in metal contaminated, hypoxic, and sulfide rich field sediments were exposed to surface water with 40% or 90% oxygen. High oxygen concentrations in the 90% treatment resulted in dissolution of the metal-sulfide complexes and a gradual increase in labile metal concentrations during the experiment. However, the general trend of increasing availability in the sediment with time was not translated in rising M. aquaticum metal concentrations. Processes at the root-sediment interface, e.g., radial oxygen loss (ROL) or the release of organic compounds by plant roots and their effect on metal availability in the rhizosphere may be of larger importance for metal accumulation than the bulk metal mobility predicted by the SEM-AVS model.

  20. Isolation and Expression of the Lysis Genes of Actinomyces naeslundii Phage Av-1

    PubMed Central

    Delisle, Allan L.; Barcak, Gerard J.; Guo, Ming

    2006-01-01

    Like most gram-positive oral bacteria, Actinomyces naeslundii is resistant to salivary lysozyme and to most other lytic enzymes. We are interested in studying the lysins of phages of this important oral bacterium as potential diagnostic and therapeutic agents. To identify the Actinomyces phage genes encoding these species-specific enzymes in Escherichia coli, we constructed a new cloning vector, pAD330, that can be used to enrich for and isolate phage holin genes, which are located adjacent to the lysin genes in most phage genomes. Cloned holin insert sequences were used to design sequencing primers to identify nearby lysin genes by using whole phage DNA as the template. From partial digestions of A. naeslundii phage Av-1 genomic DNA we were able to clone, in independent experiments, inserts that complemented the defective λ holin in pAD330, as evidenced by extensive lysis after thermal induction. The DNA sequence of the inserts in these plasmids revealed that both contained the complete lysis region of Av-1, which is comprised of two holin-like genes, designated holA and holB, and an endolysin gene, designated lysA. We were able to subclone and express these genes and determine some of the functional properties of their gene products. PMID:16461656

  1. Early Warning Systems of natural disasters in the frame of EUNADICS-AV

    NASA Astrophysics Data System (ADS)

    Brenot, Hugues; Theys, Nicolas; Clarisse, Lieven; Kopp, Anna; Graf, Kaspar; Mona, Lucia; Coltelli, Mauro; Peltonen, Tuomas; Hirtl, Marcus; Virtanen, Timo; Nína Petersen, Guðrún

    2017-04-01

    Aviation is one of the most critical infrastructures of the 21st century. In Europe, safe flight operations, air traffic management and air traffic control are shared responsibilities of EUROCONTROL, national authorities, airlines and pilots. All stakeholders have one common goal, namely to warrant and maintain the safety of flight crews and passengers. Currently, however, there is a significant gap in the availability of real-time hazard measurement and monitoring information for airborne hazards. The main objective of the new Horizon 2020 project EUNADICS-AV (European Natural Airborne Disaster Information and Coordination System for Aviation; http://www.eunadics.eu) is to close this gap in data and information availability, enabling all stakeholders in the aviation system to obtain fast, coherent, and consistent information. Here we report on WP5 of EUNADICS-AV, the objective of which is to develop a prototype multi-hazard monitoring and early warning system. This task includes the development of a service for improved near real-time analyses (delay of a few hours maximum) of observations from satellite and ground-based platforms in order to detect ash and SO2 plumes (at the global scale), as well as desert sand dusts, fire plumes, and radioactive plumes.

  2. The use of C(av) rather than AUC in safety assessment.

    PubMed

    Smith, D A; Morgan, P; Vogel, W M; Walker, D K

    2010-06-01

    Toxicokinetic data have traditionally been presented as maximum observed plasma concentrations (C(max)) and area under the concentration time curve (AUC) values. These values have been used to compare exposures across studies and species to provide valuable interpretation of drug safety data. Increasingly, questions are asked of toxicology studies to more accurately describe the concentration effect relationships in terms of compound affinity for target and off-target receptors. C(max) values can immediately be referenced to known pharmacological activities, particularly when the extent of plasma protein binding is taken into account. This provides a measure of the more pharmacologically relevant free drug exposure. AUC values on the other hand contain the component of time, which means that direct comparison to pharmacological activity values are not immediately possible. Conversion of AUC to average plasma concentration (C(av)) provides a simple and convenient means to allow such a comparison without losing any information imparted by AUC values. In this paper, the benefit and advantage of applying C(av) values is illustrated using examples taken from the literature. (c) 2010 Elsevier Inc. All rights reserved.

  3. VizieR Online Data Catalog: NH and AV Towards YSOs in the ONC (Hasenberger+, 2016)

    NASA Astrophysics Data System (ADS)

    Hasenberger, B.; Forbrich, J.; Alves, J.; Wolk, S. J.; Meingast, S.; Getman, K. V.; Pillitteri, I.

    2016-07-01

    Column density (NH) and extinction (AV) values are sample of YSO sources in the ONC. Near-infrared colours based on the VISION (Meingast et al., 2016A&A...587A.153M) catalogue were employed to calculate extinction values using the NICER algorithm (Lombardi et al., 2001A&A...377.1023L) and assuming RV=3.1. Column densities were adopted from the COUP (Getman et al., 2005, Cat. J/ApJS/160/319) catalogue. In addition to NH and AV, the following quantities are provided: JHK_s magnitudes, taken from the VISION catalogue; spectral types, adopted from the catalogue by Hillenbrand et al. (2013, Cat. J/AJ/146/85); intrinsic near-infrared colours, deduced from spectral types and data by Scandariato et al. (2012A&A...545A..19S); and the YSO classification, based on the classification by Megeath et al. (2012, Cat. J/AJ/144/192). 1-Sigma error estimates are given for all quantities in the table. (1 data file).

  4. Effects of AvGard treatment on the microbiological flora of poultry carcases.

    PubMed

    Salvat, G; Coppen, P; Allo, J C; Fenner, S; Laisney, M J; Toquin, M T; Humbert, F; Colin, P

    1997-12-01

    1. The efficiency of the AvGard (or Assur-Rince in the USA) trisodium phosphate poultry carcase decontamination process was evaluated during both manual and industrial trials against total aerobic mesophilic count (TAMC), thermotolerant coliforms, Pseudomonas, Enterobacteriaceae, Campylobacter, Listeria monocytogenes and Salmonella. 2. The TSP treatment proved to have significant effects on the bacterial decontamination of poultry neck skin, lowering the contamination by a factor of about 10 for TAMC and of 100 for Coliform and Pseudomonas. 3. Numeration of Salmonella with an innovative miniaturised most probable number method has proved that the effect upon these micro-organisms was also close to 2 log10 reduction. 4. The effect of TSP treatment on the ecological balance of psychrotrophic bacterial flora was also investigated to study the origin of the shelf-life flora of treated carcases (Pseudomonas being reduced to the limit of detection) and to ascertain whether L. monocytogenes might gain a competitive advantage. In fact AvGard reduced the number of L. monocytogenes on poultry carcases. 5. As a consequence of the virtual elimination of the Pseudomonas usually present, Brochothrix thermosphacta became the main species responsible for putrefaction. 6. Because the growth rate of Brochothrix thermosphacta was greater than that of L. monocytogenes at refrigeration temperature, it was considered that putrefaction would occur before the emergence of large numbers of L. monocytogenes.

  5. Slow pathway modification in patients presenting with only two consecutive AV nodal echo beats.

    PubMed

    Wegner, Felix K; Silvano, Maria; Bögeholz, Nils; Leitz, Patrick R; Frommeyer, Gerrit; Dechering, Dirk G; Zellerhoff, Stephan; Kochhäuser, Simon; Lange, Philipp S; Köbe, Julia; Wasmer, Kristina; Mönnig, Gerold; Eckardt, Lars; Pott, Christian

    2017-02-01

    Slow pathway modification (SPM) is the therapy of choice for AV-nodal reentry tachycardia (AVNRT). When AVNRT is not inducible, empirical ablation can be considered, however, the outcome in patients with two AV nodal echo beats (AVNEBs) is unknown. Out of a population of 3003 patients who underwent slow pathway modification at our institution between 1993 and 2013, we retrospectively included 32 patients with a history of symptomatic tachycardia, lack of paroxysmal supraventricular tachycardia (pSVT) inducibility but occurrence of two AVNEBs. pSVT documentation by electrocardiography (ECG) was present in 20 patients. The procedural endpoint was inducibility of less than two AVNEBs. This was reached in 31 (97%) patients. Long-term success was assessed by a telephone questionnaire (follow-up time 63±9 months). A total 94% of the patients benefited from the procedure (59% freedom from symptoms; 34% improvement in symptoms). Among those patients in whom ECG documentation was not present, 100% benefited (58% freedom from symptoms, 42% improvement). This is the first collective analysis of a group of patients presenting with symptoms of pSVT and inducibility of only two AVNEBs. Procedural success and clinical long-term follow-up were in the range of the reported success rates of slow pathway modification of inducible AVNRT, independent of whether ECG documentation was present. Thus, SPM is a safe and effective therapy in patients with two AVNEBs. Copyright © 2016. Published by Elsevier Ltd.

  6. Geologic Mapping of the Av-9 Numisia Quadrangle of Asteroid 4Vesta

    NASA Astrophysics Data System (ADS)

    Buczkowski, D.; Wyrick, D.; Capaccioni, F.; Scully, J.; Williams, D.; Hiesinger, H.; Garry, W.; Yingst, R.; LeCorre, L.; Nathues, A.; Schenk, P.; Jaumann, R.; Raymond, C.; Pieters, C.; Roatsch, T.; Preusker, F.; Russell, C.

    2012-04-01

    NASA's Dawn spacecraft arrived at the asteroid 4Vesta on July 16, 2011, and is now collecting imaging, spectroscopic, and elemental abundance data during its one-year orbital mission. As part of the geological analysis of the surface, the Dawn Science Team has begun geologic map-ping of Vesta's surface at the global scale and as a series of 15 quadrangle maps that are being produced based on Framing Camera (FC) images, along with Visible & Infrared Spectrometer data (VIR) obtained during the High-Altitude Mapping Orbit (HAMO). We here concentrate on our geologic analysis and mapping of quadrangle Av-9 Numisia, located in the equatorial region of Vesta, extending from 22˚N - 22˚S and from 216° - 288° E. Clear filter (monochrome) FC HAMO images (~70 m/p) were mosaicked to make a base for this quadrangle. Topography of Av-9, is observed in a colorized Digital Terrain Model (DTM) derived from Survey orbit FC data. Variations in surface composition are revealed by VIR hyperspectral images from Survey (700 m/p) and HAMO (200 m/p) orbits and FC color ratio images (250 m/p) from Survey orbit. Av-9 Numisia is dominated by Vestalia Terra, a distinct, albedo-bright, topographically high region of Vesta bound by steep scarps and crossed by a roughly linear unit of dark material from the northwest to the southeast. This "dark ribbon" is primarily evident in FC color ratio data but is also discernable in clear filter data. The dark material appears to fill a locally low region on top of Vestalia Terra. The ribbon-like feature is cut by Numisia crater, which shows both bright and dark layers in its walls; the dark layers may thus be exposures of subsurface "dark ribbon" material. The origin of the "dark ribbon" material has yet to be determined, but possibilities include impact ejecta flow and/or volcanism. FC color ratio images using standard Clementine ratios [Red (750/430 nm); Green (750/920 nm); Blue (430/750 nm)] show that many of the impact craters in Av-9 have

  7. AV Reviews.

    ERIC Educational Resources Information Center

    Hays, Rachel, Ed.

    1990-01-01

    Reviewed are four videotapes for use in biology classrooms. Included are "The Biochemical Basis of Biology. Part 2--DNA and Protein Synthesis,""The Rocky Shores,""A Visit to the Rocky Shores," and "Our Immune System." Described are the content, cost, and availability of each video. (CW)

  8. COORDINATED AV.

    ERIC Educational Resources Information Center

    CLEAVES, PAUL C.; AND OTHERS

    THE INSTRUCTIONAL MATERIALS CENTER IS LOCATED IN THE LOCAL HIGH SCHOOL AND SUPPLIES ALL SCHOOLS IN THE AREA. AUDIOVISUAL EQUIPMENT ORDERS, AFTER SELECTIONS ARE MADE BY THE CLASSROOM TEACHER, ARE PROCESSED BY THE CENTER, CONFIRMED AND DELIVERED BY TRUCK THREE TIMES EACH WEEK. EACH SCHOOL HAS A BUILDING COORDINATOR WHO CHECKS THE ORDERS INTO THE…

  9. COORDINATED AV.

    ERIC Educational Resources Information Center

    CLEAVES, PAUL C.; AND OTHERS

    THE INSTRUCTIONAL MATERIALS CENTER IS LOCATED IN THE LOCAL HIGH SCHOOL AND SUPPLIES ALL SCHOOLS IN THE AREA. AUDIOVISUAL EQUIPMENT ORDERS, AFTER SELECTIONS ARE MADE BY THE CLASSROOM TEACHER, ARE PROCESSED BY THE CENTER, CONFIRMED AND DELIVERED BY TRUCK THREE TIMES EACH WEEK. EACH SCHOOL HAS A BUILDING COORDINATOR WHO CHECKS THE ORDERS INTO THE…

  10. AV Reviews.

    ERIC Educational Resources Information Center

    Hays, Rachel, Ed.

    1989-01-01

    Presents teacher comments on audiovisual materials dealing with: biotechnology applications in immunology, agriculture, and cancer research; efforts to halt the eutrophication of Lake Tahoe; and banana slugs. Availability and costs of materials are included. (RT)

  11. AV Review.

    ERIC Educational Resources Information Center

    Friedstein, Harriet, Ed.

    1981-01-01

    Presents a list of the producer, catalog number, format, and price of audiovisual aids for: acids, bases, and salts; atomic structure and atoms; biochemistry; bonds; water chemistry (solutions); changes of state; and electrochemistry. Includes a separate list of names and addresses of randomly selected producers of audiovisual materials. (SK)

  12. AV Reviews.

    ERIC Educational Resources Information Center

    Hays, Rachel, Ed.

    1989-01-01

    Presents teacher comments on audiovisual materials dealing with: biotechnology applications in immunology, agriculture, and cancer research; efforts to halt the eutrophication of Lake Tahoe; and banana slugs. Availability and costs of materials are included. (RT)

  13. AV Reviews.

    ERIC Educational Resources Information Center

    Hays, Rachel, Ed.

    1990-01-01

    Reviewed are four videotapes for use in biology classrooms. Included are "The Biochemical Basis of Biology. Part 2--DNA and Protein Synthesis,""The Rocky Shores,""A Visit to the Rocky Shores," and "Our Immune System." Described are the content, cost, and availability of each video. (CW)

  14. AV Corner.

    ERIC Educational Resources Information Center

    Berry, Donna A., Ed.

    1990-01-01

    Reviewed are two 35MM slide sets "Halley's Comet Revealed" and "Supernova 1987A"; and a videotape entitled "Experiments; Physics Level 1. Magnetic Fields." Features, availability, strengths and weaknesses are discussed. (CW)

  15. AV Corner.

    ERIC Educational Resources Information Center

    Berry, Donna A., Ed.

    1990-01-01

    Reviews three videotapes for physics teachers: (1) "Determination of the Newtonian Constant of Gravitation" showing the Cavendish experiment; (2) "Preview Film for RAM-Tutor Media" introducing a series of seven videocassettes covering physics; and (3) "Determination of the Velocity of Light" using a rotating mirror. (YP)

  16. AV Corner.

    ERIC Educational Resources Information Center

    Berry, Donna A., Ed.

    1990-01-01

    Reviews three videotapes for physics teachers: (1) "Determination of the Newtonian Constant of Gravitation" showing the Cavendish experiment; (2) "Preview Film for RAM-Tutor Media" introducing a series of seven videocassettes covering physics; and (3) "Determination of the Velocity of Light" using a rotating mirror. (YP)

  17. AV Corner.

    ERIC Educational Resources Information Center

    Berry, Donna A., Ed.

    1990-01-01

    Reviewed are two 35MM slide sets "Halley's Comet Revealed" and "Supernova 1987A"; and a videotape entitled "Experiments; Physics Level 1. Magnetic Fields." Features, availability, strengths and weaknesses are discussed. (CW)

  18. What Engages Students in MetaL-FrOG? A Triarchy Perspective on Meta-Cognitive Learning

    ERIC Educational Resources Information Center

    Fa, Ng Sen; Hussin, Firuz Hussin

    2008-01-01

    This paper presents the central ideas of a grounded theory research by the name of Triarchy Perspective on Metacognitive Learning in Free Online Groups, or "TriP on MetaL-FrOG" in short. The research setting was online learning community on the platform of Free Online Group web (FrOG) intended for post-graduate students. The research…

  19. Transcriptomic differences of genes in the avian target of rapamycin (avTOR) pathway in a divergent line of meat-type chickens selected for feed efficiency.

    PubMed

    Lee, J; Aggrey, S E

    2016-06-30

    Avian target of rapamycin (avTOR) is a highly conserved serine-threonine kinase that serves as an intracellular energy and nutrient sensor and regulates cell division, growth, and apoptosis. The role of avTOR in mediating feed intake and growth in poultry is unknown. We studied avTOR signaling activities in duodenum and liver tissues at days 35 and 42 in chickens divergently selected for low (LRFI) or high (HRFI) residual feed intake. The differential expression of genes involved in the avTOR pathway was assayed using real-time polymerase chain reaction. In the duodenum, avTOR was up-regulated in the LRFI chickens at both time points as compared with the HRFI chickens. Other genes found to be differentially expressed at day 35 included v-akt murine thymoma viral oncogene homolog, eukaryotic translation elongation factor 2, eukaryotic translation initiation factor 4E binding protein 1, 3-phosphoinositide dependent protein kinase-1, ribosomal protein S6 kinase, 70 kDa, polypeptide 1 (RPS6KP1), avTOR associated protein, LST8 homolog, ghrelin, phosphoinositide-3-kinase (PI3K), forkhead box O1, and p53 E3 ubiquitin protein ligase homolog (MDM2). At day 42, there was no change in the expression of the avTOR target RPS6KP1 or MDM2. In the liver, changes in the expression of components of the avTOR pathway primarily occurred at day 42, and differential gene expression suggests that avTOR complex 1 (avTORC1) affects feed efficiency at day 42. avTORC1 may be activated in the duodenum of feed-efficient birds to increase nutrient mobilization to other peripheral tissues. Furthermore, activation of avTOR in relation to feed efficiency may be tissue specific and may depend on the tissue's need for growth and nutrient transport. Genetic markers in key genes involved in the avTOR/PI3K pathway could be developed to improve feed efficiency in meat-type chickens.

  20. Balloon launched decelerator test program: Post-flight test report, BLDT vehicle AV-3, Viking 1975 project

    NASA Technical Reports Server (NTRS)

    Dickinson, D.; Hicks, F.; Schlemmer, J.; Michel, F.; Moog, R. D.

    1973-01-01

    The pertinent events concerned with the launch, float, and flight of balloon launched decelerator test vehicle AV-3 are discussed. The performance of the decelerator system is analyzed. Data on the flight trajectory and decelerator test points at the time of decelerator deployment are provided. A description of the time history of vehicle events and anaomalies encounters during the mission is included.

  1. Aeromonas molluscorum Av27 is a potential tributyltin (TBT) bioremediator: phenotypic and genotypic characterization indicates its safe application.

    PubMed

    Cruz, Andreia; Areias, Dário; Duarte, Ana; Correia, António; Suzuki, Satoru; Mendo, Sónia

    2013-09-01

    Aeromonas molluscorum Av27 is an estuarine bacterium highly resistant to tributyltin (TBT). Also, the strain is able to degrade TBT into the less toxic compounds dibutyltin and monobutyltin. Therefore, this bacterium has potential to be employed in bioremediation processes. In this context, defining its biological safety is crucial. With that purpose a number of intrinsic characteristics, usually present/associated with virulent strains, were investigated. Few virulence factors were detected in strain Av27. For instance, a DNase gene is present, but it is not apparently expressed in vitro. Motility, adherence factor and phospholipase activity were also detected. Additionally, cytotoxicity to Vero cells was negative. Resistance to penicillin (10 μg ml(-1)), amoxicillin/clavulanic acid (30 μg ml(-1)) and cephalothin (30 μg ml(-1)) and also to the vibriostatic agent O/129 was observed. Five plasmids (4, 7, 10, 100 kb and one greater than 100 kb) were identified. No Class I and II integrons were detected. Study of the optimal growth conditions showed that Av27 easily adapts to different environmental conditions. Overall, the results suggest that A. molluscorum Av27 can be considered safe to use to bioremediate TBT in contaminated environments.

  2. 18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers.

    PubMed

    Smith, Ruben; Puschmann, Andreas; Schöll, Michael; Ohlsson, Tomas; van Swieten, John; Honer, Michael; Englund, Elisabet; Hansson, Oskar

    2016-09-01

    Tau positron emission tomography ligands provide the novel possibility to image tau pathology in vivo However, little is known about how in vivo brain uptake of tau positron emission tomography ligands relates to tau aggregates observed post-mortem. We performed tau positron emission tomography imaging with (18)F-AV-1451 in three patients harbouring a p.R406W mutation in the MAPT gene, encoding tau. This mutation results in 3- and 4-repeat tau aggregates similar to those in Alzheimer's disease, and many of the mutation carriers initially suffer from memory impairment and temporal lobe atrophy. Two patients with short disease duration and isolated memory impairment exhibited (18)F-AV-1451 uptake mainly in the hippocampus and adjacent temporal lobe regions, correlating with glucose hypometabolism in corresponding regions. One patient died after 26 years of disease duration with dementia and behavioural deficits. Pre-mortem, there was (18)F-AV-1451 uptake in the temporal and frontal lobes, as well as in the basal ganglia, which strongly correlated with the regional extent and amount of tau pathology in post-mortem brain sections. Amyloid-β ((18)F-flutemetamol) positron emission tomography scans were negative in all cases, as were stainings of brain sections for amyloid. This provides strong evidence that (18)F-AV-1451 positron emission tomography can be used to accurately quantify in vivo the regional distribution of hyperphosphorylated tau protein.

  3. Structural features and formation of lower Cretaceous AV1 layer in the Soviet oil field (Tomsk Oblast)

    NASA Astrophysics Data System (ADS)

    Zhamsaranova, A. B.; Osipova, E. N.; Gaydukova, T. A.; Aksenova, N. V.

    2016-09-01

    The analysis of the collected geological and geophysical information on AV1 layer known as Ryabchik formation is carried out. The facial conditions of this formation which define structural features of «Ryabchik» sandstones formations are considered. Maps characterizing permeability and porosity of reservoir are plotted. Areal tracking technique of sand streaks is given.

  4. Selective autonomic stimulation of the AV node fat pad to control rapid post-operative atrial arrhythmias.

    PubMed

    Mercader, Marco A; He, Dingchao; Sharma, Aditya C; Marchitto, Mark C; Trachiotis, Gregory; Bornzin, Gene A; Jonas, Richard; Moak, Jeffrey P

    2017-01-01

    Junctional ectopic tachycardia (JET) and atrial fibrillation (AF) occur in patients recovering from open-heart surgery (OHS). Pharmacologic treatment is used for the control of post-operative atrial arrhythmias (POAA), but is associated with side effects. There is a need for a reversible, modulated solution to rate control. We propose a non-pharmacologic technique that can modulate AV nodal conduction in a selective fashion. Ten mongrel dogs underwent OHS. Stimulation of the anterior right (AR) and inferior right (IR) fat pad (FP) was done using a 7-pole electrode. The IR was more effective in slowing the ventricular rate (VR) to AF (52 +/- 20 vs. 15 +/- 10%, p = 0.003) and JET (12 +/- 7 vs. 0 +/- 0%, p = 0.02). Selective site stimulation within a FP region could augment the effect of stimulation during AF (57 +/- 20% (maximum effect) vs. 0 +/- 0% (minimum effect), p<0.001). FP stimulation at increasing stimulation voltage (SV) demonstrated a voltage-dependent effect (8 +/- 14% (low V) vs. 63 +/- 17 (high V) %, p<0.001). In summary, AV node fat pad stimulation had a selective effect on the AV node by decreasing AV nodal conduction, with little effect on atrial activity.

  5. 18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers

    PubMed Central

    Puschmann, Andreas; Schöll, Michael; Ohlsson, Tomas; van Swieten, John; Honer, Michael; Englund, Elisabet

    2016-01-01

    Tau positron emission tomography ligands provide the novel possibility to image tau pathology in vivo. However, little is known about how in vivo brain uptake of tau positron emission tomography ligands relates to tau aggregates observed post-mortem. We performed tau positron emission tomography imaging with 18F-AV-1451 in three patients harbouring a p.R406W mutation in the MAPT gene, encoding tau. This mutation results in 3- and 4-repeat tau aggregates similar to those in Alzheimer’s disease, and many of the mutation carriers initially suffer from memory impairment and temporal lobe atrophy. Two patients with short disease duration and isolated memory impairment exhibited 18F-AV-1451 uptake mainly in the hippocampus and adjacent temporal lobe regions, correlating with glucose hypometabolism in corresponding regions. One patient died after 26 years of disease duration with dementia and behavioural deficits. Pre-mortem, there was 18F-AV-1451 uptake in the temporal and frontal lobes, as well as in the basal ganglia, which strongly correlated with the regional extent and amount of tau pathology in post-mortem brain sections. Amyloid-β (18F-flutemetamol) positron emission tomography scans were negative in all cases, as were stainings of brain sections for amyloid. This provides strong evidence that 18F-AV-1451 positron emission tomography can be used to accurately quantify in vivo the regional distribution of hyperphosphorylated tau protein. PMID:27357347

  6. Spectroscopic Classification of ASASSN-16ar, ASASSN-16av and ASASSN-16ax as Type Ia SNe

    NASA Astrophysics Data System (ADS)

    Falco, E.; Macri, L.; Stringer, K.; Prieto, J. L.; Challis, P.; Kirshner, R.

    2016-02-01

    We obtained optical spectra (range 350-760 nm) of ASASSN-16ar (ATel #8565), ASASSN-16av (ATel #8569), and ASASSN-16ax (ATel #8594) on UT 2016 Feb 4 with the F. L. Whipple Observatory 1.5-m telescope (+ FAST).

  7. Assessment of the use of the AVS concept for the routine toxicity monitoring of contaminated freshwater sediments

    SciTech Connect

    Vangheluwe, M.L.; Janssen, C.R.; Goyvaerts, M.P.; Cooman, P.

    1995-12-31

    Acid volatile sulfides (AVS) have been shown to be an important factor mediating the bioavailability of heavy metals in sediments and have consequently been suggested as a possible predictive tool for toxicity assessment of these matrices. The potential use and limitations of the AVS method for predictive toxicity screening and priority setting was assessed in a large scale sediment monitoring study (Flanders, Belgium). The acute toxicity of 50 metal contaminated freshwater sediments, with varying metal concentrations and sediment characteristics, were tested using the Microtox{reg_sign} Solid Phase test and the 10 day test with Chironomus riparius and Hyalella azteca. Uni and multivariate statistical techniques were used to asses the relations between acute toxicity and SEM/AVS ratio`s and to evaluate the influence of sediment characteristics on metal bioavailability and toxicity. In general, the results of this study indicate that the AVS-toxicity relationship proposed in literature does have certain limitations. Finally, the potential use of a concentration-addition model for predicting metal-mixture toxicity in sediments will be presented and discussed.

  8. Balloon launched decelerator test program: Post-flight test report, BLDT vehicle AV-2, Viking 1975 project

    NASA Technical Reports Server (NTRS)

    Dickinson, D.; Hicks, F.; Schlemmer, J.; Michel, F.; Moog, R. D.

    1972-01-01

    The pertinent events concerned with the launch, float, and flight of balloon launched decelerator test vehicle AV-2 are discussed. The performance of the decelerator system is analyzed. Data on the flight trajectory and decelerator test points at the time of decelerator deployment are provided. A description of the time history of vehicle events and anomalies encounters during the mission is included.

  9. Location Capability and Site Characterization Installing a Borehole VBB Seismometer: the OGS Experience in Ferrara (Italy)

    NASA Astrophysics Data System (ADS)

    Pesaresi, D.; Barnaba, C.

    2014-12-01

    The Centro di Ricerche Sismologiche (CRS, Seismological Research Centre) of the Istituto Nazionale di Oceanografia e di Geofisica Sperimentale (OGS, Italian National Institute for Oceanography and Experimental Geophysics) in Udine (Italy) after the strong earthquake of magnitude M=6.4 occurred in 1976 in the Italian Friuli-Venezia Giulia region, started to operate the Northeastern Italy Seismic Network: it currently consists of 19 very sensitive broad band and 17 simpler short period seismic stations, all telemetered to and acquired in real time at the OGS CRS data centre in Udine. The southwestern edge of the OGS seismic network stands on the Po alluvial basin: earthquake localization and characterization in this area is affected by the presence of soft alluvial deposits. Following the ML=5.9 earthquake that struck the Emilia region around Ferrara in Northern Italy on May 20, 2012, a cooperation of Istituto Nazionale di Geofisica e Vulcanologia, OGS, the Comune di Ferrara and the University of Ferrara lead to the reinstallation of a previously existing very broad band (VBB) borehole seismic station in Ferrara and to the deployment of a temporary seismographic network consisting of eight portable seismological stations, to record the local earthquakes that occurred during the seismic sequence. The aim of the OGS intervention was on one hand to extend its real time seismic monitoring capabilities toward South-West, including Ferrara and its surroundings, and on the other hand to evaluate seismic site responses in the area. We will introduce details of the Ferrara VBB borehole station and the OGS temporary seismographic network configuration and installation. We will then illustrate the location capability performances, and finally we will shortly describe seismic site characterization with surface/borehole comparisons in terms of seismic noise, site amplification and resonance frequencies.

  10. The glial cell modulators, ibudilast and its amino analog, AV1013, attenuate methamphetamine locomotor activity and its sensitization in mice

    PubMed Central

    SNIDER, SARAH E.; VUNCK, SARAH A.; VAN DEN OORD, EDWIN J.C.G.; ADKINS, DANIEL E.; MCCLAY, JOSEPH L.; BEARDSLEY, PATRICK M.

    2014-01-01

    Over 800,000 Americans abuse the psychomotor stimulant, methamphetamine, yet its abuse is without an approved medication. Methamphetamine induces hypermotor activity, and sensitization to this effect is suggested to represent aspects of the addiction process. Methamphetamine’s regulation of 3'-5'-cyclic adenosine monophosphate (cAMP) levels may be partially responsible for its behavioral effects, and compounds that inhibit phosphodiesterase (PDE), the enzyme that degrades cAMP, can alter methamphetamine-induced behaviors. Methamphetamine also activates glial cells and causes a subsequent increase in pro-inflammatory cytokine levels. Modulation of glial cell activation is associated with changes in behavioral responses, and substances that oppose inflammatory activity can attenuate drug-induced behaviors. Ibudilast (aka AV411; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine), inhibits both PDE and glial pro-inflammatory activity. Ibudilast’s amino analogue, AV1013, modulates similar glial targets but negligibly inhibits PDE. The present study determined whether ibudilast and AV1013 would attenuate methamphetamine-induced locomotor activity and its sensitization in C57BL/6J mice. Mice were treated b.i.d. with ibudilast (1.8-13 mg/kg), AV1013 (10-56mg/kg) or their vehicles intraperitoneally for 7 days, beginning 48 h before 5 days of daily 1-h locomotor activity tests. Each test was initiated by either a methamphetamine (3 mg/kg) or a saline injection. Ibudilast significantly (P<0.05) reduced the acute, chronic, and sensitization effects of methamphetamine's locomotor activity without significantly affecting activity by itself. AV1013 had similar anti-methamphetamine effects, suggesting that glial cell activity, by itself, can modulate methamphetamine's effects and perhaps serve as a medication target for its abuse. PMID:22306241

  11. A microcosm approach to evaluate the degradation of tributyltin (TBT) by Aeromonas molluscorum Av27 in estuarine sediments.

    PubMed

    Cruz, Andreia; Henriques, Isabel; Sousa, Ana C A; Baptista, Inês; Almeida, Adelaide; Takahashi, Shin; Tanabe, Shinsuke; Correia, António; Suzuki, Satoru; Anselmo, Ana Maria; Mendo, Sónia

    2014-07-01

    Tributyltin (TBT) is a biocide extremely toxic to a wide range of organisms, which has been used for decades in antifouling paints. Despite its global ban in 2008, TBT is still a problem of great concern due to the high levels trapped in sediments. Aeromonas molluscorum Av27 is a TBT degrading bacterium that was isolated from an estuarine system. We investigated the ability and the role of this bacterium on TBT degradation in this estuarine system, using a microcosm approach in order to mimic environmental conditions. The experiment was established and followed for 150 days. Simultaneously, changes in the indigenous bacterial community structure were also investigated. The results revealed a maximum TBT degradation rate of 28% accompanied by the detection of the degradation products over time. Additionally, it was observed that TBT degradation was significantly enhanced by the presence of Av27. In addition a significantly higher TBT degradation occurred when the concentration of Av27 was higher. TBT degradation affected the bacterial community composition as revealed by the changes in the prevalence of Proteobacteria subdivisions, namely the increase of Deltaproteobacteria and the onset of Epsilonproteobacteria. However, the addition of Av27 strain did not affect the dominant phylotypes. Total bacterial number, bacterial biomass productivity, 16S rRNA gene and denaturing gradient gel electrophoresis (DGGE) analyses also indicated alterations on the bacterial community structure over time, with bacteria non-tolerant to pollutants increasing their representativeness, as, for instance, the increase of the number of Alphaproteobacteria clones from 6% in the beginning to 12% at the end of the experiment. The work herein presented confirms the potential of Av27 strain to be used in the decontamination of TBT-polluted environments.

  12. The Pattern of Brain Amyloid Load in Posterior Cortical Atrophy Using 18F-AV45: Is Amyloid the Principal Actor in the Disease?

    PubMed Central

    Beaufils, Emilie; Ribeiro, Maria Joao; Vierron, Emilie; Vercouillie, Johnny; Dufour-Rainfray, Diane; Cottier, Jean-Philippe; Camus, Vincent; Mondon, Karl; Guilloteau, Denis; Hommet, Caroline

    2014-01-01

    Background Posterior cortical atrophy (PCA) is characterized by progressive higher-order visuoperceptual dysfunction and praxis declines. This syndrome is related to a number of underlying diseases, including, in most cases, Alzheimer's disease (AD). The aim of this study was to compare the amyloid load with 18F-AV45 positron emission tomography (PET) between PCA and AD subjects. Methods We performed 18F-AV45 PET, cerebrospinal fluid (CSF) biomarker analysis and a neuropsychological assessment in 11 PCA patients and 12 AD patients. Results The global and regional 18F-AV45 uptake was similar in the PCA and AD groups. No significant correlation was observed between global 18F-AV45 uptake and CSF biomarkers or between regional 18F-AV45 uptake and cognitive and affective symptoms. Conclusion This 18F-AV45 PET amyloid imaging study showed no specific regional pattern of cortical 18F-AV45 binding in PCA patients. These results confirm that a distinct clinical phenotype in amnestic AD and PCA is not related to amyloid distribution. PMID:25538727

  13. Preparation and stability of ethanol-free solution of [18F]florbetapir ([18F]AV-45) for positron emission tomography amyloid imaging.

    PubMed

    Hayashi, Kazutaka; Tachibana, Akiko; Tazawa, Shusaku; Mizukawa, Yosuke; Osaki, Katsuhiko; Morimoto, Yoko; Zochi, Riyo; Kurahashi, Masahiro; Aki, Hatsumi; Takahashi, Kazuhiro

    2013-05-15

    We have developed an ethanol-free formulation method of [(18) F]florbetapir ([(1) (8) F]AV-45) using a commercially available automated JFE multi-purpose synthesizer. We have also evaluated the radiochemical stability in an ethanol-free solution of [(18) F]AV-45 under visible light irradiation and dark conditions by comparison with a conventional 10% ethanol solution of [(18) F]AV-45. [(18) F]AV-45 was obtained with a radiochemical yield of 55.1 ± 2.2% (decay-corrected to end of bombardment), specific activity of 591.6 ± 90.3 GBq/µmol and radiochemical purity of >99% within a total synthesis time of about 73 min. The radiochemical purity of [(18) F]AV-45 formulated by dissolving the ethanol-free solution was found to decrease as a function of the period of exposure to visible light. In contrast, the visible light photolysis could be suppressed by adding 10% ethanol to the formulation or by avoiding exposure to visible light. In the radiosynthesis of [(18) F]AV-45 formulated by dissolving the ethanol-free solution, [(18) F]AV-45 could be obtained with high radiochemical purity and high stability by avoiding exposure to visible light.

  14. Circulating Fibroblast Growth Factor-23 Level and Paraoxonase-1 Lactonase Activity in Chronic Hemodialysis Patients: Their Impact on the Incidence of Native AV Fistula Thrombosis.

    PubMed

    Zohny, Samir F; El-Fattah, Mahmoud Abd; Khan, Jalaluddin A

    2016-10-14

    Thrombosis of native arteriovenous (AV) fistula is an important cause of complications in hemodialysis (HD) patients. The purpose of this study was to investigate the usefulness of measuring circulating fibroblast growth factor-23 (FGF-23) level and paraoxonase-1 (PON1) lactonase activity as potential predictors of native AV fistula thrombosis in chronic HD patients. This study included 83 HD patients (48 with thrombosed and 35 with non-thrombosed native AV fistulas) and 38 healthy volunteers. Serum FGF-23 level was measured using the ELISA technique, while serum PON1 lactonase activity was measured spectrophotometrically using gamma-thiobutyrolactone as a substrate. FGF-23 was significantly increased while PON1 lactonase was markedly decreased in both thrombosed and non-thrombosed HD patients compared with controls (P < 0.001). FGF-23 was elevated whereas PON1 lactonase was decreased in HD patients with thrombosed native AV fistulas compared with HD patients with non-thrombosed native AV fistulas (P = 0.001 and 0.002, respectively). A significant negative correlation was found between FGF-23 and PON1 lactonase in HD patients with thrombosed native AV fistulas (r = -0.342, P = 0.017). This study shows a potential value of FGF-23 and PON1 lactonase as predictors of native AV fistula thrombosis in HD patients.

  15. Evaluating the Effects of Metals on Microorganisms in Flooded Paddy Soils Using the SEM/AVS-Based Approach and Measurements of Exchangeable Metal Concentrations.

    PubMed

    Kunito, Takashi; Toya, Hitomi; Sumi, Hirotaka; Ishikawa, Yuichi; Toda, Hideshige; Nagaoka, Kazunari; Saeki, Kazutoshi; Aikawa, Yoshio; Matsumoto, Satoshi

    2017-04-01

    We examined possible adverse effects of heavy metals on microbial activity, biomass, and community composition using the simultaneously extracted metals (SEM)/acid-volatile sulfide (AVS)-based approach and measurements of exchangeable metal concentrations in three paddy soils (wastewater-contaminated soil, mine-contaminated soil, and noncontaminated soil) incubated for 60 days under flooded conditions. Incubation under flooding increased pH and decreased Eh in all samples. AVS increased when Eh decreased to approximately -200 mV for the mine-contaminated and noncontaminated soils, while the wastewater-contaminated soil originally had a high concentration of AVS despite its air-dried condition. Addition of rice straw or alkaline material containing calcium carbonate and gypsum increased AVS levels under flooded conditions. We observed no apparent relationship between soil enzyme activity (β-D-glucosidase and acid phosphatase) and concentrations of SEM, [∑SEM - AVS], and exchangeable metals. Bacterial and fungal community composition, assessed using polymerase chain reaction-denaturing gradient gel electrophoresis (DGGE) analysis targeting rRNA genes, was largely influenced by site of collection and incubation time, but metal contamination did not influence community composition. We observed significant negative correlations between biomass C and [∑SEM - AVS] and between biomass C and ∑SEM, suggesting that [∑SEM - AVS] and ∑SEM might reflect the bioavailability of organic matter to microorganisms in these soils.

  16. Introduction to COFFE: The Next-Generation HPCMP CREATE-AV CFD Solver

    NASA Technical Reports Server (NTRS)

    Glasby, Ryan S.; Erwin, J. Taylor; Stefanski, Douglas L.; Allmaras, Steven R.; Galbraith, Marshall C.; Anderson, W. Kyle; Nichols, Robert H.

    2016-01-01

    HPCMP CREATE-AV Conservative Field Finite Element (COFFE) is a modular, extensible, robust numerical solver for the Navier-Stokes equations that invokes modularity and extensibility from its first principles. COFFE implores a flexible, class-based hierarchy that provides a modular approach consisting of discretization, physics, parallelization, and linear algebra components. These components are developed with modern software engineering principles to ensure ease of uptake from a user's or developer's perspective. The Streamwise Upwind/Petrov-Galerkin (SU/PG) method is utilized to discretize the compressible Reynolds-Averaged Navier-Stokes (RANS) equations tightly coupled with a variety of turbulence models. The mathematics and the philosophy of the methodology that makes up COFFE are presented.

  17. Geologic Mapping of the Av-14 Urbinia Quadrangle of Asteroid 4 Vesta

    NASA Astrophysics Data System (ADS)

    Mest, S. C.; Yingst, R. A.; Williams, D. A.; Garry, W. B.; Pieters, C. M.; Jaumann, R.; Buczkowski, D. L.; Sykes, M. V.; Wyrick, D. Y.; Schenk, P. M.; Russell, C. T.; Raymond, C. A.; Neukum, G.; Schmedemann, N.; Roatsch, T.; Preusker, F.; Ammannito, E.

    2012-04-01

    NASA's Dawn spacecraft is providing unprecedented views of the surface of 4 Vesta since it went into orbit in July 2011. Dawn is actively gathering an abundance of image, spectral and topographic data to characterize the geology, composition, shape and internal structure of the ~560-km-diameter asteroid. Geologic mapping of Vesta's surface is being undertaken at the global and regional scales by subdividing Vesta into 15 quadrangles. Here, we report the mapping results for quadrangle Av-14, the Urbinia quadrangle of Vesta, derived from data acquired during the High Altitude Mapping Orbit (HAMO) and Survey orbit. Base materials for mapping include HAMO-derived monochrome (clear filter) Framing Camera (FC) mosaic (~70 m/pixel and a Digital Terrain Model (DTM) derived from Survey orbit FC data (450 m/pixel). We also use FC color ratio images (~250 m/pixel) from Survey orbit and Visible and InfraRed (VIR) hyperspectral images from Survey (700 m/pixel) and HAMO (200 m/pixel) orbits to provide information on surface composition and refine unit boundaries. The Av-14 Quadrangle covers the region between 21°-66°S latitude and 270°-360°E longitude. The quadrangle is named after crater Urbinia (D=24 km; 30°S, 276°E), which displays an ejecta blanket with moderate albedo and a smooth, lightly cratered surface. The map area is dominated by moderately cratered equatorial terrains and lightly cratered, but highly deformed, southern terrains. The topographic gradient of the map area is declined toward the south from the more elevated equatorial terrain to the relatively lower interior of the Rheasilivia impact basin. Av-14 contains two dominant terrains - (1) intermediately-cratered equatorial terrain bearing flat-floored, E-W-trending troughs, and (2) relatively lightly-cratered south polar terrain, which contains the Rheasilvia impact basin and related terrains. The northern part of the quadrangle is covered by the moderately cratered equatorial ridge-and-trough terrain

  18. The dependence of the AV prior for SN Ia on host mass and disc inclination

    NASA Astrophysics Data System (ADS)

    Holwerda, B. W.; Keel, W. C.; Kenworthy, M. A.; Mack, K. J.

    2015-08-01

    Type Ia supernovae (SNe Ia) are used as `standard candles' for cosmological distance scales. To fit their light-curve shape-absolute luminosity relation, one needs to assume an intrinsic colour and a likelihood of host galaxy extinction or a convolution of these, a colour distribution prior. The host galaxy extinction prior is typically assumed to be an exponential drop-off for the current supernova programmes (P(A_V) ∝ e^{-A_V/τ_0}). We explore the validity of this prior using the distribution of extinction values inferred when two galaxies accidentally overlap (an occulting galaxy pair). We correct the supernova luminosity distances from the SDSS-III supernova projects (SDSS-SN) by matching the host galaxies to one of three templates from occulting galaxy pairs based on the host galaxy mass and the AV-bias-prior-scale (τ0) relation from Jha et al. We find that introducing an AV prior that depends on host mass results in lowered luminosity distances for the SDSS-SN on average but it does not reduce the scatter in individual measurements. This points, in our view, to the need for many more occulting galaxy templates to match to SN Ia host galaxies to rule out this possible source of scatter in the SN Ia distance measurements. We match occulting galaxy templates based on both mass and projected radius and we find that one should match by stellar mass first with radius as a secondary consideration. We discuss the caveats of the current approach: the lack of enough radial coverage, the small sample of priors (occulting pairs with HST data), the effect of gravitationally interacting as well as occulting pairs, and whether an exponential distribution is appropriate. Our aim is to convince the reader that a library of occulting galaxy pairs observed with HST will provide sufficient priors to improve (optical) SN Ia measurements to the next required accuracy in cosmology.

  19. Independent effects of apolipoprotein AV and apolipoprotein CIII on plasma triglyceride concentrations

    SciTech Connect

    Baroukh, Nadine N.; Bauge, Eric; Akiyama, Jennifer; Chang, Jessie; Fruchart, Jean-Charles; Rubin, Edward M.; Fruchart, Jamila; Pennacchio, Len A.

    2003-08-15

    Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. In mice, transgenic and knockout experiments indicate that plasma triglyceride levels are negatively and positively correlated with APOA5 and APOC3 expression, respectively. In humans, common polymorphisms in both genes have also been associated with plasma triglyceride concentrations. The evolutionary relationship among these two apolipoprotein genes and their close proximity on human chromosome 11q23 have largely precluded the determination of their relative contribution to altered Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. In mice, transgenic and knockout experiments indicate that plasma triglyceride levels are negatively and positively correlated with APOA5 and APOC3 expression, respectively. In humans, common polymorphisms in both genes have also been associated with plasma triglyceride concentrations. The evolutionary relationship among these two apolipoprotein genes and their close proximity on human chromosome 11q23 have largely precluded the determination of their relative contribution to altered triglycerides. To overcome these confounding factors and address their relationship, we generated independent lines of mice that either over-expressed (''double transgenic'') or completely lacked (''double knockout'') both apolipoprotein genes. We report that both ''double transgenic'' and ''double knockout'' mice display intermedia tetriglyceride concentrations compared to over-expression or deletion of either gene alone. Furthermore, we find that human ApoAV plasma protein levels in the ''double transgenic'' mice are approximately 500-fold lower than human ApoCIII levels, supporting ApoAV is a potent triglyceride modulator despite its low concentration. Together, these data indicate

  20. Randomized, double-blind, placebo-controlled, safety and immunogenicity study of 4 formulations of Anthrax Vaccine Adsorbed plus CPG 7909 (AV7909) in healthy adult volunteers.

    PubMed

    Hopkins, Robert J; Daczkowski, Nancy F; Kaptur, Paulina E; Muse, Derek; Sheldon, Eric; LaForce, Craig; Sari, Suha; Rudge, Thomas L; Bernton, Edward

    2013-06-26

    A new anthrax vaccine that could accelerate the immune response and possibly reduce the number of injections needed for protection would be desirable in a post-exposure setting. This Phase 1 study compared the safety and immunogenicity of 2 IM doses (Days 0 and 14) of 4 formulations of AV7909 (AVA plus CPG 7909) with 2 IM doses of BioThrax(®) (Anthrax Vaccine Adsorbed) and 2 IM doses of saline placebo administered on Days 0 and 14. A total of 105 healthy adults 18-50 years of age were randomized to 1 of 6 study groups: BioThrax (0.5 mL), AV7909 Formulation 1 (0.5 mL AVA+0.5mg CPG 7909), AV7909 Formulation 2 (0.5 mL AVA+0.25mg CPG 7909), AV7909 Formulation 3 (0.25 mL AVA+0.5mg CPG 7909), AV7909 Formulation 4 (0.25 mL AVA+0.25mg CPG 7909), or saline placebo (0.5 mL). All randomized subjects received at least 1 vaccination, and 100 subjects completed the trial. After 2 doses, mean peak normalized toxin neutralizing antibody responses (TNA NF50) in the AV7909 groups were higher than in the BioThrax group. Differences among the 4 AV7909 groups were not statistically significant. Subjects who received AV7909 reached peak titers on Day 28 vs. Day 35 in the BioThrax group. The most common adverse events (AEs) in the BioThrax and AV7909 groups assessed as related to vaccination were injection site reactions. Transient lymphopenia was observed after the first dose in each AV7909 group. Frequencies of injection site and systemic reactions recorded by subjects in diaries for 7 days after each injection were highest with AV7909 Formulation 1. No AEs of special interest (autoimmune events) were observed in the study. Further studies of doses and dosing regimens are planned to assess the immunogenicity and reactogenicity of AV7909.

  1. Randomized, Double-Blind, Placebo-Controlled, Safety and Immunogenicity Study of 4 Formulations of Anthrax Vaccine Adsorbed Plus CPG 7909 (AV7909) in Healthy Adult Volunteers

    PubMed Central

    Hopkins, Robert J.; Daczkowski, Nancy F.; Kaptur, Paulina E.; Muse, Derek; Sheldon, Eric; LaForce, Craig; Sari, Suha; Rudge, Thomas L.; Bernton, Edward

    2013-01-01

    A new anthrax vaccine that could accelerate the immune response and possibly reduce the number of injections needed for protection would be desirable in a post-exposure setting. This Phase 1 study compared the safety and immunogenicity of 2 IM doses (Days 0 and 14) of 4 formulations of AV7909 (AVA plus CPG 7909) with 2 IM doses of BioThrax® (Anthrax Vaccine Adsorbed) and 2 IM doses of saline placebo administered on Days 0 and 14. A total of 105 healthy adults 18 to 50 years of age were randomized to 1 of 6 study groups: BioThrax (0.5 mL), AV7909 Formulation 1 (0.5 mL AVA + 0.5 mg CPG 7909), AV7909 Formulation 2 (0.5 mL AVA + 0.25 mg CPG 7909), AV7909 Formulation 3 (0.25 mL AVA + 0.5 mg CPG 7909), AV7909 Formulation 4 (0.25 mL AVA + 0.25 mg CPG 7909), or saline placebo (0.5 mL). All randomized subjects received at least 1 vaccination, and 100 subjects completed the trial. After 2 doses, mean peak normalized toxin neutralizing antibody responses (TNA NF50) in the AV7909 groups were higher than in the BioThrax group. Differences among the 4 AV7909 groups were not statistically significant. Subjects who received AV7909 reached peak titers on Day 28 vs. Day 35 in the BioThrax group. The most common adverse events (AEs) in the BioThrax and AV7909 groups assessed as related to vaccination were injection site reactions. Transient lymphopenia was observed after the first dose in each AV7909 group. Frequencies of injection site and systemic reactions recorded by subjects in diaries for 7 days after each injection were highest with AV7909 Formulation 1. No AEs of special interest (autoimmune events) were observed in the study. Further studies of doses and dosing regimens are planned to assess the immunogenicity and reactogenicity of AV7909. PMID:23701746

  2. Imaging of VMAT2 binding sites in the brain by (18)F-AV-133: the effect of a pseudo-carrier.

    PubMed

    Zhu, Lin; Qiao, Hongwen; Lieberman, Brian P; Wu, Jingxiao; Liu, Yajing; Pan, Zhongyun; Ploessl, Karl; Choi, Seok Rye; Chan, Piu; Kung, Hank F

    2012-10-01

    Recently, 9-[(18)F]fluoropropyl-(+)-dihydrotetrabenazine ((18)F-AV-133) was reported as a new vesicular monoamine transporter (VMAT2) imaging agent for diagnosis of Parkinson's disease (PD). To shorten the preparation of (18)F-AV-133 and to make it more widely available, we evaluated a simple, rapid purification with a solid-phase extraction method (SPE) using an Oasis HLB cartridge instead of high pressure liquid chromatography (HPLC). The SPE method produced doses containing a pseudo-carrier, 9-hydroxypropyl-(+)-dihydrotetrabenazine (AV-149). To test the possible side effects of this pseudo-carrier, comparative dynamic PET scans of the brains of normal monkeys (2 each) and uni-laterally 6-OH-dopamine-lesioned PD monkeys (2 each) were performed using (18)F-AV-133 doses prepared by either SPE (containing pseudo-carrier) or HPLC (containing no pseudo-carrier). Autoradiographs of post mortem monkey brain sections were evaluated to confirm the relative (18)F-AV-133 uptake in the PD monkey brains and the effects of the pseudo-carrier on VMAT2 binding. The radiochemical purity of the (18)F-AV-133, whether prepared by SPE or by HPLC, was excellent (>99%). PET scans of normal and PD monkey brains showed an expected reduction of VMAT2 in the lesioned areas of the striatum. It was not affected by the presence of the pseudo-carrier, AV-149 (maximally 250 μg/dose). The reduced uptake in the striatum of the lesioned monkey brains was confirmed by autoradiography. Ex vivo inhibition studies of (18)F-AV-133 binding in rat brains, conducted with increasing amounts of AV-149, suggested that at the highest concentration (3.5mg/kg) the VMAT2 binding in the striatum was only moderately blocked (20% reduction). The pseudo-carrier, AV-149, did not affect the (18)F-AV-133/PET imaging of VMAT2 binding sites in normal or uni-laterally lesioned monkey brains. The new streamlined SPE purification method will enable (18)F-AV-133 to be widely available for routine clinical application in

  3. From Black Power to Hip-Hop: Jeffrey O.G. Ogbar

    ERIC Educational Resources Information Center

    Smiles, Robin V.

    2005-01-01

    While history for most conjures up images of places and experiences far removed, for Dr. Jeffrey O.G. Ogbar, the field provides a "wonderful medium" to illuminate contemporary issues as well. Much of Ogbar's current research centers on events occurring in the latter half of the 20th century, such as the civil rights and Black power…

  4. Coleman works at the AR OGS Rack in the Node 3

    NASA Image and Video Library

    2011-02-08

    ISS026-E-025143 (8 Feb. 2011) --- NASA astronaut Catherine (Cady) Coleman, Expedition 26 flight engineer, works at the Atmosphere Revitalization / Oxygen Generation System (AR OGS) rack in the Harmony node of the International Space Station. Coleman collected recirculation loop samples for subsequent analysis for pH value.

  5. Coleman works at the AR OGS Rack in the Node 3

    NASA Image and Video Library

    2011-02-08

    ISS026-E-025142 (8 Feb. 2011) --- NASA astronaut Catherine (Cady) Coleman, Expedition 26 flight engineer, works at the Atmosphere Revitalization / Oxygen Generation System (AR OGS) rack in the Harmony node of the International Space Station. Coleman collected recirculation loop samples for subsequent analysis for pH value.

  6. OGS improvements in the year 2011 in running the Northeastern Italy Seismic Network

    NASA Astrophysics Data System (ADS)

    Bragato, P. L.; Pesaresi, D.; Saraò, A.; Di Bartolomeo, P.; Durı, G.

    2012-04-01

    The Centro di Ricerche Sismologiche (CRS, Seismological Research Center) of the Istituto Nazionale di Oceanografia e di Geofisica Sperimentale (OGS, Italian National Institute for Oceanography and Experimental Geophysics) in Udine (Italy) after the strong earthquake of magnitude M=6.4 occurred in 1976 in the Italian Friuli-Venezia Giulia region, started to operate the Northeastern Italy Seismic Network: it currently consists of 15 very sensitive broad band and 21 simpler short period seismic stations, all telemetered to and acquired in real time at the OGS-CRS data center in Udine. Real time data exchange agreements in place with other Italian, Slovenian, Austrian and Swiss seismological institutes lead to a total number of about 100 seismic stations acquired in real time, which makes the OGS the reference institute for seismic monitoring of Northeastern Italy. Since 2002 OGS-CRS is using the Antelope software suite on several workstations plus a SUN Cluster as the main tool for collecting, analyzing, archiving and exchanging seismic data, initially in the framework of the EU Interreg IIIA project "Trans-national seismological networks in the South-Eastern Alps". SeisComP is also used as a real time data exchange server tool. In order to improve the seismological monitoring of the Northeastern Italy area, at OGS-CRS we tuned existing programs and created ad hoc ones like: a customized web server named PickServer to manually relocate earthquakes, a script for automatic moment tensor determination, scripts for web publishing of earthquake parametric data, waveforms, state of health parameters and shaking maps, noise characterization by means of automatic spectra analysis, and last but not least scripts for email/SMS/fax alerting. The OGS-CRS Real Time Seismological website (RTS, http://rts.crs.inogs.it/) operative since several years was initially developed in the framework of the Italian DPC-INGV S3 Project: the RTS website shows classic earthquake locations

  7. ogs6 - a new concept for porous-fractured media simulations

    NASA Astrophysics Data System (ADS)

    Naumov, Dmitri; Bilke, Lars; Fischer, Thomas; Rink, Karsten; Wang, Wenqing; Watanabe, Norihiro; Kolditz, Olaf

    2015-04-01

    OpenGeoSys (OGS) is a scientific open-source initiative for numerical simulation of thermo-hydro-mechanical/chemical (THMC) processes in porous and fractured media, continuously developed since the mid-eighties. The basic concept is to provide a flexible numerical framework for solving coupled multi-field problems. OGS is targeting mainly on applications in environmental geoscience, e.g. in the fields of contaminant hydrology, water resources management, waste deposits, or geothermal energy systems, but it has also been successfully applied to new topics in energy storage recently. OGS is actively participating several international benchmarking initiatives, e.g. DECOVALEX (waste management), CO2BENCH (CO2 storage and sequestration), SeSBENCH (reactive transport processes) and HM-Intercomp (coupled hydrosystems). Despite the broad applicability of OGS in geo-, hydro- and energy-sciences, several shortcomings became obvious concerning the computational efficiency as well as the code structure became too sophisticated for further efficient development. OGS-5 was designed for object-oriented FEM applications. However, in many multi-field problems a certain flexibility of tailored numerical schemes is essential. Therefore, a new concept was designed to overcome existing bottlenecks. The paradigms for ogs6 are: - Flexibility of numerical schemes (FEM#FVM#FDM), - Computational efficiency (PetaScale ready), - Developer- and user-friendly. ogs6 has a module-oriented architecture based on thematic libraries (e.g. MeshLib, NumLib) on the large scale and uses object-oriented approach for the small scale interfaces. Usage of a linear algebra library (Eigen3) for the mathematical operations together with the ISO C++11 standard increases the expressiveness of the code and makes it more developer-friendly. The new C++ standard also makes the template meta-programming technique code used for compile-time optimizations more compact. We have transitioned the main code development to

  8. Adverse effects of first-degree AV-block in patients with sinus node dysfunction: data from the mode selection trial.

    PubMed

    Holmqvist, Fredrik; Hellkamp, Anne S; Lee, Kerry L; Lamas, Gervasio A; Daubert, James P

    2014-09-01

    Patients with a pacing indication and first-degree atrioventricular (AV)-block pose a clinical challenge. The prognostic impact of first-degree AV-block in patients with sinus node dysfunction and the impact of pacing in this setting are not known. In the Mode Selection Trial (MOST), 2,010 patients with sinus node dysfunction were randomized to either dual-chamber (DDD-R) or ventricular (VVI-R) pacing and followed for a median of 33 months. We report on clinical outcomes in patients with first-degree AV-block (PR interval > 200 ms) compared with patients who had a normal PR interval at baseline. Patients with first-degree AV-block (n = 378) were older (median [Q1, Q3]; 76 [70, 82] years vs 73 [66, 79] years, P< 0.0001), more often male (57% vs 49%, P = 0.0049), and had more comorbidity, such as hypertension (66% vs 60%, P = 0.034) and heart failure (24% vs 17%, P = 0.0050) than patients with normal AV-conduction (n = 1,159). In multivariable analyses, patients with first-degree AV-block were at greater risk of death, stroke, or heart failure hospitalization (hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.06-1.61, P = 0.013). A trend towards a higher incidence of atrial fibrillation was seen (HR 1.24, 95% CI 0.98-1.55, P = 0.069). No significant interactions between pacing arm and prolonged versus normal PR were found for any endpoint, and hazard ratios were consistent across subgroups. First-degree AV-block is associated with more advanced disease but is still an independent predictor of poor clinical outcome. Neither DDD-R nor VVI-R pacing, as employed in MOST, eliminate the negative effects associated with first-degree AV-block. ©2014 Wiley Periodicals, Inc.

  9. Neuregulin 1 expression is a predictive biomarker for response to AV-203, an ERBB3 inhibitory antibody, in human tumor models.

    PubMed

    Meetze, Kristan; Vincent, Sylvie; Tyler, Steven; Mazsa, Elizabeth K; Delpero, Andrea R; Bottega, Steve; McIntosh, Donna; Nicoletti, Richard; Winston, William M; Weiler, Solly; Feng, Bin; Gyuris, Jeno; Weng, Zhigang

    2015-03-01

    ERBB3 is overexpressed in a broad spectrum of human cancers, and its aberrant activation is associated with tumor pathogenesis and therapeutic resistance to various anticancer agents. Neuregulin 1 (NRG1) is the predominant ligand for ERBB3 and can promote the heterodimerization of ERBB3 with other ERBB family members, resulting in activation of multiple intracellular signaling pathways. AV-203 is a humanized IgG1/κ ERBB3 inhibitory antibody that completed a first-in-human phase I clinical trial in patients with advanced solid tumors. The purpose of this preclinical study was to identify potential biomarker(s) that may predict response to AV-203 treatment in the clinic. We conducted in vivo efficacy studies using a broad panel of xenograft models representing a wide variety of human cancers. To identify biomarkers that can predict response to AV-203, the relationship between tumor growth inhibition (TGI) by AV-203 and the expression levels of ERBB3 and NRG1 were evaluated in these tumor models. A significant correlation was observed between the levels of NRG1 expression and TGI by AV-203. In contrast, TGI was not correlated with ERBB3 expression. The correlation between the levels of NRG1 expression in tumors and their response to ERBB3 inhibition by AV-203 was further validated using patient-derived tumor explant models. NRG1 is a promising biomarker that can predict response to ERBB3 inhibition by AV-203 in preclinical human cancer models. NRG1 warrants further clinical evaluation and validation as a potential predictive biomarker of response to AV-203. ©2014 American Association for Cancer Research.

  10. The Streptomyces venezuelae pikAV gene contains a transcription unit essential for expression of enzymes involved in glycosylation of narbonolide and 10-deoxymethynolide.

    PubMed

    Chen, S; Roberts, J B; Xue, Y; Sherman, D H; Reynolds, K A

    2001-01-24

    In Streptomyces venezuelae, four polyketide synthase (PKS) polypeptides encoded by pikAI-pikAIV are used to generate 10 and 12-membered macrocyclic structures, narbonolide and 10-deoxymethynolide. Sequence analysis suggests these genes are translationally coupled with downstream genes, pikAV (encoding a type II thioesterase), desVIII-desVI (encoding enzymes responsible for production of the final glycosylated products pikromycin, narbomycin, methymycin and neomethymycin) and desR (a resistance gene). Type II thioesterases have been suggested to have an editing function in polyketide biosynthesis and deletion of the corresponding genes often leads to decreased levels of polyketide production. Surprisingly an in-frame deletion of 687 bp of the 843 bp pikAV ORF led to a strain SC1022 that produced normal yields of polyketide products, but only in the aglycone form. Plasmid-based expression of the desVIII-VI and desR in the SC1022 strain completely restored production of glycosylated products, despite the absence of a functional pikAV gene product. Under these conditions the PikAV TEII therefore does not play an important role in polyketide biosynthesis, and its function remains an enigma. These observations also demonstrate that the region of pikAV DNA deleted in strain SC1022 contains a transcription unit essential for expression of the des genes. A sequence alignment of PikAV with members of the highly conserved type II thioesterases revealed a short divergent region at the carboxy terminus, suggesting a region of pikAV that might contain such a transcription unit. DNA containing this region of pikAV was shown to be able to increase plasmid-based expression of both crotonyl CoA reductase gene (ccr) and the erythromycin resistance gene (ermE) in S. venezuelae.

  11. The GRB Detected by Avs-F Apparatus Onboard Coronas-F Satellite in 2001-2005 Years

    NASA Astrophysics Data System (ADS)

    Arkhangelskaja, Irene V.; Arkhangelskiy, Andrey I.; Glyanenko, Alexander S.; Kotov, Yuri D.; Kuznetsov, Sergey N.

    2008-09-01

    The AVS-F apparatus onboard CORONAS-F satellite operated from 31.07.2001 up to 06.12.2005. This instrument constitutes the system for data processing from two detectors: SONG-D (CsI(TI) detector Ø200 mm and 100 mm height, fully surrounded by plastic anticoincidence shield) and XSS-1 (CdTe detector 4.9 mm × 4.9 mm). Despite of this satellite was Solar-oriented, over 30 GRB during August 2001 - December 2005 period were registered in the energy band of ~0.1-20 MeV by preliminary data analysis. The characteristics of GRB detected by AVS-F device are discussed.

  12. Use of expanded polytetrafluoroethylen (ePTFE) stent graft in autogenic AV fistula with false aneurysm in lower extremity.

    PubMed

    Sieroń, Dominik; Wiggermann, Philipp; Knap, Daniel; Wawrzynek, Wojciech; Stroszczynski, Christian

    2012-04-01

    A 28-year-old German-Caucasian man arrived with deep vein thrombosis DVT, pain, oedema and rubor of right lower limb and drug abuse. The US Doppler imaging showed an autogenic AV fistula and false aneurysm of the right superficial femoral artery and femoral vein. The CT imaging showed additional closing of the left external iliac artery and common femoral artery, and of the distal and middle parts of the superficial femoral artery. The patient was treated within the angiography suite using a 8/25 mm (8 mm diameter/25 mm length) peripheral graft with expanded polytetrafluoroethylen ePTFE stent. After stent deployment, the dilatation was performed using 8/20 mm (8 mm diameter/20 mm length) balloons. After intervention, the digital subtraction angiography showed a good stent position with complete exclusion of false aneurysm and AV fistula. The outcome of US Doppler imaging also confirmed successful intervention.

  13. Modularization and Validation of FUN3D as a CREATE-AV Helios Near-Body Solver

    NASA Technical Reports Server (NTRS)

    Jain, Rohit; Biedron, Robert T.; Jones, William T.; Lee-Rausch, Elizabeth M.

    2016-01-01

    Under a recent collaborative effort between the US Army Aeroflightdynamics Directorate (AFDD) and NASA Langley, NASA's general unstructured CFD solver, FUN3D, was modularized as a CREATE-AV Helios near-body unstructured grid solver. The strategies adopted in Helios/FUN3D integration effort are described. A validation study of the new capability is performed for rotorcraft cases spanning hover prediction, airloads prediction, coupling with computational structural dynamics, counter-rotating dual-rotor configurations, and free-flight trim. The integration of FUN3D, along with the previously integrated NASA OVERFLOW solver, lays the ground for future interaction opportunities where capabilities of one component could be leveraged with those of others in a relatively seamless fashion within CREATE-AV Helios.

  14. A Comparison of the AVS-9 and the Panoramic Night Vision Goggle During Rotorcraft Hover and Landing

    NASA Technical Reports Server (NTRS)

    Szoboszlay, Zoltan; Haworth, Loran; Simpson, Carol; Rutkowski, Michael (Technical Monitor)

    2001-01-01

    The purpose of this flight test was to measure any differences in pilot-vehicle performance and pilot opinion between the use of the current generation AVS-9 Night Vision Goggle and one variant of the prototype Panoramic Night Vision Goggle (the PNV.GII). The PNVGII has more than double the horizontal field-of-view of the AVS-9, but reduced image quality. The flight path of the AH-1S helicopter was used as a measure of pilot-vehicle performance. Also recorded were subjective measures of flying qualities, physical reserves of the pilot, situational awareness, and display usability. Pilot comment and data indicate that the benefits of additional FOV with the PNVGIIs are to some extent negated by the reduced image quality of the PNVGIIs.

  15. Turbulent Fluxes of Sensible Heat Measured by Research UAV 'M2AV Carolo'

    NASA Astrophysics Data System (ADS)

    Martin, S.; Bange, J.

    2009-09-01

    Research aircraft equipped for turbulence measurements in the atmospheric boundary layer (ABL) are suitable platforms to measure area-representative mean values and statistical moments of second order - like variance, spectral distribution and turbulent fluxes - in situ i.e. without the use of any theoretical assumptions. Since manned research aircraft are expensive the use of small unmanned aerial vehicle (UAV) or mini aerial vehicles (MAV) is attractive. Such research UAV are able to measure vertical profiles of the lower troposphere, for instance. The next, more challenging league is the measurement of the turbulent fluctuations of the wind vector and simultaneously at least one scalar quantity in order to calculate turbulent fluxes using eddy covariance. To do this, fast and accurate sensors are required, with small weight, small dimensions and small power consumption, in order to be operated on a small research UAV. Beside absolute and relative measurement accuracy, the response time of the sensors has to be short (in the order of several 10 Hz) to resolve turbulent eddies also in stable stratification (i.e. sub-metre range). Since light, small and fast sensors for air humidity and trace gases are not available currently, the first step is to measure the vertical flux of sensible heat H. Beside a slow (about 1 Hz) water vapour sensor, the automatically operating meteorological mini aerial vehicles (M2AV) are equipped with two temperature sensors and a wind measurement unit. One of the temperature sensors is slow but offers a high absolute accuracy, while the fast sensor (up to 100 Hz) has a high relative accuracy but is unstable in time. The two signals are blended using a complementary filter. The wind vector can be calculated using the inertial velocity (aircraft speed relative to the earth) and the true airspeed (aircraft speed relative to the airflow). The true airspeed of M2AV is computed from five-hole-probe pressure measurements whereas the aircraft

  16. Observation infrastructure for airborne hazards in the framework of the EUNADICS-AV project

    NASA Astrophysics Data System (ADS)

    Mona, Lucia; Pappalardo, Gelsomina; Stammes, Piet; Lihavainen, Heikki; Paatero, Jussi; Hirtl, Marcus; Schlager, Hans; Graf, Kaspar; Hedelt, Pascal; Theys, Nicolas; Coltelli, Mauro; Vargas, Arturo; Clarisse, Lieven; Nína Petersen, Guðrún; de Leeuw, Gerrit; Papagiannopoulos, Nikolaos; Apituley, Arnoud; Haefele, Alexander; Delcloo, Andy; Wotawa, Gerhard

    2017-04-01

    During the 2010 and 2011 Icelandic volcanic eruptions, the availability of integrated, validated data sets was identified as a major challenge in the effort to gain a rapid situation assessment. These environmental crisis situations may happen again, also from other types ofairborne hazards, like big fires. Currently, the issue is not so much that data and observations do not exist, it is rather the rapid accessibility, the cross-calibration of different sensors, the integration of new platforms and the harmonization of standards and protocols that needs further work and attention. A specific activity is planned within the H-2020 project EUNADICS -AV ("European Natural Disaster Coordination and Information System for Aviation") for addressing this critical issue. In order to achieve the rapid data accessibility, work will be carried out with full consideration of the main European Research Infrastructures, projects and national/international monitoring networks that are able to provide crucial information related to the dispersion of airborne hazards. The integrated data sets are based on satellite and ground-based remote sensing as well as in situ ground-based and aircraft observations. Networks of ground based remote sensing of atmospheric profiles are particularly important, since these will provide the needed height information that cannot be obtained unambiguously from the vast majority of space borne sensors. A new aspect not treated in any project and initiative so far is the integration of special crisis measurements, for example by aircraft or UAV systems. Particularly suited for the purposes of the project are satellite data from operational sensors aboard EUMETSAT and ESA satellites. Improved retrievals are investigated, and the new generation of Sentinel satellites currently being launched under the Copernicus umbrella and their added value are considered. Especially when the ground based and space borne observations are combined, the much needed

  17. Videos for Science Communication and Nature Interpretation: The TIB|AV-Portal as Resource.

    NASA Astrophysics Data System (ADS)

    Marín Arraiza, Paloma; Plank, Margret; Löwe, Peter

    2016-04-01

    Scientific audiovisual media such as videos of research, interactive displays or computer animations has become an important part of scientific communication and education. Dynamic phenomena can be described better by audiovisual media than by words and pictures. For this reason, scientific videos help us to understand and discuss environmental phenomena more efficiently. Moreover, the creation of scientific videos is easier than ever, thanks to mobile devices and open source editing software. Video-clips, webinars or even the interactive part of a PICO are formats of scientific audiovisual media used in the Geosciences. This type of media translates the location-referenced Science Communication such as environmental interpretation into computed-based Science Communication. A new way of Science Communication is video abstracting. A video abstract is a three- to five-minute video statement that provides background information about a research paper. It also gives authors the opportunity to present their research activities to a wider audience. Since this kind of media have become an important part of scientific communication there is a need for reliable infrastructures which are capable of managing the digital assets researchers generate. Using the reference of the usecase of video abstracts this paper gives an overview over the activities by the German National Library of Science and Technology (TIB) regarding publishing and linking audiovisual media in a scientifically sound way. The German National Library of Science and Technology (TIB) in cooperation with the Hasso Plattner Institute (HPI) developed a web-based portal (av.tib.eu) that optimises access to scientific videos in the fields of science and technology. Videos from the realms of science and technology can easily be uploaded onto the TIB|AV Portal. Within a short period of time the videos are assigned a digital object identifier (DOI). This enables them to be referenced, cited, and linked (e.g. to the

  18. Effects of an ascovirus (HvAV-3e) on diamondback moth, Plutella xylostella, and evidence for virus transmission by a larval parasitoid.

    PubMed

    Furlong, Michael J; Asgari, Sassan

    2010-02-01

    Ascoviruses (AVs) are pathogenic to lepidopteran larvae, and most commonly attack species in the Noctuidae. The unique pathology includes cleavage of host cells into virion-containing vesicles which leads to the milky white colouration of the hemolymph as opposed to the clear hemolymph of healthy larvae. Recently, we showed that a Heliothis virescens AV (HvAV-3e) isolate is able to induce disease in Crocidolomia pavonana F. (Lepidoptera: Crambidae), affecting feeding, growth and survival of infected larvae. In this study, we investigated the effect of different variants of HvAV-3e on diamondback moth, Plutella xylostella (Lepidoptera: Plutellidae) larvae, another non-noctuid host. In hemolymph inoculation bioassays fourth instar larvae showed a significant dose response to each of the HvAV-3e variants and significant differences between the virulence of the three variants were detected. Both second and fourth instars were readily infected with the virus and infected individuals demonstrated significant reductions in food consumption and growth. The majority of infected individuals died at the larval or pupal stage and individuals which developed into adults were usually deformed, less fecund than non-infected controls and died shortly after emergence. In transmission studies, Diadegmasemiclausum (Hymenoptera: Ichneumonidae), a key parasitoid of diamondback moth, infected healthy host larvae during oviposition following previous attack of HvAV-3e infected hosts. In choice tests D. semiclausum did not discriminate between infected individuals but host infection had no detectable impact on the development of immature D. semiclausum or on subsequent adults.

  19. Sediment nickel bioavailability and toxicity to estuarine crustaceans of contrasting bioturbative behaviors--an evaluation of the SEM-AVS paradigm.

    PubMed

    Chandler, G Thomas; Schlekat, Christian E; Garman, Emily R; He, Lijian; Washburn, Katherine M; Stewart, Emily R; Ferry, John L

    2014-11-04

    Robust sediment quality criteria require chemistry and toxicity data predictive of concentrations where population/community response should occur under known geochemical conditions. Understanding kinetic and geochemical effects on toxicant bioavailability is key, and these are influenced by infaunal sediment bioturbation. This study used fine-scale sediment and porewater measurement of contrasting infaunal effects on carbon-normalized SEM-AVS to evaluate safe or potentially toxic nickel concentrations in a high-binding Spartina saltmarsh sediment (4%TOC; 35-45 μmol-S2-·g(-1)). Two crustaceans producing sharply contrasting bioturbation--the copepod Amphiascus tenuiremis and amphipod Leptocheirus plumulosus--were cultured in oxic to anoxic sediments with SEM[Ni]-AVS, TOC, porewater [Ni], and porewater DOC measured weekly. From 180 to 750 μg-Ni·g(-1) sediment, amphipod bioturbation reduced [AVS] and enhanced porewater [Ni]. Significant amphipod uptake, mortality, and growth-depression occurred at the higher sediment [Ni] even when [SEM-AVS]/foc suggested acceptable risk. Less bioturbative copepods produced higher AVS and porewater DOC but exhibited net population growth despite porewater [Ni] 1.3-1.7× their aqueous [Ni] LOEC. Copepod aqueous tests with/without dissolved organic matter showed significant aqueous DOC protection, which suggests porewater DOC attenuates sediment Ni toxicity. The SEM[Ni]-AVS relationship was predictive of acceptable risk for copepods at the important population-growth level.

  20. Horizon-specific oxidation of acid volatile sulfide (AVS) in relation to the toxicity of cadmium spiked into a freshwater sediment

    SciTech Connect

    Leonard, E.N.; Mattson, V.R.; Ankley, G.T.

    1994-12-31

    To evaluate the effects of oxidative processes on acid volatile sulfide concentrations in various horizons of whole sediment cores, in relation to the toxicity of a metal (cadmium), the authors used an artificial system to ``age`` Cd-spiked sediment samples under a constant flow of fresh Lake Superior water. Sediments from Pequaywan Lake, MN (ca. 12 umol AVS/g) were spiked so as to achieve (nominal) cadmium: AVS molar ratios of 0.02 (control), 0.2, 0.8, 1.2 and 3.0. At 0, 24 and 48 days post-spiking, sediment cores were removed from the aging system and tested for toxicity to the amphipod Hyalella azteca. At the same time, horizons from replicate sediment cores were prepared for analysis by freezing, and then cutting them into 10--20 mm increments. The sediment horizons were analyzed for AVS and simultaneously extracted cadmium concentrations, and pore water concentrations of cadmium. Relatively little oxidation of surficial AVS concentrations was observed, even at aging times up to 48 d. By 48 d, pore water concentrations of cadmium were slightly elevated at all spiking concentrations, but were increased greatly at cadmium:AVS ratios greater than one. Hyalella azteca mortality was generally predictable based on surficial cadmium:AVS ratios or pore water cadmium concentrations.

  1. The glial cell modulator and phosphodiesterase inhibitor, AV411 (ibudilast), attenuates prime- and stress-induced methamphetamine relapse.

    PubMed

    Beardsley, Patrick M; Shelton, Keith L; Hendrick, Elizabeth; Johnson, Kirk W

    2010-07-10

    Stress and renewed contact with drug (a "slip") have been linked to persisting relapse of methamphetamine abuse. Human brain microglial activation has been linked with methamphetamine abuse, and inhibitors of glial cell activation, certain phosphodiesterase (PDE) inhibitors, and glial cell derived neurotrophic factor (GDNF) have been reported to modulate drug abuse effects. Our objective was to determine whether the glial cell attenuator, 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine (AV411, ibudilast), a non-selective PDE inhibitor and promoter of GDNF, could reduce stress- and methamphetamine prime-induced reinstatement of methamphetamine-seeking behavior. Male Long-Evans hooded rats were trained to lever press reinforced with 0.1 mg/kg i.v. methamphetamine infusion according to fixed-ratio 1 (FR1) reinforcement schedules during daily, 2-hour experimental sessions. After performance had stabilized, lever pressing was extinguished for 12 consecutive sessions and doses of 0 (vehicle), 2.5 and 7.5 mg/kg AV411 were then administered intraperitoneally b.i.d. on the last 2 days of extinction and then once on the testday to separate groups of 12 rats. During testing, the rats were given 15 min of intermittent footshock or a 1 mg/kg i.p. methamphetamine prime followed by a 2-hour reinstatement test session. AV411 significantly reduced response levels of footshock-induced (2.5 and 7.5 mg/kg) and prime-induced (7.5 mg/kg) reinstatement of extinguished methamphetamine-maintained responding. AV411 has properties consistent with the ability to attenuate relapse precipitated by stress and methamphetamine "slips" during abstinence. These results thus reinforce interest in atypical neurobiological mechanisms which could be exploited for developing novel medications for treating drug abuse disorders.

  2. Transient A-V dissociation and severe hypotension due to consumption of Ayurvedic medicine--Vatsanabha (aconitum ferox).

    PubMed

    Laddhad, Deepak; Sancheti, Saurabh R; Dinde, Yogita

    2014-05-01

    A 24 year old married, well educated, female patient presented with complaints of giddiness and blackouts. On evaluation, patient had hypotension and bradycardia. ECG findings were suggestive of complete A-V dissociation. On detailed history patient revealed consumption. of Ayurvedic medicine Vatsanabha for arthritis. This study impresses upon the need for complete history talking and generating awareness regarding the correct and observed use of any drug including alternative medicines.

  3. Assessment of heavy metals pollution using AVS-SEM and fractionation techniques in Edku Lagoon sediments, Mediterranean Sea, Egypt.

    PubMed

    El Zokm, Gehan M; Okbah, Mohamed A; Younis, Alaa M

    2015-01-01

    A method is presented to evaluate the fractionation of metals (Fe, Zn, Cu, Pb, Cd and Ni), acid volatile sulfide (AVS) and simultaneously extracted metals (SEM) in Edku lagoon sediments. Thirteen sediment samples were collected from the study area in the period of 2010-2011 to assess the potential bioavailability and toxicity of the selected metals. According to classification of the Interim Sediment Quality Quidelines (ISQG), five stations near the drains exhibited 10% toxic probability. The high AVS and low ∑SEM ranges in Summer were identified as 6-138 and 0.86-3.3 µmol g(-1) dry wet, respectively which are referring to the low mobility of heavy metals in this season and vice versa for winter (2.5-23.9 and 1.16-3.82 µmol g(-1) dry wet, respectively). According to the evaluation of USEPA, all sediment samples showed ∑SEM/AVS < 1 and ΣSEM-AVS < 0 and this indicates that Edku lagoon sediments didn't cause any adverse effects. Meanwhile, the calculations of the global contamination factor (GCF) and the individual contamination factors (ICF) using fractionation technique gave values of 111.644 and 84.555 in El Bosily drain and station 1 near the cages of fish farm, respectively due to possible contamination. Interestingly, the collected data refer that the mobility and bioavailability of heavy metals in Edku lagoon sediments posed a low risk of adverse biological effects due to cadmium, copper, lead, nickel and zinc in all evaluated stations.

  4. AvBD1 nucleotide polymorphisms, peptide antimicrobial activities and microbial colonisation of the broiler chicken gut.

    PubMed

    Cadwell, Kevin; Niranji, Sherko S; Armstrong, Vanessa L; Mowbray, Catherine A; Bailey, Richard; Watson, Kellie A; Hall, Judith

    2017-08-18

    The importance of poultry as a global source of protein underpins the chicken genome and associated SNP data as key tools in selecting and breeding healthy robust birds with improved disease resistance. SNPs affecting host peptides involved in the innate defences tend to be rare, but three non-synonymous SNPs in the avian β-defensin (AvBD1) gene encoding the variant peptides NYH, SSY and NYY were identified that segregated specifically to three lines of commercial broiler chickens Line X (LX), Line Y(LY) and Line Z. The impacts of such amino acid changes on peptide antimicrobial properties were analysed in vitro and described in relation to the caecal microbiota and gut health of LX and LY birds. Time-kill and radial immune diffusion assays indicated all three peptides to have antimicrobial properties against gram negative and positive bacteria with a hierarchy of NYH > SSY > NYY. Calcein leakage assays supported AvBD1 NYH as the most potent membrane permeabilising agent although no significant differences in secondary structure were identified to explain this. However, distinct claw regions, identified by 3D modelling and proposed to play a key role in microbial membrane attachment, and permeation, were more distinct in the NYH model. In vivo AvBD1 synthesis was detected in the bird gut epithelia. Analyses of the caecal gut microbiota of young day 4 birds suggested trends in Lactobacilli sp. colonisation at days 4 (9% LX vs × 30% LY) and 28 (20% LX vs 12% LY) respectively, but these were not statistically significant (P > 0.05). Amino acid changes altering the killing capacity of the AvBD1 peptide were associated with two different bird lines, but such changes did not impact significantly on caecal gut microbiota.

  5. Adaptive CRT in patients with normal AV conduction and left bundle branch block: Does QRS duration matter?

    PubMed

    Yamasaki, Hiro; Lustgarten, Daniel; Cerkvenik, Jeffrey; Birnie, David; Gasparini, Maurizio; Lee, Kathy Lia-Fun; Sekiguchi, Yukio; Varma, Niraj; Lemke, Bernd; Starling, Randall C; Aonuma, Kazutaka

    2017-08-01

    Adaptive cardiac resynchronization therapy (aCRT) is a dynamic optimization algorithm which paces only the left ventricle (LV) when atrio-ventricular (AV) conduction is normal, thus reducing right ventricular (RV) pacing. However, the impact of QRS duration on aCRT efficacy remains uncertain. We examined whether QRS duration impacts aCRT effectiveness in patients with left bundle branch block (LBBB) and preserved AV conduction. Randomized patients in the Adaptive CRT trial, which enrolled NYHA III/IV patients, were used in this analysis. Patients were randomized to receive aCRT or echo-optimized bi-ventricular CRT (control arm). Endpoints for this analysis were clinical composite score (CCS) at 6months post-implant and time to first heart failure (HF) hospitalization or death. Among the 199 patients with LBBB and normal AV intervals at baseline, 80 patients (40%) had a baseline moderately wide QRS of 120-150ms. In this subgroup, a greater proportion of aCRT patients had an improved CCS (79% vs. 50%) at 6months compared to the control group (p=0.03). There was also a trend toward a lower risk of death or HF hospitalization (hazard ratio: 0.53; 95% CI: 0.24-1.15; p=0.10) in the moderately wide QRS subgroup with aCRT compared to the control arm. In the wide QRS subgroup, the efficacy was comparable in both treatment arms. Adaptive CRT was associated with improved patient outcomes over echo-optimized bi-ventricular CRT in patients with preserved AV conduction, LBBB, and moderately wide QRS. The adaptive cardiac resynchronization therapy trial (ClinicalTrials.gov Identifier: NCT00980057) was sponsored by Medtronic plc, Mounds View, MN. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. The glial cell modulator and phosphodiesterase inhibitor, AV411 (ibudilast), attenuates prime- and stress-induced methamphetamine relapse

    PubMed Central

    Beardsley, Patrick M.; Shelton, Keith L.; Hendrick, Elizabeth; Johnson, Kirk W.

    2010-01-01

    Stress and renewed contact with drug (a “slip”) have been linked to persisting relapse of methamphetamine abuse. Human brain microglial activation has been linked with methamphetamine abuse, and inhibitors of glial cell activation, certain phosphodiesterase (PDE) inhibitors, and glial cell derived neurotrophic factor (GDNF) have been reported to modulate drug abuse effects. Our objective was to determine whether the glial cell attenuator, 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine (AV411, ibudilast), a non-selective PDE inhibitor and promoter of GDNF, could reduce stress- and methamphetamine prime-induced reinstatement of methamphetamine-seeking behavior. Male Long-Evans hooded rats were trained to lever press reinforced with 0.1 mg/kg i.v. methamphetamine infusion according to fixed-ratio 1 (FR1) reinforcement schedules during daily, 2-h experimental sessions. After performance had stabilized, lever pressing was extinguished for 12 consecutive sessions and doses of 0 (vehicle), 2.5 and 7.5 mg/kg AV411 were then administered intraperitoneally b.i.d. on the last two days of extinction and then once on the testday to separate groups of 12 rats. During testing, the rats were given 15 min of intermittent footshock or a 1 mg/kg i.p. methamphetamine prime followed by a 2-h reinstatement test session. AV411 significantly reduced response levels of footshock-induced (2.5 and 7.5 mg/kg) and prime-induced (7.5 mg/kg) reinstatement of extinguished methamphetamine-maintained responding. AV411 has properties consistent with the ability to attenuate relapse precipitated by stress and methamphetamine “slips” during abstinence. These results thus reinforce interest in atypical neurobiological mechanisms which could be exploited for developing novel medications for treating drug abuse disorders. PMID:20399770

  7. Geosciences Information for Teachers (GIFT) Workshops held in Conjunction with Alexander von Humboldt (AvH) EGU Conferences

    NASA Astrophysics Data System (ADS)

    Laj, Carlo; Cifelli, Francesca

    2015-04-01

    The Alexander von Humboldt Conference Series of the European Geosciences Union are a series of meetings held outside of Europe, in particular in South America, Africa or Asia, on selected topics of geosciences with a socio-economic impact for regions on these continents, jointly organised with the scientists and their institutes and the institutions of these regions. Given the increasing success of the GIFT workshops held in conjunction with the General Assemblies, since 2010 EGU has also developed a series of GIFT workshops held in conjunction with AvH conferences. Associated GIFT workshops were held in Merida, Yucatan, on the theme of Climate Change, Natural Hazards and Societies (March 2010), then in Penang, Malaysia (June 2011) on the theme of Ocean Acidification, in November 2012 in Cusco (Peru) on the theme of Natural Disasters, Global Change and the Preservation of World Heritage Sites, finally in Istanbul (March 2014) on "High Impact Natural Hazards Related to the Euro-Mediterranean Region. The next GIFT workshop is already planned for October 2015 in Adis Ababa (Ethiopia) on the theme "Water". In each case, the GIFT workshop was held on the last two days of the AvH conference and reunited 40-45 teachers from the nation where the AvH was held. Keynote speakers from AvH were speakers to the GIFT workshops which also included hands-on activities animated by sciences educators. These GIFT workshops represented the first workshops specifically aimed at teachers held in the country, and therefore represents a significant Earth Sciences contribution to secondary education in non European countries.

  8. Geosciences Information for Teachers (GIFT) Workshops held in Conjunction with Alexander von Humboldt (AvH) EGU Conferences.

    NASA Astrophysics Data System (ADS)

    Laj, C. E.; Cifelli, F.

    2014-12-01

    Given the increasing success of the GIFT workshops held in conjunction with the General Assemblies, since 2010 EGU has also developed a series of GIFT workshops held in conjunction with AvH conferences. The Alexander von Humboldt Conference Series of the European Geosciences Union are a series of meetings held outside of Europe, in particular in South America, Africa or Asia, on selected topics of geosciences with a socio-economic impact for regions on these continents, jointly organised with the scientists and their institutes and the institutions of these regions. Associated GIFT workshops were held in Merida, Yucatan, on the theme of Climate Change, Natural Hazards and Societies (March 2010), then in Penang, Malaysia (June 2011) on the theme of Ocean Acidification, in November 2012 in Cusco (Peru) on the theme of Natural Disasters, Global Change and the Preservation of World Heritage Sites, finally in Istanbul (March 2014) on "High Impact Natural Hazards Related to the Euro-Mediterranean Region. The next GIFT workshop is already planned for October 2015 in Adis Ababa (Ethiopia) on the theme "Water". In each case, the GIFT workshop was held on the last two days of the AvH conference and reunited 40-45 teachers from the nation where the AvH was held. Keynote speakers from AvH were speakers to the GIFT workshops which also included hands-on activities animated by sciences educators. In 3 cases of the 4 cases, these GIFT workshops represented the first workshop specifically aimed at teachers held in the country, and therefore represents a significant Earth Sciences contribution to secondary education in non European countries.

  9. A technique for the rapid diagnosis of wide complex tachycardia with 1:1 AV relationship in the electrophysiology laboratory.

    PubMed

    Abdelwahab, Amir; Gardner, Martin J; Basta, Magdy N; Parkash, Ratika; Khan, Aamir; Sapp, John L

    2009-04-01

    The differential diagnosis of wide complex tachycardia (WCT) with 1:1 atrioventricular (AV) relationship is broad. Accurate identification of the tachycardia mechanism is essential for successful ablation. We suggest a simple pacing maneuver that can immediately clarify the tachycardia mechanism in the electrophysiology laboratory. Eight consecutive patients (four males, 32 +/- 14 years) demonstrating stable sustained WCT with persistent 1:1 AV relationship during electrophysiologic testing were included in this study. During the tachycardia, atrial overdrive pacing was performed. The following responses were observed: (1) a change of the QRS morphology during atrial pacing and (2) the first return electrogram of the tachycardia, whether occurring in the atrium (AVA response) or in the ventricle (AVVA response). Atrial overdrive pacing was successfully performed in all patients. It was associated with either a change or narrowing of the QRS in all ventricular tachycardia (VT) patients but not in supraventricular tachycardia (SVT) patients. All VT patients had an AVVA response upon cessation of atrial overdrive pacing as opposed to AVA response in SVT patients, P = 0.029. The response to atrial overdrive pacing during WCT with 1:1 AV relationship can rapidly diagnose or rule out VT as a mechanism of tachycardia.

  10. Trifascicular block progressing to complete AV block on exercise: a rare presentation demonstrating the usefulness of exercise testing

    PubMed Central

    Shetty, Ranjan K; Agarwal, Sumit; Ganiga Sanjeeva, Naveen Chandra; Rao, M Sudhakar

    2015-01-01

    A 41-year-old man presented with dyspnoea and giddiness on exertion for the last 1 month. A resting ECG during showed trifascicular block with complete right bundle branch block, left anterior fascicular block and a prolonged PR interval of >0.24 s. His echocardiography showed no evidence of wall motion abnormality. He was subjected to a treadmill test for exercise-induced ischaemia, which showed complete atrioventricular (AV) block during first stage of Bruce protocol. His symptoms of dyspnoea and giddiness were also reproduced. The test was terminated and ECG returned to trifascicular block, similar to that at his baseline ECG during recovery. Coronary angiogram (CAG) was performed to rule out any ischaemic cause for this exercise-induced AV block, which was normal. In view of his reproducible symptoms and demonstration of complete AV block on exercise, a dual-chamber pacemaker (DDD) was implanted. His symptoms disappeared and he remained asymptomatic on follow-up. PMID:25819829

  11. Re-entrant tachycardia using two bypass tracts and excluding AV node in short PR interval, normal QRS syndrome.

    PubMed Central

    Ward, D E; Camm, A J; Spurrell, R A

    1978-01-01

    In patients with the short PR interval, normal QRS complex syndrome, paroxysmal tachycardias are usually the result of circus movement involving the AV node and a partial or complete AV nodal bypass. We report 2 patients with this syndrome who suffered distressing rapid paroxysms of tachycardia but in whom there was evidence of a concealed direct VA connection. In both patients, tachycardia was initiated with critical AV prolongation distal to the His bundle, in response to programmed atrial premature stimuli. The constancy of the timing of the atrial echo from the onset of the QRS complex in the presence of a varying HV interval is evidence for involvement of the ventricles in the re-entry pathway. In addition, in both patients the appearance of left bundle-branch block during tachycardia was associated with appropriate prolongation of tachycardia cycle length consistent with the presence of a direct VA connection. The short AH interval during tachycardia and the absence of critical AH prolongation suggests the participation of a rapidly conducting pathway in the anterograde limb of the tachycardia circuit. PMID:708514

  12. Authentication of Angelica anomala Avé-Lall cultivars through DNA barcodes.

    PubMed

    He, Yang; Hou, Pei; Fan, Gang; Song, Zhen; Arain, Saima; Shu, Hao; Tang, Ce; Yue, Qinghong; Zhang, Yi

    2012-04-01

    Angelica anomala Avé-Lall (Chuanbaizhi in Chinese) is an important medicinal plant which can be used in traditional Chinese medicines; however, there are no authentic and universal methods to differentiate this Sichuan famous-region drug of A. anomala from a large number of non-famous-region and false drugs. It has been demonstrated that DNA barcoding is a molecular diagnostic method for species identification, which uses a single standardized DNA fragment. In this study, we tested five DNA barcoding candidates (matK, ITS, ITS2, rbcL, and psbA-trnH), and we found that ITS was the best candidate to authenticate the famous-region drug of A. anomala. Moreover, through comparative analysis of these five DNA barcodes between A. anomala and Angelica dahurica, we found that ITS had the most and ITS2 had more variable regions, but the psbA-trnH, rbcL, and matK regions were identical. Hence, we suggest ITS as the DNA barcoding to identify A. anomala and A. dahurica. Moreover, we are determined to adopt the A. anomala as the accurate Latin name of Chuanbaizhi.

  13. Unified transform architecture for AVC, AVS, VC-1 and HEVC high-performance codecs

    NASA Astrophysics Data System (ADS)

    Dias, Tiago; Roma, Nuno; Sousa, Leonel

    2014-12-01

    A unified architecture for fast and efficient computation of the set of two-dimensional (2-D) transforms adopted by the most recent state-of-the-art digital video standards is presented in this paper. Contrasting to other designs with similar functionality, the presented architecture is supported on a scalable, modular and completely configurable processing structure. This flexible structure not only allows to easily reconfigure the architecture to support different transform kernels, but it also permits its resizing to efficiently support transforms of different orders (e.g. order-4, order-8, order-16 and order-32). Consequently, not only is it highly suitable to realize high-performance multi-standard transform cores, but it also offers highly efficient implementations of specialized processing structures addressing only a reduced subset of transforms that are used by a specific video standard. The experimental results that were obtained by prototyping several configurations of this processing structure in a Xilinx Virtex-7 FPGA show the superior performance and hardware efficiency levels provided by the proposed unified architecture for the implementation of transform cores for the Advanced Video Coding (AVC), Audio Video coding Standard (AVS), VC-1 and High Efficiency Video Coding (HEVC) standards. In addition, such results also demonstrate the ability of this processing structure to realize multi-standard transform cores supporting all the standards mentioned above and that are capable of processing the 8k Ultra High Definition Television (UHDTV) video format (7,680 × 4,320 at 30 fps) in real time.

  14. Electronic band structures of AV(2) (A = Ta, Ti, Hf and Nb) Laves phase compounds.

    PubMed

    Charifi, Z; Reshak, Ali Hussain; Baaziz, H

    2009-01-14

    First-principles density functional calculations, using the all-electron full potential linearized augmented plane wave method, have been performed in order to investigate the structural and electronic properties for Laves phase AV(2) (A = Ta, Ti, Hf and Nb) compounds. The generalized gradient approximation and the Engel-Vosko-generalized gradient approximation were used. Our calculations show that these compounds are metallic with more bands cutting the Fermi energy (E(F)) as we move from Nb to Ta, Hf and Ti, consistent with the increase in the values of the density of states at the Fermi level N(E(F)). N(E(F)) is controlled by the overlapping of V-p/d, A-d and A-p states around the Fermi energy. The ground state properties of these compounds, such as equilibrium lattice constant, are calculated and compared with the available literature. There is a strong/weak hybridization between the states, V-s states are strongly hybridized with A-s states below and above E(F). Around the Fermi energy we notice that V-p shows strong hybridization with A-p states.

  15. Discovery of novel highly potent hepatitis C virus NS5A inhibitor (AV4025).

    PubMed

    Ivachtchenko, Alexandre V; Mitkin, Oleg D; Yamanushkin, Pavel M; Kuznetsova, Irina V; Bulanova, Elena A; Shevkun, Natalia A; Koryakova, Angela G; Karapetian, Ruben N; Bichko, Vadim V; Trifelenkov, Andrey S; Kravchenko, Dmitry V; Vostokova, Natalia V; Veselov, Mark S; Chufarova, Nina V; Ivanenkov, Yan A

    2014-09-25

    A series of next in class small-molecule hepatitis C virus (HCV) NS5A inhibitors with picomolar potency containing 2-pyrrolidin-2-yl-5-{4-[4-(2-pyrrolidin-2-yl-1H-imidazol-5-yl)buta-1,3-diynyl]phenyl}-1H-imidazole cores was designed based on the SAR studies available for the reported NS5A inhibitors. Compound 13a (AV4025), with (S,S,S,S)-stereochemistry (EC50 = 3.4 ± 0.2 pM, HCV replicon genotype 1b), was dramatically more active than were the compounds with two (S)- and two (R)-chiral centers. Human serum did not significantly reduce the antiviral activity (<4-fold). Relatively favorable pharmacokinetic features and good oral bioavailability were observed during animal studies. Compound 13a was well tolerated in rodents (in mice, LD50 = 2326 mg/kg or higher), providing a relatively high therapeutic index. During safety, pharmacology and subchronic toxicity studies in rats and dogs, it was not associated with any significant pathological or clinical findings. This compound is currently being evaluated in phase I/II clinical trials for the treatment of HCV infection.

  16. Kinetic Modeling of the Tau PET Tracer (18)F-AV-1451 in Human Healthy Volunteers and Alzheimer Disease Subjects.

    PubMed

    Barret, Olivier; Alagille, David; Sanabria, Sandra; Comley, Robert A; Weimer, Robby M; Borroni, Edilio; Mintun, Mark; Seneca, Nicholas; Papin, Caroline; Morley, Thomas; Marek, Ken; Seibyl, John P; Tamagnan, Gilles D; Jennings, Danna

    2017-07-01

    (18)F-AV-1451 is currently the most widely used of several experimental tau PET tracers. The objective of this study was to evaluate (18)F-AV-1451 binding with full kinetic analysis using a metabolite-corrected arterial input function and to compare parameters derived from kinetic analysis with SUV ratio (SUVR) calculated over different imaging time intervals. Methods:(18)F-AV-1451 PET brain imaging was completed in 16 subjects: 4 young healthy volunteers (YHV), 4 aged healthy volunteers (AHV), and 8 Alzheimer disease (AD) subjects. Subjects were imaged for 3.5 h, with arterial blood samples obtained throughout. PET data were analyzed using plasma and reference tissue-based methods to estimate the distribution volume, binding potential (BPND), and SUVR. BPND and SUVR were calculated using the cerebellar cortex as a reference region and were compared across the different methods and across the 3 groups (YHV, AHV, and AD). Results: AD demonstrated increased (18)F-AV-1451 retention compared with YHV and AHV based on both invasive and noninvasive analyses in cortical regions in which paired helical filament tau accumulation is expected in AD. A correlation of R(2) > 0.93 was found between BPND (130 min) and SUVR-1 at all time intervals. Cortical SUVR curves reached a relative plateau around 1.0-1.2 for YHV and AHV by approximately 50 min, but increased in AD by up to approximately 20% at 110-130 min and approximately 30% at 160-180 min relative to 80-100 min. Distribution volume (130 min) was lower by 30%-35% in the YHV than AHV. Conclusion: Our data suggest that although (18)F-AV-1451 SUVR curves do not reach a plateau and are still increasing in AD, an SUVR calculated over an imaging window of 80-100 min (as currently used in clinical studies) provides estimates of paired helical filament tau burden in good correlation with BPND, whereas SUVR sensitivity to regional cerebral blood changes needs further investigation. © 2017 by the Society of Nuclear Medicine and

  17. Perfusion-like template and standardized normalization-based brain image analysis using 18F-florbetapir (AV-45/Amyvid) PET.

    PubMed

    Hsiao, Ing-Tsung; Huang, Chin-Chang; Hsieh, Chia-Ju; Wey, Shiaw-Pyng; Kung, Mei-Ping; Yen, Tzu-Chen; Lin, Kun-Ju

    2013-06-01

    Amyloid positron emission tomography (PET) is an important noninvasive method for detecting amyloid burden in Alzheimer's disease (AD) patients. As amyloid PET images have limited anatomical information, magnetic resonance (MR) imaging is usually acquired to perform reliable spatial normalization needed for large-scale analysis. This work proposed and evaluated the performance of new MR-free spatial normalization methods using a perfusion-like template for amyloid PET imaging. Amyloid PET and MR images were collected in 35 subjects (cohort 1: 8 AD patients and 6 controls; cohort 2: 15 AD patients and 6 controls). Three ligand-related templates (AD, control, mixed group) and a perfusion-like template (pAV-45) from early time frames of amyloid PET images were constructed from cohort 1. The variations of (18)F-AV-45 standardized uptake value ratios (SUVRs) among AD patients, controls, and all subjects were tested with repeated two-way (template × brain region) analysis of variance (ANOVA) in cohort 2. (18)F-AV-45 SUVRs by region of interest analysis and voxelwise analysis between MR-based and MR-free approaches were compared and correlated to clinical and image parameters. Effect size (group mean SUVR difference between AD and control/standard deviation) was also evaluated for each template method. Significantly different (18)F-AV-45 SUVRs between MR-free spatial normalization and MR-based reference images were found among AD patients, controls, and all subjects by the effect of template and brain regions. The highest correlation (r=0.991) of (18)F-AV-45 SUVR to MR-based reference was found in the pAV-45 group. The SUVR percentage difference to MR-based reference showed the least variation and bias (control: -1.31±3.47 %; AD: -0.36±2.50 %) in the pAV-45 group as well. The voxelwise analysis showed the smallest t statistic value in pAV-45 followed by mixed, control, and AD groups when compared to MR-based reference images. Moreover, an overall larger effect size but

  18. Molecular analysis of the sea anemone toxin Av3 reveals selectivity to insects and demonstrates the heterogeneity of receptor site-3 on voltage-gated Na+ channels.

    PubMed

    Moran, Yehu; Kahn, Roy; Cohen, Lior; Gur, Maya; Karbat, Izhar; Gordon, Dalia; Gurevitz, Michael

    2007-08-15

    Av3 is a short peptide toxin from the sea anemone Anemonia viridis shown to be active on crustaceans and inactive on mammals. It inhibits inactivation of Na(v)s (voltage-gated Na+ channels) like the structurally dissimilar scorpion alpha-toxins and type I sea anemone toxins that bind to receptor site-3. To examine the potency and mode of interaction of Av3 with insect Na(v)s, we established a system for its expression, mutagenized it throughout, and analysed it in toxicity, binding and electrophysiological assays. The recombinant Av3 was found to be highly toxic to blowfly larvae (ED50=2.65+/-0.46 pmol/100 mg), to compete well with the site-3 toxin LqhalphaIT (from the scorpion Leiurus quinquestriatus) on binding to cockroach neuronal membranes (K(i)=21.4+/-7.1 nM), and to inhibit the inactivation of Drosophila melanogaster channel, DmNa(v)1, but not that of mammalian Na(v)s expressed in Xenopus oocytes. Moreover, like other site-3 toxins, the activity of Av3 was synergically enhanced by ligands of receptor site-4 (e.g. scorpion beta-toxins). The bioactive surface of Av3 was found to consist mainly of aromatic residues and did not resemble any of the bioactive surfaces of other site-3 toxins. These analyses have portrayed a toxin that might interact with receptor site-3 in a different fashion compared with other ligands of this site. This assumption was corroborated by a D1701R mutation in DmNa(v)1, which has been shown to abolish the activity of all other site-3 ligands, except Av3. All in all, the present study provides further evidence for the heterogeneity of receptor site-3, and raises Av3 as a unique model for design of selective anti-insect compounds.

  19. Protective effect of AVS073, a polyherbal formula, against UVA-induced melanogenesis through a redox mechanism involving glutathione-related antioxidant defense.

    PubMed

    Panich, Uraiwan; Pluemsamran, Thanyawan; Tangsupa-a-nan, Vanida; Wattanarangsan, Jantanee; Phadungrakwittaya, Rattana; Akarasereenont, Pravit; Laohapand, Tawee

    2013-07-05

    Ayurved Siriraj Brand Wattana formula (AVS073), a Thai herbal formula, has traditionally been used for health promotion and prevention of age-related problems. Ultraviolet A (UVA) is recognized to play a vital role in stimulation of melanin synthesis responsible for abnormal skin pigmentation possibly mediated by photooxidative stress. We thus aimed to study the inhibitory effect of AVS073 extracts on UVA-induced melanogenesis via a redox mechanism involving glutathione (GSH) synthesis and glutathione S-transferase (GST) using human melanoma (G361) cell culture. The standardization of AVS073 extracts was carried out by TLC and UHPLC to obtain fingerprinting profiles of the formula, which identified several phenolic compounds including gallic acid (GA) in the formula. Antimelanogenic actions of AVS073 (up to 60 μg/ml) and GA (up to 10 μg/ml) were investigated by measuring tyrosinase activity and mRNA as well as melanin level in G361 cells irradiated with UVA. Moreover, antioxidant actions of the herbal formula and GA were determined by evaluating oxidant formation and modulation of GSH-related antioxidant defenses including GSH content, GST activity and mRNA level of γ-glutamate cysteine ligase catalytic (γ-GCLC) and modifier (γ-GCLM) subunit and GST. AVS073 extracts and GA, used as a reference compound, suppressed UVA-augmented tyrosinase activity and mRNA and melanin formation. In addition, pretreatment with AVS073 and GA was able to inhibit cellular oxidative stress, GSH depletion, GST inactivation and downregulation of γ-GCLC, γ-GCLM and GST mRNA in G361 cells exposed to UVA radiation. AVS073 formula exerted antimelanogenic effects possibly through improving the redox state by upregulation of GSH and GST. Moreover, pharmacological activity of the polyherbal formula would be attributed to combined action of different phenolic compounds present in the formula.

  20. Molecular analysis of the sea anemone toxin Av3 reveals selectivity to insects and demonstrates the heterogeneity of receptor site-3 on voltage-gated Na+ channels

    PubMed Central

    Moran, Yehu; Kahn, Roy; Cohen, Lior; Gur, Maya; Karbat, Izhar; Gordon, Dalia; Gurevitz, Michael

    2007-01-01

    Av3 is a short peptide toxin from the sea anemone Anemonia viridis shown to be active on crustaceans and inactive on mammals. It inhibits inactivation of Navs (voltage-gated Na+ channels) like the structurally dissimilar scorpion α-toxins and type I sea anemone toxins that bind to receptor site-3. To examine the potency and mode of interaction of Av3 with insect Navs, we established a system for its expression, mutagenized it throughout, and analysed it in toxicity, binding and electrophysiological assays. The recombinant Av3 was found to be highly toxic to blowfly larvae (ED50=2.65±0.46 pmol/100 mg), to compete well with the site-3 toxin LqhαIT (from the scorpion Leiurus quinquestriatus) on binding to cockroach neuronal membranes (Ki=21.4±7.1 nM), and to inhibit the inactivation of Drosophila melanogaster channel, DmNav1, but not that of mammalian Navs expressed in Xenopus oocytes. Moreover, like other site-3 toxins, the activity of Av3 was synergically enhanced by ligands of receptor site-4 (e.g. scorpion β-toxins). The bioactive surface of Av3 was found to consist mainly of aromatic residues and did not resemble any of the bioactive surfaces of other site-3 toxins. These analyses have portrayed a toxin that might interact with receptor site-3 in a different fashion compared with other ligands of this site. This assumption was corroborated by a D1701R mutation in DmNav1, which has been shown to abolish the activity of all other site-3 ligands, except Av3. All in all, the present study provides further evidence for the heterogeneity of receptor site-3, and raises Av3 as a unique model for design of selective anti-insect compounds. PMID:17492942

  1. Effects of breeds and dietary protein levels on the growth performance, energy expenditure and expression of avUCP mRNA in chickens.

    PubMed

    Li, Qihua; Xu, Zhiqiang; Liu, L; Yu, Hongxin; Rong, Hua; Tao, Linli; Zhang, Xi; Chen, Xiaobo; Gu, Dahai; Fan, Yueyuan; Li, Xiaoqin; Ge, Changrong; Tian, Yunbo; Jia, Junjing

    2013-04-01

    The physiological mechanisms of thermogenesis, energy balance and energy expenditure are poorly understood in poultry. The aim of this study was designed to investigate the physiological roles of avian uncoupling protein (avUCP) regulating in energy balance and thermogenesis by using three chicken breeds of existence striking genetic difference and feeding with different dietary protein levels. Three chicken breeds including broilers, hybrid chickens, and non-selection Wuding chickens were used in this study. Total 150 chicks of 1 day of age, with 50 from each breed were reared under standard conditions on starter diets to 30 days. At 30 days of age, forty chicks from each breed chicks were divided into two groups. One group was fed low protein diet (LP, 17.0 %), and the other group was fed high protein diet (HP, 19.5 %) for 60 days. Wuding chickens showed the lowest feed conversion efficiency (FCE) and the highest expressions of avUCP mRNA association with high plasma T3 and insulin concentrations. Hybrid chickens showed the lowest expressions of avUCP mRNA association with high FCE and energy efficiency. Expressions of avUCP mRNA association with diet-induced thermogenesis (DIT) were only observed in broiler and hybrid chickens. The expressions of avUCP mRNA were positive association with plasma insulin, T3 and NEFA concentrations. Age influence on the expression of avUCP mRNA were observed only for hybrid and broiler chickens. It seems that both roles of avUCP regulation thermogenesis and lipid utilisation as fuel were observed in the present study response to variation in dietary protein and breeds.

  2. Effects of AV delay and VV delay on left atrial pressure and waveform in ambulant heart failure patients: insights into CRT optimization.

    PubMed

    Chan, W Y Wandy; Blomqvist, Andreas; Melton, Iain C; Norén, Kjell; Crozier, Ian G; Benser, Michael E; Eigler, Neal L; Gutfinger, Dan; Troughton, Richard W

    2014-07-01

    We hypothesized that left atrial pressure (LAP) obtained by a permanent implantable sensor is sensitive to changes in cardiac resynchronization therapy (CRT) settings and could guide CRT optimization to improve the response rate. We investigated the effect of CRT optimization on LAP and its waveform parameters in ambulant heart failure (HF) patients. CRT optimization was performed in eight ambulant HF patients, using echocardiography as reference. LAP waveform was acquired at each of eight atrioventricular (AV) intervals and five inter-ventricular (VV) intervals. Selected waveform parameters were also evaluated for their sensitivity to CRT changes and agreement with echocardiography-guided optimal settings. Optimal AV and VV intervals varied considerably between patients. All patients exhibited significant changes in waveform morphology with AV optimization. Optimal AV delay determined from echocardiography ranged between 140 ms and 225 ms. Mean LAP tended to be lower at optimal setting 14 ± 3 mmHg compared to shorter (<100 ms) or longer (>160 ms) AV settings (P = 0.16). There were clear trends to smaller peak a-wave (P = 0.11) and gentler positive a-slope (P = 0.15) and positive v-slope (P = 0.09) with longer AV delays. Mean LAP and negative v-wave slope correlated well with echo-guided optimal setting, r = 0.91 (P = 0.001) and 0.79 (P = 0.03), respectively. No significant effects on LAP or waveform were seen during VV optimization. LAP and its waveform changes considerably with AV optimization. There is good agreement between echo-guided optimal setting and LAP. LAP could provide an objective guide to CRT optimization. (Clinical Trial Registry information: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00632372). ©2014 Wiley Periodicals, Inc.

  3. [(18)F]AV-1451 binding in vivo mirrors the expected distribution of TDP-43 pathology in the semantic variant of primary progressive aphasia.

    PubMed

    Bevan-Jones, W R; Cope, Thomas E; Jones, P Simon; Passamonti, Luca; Hong, Young T; Fryer, Tim D; Arnold, Robert; Allinson, Kieren S J; Coles, Jonathan P; Aigbirhio, Franklin I; Patterson, Karalyn; O'Brien, John T; Rowe, James B

    2017-09-14

    Semantic dementia, including the semantic variant of primary progressive aphasia (svPPA), is strongly associated with TAR-DNA binding protein 43 (TDP-43) type C pathology. It provides a useful model in which to test the specificity of in vivo binding of the putative tau ligand [(18)F]AV-1451, which is elevated in frontotemporal lobar degeneration tauopathies. Seven patients (five with svPPA and two with 'right' semantic dementia) and 12 healthy controls underwent positron emission tomography brain imaging with [(18)F]AV-1451. Two independent preprocessing methods were used. For both methods, all patients had clearly elevated binding potential (BPND (non-displaceable binding potential)) in temporal lobes, lateralising according to their clinical syndrome and evident in raw images. Region of interest analyses confirmed that BPND was significantly increased in temporal regions, insula and fusiform gyrus, consistent with those areas known to be most affected in semantic dementia. Hierarchical cluster analysis, based on the distribution of [(18)F]AV-1451 binding potential, separated semantic dementia from controls with 86% sensitivity and 100% specificity. [(18)F]AV-1451 binds in vivo regions that are likely to contain TDP-43 and not significant tau pathology. While this suggests a non-tau target for [(18)F]AV-1451, the pathological regions in semantic dementia do not normally contain significant levels of recently proposed 'off target' binding sites for [(18)F]AV-1451, such as neuronal monoamine oxidase or neuromelanin. Postmortem and longitudinal data will be useful to assess the utility of [(18)F]AV-1451 to differentiate and track different types of frontotemporal lobar degeneration. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  4. ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis.

    PubMed

    Schaap, Frank G; Rensen, Patrick C N; Voshol, Peter J; Vrins, Carlos; van der Vliet, Hendrik N; Chamuleau, Robert A F M; Havekes, Louis M; Groen, Albert K; van Dijk, Ko Willems

    2004-07-02

    ApoAV has been discovered recently as a novel modifier of triglyceride (TG) metabolism, but the pathways involved are currently unknown. To gain insight into the function of apoAV, adenovirus-mediated gene transfer of murine apoa5 to C57Bl/6 mice was employed. The injection of low doses of Ad-apoa5 (1-5 x 10(8) plaqueforming units/mouse) dose-dependently reduced plasma very low density lipoprotein (VLDL)-TG levels. First, we evaluated whether a reduced hepatic VLDL production contributed to the TG-lowering effect. Ad-apoa5 treatment dose-dependently diminished (29-37%) the VLDL-TG production rate without affecting VLDL particle production, suggesting that apoAV impairs the lipidation of apoB. Second, Ad-apoa5 treatment dose-dependently reduced (68-88%) the postprandial hypertriglyceridemia following an intragastric fat load, suggesting that apoAV also stimulates the lipoprotein lipase (LPL)-dependent clearance of TG-rich lipoproteins. Indeed, recombinant apoAV was found to dose-dependently stimulate LPL activity up to 2.3-fold in vitro. Accordingly, intravenously injected VLDL-like TG-rich emulsions were cleared at an accelerated rate concomitant with the increased uptake of emulsion TG-derived fatty acids by skeletal muscle and white adipose tissue in Ad-apoa5-treated mice. From these data, we conclude that apoAV is a potent stimulator of LPL activity. Thus, apoAV lowers plasma TG by both reducing the hepatic VLDL-TG production rate and by enhancing the lipolytic conversion of TG-rich lipoproteins.

  5. Management of gestational trophoblastic disease: a survey of New Zealand O&G practice.

    PubMed

    Kladnitski, Maria; Kenwright, Diane

    2016-03-11

    The aim of the study was to obtain information on pathways for diagnosis and management of molar pregnancy/gestational trophoblastic disease (GTD) across New Zealand, the protocols used, and, in addition, to consider the view of O&G Specialists on a national GTD reference centre. An electronic survey approved by the RANZCOG Continues Professional Development Committee was distributed amongst registered O&G Specialists currently working in New Zealand. Data were analysed using Microsoft Excel 2011. Frequency distributions were used to determine the percentage of participants responding to the listed alternatives for each question. There were 234 potential responders, but only 68 complete questionnaires were received and available for analysis. The diagnosis of GTD requires histopathological analysis of pregnancy tissue, however only 79.7% of participants request this test routinely. Sixty-five percent of Fellows thought that a number of molar pregnancies can be missed with increasing proportion of medically-managed miscarriages, reliance on ultrasound and appearance of the tissue being contributing factors. Sixty-six percent of specialists were directly involved in the management of patients with GTD to various degrees. Follow-up responsibilities were divided between designated O&G specialists (52.3%), specialised gynaecology clinics (29.2%), acute assessment units (13.8%), nurse specialists (12%), O&G registrars (10.8%), GPs (6.2%), and others (6.2%). NZGCG guidelines were used by the majority of responders (54.8%), followed by local (29%) and RCOG (27.4%) guidelines. Seventy-two percent of specialists felt that some form of centralisation in the management of GTD is needed. In spite of the low response rate, our research demonstrates existing practice heterogeneity at every level of care. It also confirms that there is a desire for some form of centralisation in diagnosis and management of GTD, and a definite need for data collection in the form of a national

  6. Geologic Mapping of the Av-5 Floronia Quadrangle of Asteroid 4 Vesta

    NASA Astrophysics Data System (ADS)

    Williams, D. A.; Hiesinger, H.; Scully, J. E. C.; Blewett, D. T.; Buczkowski, D. L.; Jaumann, R.; Schenk, P. M.; Yingst, R. A.; Garry, W. B.; Roatsch, T.; Preusker, F.; Pieters, C. M.; Russell, C. T.; Raymond, C. A.; De Sanctis, M. C.

    2012-04-01

    NASA's Dawn spacecraft is spending one year in orbit of asteroid 4Vesta to characterize its geology, chemical and mineralogical composition, topography, shape, and internal structure. The Dawn Team is conducting geological mapping of the surface in the form of 15 quadrangle maps, and here we report results from the mapping of Floronia quadrangle Av-5. Mapping is based on a Framing Camera (FC) mosaic produced from High Altitude Mapping Orbit (HAMO) data with a spatial resolution of ~70 m/pixel, supplemented by a Digital Terrain Model (DTM: lateral spacing of 450 m/pixel and vertical accuracy of ~30 meters), FC color images, and Visible and InfraRed (VIR) hyperspectral images. Av-5 Floronia Quadrangle is located between ~20-66˚N and 270˚-360˚E and covers a portion of the heavily-cratered northern hemisphere of Vesta. This very heavily-cratered terrain is partly obscured by shadows from topographic highs such as crater rims. Crater Floronia is 17 km (W-E) x 19 km (N-S), and its floor is also obscured. A NW-SE-trending trough extends for ~56 km across the SW corner of this quad. As of April 2012 only the southern half of the quad (~20-45˚N) has been illuminated. The northern cratered terrain on Vesta is the most heavily cratered surface on the asteroid, suggesting that it represents the oldest exposed surface. Craters are overlapping and many are heavily degraded, with smooth rims and flat rather than bowl-shaped floors indicative of mass wasting processes. In several locations, old craters overlap to form irregularly-shaped depressions, perhaps influenced by tectonic fractures. Bright ejecta from several younger, large impact craters has smoothed the underlying older cratered surface. Part of a NW-SE-trending trough occurs in the SW corner of this quadrangle. This trough has been degraded by superposed impacts, and has a relatively flatter floor compared to the equatorial troughs. Structural analysis suggests that the formation of this NW-SE-trending trough (and

  7. Apolipoprotein A-V gene therapy for disease prevention / treatment: a critical analysis.

    PubMed

    Forte, Trudy M; Sharma, Vineeta; Ryan, Robert O

    2016-03-01

    Apolipoprotein (apo) A-V is a novel member of the class of exchangeable apo's involved in triacylglycerol (TG) homeostasis. Whereas a portion of hepatic-derived apoA-V is secreted into plasma and functions to facilitate lipoprotein lipase-mediated TG hydrolysis, another portion is recovered intracellularly, in association with cytosolic lipid droplets. Loss of apoA-V function is positively correlated with elevated plasma TG and increased risk of cardiovascular disease. Single nucleotide polymorphisms (SNP) in the APOA5 locus can affect transcription efficiency or introduce deleterious amino acid substitutions. Likewise, rare mutations in APOA5 that compromise functionality are associated with increased plasma TG and premature myocardial infarction. Genetically engineered mouse models and human population studies suggest that, in certain instances, supplementation with wild type (WT) apoA-V may have therapeutic benefit. It is hypothesized that individuals that manifest elevated plasma TG owing to deleterious APOA5 SNPs or rare mutations would respond to WT apoA-V supplementation with improved plasma TG clearance. On the other hand, subjects with hypertriglyceridemia of independent origin (unrelated to apoA-V function) may not respond to apoA-V augmentation in this manner. Improvement in the ability to identify individuals predicted to benefit, advances in gene transfer technology and the strong connection between HTG and heart disease, point to apoA-V supplementation as a viable disease prevention / therapeutic strategy. Candidates would include individuals that manifest chronic TG elevation, have low plasma apoA-V due to an APOA5 mutation/polymorphism and not have deleterious mutations/polymorphisms in other genes known to influence plasma TG levels.

  8. European Natural Disaster Coordination and Information System for Aviation (EUNADICS-AV)

    NASA Astrophysics Data System (ADS)

    Wotawa, Gerhard; Hirtl, Marcus; Arnold, Delia; Katzler-Fuchs, Susanne; Pappalardo, Gelsomina; Mona, Lucia; Sofiev, Mikhail; de Leeuw, Gerrit; Theys, Nicolas; Brenot, Hugues; Plu, Matthieu; Rockitansky, Carl-Herbert; Eschbacher, Kurt; Apituley, Arnoud; Som de Cerff, Wim

    2017-04-01

    Commercial aviation is one of the key infrastructures of our modern world. Even short interruptions can cause economic damages summing up to the Billion-Euro range. As evident from the past, aviation shows vulnerability with regard to natural hazards. Safe flight operations, air traffic management and air traffic control is a shared responsibility of EUROCONTROL, national authorities, airlines and pilots. All stakeholders have one common goal, namely to warrant and maintain the safety of flight crews and passengers. Currently, however, there is a significant gap in the Europe-wide availability of real time hazard measurement and monitoring information for airborne hazards describing "what, where, how much" in 3 dimensions, combined with a near-real-time European data analysis and assimilation system. This gap creates circumstances where various stakeholders in the system may base their decisions on different data and information. The H-2020 project EUNADICS-AV ("European Natural Disaster Coordination and Information System for Aviation"), started in October 2016, intends to close this gap in data and information availability, enabling all stakeholders in the aviation system to obtain fast, coherent and consistent information. The project intends to combine and harmonize data from satellite earth observation, ground based and airborne platforms, and to integrate them into state-of-the art data assimilation and analysis systems. Besides operational data sources, data from the research community are integrated as well. Hazards considered in the project include volcano eruptions, nuclear accidents and events, and forest fires. The availability of consistent and coherent data analysis fields based on all available measurements will greatly enhances our capability to respond to disasters effectively and efficiently, minimizing system downtimes and thus economic damage while maintaining the safety of millions of passengers.

  9. The First Observation of the Submillimeter Polarization Spectrum in a Low-AV Molecular Cloud

    NASA Astrophysics Data System (ADS)

    Campbell Ashton, Peter; Ade, Peter; Angilè, Francesco E.; Benton, Steven J.; Devlin, Mark J.; Dober, Bradley; Fissel, Laura M.; Fukui, Yasuo; Galitzki, Nicholas; Gandilo, Natalie; Klein, Jeffrey; Li, Zhi-Yun; Korotkov, Andrei; Martin, Peter G.; Matthews, Tristan; Moncelsi, Lorenzo; nakamura, fumitaka; Barth Netterfield, Calvin; Novak, Giles; Pascale, Enzo; Poidevin, Frédérick; Santos, Fabio P.; Savini, Giorgio; Scott, Douglas; Shariff, Jamil; Soler, Juan D.; Thomas, Nicholas; tucker, carole; Tucker, Gregory S.; Ward-Thompson, Derek; BLASTPol

    2017-01-01

    Polarized emission from aligned interstellar dust is both a crucial tool for studies of magnetism in the interstellar medium and a troublesome contaminant in studies of the polarized cosmic microwave background. In each case, an understanding of the significance of the dust polarization signal requires well-calibrated models that accurately describe dust grains’ physical properties and interactions with their environment. Despite decades of progress in both theory and observation, polarized dust emission models remain largely underconstrained. During its 2012 flight, BLASTPol (the Balloon-borne Large Aperture Submillimeter Telescope for Polarimetry) obtained simultaneous broad-band polarimetric maps at 250, 350, and 500 μm of a several degree-scale region containing several low-AV molecular clouds. Combining these data with polarimetric observations from the Planck 850 μm band, we have produced a submillimeter polarization spectrum for one of these objects for the first time. We find the polarization degree to be largely constant across the four submillimeter bands. This result introduces a new observable with the potential to place strong empirical constraints on polarized dust models of the ISM in a density regime that has not been accessible to previous experiments. Comparing with the work of Draine & Fraisse (2009), our result is inconsistent with two of their four models. In particular, the two models for which all polarization arises from the aligned silicate component yield submillimeter polarization spectra that rise steeply with wavelength, in disagreement with our observations. This line of investigation will continue in the near future, as new experiments like The Next-Generation BLAST Polarimeter (BLAST-TNG) use their enhanced sensitivities to characterize polarized dust emission in even more diffuse environments.

  10. Immunomodulation by duck defensin, Apl_AvBD2: in vitro dendritic cell immunoreceptor (DCIR) mRNA suppression, and B- and T-lymphocyte chemotaxis.

    PubMed

    Soman, Soja Saghar; Nair, Sajith; Issac, Aneesh; Arathy, D S; Niyas, K P; Anoop, M; Sreekumar, E

    2009-09-01

    The present study analyzed the immunomodulatory potential of a newly identified duck beta-defensin, Apl_AvBD2. Recombinant Apl_AvBD2 expressed in HEK293T cells induced a concentration dependent in vitro migration of duck splenocytes, and spleen B- and T-lymphocytes, which was specifically inhibited by anti-Apl_AvBD2 polyclonal antibodies. Among the transcripts of 13 immunologically important genes analyzed in cultured splenocytes for the early immunomodulatory effect of Apl_AvBD2, dendritic cell immunoreceptor (DCIR) mRNA was found to be significantly down-regulated. However, there were no major changes in the expression levels of transcripts for cell surface proteins (MHC I, MHC II 2 beta-chain, TCR-beta, TLR-7, DCAR, CD44, and CD58) and cytokines (IL-2, IFN-gamma, RANTES, MIP-1beta-like and MCP-1 like chemokines). Our results reveal chemotactic and immunomodulatory properties of Apl_AvBD2, two important functions that would help in employing this protein as a molecular adjuvant with avian vaccines.

  11. The apolipoprotein CIII enhancer regulates both extensive histone modification and intergenic transcription of human apolipoprotein AI/CIII/AIV genes but not apolipoprotein AV.

    PubMed

    Li, Ya-Jun; Wei, Yu-Sheng; Fu, Xiang-Hui; Hao, De-Long; Xue, Zheng; Gong, Huan; Zhang, Zhu-Qin; Liu, De-Pei; Liang, Chih-Chuan

    2008-10-17

    The apolipoprotein (apo) AI/CIII/AIV/AV cluster genes are expressed at different levels in the liver and intestine. The apoCIII enhancer, a common regulatory element, regulates the tissue-specific expression of apoAI, apoCIII, and apoAIV but not apoAV. To study this regulation at the chromatin level, the histone modifications and intergenic transcription in the human apoAI/CIII/AIV/AV cluster were investigated in HepG2 and Caco-2 cells and in the livers of transgenic mice carrying the human gene cluster constructs with or without the apoCIII enhancer. We found that both the promoters and the intergenic regions of the apoAI/CIII/AIV genes were hyperacetylated and formed an open subdomain that did not include the apoAV gene. Hepatic and intestinal intergenic transcripts were identified to transcribe bidirectionally with strand preferences along the cluster. The deletion of the apoCIII enhancer influenced both histone modification and intergenic transcription in the apoAI/CIII/AIV gene region. These results demonstrate that the apoCIII enhancer contributes to the maintenance of an active chromatin subdomain of the apoAI/CIII/AIV genes, but not apoAV.

  12. Evaluation of A-V impulse technology as a treatment for oedema following polytetrafluoroethylene femoropopliteal surgery in a randomised controlled trial.

    PubMed

    te Slaa, A; Dolmans, D E J G J; Ho, G H; Mulder, P G H; van der Waal, J C H; de Groot, H G W; van der Laan, L

    2010-11-01

    To investigate the efficacy of A-V impulse technology (A-V) for oedema prevention and treatment following PTFE femoropopliteal surgery. Prospective randomized clinical trial. 36 patients undergoing PTFE femoropopliteal bypass reconstructions, either being treated postoperatively with a compression stocking (CS) (Group-1, n = 19) or with A-V (Group-2, n = 17). Patients in treatment group-1 used a CS postoperatively during 1 week day and night, patients in group-2 were treated with A-V postoperatively at night during one week. The lower leg circumference was measured preoperatively and at five postoperative time points. Limb circumference has increased postoperatively on day 1 (CS 1.5%/A-V 1.4%), on day 4 (5.7%/6.3%), on day 7 (6.6%/6.1%), on day 14 (7.9%/7.7%) and on day 90 (5.8%/5.2%). Differences between treatment groups were not significant. A re-operation gives a significant 3.9% increase in circumference as compared to a first operation (95% CI: 1.5-6.4%; p = 0.002). No significant differences were found in the extent of developed edema between the groups following PTFE femoropopliteal bypass surgery. A redo peripheral bypass operation results in significantly more postoperative oedema than a first-time performed bypass operation. Copyright © 2010 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

  13. Assessment of Multiple Risk Outcomes, Strengths, and Change with the START:AV: A Short-Term Prospective Study with Adolescent Offenders

    PubMed Central

    Viljoen, Jodi L.; Beneteau, Jennifer L.; Gulbransen, Erik; Brodersen, Etta; Desmarais, Sarah L.; Nicholls, Tonia L.; Cruise, Keith R.

    2012-01-01

    The Short-Term Assessment of Risk and Treatability: Adolescent Version (START:AV; Nicholls, Viljoen, Cruise, Desmarais, & Webster, 2010; Viljoen, Cruise, Nicholls, Desmarais, & Webster, in preparation) is a clinical guide designed to assist in the assessment and management of adolescents’ risk for adverse events (e.g., violence, general offending, suicide, victimization). In this initial validation study, START:AV assessments were conducted on 90 adolescent offenders (62 male, 28 female), who were prospectively followed for a 3-month period. START:AV assessments had good to excellent inter-rater reliability and strong concurrent validity with Structured Assessment of Violence Risk in Youth assessments (SAVRY; Borum, Bartel, & Forth, 2006). START:AV risk estimates and Vulnerability total scores predicted multiple adverse outcomes, including violence towards others, offending, victimization, suicidal ideation, and substance abuse. In addition, Strength total scores inversely predicted violence, offending, and street drug use. During the 3-month follow-up, risk estimates changed in at least one domain for 92% of youth, and 27% of youth showed reliable changes in Strength and/or Vulnerability total scores (reliable change index, 90% confidence interval; Jacobsen & Truax, 1991). While these findings are promising, a strong need exists for further research on the START:AV, the measurement of change, and on the role of strengths in risk assessment and treatment-planning. PMID:23436983

  14. OGS improvements in 2012 in running the Northeastern Italy Seismic Network: the Ferrara VBB borehole seismic station

    NASA Astrophysics Data System (ADS)

    Pesaresi, Damiano; Romanelli, Marco; Barnaba, Carla; Bragato, Pier Luigi; Durì, Giorgio

    2013-04-01

    The Centro di Ricerche Sismologiche (CRS, Seismological Research Center) of the Istituto Nazionale di Oceanografia e di Geofisica Sperimentale (OGS, Italian National Institute for Oceanography and Experimental Geophysics) in Udine (Italy) after the strong earthquake of magnitude M=6.4 occurred in 1976 in the Italian Friuli-Venezia Giulia region, started to operate the Northeastern Italy Seismic Network: it currently consists of 17 very sensitive broad band and 18 simpler short period seismic stations, all telemetered to and acquired in real time at the OGS-CRS data center in Udine. Real time data exchange agreements in place with other Italian, Slovenian, Austrian and Swiss seismological institutes lead to a total number of about 100 seismic stations acquired in real time, which makes the OGS the reference institute for seismic monitoring of Northeastern Italy. The southwestern edge of the OGS seismic network stands on the Po alluvial basin: earthquake localization and characterization in this area is affected by the presence of soft alluvial deposits. OGS ha already experience in running a local seismic network in high noise conditions making use of borehole installations in the case of the micro-seismicity monitoring of a local gas storage site for a private company. Following the ML=5.9 earthquake that struck the Emilia region around Ferrara in Northern Italy on May 20, 2012 at 02:03:53 UTC, a cooperation of Istituto Nazionale di Geofisica e Vulcanologia, OGS, the Comune di Ferrara and the University of Ferrara lead to the reinstallation of a previously existing very broad band (VBB) borehole seismic station in Ferrara. The aim of the OGS intervention was on one hand to extend its real time seismic monitoring capabilities toward South-West, including Ferrara and its surroundings, and on the other hand to evaluate the seismic response at the site. We will describe improvements in running the Northeastern Italy Seismic Network, including details of the Ferrara VBB

  15. ND2 AV: N-dimensional data analysis and visualization analysis for the National Ignition Campaign

    SciTech Connect

    Bremer, Peer -Timo; Maljovec, Dan; Saha, Avishek; Wang, Bei; Gaffney, Jim; Spears, Brian K.; Pascucci, Valerio

    2015-07-01

    Here, one of the biggest challenges in high-energy physics is to analyze a complex mix of experimental and simulation data to gain new insights into the underlying physics. Currently, this analysis relies primarily on the intuition of trained experts often using nothing more sophisticated than default scatter plots. Many advanced analysis techniques are not easily accessible to scientists and not flexible enough to explore the potentially interesting hypotheses in an intuitive manner. Furthermore, results from individual techniques are often difficult to integrate, leading to a confusing patchwork of analysis snippets too cumbersome for data exploration. This paper presents a case study on how a combination of techniques from statistics, machine learning, topology, and visualization can have a significant impact in the field of inertial confinement fusion. We present the $\\mathrm{ND}^2\\mathrm{AV}$: N-dimensional data analysis and visualization framework, a user-friendly tool aimed at exploiting the intuition and current workflow of the target users. The system integrates traditional analysis approaches such as dimension reduction and clustering with state-of-the-art techniques such as neighborhood graphs and topological analysis, and custom capabilities such as defining combined metrics on the fly. All components are linked into an interactive environment that enables an intuitive exploration of a wide variety of hypotheses while relating the results to concepts familiar to the users, such as scatter plots. $\\mathrm{ND}^2\\mathrm{AV}$ uses a modular design providing easy extensibility and customization for different applications. $\\mathrm{ND}^2\\mathrm{AV}$ is being actively used in the National Ignition Campaign and has already led to a number of unexpected discoveries.

  16. Massive stars exploding in a He-rich circumstellar medium - IX. SN 2014av, and characterization of Type Ibn SNe

    NASA Astrophysics Data System (ADS)

    Pastorello, A.; Wang, X.-F.; Ciabattari, F.; Bersier, D.; Mazzali, P. A.; Gao, X.; Xu, Z.; Zhang, J.-J.; Tokuoka, S.; Benetti, S.; Cappellaro, E.; Elias-Rosa, N.; Harutyunyan, A.; Huang, F.; Miluzio, M.; Mo, J.; Ochner, P.; Tartaglia, L.; Terreran, G.; Tomasella, L.; Turatto, M.

    2016-02-01

    We present spectroscopic and photometric data of the Type Ibn supernova (SN) 2014av, discovered by the Xingming Observatory Sky Survey. Stringent pre-discovery detection limits indicate that the object was detected for the first time about 4 d after the explosion. A prompt follow-up campaign arranged by amateur astronomers allowed us to monitor the rising phase (lasting 10.6 d) and to accurately estimate the epoch of the maximum light, on 2014 April 23 (JD = 245 6771.1 ± 1.2). The absolute magnitude of the SN at the maximum light is MR = -19.76 ± 0.16. The post-peak light curve shows an initial fast decline lasting about three weeks, and is followed by a slower decline in all bands until the end of the monitoring campaign. The spectra are initially characterized by a hot continuum. Later on, the temperature declines and a number of lines become prominent mostly in emission. In particular, later spectra are dominated by strong and narrow emission features of He I typical of Type Ibn supernovae (SNe), although there is a clear signature of lines from heavier elements (in particular O I, Mg II and Ca II). A forest of relatively narrow Fe II lines is also detected showing P-Cygni profiles, with the absorption component blueshifted by about 1200 km s-1. Another spectral feature often observed in interacting SNe, a strong blue pseudo-continuum, is seen in our latest spectra of SN 2014av. We discuss in this paper the physical parameters of SN 2014av in the context of the Type Ibn SN variety.

  17. Modulation of Interleukin-8 and staphylococcal flora by Avène hydrotherapy in patients suffering from chronic inflammatory dermatoses.

    PubMed

    Casas, C; Ribet, V; Alvarez-Georges, S; Sibaud, V; Guerrero, D; Schmitt, A-M; Redoulès, D

    2011-02-01

    A number of studies argue in favour of an important role of microbial colonization, in particular of Staphylococcus aureus, in triggering atopic dermatitis (AD) flare-up and psoriasis, in particular through the superantigenic properties of toxins generated by S. aureus. The aim of this study was to assess the efficacy of a 3-week Avène hydrotherapy on the skin surface of patients suffering from psoriasis or atopic dermatitis. Skin samples were taken from healthy subjects or atopic (n = 18) or psoriatic patients (n = 39) undergoing hydrotherapy at Avène at the beginning (D0) and the end of treatment (D18). The severity of the dermatosis was evaluated according to SCORing Atopic Dermatitis (SCORAD) or Psoriasis Area Severity Index (PASI) scores at D0 and D18. Marker of inflammation interleukin 8 (IL-8), S. aureus colonization (protein A) and enterotoxins were assessed in skin samples using RT-PCR. At D0, significant differences were observed between healthy subjects and atopic or psoriatic patients in all the parameters evaluated (IL-8, protein A). At the end of the hydrotherapy, a significant decrease in SCORAD was associated with a significant reduction of IL-8, S. aureus colonization and enterotoxin D in patients with atopic dermatitis. Similarly, a significant decrease in PASI was associated with a significant reduction of IL-8, S. aureus colonization and enterotoxin N in patients with psoriasis. This study demonstrates the positive effects of Avène hydrotherapy on the skin of patients suffering from chronic dermatosis, with decreased inflammation and reduced colonization by S. aureus. © 2010 The Authors. JEADV © 2010 European Academy of Dermatology and Venereology.

  18. HPCMP CREATE (trademark)-AV Quality Assurance: Best Practices for Validating and Supporting Computation-Based Engineering Software

    DTIC Science & Technology

    2015-09-30

    30/2015 Oct 2008-Sep 2015 HPCMP CREATE™-AV Quality Assurance: Best Practices for Validating and Supporting Computation-Based Engineering Software ...user of computational-based engineering software , the two most relevant questions are: (1) “Does this tool adequately perform the analysis I need?” and... Software 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7

  19. Single primitive ventricle with normally related great arteries and atresia of the left A-V valve.

    PubMed Central

    Coto, E O; Raggio, J M; Malo, P; Sainz, C; Aparisi, R; Gomez-Ullate, J M

    1978-01-01

    A child aged 2 years and 9 months was angiocardiographically diagnosed to have a single ventricle with normally related great arteries and atresia of the left A-V valve. A Blalock-Hanlon procedure and division of a large patent ductus arteriosus were followed by reduction in pulmonary artery pressure, but after operation the patient showed signs of left ventricular failure unresponsive to medical treatment, necessitating pulmonary artery banding. We have found only three similar published cases, and this is the only one with full angiographic documentation. Images PMID:725830

  20. Thromboresistant surface coatings for the measurement of cardiac output through continuous low flow peripheral A-V shunts.

    PubMed Central

    Deeb, G M; Borovetz, H S; Griffith, B P; Hardesty, R L

    1980-01-01

    The dilution technique for determining cardiac output using indocyanine green dye is limited in patients weighing less than 20 kg because of the obligatory volume loss. Reproducible achieved using the green dye dilution method by the establishment of a low flow peripheral arteriovenous shunt. The shunt materials were treated with thromboresistant agents--TDMAC (7%) and albumin (1 g/dl)--to facilitate the use of this technique without heparin. For A-V shunt flow rates of 8-30 cc/min reproducible values of cardiac output were obtained for up to 38 hours which were in good agreement with determinations made using the conventional technique of dye dilution. PMID:6986120

  1. Novel measure of electrical dyssynchrony predicts response in cardiac resynchronization therapy: Results from the SMART-AV Trial.

    PubMed

    Tereshchenko, Larisa G; Cheng, Alan; Park, Jason; Wold, Nicholas; Meyer, Timothy E; Gold, Michael R; Mittal, Suneet; Singh, Jagmeet; Stein, Kenneth M; Ellenbogen, Kenneth A

    2015-12-01

    Cardiac resynchronization therapy (CRT) reduces mortality and morbidity in selected heart failure patients. However, not all patients respond to CRT. We hypothesized that a novel measure of electrical dyssynchrony, sum absolute QRST integral (SAI QRST), predicts CRT response independent of QRS duration and morphology. We retrospectively analyzed baseline 12-lead electrocardiograms of SmartDelay Determined AV Optimization: A comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial study participants (N = 234; mean age 67 years; 163 (70%) men; 140 (60%) ischemic cardiomyopathy; mean left ventricular ejection fraction 25%; mean QRS duration 152 ms; 179 (77%) had left bundle branch block). Baseline pre-implant electrocardiograms were digitized, transformed into orthogonal XYZ, and analyzed automatically by customized MATLAB software. SAI QRST was measured as an averaged arithmetic sum of absolute areas under the QRST curve. Patients were followed prospectively 6 months after CRT-defibrillator implantation. Patients with a decrease in left ventricular end-systolic volume ≥15 mL after 6 months of CRT were considered responders. The logistic regression model was adjusted for age, sex, bundle branch block morphology, left ventricular ejection fraction, cardiomyopathy type, and QRS duration. Patients with the high mean SAI QRST (third tertile) had 2.5 times greater odds of response than those with the low mean SAI QRST (first tertile: odds ratio [OR] 2.5; 95% confidence interval [CI] 1.3-5.0; P = .010) and 1.9 times greater than the lower 2 tertiles combined (OR 1.9; 95% CI 1.1-3.5; P = .03). Adjustment for renal function (OR 2.33; 95% CI 1.32-4.11; P = .003) and left ventricular lead position in right anterior oblique and left anterior oblique views (OR 1.7; 95% CI 0.9-3.2; P = .087) did not attenuate association of SAI QRST with outcome. High SAI QRST independently predicts CRT response in the SMART-AV study. Copyright © 2015

  2. [Role of the AV node and adrenergic stimulation in initiation of fascicular and atrioventricular nodal tachycardias--a case report].

    PubMed

    Szumowski, Łukasz; Miszczak-Knecht, Maria; Bieganowska, Katarzyna; Rekawek, Joanna; Szymaniak, Elzbieta; Kawalec, Wanda; Walczak, Franciszek

    2008-05-01

    Fascicular tachycardia is an uncommon form of left ventricular tachycardia in young patients with normal heart. Ventriculo-atrial conduction during VT is usually absent. Retrograde conduction was observed in a 14-year old boy with left posterior fascicular VT (LPF-VT) triggered by exercise. During isoproterenol infusion, atrial stimulation induced a cascade of arrhythmias--echo, pair or runs of AVNRT and fascicular tachycardia triggered by fascicular beats. Also, during infusion LPF-VT was initiated spontaneously. After successful ablation of VT, sustained typical AVNRT was inducible. Finally, ablation of slow pathway of AV node was performed. After ablation,no arrhythmia was inducible following isoproterenol and exercise.

  3. Ectopic expression of ubiquitin-conjugating enzyme gene from wild rice, OgUBC1, confers resistance against UV-B radiation and Botrytis infection in Arabidopsis thaliana

    SciTech Connect

    Jeon, En Hee; Pak, Jung Hun; Kim, Mi Jin; Kim, Hye Jeong; Shin, Sang Hyun; Lee, Jai Heon; Kim, Doh Hoon; Oh, Ju Sung; Oh, Boung-Jun; Jung, Ho Won; Chung, Young Soo

    2012-10-19

    Highlights: Black-Right-Pointing-Pointer We isolated a novel E2 ubiquitin-conjugating enzyme from leaves of wild rice plants. Black-Right-Pointing-Pointer The OgUBC1 was highly expressed in leaves treated with SA and UV-B radiation. Black-Right-Pointing-Pointer The recombinant OgUBC1 has an enzymatic activity of E2 in vitro. Black-Right-Pointing-Pointer The OgUBC1 could protect disruption of plant cells by UV-B radiation. Black-Right-Pointing-Pointer OgUBC1 confers disease resistance and UV-B tolerance in transgenic Arabidopsis plants. -- Abstract: A previously unidentified gene encoding ubiquitin-conjugating enzyme was isolated from leaves of wild rice plant treated with wounding and microbe-associated molecular patterns. The OgUBC1 gene was composed of 148 amino acids and contained a typical active site and 21 ubiquitin thioester intermediate interaction residues and 4 E3 interaction residues. Both exogenous application of salicylic acid and UV-B irradiation triggered expression of OgUBC1 in leaves of wild rice. Recombinant OgUBC1 proteins bound to ubiquitins in vitro, proposing that the protein might act as E2 enzyme in planta. Heterologous expression of the OgUBC1 in Arabidopsis thaliana protected plants from cellular damage caused by an excess of UV-B radiation. A stable expression of chalcone synthase gene was detected in leaves of OgUBC1-expressing Arabidopsis, resulting in producing higher amounts of anthocyanin than those in wild-type Col-0 plants. Additionally, both pathogenesis-related gene1 and 5 were transcribed in the transgenic Arabidopsis in the absence of pathogen infection. The OgUBC1-expressing plants were resistant to the infection of Botrytis cinerea. Taken together, we suggested that the OgUBC1 is involved in ubiquitination process important for cellular response against biotic and abiotic stresses in plants.

  4. Cerebral [(18) F]T807/AV1451 retention pattern in clinically probable CTE resembles pathognomonic distribution of CTE tauopathy.

    PubMed

    Dickstein, D L; Pullman, M Y; Fernandez, C; Short, J A; Kostakoglu, L; Knesaurek, K; Soleimani, L; Jordan, B D; Gordon, W A; Dams-O'Connor, K; Delman, B N; Wong, E; Tang, C Y; DeKosky, S T; Stone, J R; Cantu, R C; Sano, M; Hof, P R; Gandy, S

    2016-09-27

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder most commonly associated with repetitive traumatic brain injury (TBI) and characterized by the presence of neurofibrillary tangles of tau protein, known as a tauopathy. Currently, the diagnosis of CTE can only be definitively established postmortem. However, a new positron emission tomography (PET) ligand, [(18)F]T807/AV1451, may provide the antemortem detection of tau aggregates, and thus various tauopathies, including CTE. Our goal was to examine [(18)F]T807/AV1451 retention in athletes with neuropsychiatric symptoms associated with a history of multiple concussions. Here we report a 39-year-old retired National Football League player who suffered 22 concussions and manifested progressive neuropsychiatric symptoms. Emotional lability and irritability were the chief complaints. Serial neuropsychological exams revealed a decline in executive functioning, processing speed and fine motor skills. Naming was below average but other cognitive functions were preserved. Structural analysis of longitudinally acquired magenetic resonance imaging scans revealed cortical thinning in the left frontal and lateral temporal areas, as well as volume loss in the basal ganglia. PET with [(18)F]florbetapir was negative for amyloidosis. The [(18)F]T807/AV1451 PET showed multifocal areas of retention at the cortical gray matter-white matter junction, a distribution considered pathognomonic for CTE. [(18)F]T807/AV1451 standard uptake value (SUV) analysis showed increased uptake (SUVr⩾1.1) in bilateral cingulate, occipital, and orbitofrontal cortices, and several temporal areas. Although definitive identification of the neuropathological underpinnings basis for [(18)F]T807/AV1451 retention requires postmortem correlation, our data suggest that [(18)F]T807/AV1451 tauopathy imaging may be a promising tool to detect and diagnose CTE-related tauopathy in living subjects.

  5. Cerebral [18 F]T807/AV1451 retention pattern in clinically probable CTE resembles pathognomonic distribution of CTE tauopathy

    PubMed Central

    Dickstein, D L; Pullman, M Y; Fernandez, C; Short, J A; Kostakoglu, L; Knesaurek, K; Soleimani, L; Jordan, B D; Gordon, W A; Dams-O'Connor, K; Delman, B N; Wong, E; Tang, C Y; DeKosky, S T; Stone, J R; Cantu, R C; Sano, M; Hof, P R; Gandy, S

    2016-01-01

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder most commonly associated with repetitive traumatic brain injury (TBI) and characterized by the presence of neurofibrillary tangles of tau protein, known as a tauopathy. Currently, the diagnosis of CTE can only be definitively established postmortem. However, a new positron emission tomography (PET) ligand, [18F]T807/AV1451, may provide the antemortem detection of tau aggregates, and thus various tauopathies, including CTE. Our goal was to examine [18F]T807/AV1451 retention in athletes with neuropsychiatric symptoms associated with a history of multiple concussions. Here we report a 39-year-old retired National Football League player who suffered 22 concussions and manifested progressive neuropsychiatric symptoms. Emotional lability and irritability were the chief complaints. Serial neuropsychological exams revealed a decline in executive functioning, processing speed and fine motor skills. Naming was below average but other cognitive functions were preserved. Structural analysis of longitudinally acquired magenetic resonance imaging scans revealed cortical thinning in the left frontal and lateral temporal areas, as well as volume loss in the basal ganglia. PET with [18F]florbetapir was negative for amyloidosis. The [18F]T807/AV1451 PET showed multifocal areas of retention at the cortical gray matter–white matter junction, a distribution considered pathognomonic for CTE. [18F]T807/AV1451 standard uptake value (SUV) analysis showed increased uptake (SUVr⩾1.1) in bilateral cingulate, occipital, and orbitofrontal cortices, and several temporal areas. Although definitive identification of the neuropathological underpinnings basis for [18F]T807/AV1451 retention requires postmortem correlation, our data suggest that [18F]T807/AV1451 tauopathy imaging may be a promising tool to detect and diagnose CTE-related tauopathy in living subjects. PMID:27676441

  6. Cloning and characterization of trichome-specific promoter of cpr71av1 gene involved in artemisinin biosynthesis in Artemisia annua L.

    PubMed

    Wang, Yueyue; Yang, Ke; Jing, Fuyuan; Li, Meiya; Deng, Ting; Huang, Runze; Wang, Boshi; Wang, Guofeng; Sun, Xiaofen; Tang, Ke-Xuan

    2011-01-01

    Artemisinin, a sesquiterpene lactone endoperoxide derived from Artemisia annua L. (Asteraceae), is the most effective antimalarial drug. We used two methods: genome walking and thermal asymmetric interlaced polymerase chain reaction, to isolate the unknown 5'-flanking sequence of the cyp71av1 gene. The subsequent sequence analysis using bioinformatics software revealed that there are several cis-acting elements inside the cyp71av1 promoter. The 5'-rapid amplification of the cDNA ends method was used to determine the transcription start site of the cyp71av1 gene. We then mapped it at the 18 base upstream of the ATG initiation codon. For simple functional characterization, we built fusion vectors between the 5'-deletion promoter and the gas reporter gene. The expression levels of the transferred vectors into A. annua L. were analyzed by the transient expression way. The beta-glucuronidase assay results indicated that deletion of the region to -1551 bp did not lead to much damage in the GUS activity, whereas further deletion, to -1155 bp, resulted in a 5.5-fold reduction of GUS activity. In stabilized transgenic A. annua L. seedlings we observed that GUS expression was restricted to trichomes, which means that the promoter of the cyp71av1 gene is trichome-specific. Compared with the constitutive CaMV 35S promoter, which can express genes throughout the plant, influence on the trichome system through the trichome-specific expression promoter merely imperils plant growth. In addition, the promoter of the cyp71av1 gene contains several binding sites for transcription factors, which implies that the cyp71av1 promoter responds to more than one form of stimulation.

  7. Regional Amyloid Deposition in Amnestic Mild Cognitive Impairment and Alzheimer's Disease Evaluated by [18F]AV-45 Positron Emission Tomography in Chinese Population

    PubMed Central

    Hsiao, Ing-Tsung; Kuo, Hung-Chou; Hsu, Wen-Chuin; Chuang, Wen-Li; Kung, Mei-Ping; Wey, Shiaw-Pyng; Hsieh, Chia-Ju; Wai, Yau-Yau; Yen, Tzu-Chen; Huang, Chin-Chang

    2013-01-01

    Background To compare the neocortical amyloid loads among cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and Alzheimer's disease (AD) subjects with [18F]AV-45 positron emission tomography (PET). Materials and Methods [18F]AV-45 PET was performed in 11 CN, 13 aMCI, and 12 AD subjects to compare the cerebral cortex-to-whole cerebellum standard uptake value ratios (SUVRs) of global and individual volumes of interest (VOIs) cerebral cortex. The correlation between global cortical [18F]AV-45 SUVRs and Mini-Mental State Examination (MMSE) scores was analyzed. Results The global cortical [18F]AV-45 SUVRs were significantly different among the CN (1.08±0.08), aMCI (1.27±0.06), and AD groups (1.34±0.13) (p = 0.0003) with amyloidosis positivity rates of 9%, 62%, and 92% in the three groups respectively. Compared to CN subjects, AD subjects had higher SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, and posterior cingulate areas; while aMCI subjects had higher values in the global cortical, precuneus, frontal, occipital and posterior cingulate areas. There were negative correlations of MMSE scores with SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, posterior cingulate and anterior cingulate areas on a combined subject pool of the three groups after age and education attainment adjustment. Conclusions Amyloid deposition occurs relatively early in precuneus, frontal and posterior cingulate in aMCI subjects. Higher [18F]AV-45 accumulation is present in parietal, occipital and temporal gyri in AD subjects compared to the aMCI group. Significant correlation between MMSE scores and [18F]AV-45 SUVRs can be observed among CN, aMCI and AD subjects. PMID:23516589

  8. Regional amyloid deposition in amnestic mild cognitive impairment and Alzheimer's disease evaluated by [18F]AV-45 positron emission tomography in Chinese population.

    PubMed

    Huang, Kuo-Lun; Lin, Kun-Ju; Hsiao, Ing-Tsung; Kuo, Hung-Chou; Hsu, Wen-Chuin; Chuang, Wen-Li; Kung, Mei-Ping; Wey, Shiaw-Pyng; Hsieh, Chia-Ju; Wai, Yau-Yau; Yen, Tzu-Chen; Huang, Chin-Chang

    2013-01-01

    To compare the neocortical amyloid loads among cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and Alzheimer's disease (AD) subjects with [(18)F]AV-45 positron emission tomography (PET). [(18)F]AV-45 PET was performed in 11 CN, 13 aMCI, and 12 AD subjects to compare the cerebral cortex-to-whole cerebellum standard uptake value ratios (SUVRs) of global and individual volumes of interest (VOIs) cerebral cortex. The correlation between global cortical [(18)F]AV-45 SUVRs and Mini-Mental State Examination (MMSE) scores was analyzed. The global cortical [(18)F]AV-45 SUVRs were significantly different among the CN (1.08±0.08), aMCI (1.27±0.06), and AD groups (1.34±0.13) (p = 0.0003) with amyloidosis positivity rates of 9%, 62%, and 92% in the three groups respectively. Compared to CN subjects, AD subjects had higher SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, and posterior cingulate areas; while aMCI subjects had higher values in the global cortical, precuneus, frontal, occipital and posterior cingulate areas. There were negative correlations of MMSE scores with SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, posterior cingulate and anterior cingulate areas on a combined subject pool of the three groups after age and education attainment adjustment. Amyloid deposition occurs relatively early in precuneus, frontal and posterior cingulate in aMCI subjects. Higher [(18)F]AV-45 accumulation is present in parietal, occipital and temporal gyri in AD subjects compared to the aMCI group. Significant correlation between MMSE scores and [(18)F]AV-45 SUVRs can be observed among CN, aMCI and AD subjects.

  9. A dual mechanism involved in membrane and nucleic acid disruption of AvBD103b, a new avian defensin from the king penguin, against Salmonella enteritidis CVCC3377.

    PubMed

    Teng, Da; Wang, Xiumin; Xi, Di; Mao, Ruoyu; Zhang, Yong; Guan, Qingfeng; Zhang, Jun; Wang, Jianhua

    2014-10-01

    The food-borne bacterial gastrointestinal infection is a serious public health threat. Defensins are evolutionarily conserved innate immune components with broad-spectrum antibacterial activity that do not easily induce resistance. AvBD103b, an avian defensin with potent activity against Salmonella enteritidis, was isolated from the stomach contents of the king penguin (Aptenodytes patagonicus). To elucidate further the antibacterial mechanism of AvBD103b, its effect on the S. enteritidis CVCC3377 cell membrane and intracellular DNA was researched. The cell surface hydrophobicity and a N-phenyl-1-naphthylamine uptake assay demonstrated that AvBD103b treatment increased the cell surface hydrophobicity and outer membrane permeability. Atomic absorption spectrometry, ultraviolet spectrophotometry, flow cytometry, and transmission electron microscopy (TEM) indicated that AvBD103b treatment can lead to the release of the cellular contents and cell death through damage of the membrane. DNA gel retardation and circular dichroism analysis demonstrated that AvBD103b interacted with DNA and intercalated into the DNA base pairs. A cell cycle assay demonstrated that AvBD103b affected cellular functions, such as DNA synthesis. Our results confirmed that AvBD103b exerts its antibacterial activity by damaging the cell membrane and interfering with intracellular DNA, ultimately causing cell death, and suggested that AvBD103b may be a promising candidate as an alternative to antibiotics against S. enteritidis.

  10. Postoperative Quality of Life after Total Gastrectomy Compared with Partial Gastrectomy: Longitudinal Evaluation by European Organization for Research and Treatment of Cancer-OG25 and STO22.

    PubMed

    Lee, Jeong-Hwan; Lee, Hyuk-Joon; Choi, Yun Suk; Kim, Tae Han; Huh, Yeon-Ju; Suh, Yun-Suhk; Kong, Seong-Ho; Yang, Han-Kwang

    2016-12-01

    The European Organization for Research and Treatment of Cancer quality-of-life questionnaire-OG25 was developed to evaluate the quality of life in patients with stomach and esophageal cancer. The following are included in the OG25 but not in the STO22: odynophagia, choked when swallowing, weight loss, trouble eating with others, trouble swallowing saliva, trouble talking, and trouble with coughing. In this study, we evaluated the quality of life of gastrectomized patients using both, the OG25 and the STO22. A total of 138 patients with partial gastrectomy (PG) (distal gastrectomy=91; pylorus-preserving gastrectomy= 47) and 44 patients with total gastrectomy (TG) were prospectively evaluated. Body weight and scores from the OG25 and STO22 were evaluated preoperatively and at 3 weeks, 3 months, and 6 months after surgery. Patients with TG had significant weight loss compared to patients with PG. At 3 months, TG was associated with worse scores for dysphagia, eating, odynophagia, trouble eating with others, trouble with taste, and weight loss on the OG25. TG was also associated with dysphagia, eating restrictions, and anxiety on the STO22. The OG25 helped differentiate between the groups with respect to weight loss, odynophagia, choked when swallowing, and trouble eating with others. The OG25 scores changed over time and were significantly different. The OG25 is a more sensitive and useful scale than the STO22 for evaluating the quality of life of gastrectomized patients, especially those with total gastrectomy.

  11. Influence of reactive sulfide (AVS) and supplementary food on Ag, Cd and Zn bioaccumulation in the marine polychaete Neanthes arenaceodentata

    USGS Publications Warehouse

    Lee, J.-S.; Lee, B.-G.; Yoo, H.; Koh, C.-H.; Luoma, S.N.

    2001-01-01

    A laboratory bioassay determined the relative contribution of various pathways of Ag, Cd and Zn bioaccumulation in the marine polychaete Neanthes arenaceodentata exposed to moderately contaminated sediments. Juvenile worms were exposed for 25 d to experimental sediments containing 5 different reactive sulfide (acid volatile sulfides, AVS) concentrations (1 to 30 ??mol g-1), but with constant Ag, Cd, and Zn concentrations of 0.1, 0.1 and 7 ??mol g-1, respectively. The sediments were supplemented with contaminated food (TetraMin??) containing 3 levels of Ag-Cd-Zn (uncontaminated, 1?? or 5??1 metal concentrations in the contaminated sediment). The results suggest that bioaccumulation of Ag, Cd and Zn in the worms occurred predominantly from ingestion of contaminated sediments and contaminated supplementary food. AVS or dissolved metals (in porewater and overlying water) had a minor effect on bioaccumulation of the 3 metals in most of the treatments. The contribution to uptake from the dissolved source was most important in the most oxic sediments, with maximum contributions of 8% for Ag, 30% for Cd and 20% for Zn bioaccumulation. Sediment bioassays where uncontaminated supplemental food is added could seriously underestimate metal exposures in an equilibrated system; N. arenaceodentata feeding on uncontaminated food would be exposed to 40-60% less metal than if the food source was equilibrated (as occurs in nature). Overall, the results show that pathways of metal exposure are dynamically linked in contaminated sediments and shift as external geochemical characteristics and internal biological attributes vary.

  12. Large-scale atmospheric processes in the Arctic region reproduced by Sl-AV model and reanalysis data

    NASA Astrophysics Data System (ADS)

    Kulikova, Irina; Kruglova, Ekaterina; Khan, Valentina; Kiktev, Dmitry; Tischenko, Vladimir

    2015-04-01

    The variability of large-scale atmospheric processes in the Arctic region was analyzed on the base of the NCEP/DOE reanalysis data and seasonal hindcasts from global semi-Lagrangian model (SL-AV), developed in collaboration of Hydrometeorological Centre of Russia with Institute of Numerical Mathematics. Using the factor analysis it was shown that the model reproduces well the first major variability modes to explain 85-90% of the accumulated dispersion. Teleconnection indices as the quantitative characteristics of low-frequency variability are used to identify zonal and meridional flow regimes. Composite maps indicating the spatial distribution of anomalies of the main meteorological variables (500 hPa geopotential height, the sea level atmospheric pressure, the temperature at 850 hPa, 2m air temperature, precipitation, zonal and meridional wind component) for positive and negative phases of each index of atmospheric circulation are created. Average values of composite maps are accompanied with their statistical significance assessed using the "bootstrap" technique. Main characteristics of field configuration in Arctic region of cited above meteorological parameters corresponding to positive and negative phases of circulation indices are analyzed and discussed. Ability of SL-AV model to reproduce these characteristics at monthly and seasonal time scale is discussed as well. Results of this study are aimed to improve the quality of long-range forecasts and increase the "limit of predictability" and can be useful in the practice to develop monthly and seasonal weather forecasts for the Arctic region.

  13. Quantitative analysis of binding sites for 9-fluoropropyl-(+)-dihydrotetrabenazine ([¹⁸F]AV-133) in a MPTP-lesioned PD mouse model.

    PubMed

    Chao, Ko-Ting; Tsao, Hsin-Hsin; Weng, Yi-Hsin; Hsiao, Ing-Tsung; Hsieh, Chia-Ju; Wey, Shiaw-Pyng; Yen, Tzu-Chen; Kung, Mei-Ping; Lin, Kun-Ju

    2012-09-01

    [¹⁸F]AV-133 is a novel PET tracer for targeting the vesicular monoamine transporter 2 (VMAT2). The aim of this study is to characterize and quantify the loss of monoamine neurons with [¹⁸F]AV-133 in the MPTP-lesioned PD mouse model using animal PET imaging and ex vivo quantitative autoradiography (QARG). Optimal imaging time window of [¹⁸F]AV-133 was first determined in normal C57BL/6 mice (n = 3) with a 90-min dynamic scan. The reproducibility of [¹⁸F]AV-133 PET imaging was evaluated by performing a test-retest study within 1 week for the normal group (n = 6). For MPTP-lesioned studies, normal, and MPTP-treated [25 mg mg/kg once (Group A) and twice (Group B), respectively, daily for 5 days, i.p., groups of four normal and MPTP-treated] mice were used. PET imaging studies at baseline and at Day 4 post-MPTP injections were performed at the optimal time window after injection of 11.1 MBq [¹⁸F]AV-133. Specific uptake ratio (SUr) of [¹⁸F]AV-133 was calculated by [(target uptake-cerebellar uptake)/cerebellar uptake] with cerebellum as the reference region. Ex vitro QARG and immunohistochemistry (IHC) studies with tyrosine hydroxylase antibody were carried out to confirm the abundance of dopaminergic neurons. The variability between [¹⁸F]AV-133 test-retest striatal SUr was 6.60 ± 3.61% with less than 5% standard deviation between animals (intervariability). The percentages of MPTP lesions were Group A 0.94 ± 0.29, -42.1% and Group B 0.65 ± 0.09, -60.4%. By QARG, specific binding of [¹⁸F]AV-133 was reduced relative to the control groups by 50.6% and 60.7% in striatum and by 30.6% and 46.4% in substantia nigra (Groups A and B, respectively). Relatively small [¹⁸F]AV-133 SUr decline was noted in the serotonin and norepinephrine-enriched regions (7.9% and 9.4% in mid-brain). Results obtained from IHC consistently confirmed the sensitivity and selectivity of dopaminergic neuron loss after MPTP treatment. [¹⁸F]AV-133 PET SUr displayed a high

  14. Og4C3 circulating antigen: a marker of infection and adult worm burden in Wuchereria bancrofti filariasis.

    PubMed

    Chanteau, S; Moulia-Pelat, J P; Glaziou, P; Nguyen, N L; Luquiaud, P; Plichart, C; Martin, P M; Cartel, J L

    1994-07-01

    Og4C3 circulating filarial antigen was detected in the sera of 94.5% (259/274) of microfilaremic patients, 32% (239/751) of persons with presumption of filariasis, and 23% (11/48) of chronic filariasis patients. The antigen level was correlated with the microfilariae (Mf) density and patient age (P < .01). It remained stable in patients treated with microfilaricidal drugs. Og4C3 antigen, undetectable in Mf culture media, was demonstrated to be a rare somatic Mf antigen. It appears to be an excreted or secreted antigen from adult filaria. It could be used as a marker of infection and an indicator of adult worm burden.

  15. Imaging characteristic of dual-phase (18)F-florbetapir (AV-45/Amyvid) PET for the concomitant detection of perfusion deficits and beta-amyloid deposition in Alzheimer's disease and mild cognitive impairment.

    PubMed

    Lin, Kun-Ju; Hsiao, Ing-Tsung; Hsu, Jung-Lung; Huang, Chin-Chang; Huang, Kuo-Lun; Hsieh, Chia-Ju; Wey, Shiaw-Pyng; Yen, Tzu-Chen

    2016-07-01

    We investigated dual-phase (18)F-florbetapir (AV-45/Amyvid) PET imaging for the concomitant detection of brain perfusion deficits and beta-amyloid deposition in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI), and in cognitively healthy controls (HCs). A total of 82 subjects (24 AD patients, 44 MCI patients and 14 HCs) underwent both dual-phase (18)F-AV-45 PET and MRI imaging. Dual-phase dynamic PET imaging consisted of (1) five 1-min scans obtained 1 - 6 min after tracer injection (perfusion (18)F-AV-45 imaging, pAV-45), and (2) ten 1-min scans obtained 50 - 60 min after tracer injection (amyloid (18)F-AV-45 imaging). Amyloid-negative MCI/AD patients were excluded. Volume of interest analysis and statistical parametric mapping of pAV-45 and (18)F-AV-45 images were performed to investigate the perfusion deficits and the beta-amyloid burden in the three study groups. The associations between Mini-Mental State Examination (MMSE) scores and global perfusion deficits and amyloid deposition were investigated with linear and segmental linear correlation analyses. HCs generally had normal pAV-45 findings, whereas perfusion deficits were evident in the hippocampus, and temporal, parietal and middle frontal cortices in both MCI and AD patients. The motor-sensory cortex was relatively preserved. MMSE scores in the entire study cohort were significantly associated with the degree of perfusion impairment as assessed by pAV-45 imaging (r = 0.5156, P < 0.0001). (18)F-AV-45 uptake was significantly higher in AD patients than in the two other study groups. However, the correlation between MMSE scores and (18)F-AV-45 uptake in MCI patients was more of a binary phenomenon and began in MCI patients with MMSE score 23.14 when (18)F-AV-45 uptake was higher and MMSE score lower than in patients with early MCI. Amyloid deposition started in the precuneus and the frontal and temporal regions in early MCI, ultimately reaching the

  16. AVS: Experimental Tests of a New Process to Inductively Vitrify HLW Inside the Final Disposal Containers at Very High Waste Loadings

    SciTech Connect

    Powell, J.; Reich, M.; Jordan, J.; Ventre, L.; Barletta, R.; Manowitz, B.; Steinberg, M.; Grossman, W.; Maise, G.; Salzano, F.; Hess, C.; Ramsey, W. G.; Plodinec, M. J.

    2002-02-26

    The design and performance capabilities of the Advanced Vitrification System (AVS) are described, together with the results of experimental tests. The AVS is an in-can melting system in which high-level waste (HLW) is vitrified directly inside the final disposal container. The AVS container, or module, consists of an outer stainless steel canister and an alumina-lined, inner graphite crucible, which is thermally insulated from the outer stainless canister. The graphite crucible is inductively heated to very high temperatures (up to 1500 C) by an external low frequency (30 Hertz) alternating current (AC) transformer coil. The actively cooled outer stainless canister remains at near ambient temperature. The HLW/frit mixture is fed into the hot graphite crucible, where it is vitrified. After cooldown, the HLW/frit feed and off-gas pipes are disconnected from the top of the module, which is then sealed and readied for shipment or storage. All radioactively contaminated melter components inside the module are disposed of along with the vitrified waste. The graphite crucible also provides a geologically stable barrier for the vitrified product. The AVS potentially can double HLW loading over that obtained from Joule melters; lower vitrification costs by about half; reduce the number of disposal canisters required by about half; handle diverse waste feeds with high concentrations of problem elements such as chromium and zirconium; and reduce the time needed to vitrify a given inventory of HLW.

  17. Apolipoprotein A-V Deficiency Results in MarkedHypertriglyceridemia Attributable to Decreased Lipolysis ofTriglyceride-Rich Lipoproteins and Removal of Their Remnants

    SciTech Connect

    Grosskopf, Itamar; Baroukh, Nadine; Lee, Sung-Joon; Kamari,Yehuda; Harats, Dror; Rubin, Edward M.; Pennacchio, Len A.; Cooper, AllenD.

    2005-09-01

    Objective--ApoAV, a newly discovered apoprotein, affectsplasma triglyceride level. To determine how this occurs, we studiedtriglyceride-rich lipoprotein (TRL) metabolism in mice deficient inapoAV. Methods and Results No significant difference in triglycerideproduction rate was found between apoa5_/_ mice and controls. Thepresence or absence of apoAV affected TRL catabolism. After the injectionof 14C-palmitate and 3H-cholesterol labeled chylomicrons and 125I-labeledchylomicron remnants, the disappearance of 14C, 3H, and 125I wassignificantly slower in apoa5_/_ mice relative to controls. This wasbecause of diminished lipolysis of TRL and the reduced rate of uptake oftheir remnants in apoa5_/_ mice. Observed elevated cholesterol level wascaused by increased high-density lipoprotein (HDL) cholesterol inapoa5_/_ mice. VLDL from apoa5_/_ mice were poor substrate forlipoprotein lipase, and did not bind to the low-density lipoprotein (LDL)receptor as well as normal very-low-density lipoprotein (VLDL). LDLreceptor levels were slightly elevated in apoa5_/_ mice consistent withlower remnant uptake rates. These alterations may be the result of thelower apoE-to-apoC ratio found in VLDL isolated from apoa5_/_mice.Conclusions These results support the hypothesis that the absence ofapoAV slows lipolysis of TRL and the removal of their remnants byregulating their apoproteins content after secretion.

  18. Cytochrome P450s from Cynara cardunculus L. CYP71AV9 and CYP71BL5, catalyze distinct hydroxylations in the sesquiterpene lactone biosynthetic pathway.

    PubMed

    Eljounaidi, Kaouthar; Cankar, Katarina; Comino, Cinzia; Moglia, Andrea; Hehn, Alain; Bourgaud, Frédéric; Bouwmeester, Harro; Menin, Barbara; Lanteri, Sergio; Beekwilder, Jules

    2014-06-01

    Cynara cardunculus (Asteraceae) is a cross pollinated perennial crop which includes the two cultivated taxa globe artichoke and cultivated cardoon. The leaves of these plants contain high concentrations of sesquiterpene lactones (STLs) among which cynaropicrin is the most represented, and has recently attracted attention because of its therapeutic potential as anti-tumor and anti-photoaging agent. Costunolide is considered the common precursor of the STLs and three enzymes are involved in its biosynthetic pathway: i.e. the germacrene A synthase (GAS), the germacrene A oxidase (GAO) and the costunolide synthase (COS). Here we report on the isolation of two P450 genes, (i.e. CYP71AV9 and CYP71BL5), in a set of ∼19,000 C. cardunculus unigenes, and their functional characterization in yeast and in planta. The metabolite analyses revealed that the co-expression of CYP71AV9 together with GAS resulted in the biosynthesis of germacra-1(10),4,11(13)-trien-12-oic acid in yeast. The co-expression of CYP71BL5 and CYP71AV9 with GAS led to biosynthesis of the free costunolide in yeast and costunolide conjugates in Nicotiana benthamiana, demonstrating their involvement in STL biosynthesis as GAO and COS enzymes. The substrate specificity of CYP71AV9 was investigated by testing its ability to convert amorpha-4,11-diene, (+)-germacrene D and cascarilladiene to their oxidized products when co-expressed in yeast with the corresponding terpene synthases.

  19. The risk assessment of heavy metals in Futian mangrove forest sediment in Shenzhen Bay (South China) based on SEM-AVS analysis.

    PubMed

    Chai, Minwei; Shen, Xiaoxue; Li, Ruili; Qiu, Guoyu

    2015-08-15

    The risks of heavy metal in Futian mangrove forest sediment were assessed using the acid-volatile sulfide (AVS) and simultaneously extracted metals (SEM) methods. The results indicated that AVS distributions were more variable than the SEM distributions at all 16 sampling sites. The positive correlation between AVS and SEM indicated that their similar formative and existing conditions and that AVS acted as an important carrier for SEM. The major SEM component was Zn (69.7.3-94.2%), whereas the Cd contribution (the most toxic metal present) to SEM was no more than 1%. The possible adverse effects caused by heavy metals at ten sampling sites may be due to higher levels of SEMs, rather than AVSs. The total organic carbon (TOC) was an important metal-binding phase in the sediments. Taking into account the TOC concentration, there were no adverse effects due to heavy metals in any of the Futian mangrove forest sediments. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Effects of AV119, a natural sugar from avocado, on Malassezia furfur invasiveness and on the expression of HBD-2 and cytokines in human keratinocytes.

    PubMed

    Donnarumma, Giovanna; Buommino, Elisabetta; Baroni, Adone; Auricchio, Lucia; De Filippis, Anna; Cozza, Valentina; Msika, Philippe; Piccardi, Nathalie; Tufano, Maria Antonietta

    2007-11-01

    AV119 is a patented blend of two sugars from avocado that can induce human beta-defensin-2 production by normal human keratinocytes. In this study, we analysed the effect of AV119 on growth and invasiveness of Malassezia furfur, a dimorphic, lipid-dependent yeast that is part of the normal human cutaneous commensal flora. The ability to modulate the expression of the proinflammatory and immunomodulatory cytokines in normal human keratinocytes was also investigated. Microbiological assay demonstrated that this sugar induced the aggregation of yeast cells and inhibited the invasiveness of M. furfur, without affecting its growth. Real-time PCR analysis demonstrated that AV119 was able to modulate the HBD-2 response in treated keratinocytes, reaching a maximum after 48-h treatment, and to induce the recovery of a satisfactory proinflammatory response in human keratinocytes. As AV119 can induce aggregation of yeast cells, thus inhibiting their penetration into the keratinocytes, the sugar could be used in the preparation of cosmetics or pharmacological drugs to inhibit colonization of the skin by pathogenic strains of M. furfur.

  1. Modeling Strategies for Quantification of In Vivo (18)F-AV-1451 Binding in Patients with Tau Pathology.

    PubMed

    Hahn, Andreas; Schain, Martin; Erlandsson, Maria; Sjölin, Petter; James, Gregory M; Strandberg, Olof T; Hägerström, Douglas; Lanzenberger, Rupert; Jögi, Jonas; Olsson, Tomas G; Smith, Ruben; Hansson, Oskar

    2017-04-01

    Aggregation of hyperphosphorylated tau is a major hallmark of many neurodegenerative diseases, including Alzheimer disease (AD). In vivo imaging with PET may offer important insights into pathophysiologic mechanisms, diagnosis, and disease progression. We describe different strategies for quantification of (18)F-AV-1451 (T807) tau binding, including models with blood sampling and noninvasive alternatives. Methods: Fifteen subjects (4 controls, 6 AD, 3 progressive supranuclear palsy, 2 cortico basal syndrome) underwent 180-min PET with (18)F-AV-1451 and arterial blood sampling. Modeling with arterial input functions included 1-, 2-, and 3-tissue-compartment models and the Logan plot. Using the cerebellum as reference region, we applied the simplified reference tissue model 2 and Logan reference plot. Finally, simplified outcome measures were calculated as ratio, with reference to cerebellar concentrations (SUV ratio [SUVR]) and SUVs. Results: Tissue compartment models were not able to describe the kinetics of (18)F-AV-1451, with poor fits in 33%-53% of cortical regions and 80% in subcortical areas. In contrast, the Logan plot showed excellent fits and parameter variance (total volume of distribution SE < 5%). Compared with the 180-min arterial-based Logan model, strong agreement was obtained for the Logan reference plot also for a reduced scan time of 100 min (R(2) = 0.91) and SUVR 100-120 min (R(2) = 0.94), with 80-100 min already representing a reasonable compromise between duration and accuracy (R(2) = 0.93). Time-activity curves and kinetic parameters were equal for cortical regions and the cerebellum in control subjects but different in the putamen. Cerebellar total volumes of distribution were higher in controls than patients. For these methods, increased cortical binding was observed for AD patients and to some extent for cortico basal syndrome, but not progressive supranuclear palsy. Conclusion: The Logan plot provided the best estimate of tau binding using

  2. Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages.

    PubMed

    Schwarz, Adam J; Yu, Peng; Miller, Bradley B; Shcherbinin, Sergey; Dickson, James; Navitsky, Michael; Joshi, Abhinay D; Devous, Michael D; Mintun, Mark S

    2016-05-01

    SEE THAL AND VANDENBERGHE DOI101093/BRAIN/AWW057 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Post-mortem Braak staging of neurofibrillary tau tangle topographical distribution is one of the core neuropathological criteria for the diagnosis of Alzheimer's disease. The recent development of positron emission tomography tracers targeting neurofibrillary tangles has enabled the distribution of tau pathology to be imaged in living subjects. Methods for extraction of classic Braak staging from in vivo imaging of neurofibrillary tau tangles have not yet been explored. Standardized uptake value ratio images were calculated from 80-100 minute (18)F-AV-1451 (also known as T807) positron emission tomography scans obtained from n = 14 young reference subjects (age 21-39 years, Mini-Mental State Examination 29-30) and n = 173 older test subjects (age 50-95 years) comprising amyloid negative cognitively normal (n = 42), clinically-diagnosed mild cognitive impairment (amyloid positive, n = 47, and amyloid negative, n = 40) and Alzheimer's disease (amyloid positive, n = 28, and amyloid negative, n = 16). We defined seven regions of interest in anterior temporal lobe and occipital lobe sections corresponding closely to those used as decision points in Braak staging. An algorithm based on the Braak histological staging procedure was applied to estimate Braak stages directly from the region of interest profiles in each subject. Quantitative region-based analysis of (18)F-AV-1451 images yielded region of interest and voxel level profiles that mirrored key features of neuropathological tau progression including profiles consistent with Braak stages 0 through VI. A simple set of decision rules enabled plausible Braak stages corresponding to stereotypical progression patterns to be objectively estimated in 149 (86%) of test subjects. An additional 12 (7%) subjects presented with predefined variant profiles (relative sparing of the hippocampus and/or occipital lobe). The estimated Braak

  3. Comparison of 99mTc-TRODAT-1 SPECT and 18 F-AV-133 PET imaging in healthy controls and Parkinson's disease patients.

    PubMed

    Hsiao, Ing-Tsung; Weng, Yi-Hsin; Lin, Wey-Yil; Hsieh, Chia-Ju; Wey, Shiaw-Pyng; Yen, Tzu-Chen; Kung, Mei-Ping; Lu, Chin-Song; Lin, Kun-Ju

    2014-04-01

    (99m)Tc-TRODAT-1 is the first clinical routine (99m)Tc radiopharmaceutical to evaluate dopamine neurons loss in Parkinson's disease (PD). (18)F-AV-133 is a novel PET radiotracer targeting the vesicular monoamine transporter type 2 (VMAT2) to detect monoaminergic terminal reduction in PD patients. The aim of this study is to compare both images in the same health control (HC) and PD subjects. Eighteen subjects (8 HC and 10 PD) were recruited for (99m)Tc-TRODAT-1 SPECT, (18)F-AV-133 PET and MRI scans within two weeks. The SPECT images were performed at 4-h post-injection for 45 min, and the PET images were performed at 90 min post-injection for 10 min. Each PET and SPECT image was normalized into Montreal Neurological Institute template aided from individual MRI for comparison. For regional analysis, volume of interest (VOIs) of bilateral caudate nuclei, anterior, posterior putamen and occipital cortex (as reference region) were delineated from the normalized MRI. The specific uptake ratio (SUR) was calculated as (regional mean counts/reference mean counts-1). The nonparametric Mann-Whitney U test was used to evaluate the power of differentiating control from PD subjects for both image modalities. The correlations of the SURs to the clinical parameters were examined. For voxelwise analysis, two-sample t-test for group comparison between HC and PD was computed in both image modalities. The SURs of caudate nucleus and putamen correlated well between two image modalities (r = 0.81, p<0.001), and showed significant different between HC and PD subjects. Of note, the (18)F-AV-133 SUR displayed a better correlation to PD clinical laterality index as compared to (99m)Tc-TRODAT-1 (r = 0.73 vs. r = 0.33). Voxelwise analysis showed more lesions for PD subjects from (18)F-AV-133 image as compared to (99m)Tc-TRODAT-1 especially at the substantia nigra region. (18)F-AV-133 PET demonstrated similar performance in differentiation PD from control, and a better correlation to clinical

  4. Comparison between IEGM-based approach and echocardiography in AV/PV and VV delay optimization in CRT-D recipients (Quicksept study).

    PubMed

    Giammaria, Massimo; Quirino, Gianluca; Cecchi, Enrico; Senatore, Gaetano; Pistelli, Paolo; Bocchiardo, Mario; Mureddu, Roberto; Diotallevi, Paolo; Occhetta, Eraldo; Magnani, Andrea; Bensoni, Mauro; Checchinato, Catia; Conti, Valentina; Badolati, Sandra; Mazza, Antonio

    2016-01-01

    AtrioVentricular (AV) and InterVentricular (VV) delay optimization can improve ventricular function in Cardiac Resynchronization Therapy (CRT) and is usually performed by means of echocardiography. St Jude Medical has developed an automated algorhythm which calculates the optimal AV and VV delays (QuickOpt™) based on Intracardiac ElectroGrams, (IEGM), within 2 min. So far, the efficacy of the algorhythm has been tested acutely with standard lead position at right ventricular (RV) apex. Aim of this project is to evaluate the algorhythm performance in the mid- and long-term with RV lead located in mid-septum. AV and VV delays optimization data were collected in 13 centers using both echocardiographic and QuickOpt™ guidance in CRTD implanted patients provided with this algorhythm. Measurements of the aortic Velocity Time Integral (aVTI) were performed with both methods in a random order at pre-discharge, 6-month and 12-month follow-up. Fifty-three patients were studied (46 males; age 68 ± 10y; EF 28 ± 7%). Maximum aVTI obtained by echocardiography at different AV delays, were compared with aVTI acquired at AV delays suggested by QuickOpt. The AV Pearson correlations were 0.96 at pre-discharge, 0.95 and 0,98 at 6- and 12- month follow-up respectively. After programming optimal AV, the same approach was used to compare echocardiographic aVTI with aVTI corresponding to the VV values provided by QuickOpt. The VV Pearson Correlation were 0,92 at pre-discharge, 0,88 and 0.90 at 6-month and 12- month follow-up respectively. IEGM-based optimization provides comparable results with echocardiographic method (maximum aVTI) used as reference with mid-septum RV lead location. Copyright © 2016 Indian Heart Rhythm Society. Production and hosting by Elsevier B.V. All rights reserved.

  5. Screening Analogs of β-OG Pocket Binder as Fusion Inhibitor of Dengue Virus 2

    PubMed Central

    Tambunan, Usman SF; Zahroh, Hilyatuz; Parikesit, Arli A; Idrus, Syarifuddin; Kerami, Djati

    2015-01-01

    Dengue is an infectious disease caused by dengue virus (DENV) and transmitted between human hosts by mosquitoes. Recently, Indonesia was listed as a country with the highest cases of dengue by the Association of Southeast Asian Nations. The current treatment for dengue disease is supportive therapy; there is no antiviral drug available in the market against dengue. Therefore, a research on antiviral drug against dengue is very important, especially to prevent outbreak explosion. In this research, the development of dengue antiviral is performed through the inhibition of n-octyl-β-D-glucoside (β-OG) binding pocket on envelope protein of DENV by using analogs of β-OG pocket binder. There are 828 compounds used in this study, and all of them were screened based on the analysis of molecular docking, pharmacological character prediction of the compounds, and molecular dynamics simulation. The result of these analyses revealed that the compound that can be used as an antiviral candidate against DENV is 5-(3,4-dichlorophenyl)-N-[2-(p-tolyl) benzotriazol-5-yl]furan-2-carboxamide. PMID:26617459

  6. Longitudinal Characterization of [18F]-FDG and [18F]-AV45 Uptake in the Double Transgenic TASTPM Mouse Model

    PubMed Central

    Waldron, Ann-Marie; wyffels, Leonie; Verhaeghe, Jeroen; Richardson, Jill C.; Schmidt, Mark; Stroobants, Sigrid; Langlois, Xavier; Staelens, Steven

    2016-01-01

    We aimed to monitor the timing of amyloid-β deposition in relation to changes in brain function using in vivo imaging with [18F]-AV45 and [18F]-FDG in a mouse model of Alzheimer’s disease. TASTPM transgenic mice and wild-type controls were scanned longitudinally with [18F]-AV45 and [18F]-FDG before (3 months of age) and at multiple time points after the onset of amyloid deposition (6, 9, 12, and 15 months of age). As expected with increasing amyloidosis, TASTPM mice demonstrated progressive age-dependent increases in [18F]-AV45 uptake that were significantly higher than for WT from 9 months onwards and correlated to ex vivo measures of amyloid burden. The metabolism of [18F]-AV45 produces several brain penetrant radiometabolites and normalization to a reference region helps to negate this non-specific binding and improve the sensitivity of [18F]-AV45. The observed trajectory of [18F]-FDG alterations deviated from our proposed hypothesis of gradual decreases with worsening amyloidosis. While [18F]-FDG uptake in TASTPM mice was significantly lower than that of WT at 9 months, reduced [18F]-FDG was not associated with aging in TASTPM mice. Moreover, [18F]-FDG uptake did not correlate to measures of ex vivo amyloid burden. Our findings suggest that while amyloid-β is sufficient to induce hypometabolism, these pathologies are not linked in a dose-dependent manner in TASTPM mice. PMID:27911309

  7. Comparison between PET template-based method and MRI-based method for cortical quantification of florbetapir (AV-45) uptake in vivo.

    PubMed

    Saint-Aubert, L; Nemmi, F; Péran, P; Barbeau, E J; Payoux, P; Chollet, F; Pariente, J

    2014-05-01

    Florbetapir (AV-45) has been shown to be a reliable tool for assessing in vivo amyloid load in patients with Alzheimer's disease from the early stages. However, nonspecific white matter binding has been reported in healthy subjects as well as in patients with Alzheimer's disease. To avoid this issue, cortical quantification might increase the reliability of AV-45 PET analyses. In this study, we compared two quantification methods for AV-45 binding, a classical method relying on PET template registration (route 1), and a MRI-based method (route 2) for cortical quantification. We recruited 22 patients at the prodromal stage of Alzheimer's disease and 17 matched controls. AV-45 binding was assessed using both methods, and target-to-cerebellum mean global standard uptake values (SUVr) were obtained for each of them, together with SUVr in specific regions of interest. Quantification using the two routes was compared between the clinical groups (intragroup comparison), and between groups for each route (intergroup comparison). Discriminant analysis was performed. In the intragroup comparison, differences in uptake values were observed between route 1 and route 2 in both groups. In the intergroup comparison, AV-45 uptake was higher in patients than controls in all regions of interest using both methods, but the effect size of this difference was larger using route 2. In the discriminant analysis, route 2 showed a higher specificity (94.1 % versus 70.6 %), despite a lower sensitivity (77.3 % versus 86.4 %), and D-prime values were higher for route 2. These findings suggest that, although both quantification methods enabled patients at early stages of Alzheimer's disease to be well discriminated from controls, PET template-based quantification seems adequate for clinical use, while the MRI-based cortical quantification method led to greater intergroup differences and may be more suitable for use in current clinical research.

  8. Trazodone and Omeprazole Interaction causing Frequent Second-Degree Mobitz Type 1 Atrioventricular (AV) Block (Wenckebach Phenomenon) and Syncope: A Case Report and Literature Review

    PubMed Central

    Akinseye, Oluwaseun A.; Alfishawy, Mostafa; Radparvar, Farshid; Bakshi, Sanjiv

    2015-01-01

    Patient: Male, 54 Final Diagnosis: Trazodone and omeprazole interaction causing second-degree Mobitz type 1 AV block and syncope Symptoms: Syncope Medication: — Clinical Procedure: Trazodone and omeprazole withheld Specialty: Cardiology Objective: Unexpected drug reaction Background: This case report highlights serious cardiovascular adverse effects with a conventional dose of trazodone as a result of its potential interaction with omeprazole. Case Report: A 54-year-old man who was a former smoker, with dyslipidemia, coronary artery disease, and anxiety disorder developed lightheadedness and syncope the morning of admission. He was taking trazodone 50 mg daily, omeprazole 20 mg daily, and simvastatin 20 mg at bedtime. He doubled the dose of trazodone 50 mg on the night prior to presentation to calm his anxiety. An electrocardiogram revealed sinus rhythm at 60 beats per minute and second-degree Mobitz type 1 atrioventricular (AV) block with 5:4 AV conduction. Results of basic metabolic panel, thyroid-stimulating hormone, and chest radiograph were normal. A transthoracic echocardiogram revealed aortic valve sclerosis. We tested for Lyme disease given his history of hunting in the woods 8 months prior to presentation, but the titer was negative. Trazodone and omeprazole were discontinued. By the 3rd day of medication discontinuation, all symptoms had resolved and the frequency of second-degree AV Mobitz type 1 AV block had decreased to once per hour. Conclusions: Due diligence and meticulous attention to detail needs to be exercised to uncover drug interactions as potential causes of lethal and nonlethal patient symptomatology, as in this case of syncope caused by concomitant use of trazodone and a widely prescribed medication, omeprazole. PMID:26017199

  9. Students' Decision Steps in Meta-Cognitive Learning in Free Online Groups (MetaL-FrOG): A Case Study

    ERIC Educational Resources Information Center

    Sen Fa, Kinsley Ng; Hussin, Firuz Hussin

    2011-01-01

    What prompts the students to respond in online dialogic discussion? Why some students chose to fall out? This case study through the lens of phenomenography observation attempts to explain the five decision steps of students to respond in Meta-cognitive Learning in Free Online Groups (MetaL-FrOG) discussion. It presents a part of a research…

  10. Novel measure of electrical dyssynchrony predicts response in cardiac resynchronization therapy: Results from the SMART-AV Trial

    PubMed Central

    Tereshchenko, Larisa G.; Cheng, Alan; Park, Jason; Wold, Nicholas; Meyer, Timothy E.; Gold, Michael R.; Mittal, Suneet; Singh, Jagmeet; Stein, Kenneth M.; Ellenbogen, Kenneth A.

    2015-01-01

    Background Cardiac resynchronization therapy (CRT) reduces mortality and morbidity in selected heart failure (HF) patients. However, not all patients respond to CRT. Objective We hypothesized that a novel measure of electrical dyssynchrony, sum absolute QRST integral (SAI), predicts CRT response independent of QRS duration and morphology. Methods We retrospectively analyzed baseline 12-lead electrocardiograms (ECGs) of SMART-AV study participants [N=234, mean age 67 y, 70% male, 60% ischemic cardiomyopathy (ICM), mean left ventricular ejection fraction (LVEF) 25%, mean QRS duration 152ms, 77% had left bundle branch block (LBBB)]. Baseline pre-implant ECGs were digitized, transformed into orthogonal XYZ, and analyzed automatically by customized Matlab software. SAI was measured as an averaged arithmetic sum of absolute areas under the QRST curve. Patients were followed prospectively 6 months after CRT-D implantation. Patients with a decrease in left ventricular end-systolic volume ≥ 15mls after 6 months of CRT were considered responders. Logistic regression model was adjusted for age, gender, BBB morphology, LVEF, type of cardiomyopathy and QRS duration. Results Patients with the high mean SAI (3rd tertile) had 2.5 times greater odds of response than those with low mean SAI (1st tertile; OR 2.5, 95% CI 1.3–5.0, p=0.010), and 1.9 times greater than the lower two tertiles combined (OR 1.9, 95%CI 1.1–3.5; P=0.03). Adjustment for renal function (OR 2.33 (95%CI 1.32, 4.11); P=0.003) and LV lead position in RAO/LAO (OR 1.7 (95%CI 0.9, 3.2); P=0.087) did not attenuate association of SAI with outcome. Conclusion High SAI QRST independently predicts CRT response in the SMART-AV study. PMID:26272523

  11. Molecular dynamics simulation studies and in vitro site directed mutagenesis of avian beta-defensin Apl_AvBD2

    PubMed Central

    2010-01-01

    Background Defensins comprise a group of antimicrobial peptides, widely recognized as important elements of the innate immune system in both animals and plants. Cationicity, rather than the secondary structure, is believed to be the major factor defining the antimicrobial activity of defensins. To test this hypothesis and to improve the activity of the newly identified avian β-defensin Apl_AvBD2 by enhancing the cationicity, we performed in silico site directed mutagenesis, keeping the predicted secondary structure intact. Molecular dynamics (MD) simulation studies were done to predict the activity. Mutant proteins were made by in vitro site directed mutagenesis and recombinant protein expression, and tested for antimicrobial activity to confirm the results obtained in MD simulation analysis. Results MD simulation revealed subtle, but critical, structural variations between the wild type Apl_AvBD2 and the more cationic in silico mutants, which were not detected in the initial structural prediction by homology modelling. The C-terminal cationic 'claw' region, important in antimicrobial activity, which was intact in the wild type, showed changes in shape and orientation in all the mutant peptides. Mutant peptides also showed increased solvent accessible surface area and more number of hydrogen bonds with the surrounding water molecules. In functional studies, the Escherichia coli expressed, purified recombinant mutant proteins showed total loss of antimicrobial activity compared to the wild type protein. Conclusion The study revealed that cationicity alone is not the determining factor in the microbicidal activity of antimicrobial peptides. Factors affecting the molecular dynamics such as hydrophobicity, electrostatic interactions and the potential for oligomerization may also play fundamental roles. It points to the usefulness of MD simulation studies in successful engineering of antimicrobial peptides for improved activity and other desirable functions. PMID

  12. Intrapatient comparison between chronic VVIR and DDD pacing in patients affected by high degree AV block without heart failure.

    PubMed

    Menozzi, C; Brignole, M; Moracchini, P V; Lolli, G; Bacchi, M; Tesorieri, M C; Tosoni, G D; Bollini, R

    1990-12-01

    In patients affected by high degree AV block without preexisting congestive heart failure there is no definite demonstration that DDD pacing gives real clinical advantages in respect to VVIR pacing. We performed an intrapatient, long-term study between the two pacing modes in 14 high degree AV block patients, using the Medtronic Synergyst 7027 dual chamber pacemaker, who could be programmed alternatively in DDD or VVIR mode. After a 4-week run-in period following the pacemaker implant, patients completed a randomized, double-blind, cross-over study to compare the effect of 6-week period VVIR and DDD pacing on symptoms and cardiovascular parameters. A semiquantitative score scale was used to quantify the symptoms of general well-being, palpitations, dizziness, pulsating sensation in the neck or abdomen, shortness of breath at rest and during effort, chest pain, and NYHA classification. The sum of symptom scores was 10.4 +/- 6.7 in VVIR period and 4.6 +/- 2.7 in DDD period (P less than 0.001); five patients (36%) crossed over early from VVIR to DDD because of intolerable symptoms; overall, eight patients preferred the DDD mode and no one preferred the VVIR. Cardiac output at rest (echo-Doppler method) was 4.7 +/- 1.4 versus 5.7 +/- 1.6 liter/min (P less than 0.01), body weight was 65.9 +/- 6.6 versus 64.9 +/- 6.1 kg (P less than 0.02), atrial natriuretic peptide was 236 +/- 112 versus 198 +/- 110 pg/mL (P less than 0.01), respectively, during VVIR and DDD modes. Effort tolerance was similar with the two modes of pacing (68 +/- 15 vs 70 +/- 18 watts/min).(ABSTRACT TRUNCATED AT 250 WORDS)

  13. A Study of Subseasonal Predictability of the Atmospheric Circulation Low-frequency Modes based on SL-AV forecasts

    NASA Astrophysics Data System (ADS)

    Kruglova, Ekaterina; Kulikova, Irina; Khan, Valentina; Tischenko, Vladimir

    2017-04-01

    The subseasonal predictability of low-frequency modes and the atmospheric circulation regimes is investigated based on the using of outputs from global Semi-Lagrangian (SL-AV) model of the Hydrometcentre of Russia and Institute of Numerical Mathematics of Russian Academy of Science. Teleconnection indices (AO, WA, EA, NAO, EU, WP, PNA) are used as the quantitative characteristics of low-frequency variability to identify zonal and meridional flow regimes with focus on control distribution of high impact weather patterns in the Northern Eurasia. The predictability of weekly and monthly averaged indices is estimated by the methods of diagnostic verification of forecast and reanalysis data covering the hindcast period, and also with the use of the recommended WMO quantitative criteria. Characteristics of the low frequency variability have been discussed. Particularly, it is revealed that the meridional flow regimes are reproduced by SL-AV for summer season better comparing to winter period. It is shown that the model's deterministic forecast (ensemble mean) skill at week 1 (days 1-7) is noticeably better than that of climatic forecasts. The decrease of skill scores at week 2 (days 8-14) and week 3( days 15-21) is explained by deficiencies in the modeling system and inaccurate initial conditions. It was noticed the slightly improvement of the skill of model at week 4 (days 22-28), when the condition of atmosphere is more determined by the flow of energy from the outside. The reliability of forecasts of monthly (days 1-30) averaged indices is comparable to that at week 1 (days 1-7). Numerical experiments demonstrated that the forecast accuracy can be improved (thus the limit of practical predictability can be extended) through the using of probabilistic approach based on ensemble forecasts. It is shown that the quality of forecasts of the regimes of circulation like blocking is higher, than that of zonal flow.

  14. OGS improvements in 2012 in running the North-eastern Italy Seismic Network: the Ferrara VBB borehole seismic station

    NASA Astrophysics Data System (ADS)

    Pesaresi, D.; Romanelli, M.; Barnaba, C.; Bragato, P. L.; Durì, G.

    2014-07-01

    The Centro di Ricerche Sismologiche (CRS, Seismological Research Centre) of the Istituto Nazionale di Oceanografia e di Geofisica Sperimentale (OGS, Italian National Institute for Oceanography and Experimental Geophysics) in Udine (Italy) after the strong earthquake of magnitude M=6.4 occurred in 1976 in the Italian Friuli-Venezia Giulia region, started to operate the North-eastern Italy Seismic Network: it currently consists of 17 very sensitive broad band and 18 simpler short period seismic stations, all telemetered to and acquired in real time at the OGS-CRS data centre in Udine. Real time data exchange agreements in place with other Italian, Slovenian, Austrian and Swiss seismological institutes lead to a total number of about 100 seismic stations acquired in real time, which makes the OGS the reference institute for seismic monitoring of North-eastern Italy. The south-western edge of the OGS seismic network (Fig. 1) stands on the Po alluvial basin: earthquake localization and characterization in this area is affected by the presence of soft alluvial deposits. OGS ha already experience in running a local seismic network in high noise conditions making use of borehole installations in the case of the micro-seismicity monitoring of a local gas storage site for a private company. Following the ML = 5.9 earthquake that struck the Emilia region around Ferrara in Northern Italy on 20 May 2012 at 02:03:53 UTC, a cooperation of Istituto Nazionale di Geofisica e Vulcanologia, OGS, the Comune di Ferrara and the University of Ferrara lead to the reinstallation of a previously existing very broad band (VBB) borehole seismic station in Ferrara. The aim of the OGS intervention was on one hand to extend its real time seismic monitoring capabilities toward South-West, including Ferrara and its surroundings, and on the other hand to evaluate the seismic response at the site. We will describe improvements in running the North-eastern Italy Seismic Network, including details of

  15. Reactive transport modeling in variably saturated porous media with OGS-IPhreeqc

    NASA Astrophysics Data System (ADS)

    He, W.; Beyer, C.; Fleckenstein, J. H.; Jang, E.; Kalbacher, T.; Shao, H.; Wang, W.; Kolditz, O.

    2014-12-01

    Worldwide, sustainable water resource management becomes an increasingly challenging task due to the growth of population and extensive applications of fertilizer in agriculture. Moreover, climate change causes further stresses to both water quantity and quality. Reactive transport modeling in the coupled soil-aquifer system is a viable approach to assess the impacts of different land use and groundwater exploitation scenarios on the water resources. However, the application of this approach is usually limited in spatial scale and to simplified geochemical systems due to the huge computational expense involved. Such computational expense is not only caused by solving the high non-linearity of the initial boundary value problems of water flow in the unsaturated zone numerically with rather fine spatial and temporal discretization for the correct mass balance and numerical stability, but also by the intensive computational task of quantifying geochemical reactions. In the present study, a flexible and efficient tool for large scale reactive transport modeling in variably saturated porous media and its applications are presented. The open source scientific software OpenGeoSys (OGS) is coupled with the IPhreeqc module of the geochemical solver PHREEQC. The new coupling approach makes full use of advantages from both codes: OGS provides a flexible choice of different numerical approaches for simulation of water flow in the vadose zone such as the pressure-based or mixed forms of Richards equation; whereas the IPhreeqc module leads to a simplification of data storage and its communication with OGS, which greatly facilitates the coupling and code updating. Moreover, a parallelization scheme with MPI (Message Passing Interface) is applied, in which the computational task of water flow and mass transport is partitioned through domain decomposition, whereas the efficient parallelization of geochemical reactions is achieved by smart allocation of computational workload over

  16. Reactive transport modeling in the subsurface environment with OGS-IPhreeqc

    NASA Astrophysics Data System (ADS)

    He, Wenkui; Beyer, Christof; Fleckenstein, Jan; Jang, Eunseon; Kalbacher, Thomas; Naumov, Dimitri; Shao, Haibing; Wang, Wenqing; Kolditz, Olaf

    2015-04-01

    Worldwide, sustainable water resource management becomes an increasingly challenging task due to the growth of population and extensive applications of fertilizer in agriculture. Moreover, climate change causes further stresses to both water quantity and quality. Reactive transport modeling in the coupled soil-aquifer system is a viable approach to assess the impacts of different land use and groundwater exploitation scenarios on the water resources. However, the application of this approach is usually limited in spatial scale and to simplified geochemical systems due to the huge computational expense involved. Such computational expense is not only caused by solving the high non-linearity of the initial boundary value problems of water flow in the unsaturated zone numerically with rather fine spatial and temporal discretization for the correct mass balance and numerical stability, but also by the intensive computational task of quantifying geochemical reactions. In the present study, a flexible and efficient tool for large scale reactive transport modeling in variably saturated porous media and its applications are presented. The open source scientific software OpenGeoSys (OGS) is coupled with the IPhreeqc module of the geochemical solver PHREEQC. The new coupling approach makes full use of advantages from both codes: OGS provides a flexible choice of different numerical approaches for simulation of water flow in the vadose zone such as the pressure-based or mixed forms of Richards equation; whereas the IPhreeqc module leads to a simplification of data storage and its communication with OGS, which greatly facilitates the coupling and code updating. Moreover, a parallelization scheme with MPI (Message Passing Interface) is applied, in which the computational task of water flow and mass transport is partitioned through domain decomposition, whereas the efficient parallelization of geochemical reactions is achieved by smart allocation of computational workload over

  17. Association of In Vivo [18F]AV-1451 Tau PET Imaging Results With Cortical Atrophy and Symptoms in Typical and Atypical Alzheimer Disease.

    PubMed

    Xia, Chenjie; Makaretz, Sara J; Caso, Christina; McGinnis, Scott; Gomperts, Stephen N; Sepulcre, Jorge; Gomez-Isla, Teresa; Hyman, Bradley T; Schultz, Aaron; Vasdev, Neil; Johnson, Keith A; Dickerson, Bradford C

    2017-04-01

    Previous postmortem studies have long demonstrated that neurofibrillary tangles made of hyperphosphorylated tau proteins are closely associated with Alzheimer disease clinical phenotype and neurodegeneration pattern. Validating these associations in vivo will lead to new diagnostic tools for Alzheimer disease and better understanding of its neurobiology. To examine whether topographical distribution and severity of hyperphosphorylated tau pathologic findings measured by fluorine 18-labeled AV-1451 ([18F]AV-1451) positron emission tomographic (PET) imaging are linked with clinical phenotype and cortical atrophy in patients with Alzheimer disease. This observational case series, conducted from July 1, 2012, to July 30, 2015, in an outpatient referral center for patients with neurodegenerative diseases, included 6 patients: 3 with typical amnesic Alzheimer disease and 3 with atypical variants (posterior cortical atrophy, logopenic variant primary progressive aphasia, and corticobasal syndrome). Patients underwent [18F]AV-1451 PET imaging to measure tau burden, carbon 11-labeled Pittsburgh Compound B ([11C]PiB) PET imaging to measure amyloid burden, and structural magnetic resonance imaging to measure cortical thickness. Seventy-seven age-matched controls with normal cognitive function also underwent structural magnetic resonance imaging but not tau or amyloid PET imaging. Tau burden, amyloid burden, and cortical thickness. In all 6 patients (3 women and 3 men; mean age 61.8 years), the underlying clinical phenotype was associated with the regional distribution of the [18F]AV-1451 signal. Furthermore, within 68 cortical regions of interest measured from each patient, the magnitude of cortical atrophy was strongly correlated with the magnitude of [18F]AV-1451 binding (3 patients with amnesic Alzheimer disease, r = -0.82; P < .001; r = -0.70; P < .001; r = -0.58; P < .001; and 3 patients with nonamnesic Alzheimer disease, r = -0.51; P

  18. PHDs inhibitor DMOG promotes the vascularization process in the AV loop by HIF-1a up-regulation and the preliminary discussion on its kinetics in rat.

    PubMed

    Yuan, Quan; Bleiziffer, Oliver; Boos, Anja M; Sun, Jiaming; Brandl, Andreas; Beier, Justus P; Arkudas, Andreas; Schmitz, Marweh; Kneser, Ulrich; Horch, Raymund E

    2014-12-28

    The Arterovenous Loop (AV Loop) model is a vascularization model in tissue engineering research, which is capable of generating a three dimensional in vivo unit with cells as well as the supporting vessels within an isolation chmaber. In our previous studies the AV loop in the isolation chamber was discovered to undergo hypoxia, characterized by Hypoxia Inducible Factor (HIF) up-regulation. The vascularization followed the increase of HIF-α temporally, while it was spatially positively correlated with the HIF-α level, as well. This study aims to prove that HIF-1a up-regulation is the stimulus for vascularization in the AV loop model. The AV loop model in rats was created by interposing a femoral vein graft into the distal ends of the contralateral femoral artery and vein, and the loop was embeded in fibrin matrix and fixed in isolation chamber. PHD (prolyl hydroxylases) inhibitor DMOG (Dimethyloxallyl Glycine) was applied systemically in the rats in 40 mg/KG at day 0 and day 3 (DMOG-1), or in 15 mg/KG at day 8, day10 and day12 (DMOG-2). Two weeks later the specimens were explanted and underwent morphological and molecular evaluations. Compared to the control group, in the DMOG-2 group the HIF-1α positive rate was siginicantly raised as shown in immunohistochemistry staining, accompanied with a smaller cross section area and greater vessel density, and a HIF-1α accumulation in the kidney. The mRNA of HIF-1α and its angiogenic target gene all increased in different extends. Ki67 IHC demostrate more positive cells. There were no significant change in the DMOG-1 group. By applying DMOG systemically, HIF-1α was up-regulated at the protein level and at the mRNA level, acompanied with angiogenic target gene up-regulateion, and the vascularization was promoted correspondingly. DMOG given at lower dosage constantly after one week tends to have better effect than the group given at larger dosage in the early stage in this model, and promotes cell proliferation, as

  19. Rhamnolipid production by Pseudomonas aeruginosa OG1 using waste frying oil and ram horn peptone

    NASA Astrophysics Data System (ADS)

    Özdal, Murat; Gürkök, Sümeyra; Özdal, Özlem Gür; Kurbanoǧlu, Esabi Başaran

    2017-04-01

    Agro-industrial by-products are being explored as alternative low-cost nutrients for various bioprocesses. In this work, the applicability of ram horn peptone (RHP) and waste frying oil were investigated for rhamnolipid production by Pseudomonas aeruginosa as the sole nitrogen and carbon sources, respectively. The rhamnolipid yield was considerably influenced by the type of organic nitrogen source. Among the tested organic nitrogen sources, RHP proved to be the best nitrogen source for both biomass and rhamnolipid production. RHP was also tested at different concentrations and 10 g/L RHP resulted in the greatest yield of rhamnolipid (12.1 g/L) in the presence of waste frying oil as the sole carbon source. These results revealed that rhamnolipid could be produced efficiently and cost effectively by P. aeruginosa OG1 using RHP and waste frying oil.

  20. RsaOG, a new staphylococcal family of highly transcribed non-coding RNA.

    PubMed

    Marchais, Antonin; Bohn, Chantal; Bouloc, Philippe; Gautheret, Daniel

    2010-01-01

    The expression of trans-acting small RNAs in firmicutes has been poorly documented to date. This gap is being filled quickly in the genus Staphylococcus, which is both a model firmicute and an important human pathogen. Here we analyze RsaOG, a novel small RNA family specific to Staphylococcus and highly transcribed. This well conserved element, first discovered in a computational screen, was precisely mapped in the genome by RACE mapping and the identification of a putative transcriptional promoter. The proposed secondary structure presents two highly conserved unpaired sequences, part of which can form a pseudoknot. We suggest a possible involvement of the remaining conserved single stranded region in trans regulatory interactions.

  1. Ex vivo, microelectrode analysis of conduction through the AV node of wild-type and Nkx2-5 mutant mouse hearts as guided by a Cx40-eGFP transgenic reporter.

    PubMed

    Gazit, Avihu Z; Li, Alex; Choi, Jacob S; Miquerol, Lucile; Jay, Patrick Y

    2014-01-01

    Abstract Mutations of the cardiac transcription factor NKX2-5 cause hypoplastic development of the AV node and conduction block. How the anatomy of the mutant AV node relates to its function is unknown. We thus studied conduction through the AV nodal region in ex vivo preparations of wild-type and Nkx2-5(+/-) mouse hearts in which the central conduction system was highlighted by a transgenic Cx40-eGFP reporter. Fluorescence imaging guided electrode placement and pacing of the inferior and superior approaches to the AV node. Nkx2-5(+/-) hearts had a prolonged atrio-His interval compared to the wild type, consistent with previous in vivo observations. The conduction time to the His bundle from the Cx40(-) AV nodal region that is superior to and immediately adjacent to the Cx40(+) lower node is slightly, but not significantly greater in Nkx2-5(+/-) than wild-type hearts. A novel phenotype was also observed. Pacing the Cx40(-) inferior approach to the AV node with increasing stimulus strength led to progressive shortening of the stimulus-to-His conduction interval in wild-type but not Nkx2-5(+/-) hearts. The strength of pacing at the Cx40(-) superior approach had no effect on the conduction interval in either group. The prolonged AV delay in the Nkx2-5(+/-) heart appears to arise before the Cx40(+) lower node. Whether the pacing phenotype explains the mutant's conduction defect is uncertain, but the observation adds to a number of unique properties of the inferior approach to the AV node.

  2. The specificity of Av3 sea anemone toxin for arthropods is determined at linker DI/SS2-S6 in the pore module of target sodium channels.

    PubMed

    Gur Barzilai, Maya; Kahn, Roy; Regev, Noa; Gordon, Dalia; Moran, Yehu; Gurevitz, Michael

    2014-10-15

    Av3 is a peptide neurotoxin from the sea anemone Anemonia viridis that shows specificity for arthropod voltage-gated sodium channels (Navs). Interestingly, Av3 competes with a scorpion α-toxin on binding to insect Navs and similarly inhibits the inactivation process, and thus has been classified as 'receptor site-3 toxin', although the two peptides are structurally unrelated. This raises questions as to commonalities and differences in the way both toxins interact with Navs. Recently, site-3 was partly resolved for scorpion α-toxins highlighting S1-S2 and S3-S4 external linkers at the DIV voltage-sensor module and the juxtaposed external linkers at the DI pore module. To uncover channel determinants involved in Av3 specificity for arthropods, the toxin was examined on channel chimaeras constructed with the external linkers of the mammalian brain Nav1.2a, which is insensitive to Av3, in the background of the Drosophila DmNav1. This approach highlighted the role of linker DI/SS2-S6, adjacent to the channel pore, in determining Av3 specificity. Point mutagenesis at DI/SS2-S6 accompanied by functional assays highlighted Trp404 and His405 as a putative point of Av3 interaction with DmNav1. His405 conservation in arthropod Navs compared with tyrosine in vertebrate Navs may represent an ancient substitution that explains the contemporary selectivity of Av3. Trp404 and His405 localization near the membrane surface and the hydrophobic bioactive surface of Av3 suggest that the toxin possibly binds at a cleft by DI/S6. A partial overlap in receptor site-3 of both toxins nearby DI/S6 may explain their binding competition capabilities.

  3. Confirmation that DNA encoding the major fimbrial subunit of Av24 fimbriae is homologous to DNA encoding the major fimbrial subunit of F107 fimbriae.

    PubMed

    Kennan, R M; Moncktor, R P; McDougall, B M; Conway, P L

    1995-01-01

    Plasmid DNA from porcine enterotoxigenic Escherichia coli strain Av24 (O141:K85ab) was cloned into recipient E. coli strain JM105 using the plasmid vector pUC18. Clones were obtained that produced fimbriae which reacted with antisera specific to the fimbriae produced by strain Av24. Restriction mapping of cloned DNA, PCR with fedA primers and DNA sequencing showed a portion of the cloned DNA to be homologous to that encoding the major fimbrial subunit of F107 fimbriae. This confirms that the fimbriae possessed by strains of E. coli causing both edema disease and post-weaning diarrhoea in piglets are variants of the same fimbriae.

  4. Application of variable structure system theory to aircraft flight control. [AV-8A and the Augmentor Wing Jet STOL Research Aircraft

    NASA Technical Reports Server (NTRS)

    Calise, A. J.; Kadushin, I.; Kramer, F.

    1981-01-01

    The current status of research on the application of variable structure system (VSS) theory to design aircraft flight control systems is summarized. Two aircraft types are currently being investigated: the Augmentor Wing Jet STOL Research Aircraft (AWJSRA), and AV-8A Harrier. The AWJSRA design considers automatic control of longitudinal dynamics during the landing phase. The main task for the AWJSRA is to design an automatic landing system that captures and tracks a localizer beam. The control task for the AV-8A is to track velocity commands in a hovering flight configuration. Much effort was devoted to developing computer programs that are needed to carry out VSS design in a multivariable frame work, and in becoming familiar with the dynamics and control problems associated with the aircraft types under investigation. Numerous VSS design schemes were explored, particularly for the AWJSRA. The approaches that appear best suited for these aircraft types are presented. Examples are given of the numerical results currently being generated.

  5. Case report: Manual lymphatic drainage and kinesio taping in the secondary malignant breast cancer-related lymphedema in an arm with arteriovenous (A-V) fistula for hemodialysis.

    PubMed

    Chou, Ya-Hui; Li, Shu-Hua; Liao, Su-Fen; Tang, Hao-Wei

    2013-08-01

    Lymphedema is a dreaded complication of breast cancer treatment. The standard care for lymphedema is complex decongestive physiotherapy, which includes manual lymphatic drainage (MLD), short stretch bandaging, exercise, and skin care. The Kinesio Taping could help to improve lymphatic uptake. We reported a patient with unilateral secondary malignant breast cancer-related lymphedema and arteriovenous (A-V) fistula for hemodialysis happened in the same arm, and used kinesio taping, MLD, and exercise to treat this patient because no pressure could be applied to the A-V fistula. The 12-session therapy created an excellent effect. We do not think the kinesio taping could replace short stretch bandaging, but it could be another choice for contraindicating pressure therapy patients, and we should pay attention to wounds induced by kinesio tape.

  6. Vesta's north pole quadrangle Av-1 (Albana): Geologic map and the nature of the south polar basin antipodes

    NASA Astrophysics Data System (ADS)

    Blewett, David T.; Buczkowski, Debra L.; Ruesch, Ottaviano; Scully, Jennifer E.; O'Brien, David P.; Gaskell, Robert; Roatsch, Thomas; Bowling, Timothy J.; Ermakov, Anton; Hiesinger, Harald; Williams, David A.; Raymond, Carol A.; Russell, Christopher T.

    2014-12-01

    As part of systematic global mapping of Vesta using data returned by the Dawn spacecraft, we have produced a geologic map of the north pole quadrangle, Av-1 Albana. Extensive seasonal shadows were present in the north polar region at the time of the Dawn observations, limiting the ability to map morphological features and employ color or spectral data for determination of composition. The major recognizable units present include ancient cratered highlands and younger crater-related units (undivided ejecta, and mass-wasting material on crater floors). The antipode of Vesta's large southern impact basins, Rheasilvia and Veneneia, lie within or near the Av-1 quadrangle. Therefore it is of particular interest to search for evidence of features of the kind that are found at basin antipodes on other planetary bodies. Albedo markings known as lunar swirls are correlated with basin antipodes and the presence of crustal magnetic anomalies on the Moon, but lighting conditions preclude recognition of such albedo features in images of the antipode of Vesta's Rheasilvia basin. “Hilly and lineated terrain,” found at the antipodes of large basins on the Moon and Mercury, is not present at the Rheasilvia or Veneneia antipodes. We have identified small-scale linear depressions that may be related to increased fracturing in the Rheasilvia and Veneneia antipodal areas, consistent with impact-induced stresses (Buczkowski, D. et al. [2012b]. Analysis of the large scale troughs on Vesta and correlation to a model of giant impact into a differentiated asteroid. Geol. Soc. of America Annual Meeting. Abstract 152-4; Bowling, T.J. et al. [2013]. J. Geophys. Res. - Planets, 118. http://dx.doi.org/10.1002/jgre.20123). The general high elevation of much of the north polar region could, in part, be a result of uplift caused by the Rheasilvia basin-forming impact, as predicted by numerical modeling (Bowling, T.J. et al. [2013]. J. Geophys. Res. - Planets, 118. http://dx.doi.org/10.1002/jgre

  7. Impact of Avène hydrotherapy on the quality of life of atopic and psoriatic patients.

    PubMed

    Taieb, C; Sibaud, V; Merial-Kieny, C

    2011-02-01

    Atopic dermatitis and psoriasis engender a significant deterioration in patients' quality of life. Although the efficacy of patient management at the Avène hydrotherapy centre has been demonstrated by clinical studies, few data relating to changes in the quality of life following therapeutic management are available. The objective of this study was to evaluate the short- and medium-term effects of hydrotherapy not only on the patients' quality of life, but also on the quality of life of the parents of the treated children. In this 6-month longitudinal observational study, adult (n = 174) and paediatric (n = 212) atopic patients and psoriatic patients (n = 262) had to complete questionnaires relating to the quality of life at the beginning (D0) and after 3 weeks hydrotherapy (W3), and then, 3 (M3) and 6 months (M6) later. The dermatology life quality index (DLQI) and the Short-Form-12 Health Survey (SF-12) generic questionnaire were given to adult patients. The children's dermatological life quality index (CDLQI) was given to paediatric patients, and the SF-12 to their parents. At D0, the DLQI score was 29.7 ± 20.1 and 26.9 ± 18.9 for atopic and psoriatic patients, respectively. At W3, this score had decreased significantly to reach 16.8 ± 14.9 (P < 0.01) and 10.0 ± 10.5 (P < 0.001) for atopic and psoriatic patients, respectively. The DLQI scores at M3 and M6 were 20.7 ± 16.4 and 23.1 ± 18.8 for atopic patients and 18.8 ± 16.7 and 21.9 ± 19.6 for psoriatic patients and remained significantly lower in comparison with D0 values (P < 0.05). A 3-week course of treatment at the Avène hydrotherapy centre significantly improved the quality of life of patients suffering from skin diseases. This improvement persisted 3 and 6 months after management by hydrotherapy. © 2010 The Authors. JEADV © 2010 European Academy of Dermatology and Venereology.

  8. Comparison of different invasive hemodynamic methods for AV delay optimization in patients with cardiac resynchronization therapy: Implications for clinical trial design and clinical practice☆☆☆

    PubMed Central

    Whinnett, Zachary I.; Francis, Darrel P.; Denis, Arnaud; Willson, Keith; Pascale, Patrizio; van