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Sample records for arenaviruses provide broad

  1. Arenaviruses,

    Science.gov (United States)

    characteristics. All arenaviruses establish chronic viremias in specific mammalian hosts (2), from which these viruses are routinely isolated (Table 1). The four... arenaviruses which are pathogenic for humans were originally isolated from patients, and subsequently from the rodent reservoirs. Lymphocytic...and most recently Lassa virus from Lassa fever patients in Nigeria in 1969. The other arenaviruses listed in Table 1 have not been associated with

  2. Current drug discovery strategies against arenavirus infections.

    Science.gov (United States)

    Pasquato, Antonella; Burri, Dominique J; Kunz, Stefan

    2012-11-01

    Arenaviruses are a large group of emerging viruses including several causative agents of severe hemorrhagic fevers with high mortality in man. Considering the number of people affected and the currently limited therapeutic options, novel efficacious therapeutics against arenaviruses are urgently needed. Over the past decade, significant advances in knowledge about the basic virology of arenaviruses have been accompanied by the development of novel therapeutics targeting different steps of the arenaviral life cycle. High-throughput, small-molecule screens identified potent and broadly active inhibitors of arenavirus entry that were instrumental for the dissection of unique features of arenavirus fusion. Novel inhibitors of arenavirus replication have been successfully tested in animal models and hold promise for application in humans. Late in the arenavirus life cycle, the proteolytic processing of the arenavirus envelope glycoprotein precursor and cellular factors critically involved virion assembly and budding provide further promising 'druggable' targets for novel therapeutics to combat human arenavirus infection.

  3. [Arenavirus infections].

    Science.gov (United States)

    Tani, Hideki; Fukushi, Shuetsu; Yoshikawa, Tomoki; Saijo, Masayuki; Morikawa, Shigeru

    2012-01-01

    Arenaviruses are the collective name for viruses, which belong to the family Arenaviridae. They replicate in the cytoplasm of cells, and were named after the sandy (Latin, arenosus) appearance of the ribosomes often seen in thin sections of virions under electron microscope. Several arenaviruses, such as Lassa virus in West Africa, and Junin, Guanarito, Sabia, Machupo, and Chapare viruses in South America, cause sever viral hemorrhagic fevers (VHF) in humans and represent a serious public health problem. These viruses are categorized as category 1 pathogens thus should be handles in a BSL4 laboratory. Recently, Lujo virus was isolated as a newly discovered novel arenavirus associated with a VHF outbreak in southern Africa in 2008. Although, we have no VHF patients caused by arenaviruses in Japan, except for a single imported Lassa fever case in 1987, it is possible that VHF patients occur as imported cases as for other VHF in the future. Therefore, it is necessary to develop the diagnostics and therapeutics in consideration of patient's severe symptoms and high mortality even in the disease-free countries. In this review, we will broadly discuss the current knowledge from the basic researches to diagnostics and vaccine developments for arenavirus diseases.

  4. Arenavirus Budding

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    Shuzo Urata

    2011-01-01

    Full Text Available Several arenaviruses cause hemorrhagic fever disease in humans and pose a significant public health concern in their endemic regions. On the other hand, the prototypic arenavirus LCMV is a superb workhorse for the investigation of virus-host interactions and associated disease. The arenavirus small RING finger protein called Z has been shown to be the main driving force of virus budding. The budding activity of Z is mediated by late (L domain motifs, PT/SAP, and PPXY, located at the C-terminus of Z. This paper will present the current knowledge on arenavirus budding including the diversity of L domain motifs used by different arenaviruses. We will also discuss how improved knowledge of arenavirus budding may facilitate the development of novel antiviral strategies to combat human pathogenic arenaviruses.

  5. Pathogenesis of arenavirus hemorrhagic fevers.

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    Moraz, Marie-Laurence; Kunz, Stefan

    2011-01-01

    Viral hemorrhagic fevers (VHFs) caused by arenaviruses belong to the most devastating emerging human diseases and represent serious public health problems. Arenavirus VHFs in humans are acute diseases characterized by fever and, in severe cases, different degrees of hemorrhages associated with a shock syndrome in the terminal stage. Over the past years, much has been learned about the pathogenesis of arenaviruses at the cellular level, in particular their ability to subvert the host cell's innate antiviral defenses. Clinical studies and novel animal models have provided important new information about the interaction of hemorrhagic arenaviruses with the host's adaptive immune system, in particular virus-induced immunosuppression, and have provided the first hints towards an understanding of the terminal hemorrhagic shock syndrome. The scope of this article is to review our current knowledge on arenavirus VHF pathogenesis with an emphasis on recent developments.

  6. Reverse Genetics Approaches to Control Arenavirus.

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    Martínez-Sobrido, Luis; Cheng, Benson Yee Hin; de la Torre, Juan Carlos

    2016-01-01

    Several arenavirus cause hemorrhagic fever disease in humans and pose a significant public health problem in their endemic regions. To date, no licensed vaccines are available to combat human arenavirus infections, and anti-arenaviral drug therapy is limited to an off-label use of ribavirin that is only partially effective. The development of arenavirus reverse genetics approaches provides investigators with a novel and powerful approach for the investigation of the arenavirus molecular and cell biology. The use of cell-based minigenome systems has allowed examining the cis- and trans-acting factors involved in arenavirus replication and transcription and the identification of novel anti-arenaviral drug targets without requiring the use of live forms of arenaviruses. Likewise, it is now feasible to rescue infectious arenaviruses entirely from cloned cDNAs containing predetermined mutations in their genomes to investigate virus-host interactions and mechanisms of pathogenesis, as well as to facilitate screens to identify anti-arenaviral drugs and development of novel live-attenuated arenavirus vaccines. Recently, reverse genetics have also allowed the generation of tri-segmented arenaviruses expressing foreign genes, facilitating virus detection and opening the possibility of implementing live-attenuated arenavirus-based vaccine vector approaches. Likewise, the development of single-cycle infectious, reporter-expressing, arenaviruses has provided a new experimental method to study some aspects of the biology of highly pathogenic arenaviruses without the requirement of high-security biocontainment required to study HF-causing arenaviruses. In this chapter we summarize the current knowledge on arenavirus reverse genetics and the implementation of plasmid-based reverse genetics techniques for the development of arenavirus vaccines and vaccine vectors.

  7. Novel arenavirus, Zambia.

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    Ishii, Akihiro; Thomas, Yuka; Moonga, Ladslav; Nakamura, Ichiro; Ohnuma, Aiko; Hang'ombe, Bernard; Takada, Ayato; Mweene, Aaron; Sawa, Hirofumi

    2011-10-01

    To investigate arenavirus in Zambia, we characterized virus from the kidneys of 5 arenavirus RNA-positive rodents (Mastomys natalensis) among 263 captured. Full-genome sequences of the viruses suggested that they were new strains similar to Lassa virus-related arenaviruses. Analyzing samples from additional rodents and other species can elucidate epizootiologic aspects of arenaviruses.

  8. Novel Arenavirus, Zambia

    OpenAIRE

    Ishii, Akihiro; Thomas, Yuka; Moonga, Ladslav; Nakamura, Ichiro; OHNUMA, Aiko; Hang’ombe, Bernard; Takada, Ayato; MWEENE, Aaron; Sawa, Hirofumi

    2011-01-01

    To investigate arenavirus in Zambia, we characterized virus from the kidneys of 5 arenavirus RNA–positive rodents (Mastomys natalensis) among 263 captured. Full-genome sequences of the viruses suggested that they were new strains similar to Lassa virus–related arenaviruses. Analyzing samples from additional rodents and other species can elucidate epizootiologic aspects of arenaviruses.

  9. Reporter-Expressing, Replicating-Competent Recombinant Arenaviruses

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    Luis Martínez-Sobrido

    2016-07-01

    Full Text Available Several arenaviruses cause hemorrhagic fever (HF disease in humans and pose an important public health problem in their endemic regions. To date, no Food and Drug Administration (FDA-licensed vaccines are available to combat human arenavirus infections, and current anti-arenaviral drug therapy is limited to an off-label use of ribavirin that is only partially effective. The development of arenavirus reverse genetic approaches has provided investigators with a novel and powerful approach for the study of arenavirus biology including virus–host interactions underlying arenavirus induced disease. The use of cell-based minigenome systems has allowed examining the cis- and trans-acting factors involved in arenavirus replication and transcription, as well as particle assembly and budding. Likewise, it is now feasible to rescue infectious arenaviruses containing predetermined mutations in their genomes to investigate virus-host interactions and mechanisms of pathogenesis. The use of reverse genetics approaches has also allowed the generation of recombinant arenaviruses expressing additional genes of interest. These advances in arenavirus molecular genetics have also facilitated the implementation of novel screens to identify anti-arenaviral drugs, and the development of novel strategies for the generation of arenavirus live-attenuated vaccines. In this review, we will summarize the current knowledge on reporter-expressing, replicating-competent arenaviruses harboring reporter genes in different locations of the viral genome and their use for studying and understanding arenavirus biology and the identification of anti-arenaviral drugs to combat these important human pathogens.

  10. Reporter-Expressing, Replicating-Competent Recombinant Arenaviruses.

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    Martínez-Sobrido, Luis; de la Torre, Juan Carlos

    2016-07-20

    Several arenaviruses cause hemorrhagic fever (HF) disease in humans and pose an important public health problem in their endemic regions. To date, no Food and Drug Administration (FDA)-licensed vaccines are available to combat human arenavirus infections, and current anti-arenaviral drug therapy is limited to an off-label use of ribavirin that is only partially effective. The development of arenavirus reverse genetic approaches has provided investigators with a novel and powerful approach for the study of arenavirus biology including virus-host interactions underlying arenavirus induced disease. The use of cell-based minigenome systems has allowed examining the cis- and trans-acting factors involved in arenavirus replication and transcription, as well as particle assembly and budding. Likewise, it is now feasible to rescue infectious arenaviruses containing predetermined mutations in their genomes to investigate virus-host interactions and mechanisms of pathogenesis. The use of reverse genetics approaches has also allowed the generation of recombinant arenaviruses expressing additional genes of interest. These advances in arenavirus molecular genetics have also facilitated the implementation of novel screens to identify anti-arenaviral drugs, and the development of novel strategies for the generation of arenavirus live-attenuated vaccines. In this review, we will summarize the current knowledge on reporter-expressing, replicating-competent arenaviruses harboring reporter genes in different locations of the viral genome and their use for studying and understanding arenavirus biology and the identification of anti-arenaviral drugs to combat these important human pathogens.

  11. Arenavirus genetic diversity and its biological implications.

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    Emonet, Sebastien F; de la Torre, Juan C; Domingo, Esteban; Sevilla, Noemí

    2009-07-01

    The Arenaviridae family currently comprises 22 viral species, each of them associated with a rodent species. This viral family is important both as tractable experimental model systems to study acute and persistent infections and as clinically important human pathogens. Arenaviruses are enveloped viruses with a bi-segmented negative-strand RNA genome. The interaction with the cellular receptor and subsequent entry into the host cell differs between Old World and New World arenavirus that use alpha-dystoglycan or human transferring receptor 1, respectively, as main receptors. The recent development of reverse genetic systems for several arenaviruses has facilitated progress in understanding the molecular biology and cell biology of this viral family, as well as opening new approaches for the development of novel strategies to combat human pathogenic arenaviruses. On the other hand, increased availability of genetic data has allowed more detailed studies on the phylogeny and evolution of arenaviruses. As with other riboviruses, arenaviruses exist as viral quasispecies, which allow virus adaptation to rapidly changing environments. The large number of different arenavirus host reservoirs and great genetic diversity among virus species provide the bases for the emergence of new arenaviruses potentially pathogenic for humans.

  12. Generation of recombinant arenavirus for vaccine development in FDA-approved Vero cells.

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    Cheng, Benson Y H; Ortiz-Riaño, Emilio; de la Torre, Juan Carlos; Martínez-Sobrido, Luis

    2013-08-01

    The development and implementation of arenavirus reverse genetics represents a significant breakthrough in the arenavirus field. The use of cell-based arenavirus minigenome systems together with the ability to generate recombinant infectious arenaviruses with predetermined mutations in their genomes has facilitated the investigation of the contribution of viral determinants to the different steps of the arenavirus life cycle, as well as virus-host interactions and mechanisms of arenavirus pathogenesis. In addition, the development of trisegmented arenaviruses has permitted the use of the arenavirus genome to express additional foreign genes of interest, thus opening the possibility of arenavirus-based vaccine vector applications. Likewise, the development of single-cycle infectious arenaviruses capable of expressing reporter genes provides a new experimental tool to improve the safety of research involving highly pathogenic human arenaviruses. The generation of recombinant arenaviruses using plasmid-based reverse genetics techniques has so far relied on the use of rodent cell lines, which poses some barriers for the development of Food and Drug Administration (FDA)-licensed vaccine or vaccine vectors. To overcome this obstacle, we describe here the efficient generation of recombinant arenaviruses in FDA-approved Vero cells.

  13. Envelope glycoprotein of arenaviruses.

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    Burri, Dominique J; da Palma, Joel Ramos; Kunz, Stefan; Pasquato, Antonella

    2012-10-17

    Arenaviruses include lethal human pathogens which pose serious public health threats. So far, no FDA approved vaccines are available against arenavirus infections, and therapeutic options are limited, making the identification of novel drug targets for the development of efficacious therapeutics an urgent need. Arenaviruses are comprised of two RNA genome segments and four proteins, the polymerase L, the envelope glycoprotein GP, the matrix protein Z, and the nucleoprotein NP. A crucial step in the arenavirus life-cycle is the biosynthesis and maturation of the GP precursor (GPC) by cellular signal peptidases and the cellular enzyme Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P) yielding a tripartite mature GP complex formed by GP1/GP2 and a stable signal peptide (SSP). GPC cleavage by SKI-1/S1P is crucial for fusion competence and incorporation of mature GP into nascent budding virion particles. In a first part of our review, we cover basic aspects and newer developments in the biosynthesis of arenavirus GP and its molecular interaction with SKI-1/S1P. A second part will then highlight the potential of SKI-1/S1P-mediated processing of arenavirus GPC as a novel target for therapeutic intervention to combat human pathogenic arenaviruses.

  14. Envelope Glycoprotein of Arenaviruses

    Directory of Open Access Journals (Sweden)

    Antonella Pasquato

    2012-10-01

    Full Text Available Arenaviruses include lethal human pathogens which pose serious public health threats. So far, no FDA approved vaccines are available against arenavirus infections, and therapeutic options are limited, making the identification of novel drug targets for the development of efficacious therapeutics an urgent need. Arenaviruses are comprised of two RNA genome segments and four proteins, the polymerase L, the envelope glycoprotein GP, the matrix protein Z, and the nucleoprotein NP. A crucial step in the arenavirus life-cycle is the biosynthesis and maturation of the GP precursor (GPC by cellular signal peptidases and the cellular enzyme Subtilisin Kexin Isozyme-1 (SKI-1/Site-1 Protease (S1P yielding a tripartite mature GP complex formed by GP1/GP2 and a stable signal peptide (SSP. GPC cleavage by SKI-1/S1P is crucial for fusion competence and incorporation of mature GP into nascent budding virion particles. In a first part of our review, we cover basic aspects and newer developments in the biosynthesis of arenavirus GP and its molecular interaction with SKI-1/S1P. A second part will then highlight the potential of SKI-1/S1P-mediated processing of arenavirus GPC as a novel target for therapeutic intervention to combat human pathogenic arenaviruses.

  15. Arenavirus Quasispecies and Their Biological Implications.

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    Grande-Pérez, Ana; Martin, Veronica; Moreno, Hector; de la Torre, Juan C

    2016-01-01

    The family Arenaviridae currently comprises over 20 viral species, each of them associated with a main rodent species as the natural reservoir and in one case possibly phyllostomid bats. Moreover, recent findings have documented a divergent group of arenaviruses in captive alethinophidian snakes. Human infections occur through mucosal exposure to aerosols or by direct contact of abraded skin with infectious materials. Arenaviruses merit interest both as highly tractable experimental model systems to study acute and persistent infections and as clinically important human pathogens including Lassa (LASV) and Junin (JUNV) viruses, the causative agents of Lassa and Argentine hemorrhagic fevers (AHFs), respectively, for which there are no FDA-licensed vaccines, and current therapy is limited to an off-label use of ribavirin (Rib) that has significant limitations. Arenaviruses are enveloped viruses with a bi-segmented negative strand (NS) RNA genome. Each genome segment, L (ca 7.3 kb) and S (ca 3.5 kb), uses an ambisense coding strategy to direct the synthesis of two polypeptides in opposite orientation, separated by a noncoding intergenic region (IGR). The S genomic RNA encodes the virus nucleoprotein (NP) and the precursor (GPC) of the virus surface glycoprotein that mediates virus receptor recognition and cell entry via endocytosis. The L genome RNA encodes the viral RNA-dependent RNA polymerase (RdRp, or L polymerase) and the small (ca 11 kDa) RING finger protein Z that has functions of a bona fide matrix protein including directing virus budding. Arenaviruses were thought to be relatively stable genetically with intra- and interspecies amino acid sequence identities of 90-95 % and 44-63 %, respectively. However, recent evidence has documented extensive arenavirus genetic variability in the field. Moreover, dramatic phenotypic differences have been documented among closely related LCMV isolates. These data provide strong evidence of viral quasispecies involvement in

  16. 3D-QSAR analysis on broad-spectrum arenavirus inhibitors%广谱沙粒病毒抑制剂的3D-QSAR分析

    Institute of Scientific and Technical Information of China (English)

    杨银凤; 王斌; 王景辉; 李燕; 杨凌

    2014-01-01

    沙粒病毒(Arenaviruses)遍布全球,其中的拉沙热病毒可引起致命的拉沙热.通过应用比较分子场分析(CoMFA)和比较相似性指数分析法(CoMSIA)对47个广谱沙粒病毒抑制剂进行了三维定量构效关系(3D-QSAR)分析.使用立体场、静电场、疏水场和氢键受体场组合获得最优模型CoMSIA的统计结果为Q2=0.518,Rncv2=0.972,Rpre2=0.911,说明该模型的可靠性和较好预测能力.此外,模型等势线图直观地解释了分子结构与其活性的关系,为进一步设计新型高效的沙粒病毒抑制剂提供了理论依据.

  17. Enhanced methanol production in plants provides broad spectrum insect resistance.

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    Sameer Dixit

    Full Text Available Plants naturally emit methanol as volatile organic compound. Methanol is toxic to insect pests; but the quantity produced by most of the plants is not enough to protect them against invading insect pests. In the present study, we demonstrated that the over-expression of pectin methylesterase, derived from Arabidopsis thaliana and Aspergillus niger, in transgenic tobacco plants enhances methanol production and resistance to polyphagous insect pests. Methanol content in the leaves of transgenic plants was measured using proton nuclear spectroscopy (1H NMR and spectra showed up to 16 fold higher methanol as compared to control wild type (WT plants. A maximum of 100 and 85% mortality in chewing insects Helicoverpa armigera and Spodoptera litura larvae was observed, respectively when fed on transgenic plants leaves. The surviving larvae showed less feeding, severe growth retardation and could not develop into pupae. In-planta bioassay on transgenic lines showed up to 99 and 75% reduction in the population multiplication of plant sap sucking pests Myzus persicae (aphid and Bemisia tabaci (whitefly, respectively. Most of the phenotypic characters of transgenic plants were similar to WT plants. Confocal microscopy showed no deformities in cellular integrity, structure and density of stomata and trichomes of transgenic plants compared to WT. Pollen germination and tube formation was also not affected in transgenic plants. Cell wall enzyme transcript levels were comparable with WT. This study demonstrated for the first time that methanol emission can be utilized for imparting broad range insect resistance in plants.

  18. A Systems Biology Starter Kit for Arenaviruses

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    Magali E. Droniou-Bonzom

    2012-12-01

    Full Text Available Systems biology approaches in virology aim to integrate viral and host biological networks, and thus model the infection process. The growing availability of high-throughput “-omics” techniques and datasets, as well as the ever-increasing sophistication of in silico modeling tools, has resulted in a corresponding rise in the complexity of the analyses that can be performed. The present study seeks to review and organize published evidence regarding virus-host interactions for the arenaviruses, from alterations in the host proteome during infection, to reported protein-protein interactions. In this way, we hope to provide an overview of the interplay between arenaviruses and the host cell, and lay the foundations for complementing current arenavirus research with a systems-level approach.

  19. A systems biology starter kit for arenaviruses.

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    Droniou-Bonzom, Magali E; Cannon, Paula M

    2012-12-01

    Systems biology approaches in virology aim to integrate viral and host biological networks, and thus model the infection process. The growing availability of high-throughput “-omics” techniques and datasets, as well as the ever-increasing sophistication of in silico modeling tools, has resulted in a corresponding rise in the complexity of the analyses that can be performed. The present study seeks to review and organize published evidence regarding virus-host interactions for the arenaviruses, from alterations in the host proteome during infection, to reported protein-protein interactions. In this way, we hope to provide an overview of the interplay between arenaviruses and the host cell, and lay the foundations for complementing current arenavirus research with a systems-level approach.

  20. T-705 (favipiravir) inhibition of arenavirus replication in cell culture.

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    Mendenhall, Michelle; Russell, Andrew; Juelich, Terry; Messina, Emily L; Smee, Donald F; Freiberg, Alexander N; Holbrook, Michael R; Furuta, Yousuke; de la Torre, Juan-Carlos; Nunberg, Jack H; Gowen, Brian B

    2011-02-01

    A number of New World arenaviruses (Junín [JUNV], Machupo [MACV], and Guanarito [GTOV] viruses) can cause human disease ranging from mild febrile illness to a severe and often fatal hemorrhagic fever syndrome. These highly pathogenic viruses and the Old World Lassa fever virus pose a significant threat to public health and national security. The only licensed antiviral agent with activity against these viruses, ribavirin, has had mixed success in treating severe arenaviral disease and is associated with significant toxicities. A novel pyrazine derivative currently in clinical trials for the treatment of influenza virus infections, T-705 (favipiravir), has demonstrated broad-spectrum activity against a number of RNA viruses, including arenaviruses. T-705 has also been shown to be effective against Pichinde arenavirus infection in a hamster model. Here, we demonstrate the robust antiviral activity of T-705 against authentic highly pathogenic arenaviruses in cell culture. We show that T-705 disrupts an early or intermediate stage in viral replication, distinct from absorption or release, and that its antiviral activity in cell culture is reversed by the addition of purine bases and nucleosides, but not with pyrimidines. Specific inhibition of viral replication/transcription by T-705 was demonstrated using a lymphocytic choriomeningitis arenavirus replicon system. Our findings indicate that T-705 acts to inhibit arenavirus replication/transcription and may directly target the viral RNA-dependent RNA polymerase.

  1. Zoonotic aspects of arenavirus infections.

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    Charrel, R N; de Lamballerie, X

    2010-01-27

    To date, the International Committee for Taxonomy of Viruses recognizes that the family Arenaviridae contains a unique genus Arenavirus that includes 22 viral species. There are nine additional arenaviruses that either have been discovered recently, or which taxonomic status remains pending. Arenaviruses have been classified according to their antigenic properties into two groups, the Lassa-Lymphocytic choriomeningitis (LCM) serocomplex and the Tacaribe serocomplex which has been further divided into four evolutionary lineages. Each arenavirus is more or less tightly associated with a mammal host. The distribution of the host dictates the distribution of the virus. Humans may become infected by arenaviruses through direct contact with infected rodents, including bites, or through inhalation of infectious rodent excreta and secreta. Lassa, Junin, Machupo, Guanarito, and Sabia viruses are known to cause a severe hemorrhagic fever, in western Africa, Argentina, Bolivia, Venezuela, and Brazil, respectively. Infection by LCM virus can result in acute central nervous system disease, congenital malformations, and infection in organ transplantation recipients. Detection of arenaviruses in their animal host can be achieved by virus isolation, and has recently taken advantage of PCR-based techniques. The approach based on consensus degenerate primers has shown efficient for both detection of known arenaviruses, and discovery of new arenaviruses.

  2. Inhibition of arenavirus by A3, a pyrimidine biosynthesis inhibitor.

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    Ortiz-Riaño, Emilio; Ngo, Nhi; Devito, Stefanie; Eggink, Dirk; Munger, Joshua; Shaw, Megan L; de la Torre, Juan Carlos; Martínez-Sobrido, Luis

    2014-01-01

    Arenaviruses merit significant interest as important human pathogens, since several of them cause severe hemorrhagic fever disease that is associated with high morbidity and significant mortality. Currently, there are no FDA-licensed arenavirus vaccines available, and current antiarenaviral therapy is limited to an off-labeled use of the nucleoside analog ribavirin, which has limited prophylactic efficacy. The pyrimidine biosynthesis inhibitor A3, which was identified in a high-throughput screen for compounds that blocked influenza virus replication, exhibits a broad-spectrum antiviral activity against negative- and positive-sense RNA viruses, retroviruses, and DNA viruses. In this study, we evaluated the antiviral activity of A3 against representative Old World (lymphocytic choriomeningitis virus) and New World (Junin virus) arenaviruses in rodent, monkey, and human cell lines. We show that A3 is significantly more efficient than ribavirin in controlling arenavirus multiplication and that the A3 inhibitory effect is in part due to its ability to interfere with viral RNA replication and transcription. We document an additive antiarenavirus effect of A3 and ribavirin, supporting the potential combination therapy of ribavirin and pyrimidine biosynthesis inhibitors for the treatment of arenavirus infections.

  3. Arenaviruses. Genes, proteins, and expression

    Energy Technology Data Exchange (ETDEWEB)

    Oldstone, M.B.A.

    1987-01-01

    This book provides a discussion of current knowledge on Arenaviruses. These viruses are the cause of major health problems, such as Lassa fever and Junin virus disease, and have been the Rosetta stone on which many of the major concepts in viral pathogenesis and immunobiology have been built. For example, study of lymphocytic choriomeningitis naturally and experimentally induced infection in the normal mouse host presented the scientific community with the first and definitive work on the following topics: virus induced immune response disease, immunologic tolerance, virus induced immune complex disease, presence and generation of cytotoxic T cells in vitro and in vivo, H-2 restriction and dual recognition phenomena, and viral disease induced by altering physiologic or differential functions of a cell without causing alterations of house keeping or vital functions, i.e. pathology in the absence of cell or tissue lysis.

  4. Differences in Glycoprotein Complex Receptor Binding Site Accessibility Prompt Poor Cross-Reactivity of Neutralizing Antibodies between Closely Related Arenaviruses.

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    Brouillette, Rachel B; Phillips, Elisabeth K; Ayithan, Natarajan; Maury, Wendy

    2017-04-01

    The glycoprotein complex (GPC) of arenaviruses, composed of stable signal peptide, GP1, and GP2, is the only antigen correlated with antibody-mediated neutralization. However, despite strong cross-reactivity of convalescent antisera between related arenavirus species, weak or no cross-neutralization occurs. Two closely related clade B viruses, Machupo virus (MACV) and Junín virus (JUNV), have nearly identical overall GPC architecture and share a host receptor, transferrin receptor 1 (TfR1). Given structural and functional similarities of the GP1 receptor binding site (RBS) of these viruses and the recent demonstration that the RBS is an important target for neutralizing antibodies, it is not clear how these viruses avoid cross-neutralization. To address this, MACV/JUNV chimeric GPCs were assessed for interaction with a group of α-JUNV GPC monoclonal antibodies (MAbs) and mouse antisera against JUNV or MACV GPC. All six MAbs targeted GP1, with those that neutralized JUNV GPC-pseudovirions competing with each other for RBS binding. However, these MAbs were unable to bind to a chimeric GPC composed of JUNV GP1 containing a small disulfide bonded loop (loop 10) unique to MACV GPC, suggesting that this loop may block MAbs interaction with the GP1 RBS. Consistent with this loop causing interference, mouse anti-JUNV GPC antisera that solely neutralized pseudovirions bearing autologous GP1 provided enhanced neutralization of MACV GPC when this loop was removed. Our studies provide evidence that loop 10, which is unique to MACV GP1, is an important impediment to binding of neutralizing antibodies and contributes to the poor cross-neutralization of α-JUNV antisera against MACV.IMPORTANCE Multiple New World arenaviruses can cause severe disease in humans, and some geographic overlap exists among these viruses. A vaccine that protects against a broad range of New World arenaviruses is desirable for purposes of simplicity, cost, and broad protection against multiple National

  5. Past, present, and future of arenavirus taxonomy.

    Science.gov (United States)

    Radoshitzky, Sheli R; Bào, Yīmíng; Buchmeier, Michael J; Charrel, Rémi N; Clawson, Anna N; Clegg, Christopher S; DeRisi, Joseph L; Emonet, Sébastien; Gonzalez, Jean-Paul; Kuhn, Jens H; Lukashevich, Igor S; Peters, Clarence J; Romanowski, Victor; Salvato, Maria S; Stenglein, Mark D; de la Torre, Juan Carlos

    2015-07-01

    Until recently, members of the monogeneric family Arenaviridae (arenaviruses) have been known to infect only muroid rodents and, in one case, possibly phyllostomid bats. The paradigm of arenaviruses exclusively infecting small mammals shifted dramatically when several groups independently published the detection and isolation of a divergent group of arenaviruses in captive alethinophidian snakes. Preliminary phylogenetic analyses suggest that these reptilian arenaviruses constitute a sister clade to mammalian arenaviruses. Here, the members of the International Committee on Taxonomy of Viruses (ICTV) Arenaviridae Study Group, together with other experts, outline the taxonomic reorganization of the family Arenaviridae to accommodate reptilian arenaviruses and other recently discovered mammalian arenaviruses and to improve compliance with the Rules of the International Code of Virus Classification and Nomenclature (ICVCN). PAirwise Sequence Comparison (PASC) of arenavirus genomes and NP amino acid pairwise distances support the modification of the present classification. As a result, the current genus Arenavirus is replaced by two genera, Mammarenavirus and Reptarenavirus, which are established to accommodate mammalian and reptilian arenaviruses, respectively, in the same family. The current species landscape among mammalian arenaviruses is upheld, with two new species added for Lunk and Merino Walk viruses and minor corrections to the spelling of some names. The published snake arenaviruses are distributed among three new separate reptarenavirus species. Finally, a non-Latinized binomial species name scheme is adopted for all arenavirus species. In addition, the current virus abbreviations have been evaluated, and some changes are introduced to unequivocally identify each virus in electronic databases, manuscripts, and oral proceedings.

  6. A multivalent and cross-protective vaccine strategy against arenaviruses associated with human disease.

    Directory of Open Access Journals (Sweden)

    Maya F Kotturi

    2009-12-01

    Full Text Available Arenaviruses are the causative pathogens of severe hemorrhagic fever and aseptic meningitis in humans, for which no licensed vaccines are currently available. Pathogen heterogeneity within the Arenaviridae family poses a significant challenge for vaccine development. The main hypothesis we tested in the present study was whether it is possible to design a universal vaccine strategy capable of inducing simultaneous HLA-restricted CD8+ T cell responses against 7 pathogenic arenaviruses (including the lymphocytic choriomeningitis, Lassa, Guanarito, Junin, Machupo, Sabia, and Whitewater Arroyo viruses, either through the identification of widely conserved epitopes, or by the identification of a collection of epitopes derived from multiple arenavirus species. By inoculating HLA transgenic mice with a panel of recombinant vaccinia viruses (rVACVs expressing the different arenavirus proteins, we identified 10 HLA-A02 and 10 HLA-A03-restricted epitopes that are naturally processed in human antigen-presenting cells. For some of these epitopes we were able to demonstrate cross-reactive CD8+ T cell responses, further increasing the coverage afforded by the epitope set against each different arenavirus species. Importantly, we showed that immunization of HLA transgenic mice with an epitope cocktail generated simultaneous CD8+ T cell responses against all 7 arenaviruses, and protected mice against challenge with rVACVs expressing either Old or New World arenavirus glycoproteins. In conclusion, the set of identified epitopes allows broad, non-ethnically biased coverage of all 7 viral species targeted by our studies.

  7. Pinhal Virus, a New Arenavirus Isolated from Calomys tener in Brazil.

    Science.gov (United States)

    Bisordi, Ivani; Levis, Silvana; Maeda, Adriana Y; Suzuki, Akemi; Nagasse-Sugahara, Teresa K; de Souza, Renato P; Pereira, Luiz E; Garcia, Jorge B; Cerroni, Matheus de P; de A e Silva, Franko; dos Santos, Cecília L S; da Fonseca, Benedito A L

    2015-11-01

    Arenavirus Sabiá was originally isolated from a fatal human infection in Brazil, and after the occurrence of the second fatal human case in São Paulo state, epidemiologic and virologic studies were performed in the area where the patient lived, aiming at the identification of the Sabiá natural rodent reservoir. A broadly cross-reactive enzyme-linked immunosorbent assay (ELISA) was used to screen for antibody-positive samples. Antibodies to arenavirus were detected in two of the 55 samples of Calomys tener, and from these results, samples of rodents were analyzed by a broad RT-PCR assay. RT-PCR amplification detected arenavirus sequences in five of the 55 C. tener samples, and sequencing showed that this virus is a distinct form of Sabiá virus. Thus, we describe here the evidence for the circulation of a new arenavirus in Brazil (proposed name Pinhal virus) and its genetic characterization compared to other arenaviruses. This study also suggests C. tener as a probable rodent reservoir for this virus and associates this new virus with the lineage C of New World arenaviruses. Although we have defined some characteristics of this virus, so far, there is no evidence of its involvement in human disease.

  8. Reverse genetics approaches to combat pathogenic arenaviruses.

    Science.gov (United States)

    de la Torre, Juan C

    2008-12-01

    Several arenaviruses cause hemorrhagic fever (HF) in humans, and evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen of clinical significance. Moreover, arenaviruses pose a biodefense threat. No licensed anti-arenavirus vaccines are available, and current anti-arenavirus therapy is limited to the use of ribavirin, which is only partially effective and is associated with anemia and other side effects. Therefore, it is important to develop effective vaccines and better antiviral drugs to combat the dual threats of naturally occurring and intentionally introduced arenavirus infections. The development of arenavirus reverse genetic systems is allowing investigators to conduct a detailed molecular characterization of the viral cis-acting signals and trans-acting factors that control each of the steps of the arenavirus life cycle, including RNA synthesis, packaging and budding. Knowledge derived from these studies is uncovering potential novel targets for therapeutic intervention, as well as facilitating the establishment of assays to identify and characterize candidate antiviral drugs capable of interfering with specific steps of the virus life cycle. Likewise, the ability to generate predetermined specific mutations within the arenavirus genome and analyze their phenotypic expression would significantly contribute to the elucidation of arenavirus-host interactions, including the basis of their ability to cause severe HF. This, in turn, could lead to the development of novel, potent and safe arenavirus vaccines.

  9. Cell entry by human pathogenic arenaviruses.

    Science.gov (United States)

    Rojek, Jillian M; Kunz, Stefan

    2008-04-01

    The arenaviruses Lassa virus (LASV) in Africa and Machupo (MACV), Guanarito (GTOV) and Junin viruses (JUNV) in South America cause severe haemorrhagic fevers in humans with fatality rates of 15-35%. The present review focuses on the first steps of infection with human pathogenic arenaviruses, the interaction with their cellular receptor molecules and subsequent entry into the host cell. While similarities exist in genomic organization, structure and clinical disease caused by pathogenic Old World and New World arenaviruses these pathogens use different primary receptors. The Old World arenaviruses employ alpha-dystroglycan, a cellular receptor for proteins of the extracellular matrix, and the human pathogenic New World arenaviruses use the cellular cargo receptor transferrin receptor 1. While the New World arenavirus JUNV enters cells via clathrin-dependent endocytosis, evidence occurred for clathrin-independent entry of the prototypic Old World arenavirus lymphocytic choriomeningitis virus. Upon internalization, arenaviruses are delivered to the endosome, where pH-dependent membrane fusion is mediated by the envelope glycoprotein (GP). While arenavirus GPs share characteristics with class I fusion GPs of other enveloped viruses, unusual mechanistic features of GP-mediated membrane fusion have recently been discovered for arenaviruses with important implications for viral entry.

  10. Molecular and cell biology of the prototypic arenavirus LCMV: implications for understanding and combating hemorrhagic fever arenaviruses.

    Science.gov (United States)

    de la Torre, Juan C

    2009-09-01

    Arenaviruses merit interest as experimental model systems to study virus-host interactions and as clinically important human pathogens. Several arenaviruses, chiefly Lassa virus (LASV), cause hemorrhagic fever (HF) in humans. In addition, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen. Moreover, arenaviruses pose a biodefense threat. No licensed arenavirus vaccines are available, and current therapy is limited to the use of ribavirin, which is only partially effective and associated with significant side effects. The development of arenavirus reverse genetics systems has made it possible to manipulate the arenavirus genome, which is contributing to significant progress in understanding arenavirus molecular and cell biology, as well as arenavirus-host interactions underlying arenavirus-induced HF disease in humans. This, in turn, should facilitate the development of novel both vaccines and antiviral drugs to combat the dual threats of naturally occurring and intentionally introduced arenavirus infections.

  11. Sympatric Occurrence of 3 Arenaviruses, Tanzania

    OpenAIRE

    Goüy de Bellocq, Joëlle; Borremans, Benny; Katakweba, Abdul; Makundi, Rhodes; Baird, Stuart J. E.; Becker-Ziaja, Beate; Günther, Stephan; Leirs, Herwig

    2010-01-01

    To determine the specificity of Morogoro virus for its reservoir host, we studied its host range and genetic diversity in Tanzania. We found that 2 rodent species other than Mastomys natalensis mice carry arenaviruses. Analysis of 340 nt of the viral RNA polymerase gene showed sympatric occurrence of 3 distinct arenaviruses.

  12. DH&S: providing a broad array of services to healthcare. Interview by Bill W. Childs.

    Science.gov (United States)

    Englehart, M; Bell, R

    1988-10-01

    Deloitte Haskins & Sells (DH&S) is an international professional services firm employing more than 8,700 accountants and consultants in the United States in more than 100 offices. Worldwide, the firm serves clients through a network of 400 offices in 70 countries and employs nearly 26,000 people. DH&S has the reputation of providing high quality services to organizations in all major segments of the economy, including healthcare organizations. Healthcare is one of the firm's primary specialties which has seen rapid growth in the past five years, making it DH&S' fastest growing industry group. And, according to Mike Engelhart, the National Industry director for DH&S' Health Care Services, the firm sincerely believes that the commitments it has made, and continues to make, in providing a broad array of specialized services for the healthcare industry gives those organizations "the competitive edge in healthcare." Recently, U.S. Healthcare Editor/Publisher Bill W. Childs had the opportunity to interview Engelhart and Raeford Bell, who directs DH&S' Health Care Information Systems Practice.

  13. Ribavirin can be mutagenic for arenaviruses.

    Science.gov (United States)

    Moreno, Héctor; Gallego, Isabel; Sevilla, Noemí; de la Torre, Juan Carlos; Domingo, Esteban; Martín, Verónica

    2011-07-01

    Arenaviruses include several important human pathogens, and there are very limited options of preventive or therapeutic interventions to combat these viruses. An off-label use of the purine nucleoside analogue ribavirin (1-β-d-ribofuranosyl-1-H-1,2,4-triazole-3-carboxamide) is the only antiviral treatment currently available for arenavirus infections. However, the ribavirin antiviral mechanism action against arenaviruses remains unknown. Here we document that ribavirin is mutagenic for the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) in cell culture. The mutagenic activity of ribavirin on LCMV was observed under single- and multiple-passage regimes and could not be accounted for by a decrease of the intracellular GTP pool promoted by ribavirin-mediated inhibition of inosine monophosphate dehydrogenase (IMPDH). Our findings suggest that the antiviral activity of ribavirin on arenaviruses might be exerted, at least partially, by lethal mutagenesis. Implications for antiarenavirus therapy are discussed.

  14. Symbionts commonly provide broad spectrum resistance to viruses in insects: a comparative analysis of Wolbachia strains.

    Science.gov (United States)

    Martinez, Julien; Longdon, Ben; Bauer, Simone; Chan, Yuk-Sang; Miller, Wolfgang J; Bourtzis, Kostas; Teixeira, Luis; Jiggins, Francis M

    2014-09-01

    In the last decade, bacterial symbionts have been shown to play an important role in protecting hosts against pathogens. Wolbachia, a widespread symbiont in arthropods, can protect Drosophila and mosquito species against viral infections. We have investigated antiviral protection in 19 Wolbachia strains originating from 16 Drosophila species after transfer into the same genotype of Drosophila simulans. We found that approximately half of the strains protected against two RNA viruses. Given that 40% of terrestrial arthropod species are estimated to harbour Wolbachia, as many as a fifth of all arthropods species may benefit from Wolbachia-mediated protection. The level of protection against two distantly related RNA viruses--DCV and FHV--was strongly genetically correlated, which suggests that there is a single mechanism of protection with broad specificity. Furthermore, Wolbachia is making flies resistant to viruses, as increases in survival can be largely explained by reductions in viral titer. Variation in the level of antiviral protection provided by different Wolbachia strains is strongly genetically correlated to the density of the bacteria strains in host tissues. We found no support for two previously proposed mechanisms of Wolbachia-mediated protection--activation of the immune system and upregulation of the methyltransferase Dnmt2. The large variation in Wolbachia's antiviral properties highlights the need to carefully select Wolbachia strains introduced into mosquito populations to prevent the transmission of arboviruses.

  15. Symbionts commonly provide broad spectrum resistance to viruses in insects: a comparative analysis of Wolbachia strains.

    Directory of Open Access Journals (Sweden)

    Julien Martinez

    2014-09-01

    Full Text Available In the last decade, bacterial symbionts have been shown to play an important role in protecting hosts against pathogens. Wolbachia, a widespread symbiont in arthropods, can protect Drosophila and mosquito species against viral infections. We have investigated antiviral protection in 19 Wolbachia strains originating from 16 Drosophila species after transfer into the same genotype of Drosophila simulans. We found that approximately half of the strains protected against two RNA viruses. Given that 40% of terrestrial arthropod species are estimated to harbour Wolbachia, as many as a fifth of all arthropods species may benefit from Wolbachia-mediated protection. The level of protection against two distantly related RNA viruses--DCV and FHV--was strongly genetically correlated, which suggests that there is a single mechanism of protection with broad specificity. Furthermore, Wolbachia is making flies resistant to viruses, as increases in survival can be largely explained by reductions in viral titer. Variation in the level of antiviral protection provided by different Wolbachia strains is strongly genetically correlated to the density of the bacteria strains in host tissues. We found no support for two previously proposed mechanisms of Wolbachia-mediated protection--activation of the immune system and upregulation of the methyltransferase Dnmt2. The large variation in Wolbachia's antiviral properties highlights the need to carefully select Wolbachia strains introduced into mosquito populations to prevent the transmission of arboviruses.

  16. Arenavirus reverse genetics for vaccine development.

    Science.gov (United States)

    Ortiz-Riaño, Emilio; Cheng, Benson Yee Hin; Carlos de la Torre, Juan; Martínez-Sobrido, Luis

    2013-06-01

    Arenaviruses are important human pathogens with no Food and Drug Administration (FDA)-licensed vaccines available and current antiviral therapy being limited to an off-label use of the nucleoside analogue ribavirin of limited prophylactic efficacy. The development of reverse genetics systems represented a major breakthrough in arenavirus research. However, rescue of recombinant arenaviruses using current reverse genetics systems has been restricted to rodent cells. In this study, we describe the rescue of recombinant arenaviruses from human 293T cells and Vero cells, an FDA-approved line for vaccine development. We also describe the generation of novel vectors that mediate synthesis of both negative-sense genome RNA and positive-sense mRNA species of lymphocytic choriomeningitis virus (LCMV) directed by the human RNA polymerases I and II, respectively, within the same plasmid. This approach reduces by half the number of vectors required for arenavirus rescue, which could facilitate virus rescue in cell lines approved for human vaccine production but that cannot be transfected at high efficiencies. We have shown the feasibility of this approach by rescuing both the Old World prototypic arenavirus LCMV and the live-attenuated vaccine Candid#1 strain of the New World arenavirus Junín. Moreover, we show the feasibility of using these novel strategies for efficient rescue of recombinant tri-segmented both LCMV and Candid#1.

  17. Widespread recombination, reassortment, and transmission of unbalanced compound viral genotypes in natural arenavirus infections.

    Directory of Open Access Journals (Sweden)

    Mark D Stenglein

    2015-05-01

    Full Text Available Arenaviruses are one of the largest families of human hemorrhagic fever viruses and are known to infect both mammals and snakes. Arenaviruses package a large (L and small (S genome segment in their virions. For segmented RNA viruses like these, novel genotypes can be generated through mutation, recombination, and reassortment. Although it is believed that an ancient recombination event led to the emergence of a new lineage of mammalian arenaviruses, neither recombination nor reassortment has been definitively documented in natural arenavirus infections. Here, we used metagenomic sequencing to survey the viral diversity present in captive arenavirus-infected snakes. From 48 infected animals, we determined the complete or near complete sequence of 210 genome segments that grouped into 23 L and 11 S genotypes. The majority of snakes were multiply infected, with up to 4 distinct S and 11 distinct L segment genotypes in individual animals. This S/L imbalance was typical: in all cases intrahost L segment genotypes outnumbered S genotypes, and a particular S segment genotype dominated in individual animals and at a population level. We corroborated sequencing results by qRT-PCR and virus isolation, and isolates replicated as ensembles in culture. Numerous instances of recombination and reassortment were detected, including recombinant segments with unusual organizations featuring 2 intergenic regions and superfluous content, which were capable of stable replication and transmission despite their atypical structures. Overall, this represents intrahost diversity of an extent and form that goes well beyond what has been observed for arenaviruses or for viruses in general. This diversity can be plausibly attributed to the captive intermingling of sub-clinically infected wild-caught snakes. Thus, beyond providing a unique opportunity to study arenavirus evolution and adaptation, these findings allow the investigation of unintended anthropogenic impacts on

  18. Widespread recombination, reassortment, and transmission of unbalanced compound viral genotypes in natural arenavirus infections.

    Science.gov (United States)

    Stenglein, Mark D; Jacobson, Elliott R; Chang, Li-Wen; Sanders, Chris; Hawkins, Michelle G; Guzman, David S-M; Drazenovich, Tracy; Dunker, Freeland; Kamaka, Elizabeth K; Fisher, Debbie; Reavill, Drury R; Meola, Linda F; Levens, Gregory; DeRisi, Joseph L

    2015-05-01

    Arenaviruses are one of the largest families of human hemorrhagic fever viruses and are known to infect both mammals and snakes. Arenaviruses package a large (L) and small (S) genome segment in their virions. For segmented RNA viruses like these, novel genotypes can be generated through mutation, recombination, and reassortment. Although it is believed that an ancient recombination event led to the emergence of a new lineage of mammalian arenaviruses, neither recombination nor reassortment has been definitively documented in natural arenavirus infections. Here, we used metagenomic sequencing to survey the viral diversity present in captive arenavirus-infected snakes. From 48 infected animals, we determined the complete or near complete sequence of 210 genome segments that grouped into 23 L and 11 S genotypes. The majority of snakes were multiply infected, with up to 4 distinct S and 11 distinct L segment genotypes in individual animals. This S/L imbalance was typical: in all cases intrahost L segment genotypes outnumbered S genotypes, and a particular S segment genotype dominated in individual animals and at a population level. We corroborated sequencing results by qRT-PCR and virus isolation, and isolates replicated as ensembles in culture. Numerous instances of recombination and reassortment were detected, including recombinant segments with unusual organizations featuring 2 intergenic regions and superfluous content, which were capable of stable replication and transmission despite their atypical structures. Overall, this represents intrahost diversity of an extent and form that goes well beyond what has been observed for arenaviruses or for viruses in general. This diversity can be plausibly attributed to the captive intermingling of sub-clinically infected wild-caught snakes. Thus, beyond providing a unique opportunity to study arenavirus evolution and adaptation, these findings allow the investigation of unintended anthropogenic impacts on viral ecology

  19. The Curious Case of Arenavirus Entry, and Its Inhibition

    Directory of Open Access Journals (Sweden)

    Joanne York

    2012-01-01

    Full Text Available Arenaviruses comprise a diverse family of enveloped negative-strand RNA viruses that are endemic to specific rodent hosts worldwide. Several arenaviruses cause severe hemorrhagic fevers in humans, including Junín and Machupo viruses in South America and Lassa fever virus in western Africa. Arenavirus entry into the host cell is mediated by the envelope glycoprotein complex, GPC. The virion is endocytosed on binding to a cell-surface receptor, and membrane fusion is initiated in response to physiological acidification of the endosome. As with other class I virus fusion proteins, GPC-mediated membrane fusion is promoted through a regulated sequence of conformational changes leading to formation of the classical postfusion trimer-of-hairpins structure. GPC is, however, unique among the class I fusion proteins in that the mature complex retains a stable signal peptide (SSP as a third subunit, in addition to the canonical receptor-binding and fusion proteins. We will review the curious properties of the tripartite GPC complex and describe evidence that SSP interacts with the fusion subunit to modulate pH-induced activation of membrane fusion. This unusual solution to maintaining the metastable prefusion state of GPC on the virion and activating the class I fusion cascade at acidic pH provides novel targets for antiviral intervention.

  20. The New World arenavirus Tacaribe virus induces caspase-dependent apoptosis in infected cells.

    Science.gov (United States)

    Wolff, Svenja; Groseth, Allison; Meyer, Bjoern; Jackson, David; Strecker, Thomas; Kaufmann, Andreas; Becker, Stephan

    2016-04-01

    The Arenaviridae is a diverse and growing family of viruses that already includes more than 25 distinct species. While some of these viruses have a significant impact on public health, others appear to be non-pathogenic. At present little is known about the host cell responses to infection with different arenaviruses, particularly those found in the New World; however, apoptosis is known to play an important role in controlling infection of many viruses. Here we show that infection with Tacaribe virus (TCRV), which is widely considered the prototype for non-pathogenic arenaviruses, leads to stronger induction of apoptosis than does infection with its human-pathogenic relative Junín virus. TCRV-induced apoptosis occurred in several cell types during late stages of infection and was shown to be caspase-dependent, involving the activation of caspases 3, 7, 8 and 9. Further, UV-inactivated TCRV did not induce apoptosis, indicating that the activation of this process is dependent on active viral replication/transcription. Interestingly, when apoptosis was inhibited, growth of TCRV was not enhanced, indicating that apoptosis does not have a direct negative effect on TCRV infection in vitro. Taken together, our data identify and characterize an important virus-host cell interaction of the prototypic, non-pathogenic arenavirus TCRV, which provides important insight into the growing field of arenavirus research aimed at better understanding the diversity in responses to different arenavirus infections and their functional consequences.

  1. Novel Arenavirus Isolates from Namaqua Rock Mice, Namibia, Southern Africa.

    Science.gov (United States)

    Witkowski, Peter T; Kallies, René; Hoveka, Julia; Auste, Brita; Ithete, Ndapewa L; Šoltys, Katarína; Szemes, Tomáš; Drosten, Christian; Preiser, Wolfgang; Klempa, Boris; Mfune, John K E; Kruger, Detlev H

    2015-07-01

    Arenaviruses are feared as agents that cause viral hemorrhagic fevers. We report the identification, isolation, and genetic characterization of 2 novel arenaviruses from Namaqua rock mice in Namibia. These findings extend knowledge of the distribution and diversity of arenaviruses in Africa.

  2. A multivalent vaccination strategy for the prevention of Old World arenavirus infection in humans.

    Science.gov (United States)

    Botten, Jason; Whitton, J Lindsay; Barrowman, Polly; Sidney, John; Whitmire, Jason K; Alexander, Jeff; Kotturi, Maya F; Sette, Alessandro; Buchmeier, Michael J

    2010-10-01

    Arenaviruses cause severe human disease ranging from aseptic meningitis following lymphocytic choriomeningitis virus (LCMV) infection to hemorrhagic fever syndromes following infection with Guanarito virus (GTOV), Junin virus (JUNV), Lassa virus (LASV), Machupo virus (MACV), Sabia virus (SABV), or Whitewater Arroyo virus (WWAV). Cellular immunity, chiefly the CD8(+) T-cell response, plays a critical role in providing protective immunity following infection with the Old World arenaviruses LASV and LCMV. In the current study, we evaluated whether HLA class I-restricted epitopes that are cross-reactive among pathogenic arenaviruses could be identified for the purpose of developing an epitope-based vaccination approach that would cross-protect against multiple arenaviruses. We were able to identify a panel of HLA-A*0201-restricted peptides derived from the same region of the glycoprotein precursor (GPC) of LASV (GPC spanning residues 441 to 449 [GPC(441-449)]), LCMV (GPC(447-455)), JUNV (GPC(429-437)), MACV (GPC(444-452)), GTOV (GPC(427-435)), and WWAV (GPC(428-436)) that displayed high-affinity binding to HLA-A*0201 and were recognized by CD8(+) T cells in a cross-reactive manner following LCMV infection or peptide immunization of HLA-A*0201 transgenic mice. Immunization of HLA-A*0201 mice with the Old World peptide LASV GPC(441-449) or LCMV GPC(447-455) induced high-avidity CD8(+) T-cell responses that were able to kill syngeneic target cells pulsed with either LASV GPC(441-449) or LCMV GPC(447-455) in vivo and provided significant protection against viral challenge with LCMV. Through this study, we have demonstrated that HLA class I-restricted, cross-reactive epitopes exist among diverse arenaviruses and that individual epitopes can be utilized as effective vaccine determinants for multiple pathogenic arenaviruses.

  3. Investigation of type-I interferon dysregulation by arenaviruses : a multidisciplinary approach.

    Energy Technology Data Exchange (ETDEWEB)

    Kozina, Carol L.; Moorman, Matthew Wallace; Branda, Catherine; Wu, Meiye; Manginell, Ronald Paul; Ricken, James Bryce; James, Conrad D.; Negrete, Oscar A.; Misra, Milind; Carson, Bryan D.

    2011-09-01

    This report provides a detailed overview of the work performed for project number 130781, 'A Systems Biology Approach to Understanding Viral Hemorrhagic Fever Pathogenesis.' We report progress in five key areas: single cell isolation devices and control systems, fluorescent cytokine and transcription factor reporters, on-chip viral infection assays, molecular virology analysis of Arenavirus nucleoprotein structure-function, and development of computational tools to predict virus-host protein interactions. Although a great deal of work remains from that begun here, we have developed several novel single cell analysis tools and knowledge of Arenavirus biology that will facilitate and inform future publications and funding proposals.

  4. Molecular mechanism of arenavirus assembly and budding.

    Science.gov (United States)

    Urata, Shuzo; Yasuda, Jiro

    2012-10-10

    Arenaviruses have a bisegmented negative-strand RNA genome, which encodes four viral proteins: GP and NP by the S segment and L and Z by the L segment. These four viral proteins possess multiple functions in infection, replication and release of progeny viruses from infected cells. The small RING finger protein, Z protein is a matrix protein that plays a central role in viral assembly and budding. Although all arenaviruses encode Z protein, amino acid sequence alignment showed a huge variety among the species, especially at the C-terminus where the L-domain is located. Recent publications have demonstrated the interactions between viral protein and viral protein, and viral protein and host cellular protein, which facilitate transportation and assembly of viral components to sites of virus egress. This review presents a summary of current knowledge regarding arenavirus assembly and budding, in comparison with other enveloped viruses. We also refer to the restriction of arenavirus production by the antiviral cellular factor, Tetherin/BST-2.

  5. Molecular Mechanism of Arenavirus Assembly and Budding

    Directory of Open Access Journals (Sweden)

    Shuzo Urata

    2012-10-01

    Full Text Available Arenaviruses have a bisegmented negative-strand RNA genome, which encodes four viral proteins: GP and NP by the S segment and L and Z by the L segment. These four viral proteins possess multiple functions in infection, replication and release of progeny viruses from infected cells. The small RING finger protein, Z protein is a matrix protein that plays a central role in viral assembly and budding. Although all arenaviruses encode Z protein, amino acid sequence alignment showed a huge variety among the species, especially at the C-terminus where the L-domain is located. Recent publications have demonstrated the interactions between viral protein and viral protein, and viral protein and host cellular protein, which facilitate transportation and assembly of viral components to sites of virus egress. This review presents a summary of current knowledge regarding arenavirus assembly and budding, in comparison with other enveloped viruses. We also refer to the restriction of arenavirus production by the antiviral cellular factor, Tetherin/BST-2.

  6. Sympatric Occurrence of 3 Arenaviruses, Tanzania

    DEFF Research Database (Denmark)

    de Bellocq, Joëlle Goüy; Borremans, Benny; Katakweba, Abdul

    2010-01-01

    To determine the specificity of Morogoro virus for its reservoir host, we studied its host range and genetic diversity in Tanzania. We found that 2 rodent species other than Mastomys natalensis mice carry arenaviruses. Analysis of 340 nt of the viral RNA polymerase gene showed sympatric occurrence...

  7. Biological roles and functional mechanisms of arenavirus Z protein in viral replication.

    Science.gov (United States)

    Wang, Jialong; Danzy, Shamika; Kumar, Naveen; Ly, Hinh; Liang, Yuying

    2012-09-01

    Arenaviruses can cause severe hemorrhagic fever diseases in humans, with limited prophylactic or therapeutic measures. A small RING-domain viral protein Z has been shown to mediate the formation of virus-like particles and to inhibit viral RNA synthesis, although its biological roles in an infectious viral life cycle have not been directly addressed. By taking advantage of the available reverse genetics system for a model arenavirus, Pichinde virus (PICV), we provide the direct evidence for the essential biological roles of the Z protein's conserved residues, including the G2 myristylation site, the conserved C and H residues of RING domain, and the poorly characterized C-terminal L79 and P80 residues. Dicodon substitutions within the late (L) domain (PSAPPYEP) of the PICV Z protein, although producing viable mutant viruses, have significantly reduced virus growth, a finding suggestive of an important role for the intact L domain in viral replication. Further structure-function analyses of both PICV and Lassa fever virus Z proteins suggest that arenavirus Z proteins have similar molecular mechanisms in mediating their multiple functions, with some interesting variations, such as the role of the G2 residue in blocking viral RNA synthesis. In summary, our studies have characterized the biological roles of the Z protein in an infectious arenavirus system and have shed important light on the distinct functions of its domains in virus budding and viral RNA regulation, the knowledge of which may lead to the development of novel antiviral drugs.

  8. Assembly of arenavirus envelope glycoprotein GPC in detergent-soluble membrane microdomains.

    Science.gov (United States)

    Agnihothram, Sudhakar S; Dancho, Brooke; Grant, Kenneth W; Grimes, Mark L; Lyles, Douglas S; Nunberg, Jack H

    2009-10-01

    The family Arenaviridae includes a number of highly pathogenic viruses that are responsible for acute hemorrhagic fevers in humans. Genetic diversity among arenavirus species in their respective rodent hosts supports the continued emergence of new pathogens. In the absence of available vaccines or therapeutic agents, the hemorrhagic fever arenaviruses remain a serious public health and biodefense concern. Arenaviruses are enveloped virions that assemble and bud from the plasma membrane. In this study, we have characterized the microdomain organization of the virus envelope glycoprotein (GPC) on the cell surface by using immunogold electron microscopy. We find that Junín virus (JUNV) GPC clusters into discrete microdomains of 120 to 160 nm in diameter and that this property of GPC is independent of its myristoylation and of coexpression with the virus matrix protein Z. In cells infected with the Candid#1 strain of JUNV, and in purified Candid#1 virions, these GPC microdomains are soluble in cold Triton X-100 detergent and are thus distinct from conventional lipid rafts, which are utilized by numerous other viruses for assembly. Virion morphogenesis ultimately requires colocalization of viral components, yet our dual-label immunogold staining studies failed to reveal a spatial association of Z with GPC microdomains. This observation may reflect either rapid Z-dependent budding of virus-like particles upon coassociation or a requirement for additional viral components in the assembly process. Together, these results provide new insight into the molecular basis for arenavirus morphogenesis.

  9. A cell-based luciferase assay amenable to high-throughput screening of inhibitors of arenavirus budding.

    Science.gov (United States)

    Capul, Althea A; de la Torre, Juan Carlos

    2008-12-05

    Several arenaviruses cause hemorrhagic fever (HF) disease in humans for which there are no licensed vaccines, and current therapy is limited to the use of ribavirin (Rib) that is only partially effective and associated with significant side effects. In addition, compelling evidence indicates that the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen of clinical significance. Therefore, it is important to develop novel and effective anti-arenaviral drugs. The arenavirus Z protein is the driving force of arenavirus budding, and PPPY and PTAP late (L) domain motifs within Z are critical for Z-mediated budding, which involves the interaction of Z with a variety of host cellular factors. Compounds capable of inhibiting these virus-host cell interactions represent candidate anti-arenaviral drugs. The identification of these candidate compounds would be facilitated by the availability of a Z budding assay amenable to high-throughput screens (HTS). To this end, we have developed a novel assay that allows for rapid and quantitative assessment of Z-mediated budding. We provide evidence that this novel assay is amenable to HTS to identify small molecule inhibitors of Z-mediated budding, as well as to uncover cellular genes contributing to arenavirus budding.

  10. Two novel arenaviruses detected in pygmy mice, Ghana.

    Science.gov (United States)

    Kronmann, Karl C; Nimo-Paintsil, Shirley; Guirguis, Fady; Kronmann, Lisha C; Bonney, Kofi; Obiri-Danso, Kwasi; Ampofo, William; Fichet-Calvet, Elisabeth

    2013-11-01

    Two arenaviruses were detected in pygmy mice (Mus spp.) by screening 764 small mammals in Ghana. The Natal multimammate mouse (Mastomys natalensis), the known Lassa virus reservoir, was the dominant indoor rodent species in 4 of 10 sites, and accounted for 27% of all captured rodents. No rodent captured indoors tested positive for an arenavirus.

  11. Unique small molecule entry inhibitors of hemorrhagic fever arenaviruses.

    Science.gov (United States)

    Lee, Andrew M; Rojek, Jillian M; Spiropoulou, Christina F; Gundersen, Anette T; Jin, Wei; Shaginian, Alex; York, Joanne; Nunberg, Jack H; Boger, Dale L; Oldstone, Michael B A; Kunz, Stefan

    2008-07-04

    Viral hemorrhagic fevers caused by the arenaviruses Lassa virus in Africa and Machupo, Guanarito, Junin, and Sabia virus in South America are among the most devastating emerging human diseases with fatality rates of 15-35% and a limited antiviral therapeutic repertoire available. Here we used high throughput screening of synthetic combinatorial small molecule libraries to identify inhibitors of arenavirus infection using pseudotyped virion particles bearing the glycoproteins (GPs) of highly pathogenic arenaviruses. Our screening efforts resulted in the discovery of a series of novel small molecule inhibitors of viral entry that are highly active against both Old World and New World hemorrhagic arenaviruses. We observed potent inhibition of infection of human and primate cells with live hemorrhagic arenaviruses (IC(50)=500-800 nm). Investigations of the mechanism of action revealed that the candidate compounds efficiently block pH-dependent fusion by the arenavirus GPs (IC(50) of 200-350 nm). Although our lead compounds were potent against phylogenetically distant arenaviruses, they did not show activity against other enveloped viruses with class I viral fusion proteins, indicating specificity for arenavirus GP-mediated membrane fusion.

  12. Molecular characterization of the processing of arenavirus envelope glycoprotein precursors by subtilisin kexin isozyme-1/site-1 protease.

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    Burri, Dominique J; Pasqual, Giulia; Rochat, Cylia; Seidah, Nabil G; Pasquato, Antonella; Kunz, Stefan

    2012-05-01

    A crucial step in the life cycle of arenaviruses is the biosynthesis of the mature fusion-active viral envelope glycoprotein (GP) that is essential for virus-host cell attachment and entry. The maturation of the arenavirus GP precursor (GPC) critically depends on proteolytic processing by the cellular proprotein convertase (PC) subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P). Here we undertook a molecular characterization of the SKI-1/S1P processing of the GPCs of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) and the pathogenic Lassa virus (LASV). Previous studies showed that the GPC of LASV undergoes processing in the endoplasmic reticulum (ER)/cis-Golgi compartment, whereas the LCMV GPC is cleaved in a late Golgi compartment. Herein we confirm these findings and provide evidence that the SKI-1/S1P recognition site RRLL, present in the SKI-1/S1P prodomain and LASV GPC, but not in the LCMV GPC, is crucial for the processing of the LASV GPC in the ER/cis-Golgi compartment. Our structure-function analysis revealed that the cleavage of arenavirus GPCs, but not cellular substrates, critically depends on the autoprocessing of SKI-1/S1P, suggesting differences in the processing of cellular and viral substrates. Deletion mutagenesis showed that the transmembrane and intracellular domains of SKI-1/S1P are dispensable for arenavirus GPC processing. The expression of a soluble form of the protease in SKI-I/S1P-deficient cells resulted in the efficient processing of arenavirus GPCs and rescued productive virus infection. However, exogenous soluble SKI-1/S1P was unable to process LCMV and LASV GPCs displayed at the surface of SKI-I/S1P-deficient cells, indicating that GPC processing occurs in an intracellular compartment. In sum, our study reveals important differences in the SKI-1/S1P processing of viral and cellular substrates.

  13. Animal Models, Prophylaxis, and Therapeutics for Arenavirus Infections

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    Eric Vela

    2012-09-01

    Full Text Available Arenaviruses are enveloped, bipartite negative single-stranded RNA viruses that can cause a wide spectrum of disease in humans and experimental animals including hemorrhagic fever. The majority of these viruses are rodent-borne and the arenavirus family can be divided into two groups: the Lassa-Lymphocytic choriomeningitis serocomplex and the Tacaribe serocomplex. Arenavirus-induced disease may include characteristic symptoms ranging from fever, malaise, body aches, petechiae, dehydration, hemorrhage, organ failure, shock, and in severe cases death. Currently, there are few prophylactic and therapeutic treatments available for arenavirus-induced symptoms. Supportive care and ribavirin remain the predominant strategies for treating most of the arenavirus-induced diseases. Therefore, efficacy testing of novel therapeutic and prophylactic strategies in relevant animal models is necessary. Because of the potential for person-to-person spread, the ability to cause lethal or debilitating disease in humans, limited treatment options, and potential as a bio-weapon, the development of prophylactics and therapeutics is essential. This article reviews the current arenavirus animal models and prophylactic and therapeutic strategies under development to treat arenavirus infection.

  14. Animal models, prophylaxis, and therapeutics for arenavirus infections.

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    Vela, Eric

    2012-09-01

    Arenaviruses are enveloped, bipartite negative single-stranded RNA viruses that can cause a wide spectrum of disease in humans and experimental animals including hemorrhagic fever. The majority of these viruses are rodent-borne and the arenavirus family can be divided into two groups: the Lassa-Lymphocytic choriomeningitis serocomplex and the Tacaribe serocomplex. Arenavirus-induced disease may include characteristic symptoms ranging from fever, malaise, body aches, petechiae, dehydration, hemorrhage, organ failure, shock, and in severe cases death. Currently, there are few prophylactic and therapeutic treatments available for arenavirus-induced symptoms. Supportive care and ribavirin remain the predominant strategies for treating most of the arenavirus-induced diseases. Therefore, efficacy testing of novel therapeutic and prophylactic strategies in relevant animal models is necessary. Because of the potential for person-to-person spread, the ability to cause lethal or debilitating disease in humans, limited treatment options, and potential as a bio-weapon, the development of prophylactics and therapeutics is essential. This article reviews the current arenavirus animal models and prophylactic and therapeutic strategies under development to treat arenavirus infection.

  15. Arenaviruses and Lethal Mutagenesis. Prospects for New Ribavirin-based Interventions

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    Ana Grande-Pérez

    2012-11-01

    Full Text Available Lymphocytic choriomeningitis virus (LCMV has contributed to unveil some of the molecular mechanisms of lethal mutagenesis, or loss of virus infectivity due to increased mutation rates. Here we review these developments, and provide additional evidence that ribavirin displays a dual mutagenic and inhibitory activity on LCMV that can be relevant to treatment designs. Using 5-fluorouracil as mutagenic agent and ribavirin either as inhibitor or mutagen, we document an advantage of a sequential inhibitor-mutagen administration over the corresponding combination treatment to achieve a low LCMV load in cell culture. This advantage is accentuated in the concentration range in which ribavirin acts mainly as an inhibitor, rather than as mutagen. This observation reinforces previous theoretical and experimental studies in supporting a sequential inhibitor-mutagen administration as a possible antiviral design. Given recent progress in the development of new inhibitors of arenavirus replication, our results suggest new options of ribavirin-based anti-arenavirus treatments.

  16. Arenaviruses and lethal mutagenesis. Prospects for new ribavirin-based interventions.

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    Moreno, Héctor; Grande-Pérez, Ana; Domingo, Esteban; Martín, Verónica

    2012-11-06

    Lymphocytic choriomeningitis virus (LCMV) has contributed to unveil some of the molecular mechanisms of lethal mutagenesis, or loss of virus infectivity due to increased mutation rates. Here we review these developments, and provide additional evidence that ribavirin displays a dual mutagenic and inhibitory activity on LCMV that can be relevant to treatment designs. Using 5-fluorouracil as mutagenic agent and ribavirin either as inhibitor or mutagen, we document an advantage of a sequential inhibitor-mutagen administration over the corresponding combination treatment to achieve a low LCMV load in cell culture. This advantage is accentuated in the concentration range in which ribavirin acts mainly as an inhibitor, rather than as mutagen. This observation reinforces previous theoretical and experimental studies in supporting a sequential inhibitor-mutagen administration as a possible antiviral design. Given recent progress in the development of new inhibitors of arenavirus replication, our results suggest new options of ribavirin-based anti-arenavirus treatments.

  17. Animal Models for the Study of Rodent-Borne Hemorrhagic Fever Viruses: Arenaviruses and Hantaviruses

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    Joseph W. Golden

    2015-01-01

    Full Text Available Human pathogenic hantaviruses and arenaviruses are maintained in nature by persistent infection of rodent carrier populations. Several members of these virus groups can cause significant disease in humans that is generically termed viral hemorrhagic fever (HF and is characterized as a febrile illness with an increased propensity to cause acute inflammation. Human interaction with rodent carrier populations leads to infection. Arenaviruses are also viewed as potential biological weapons threat agents. There is an increased interest in studying these viruses in animal models to gain a deeper understating not only of viral pathogenesis, but also for the evaluation of medical countermeasures (MCM to mitigate disease threats. In this review, we examine current knowledge regarding animal models employed in the study of these viruses. We include analysis of infection models in natural reservoirs and also discuss the impact of strain heterogeneity on the susceptibility of animals to infection. This information should provide a comprehensive reference for those interested in the study of arenaviruses and hantaviruses not only for MCM development but also in the study of viral pathogenesis and the biology of these viruses in their natural reservoirs.

  18. Animal Models for the Study of Rodent-Borne Hemorrhagic Fever Viruses: Arenaviruses and Hantaviruses.

    Science.gov (United States)

    Golden, Joseph W; Hammerbeck, Christopher D; Mucker, Eric M; Brocato, Rebecca L

    2015-01-01

    Human pathogenic hantaviruses and arenaviruses are maintained in nature by persistent infection of rodent carrier populations. Several members of these virus groups can cause significant disease in humans that is generically termed viral hemorrhagic fever (HF) and is characterized as a febrile illness with an increased propensity to cause acute inflammation. Human interaction with rodent carrier populations leads to infection. Arenaviruses are also viewed as potential biological weapons threat agents. There is an increased interest in studying these viruses in animal models to gain a deeper understating not only of viral pathogenesis, but also for the evaluation of medical countermeasures (MCM) to mitigate disease threats. In this review, we examine current knowledge regarding animal models employed in the study of these viruses. We include analysis of infection models in natural reservoirs and also discuss the impact of strain heterogeneity on the susceptibility of animals to infection. This information should provide a comprehensive reference for those interested in the study of arenaviruses and hantaviruses not only for MCM development but also in the study of viral pathogenesis and the biology of these viruses in their natural reservoirs.

  19. Arenavirus Variations Due to Host-Specific Adaptation

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    Juan C. Zapata

    2013-01-01

    Full Text Available Arenavirus particles are enveloped and contain two single-strand RNA genomic segments with ambisense coding. Genetic plasticity of the arenaviruses comes from transcription errors, segment reassortment, and permissive genomic packaging, and results in their remarkable ability, as a group, to infect a wide variety of hosts. In this review, we discuss some in vitro studies of virus genetic and phenotypic variation after exposure to selective pressures such as high viral dose, mutagens and antivirals. Additionally, we discuss the variation in vivo of selected isolates of Old World arenaviruses, particularly after infection of different animal species. We also discuss the recent emergence of new arenaviruses in the context of our observations of sequence variations that appear to be host-specific.

  20. Arenavirus variations due to host-specific adaptation.

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    Zapata, Juan C; Salvato, Maria S

    2013-01-17

    Arenavirus particles are enveloped and contain two single-strand RNA genomic segments with ambisense coding. Genetic plasticity of the arenaviruses comes from transcription errors, segment reassortment, and permissive genomic packaging, and results in their remarkable ability, as a group, to infect a wide variety of hosts. In this review, we discuss some in vitro studies of virus genetic and phenotypic variation after exposure to selective pressures such as high viral dose, mutagens and antivirals. Additionally, we discuss the variation in vivo of selected isolates of Old World arenaviruses, particularly after infection of different animal species. We also discuss the recent emergence of new arenaviruses in the context of our observations of sequence variations that appear to be host-specific.

  1. Arenavirus nucleoprotein targets interferon regulatory factor-activating kinase IKKε.

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    Pythoud, Christelle; Rodrigo, W W Shanaka I; Pasqual, Giulia; Rothenberger, Sylvia; Martínez-Sobrido, Luis; de la Torre, Juan Carlos; Kunz, Stefan

    2012-08-01

    Arenaviruses perturb innate antiviral defense by blocking induction of type I interferon (IFN) production. Accordingly, the arenavirus nucleoprotein (NP) was shown to block activation and nuclear translocation of interferon regulatory factor 3 (IRF3) in response to virus infection. Here, we sought to identify cellular factors involved in innate antiviral signaling targeted by arenavirus NP. Consistent with previous studies, infection with the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) prevented phosphorylation of IRF3 in response to infection with Sendai virus, a strong inducer of the retinoic acid-inducible gene I (RIG-I)/mitochondrial antiviral signaling (MAVS) pathway of innate antiviral signaling. Using a combination of coimmunoprecipitation and confocal microscopy, we found that LCMV NP associates with the IκB kinase (IKK)-related kinase IKKε but that, rather unexpectedly, LCMV NP did not bind to the closely related TANK-binding kinase 1 (TBK-1). The NP-IKKε interaction was highly conserved among arenaviruses from different clades. In LCMV-infected cells, IKKε colocalized with NP but not with MAVS located on the outer membrane of mitochondria. LCMV NP bound the kinase domain (KD) of IKKε (IKBKE) and blocked its autocatalytic activity and its ability to phosphorylate IRF3, without undergoing phosphorylation. Together, our data identify IKKε as a novel target of arenavirus NP. Engagement of NP seems to sequester IKKε in an inactive complex. Considering the important functions of IKKε in innate antiviral immunity and other cellular processes, the NP-IKKε interaction likely plays a crucial role in arenavirus-host interaction.

  2. Arenavirus Glycan Shield Promotes Neutralizing Antibody Evasion and Protracted Infection.

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    Rami Sommerstein

    2015-11-01

    Full Text Available Arenaviruses such as Lassa virus (LASV can cause severe hemorrhagic fever in humans. As a major impediment to vaccine development, delayed and weak neutralizing antibody (nAb responses represent a unifying characteristic of both natural infection and all vaccine candidates tested to date. To investigate the mechanisms underlying arenavirus nAb evasion we engineered several arenavirus envelope-chimeric viruses and glycan-deficient variants thereof. We performed neutralization tests with sera from experimentally infected mice and from LASV-convalescent human patients. NAb response kinetics in mice correlated inversely with the N-linked glycan density in the arenavirus envelope protein's globular head. Additionally and most intriguingly, infection with fully glycosylated viruses elicited antibodies, which neutralized predominantly their glycan-deficient variants, both in mice and humans. Binding studies with monoclonal antibodies indicated that envelope glycans reduced nAb on-rate, occupancy and thereby counteracted virus neutralization. In infected mice, the envelope glycan shield promoted protracted viral infection by preventing its timely elimination by the ensuing antibody response. Thus, arenavirus envelope glycosylation impairs the protective efficacy rather than the induction of nAbs, and thereby prevents efficient antibody-mediated virus control. This immune evasion mechanism imposes limitations on antibody-based vaccination and convalescent serum therapy.

  3. Arenavirus Glycan Shield Promotes Neutralizing Antibody Evasion and Protracted Infection.

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    Sommerstein, Rami; Flatz, Lukas; Remy, Melissa M; Malinge, Pauline; Magistrelli, Giovanni; Fischer, Nicolas; Sahin, Mehmet; Bergthaler, Andreas; Igonet, Sebastien; Ter Meulen, Jan; Rigo, Dorothée; Meda, Paolo; Rabah, Nadia; Coutard, Bruno; Bowden, Thomas A; Lambert, Paul-Henri; Siegrist, Claire-Anne; Pinschewer, Daniel D

    2015-11-01

    Arenaviruses such as Lassa virus (LASV) can cause severe hemorrhagic fever in humans. As a major impediment to vaccine development, delayed and weak neutralizing antibody (nAb) responses represent a unifying characteristic of both natural infection and all vaccine candidates tested to date. To investigate the mechanisms underlying arenavirus nAb evasion we engineered several arenavirus envelope-chimeric viruses and glycan-deficient variants thereof. We performed neutralization tests with sera from experimentally infected mice and from LASV-convalescent human patients. NAb response kinetics in mice correlated inversely with the N-linked glycan density in the arenavirus envelope protein's globular head. Additionally and most intriguingly, infection with fully glycosylated viruses elicited antibodies, which neutralized predominantly their glycan-deficient variants, both in mice and humans. Binding studies with monoclonal antibodies indicated that envelope glycans reduced nAb on-rate, occupancy and thereby counteracted virus neutralization. In infected mice, the envelope glycan shield promoted protracted viral infection by preventing its timely elimination by the ensuing antibody response. Thus, arenavirus envelope glycosylation impairs the protective efficacy rather than the induction of nAbs, and thereby prevents efficient antibody-mediated virus control. This immune evasion mechanism imposes limitations on antibody-based vaccination and convalescent serum therapy.

  4. Arenavirus budding resulting from viral-protein-associated cell membrane curvature.

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    Schley, David; Whittaker, Robert J; Neuman, Benjamin W

    2013-09-06

    Viral replication occurs within cells, with release (and onward infection) primarily achieved through two alternative mechanisms: lysis, in which virions emerge as the infected cell dies and bursts open; or budding, in which virions emerge gradually from a still living cell by appropriating a small part of the cell membrane. Virus budding is a poorly understood process that challenges current models of vesicle formation. Here, a plausible mechanism for arenavirus budding is presented, building on recent evidence that viral proteins embed in the inner lipid layer of the cell membrane. Experimental results confirm that viral protein is associated with increased membrane curvature, whereas a mathematical model is used to show that localized increases in curvature alone are sufficient to generate viral buds. The magnitude of the protein-induced curvature is calculated from the size of the amphipathic region hypothetically removed from the inner membrane as a result of translation, with a change in membrane stiffness estimated from observed differences in virion deformation as a result of protein depletion. Numerical results are based on experimental data and estimates for three arenaviruses, but the mechanisms described are more broadly applicable. The hypothesized mechanism is shown to be sufficient to generate spontaneous budding that matches well both qualitatively and quantitatively with experimental observations.

  5. Live, attenuated influenza A H5N1 candidate vaccines provide broad cross-protection in mice and ferrets.

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    Amorsolo L Suguitan

    2006-09-01

    Full Text Available BACKGROUND: Recent outbreaks of highly pathogenic influenza A H5N1 viruses in humans and avian species that began in Asia and have spread to other continents underscore an urgent need to develop vaccines that would protect the human population in the event of a pandemic. METHODS AND FINDINGS: Live, attenuated candidate vaccines possessing genes encoding a modified H5 hemagglutinin (HA and a wild-type (wt N1 neuraminidase from influenza A H5N1 viruses isolated in Hong Kong and Vietnam in 1997, 2003, and 2004, and remaining gene segments derived from the cold-adapted (ca influenza A vaccine donor strain, influenza A/Ann Arbor/6/60 ca (H2N2, were generated by reverse genetics. The H5N1 ca vaccine viruses required trypsin for efficient growth in vitro, as predicted by the modification engineered in the gene encoding the HA, and possessed the temperature-sensitive and attenuation phenotypes specified by the internal protein genes of the ca vaccine donor strain. More importantly, the candidate vaccines were immunogenic in mice. Four weeks after receiving a single dose of 10(6 50% tissue culture infectious doses of intranasally administered vaccines, mice were fully protected from lethality following challenge with homologous and antigenically distinct heterologous wt H5N1 viruses from different genetic sublineages (clades 1, 2, and 3 that were isolated in Asia between 1997 and 2005. Four weeks after receiving two doses of the vaccines, mice and ferrets were fully protected against pulmonary replication of homologous and heterologous wt H5N1 viruses. CONCLUSIONS: The promising findings in these preclinical studies of safety, immunogenicity, and efficacy of the H5N1 ca vaccines against antigenically diverse H5N1 vaccines provide support for their careful evaluation in Phase 1 clinical trials in humans.

  6. Isolation and characterization of a novel arenavirus harbored by Rodents and Shrews in Zhejiang province, China.

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    Li, Kun; Lin, Xian-Dan; Wang, Wen; Shi, Mang; Guo, Wen-Ping; Zhang, Xiao-He; Xing, Jian-Guang; He, Jin-Rong; Wang, Ke; Li, Ming-Hui; Cao, Jian-Hai; Jiang, Mu-Liu; Holmes, Edward C; Zhang, Yong-Zhen

    2015-02-01

    To determine the biodiversity of arenaviruses in China, we captured and screened rodents and shrews in Wenzhou city, Zhejiang province, a locality where hemorrhagic fever diseases are endemic in humans. Accordingly, arenaviruses were detected in 42 of 351 rodents from eight species, and in 12 of 272 Asian house shrews (Suncus murinus), by RT-PCR targeting the L segment. From these, a single arenavirus was successfully isolated in cell culture. The virion particles exhibited a typical arenavirus morphology under transmission electron microscopy. Comparison of the S and L segment sequences revealed high levels of nucleotide (>32.2% and >39.6%) and amino acid (>28.8% and >43.8%) sequence differences from known arenaviruses, suggesting that it represents a novel arenavirus, which we designated Wenzhou virus (WENV). Phylogenetic analysis revealed that all WENV strains harbored by both rodents and Asian house shrews formed a distinct lineage most closely related to Old World arenaviruses.

  7. Multifunctional Nature of the Arenavirus RING Finger Protein Z

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    Thomas Strecker

    2012-11-01

    Full Text Available Arenaviruses are a family of enveloped negative-stranded RNA viruses that can cause severe human disease ranging from encephalitis symptoms to fulminant hemorrhagic fever. The bi‑segmented RNA genome encodes four polypeptides: the nucleoprotein NP, the surface glycoprotein GP, the polymerase L, and the RING finger protein Z. Although it is the smallest arenavirus protein with a length of 90 to 99 amino acids and a molecular weight of approx. 11 kDa, the Z protein has multiple functions in the viral life cycle including (i regulation of viral RNA synthesis, (ii orchestration of viral assembly and budding, (iii interaction with host cell proteins, and (iv interferon antagonism. In this review, we summarize our current understanding of the structural and functional role of the Z protein in the arenavirus replication cycle.

  8. Multifunctional nature of the arenavirus RING finger protein Z.

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    Fehling, Sarah Katharina; Lennartz, Frank; Strecker, Thomas

    2012-11-09

    Arenaviruses are a family of enveloped negative-stranded RNA viruses that can cause severe human disease ranging from encephalitis symptoms to fulminant hemorrhagic fever. The bi‑segmented RNA genome encodes four polypeptides: the nucleoprotein NP, the surface glycoprotein GP, the polymerase L, and the RING finger protein Z. Although it is the smallest arenavirus protein with a length of 90 to 99 amino acids and a molecular weight of approx. 11 kDa, the Z protein has multiple functions in the viral life cycle including (i) regulation of viral RNA synthesis, (ii) orchestration of viral assembly and budding, (iii) interaction with host cell proteins, and (iv) interferon antagonism. In this review, we summarize our current understanding of the structural and functional role of the Z protein in the arenavirus replication cycle.

  9. Arenavirus nucleoproteins prevent activation of nuclear factor kappa B.

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    Rodrigo, W W Shanaka I; Ortiz-Riaño, Emilio; Pythoud, Christelle; Kunz, Stefan; de la Torre, Juan C; Martínez-Sobrido, Luis

    2012-08-01

    Arenaviruses include several causative agents of hemorrhagic fever (HF) disease in humans that are associated with high morbidity and significant mortality. Morbidity and lethality associated with HF arenaviruses are believed to involve the dysregulation of the host innate immune and inflammatory responses that leads to impaired development of protective and efficient immunity. The molecular mechanisms underlying this dysregulation are not completely understood, but it is suggested that viral infection leads to disruption of early host defenses and contributes to arenavirus pathogenesis in humans. We demonstrate in the accompanying paper that the prototype member in the family, lymphocytic choriomeningitis virus (LCMV), disables the host innate defense by interfering with type I interferon (IFN-I) production through inhibition of the interferon regulatory factor 3 (IRF3) activation pathway and that the viral nucleoprotein (NP) alone is responsible for this inhibitory effect (C. Pythoud, W. W. Rodrigo, G. Pasqual, S. Rothenberger, L. Martínez-Sobrido, J. C. de la Torre, and S. Kunz, J. Virol. 86:7728-7738, 2012). In this report, we show that LCMV-NP, as well as NPs encoded by representative members of both Old World (OW) and New World (NW) arenaviruses, also inhibits the nuclear translocation and transcriptional activity of the nuclear factor kappa B (NF-κB). Similar to the situation previously reported for IRF3, Tacaribe virus NP (TCRV-NP) does not inhibit NF-κB nuclear translocation and transcriptional activity to levels comparable to those seen with other members in the family. Altogether, our findings demonstrate that arenavirus infection inhibits NF-κB-dependent innate immune and inflammatory responses, possibly playing a key role in the pathogenesis and virulence of arenavirus.

  10. Sodium hydrogen exchangers contribute to arenavirus cell entry.

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    Iwasaki, Masaharu; Ngo, Nhi; de la Torre, Juan C

    2014-01-01

    Several arenaviruses, chiefly Lassa virus (LASV), cause hemorrhagic fever (HF) disease in humans and pose a great public health concern in the regions in which they are endemic. Moreover, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen of clinical significance. The limited existing armamentarium to combat human-pathogenic arenaviruses underscores the importance of developing novel antiarenaviral drugs, a task that would be facilitated by the identification and characterization of virus-host cell factor interactions that contribute to the arenavirus life cycle. A genome-wide small interfering RNA (siRNA) screen identified sodium hydrogen exchanger 3 (NHE3) as required for efficient multiplication of LCMV in HeLa cells, but the mechanisms by which NHE activity contributed to the life cycle of LCMV remain unknown. Here we show that treatment with the NHE inhibitor 5-(N-ethyl-N-isopropyl) amiloride (EIPA) resulted in a robust inhibition of LCMV multiplication in both rodent (BHK-21) and human (A549) cells. EIPA-mediated inhibition was due not to interference with virus RNA replication, gene expression, or budding but rather to a blockade of virus cell entry. EIPA also inhibited cell entry mediated by the glycoproteins of the HF arenaviruses LASV and Junin virus (JUNV). Pharmacological and genetic studies revealed that cell entry of LCMV in A549 cells depended on actin remodeling and Pak1, suggesting a macropinocytosis-like cell entry pathway. Finally, zoniporide, an NHE inhibitor being explored as a therapeutic agent to treat myocardial infarction, inhibited LCMV propagation in culture cells. Our findings indicate that targeting NHEs could be a novel strategy to combat human-pathogenic arenaviruses.

  11. Arenavirus Evasion of Host Anti-Viral Responses

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    Melissa Hayes

    2012-10-01

    Full Text Available The innate response to infection by an Old World arenavirus is initiated and mediated by extracellular and intracellular receptors, and effector molecules. In response, the invading virus has evolved to inhibit these responses and create the best environment possible for replication and spread. Here, we will discuss both the host’s response to infection with data from human infection and lessons learned from animal models, as well as the multitude of ways the virus combats the resulting immune response. Finally, we will highlight recent work identifying TLR2 as an innate sensor for arenaviruses and how the TLR2-dependent response differs depending on the pathogenicity of the strain.

  12. Arenavirus evasion of host anti-viral responses.

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    Hayes, Melissa; Salvato, Maria

    2012-10-17

    The innate response to infection by an Old World arenavirus is initiated and mediated by extracellular and intracellular receptors, and effector molecules. In response, the invading virus has evolved to inhibit these responses and create the best environment possible for replication and spread. Here, we will discuss both the host's response to infection with data from human infection and lessons learned from animal models, as well as the multitude of ways the virus combats the resulting immune response. Finally, we will highlight recent work identifying TLR2 as an innate sensor for arenaviruses and how the TLR2-dependent response differs depending on the pathogenicity of the strain.

  13. Common antiviral cytotoxic t-lymphocyte epitope for diverse arenaviruses.

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    Oldstone, M B; Lewicki, H; Homann, D; Nguyen, C; Julien, S; Gairin, J E

    2001-07-01

    Members of the Arenaviridae family have been isolated from mammalian hosts in disparate geographic locations, leading to their grouping as Old World types (i.e., lymphocytic choriomeningitis virus [LCMV], Lassa fever virus [LFV], Mopeia virus, and Mobala virus) and New World types (i.e., Junin, Machupo, Tacaribe, and Sabia viruses) (C. J. Peters, M. J. Buchmeier, P. E. Rollin, and T. G. Ksiazek, p. 1521-1551, in B. N. Fields, D. M. Knipe, and P. M. Howley [ed.], Fields virology, 3rd ed., 1996; P. J. Southern, p. 1505-1519, in B. N. Fields, D. M. Knipe, and P. M. Howley [ed.], Fields virology, 3rd ed., 1996). Several types in both groups-LFV, Junin, Machupo, and Sabia viruses-cause severe and often lethal human diseases. By sequence comparison, we noted that eight Old World and New World arenaviruses share several amino acids with the nucleoprotein (NP) that consists of amino acids (aa) 118 to 126 (NP 118-126) (RPQASGVYM) of LCMV that comprise the immunodominant cytotoxic T-lymphocyte (CTL) epitope for H-2(d) mice (32). This L(d)-restricted epitope constituted >97% of the total bulk CTLs produced in the specific antiviral or clonal responses of H-2(d) BALB mice. NP 118-126 of the Old World arenaviruses LFV, Mopeia virus, and LCMV and the New World arenavirus Sabia virus bound at high affinity to L(d). The primary H-2(d) CTL anti-LCMV response as well as that of a CTL clone responsive to LCMV NP 118-126 recognized target cells coated with NP 118-126 peptides derived from LCMV, LFV, and Mopeia virus but not Sabia virus, indicating that a common functional NP epitope exists among Old World arenaviruses. Use of site-specific amino acid exchanges in the NP CTL epitope among these arenaviruses identified amino acids involved in major histocompatibility complex binding and CTL recognition.

  14. Innate immune response to arenaviral infection: a focus on the highly pathogenic New World hemorrhagic arenaviruses.

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    Koma, Takaaki; Huang, Cheng; Kolokoltsova, Olga A; Brasier, Allan R; Paessler, Slobodan

    2013-12-13

    Arenaviruses are enveloped, negative-stranded RNA viruses that belong to the family Arenaviridae. This diverse family can be further classified into OW (Old World) and NW (New World) arenaviruses based on their antigenicity, phylogeny, and geographical distribution. Many of the NW arenaviruses are highly pathogenic viruses that cause systemic human infections characterized by hemorrhagic fever and/or neurological manifestations, constituting public health problems in their endemic regions. NW arenavirus infection induces a variety of host innate immune responses, which could contribute to the viral pathogenesis and/or influence the final outcome of virus infection in vitro and in vivo. On the other hand, NW arenaviruses have also developed several strategies to counteract the host innate immune response. We will review current knowledge regarding the interplay between the host innate immune response and NW arenavirus infection in vitro and in vivo, with emphasis on viral-encoded proteins and their effect on the type I interferon response.

  15. Principal host relationships and evolutionary history of the North American arenaviruses

    OpenAIRE

    Cajimat, Maria N. B.; Milazzo, Mary Louise; Hess, Barry D.; Rood, Michael P.; Fulhorst, Charles F.

    2007-01-01

    A previous study suggested that the genomes of the arenaviruses native to North America are a product of genetic recombination between New World arenaviruses with significantly different phylogenetic histories. The purpose of this study was to extend our knowledge of the principal host relationships and evolutionary history of the North American arenaviruses. The results of this study suggest that the large-eared woodrat (Neotoma macrotis) is a principal host of Bear Canyon virus and that the...

  16. Development of a new tacaribe arenavirus infection model and its use to explore antiviral activity of a novel aristeromycin analog.

    Directory of Open Access Journals (Sweden)

    Brian B Gowen

    Full Text Available BACKGROUND: A growing number of arenaviruses can cause a devastating viral hemorrhagic fever (VHF syndrome. They pose a public health threat as emerging viruses and because of their potential use as bioterror agents. All of the highly pathogenic New World arenaviruses (NWA phylogenetically segregate into clade B and require maximum biosafety containment facilities for their study. Tacaribe virus (TCRV is a nonpathogenic member of clade B that is closely related to the VHF arenaviruses at the amino acid level. Despite this relatedness, TCRV lacks the ability to antagonize the host interferon (IFN response, which likely contributes to its inability to cause disease in animals other than newborn mice. METHODOLOGY/PRINCIPAL FINDINGS: Here we describe a new mouse model based on TCRV challenge of AG129 IFN-α/β and -γ receptor-deficient mice. Titration of the virus by intraperitoneal (i.p. challenge of AG129 mice resulted in an LD(50 of ∼100 fifty percent cell culture infectious doses. Virus replication was evident in the serum, liver, lung, spleen, and brain 4-8 days after inoculation. MY-24, an aristeromycin derivative active against TCRV in cell culture at 0.9 µM, administered i.p. once daily for 7 days, offered highly significant (P<0.001 protection against mortality in the AG129 mouse TCRV infection model, without appreciably reducing viral burden. In contrast, in a hamster model of arenaviral hemorrhagic fever based on challenge with clade A Pichinde arenavirus, MY-24 did not offer significant protection against mortality. CONCLUSIONS/SIGNIFICANCE: MY-24 is believed to act as an inhibitor of S-adenosyl-L-homocysteine hydrolase, but our findings suggest that it may ameliorate disease by blunting the effects of the host response that play a role in disease pathogenesis. The new AG129 mouse TCRV infection model provides a safe and cost-effective means to conduct early-stage pre-clinical evaluations of candidate antiviral therapies that target

  17. Host Cell Factors as Antiviral Targets in Arenavirus Infection

    Directory of Open Access Journals (Sweden)

    Elsa B. Damonte

    2012-09-01

    Full Text Available Among the members of the Arenaviridae family, Lassa virus and Junin virus generate periodic annual outbreaks of severe human hemorrhagic fever (HF in endemic areas of West Africa and Argentina, respectively. Given the human health threat that arenaviruses represent and the lack of a specific and safe chemotherapy, the search for effective antiviral compounds is a continuous demanding effort. Since diverse host cell pathways and enzymes are used by RNA viruses to fulfill their replicative cycle, the targeting of a host process has turned an attractive antiviral approach in the last years for many unrelated virus types. This strategy has the additional benefit to reduce the serious challenge for therapy of RNA viruses to escape from drug effects through selection of resistant variants triggered by their high mutation rate. This article focuses on novel strategies to identify inhibitors for arenavirus therapy, analyzing the potential for antiviral developments of diverse host factors essential for virus infection.

  18. Host cell factors as antiviral targets in arenavirus infection.

    Science.gov (United States)

    Linero, Florencia N; Sepúlveda, Claudia S; Giovannoni, Federico; Castilla, Viviana; García, Cybele C; Scolaro, Luis A; Damonte, Elsa B

    2012-09-01

    Among the members of the Arenaviridae family, Lassa virus and Junin virus generate periodic annual outbreaks of severe human hemorrhagic fever (HF) in endemic areas of West Africa and Argentina, respectively. Given the human health threat that arenaviruses represent and the lack of a specific and safe chemotherapy, the search for effective antiviral compounds is a continuous demanding effort. Since diverse host cell pathways and enzymes are used by RNA viruses to fulfill their replicative cycle, the targeting of a host process has turned an attractive antiviral approach in the last years for many unrelated virus types. This strategy has the additional benefit to reduce the serious challenge for therapy of RNA viruses to escape from drug effects through selection of resistant variants triggered by their high mutation rate. This article focuses on novel strategies to identify inhibitors for arenavirus therapy, analyzing the potential for antiviral developments of diverse host factors essential for virus infection.

  19. Arenaviruses and hantaviruses: from epidemiology and genomics to antivirals.

    Science.gov (United States)

    Charrel, R N; Coutard, B; Baronti, C; Canard, B; Nougairede, A; Frangeul, A; Morin, B; Jamal, S; Schmidt, C L; Hilgenfeld, R; Klempa, B; de Lamballerie, X

    2011-05-01

    The arenaviruses and hantaviruses are segmented genome RNA viruses that are hosted by rodents. Due to their association with rodents, they are globally widespread and can infect humans via direct or indirect routes of transmission, causing considerable human morbidity and mortality. Nevertheless, despite their obvious and emerging importance as pathogens, there are currently no effective antiviral drugs (except ribavirin which proved effective against Lassa virus) with which to treat humans infected by any of these viruses. The EU-funded VIZIER project (Comparative Structural Genomics of Viral Enzymes Involved in Replication) was instigated with an ultimate view of contributing to the development of antiviral therapies for RNA viruses, including the arenaviruses and bunyaviruses. This review highlights some of the major features of the arenaviruses and hantaviruses that have been investigated during recent years. After describing their classification and epidemiology, we review progress in understanding the genomics as well as the structure and function of replicative enzymes achieved under the VIZIER program and the development of new disease control strategies.

  20. Highly Sensitive Assay for Measurement of Arenavirus-cell Attachment.

    Science.gov (United States)

    Klaus, Joseph P; Botten, Jason

    2016-03-02

    Arenaviruses are a family of enveloped RNA viruses that cause severe human disease. The first step in the arenavirus life cycle is attachment of viral particles to host cells. While virus-cell attachment can be measured through the use of virions labeled with biotin, radioactive isotopes, or fluorescent dyes, these approaches typically require high multiplicities of infection (MOI) to enable detection of bound virus. We describe a quantitative (q)RT-PCR-based assay that measures Junin virus strain Candid 1 attachment via quantitation of virion-packaged viral genomic RNA. This assay has several advantages including its extreme sensitivity and ability to measure attachment over a large dynamic range of MOIs without the need to purify or label input virus. Importantly, this approach can be easily tailored for use with other viruses through the use of virus-specific qRT-PCR reagents. Further, this assay can be modified to permit measurement of particle endocytosis and genome uncoating. In conclusion, we describe a simple, yet robust assay for highly sensitive measurement of arenavirus-cell attachment.

  1. Indirect solid-phase immunosorbent assay for detection of arenavirus antigens and antibodies

    Energy Technology Data Exchange (ETDEWEB)

    Ivanov, A.P.; Rezapkin, G.V.; Dzagurova, T.K.; Tkachenko, E.A. (Institute of Poliomyelitis anU Viral Encephalities of the U.S.S.R. Academy of Medical Sciences, Moscow)

    1984-05-01

    Indirect enzyme-linked immunosorbent assay (ELISA) and solid phase radioimmunoassay (SPRIA) using either enti-human or anti-mouse IgG labelled with horseradish peroxidase and /sup 125/I, respectively, were developed for the detection of Junin, Machupo, Tacaribe, Amapari, Tamiami, Lassa and LCM arenaviruses. Both methods allow high sensitivity detection of arenavirus antigens and antibodies.

  2. Detection of novel divergent arenaviruses in boid snakes with inclusion body disease in The Netherlands

    NARCIS (Netherlands)

    R. Bodewes (Rogier); M.J.L. Kik (Marja); V.S. Stalin Raj; C.M.E. Schapendonk (Claudia); B.L. Haagmans (Bart); S.L. Smits (Saskia); A.D.M.E. Osterhaus (Albert)

    2013-01-01

    textabstractArenaviruses are bi-segmented negative-stranded RNA viruses, which were until recently only detected in rodents and humans. Now highly divergent arenaviruses have been identified in boid snakes with inclusion body disease (IBD). Here, we describe the identification of a new species and v

  3. Isolation and characterization of a novel arenavirus harbored by Rodents and Shrews in Zhejiang province, China

    Energy Technology Data Exchange (ETDEWEB)

    Li, Kun [State Key Laboratory for Infectious Disease Prevention and Control, Department of Zoonoses, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Changping, Beijing (China); Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou (China); Lin, Xian-Dan [Wenzhou Center for Disease Control and Prevention, Wenzhou, Zhejiang Province (China); Wang, Wen [State Key Laboratory for Infectious Disease Prevention and Control, Department of Zoonoses, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Changping, Beijing (China); Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou (China); Shi, Mang [State Key Laboratory for Infectious Disease Prevention and Control, Department of Zoonoses, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Changping, Beijing (China); Wencheng Center for Disease Control and Prevention, Wenzhou, Zhejiang Province (China); Guo, Wen-Ping [State Key Laboratory for Infectious Disease Prevention and Control, Department of Zoonoses, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Changping, Beijing (China); Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou (China); Zhang, Xiao-He [Wenzhou Center for Disease Control and Prevention, Wenzhou, Zhejiang Province (China); Xing, Jian-Guang [Wencheng Center for Disease Control and Prevention, Wenzhou, Zhejiang Province (China); and others

    2015-02-15

    To determine the biodiversity of arenaviruses in China, we captured and screened rodents and shrews in Wenzhou city, Zhejiang province, a locality where hemorrhagic fever diseases are endemic in humans. Accordingly, arenaviruses were detected in 42 of 351 rodents from eight species, and in 12 of 272 Asian house shrews (Suncus murinus), by RT-PCR targeting the L segment. From these, a single arenavirus was successfully isolated in cell culture. The virion particles exhibited a typical arenavirus morphology under transmission electron microscopy. Comparison of the S and L segment sequences revealed high levels of nucleotide (>32.2% and >39.6%) and amino acid (>28.8% and >43.8%) sequence differences from known arenaviruses, suggesting that it represents a novel arenavirus, which we designated Wenzhou virus (WENV). Phylogenetic analysis revealed that all WENV strains harbored by both rodents and Asian house shrews formed a distinct lineage most closely related to Old World arenaviruses. - Highlights: • A novel arenavirus (Wenzhou virus) was identified in Zhejiang province, China. • The virus is highly circulating in five species of rats and one species of shrews • More efforts are needed to infer whether it is pathogenic to humans or not.

  4. Development of live-attenuated arenavirus vaccines based on codon deoptimization of the viral glycoprotein.

    Science.gov (United States)

    Cheng, Benson Y H; Nogales, Aitor; de la Torre, Juan Carlos; Martínez-Sobrido, Luis

    2017-01-15

    Several arenaviruses, chiefly Lassa (LASV) in West Africa, cause hemorrhagic fever (HF) disease in humans and pose important public health problems in their endemic regions. To date, there are no FDA-approved arenavirus vaccines and current anti-arenaviral therapy is limited to the use of ribavirin that has very limited efficacy. In this work we document that a recombinant prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) with a codon deoptimized (CD) surface glycoprotein (GP), rLCMV/CD, exhibited wild type (WT)-like growth properties in cultured cells despite barely detectable GP expression levels in rLCMV/CD-infected cells. Importantly, rLCMV/CD was highly attenuated in vivo but able to induce complete protection against a subsequent lethal challenge with rLCMV/WT. Our findings support the feasibility of implementing an arenavirus GP CD-based approach for the development of safe and effective live-attenuated vaccines (LAVs) to combat diseases caused by human pathogenic arenaviruses.

  5. Detection of novel divergent arenaviruses in boid snakes with inclusion body disease in The Netherlands.

    Science.gov (United States)

    Bodewes, R; Kik, M J L; Raj, V Stalin; Schapendonk, C M E; Haagmans, B L; Smits, S L; Osterhaus, A D M E

    2013-06-01

    Arenaviruses are bi-segmented negative-stranded RNA viruses, which were until recently only detected in rodents and humans. Now highly divergent arenaviruses have been identified in boid snakes with inclusion body disease (IBD). Here, we describe the identification of a new species and variants of the highly divergent arenaviruses, which were detected in tissues of captive boid snakes with IBD in The Netherlands by next-generation sequencing. Phylogenetic analysis of the complete sequence of the open reading frames of the four predicted proteins of one of the detected viruses revealed that this virus was most closely related to the recently identified Golden Gate virus, while considerable sequence differences were observed between the highly divergent arenaviruses detected in this study. These findings add to the recent identification of the highly divergent arenaviruses in boid snakes with IBD in the United States and indicate that these viruses also circulate among boid snakes in Europe.

  6. Isolation, identification, and characterization of novel arenaviruses, the etiological agents of boid inclusion body disease.

    Science.gov (United States)

    Hetzel, Udo; Sironen, Tarja; Laurinmäki, Pasi; Liljeroos, Lassi; Patjas, Aino; Henttonen, Heikki; Vaheri, Antti; Artelt, Annette; Kipar, Anja; Butcher, Sarah J; Vapalahti, Olli; Hepojoki, Jussi

    2013-10-01

    Boid inclusion body disease (BIBD) is a progressive, usually fatal disease of constrictor snakes, characterized by cytoplasmic inclusion bodies (IB) in a wide range of cell types. To identify the causative agent of the disease, we established cell cultures from BIBD-positive and -negative boa constrictors. The IB phenotype was maintained in cultured cells of affected animals, and supernatants from these cultures caused the phenotype in cultures originating from BIBD-negative snakes. Viruses were purified from the supernatants by ultracentrifugation and subsequently identified as arenaviruses. Purified virus also induced the IB phenotype in naive cells, which fulfilled Koch's postulates in vitro. One isolate, tentatively designated University of Helsinki virus (UHV), was studied in depth. Sequencing confirmed that UHV is a novel arenavirus species that is distinct from other known arenaviruses including those recently identified in snakes with BIBD. The morphology of UHV was established by cryoelectron tomography and subtomographic averaging, revealing the trimeric arenavirus spike structure at 3.2-nm resolution. Immunofluorescence, immunohistochemistry, and immunoblotting with a polyclonal rabbit antiserum against UHV and reverse transcription-PCR (RT-PCR) revealed the presence of genetically diverse arenaviruses in a large cohort of snakes with BIBD, confirming the causative role of arenaviruses. Some snakes were also found to carry arenavirus antibodies. Furthermore, mammalian cells (Vero E6) were productively infected with UHV, demonstrating the potential of arenaviruses to cross species barriers. In conclusion, we propose the newly identified lineage of arenaviruses associated with BIBD as a novel taxonomic entity, boid inclusion body disease-associated arenaviruses (BIBDAV), in the family Arenaviridae.

  7. Broad-spectrum antiviral therapeutics.

    Directory of Open Access Journals (Sweden)

    Todd H Rider

    Full Text Available Currently there are relatively few antiviral therapeutics, and most which do exist are highly pathogen-specific or have other disadvantages. We have developed a new broad-spectrum antiviral approach, dubbed Double-stranded RNA (dsRNA Activated Caspase Oligomerizer (DRACO that selectively induces apoptosis in cells containing viral dsRNA, rapidly killing infected cells without harming uninfected cells. We have created DRACOs and shown that they are nontoxic in 11 mammalian cell types and effective against 15 different viruses, including dengue flavivirus, Amapari and Tacaribe arenaviruses, Guama bunyavirus, and H1N1 influenza. We have also demonstrated that DRACOs can rescue mice challenged with H1N1 influenza. DRACOs have the potential to be effective therapeutics or prophylactics for numerous clinical and priority viruses, due to the broad-spectrum sensitivity of the dsRNA detection domain, the potent activity of the apoptosis induction domain, and the novel direct linkage between the two which viruses have never encountered.

  8. Pathological and virological features of arenavirus disease in guinea pigs. Comparison of two Pichinde virus strains.

    Science.gov (United States)

    Aronson, J F; Herzog, N K; Jerrells, T R

    1994-07-01

    A guinea pig passage-adapted strain of the arena-virus Pichinde (adPIC) is highly virulent in inbred guinea pigs, whereas the related strain PIC3739 is attenuated. Both viruses were macrophage tropic and infected peritoneal, splenic, liver, and alveolar macrophages during experimental Pichinde virus infection. Infection with the virulent strain was associated with unlimited viral replication in the face of exaggerated delayed-type hypersensitivity response, manifested by the macrophage disappearance reaction. Histopathological lesions unique to adPIC-infected guinea pigs included intestinal villus blunting with mucosal infiltration by pyknotic debris-laden macrophages and apoptosis of crypt epithelial cells. Splenic red pulp necrosis was also significantly associated with adPIC infection but not PIC3739 infection. These findings may provide clues to the pathogenesis of a group of poorly understood human viral hemorrhagic fevers.

  9. An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway.

    Science.gov (United States)

    Robertson, Kevin A; Hsieh, Wei Yuan; Forster, Thorsten; Blanc, Mathieu; Lu, Hongjin; Crick, Peter J; Yutuc, Eylan; Watterson, Steven; Martin, Kimberly; Griffiths, Samantha J; Enright, Anton J; Yamamoto, Mami; Pradeepa, Madapura M; Lennox, Kimberly A; Behlke, Mark A; Talbot, Simon; Haas, Jürgen; Dölken, Lars; Griffiths, William J; Wang, Yuqin; Angulo, Ana; Ghazal, Peter

    2016-03-01

    In invertebrates, small interfering RNAs are at the vanguard of cell-autonomous antiviral immunity. In contrast, antiviral mechanisms initiated by interferon (IFN) signaling predominate in mammals. Whilst mammalian IFN-induced miRNA are known to inhibit specific viruses, it is not known whether host-directed microRNAs, downstream of IFN-signaling, have a role in mediating broad antiviral resistance. By performing an integrative, systematic, global analysis of RNA turnover utilizing 4-thiouridine labeling of newly transcribed RNA and pri/pre-miRNA in IFN-activated macrophages, we identify a new post-transcriptional viral defense mechanism mediated by miR-342-5p. On the basis of ChIP and site-directed promoter mutagenesis experiments, we find the synthesis of miR-342-5p is coupled to the antiviral IFN response via the IFN-induced transcription factor, IRF1. Strikingly, we find miR-342-5p targets mevalonate-sterol biosynthesis using a multihit mechanism suppressing the pathway at different functional levels: transcriptionally via SREBF2, post-transcriptionally via miR-33, and enzymatically via IDI1 and SC4MOL. Mass spectrometry-based lipidomics and enzymatic assays demonstrate the targeting mechanisms reduce intermediate sterol pathway metabolites and total cholesterol in macrophages. These results reveal a previously unrecognized mechanism by which IFN regulates the sterol pathway. The sterol pathway is known to be an integral part of the macrophage IFN antiviral response, and we show that miR-342-5p exerts broad antiviral effects against multiple, unrelated pathogenic viruses such Cytomegalovirus and Influenza A (H1N1). Metabolic rescue experiments confirm the specificity of these effects and demonstrate that unrelated viruses have differential mevalonate and sterol pathway requirements for their replication. This study, therefore, advances the general concept of broad antiviral defense through multihit targeting of a single host pathway.

  10. Design of indirect solid-phase immunosorbent methods for detecting arenavirus antigens and antibodies

    Energy Technology Data Exchange (ETDEWEB)

    Ivanov, A.P.; Rezapkin, G.V.; Dzagurova, T.K.; Tkachenko, E.A.

    1984-05-01

    Specifications have been elaborated for formulating indirect solid-phase enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (SPRIA) methods that employ anti-human and anti-mice G class immunoglobulin (IgG), conjugated with horseradish peroxidase and /sup 125/I for detecting the arenaviruses Junin, Machupo, Tacaribe, Amalpari, Tamiami, Lassa, and LCM (lymphocytic choriomeningitis). These methods make it possible to identify with a high degree of sensitivity arenavirus antigens and antibodies in various kinds of material.

  11. Arenavirus Coinfections Are Common in Snakes with Boid Inclusion Body Disease

    Science.gov (United States)

    Salmenperä, P.; Sironen, T.; Hetzel, U.; Korzyukov, Y.; Kipar, A.; Vapalahti, O.

    2015-01-01

    Recently, novel arenaviruses were found in snakes with boid inclusion body disease (BIBD); these form the new genus Reptarenavirus within the family Arenaviridae. We used next-generation sequencing and de novo sequence assembly to investigate reptarenavirus isolates from our previous study. Four of the six isolates and all of the samples from snakes with BIBD contained at least two reptarenavirus species. The viruses sequenced comprise four novel reptarenavirus species and a representative of a new arenavirus genus. PMID:26041290

  12. New World Arenavirus Clade C, but Not Clade A and B Viruses, Utilizes α-Dystroglycan as Its Major Receptor

    OpenAIRE

    Spiropoulou, Christina F.; Kunz, Stefan; Rollin, Pierre E.; Campbell, Kevin P; Oldstone, Michael B. A.

    2002-01-01

    α-Dystroglycan (α-DG) has been identified as a major receptor for lymphocytic choriomeningitis virus (LCMV) and Lassa virus, two Old World arenaviruses. The situation with New World arenaviruses is less clear: previous studies demonstrated that Oliveros virus also exhibited high-affinity binding to α-DG but that Guanarito virus did not. To extend these initial studies, several additional Old and New World arenaviruses were screened for entry into mouse embryonic stem cells possessing or lacki...

  13. Principal host relationships and evolutionary history of the North American arenaviruses.

    Science.gov (United States)

    Cajimat, Maria N B; Milazzo, Mary Louise; Hess, Barry D; Rood, Michael P; Fulhorst, Charles F

    2007-10-25

    A previous study suggested that the genomes of the arenaviruses native to North America are a product of genetic recombination between New World arenaviruses with significantly different phylogenetic histories. The purpose of this study was to extend our knowledge of the principal host relationships and evolutionary history of the North American arenaviruses. The results of this study suggest that the large-eared woodrat (Neotoma macrotis) is a principal host of Bear Canyon virus and that the present-day association of Bear Canyon virus with the California mouse (Peromyscus californicus) in southern California represents a successful host-jumping event from the large-eared woodrat to the California mouse. Together, the results of analyses of viral gene sequence data in this study and our knowledge of the phylogeography of the rodents that serve as principal hosts of the New World arenaviruses suggest that genetic recombination between arenaviruses with significantly different phylogenetic histories did not play a role in the evolution of the North American arenaviruses.

  14. Chapare virus, a newly discovered arenavirus isolated from a fatal hemorrhagic fever case in Bolivia.

    Directory of Open Access Journals (Sweden)

    Simon Delgado

    2008-04-01

    Full Text Available A small focus of hemorrhagic fever (HF cases occurred near Cochabamba, Bolivia, in December 2003 and January 2004. Specimens were available from only one fatal case, which had a clinical course that included fever, headache, arthralgia, myalgia, and vomiting with subsequent deterioration and multiple hemorrhagic signs. A non-cytopathic virus was isolated from two of the patient serum samples, and identified as an arenavirus by IFA staining with a rabbit polyvalent antiserum raised against South American arenaviruses known to be associated with HF (Guanarito, Machupo, and Sabiá. RT-PCR analysis and subsequent analysis of the complete virus S and L RNA segment sequences identified the virus as a member of the New World Clade B arenaviruses, which includes all the pathogenic South American arenaviruses. The virus was shown to be most closely related to Sabiá virus, but with 26% and 30% nucleotide difference in the S and L segments, and 26%, 28%, 15% and 22% amino acid differences for the L, Z, N, and GP proteins, respectively, indicating the virus represents a newly discovered arenavirus, for which we propose the name Chapare virus. In conclusion, two different arenaviruses, Machupo and Chapare, can be associated with severe HF cases in Bolivia.

  15. Use of recombinant adenovirus vectored consensus IFN-α to avert severe arenavirus infection.

    Directory of Open Access Journals (Sweden)

    Brian B Gowen

    Full Text Available Several arenaviruses can cause viral hemorrhagic fever, a severe disease with case-fatality rates in hospitalized individuals ranging from 15-30%. Because of limited prophylaxis and treatment options, new medical countermeasures are needed for these viruses classified by the National Institutes of Allergy and Infectious Diseases (NIAID as top priority biodefense Category A pathogens. Recombinant consensus interferon alpha (cIFN-α is a licensed protein with broad clinical appeal. However, while cIFN-α has great therapeutic value, its utility for biodefense applications is hindered by its short in vivo half-life, mode and frequency of administration, and costly production. To address these limitations, we describe the use of DEF201, a replication-deficient adenovirus vector that drives the expression of cIFN-α, for pre- and post-exposure prophylaxis of acute arenaviral infection modeled in hamsters. Intranasal administration of DEF201 24 h prior to challenge with Pichindé virus (PICV was highly effective at protecting animals from mortality and preventing viral replication and liver-associated disease. A significant protective effect was still observed with a single dosing of DEF201 given two weeks prior to PICV challenge. DEF201 was also efficacious when administered as a treatment 24 to 48 h post-virus exposure. The protective effect of DEF201 was largely attributed to the expression of cIFN-α, as dosing with a control empty vector adenovirus did not protect hamsters from lethal PICV challenge. Effective countermeasures that are highly stable, easily administered, and elicit long lasting protective immunity are much needed for arena and other viral infections. The DEF201 technology has the potential to address all of these issues and may serve as a broad-spectrum antiviral to enhance host defense against a number of viral pathogens.

  16. The 2010 Broad Prize

    Science.gov (United States)

    Education Digest: Essential Readings Condensed for Quick Review, 2011

    2011-01-01

    A new data analysis, based on data collected as part of The Broad Prize process, provides insights into which large urban school districts in the United States are doing the best job of educating traditionally disadvantaged groups: African-American, Hispanics, and low-income students. Since 2002, The Eli and Edythe Broad Foundation has awarded The…

  17. Serological Assays Based on Recombinant Viral Proteins for the Diagnosis of Arenavirus Hemorrhagic Fevers

    Directory of Open Access Journals (Sweden)

    Masayuki Saijo

    2012-10-01

    Full Text Available The family Arenaviridae, genus Arenavirus, consists of two phylogenetically independent groups: Old World (OW and New World (NW complexes. The Lassa and Lujo viruses in the OW complex and the Guanarito, Junin, Machupo, Sabia, and Chapare viruses in the NW complex cause viral hemorrhagic fever (VHF in humans, leading to serious public health concerns. These viruses are also considered potential bioterrorism agents. Therefore, it is of great importance to detect these pathogens rapidly and specifically in order to minimize the risk and scale of arenavirus outbreaks. However, these arenaviruses are classified as BSL-4 pathogens, thus making it difficult to develop diagnostic techniques for these virus infections in institutes without BSL-4 facilities. To overcome these difficulties, antibody detection systems in the form of an enzyme-linked immunosorbent assay (ELISA and an indirect immunofluorescence assay were developed using recombinant nucleoproteins (rNPs derived from these viruses. Furthermore, several antigen-detection assays were developed. For example, novel monoclonal antibodies (mAbs to the rNPs of Lassa and Junin viruses were generated. Sandwich antigen-capture (Ag-capture ELISAs using these mAbs as capture antibodies were developed and confirmed to be sensitive and specific for detecting the respective arenavirus NPs. These rNP-based assays were proposed to be useful not only for an etiological diagnosis of VHFs, but also for seroepidemiological studies on VHFs. We recently developed arenavirus neutralization assays using vesicular stomatitis virus (VSV-based pseudotypes bearing arenavirus recombinant glycoproteins. The goal of this article is to review the recent advances in developing laboratory diagnostic assays based on recombinant viral proteins for the diagnosis of VHFs and epidemiological studies on the VHFs caused by arenaviruses.

  18. Serological assays based on recombinant viral proteins for the diagnosis of arenavirus hemorrhagic fevers.

    Science.gov (United States)

    Fukushi, Shuetsu; Tani, Hideki; Yoshikawa, Tomoki; Saijo, Masayuki; Morikawa, Shigeru

    2012-10-12

    The family Arenaviridae, genus Arenavirus, consists of two phylogenetically independent groups: Old World (OW) and New World (NW) complexes. The Lassa and Lujo viruses in the OW complex and the Guanarito, Junin, Machupo, Sabia, and Chapare viruses in the NW complex cause viral hemorrhagic fever (VHF) in humans, leading to serious public health concerns. These viruses are also considered potential bioterrorism agents. Therefore, it is of great importance to detect these pathogens rapidly and specifically in order to minimize the risk and scale of arenavirus outbreaks. However, these arenaviruses are classified as BSL-4 pathogens, thus making it difficult to develop diagnostic techniques for these virus infections in institutes without BSL-4 facilities. To overcome these difficulties, antibody detection systems in the form of an enzyme-linked immunosorbent assay (ELISA) and an indirect immunofluorescence assay were developed using recombinant nucleoproteins (rNPs) derived from these viruses. Furthermore, several antigen-detection assays were developed. For example, novel monoclonal antibodies (mAbs) to the rNPs of Lassa and Junin viruses were generated. Sandwich antigen-capture (Ag-capture) ELISAs using these mAbs as capture antibodies were developed and confirmed to be sensitive and specific for detecting the respective arenavirus NPs. These rNP-based assays were proposed to be useful not only for an etiological diagnosis of VHFs, but also for seroepidemiological studies on VHFs. We recently developed arenavirus neutralization assays using vesicular stomatitis virus (VSV)-based pseudotypes bearing arenavirus recombinant glycoproteins. The goal of this article is to review the recent advances in developing laboratory diagnostic assays based on recombinant viral proteins for the diagnosis of VHFs and epidemiological studies on the VHFs caused by arenaviruses.

  19. Novel arenavirus sequences in Hylomyscus sp. and Mus (Nannomys setulosus from Cote d'Ivoire: implications for evolution of arenaviruses in Africa.

    Directory of Open Access Journals (Sweden)

    David Coulibaly-N'Golo

    Full Text Available This study aimed to identify new arenaviruses and gather insights in the evolution of arenaviruses in Africa. During 2003 through 2005, 1,228 small mammals representing 14 different genera were trapped in 9 villages in south, east, and middle west of Côte d'Ivoire. Specimens were screened by pan-Old World arenavirus RT-PCRs targeting S and L RNA segments as well as immunofluorescence assay. Sequences of two novel tentative species of the family Arenaviridae, Menekre and Gbagroube virus, were detected in Hylomyscus sp. and Mus (Nannomys setulosus, respectively. Arenavirus infection of Mus (Nannomys setulosus was also demonstrated by serological testing. Lassa virus was not found, although 60% of the captured animals were Mastomys natalensis. Complete S RNA and partial L RNA sequences of the novel viruses were recovered from the rodent specimens and subjected to phylogenetic analysis. Gbagroube virus is a closely related sister taxon of Lassa virus, while Menekre virus clusters with the Ippy/Mobala/Mopeia virus complex. Reconstruction of possible virus-host co-phylogeny scenarios suggests that, within the African continent, signatures of co-evolution might have been obliterated by multiple host-switching events.

  20. Prevalence of antibodies to arenaviruses in rodents from the southern and western United States: evidence for an arenavirus associated with the genus Neotoma.

    Science.gov (United States)

    Kosoy, M Y; Elliott, L H; Ksiazek, T G; Fulhorst, C F; Rollin, P E; Childs, J E; Mills, J N; Maupin, G O; Peters, C J

    1996-06-01

    The objectives of this study were to extend our knowledge of the geographic distribution and rodent host range of arenaviruses in North America. Sera from wild rodents collected from the southern and western United States were tested for antibody against Tamiami, Pichinde, Junin, and lymphocytic choriomeningitis viruses, using an indirect fluorescent antibody test. Antibody to at least one arenavirus was found in 220 (3.1%) of 7,106 rodents tested. The antibody-positive animals included Mus musculus from Florida and Texas; Neotoma albigula from Arizona, Colorado, and New Mexico; N. fuscipes and N. lepida from California: N. mexicana from Arizona, New Mexico, and Utah; N. stephensi from Arizona and New Mexico; and Oryzomys palustris and Sigmodon hispidus from Florida. Sigmodon hispidus seropositive for Tamiami virus were found only in Florida (156 [27.0%] of 578 tested), although 463 hispid cotton rats from outside that state were examined. High-titered antibodies to Tamiami virus were present in sera from S. hispidus, (geometric mean antibody titer [GMAT] of 1:792), whereas sera from Neotoma spp. reacted at high titer to both Tamiami (GMAT = 1:905) and Pichinde (GMAT = 1:433) viruses. The results suggest that arenaviruses are widely distributed in the southern United States and that one or more indigenous arenaviruses are associated with Neotoma spp. in North America.

  1. Novel arenavirus sequences in Hylomyscus sp. and Mus (Nannomys) setulosus from Côte d'Ivoire: implications for evolution of arenaviruses in Africa.

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    Coulibaly-N'Golo, David; Allali, Bernard; Kouassi, Stéphane K; Fichet-Calvet, Elisabeth; Becker-Ziaja, Beate; Rieger, Toni; Olschläger, Stephan; Dosso, Hernri; Denys, Christiane; Ter Meulen, Jan; Akoua-Koffi, Chantal; Günther, Stephan

    2011-01-01

    This study aimed to identify new arenaviruses and gather insights in the evolution of arenaviruses in Africa. During 2003 through 2005, 1,228 small mammals representing 14 different genera were trapped in 9 villages in south, east, and middle west of Côte d'Ivoire. Specimens were screened by pan-Old World arenavirus RT-PCRs targeting S and L RNA segments as well as immunofluorescence assay. Sequences of two novel tentative species of the family Arenaviridae, Menekre and Gbagroube virus, were detected in Hylomyscus sp. and Mus (Nannomys) setulosus, respectively. Arenavirus infection of Mus (Nannomys) setulosus was also demonstrated by serological testing. Lassa virus was not found, although 60% of the captured animals were Mastomys natalensis. Complete S RNA and partial L RNA sequences of the novel viruses were recovered from the rodent specimens and subjected to phylogenetic analysis. Gbagroube virus is a closely related sister taxon of Lassa virus, while Menekre virus clusters with the Ippy/Mobala/Mopeia virus complex. Reconstruction of possible virus-host co-phylogeny scenarios suggests that, within the African continent, signatures of co-evolution might have been obliterated by multiple host-switching events.

  2. Drug discovery technologies and strategies for Machupo virus and other New World arenaviruses

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    Radoshitzky, Sheli R.; Kuhn, Jens H.; de Kok-Mercado, Fabian; Jahrling, Peter B.; Bavari, Sina

    2012-01-01

    Introduction Seven arenaviruses cause viral hemorrhagic fever in humans: the Old World arenaviruses Lassa and Lujo, and the New World Clade B arenaviruses Machupo (MACV), Junín (JUNV), Guanarito (GTOV), Sabiá (SABV), and Chapare (CHPV). All of these viruses are Risk Group 4 biosafety pathogens. MACV causes human disease outbreak with high case-fatality rates. To date, at least 1,200 cases with ≈200 fatalities have been recorded 1, 2. Areas covered This review summarizes available systems and technologies for the identification of antivirals against MACV, animal models for in vivo evaluation of novel inhibitors, present treatment of arenaviral diseases, overview of efficacious small molecules and other therapeutics reported to date, and strategies to identify novel inhibitors for anti-arenaviral therapy. Expert opinion New high-throughput approaches to quantitate infection rates of areaviruses, as well as viruses modified to carry reporter genes, will accelerate compound screens and drug discovery efforts. RNAi, gene expression profiling and proteomics studies will identify host targets for therapeutic intervention. New discoveries in the cell entry mechanism of MACV and other arenaviruses as well as extensive structural studies of arenaviral L and NP could facilitate the rational design of antivirals effective against all pathogenic New World arenaviruses. PMID:22607481

  3. Transferrin receptor 1 in the zoonosis and pathogenesis of New World hemorrhagic fever arenaviruses.

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    Choe, Hyeryun; Jemielity, Stephanie; Abraham, Jonathan; Radoshitzky, Sheli R; Farzan, Michael

    2011-08-01

    At least five New World arenaviruses cause severe human hemorrhagic fevers. These viruses are transmitted to humans through contact with their respective South American rodent hosts. Each uses human transferrin receptor 1 (TfR1) as its obligate receptor. Accidental similarities between human TfR1 and TfR1 orthologs of arenaviral host species enable zoonoses, whereas mice and rats are not infectable because they lack these TfR1 determinants of infection. All pathogenic New World arenaviruses bind to a common region of the apical domain of TfR1. The ability of a New World arenavirus to use human TfR1 is absolutely predictive of its ability to cause hemorrhagic fevers in humans. Nonpathogenic arenaviruses, closely related to hemorrhagic fever arenaviruses, cannot utilize human TfR1 but efficiently enter cells through TfR1 orthologs of their native rodent hosts. Mutagenesis studies suggest that minor changes in the entry glycoproteins of these nonpathogenic viruses may allow human transmission. TfR1 is upregulated as a result of iron sequestration during the acute-phase response to infection, and the severity of disease may result from amplification of viral replication during this response.

  4. Structural basis for receptor recognition by New World hemorrhagic fever arenaviruses

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    Abraham, Jonathan; Corbett, Kevin D.; Farzan, Michael; Choe, Hyeryun; Harrison, Stephen C. (Harvard-Med)

    2010-08-18

    New World hemorrhagic fever arenaviruses are rodent-borne agents that cause severe human disease. The GP1 subunit of the surface glycoprotein mediates cell attachment through transferrin receptor 1 (TfR1). We report the structure of Machupo virus (MACV) GP1 bound with human TfR1. Atomic details of the GP1-TfR1 interface clarify the importance of TfR1 residues implicated in New World arenavirus host specificity. Analysis of sequence variation among New World arenavirus GP1s and their host-species receptors, in light of the molecular structure, indicates determinants of viral zoonotic transmission. Infectivities of pseudoviruses in cells expressing mutated TfR1 confirm that contacts at the tip of the TfR1 apical domain determine the capacity of human TfR1 to mediate infection by particular New World arenaviruses. We propose that New World arenaviruses that are pathogenic to humans fortuitously acquired affinity for human TfR1 during adaptation to TfR1 of their natural hosts.

  5. Inhibition of Innate Immune Responses Is Key to Pathogenesis by Arenaviruses.

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    Meyer, Bjoern; Ly, Hinh

    2016-04-01

    Mammalian arenaviruses are zoonotic viruses that cause asymptomatic, persistent infections in their rodent hosts but can lead to severe and lethal hemorrhagic fever with bleeding and multiorgan failure in human patients. Lassa virus (LASV), for example, is endemic in several West African countries, where it is responsible for an estimated 500,000 infections and 5,000 deaths annually. There are currently no FDA-licensed therapeutics or vaccines available to combat arenavirus infection. A hallmark of arenavirus infection (e.g., LASV) is general immunosuppression that contributes to high viremia. Here, we discuss the early host immune responses to arenavirus infection and the recently discovered molecular mechanisms that enable pathogenic viruses to suppress host immune recognition and to contribute to the high degree of virulence. We also directly compare the innate immune evasion mechanisms between arenaviruses and other hemorrhagic fever-causing viruses, such as Ebola, Marburg, Dengue, and hantaviruses. A better understanding of the immunosuppression and immune evasion strategies of these deadly viruses may guide the development of novel preventative and therapeutic options.

  6. Molecular surveillance and phylogenetic analysis of Old World arenaviruses in Zambia.

    Science.gov (United States)

    Ishii, Akihiro; Thomas, Yuka; Moonga, Ladslav; Nakamura, Ichiro; Ohnuma, Aiko; Hang'ombe, Bernard M; Takada, Ayato; Mweene, Aaron S; Sawa, Hirofumi

    2012-10-01

    In order to survey arenaviruses in the Republic of Zambia, we captured 335 rodents from three cities between 2010 and 2011. Eighteen Luna virus (LUNV) and one lymphocytic choriomeningitis virus (LCMV)-related virus RNAs were detected by one-step RT-PCR from Mastomys natalensis and Mus minutoides, respectively. Four LUNV strains and one LCMV-related virus were isolated, and the whole genome nucleotide sequence was determined by pyrosequencing. Phylogenetic analyses revealed that the LUNV clade consists of two branches that are distinguished by geographical location and that the LCMV-related virus belongs to the LCMV clade, but diverges from the typical LCMVs. Comparison of nucleoprotein amino acid sequences indicated that the LCMV-related virus could be designated a novel arenavirus, which was tentatively named as the Lunk virus. Amino acid sequences of the GP, NP, Z and L proteins showed poor similarity among the three Zambian arenavirus strains, i.e. Luna, Lunk and Lujo virus.

  7. Envelope exchange for the generation of live-attenuated arenavirus vaccines.

    Directory of Open Access Journals (Sweden)

    Andreas Bergthaler

    2006-06-01

    Full Text Available Arenaviruses such as Lassa fever virus cause significant mortality in endemic areas and represent potential bioterrorist weapons. The occurrence of arenaviral hemorrhagic fevers is largely confined to Third World countries with a limited medical infrastructure, and therefore live-attenuated vaccines have long been sought as a method of choice for prevention. Yet their rational design and engineering have been thwarted by technical limitations. In addition, viral genes had not been identified that are needed to cause disease but can be deleted or substituted to generate live-attenuated vaccine strains. Lymphocytic choriomeningitis virus, the prototype arenavirus, induces cell-mediated immunity against Lassa fever virus, but its safety for humans is unclear and untested. Using this virus model, we have developed the necessary methodology to efficiently modify arenavirus genomes and have exploited these techniques to identify an arenaviral Achilles' heel suitable for targeting in vaccine design. Reverse genetic exchange of the viral glycoprotein for foreign glycoproteins created attenuated vaccine strains that remained viable although unable to cause disease in infected mice. This phenotype remained stable even after extensive propagation in immunodeficient hosts. Nevertheless, the engineered viruses induced T cell-mediated immunity protecting against overwhelming systemic infection and severe liver disease upon wild-type virus challenge. Protection was established within 3 to 7 d after immunization and lasted for approximately 300 d. The identification of an arenaviral Achilles' heel demonstrates that the reverse genetic engineering of live-attenuated arenavirus vaccines is feasible. Moreover, our findings offer lymphocytic choriomeningitis virus or other arenaviruses expressing foreign glycoproteins as promising live-attenuated arenavirus vaccine candidates.

  8. Envelope Exchange for the Generation of Live-Attenuated Arenavirus Vaccines.

    Directory of Open Access Journals (Sweden)

    2006-06-01

    Full Text Available Arenaviruses such as Lassa fever virus cause significant mortality in endemic areas and represent potential bioterrorist weapons. The occurrence of arenaviral hemorrhagic fevers is largely confined to Third World countries with a limited medical infrastructure, and therefore live-attenuated vaccines have long been sought as a method of choice for prevention. Yet their rational design and engineering have been thwarted by technical limitations. In addition, viral genes had not been identified that are needed to cause disease but can be deleted or substituted to generate live-attenuated vaccine strains. Lymphocytic choriomeningitis virus, the prototype arenavirus, induces cell-mediated immunity against Lassa fever virus, but its safety for humans is unclear and untested. Using this virus model, we have developed the necessary methodology to efficiently modify arenavirus genomes and have exploited these techniques to identify an arenaviral Achilles' heel suitable for targeting in vaccine design. Reverse genetic exchange of the viral glycoprotein for foreign glycoproteins created attenuated vaccine strains that remained viable although unable to cause disease in infected mice. This phenotype remained stable even after extensive propagation in immunodeficient hosts. Nevertheless, the engineered viruses induced T cell-mediated immunity protecting against overwhelming systemic infection and severe liver disease upon wild-type virus challenge. Protection was established within 3 to 7 d after immunization and lasted for approximately 300 d. The identification of an arenaviral Achilles' heel demonstrates that the reverse genetic engineering of live-attenuated arenavirus vaccines is feasible. Moreover, our findings offer lymphocytic choriomeningitis virus or other arenaviruses expressing foreign glycoproteins as promising live-attenuated arenavirus vaccine candidates.

  9. Pathogenic Mechanisms Involved in the Hematological Alterations of Arenavirus-induced Hemorrhagic Fevers

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    Roberto G. Pozner

    2013-01-01

    Full Text Available Viral hemorrhagic fevers (VHFs caused by arenaviruses are acute diseases characterized by fever, headache, general malaise, impaired cellular immunity, eventual neurologic involvement, and hemostatic alterations that may ultimately lead to shock and death. The causes of the bleeding are still poorly understood. However, it is generally accepted that these causes are associated to some degree with impaired hemostasis, endothelial cell dysfunction and low platelet counts or function. In this article, we present the current knowledge about the hematological alterations present in VHF induced by arenaviruses, including new aspects on the underlying pathogenic mechanisms.

  10. Pathogenic mechanisms involved in the hematological alterations of arenavirus-induced hemorrhagic fevers.

    Science.gov (United States)

    Schattner, Mirta; Rivadeneyra, Leonardo; Pozner, Roberto G; Gómez, Ricardo M

    2013-01-21

    Viral hemorrhagic fevers (VHFs) caused by arenaviruses are acute diseases characterized by fever, headache, general malaise, impaired cellular immunity, eventual neurologic involvement, and hemostatic alterations that may ultimately lead to shock and death. The causes of the bleeding are still poorly understood. However, it is generally accepted that these causes are associated to some degree with impaired hemostasis, endothelial cell dysfunction and low platelet counts or function. In this article, we present the current knowledge about the hematological alterations present in VHF induced by arenaviruses, including new aspects on the underlying pathogenic mechanisms.

  11. Arenavirus budding: a common pathway with mechanistic differences.

    Science.gov (United States)

    Wolff, Svenja; Ebihara, Hideki; Groseth, Allison

    2013-01-31

    The Arenaviridae is a diverse and growing family of viruses that includes several agents responsible for important human diseases. Despite the importance of this family for public health, particularly in Africa and South America, much of its biology remains poorly understood. However, in recent years significant progress has been made in this regard, particularly relating to the formation and release of new enveloped virions, which is an essential step in the viral lifecycle. While this process is mediated chiefly by the viral matrix protein Z, recent evidence suggests that for some viruses the nucleoprotein (NP) is also required to enhance the budding process. Here we highlight and compare the distinct budding mechanisms of different arenaviruses, concentrating on the role of the matrix protein Z, its known late domain sequences, and the involvement of cellular endosomal sorting complex required for transport (ESCRT) pathway components. Finally we address the recently described roles for the nucleoprotein NP in budding and ribonucleoprotein complex (RNP) incorporation, as well as discussing possible mechanisms related to its involvement.

  12. Arenavirus Budding: A Common Pathway with Mechanistic Differences

    Directory of Open Access Journals (Sweden)

    Svenja Wolff

    2013-01-01

    Full Text Available The Arenaviridae is a diverse and growing family of viruses that includes several agents responsible for important human diseases. Despite the importance of this family for public health, particularly in Africa and South America, much of its biology remains poorly understood. However, in recent years significant progress has been made in this regard, particularly relating to the formation and release of new enveloped virions, which is an essential step in the viral lifecycle. While this process is mediated chiefly by the viral matrix protein Z, recent evidence suggests that for some viruses the nucleoprotein (NP is also required to enhance the budding process. Here we highlight and compare the distinct budding mechanisms of different arenaviruses, concentrating on the role of the matrix protein Z, its known late domain sequences, and the involvement of cellular endosomal sorting complex required for transport (ESCRT pathway components. Finally we address the recently described roles for the nucleoprotein NP in budding and ribonucleoprotein complex (RNP incorporation, as well as discussing possible mechanisms related to its involvement.

  13. Coverage of related pathogenic species by multivalent and cross-protective vaccine design: arenaviruses as a model system.

    Science.gov (United States)

    Botten, Jason; Sidney, John; Mothé, Bianca R; Peters, Bjoern; Sette, Alessandro; Kotturi, Maya F

    2010-06-01

    The arenaviruses are a family of negative-sense RNA viruses that cause severe human disease ranging from aseptic meningitis to hemorrhagic fever syndromes. There are currently no FDA-approved vaccines for the prevention of arenavirus disease, and therapeutic treatment is limited to the use of ribavirin and/or immune plasma for a subset of the pathogenic arenaviruses. The considerable genetic variability observed among the seven arenaviruses that are pathogenic for humans illustrates one of the major challenges for vaccine development today, namely, to overcome pathogen heterogeneity. Over the past 5 years, our group has tested several strategies to overcome pathogen heterogeneity, utilizing the pathogenic arenaviruses as a model system. Because T cells play a prominent role in protective immunity following arenavirus infection, we specifically focused on the development of human vaccines that would induce multivalent and cross-protective cell-mediated immune responses. To facilitate our vaccine development and testing, we conducted large-scale major histocompatibility complex (MHC) class I and class II epitope discovery on murine, nonhuman primate, and human backgrounds for each of the pathogenic arenaviruses, including the identification of protective HLA-restricted epitopes. Finally, using the murine model of lymphocytic choriomeningitis virus infection, we studied the phenotypic characteristics associated with immunodominant and protective T cell epitopes. This review summarizes the findings from our studies and discusses their application to future vaccine design.

  14. Old world arenaviruses enter the host cell via the multivesicular body and depend on the endosomal sorting complex required for transport.

    Science.gov (United States)

    Pasqual, Giulia; Rojek, Jillian M; Masin, Mark; Chatton, Jean-Yves; Kunz, Stefan

    2011-09-01

    The highly pathogenic Old World arenavirus Lassa virus (LASV) and the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) use α-dystroglycan as a cellular receptor and enter the host cell by an unusual endocytotic pathway independent of clathrin, caveolin, dynamin, and actin. Upon internalization, the viruses are delivered to acidified endosomes in a Rab5-independent manner bypassing classical routes of incoming vesicular trafficking. Here we sought to identify cellular factors involved in the unusual and largely unknown entry pathway of LASV and LCMV. Cell entry of LASV and LCMV required microtubular transport to late endosomes, consistent with the low fusion pH of the viral envelope glycoproteins. Productive infection with recombinant LCMV expressing LASV envelope glycoprotein (rLCMV-LASVGP) and LCMV depended on phosphatidyl inositol 3-kinase (PI3K) as well as lysobisphosphatidic acid (LBPA), an unusual phospholipid that is involved in the formation of intraluminal vesicles (ILV) of the multivesicular body (MVB) of the late endosome. We provide evidence for a role of the endosomal sorting complex required for transport (ESCRT) in LASV and LCMV cell entry, in particular the ESCRT components Hrs, Tsg101, Vps22, and Vps24, as well as the ESCRT-associated ATPase Vps4 involved in fission of ILV. Productive infection with rLCMV-LASVGP and LCMV also critically depended on the ESCRT-associated protein Alix, which is implicated in membrane dynamics of the MVB/late endosomes. Our study identifies crucial cellular factors implicated in Old World arenavirus cell entry and indicates that LASV and LCMV invade the host cell passing via the MVB/late endosome. Our data further suggest that the virus-receptor complexes undergo sorting into ILV of the MVB mediated by the ESCRT, possibly using a pathway that may be linked to the cellular trafficking and degradation of the cellular receptor.

  15. Old world arenaviruses enter the host cell via the multivesicular body and depend on the endosomal sorting complex required for transport.

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    Giulia Pasqual

    2011-09-01

    Full Text Available The highly pathogenic Old World arenavirus Lassa virus (LASV and the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV use α-dystroglycan as a cellular receptor and enter the host cell by an unusual endocytotic pathway independent of clathrin, caveolin, dynamin, and actin. Upon internalization, the viruses are delivered to acidified endosomes in a Rab5-independent manner bypassing classical routes of incoming vesicular trafficking. Here we sought to identify cellular factors involved in the unusual and largely unknown entry pathway of LASV and LCMV. Cell entry of LASV and LCMV required microtubular transport to late endosomes, consistent with the low fusion pH of the viral envelope glycoproteins. Productive infection with recombinant LCMV expressing LASV envelope glycoprotein (rLCMV-LASVGP and LCMV depended on phosphatidyl inositol 3-kinase (PI3K as well as lysobisphosphatidic acid (LBPA, an unusual phospholipid that is involved in the formation of intraluminal vesicles (ILV of the multivesicular body (MVB of the late endosome. We provide evidence for a role of the endosomal sorting complex required for transport (ESCRT in LASV and LCMV cell entry, in particular the ESCRT components Hrs, Tsg101, Vps22, and Vps24, as well as the ESCRT-associated ATPase Vps4 involved in fission of ILV. Productive infection with rLCMV-LASVGP and LCMV also critically depended on the ESCRT-associated protein Alix, which is implicated in membrane dynamics of the MVB/late endosomes. Our study identifies crucial cellular factors implicated in Old World arenavirus cell entry and indicates that LASV and LCMV invade the host cell passing via the MVB/late endosome. Our data further suggest that the virus-receptor complexes undergo sorting into ILV of the MVB mediated by the ESCRT, possibly using a pathway that may be linked to the cellular trafficking and degradation of the cellular receptor.

  16. Use of single-cycle infectious lymphocytic choriomeningitis virus to study hemorrhagic fever arenaviruses.

    Science.gov (United States)

    Rodrigo, W W Shanaka I; de la Torre, Juan C; Martínez-Sobrido, Luis

    2011-02-01

    Several arenaviruses, chiefly Lassa virus (LASV) and Junin virus in West Africa and Argentina, respectively, cause hemorrhagic fever (HF) disease in humans that is associated with high morbidity and significant mortality. The investigation of antiviral strategies to combat HF arenaviruses is hampered by the requirement of biosafety level 4 (BSL-4) facilities to work with these viruses. These biosafety hurdles could be overcome by the use of recombinant single-cycle infectious arenaviruses. To explore this concept, we have developed a recombinant lymphocytic choriomeningitis virus (LCMV) (rLCMVΔGP/GFP) where we replaced the viral glycoprotein (GP) with the green fluorescent protein (GFP). We generated high titers of GP-pseudotyped rLCMVΔGP/GFP via genetic trans complementation using stable cell lines that constitutively express LCMV or LASV GPs. Replication of these GP-pseudotyped rLCMVΔGP/GFP viruses was restricted to GP-expressing cell lines. This system allowed us to rapidly and reliably characterize and quantify the neutralization activities of serum antibodies against LCMV and LASV within a BSL-2 facility. The sensitivity of the GFP-based microneutralization assay we developed was similar to that obtained with a conventionally used focus reduction neutralization (FRNT) assay. Using GP-pseudotyped rLCMVΔGP/GFP, we have also obtained evidence supporting the feasibility of this approach to identify and evaluate candidate antiviral drugs against HF arenaviruses without the need of BSL-4 laboratories.

  17. Human Hemorrhagic Fever Causing Arenaviruses: Molecular Mechanisms Contributing to Virus Virulence and Disease Pathogenesis

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    Junjie Shao

    2015-05-01

    Full Text Available Arenaviruses include multiple human pathogens ranging from the low-risk lymphocytic choriomeningitis virus (LCMV to highly virulent hemorrhagic fever (HF causing viruses such as Lassa (LASV, Junin (JUNV, Machupo (MACV, Lujo (LUJV, Sabia (SABV, Guanarito (GTOV, and Chapare (CHPV, for which there are limited preventative and therapeutic measures. Why some arenaviruses can cause virulent human infections while others cannot, even though they are isolated from the same rodent hosts, is an enigma. Recent studies have revealed several potential pathogenic mechanisms of arenaviruses, including factors that increase viral replication capacity and suppress host innate immunity, which leads to high viremia and generalized immune suppression as the hallmarks of severe and lethal arenaviral HF diseases. This review summarizes current knowledge of the roles of each of the four viral proteins and some known cellular factors in the pathogenesis of arenaviral HF as well as of some human primary cell-culture and animal models that lend themselves to studying arenavirus-induced HF disease pathogenesis. Knowledge gained from these studies can be applied towards the development of novel therapeutics and vaccines against these deadly human pathogens.

  18. Vaccination strategies against highly pathogenic arenaviruses: the next steps toward clinical trials.

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    Stephan Olschläger

    Full Text Available Vaccination is one of the most valuable weapons against infectious diseases and has led to a significant reduction in mortality and morbidity. However, for most viral hemorrhagic fevers caused by arenaviruses, no prophylactic vaccine is available. This is particularly problematic as these diseases are notoriously difficult to diagnose and treat. Lassa fever is globally the most important of the fevers caused by arenaviruses, potentially affecting millions of people living in endemic areas, particularly in Nigeria. Annually, an estimated 300,000 humans are infected and several thousands succumb to the disease. The successful development of the vaccine "Candid#1" against Junin virus, the causative agent of Argentine hemorrhagic fever, proved that an effective arenavirus vaccine can be developed. Although several promising studies toward the development of a Lassa fever vaccine have been published, no vaccine candidate has been tested in human volunteers or patients. This review summarizes the immunology and other aspects of existing experimental arenavirus vaccine studies, discusses the reasons for the lack of a vaccine, and proposes a plan for overcoming the final hurdles toward clinical trials.

  19. Patawa Virus, a New Arenavirus Hosted by Forest Rodents in French Guiana.

    Science.gov (United States)

    Lavergne, Anne; de Thoisy, Benoit; Donato, Damien; Guidez, Amandine; Matheus, Séverine; Catzeflis, François; Lacoste, Vincent

    2015-06-01

    Molecular screening of rodents from French Guiana has detected a new arenavirus, named "Patawa," in two Oecomys species (Muridae, Sigmodontinae). Further investigations are needed to better understand the circulation of this virus in rodent and human populations and its public health impact.

  20. Biochemical reconstitution of hemorrhagic-fever arenavirus envelope glycoprotein-mediated membrane fusion.

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    Celestine J Thomas

    Full Text Available The membrane-anchored proteins of enveloped viruses form labile spikes on the virion surface, primed to undergo large-scale conformational changes culminating in virus-cell membrane fusion and viral entry. The prefusion form of these envelope glycoproteins thus represents an important molecular target for antiviral intervention. A critical roadblock to this endeavor has been our inability to produce the prefusion envelope glycoprotein trimer for biochemical and structural analysis. Through our studies of the GPC envelope glycoprotein of the hemorrhagic fever arenaviruses, we have shown that GPC is unique among class I viral fusion proteins in that the mature complex retains a stable signal peptide (SSP in addition to the conventional receptor-binding and transmembrane fusion subunits. In this report we show that the recombinant GPC precursor can be produced as a discrete native-like trimer and that its proteolytic cleavage generates the mature glycoprotein. Proteoliposomes containing the cleaved GPC mediate pH-dependent membrane fusion, a characteristic feature of arenavirus entry. This reaction is inhibited by arenavirus-specific monoclonal antibodies and small-molecule fusion inhibitors. The in vitro reconstitution of GPC-mediated membrane-fusion activity offers unprecedented opportunities for biochemical and structural studies of arenavirus entry and its inhibition. To our knowledge, this report is the first to demonstrate functional reconstitution of membrane fusion by a viral envelope glycoprotein.

  1. Vaccination strategies against highly pathogenic arenaviruses: the next steps toward clinical trials.

    Science.gov (United States)

    Olschläger, Stephan; Flatz, Lukas

    2013-01-01

    Vaccination is one of the most valuable weapons against infectious diseases and has led to a significant reduction in mortality and morbidity. However, for most viral hemorrhagic fevers caused by arenaviruses, no prophylactic vaccine is available. This is particularly problematic as these diseases are notoriously difficult to diagnose and treat. Lassa fever is globally the most important of the fevers caused by arenaviruses, potentially affecting millions of people living in endemic areas, particularly in Nigeria. Annually, an estimated 300,000 humans are infected and several thousands succumb to the disease. The successful development of the vaccine "Candid#1" against Junin virus, the causative agent of Argentine hemorrhagic fever, proved that an effective arenavirus vaccine can be developed. Although several promising studies toward the development of a Lassa fever vaccine have been published, no vaccine candidate has been tested in human volunteers or patients. This review summarizes the immunology and other aspects of existing experimental arenavirus vaccine studies, discusses the reasons for the lack of a vaccine, and proposes a plan for overcoming the final hurdles toward clinical trials.

  2. Development of peptide-conjugated morpholino oligomers as pan-arenavirus inhibitors.

    Science.gov (United States)

    Neuman, Benjamin W; Bederka, Lydia H; Stein, David A; Ting, Joey P C; Moulton, Hong M; Buchmeier, Michael J

    2011-10-01

    Members of the Arenaviridae family are a threat to public health and can cause meningitis and hemorrhagic fever, and yet treatment options remain limited by a lack of effective antivirals. In this study, we found that peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) complementary to viral genomic RNA were effective in reducing arenavirus replication in cell cultures and in vivo. PPMO complementary to the Junín virus genome were designed to interfere with viral RNA synthesis or translation or both. However, only PPMO designed to potentially interfere with translation were effective in reducing virus replication. PPMO complementary to sequences that are highly conserved across the arenaviruses and located at the 5' termini of both genomic segments were effective against Junín virus, Tacaribe virus, Pichinde virus, and lymphocytic choriomeningitis virus (LCMV)-infected cell cultures and suppressed viral titers in the livers of LCMV-infected mice. These results suggest that arenavirus 5' genomic termini represent promising targets for pan-arenavirus antiviral therapeutic development.

  3. Novel mechanism of arenavirus-induced liver pathology.

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    Juliane I Beier

    Full Text Available Viral hemorrhagic fevers (VHFs encompass a group of diseases with cardinal symptoms of fever, hemorrhage, and shock. The liver is a critical mediator of VHF disease pathogenesis and high levels of ALT/AST transaminases in plasma correlate with poor prognosis. In fact, Lassa Fever (LF, the most prevalent VHF in Africa, was initially clinically described as hepatitis. Previous studies in non-human primate (NHP models also correlated LF pathogenesis with a robust proliferative response in the liver. The purpose of the current study was to gain insight into the mechanism of liver injury and to determine the potential role of proliferation in LF pathogenesis. C57Bl/6J mice were infected with either the pathogenic (for NHPs strain of lymphocytic choriomeningitis virus (LCMV, the prototypic arenavirus, LCMV-WE, or with the non-pathogenic strain, LCMV-ARM. As expected, LCMV-WE, but not ARM, caused a hepatitis-like infection. LCMV-WE also induced a robust increase in the number of actively cycling hepatocytes. Despite this increase in proliferation, there was no significant difference in liver size between LCMV-WE and LCMV-ARM, suggesting that cell cycle was incomplete. Indeed, cells appeared arrested in the G1 phase and LCMV-WE infection increased the number of hepatocytes that were simultaneously stained for proliferation and apoptosis. LCMV-WE infection also induced expression of a non-conventional virus receptor, AXL-1, from the TAM (TYRO3/AXL/MERTK family of receptor tyrosine kinases and this expression correlated with proliferation. Taken together, these results shed new light on the mechanism of liver involvement in VHF pathogenesis. Specifically, it is hypothesized that the induction of hepatocyte proliferation contributes to expansion of the infection to parenchymal cells. Elevated levels of plasma transaminases are likely explained, at least in part, by abortive cell cycle arrest induced by the infection. These results may lead to the

  4. Inhibition of the Type I Interferon Antiviral Response During Arenavirus Infection

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    Juan Carlos de la Torre

    2010-11-01

    Full Text Available Arenaviruses merit interest both as tractable experimental model systems to study acute and persistent viral infections, and as clinically-important human pathogens. Several arenaviruses cause hemorrhagic fever (HF disease in humans. In addition, evidence indicates that the globally-distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV is a human pathogen of clinical significance in congenital infections, and also poses a great danger to immunosuppressed individuals. Arenavirus persistence and pathogenesis are facilitated by their ability to overcome the host innate immune response. Mammalian hosts have developed both membrane toll-like receptors (TLR and cytoplasmic pattern recognition receptors (PRRs that recognize specific pathogen-associated molecular patterns (PAMPs, resulting in activation of the transcription factors IRF3 or IRF7, or both, which together with NF-κB and ATF-2/c-JUN induce production of type I interferon (IFN-I. IFN-I plays a key role in host anti-microbial defense by mediating direct antiviral effects via up-regulation of IFN-I stimulated genes (ISGs, activating dendritic cells (DCs and natural killer (NK cells, and promoting the induction of adaptive responses. Accordingly, viruses have developed a plethora of strategies to disrupt the IFN-I mediated antiviral defenses of the host, and the viral gene products responsible for these disruptions are often major virulence determinants.IRF3- and IRF7-dependent induction of host innate immune responses is frequently targeted by viruses. Thus, the arenavirus nucleoprotein (NP was shown to inhibit the IFN‑I response by interfering with the activation of IRF3. This NP anti-IFN activity, together with alterations in the number and function of DCs observed in mice chronically infected with LCMV, likely play an important role in LCMV persistence in its murine host. In this review we will discuss current knowledge about the cellular and molecular mechanisms by

  5. Genetic detection and characterization of Lujo virus, a new hemorrhagic fever-associated arenavirus from southern Africa.

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    Thomas Briese

    2009-05-01

    Full Text Available Lujo virus (LUJV, a new member of the family Arenaviridae and the first hemorrhagic fever-associated arenavirus from the Old World discovered in three decades, was isolated in South Africa during an outbreak of human disease characterized by nosocomial transmission and an unprecedented high case fatality rate of 80% (4/5 cases. Unbiased pyrosequencing of RNA extracts from serum and tissues of outbreak victims enabled identification and detailed phylogenetic characterization within 72 hours of sample receipt. Full genome analyses of LUJV showed it to be unique and branching off the ancestral node of the Old World arenaviruses. The virus G1 glycoprotein sequence was highly diverse and almost equidistant from that of other Old World and New World arenaviruses, consistent with a potential distinctive receptor tropism. LUJV is a novel, genetically distinct, highly pathogenic arenavirus.

  6. The intracellular cargo receptor ERGIC-53 is required for the production of infectious arenavirus, coronavirus, and filovirus particles.

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    Klaus, Joseph P; Eisenhauer, Philip; Russo, Joanne; Mason, Anne B; Do, Danh; King, Benjamin; Taatjes, Douglas; Cornillez-Ty, Cromwell; Boyson, Jonathan E; Thali, Markus; Zheng, Chunlei; Liao, Lujian; Yates, John R; Zhang, Bin; Ballif, Bryan A; Botten, Jason W

    2013-11-13

    Arenaviruses and hantaviruses cause severe human disease. Little is known regarding host proteins required for their propagation. We identified human proteins that interact with the glycoproteins (GPs) of a prototypic arenavirus and hantavirus and show that the lectin endoplasmic reticulum (ER)-Golgi intermediate compartment 53 kDa protein (ERGIC-53), a cargo receptor required for glycoprotein trafficking within the early exocytic pathway, associates with arenavirus, hantavirus, coronavirus, orthomyxovirus, and filovirus GPs. ERGIC-53 binds to arenavirus GPs through a lectin-independent mechanism, traffics to arenavirus budding sites, and is incorporated into virions. ERGIC-53 is required for arenavirus, coronavirus, and filovirus propagation; in its absence, GP-containing virus particles form but are noninfectious, due in part to their inability to attach to host cells. Thus, we have identified a class of pathogen-derived ERGIC-53 ligands, a lectin-independent basis for their association with ERGIC-53, and a role for ERGIC-53 in the propagation of several highly pathogenic RNA virus families.

  7. Z proteins of New World arenaviruses bind RIG-I and interfere with type I interferon induction.

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    Fan, Lina; Briese, Thomas; Lipkin, W Ian

    2010-02-01

    The retinoic acid-inducible gene I product (RIG-I) is a cellular sensor of RNA virus infection that regulates the cellular beta interferon (IFN-beta) response. The nucleoproteins (NP) of arenaviruses are reported to antagonize the IFN response by inhibiting interferon regulatory factor 3 (IRF-3). Here, we demonstrate that the Z proteins of four New World (NW) arenaviruses, Guanarito virus (GTOV), Junin virus (JUNV), Machupo virus (MAVC), and Sabia virus (SABV), bind to RIG-I, resulting in downregulation of the IFN-beta response. We show that expression of the four NW arenavirus Z proteins inhibits IFN-beta mRNA induction in A549 cells in response to RNA bearing 5' phosphates (5'pppRNA). NW arenavirus Z proteins interact with RIG-I in coimmunoprecipitation studies and colocalize with RIG-I. Furthermore, expression of Z proteins interferes with the interaction between RIG-I and MAVS. Z expression also impedes the nuclear factor kappa light chain enhancer of activated B cells (NF-kappaB) and IRF-3 activation. Our results indicate that NW arenavirus Z proteins, but not Z protein of the Old World (OW) arenavirus lymphocytic choriomeningitis virus (LCMV) or Lassa virus, bind to RIG-I and inhibit downstream activation of the RIG-I signaling pathway, preventing the transcriptional induction of IFN-beta.

  8. Research efforts to control highly pathogenic arenaviruses: a summary of the progress and gaps.

    Science.gov (United States)

    Kerber, R; Reindl, S; Romanowski, V; Gómez, R M; Ogbaini-Emovon, E; Günther, S; ter Meulen, J

    2015-03-01

    Significant progress has been made in the past 10 years in unraveling the molecular biology of highly pathogenic arenaviruses that are endemic in several West African countries (Lassa fever virus) and in some regions of South America (Argentine and Bolivian hemorrhagic fever viruses). While this has resulted in proof-of-concept studies of novel vaccine candidates in non-human primates and in the discovery of several novel antiviral small molecule drug candidates, none of them has been tested in the clinic to date. The recent Ebola outbreak in West Africa has demonstrated very clearly that there is an urgent need to develop the prophylactic and therapeutic armamentarium against viral hemorrhagic fever viruses as part of a global preparedness for future epidemics. As it pertains to this goal, the present article summarizes the current knowledge of highly pathogenic arenaviruses and identifies opportunities for translational research.

  9. Spatiotemporally restricted arenavirus replication induces immune surveillance and type I interferon-dependent tumour regression

    Science.gov (United States)

    Kalkavan, Halime; Sharma, Piyush; Kasper, Stefan; Helfrich, Iris; Pandyra, Aleksandra A.; Gassa, Asmae; Virchow, Isabel; Flatz, Lukas; Brandenburg, Tim; Namineni, Sukumar; Heikenwalder, Mathias; Höchst, Bastian; Knolle, Percy A.; Wollmann, Guido; von Laer, Dorothee; Drexler, Ingo; Rathbun, Jessica; Cannon, Paula M.; Scheu, Stefanie; Bauer, Jens; Chauhan, Jagat; Häussinger, Dieter; Willimsky, Gerald; Löhning, Max; Schadendorf, Dirk; Brandau, Sven; Schuler, Martin; Lang, Philipp A.; Lang, Karl S.

    2017-01-01

    Immune-mediated effector molecules can limit cancer growth, but lack of sustained immune activation in the tumour microenvironment restricts antitumour immunity. New therapeutic approaches that induce a strong and prolonged immune activation would represent a major immunotherapeutic advance. Here we show that the arenaviruses lymphocytic choriomeningitis virus (LCMV) and the clinically used Junin virus vaccine (Candid#1) preferentially replicate in tumour cells in a variety of murine and human cancer models. Viral replication leads to prolonged local immune activation, rapid regression of localized and metastatic cancers, and long-term disease control. Mechanistically, LCMV induces antitumour immunity, which depends on the recruitment of interferon-producing Ly6C+ monocytes and additionally enhances tumour-specific CD8+ T cells. In comparison with other clinically evaluated oncolytic viruses and to PD-1 blockade, LCMV treatment shows promising antitumoural benefits. In conclusion, therapeutically administered arenavirus replicates in cancer cells and induces tumour regression by enhancing local immune responses. PMID:28248314

  10. Identification and characterization of potent small molecule inhibitor of hemorrhagic fever New World arenaviruses.

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    Bolken, Tove C; Laquerre, Sylvie; Zhang, Yuanming; Bailey, Thomas R; Pevear, Daniel C; Kickner, Shirley S; Sperzel, Lindsey E; Jones, Kevin F; Warren, Travis K; Amanda Lund, S; Kirkwood-Watts, Dana L; King, David S; Shurtleff, Amy C; Guttieri, Mary C; Deng, Yijun; Bleam, Maureen; Hruby, Dennis E

    2006-02-01

    Category A arenaviruses as defined by the National Institute of Allergy and Infectious Diseases (NIAID) are human pathogens that could be weaponized by bioterrorists. Many of these deadly viruses require biosafety level-4 (BSL-4) containment for all laboratory work, which limits traditional laboratory high-throughput screening (HTS) for identification of small molecule inhibitors. For those reasons, a related BSL-2 New World arenavirus, Tacaribe virus, 67-78% identical to Junín virus at the amino acid level, was used in a HTS campaign where approximately 400,000 small molecule compounds were screened in a Tacaribe virus-induced cytopathic effect (CPE) assay. Compounds identified in this screen showed antiviral activity and specificity against not only Tacaribe virus, but also the Category A New World arenaviruses (Junín, Machupo, and Guanarito). Drug resistant variants were isolated, suggesting that these compounds act through inhibition of a viral protein, the viral glycoprotein (GP2), and not through cellular toxicity mechanisms. A lead compound, ST-294, has been chosen for drug development. This potent and selective compound, with good bioavailability, demonstrated protective anti-viral efficacy in a Tacaribe mouse challenge model. This series of compounds represent a new class of inhibitors that may warrant further development for potential inclusion in a strategic stockpile.

  11. Comparative analysis of disease pathogenesis and molecular mechanisms of New World and Old World arenavirus infections.

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    McLay, Lisa; Liang, Yuying; Ly, Hinh

    2014-01-01

    Arenaviruses can cause fatal human haemorrhagic fever (HF) diseases for which vaccines and therapies are extremely limited. Both the New World (NW) and Old World (OW) groups of arenaviruses contain HF-causing pathogens. Although these two groups share many similarities, important differences with regard to pathogenicity and molecular mechanisms of virus infection exist. These closely related pathogens share many characteristics, including genome structure, viral assembly, natural host selection and the ability to interfere with innate immune signalling. However, members of the NW and OW viruses appear to use different receptors for cellular entry, as well as different mechanisms of virus internalization. General differences in disease signs and symptoms and pathological lesions in patients infected with either NW or OW arenaviruses are also noted and discussed herein. Whilst both the OW Lassa virus (LASV) and the NW Junin virus (JUNV) can cause disruption of the vascular endothelium, which is an important pathological feature of HF, the immune responses to these related pathogens seem to be quite distinct. Whereas LASV infection results in an overall generalized immune suppression, patients infected with JUNV seem to develop a cytokine storm. Additionally, the type of immune response required for recovery and clearance of the virus is different between NW and OW infections. These differences may be important to allow the viruses to evade host immune detection. Understanding these differences will aid the development of new vaccines and treatment strategies against deadly HF viral infections.

  12. Targeting of arenavirus RNA synthesis by a carboxamide-derivatized aromatic disulfide with virucidal activity.

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    Claudia S Sepúlveda

    Full Text Available Several arenaviruses can cause severe hemorrhagic fever (HF in humans, representing a public health threat in endemic areas of Africa and South America. The present study characterizes the potent virucidal activity of the carboxamide-derivatized aromatic disulfide NSC4492, an antiretroviral zinc finger-reactive compound, against Junín virus (JUNV, the causative agent of Argentine HF. The compound was able to inactivate JUNV in a time and temperature-dependent manner, producing more than 99 % reduction in virus titer upon incubation with virions at 37 °C for 90 min. The ability of NSC4492-treated JUNV to go through different steps of the multiplication cycle was then evaluated. Inactivated virions were able to bind and enter into the host cell with similar efficiency as control infectious particles. In contrast, treatment with NSC4492 impaired the capacity of JUNV to drive viral RNA synthesis, as measured by quantitative RT-PCR, and blocked viral protein expression, as determined by indirect immunofluorescence. These results suggest that the disulfide NSC4492 targets on the arenavirus replication complex leading to impairment in viral RNA synthesis. Additionally, analysis of VLP produced in NSC4492-treated cells expressing JUNV matrix Z protein revealed that the compound may interact with Z resulting in an altered aggregation behavior of this protein, but without affecting its intrinsic self-budding properties. The potential perspectives of NSC4492 as an inactivating vaccinal compound for pathogenic arenaviruses are discussed.

  13. Targeting of arenavirus RNA synthesis by a carboxamide-derivatized aromatic disulfide with virucidal activity.

    Science.gov (United States)

    Sepúlveda, Claudia S; García, Cybele C; Levingston Macleod, Jesica M; López, Nora; Damonte, Elsa B

    2013-01-01

    Several arenaviruses can cause severe hemorrhagic fever (HF) in humans, representing a public health threat in endemic areas of Africa and South America. The present study characterizes the potent virucidal activity of the carboxamide-derivatized aromatic disulfide NSC4492, an antiretroviral zinc finger-reactive compound, against Junín virus (JUNV), the causative agent of Argentine HF. The compound was able to inactivate JUNV in a time and temperature-dependent manner, producing more than 99 % reduction in virus titer upon incubation with virions at 37 °C for 90 min. The ability of NSC4492-treated JUNV to go through different steps of the multiplication cycle was then evaluated. Inactivated virions were able to bind and enter into the host cell with similar efficiency as control infectious particles. In contrast, treatment with NSC4492 impaired the capacity of JUNV to drive viral RNA synthesis, as measured by quantitative RT-PCR, and blocked viral protein expression, as determined by indirect immunofluorescence. These results suggest that the disulfide NSC4492 targets on the arenavirus replication complex leading to impairment in viral RNA synthesis. Additionally, analysis of VLP produced in NSC4492-treated cells expressing JUNV matrix Z protein revealed that the compound may interact with Z resulting in an altered aggregation behavior of this protein, but without affecting its intrinsic self-budding properties. The potential perspectives of NSC4492 as an inactivating vaccinal compound for pathogenic arenaviruses are discussed.

  14. Inhibition of mouse peritoneal macrophage DNA synthesis by infection with the Arenavirus Pichinde. Interim report

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    Friedlander, A.M.; Jahrling, P.B.; Merrill, P.; Tobery, S.

    1983-01-19

    Macrophage DNA synthesis and proliferation occur during the development of cell-mediated immunity and in the early non-specific reaction to infection. Arenaviruses have a predilection for infection of cells of the reticuloendothelial system and in this study we have examined the effect of the arenavirus Pichinde on macrophage DNA synthesis. We have found that infection of mouse peritoneal macrophages with Pichinde caused a profound dose dependent inhibition of the DNA synthesis induced by macrophage growth factor/colony stimulating factor. At a multiplicity of inoculum of five there is a 75-95% inhibition of DNA synthesis. Viable virus is necessary for inhibition since Pichinde inactivated by heat or cobalt irradiation had no effect. Similarly, virus pre-treated with an antiserum to Pichinde was without inhibitory effect. Inhibition was demonstrated by measuring DNA synthesis spectrofluorometrically as well as by 3H-thymidine incorporation. The inhibition of DNA synthesis was not associated with any cytopathology. There was no evidence that the inhibition was due to soluble factors, such as prostaglandins or interferon, released by infected cells. These studies demonstrate, for the first time in vitro, a significant alteration in macrophage function caused by infection with an arenavirus. It is possible that inhibition of macrophage proliferation represents a mechanism by which some microorganisms interfere with host resistance.

  15. The PI3K/Akt pathway contributes to arenavirus budding.

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    Urata, Shuzo; Ngo, Nhi; de la Torre, Juan Carlos

    2012-04-01

    Several arenaviruses, chiefly Lassa virus (LASV), cause hemorrhagic fever (HF) disease in humans and pose a significant public health concern in regions where they are endemic. On the other hand, evidence indicates that the globally distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway participates in many cellular processes, including cell survival and differentiation, and also has been shown to play important roles in different steps of the life cycles of a variety of viruses. Here we report that the inhibition of the PI3K/Akt pathway inhibited budding and to a lesser extent RNA synthesis, but not cell entry, of LCMV. Accordingly, BEZ-235, a PI3K inhibitor currently in cancer clinical trials, inhibited LCMV multiplication in cultured cells. These findings, together with those previously reported for Junin virus (JUNV), indicate that targeting the PI3K/Akt pathway could represent a novel antiviral strategy to combat human-pathogenic arenaviruses.

  16. Host-species transferrin receptor 1 orthologs are cellular receptors for nonpathogenic new world clade B arenaviruses.

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    Jonathan Abraham

    2009-04-01

    Full Text Available The ability of a New World (NW clade B arenavirus to enter cells using human transferrin receptor 1 (TfR1 strictly correlates with its ability to cause hemorrhagic fever. Amapari (AMAV and Tacaribe (TCRV, two nonpathogenic NW clade B arenaviruses that do not use human TfR1, are closely related to the NW arenaviruses that cause hemorrhagic fevers. Here we show that pseudotyped viruses bearing the surface glycoprotein (GP of AMAV or TCRV can infect cells using the TfR1 orthologs of several mammalian species, including those of their respective natural hosts, the small rodent Neacomys spinosus and the fruit bat Artibeus jamaicensis. Mutation of one residue in human TfR1 makes it a functional receptor for TCRV, and mutation of four residues makes it a functional receptor for AMAV. Our data support an in vivo role for TfR1 in the replication of most, if not all, NW clade B arenaviruses, and suggest that with modest changes in their GPs the nonpathogenic arenaviruses could use human TfR1 and emerge as human pathogens.

  17. RT-PCR assay for detection of Lassa virus and related Old World arenaviruses targeting the L gene.

    Science.gov (United States)

    Vieth, Simon; Drosten, Christian; Lenz, Oliver; Vincent, Martin; Omilabu, Sunday; Hass, Meike; Becker-Ziaja, Beate; ter Meulen, Jan; Nichol, Stuart T; Schmitz, Herbert; Günther, Stephan

    2007-12-01

    This study describes an RT-PCR assay targeting the L RNA segment of arenaviruses. Conserved regions were identified in the polymerase domain of the L gene on the basis of published sequences for Lassa virus, lymphocytic choriomeningitis virus (LCMV), Pichinde virus and Tacaribe virus, as well as 15 novel sequences for Lassa virus, LCMV, Ippy virus, Mobala virus and Mopeia virus determined in this study. Using these regions as target sites, a PCR assay for detection of all known Old World arenaviruses was developed and optimized. The concentration that yields 95% positive results in a set of replicate tests (95% detection limit) was determined to be 4290 copies of Lassa virus L RNA per ml of serum, corresponding to 30 copies per reaction. The ability of the assay to detect various Old World arenaviruses was demonstrated with in vitro transcribed RNA, material from infected cell cultures and samples from patients with Lassa fever and monkeys with LCMV-associated callitrichid hepatitis. The L gene PCR assay may be applicable: (i) as a complementary diagnostic test for Lassa virus and LCMV; (ii) to identify unknown Old World arenaviruses suspected as aetiological agents of disease; and (iii) for screening of potential reservoir hosts for unknown Old World arenaviruses.

  18. Effective oral favipiravir (T-705 therapy initiated after the onset of clinical disease in a model of arenavirus hemorrhagic Fever.

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    Michelle Mendenhall

    2011-10-01

    Full Text Available BACKGROUND: Lassa and Junín viruses are the most prominent members of the Arenaviridae family of viruses that cause viral hemorrhagic fever syndromes Lassa fever and Argentine hemorrhagic fever, respectively. At present, ribavirin is the only antiviral drug indicated for use in treatment of these diseases, but because of its limited efficacy in advanced cases of disease and its toxicity, safer and more effective antivirals are needed. METHODOLOGY/PRINCIPAL FINDINGS: Here, we used a model of acute arenaviral infection in outbred guinea pigs based on challenge with an adapted strain of Pichindé virus (PICV to further preclinical development of T-705 (Favipiravir, a promising broad-spectrum inhibitor of RNA virus infections. The guinea pig-adapted passage 19 PICV was uniformly lethal with an LD(50 of ∼5 plaque-forming units and disease was associated with fever, weight loss, thrombocytopenia, coagulation defects, increases in serum aspartate aminotransferase (AST concentrations, and pantropic viral infection. Favipiravir (300 mg/kg/day, twice daily orally for 14 days was highly effective, as all animals recovered fully from PICV-induced disease even when therapy was initiated one week after virus challenge when animals were already significantly ill with marked fevers and thrombocytopenia. Antiviral activity and reduced disease severity was evidenced by dramatic reductions in peak serum virus titers and AST concentrations in favipiravir-treated animals. Moreover, a sharp decrease in body temperature was observed shortly after the start of treatment. Oral ribavirin was also evaluated, and although effective, the slower rate of recovery may be a sign of the drug's known toxicity. CONCLUSIONS/SIGNIFICANCE: Our findings support further development of favipiravir for the treatment of severe arenaviral infections. The optimization of the experimental favipiravir treatment regimen in the PICV guinea pig model will inform critical future studies in the

  19. Gairo virus, a novel arenavirus of the widespread Mastomys natalensis: Genetically divergent, but ecologically similar to Lassa and Morogoro viruses.

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    Gryseels, Sophie; Rieger, Toni; Oestereich, Lisa; Cuypers, Bart; Borremans, Benny; Makundi, Rhodes; Leirs, Herwig; Günther, Stephan; Goüy de Bellocq, Joëlle

    2015-02-01

    Despite its near pan-African range, the Natal multimammate mouse, Mastomys natalensis, carries the human pathogen Lassa virus only in West Africa, while the seemingly non-pathogenic arenaviruses Mopeia, Morogoro, and Luna have been detected in this semi-commensal rodent in Mozambique/Zimbabwe, Tanzania and Zambia, respectively. Here, we describe a novel arenavirus in M. natalensis from Gairo district of central Tanzania, for which we propose the name "Gairo virus". Surprisingly, the virus is not closely related with Morogoro virus that infects M. natalensis only 90km south of Gairo, but clusters phylogenetically with Mobala-like viruses that infect non-M. natalensis host species in Central African Republic and Ethiopia. Despite the evolutionary distance, Gairo virus shares basic ecological features with the other M. natalensis-borne viruses Lassa and Morogoro. Our data show that M. natalensis, carrying distantly related viruses even in the same geographical area, is a potent reservoir host for a variety of arenaviruses.

  20. Isolation of Tacaribe virus, a Caribbean arenavirus, from host-seeking Amblyomma americanum ticks in Florida.

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    Katherine A Sayler

    Full Text Available Arenaviridae are a family of single stranded RNA viruses of mammals and boid snakes. Twenty-nine distinct mammalian arenaviruses have been identified, many of which cause severe hemorrhagic disease in humans, particularly in parts of sub-Saharan Africa, and in Central and South America. Humans typically become infected with an arenavirus through contact with excreta from infected rodents. Tacaribe virus (TCRV is an arenavirus that was first isolated from bats and mosquitoes during a rabies surveillance survey conducted in Trinidad from 1956 to 1958. Tacaribe virus is unusual because it has never been associated with a rodent host and since that one time isolation, the virus has not been isolated from any vertebrate or invertebrate hosts. We report the re-isolation of the virus from a pool of 100 host-seeking Amblyomma americanum (lone star ticks collected in a Florida state park in 2012. TCRV was isolated in two cell lines and its complete genome was sequenced. The tick-derived isolate is nearly identical to the only remaining isolate from Trinidad (TRVL-11573, with 99.6% nucleotide identity across the genome. A quantitative RT-PCR assay was developed to test for viral RNA in host-seeking ticks collected from 3 Florida state parks. Virus RNA was detected in 56/500 (11.2% of surveyed ticks. As this virus was isolated from ticks that parasitize humans, the ability of the tick to transmit the virus to people should be evaluated. Furthermore, reservoir hosts for the virus need to be identified in order to develop risk assessment models of human infection.

  1. Isolation of Tacaribe virus, a Caribbean arenavirus, from host-seeking Amblyomma americanum ticks in Florida.

    Science.gov (United States)

    Sayler, Katherine A; Barbet, Anthony F; Chamberlain, Casey; Clapp, William L; Alleman, Rick; Loeb, Julia C; Lednicky, John A

    2014-01-01

    Arenaviridae are a family of single stranded RNA viruses of mammals and boid snakes. Twenty-nine distinct mammalian arenaviruses have been identified, many of which cause severe hemorrhagic disease in humans, particularly in parts of sub-Saharan Africa, and in Central and South America. Humans typically become infected with an arenavirus through contact with excreta from infected rodents. Tacaribe virus (TCRV) is an arenavirus that was first isolated from bats and mosquitoes during a rabies surveillance survey conducted in Trinidad from 1956 to 1958. Tacaribe virus is unusual because it has never been associated with a rodent host and since that one time isolation, the virus has not been isolated from any vertebrate or invertebrate hosts. We report the re-isolation of the virus from a pool of 100 host-seeking Amblyomma americanum (lone star ticks) collected in a Florida state park in 2012. TCRV was isolated in two cell lines and its complete genome was sequenced. The tick-derived isolate is nearly identical to the only remaining isolate from Trinidad (TRVL-11573), with 99.6% nucleotide identity across the genome. A quantitative RT-PCR assay was developed to test for viral RNA in host-seeking ticks collected from 3 Florida state parks. Virus RNA was detected in 56/500 (11.2%) of surveyed ticks. As this virus was isolated from ticks that parasitize humans, the ability of the tick to transmit the virus to people should be evaluated. Furthermore, reservoir hosts for the virus need to be identified in order to develop risk assessment models of human infection.

  2. Diagnóstico virológico y molecular de virus transmitidos por roedores. Hantavirus y arenavirus

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    Silvana Levis

    2010-04-01

    Full Text Available Los hantavirus (familia Bunyaviridae y arenavirus (familia Arenaviridae son virus de roedores; cada uno de ellos parece estar estrictamente asociado con una especie de roedor en la que causa una infección persistente y asintomática. En las Américas tienen como reservorios primarios a roedores de la sub-familia Sigmodontinae, y son causantes de síndrome pulmonar por Hantavirus (SPH y fiebres hemorrágicas, respectivamente (1,2. El número de estos virus identificados en los últimos años ha aumentado significativamente; actualmente, el género Hantavirus está compuesto por más de 28 tipos diferentes, mientras que al menos 23 arenavirus conforman el género Arenavirus. Entre los hantavirus asociados con SPH se destacan el virus Sin Nombre en Norteamérica, y los virus Andes, Laguna Negra, Caño Delgadito, Araraquara y Juquitiba, en el cono sur de América, entre otros (2. Los arenavirus asociados a fiebres hemorrágicas reconocidos en Sud América al presente son: Junín (Argentina, Guanarito (Venezuela, Sabiá (Brasil, y Machupo y Chapare (Bolivia (3.

  3. Arenavirus envelope glycoproteins mimic autoprocessing sites of the cellular proprotein convertase subtilisin kexin isozyme-1/site-1 protease.

    Science.gov (United States)

    Pasquato, Antonella; Burri, Dominique J; Traba, Esther Gomez-Ibarlucea; Hanna-El-Daher, Layane; Seidah, Nabil G; Kunz, Stefan

    2011-08-15

    A crucial step in the arenavirus life cycle is the proteolytic processing of the viral envelope glycoprotein precursor (GPC) by the cellular proprotein convertase (PC) subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P). Here we conducted a systematic and quantitative analysis of SKI-1/S1P processing of peptides derived from the recognition sites of GPCs of different Old World and New World arenaviruses. We found that SKI-1/S1P showed a strong preference for arenaviral sequences resembling its autoprocessing sites, which are recurrent motifs in arenaviral GPCs. The African arenaviruses Lassa, Mobala, and Mopeia resemble the SKI-1/S1P autoprocessing C-site, whereas sequences derived from Clade B New World viruses Junin and Tacaribe have similarities to the autoprocessing B-site. In contrast, analogous peptides derived from cellular SKI-1/S1P substrates were remarkably poor substrates. The data suggest that arenavirus GPCs evolved to mimic SKI-1/S1P autoprocessing sites, likely ensuring efficient cleavage and perhaps avoiding competition with SKI-1/S1P's cellular substrates.

  4. An antiviral disulfide compound blocks interaction between arenavirus Z protein and cellular promyelocytic leukemia protein

    Energy Technology Data Exchange (ETDEWEB)

    Garcia, C.C. [Laboratory of Virology, Department of Biological Chemistry, School of Sciences, University of Buenos Aires, 1428 Buenos Aires (Argentina); Topisirovic, I. [Institute de Recherche en Immunologie et en Cancerologie, Universite de Montreal, Montreal, QC, Canada H3T 1J4 (Canada); Djavani, M. [Institute of Human Virology, School of Medicine, University of Maryland, Baltimore, MD 21201 (United States); Borden, K.L.B. [Institute de Recherche en Immunologie et en Cancerologie, Universite de Montreal, Montreal, QC, Canada H3T 1J4 (Canada); Damonte, E.B. [Laboratory of Virology, Department of Biological Chemistry, School of Sciences, University of Buenos Aires, 1428 Buenos Aires (Argentina); Salvato, M.S., E-mail: msalvato@ihv.umaryland.edu [Institute of Human Virology, School of Medicine, University of Maryland, Baltimore, MD 21201 (United States)

    2010-03-19

    The promyelocytic leukemia protein (PML) forms nuclear bodies (NB) that can be redistributed by virus infection. In particular, lymphocytic choriomeningitis virus (LCMV) influences disruption of PML NB through the interaction of PML with the arenaviral Z protein. In a previous report, we have shown that the disulfide compound NSC20625 has antiviral and virucidal properties against arenaviruses, inducing unfolding and oligomerization of Z without affecting cellular RING-containing proteins such as the PML. Here, we further studied the effect of the zinc-finger-reactive disulfide NSC20625 on PML-Z interaction. In HepG2 cells infected with LCMV or transiently transfected with Z protein constructs, treatment with NSC20625 restored PML distribution from a diffuse-cytoplasmic pattern to punctate, discrete NB which appeared identical to NB found in control, uninfected cells. Similar results were obtained in cells transfected with a construct expressing a Z mutant in zinc-binding site 2 of the RING domain, confirming that this Z-PML interaction requires the integrity of only one zinc-binding site. Altogether, these results show that the compound NSC20625 suppressed Z-mediated PML NB disruption and may be used as a tool for designing novel antiviral strategies against arenavirus infection.

  5. Targeting the proteolytic processing of the viral glycoprotein precursor is a promising novel antiviral strategy against arenaviruses.

    Science.gov (United States)

    Rojek, Jillian M; Pasqual, Giulia; Sanchez, Ana B; Nguyen, Ngoc-Thao; de la Torre, Juan-Carlos; Kunz, Stefan

    2010-01-01

    A crucial step in the arenavirus life cycle is the biosynthesis of the viral envelope glycoprotein (GP) responsible for virus attachment and entry. Processing of the GP precursor (GPC) by the cellular proprotein convertase site 1 protease (S1P), also known as subtilisin-kexin-isozyme 1 (SKI-1), is crucial for cell-to-cell propagation of infection and production of infectious virus. Here, we sought to evaluate arenavirus GPC processing by S1P as a target for antiviral therapy using a recently developed peptide-based S1P inhibitor, decanoyl (dec)-RRLL-chloromethylketone (CMK), and the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV). To control for off-target effects of dec-RRLL-CMK, we employed arenavirus reverse genetics to introduce a furin recognition site into the GPC of LCMV. The rescued mutant virus grew to normal titers, and the processing of its GPC critically depended on cellular furin, but not S1P. Treatment with the S1P inhibitor dec-RRLL-CMK resulted in specific blocking of viral spread and virus production of LCMV. Combination of the protease inhibitor with ribavirin, currently used clinically for treatment of human arenavirus infections, resulted in additive drug effects. In cells deficient in S1P, the furin-dependent LCMV variant established persistent infection, whereas wild-type LCMV underwent extinction without the emergence of S1P-independent escape variants. Together, the potent antiviral activity of an inhibitor of S1P-dependent GPC cleavage, the additive antiviral effect with ribavirin, and the low probability of emergence of S1P-independent viral escape variants make S1P-mediated GPC processing by peptide-derived inhibitors a promising strategy for the development of novel antiarenaviral drugs.

  6. Old World and Clade C New World Arenaviruses Mimic the Molecular Mechanism of Receptor Recognition Used by α-Dystroglycan's Host-Derived Ligands▿

    OpenAIRE

    Rojek, Jillian M.; Spiropoulou, Christina F.; Campbell, Kevin P; Kunz, Stefan

    2007-01-01

    α-Dystroglycan (DG) is an important cellular receptor for extracellular matrix (ECM) proteins and also serves as the receptor for Old World arenaviruses Lassa fever virus (LFV) and lymphocytic choriomeningitis virus (LCMV) and clade C New World arenaviruses. In the host cell, α-DG is subject to a remarkably complex pattern of O glycosylation that is crucial for its interactions with ECM proteins. Two of these unusual sugar modifications, protein O mannosylation and glycan modifications involv...

  7. Shedding dynamics of Morogoro virus, an African arenavirus closely related to Lassa virus, in its natural reservoir host Mastomys natalensis.

    Science.gov (United States)

    Borremans, Benny; Vossen, Raphaël; Becker-Ziaja, Beate; Gryseels, Sophie; Hughes, Nelika; Van Gestel, Mats; Van Houtte, Natalie; Günther, Stephan; Leirs, Herwig

    2015-05-29

    Arenaviruses can cause mild to severe hemorrhagic fevers. Humans mainly get infected through contact with infected rodents or their excretions, yet little is known about transmission dynamics within rodent populations. Morogoro virus (MORV) is an Old World arenavirus closely related to Lassa virus with which it shares the same host species Mastomys natalensis. We injected MORV in its host, and sampled blood and excretions at frequent intervals. Infection in adults was acute; viral RNA disappeared from blood after 18 days post infection (dpi) and from excretions after 39 dpi. Antibodies were present from 7 dpi and never disappeared. Neonatally infected animals acquired a chronic infection with RNA and antibodies in blood for at least 3 months. The quantified excretion and antibody patterns can be used to inform mathematical transmission models, and are essential for understanding and controlling transmission in the natural rodent host populations.

  8. Detection of arenavirus in a peripheral odontogenic fibromyxoma in a red tail boa (Boa constrictor constrictor) with inclusion body disease.

    Science.gov (United States)

    Hellebuyck, Tom; Pasmans, Frank; Ducatelle, Richard; Saey, Veronique; Martel, An

    2015-03-01

    A captive bred red tail boa (Boa constrictor constrictor) was presented with a large intraoral mass originating from the buccal gingiva, attached to the right dentary teeth row. Based on the clinical features and histological examination, the diagnosis of a peripheral odontogenic fibromyxoma was made. Sections of liver biopsies and circulating lymphocytes contained relatively few eosinophilic intracytoplasmic inclusion bodies, indistinguishable from those observed in inclusion body disease-affected snakes. Inclusion bodies were not observed in cells comprising the neoplastic mass. Using reverse transcription polymerase chain reaction (RT-PCR), arenavirus was detected in the neoplastic tissue. Two years after surgical removal of the mass, recurrence of the neoplastic lesion was observed. Numerous large inclusion body disease inclusions were abundantly present in the neoplastic cells of the recurrent fibromyxoma. Sections of liver biopsies and circulating lymphocytes contained relatively few intracytoplasmic inclusions. The RT-PCR revealed the presence of arenavirus in blood, a liver biopsy, and neoplastic tissue. The present case describes the co-occurrence of an arenavirus infection and an odontogenic fibromyxoma in a red tail boa.

  9. Dissection of the role of the stable signal peptide of the arenavirus envelope glycoprotein in membrane fusion.

    Science.gov (United States)

    Messina, Emily L; York, Joanne; Nunberg, Jack H

    2012-06-01

    The arenavirus envelope glycoprotein (GPC) retains a stable signal peptide (SSP) as an essential subunit in the mature complex. The 58-amino-acid residue SSP comprises two membrane-spanning hydrophobic regions separated by a short ectodomain loop that interacts with the G2 fusion subunit to promote pH-dependent membrane fusion. Small-molecule compounds that target this unique SSP-G2 interaction prevent arenavirus entry and infection. The interaction between SSP and G2 is sensitive to the phylogenetic distance between New World (Junín) and Old World (Lassa) arenaviruses. For example, heterotypic GPC complexes are unable to support virion entry. In this report, we demonstrate that the hybrid GPC complexes are properly assembled, proteolytically cleaved, and transported to the cell surface but are specifically defective in their membrane fusion activity. Chimeric SSP constructs reveal that this incompatibility is localized to the first transmembrane segment of SSP (TM1). Genetic changes in TM1 also affect sensitivity to small-molecule fusion inhibitors, generating resistance in some cases and inhibitor dependence in others. Our studies suggest that interactions of SSP TM1 with the transmembrane domain of G2 may be important for GPC-mediated membrane fusion and its inhibition.

  10. The Broad Foundations, 2006

    Science.gov (United States)

    Broad Foundation, 2006

    2006-01-01

    The mission of the Broad Foundations is to transform K-12 urban public education through better governance, management, labor relations and competition; make significant contributions to advance major scientific and medical research; foster public appreciation of contemporary art by increasing access for audiences worldwide; and lead and…

  11. Myristoylation of the Arenavirus Envelope Glycoprotein Stable Signal Peptide Is Critical for Membrane Fusion but Dispensable for Virion Morphogenesis

    Science.gov (United States)

    York, Joanne

    2016-01-01

    ABSTRACT Arenaviruses are responsible for severe and often fatal hemorrhagic disease. In the absence of effective antiviral therapies and vaccines, these viruses pose serious threats to public health and biodefense. Arenaviruses enter the host cell by fusion of the viral and endosomal membranes, a process mediated by the virus envelope glycoprotein GPC. Unlike other class I viral fusion proteins, GPC retains its stable signal peptide (SSP) as an essential third subunit in the mature complex. SSP spans the membrane twice and is myristoylated at its cytoplasmic N terminus. Mutations that abolish SSP myristoylation have been shown to reduce pH-induced cell-cell fusion activity of ectopically expressed GPC to ∼20% of wild-type levels. In order to examine the role of SSP myristoylation in the context of the intact virus, we used reverse genetics to generate Junín viruses (Candid #1 isolate) in which the critical glycine-2 residue in SSP was either replaced by alanine (G2A) or deleted (ΔG2). These mutant viruses produced smaller foci of infection in Vero cells and showed an ∼5-fold reduction in specific infectivity, commensurate with the defect in cell-cell fusion. However, virus assembly and GPC incorporation into budded virions were unaffected. Our findings suggest that the myristate moiety is cryptically disposed in the prefusion GPC complex and may function late in the fusion process to promote merging of the viral and cellular membranes. IMPORTANCE Hemorrhagic fever arenaviruses pose significant threats to public health and biodefense. Arenavirus entry into the host cell is promoted by the virus envelope glycoprotein GPC. Unlike other viral envelope glycoproteins, GPC contains a myristoylated stable signal peptide (SSP) as an essential third subunit. Myristoylation has been shown to be important for the membrane fusion activity of recombinantly expressed GPC. Here, we use reverse genetics to study the role of SSP myristoylation in the context of the intact

  12. Testing and validation of high density resequencing microarray for broad range biothreat agents detection.

    Directory of Open Access Journals (Sweden)

    Tomasz A Leski

    Full Text Available Rapid and effective detection and identification of emerging microbiological threats and potential biowarfare agents is very challenging when using traditional culture-based methods. Contemporary molecular techniques, relying upon reverse transcription and/or polymerase chain reaction (RT-PCR/PCR provide a rapid and effective alternative, however, such assays are generally designed and optimized to detect only a limited number of targets, and seldom are capable of differentiation among variants of detected targets. To meet these challenges, we have designed a broad-range resequencing pathogen microarray (RPM for detection of tropical and emerging infectious agents (TEI including biothreat agents: RPM-TEI v 1.0 (RPM-TEI. The scope of the RPM-TEI assay enables detection and differential identification of 84 types of pathogens and 13 toxin genes, including most of the class A, B and C select agents as defined by the Centers for Disease Control and Prevention (CDC, Atlanta, GA. Due to the high risks associated with handling these particular target pathogens, the sensitivity validation of the RPM-TEI has been performed using an innovative approach, in which synthetic DNA fragments are used as templates for testing the assay's limit of detection (LOD. Assay specificity and sensitivity was subsequently confirmed by testing with full-length genomic nucleic acids of selected agents. The LOD for a majority of the agents detected by RPM-TEI was determined to be at least 10(4 copies per test. Our results also show that the RPM-TEI assay not only detects and identifies agents, but is also able to differentiate near neighbors of the same agent types, such as closely related strains of filoviruses of the Ebola Zaire group, or the Machupo and Lassa arenaviruses. Furthermore, each RPM-TEI assay results in specimen-specific agent gene sequence information that can be used to assess pathogenicity, mutations, and virulence markers, results that are not generally

  13. Differential recognition of Old World and New World arenavirus envelope glycoproteins by subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P).

    Science.gov (United States)

    Burri, Dominique J; da Palma, Joel Ramos; Seidah, Nabil G; Zanotti, Giuseppe; Cendron, Laura; Pasquato, Antonella; Kunz, Stefan

    2013-06-01

    The arenaviruses are an important family of emerging viruses that includes several causative agents of severe hemorrhagic fevers in humans that represent serious public health problems. A crucial step of the arenavirus life cycle is maturation of the envelope glycoprotein precursor (GPC) by the cellular subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P). Comparison of the currently known sequences of arenavirus GPCs revealed the presence of a highly conserved aromatic residue at position P7 relative to the SKI-1/S1P cleavage side in Old World and clade C New World arenaviruses but not in New World viruses of clades A and B or cellular substrates of SKI-1/S1P. Using a combination of molecular modeling and structure-function analysis, we found that residue Y285 of SKI-1/S1P, distal from the catalytic triad, is implicated in the molecular recognition of the aromatic "signature residue" at P7 in the GPC of Old World Lassa virus. Using a quantitative biochemical approach, we show that Y285 of SKI-1/S1P is crucial for the efficient processing of peptides derived from Old World and clade C New World arenavirus GPCs but not of those from clade A and B New World arenavirus GPCs. The data suggest that during coevolution with their mammalian hosts, GPCs of Old World and clade C New World viruses expanded the molecular contacts with SKI-1/S1P beyond the classical four-amino-acid recognition sequences and currently occupy an extended binding pocket.

  14. Comparative Structural and Functional Analysis of Bunyavirus and Arenavirus Cap-Snatching Endonucleases

    Science.gov (United States)

    Reguera, Juan; Gerlach, Piotr; Rosenthal, Maria; Gaudon, Stephanie; Coscia, Francesca; Günther, Stephan; Cusack, Stephen

    2016-01-01

    Segmented negative strand RNA viruses of the arena-, bunya- and orthomyxovirus families uniquely carry out viral mRNA transcription by the cap-snatching mechanism. This involves cleavage of host mRNAs close to their capped 5′ end by an endonuclease (EN) domain located in the N-terminal region of the viral polymerase. We present the structure of the cap-snatching EN of Hantaan virus, a bunyavirus belonging to hantavirus genus. Hantaan EN has an active site configuration, including a metal co-ordinating histidine, and nuclease activity similar to the previously reported La Crosse virus and Influenza virus ENs (orthobunyavirus and orthomyxovirus respectively), but is more active in cleaving a double stranded RNA substrate. In contrast, Lassa arenavirus EN has only acidic metal co-ordinating residues. We present three high resolution structures of Lassa virus EN with different bound ion configurations and show in comparative biophysical and biochemical experiments with Hantaan, La Crosse and influenza ENs that the isolated Lassa EN is essentially inactive. The results are discussed in the light of EN activation mechanisms revealed by recent structures of full-length influenza virus polymerase. PMID:27304209

  15. Effect of fatty acids on arenavirus replication: inhibition of virus production by lauric acid.

    Science.gov (United States)

    Bartolotta, S; García, C C; Candurra, N A; Damonte, E B

    2001-01-01

    To study the functional involvement of cellular membrane properties on arenavirus infection, saturated fatty acids of variable chain length (C10-C18) were evaluated for their inhibitory activity against the multiplication of Junin virus (JUNV). The most active inhibitor was lauric acid (C12), which reduced virus yields of several attenuated and pathogenic strains of JUNV in a dose dependent manner, without affecting cell viability. Fatty acids with shorter or longer chain length had a reduced or negligible anti-JUNV activity. Lauric acid did not inactivate virion infectivity neither interacted with the cell to induce a state refractory to virus infection. From mechanistic studies, it can be concluded that lauric acid inhibited a late maturation stage in the replicative cycle of JUNV. Viral protein synthesis was not affected by the compound, but the expression of glycoproteins in the plasma membrane was diminished. A direct correlation between the inhibition of JUNV production and the stimulation of triacylglycerol cell content was demonstrated, and both lauric-acid induced effects were dependent on the continued presence of the fatty acid. Thus, the decreased insertion of viral glycoproteins into the plasma membrane, apparently due to the increased incorporation of triacylglycerols, seems to cause an inhibition of JUNV maturation and release.

  16. Comparative Structural and Functional Analysis of Bunyavirus and Arenavirus Cap-Snatching Endonucleases.

    Directory of Open Access Journals (Sweden)

    Juan Reguera

    2016-06-01

    Full Text Available Segmented negative strand RNA viruses of the arena-, bunya- and orthomyxovirus families uniquely carry out viral mRNA transcription by the cap-snatching mechanism. This involves cleavage of host mRNAs close to their capped 5' end by an endonuclease (EN domain located in the N-terminal region of the viral polymerase. We present the structure of the cap-snatching EN of Hantaan virus, a bunyavirus belonging to hantavirus genus. Hantaan EN has an active site configuration, including a metal co-ordinating histidine, and nuclease activity similar to the previously reported La Crosse virus and Influenza virus ENs (orthobunyavirus and orthomyxovirus respectively, but is more active in cleaving a double stranded RNA substrate. In contrast, Lassa arenavirus EN has only acidic metal co-ordinating residues. We present three high resolution structures of Lassa virus EN with different bound ion configurations and show in comparative biophysical and biochemical experiments with Hantaan, La Crosse and influenza ENs that the isolated Lassa EN is essentially inactive. The results are discussed in the light of EN activation mechanisms revealed by recent structures of full-length influenza virus polymerase.

  17. Efficient Interaction between Arenavirus Nucleoprotein (NP) and RNA-Dependent RNA Polymerase (L) Is Mediated by the Virus Nucleocapsid (NP-RNA) Template.

    Science.gov (United States)

    Iwasaki, Masaharu; Ngo, Nhi; Cubitt, Beatrice; de la Torre, Juan C

    2015-05-01

    In this study, we document that efficient interaction between arenavirus nucleoprotein (NP) and RNA-dependent RNA polymerase (L protein), the two trans-acting viral factors required for both virus RNA replication and gene transcription, requires the presence of virus-specific RNA sequences located within the untranslated 5' and 3' termini of the viral genome.

  18. Strand-Specific Quantitative Reverse Transcription-Polymerase Chain Reaction Assay for Measurement of Arenavirus Genomic and Antigenomic RNAs.

    Directory of Open Access Journals (Sweden)

    Kelsey Haist

    Full Text Available Arenaviruses are bi-segmented, single-stranded RNA viruses that cause significant human disease. The manner in which they regulate the replication of their genome is not well-understood. This is partly due to the absence of a highly sensitive assay to measure individual species of arenavirus replicative RNAs. To overcome this obstacle, we designed a quantitative reverse transcription (RT-PCR assay for selective quantitation of each of the lymphocytic choriomeningitis virus (LCMV genomic or antigenomic RNAs. During the course of assay design, we identified a nonspecific priming phenomenon whereby, in the absence of an RT primer, cDNAs complementary to each of the LCMV replicative RNA species are generated during RT. We successfully circumvented this nonspecific priming event through the use of biotinylated primers in the RT reaction, which permitted affinity purification of primer-specific cDNAs using streptavidin-coated magnetic beads. As proof of principle, we used the assay to map the dynamics of LCMV replication at acute and persistent time points and to determine the quantities of genomic and antigenomic RNAs that are incorporated into LCMV particles. This assay can be adapted to measure total S or L segment-derived viral RNAs and therefore represents a highly sensitive diagnostic platform to screen for LCMV infection in rodent and human tissue samples and can also be used to quantify virus-cell attachment.

  19. When Viruses Don’t Go Viral: The Importance of Host Phylogeographic Structure in the Spatial Spread of Arenaviruses

    Science.gov (United States)

    Baird, Stuart J. E.; Goüy de Bellocq, Joëlle

    2017-01-01

    Many emerging infections are RNA virus spillovers from animal reservoirs. Reservoir identification is necessary for predicting the geographic extent of infection risk, but rarely are taxonomic levels below the animal species considered as reservoir, and only key circumstances in nature and methodology allow intrinsic virus-host associations to be distinguished from simple geographic (co-)isolation. We sampled and genetically characterized in detail a contact zone of two subtaxa of the rodent Mastomys natalensis in Tanzania. We find two distinct arenaviruses, Gairo and Morogoro virus, each spatially confined to a single M. natalensis subtaxon, only co-occurring at the contact zone’s centre. Inter-subtaxon hybridization at this centre and a continuum of quality habitat for M. natalensis show that both viruses have the ecological opportunity to spread into the other substaxon’s range, but do not, strongly suggesting host-intrinsic barriers. Such barriers could explain why human cases of another M. natalensis-borne arenavirus, Lassa virus, are limited to West Africa. PMID:28076397

  20. The role of proteolytic processing and the stable signal peptide in expression of the Old World arenavirus envelope glycoprotein ectodomain

    Energy Technology Data Exchange (ETDEWEB)

    Burri, Dominique J.; Pasquato, Antonella; Ramos da Palma, Joel [Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne CH-1011 (Switzerland); Igonet, Sebastien; Oldstone, Michael B.A. [Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037 (United States); Kunz, Stefan, E-mail: Stefan.Kunz@chuv.ch [Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne CH-1011 (Switzerland)

    2013-02-05

    Maturation of the arenavirus GP precursor (GPC) involves proteolytic processing by cellular signal peptidase and the proprotein convertase subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P), yielding a tripartite complex comprised of a stable signal peptide (SSP), the receptor-binding GP1, and the fusion-active transmembrane GP2. Here we investigated the roles of SKI-1/S1P processing and SSP in the biosynthesis of the recombinant GP ectodomains of lymphocytic choriomeningitis virus (LCMV) and Lassa virus (LASV). When expressed in mammalian cells, the LCMV and LASV GP ectodomains underwent processing by SKI-1/S1P, followed by dissociation of GP1 from GP2. The GP2 ectodomain spontaneously formed trimers as revealed by chemical cross-linking. The endogenous SSP, known to be crucial for maturation and transport of full-length arenavirus GPC was dispensable for processing and secretion of the soluble GP ectodomain, suggesting a specific role of SSP in the stable prefusion conformation and transport of full-length GPC.

  1. Modelos animales de fiebres hemorrágicas humanas producidas por arenavirus

    Directory of Open Access Journals (Sweden)

    Juan D. Rodas

    2004-03-01

    ón cruzada entre las dos cepas de LCMV se observó también cuando 2 primates inoculados iv o ig con la cepa Armtrong (ARM sobrevivieron el desafío letal con la cepa WE. Tres de los 7 monos que experimentaron protección al desafío letal fueron también los mismos que exhibieron la más fuerte inmunidad medida por células.

     

    REFERENCIAS

    1. SALVATO, M. S., AND S. K. RAI. 1997. Arenaviruses, p. 629-650. In B. Mahy (ed., Topley and Wilson’s microbiology and microbiology and microbial infections, 9th ed. Arnold, London, United Kingdom.

    2. LUKASHEVICH, I. S., M. DJAVANI, J. D. RODAS, J. C. ZAPATA, A. USBORNE, C. EMERSON, J. MITCHEN, P. B. JAHRLING, AND M. S. SALVATO. Hemorrhagic fever occurs after intravenous, but not after intragastric, inoculation of rhesus macaques with lymphocytic choriomeningitis virus. J Med Virol 2002; 67: 171-86.

    3. LUKASHEVICH, I. S., I. TIKHONOV, J. D. RODAS, J. C. ZAPATA, Y. YANG, M. DJAVANI, AND M. S. SALVATO. Arenavirus-mediated liver pathology: acute lymphocytic choriomeningitis virus infection of rhesus macaques is characterized by high-level interleukin-6 expression and hepatocyte proliferation. J Virol 2003; 77: 1727-37.

    4. RODAS JD, LUKASHEVICH I, ZAPATA JC, CAIRO C, TIKHONOV I, DJAVANI M, PAUZA D AND SALVATO M. Mucosal arenavirus infection of primates can protect from lethal hemorrhagic fever. J Med Virol 2004. 72: 424-435.

  2. Structural characterization of the glycoprotein GP2 core domain from the CAS virus, a novel arenavirus-like species.

    Science.gov (United States)

    Koellhoffer, Jayne F; Dai, Zhou; Malashkevich, Vladimir N; Stenglein, Mark D; Liu, Yanyun; Toro, Rafael; S Harrison, Joseph; Chandran, Kartik; DeRisi, Joseph L; Almo, Steven C; Lai, Jonathan R

    2014-04-03

    Fusion of the viral and host cell membranes is a necessary first step for infection by enveloped viruses and is mediated by the envelope glycoprotein. The transmembrane subunits from the structurally defined "class I" glycoproteins adopt an α-helical "trimer-of-hairpins" conformation during the fusion pathway. Here, we present our studies on the envelope glycoprotein transmembrane subunit, GP2, of the CAS virus (CASV). CASV was recently identified from annulated tree boas (Corallus annulatus) with inclusion body disease and is implicated in the disease etiology. We have generated and characterized two protein constructs consisting of the predicted CASV GP2 core domain. The crystal structure of the CASV GP2 post-fusion conformation indicates a trimeric α-helical bundle that is highly similar to those of Ebola virus and Marburg virus GP2 despite CASV genome homology to arenaviruses. Denaturation studies demonstrate that the stability of CASV GP2 is pH dependent with higher stability at lower pH; we propose that this behavior is due to a network of interactions among acidic residues that would destabilize the α-helical bundle under conditions where the side chains are deprotonated. The pH-dependent stability of the post-fusion structure has been observed in Ebola virus and Marburg virus GP2, as well as other viruses that enter via the endosome. Infection experiments with CASV and the related Golden Gate virus support a mechanism of entry that requires endosomal acidification. Our results suggest that, despite being primarily arenavirus like, the transmembrane subunit of CASV is extremely similar to the filoviruses.

  3. Broad-spectrum antiviral agents

    Directory of Open Access Journals (Sweden)

    Jun-Da eZhu

    2015-05-01

    Full Text Available Development of highly effective, broad-spectrum antiviral agents is the major objective shared by the fields of virology and pharmaceutics. Antiviral drug development has focused on targeting viral entry and replication, as well as modulating cellular defense system. High throughput screening of molecules, genetic engineering of peptides, and functional screening of agents have identified promising candidates for development of optimal broad-spectrum antiviral agents to intervene in viral infection and control viral epidemics. This review discusses current knowledge, prospective applications, opportunities, and challenges in the development of broad-spectrum antiviral agents.

  4. Infection of type I interferon receptor-deficient mice with various old world arenaviruses: a model for studying virulence and host species barriers.

    Directory of Open Access Journals (Sweden)

    Toni Rieger

    Full Text Available Lassa virus causes hemorrhagic Lassa fever in humans, while the related Old World arenaviruses Mopeia, Morogoro, and Mobala are supposedly apathogenic to humans and cause only inapparent infection in non-human primates. Here, we studied whether the virulence of Old World arenaviruses in humans and non-human primates is reflected in type I interferon receptor deficient (IFNAR(-/- mice by testing several strains of Lassa virus vs. the apathogenic viruses Mopeia, Morogoro, and Mobala. All Lassa virus strains tested-Josiah, AV, BA366, and Nig04-10-replicated to high titers in blood, lung, kidney, heart, spleen, brain, and liver and caused disease as evidenced by weight loss and elevation of aspartate and alanine aminotransferase (AST and ALT levels with a high AST/ALT ratio. Lassa fever-like pathology included acute hepatitis, interstitial pneumonia, and pronounced disturbance of splenic cytoarchitecture. Infiltrations of activated monocytes/macrophages expressing inducible nitric oxide synthase and T cells were found in liver and lung. In contrast, Mopeia, Morogoro, and Mobala virus replicated poorly in the animals and acute inflammatory alterations were not noted. Depletion of CD4(+ and CD8(+ T cells strongly enhanced susceptibility of IFNAR(-/- mice to the apathogenic viruses. In conclusion, the virulence of Old World arenaviruses in IFNAR(-/- mice correlates with their virulence in humans and non-human primates. In addition to the type I interferon system, T cells seem to regulate whether or not an arenavirus can productively infect non-host rodent species. The observation that Lassa virus overcomes the species barrier without artificial depletion of T cells suggests it is able to impair T cell functionality in a way that corresponds to depletion.

  5. Infection of type I interferon receptor-deficient mice with various old world arenaviruses: a model for studying virulence and host species barriers.

    Science.gov (United States)

    Rieger, Toni; Merkler, Doron; Günther, Stephan

    2013-01-01

    Lassa virus causes hemorrhagic Lassa fever in humans, while the related Old World arenaviruses Mopeia, Morogoro, and Mobala are supposedly apathogenic to humans and cause only inapparent infection in non-human primates. Here, we studied whether the virulence of Old World arenaviruses in humans and non-human primates is reflected in type I interferon receptor deficient (IFNAR(-/-)) mice by testing several strains of Lassa virus vs. the apathogenic viruses Mopeia, Morogoro, and Mobala. All Lassa virus strains tested-Josiah, AV, BA366, and Nig04-10-replicated to high titers in blood, lung, kidney, heart, spleen, brain, and liver and caused disease as evidenced by weight loss and elevation of aspartate and alanine aminotransferase (AST and ALT) levels with a high AST/ALT ratio. Lassa fever-like pathology included acute hepatitis, interstitial pneumonia, and pronounced disturbance of splenic cytoarchitecture. Infiltrations of activated monocytes/macrophages expressing inducible nitric oxide synthase and T cells were found in liver and lung. In contrast, Mopeia, Morogoro, and Mobala virus replicated poorly in the animals and acute inflammatory alterations were not noted. Depletion of CD4(+) and CD8(+) T cells strongly enhanced susceptibility of IFNAR(-/-) mice to the apathogenic viruses. In conclusion, the virulence of Old World arenaviruses in IFNAR(-/-) mice correlates with their virulence in humans and non-human primates. In addition to the type I interferon system, T cells seem to regulate whether or not an arenavirus can productively infect non-host rodent species. The observation that Lassa virus overcomes the species barrier without artificial depletion of T cells suggests it is able to impair T cell functionality in a way that corresponds to depletion.

  6. Broad resonances in transport theory

    CERN Document Server

    Leupold, S

    2003-01-01

    The extension of the transport theoretical framework to include states with a broad mass distribution is discussed. The proper life-time and cross sections for a state with an arbitrarily given invariant mass is discussed in detail. (author)

  7. The Broad Autism Phenotype Questionnaire

    Science.gov (United States)

    Hurley, Robert S. E.; Losh, Molly; Parlier, Morgan; Reznick, J. Steven; Piven, Joseph

    2007-01-01

    The broad autism phenotype (BAP) is a set of personality and language characteristics that reflect the phenotypic expression of the genetic liability to autism, in non-autistic relatives of autistic individuals. These characteristics are milder but qualitatively similar to the defining features of autism. A new instrument designed to measure the…

  8. Medicare Provider Data - Hospice Providers

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Hospice Utilization and Payment Public Use File provides information on services provided to Medicare beneficiaries by hospice providers. The Hospice PUF...

  9. Broad Diphotons from Narrow States

    CERN Document Server

    An, Haipeng; Zhang, Yue

    2015-01-01

    ATLAS and CMS have each reported a modest diphoton excess consistent with the decay of a broad resonance at ~ 750 GeV. We show how this signal can arise in a weakly coupled theory comprised solely of narrow width particles. In particular, if the decaying particle is produced off-shell, then the associated diphoton resonance will have a broad, adjustable width. We present simplified models which explain the diphoton excess through the three-body decay of a scalar or fermion. Our minimal ultraviolet completion is a weakly coupled and renormalizable theory of a singlet scalar plus a heavy vector-like quark and lepton. The smoking gun of this mechanism is an asymmetric diphoton peak recoiling against missing transverse energy, jets, or leptons.

  10. The viral transmembrane superfamily: possible divergence of Arenavirus and Filovirus glycoproteins from a common RNA virus ancestor

    Directory of Open Access Journals (Sweden)

    Buchmeier Michael J

    2001-02-01

    Full Text Available Abstract Background Recent studies of viral entry proteins from influenza, measles, human immunodeficiency virus, type 1 (HIV-1, and Ebola virus have shown, first with molecular modeling, and then X-ray crystallographic or other biophysical studies, that these disparate viruses share a coiled-coil type of entry protein. Results Structural models of the transmembrane glycoproteins (GP-2 of the Arenaviruses, lymphochoriomeningitis virus (LCMV and Lassa fever virus, are presented, based on consistent structural propensities despite variation in the amino acid sequence. The principal features of the model, a hydrophobic amino terminus, and two antiparallel helices separated by a glycosylated, antigenic apex, are common to a number of otherwise disparate families of enveloped RNA viruses. Within the first amphipathic helix, demonstrable by circular dichroism of a peptide fragment, there is a highly conserved heptad repeat pattern proposed to mediate multimerization by coiled-coil interactions. The amino terminal 18 amino acids are 28% identical and 50% highly similar to the corresponding region of Ebola, a member of the Filovirus family. Within the second, charged helix just prior to membrane insertion there is also high similarity over the central 18 amino acids in corresponding regions of Lassa and Ebola, which may be further related to the similar region of HIV-1 defining a potent antiviral peptide analogue. Conclusions These findings indicate a common pattern of structure and function among viral transmembrane fusion proteins from a number of virus families. Such a pattern may define a viral transmembrane superfamily that evolved from a common precursor eons ago.

  11. Ghost imaging with broad distance

    Institute of Scientific and Technical Information of China (English)

    段德洋; 张路; 杜少将; 夏云杰

    2015-01-01

    We present a scheme that is able to achieve the ghost imaging with broad distance. The physical nature of our scheme is that the different wavelength beams are separated in free space by an optical media according to the slow light or dispersion principle. Meanwhile, the equality of the optical distance of the two light arms is not violated. The photon correlation is achieved by the rotating ground glass plate (RGGP) and spatial light modulator (SLM), respectively. Our work shows that a monochromic ghost image can be obtained in the case of RGGP. More importantly, the position (or distance) of the object can be ascertained by the color of the image. Thus, the imaging and ranging processes are combined as one process for the first time to the best of our knowledge. In the case of SLM, we can obtain a colored image regardless of where the object is.

  12. Broad Leaves in Strong Flow

    CERN Document Server

    Miller, Laura

    2013-01-01

    Flexible broad leaves are thought to reconfigure in the wind and water to reduce the drag forces that act upon them. Simple mathematical models of a flexible beam immersed in a two-dimensional flow will also exhibit this behavior. What is less understood is how the mechanical properties of a leaf in a three-dimensional flow will passively allow roll up into a cone shape and reduce both drag and vortex induced oscillations. In this fluid dynamics video, the flows around the leaves are compared with those of simplified sheets using 3D numerical simulations and physical models. For some reconfiguration shapes, large forces and oscillations due to strong vortex shedding are produced. In the actual leaf, a stable recirculation zone is formed within the wake of the reconfigured cone. In physical and numerical models that reconfigure into cones, a similar recirculation zone is observed with both rigid and flexible tethers. These results suggest that the three-dimensional cone structure in addition to flexibility is ...

  13. 76 FR 34087 - Broad Stakeholder Survey

    Science.gov (United States)

    2011-06-10

    ... SECURITY Broad Stakeholder Survey AGENCY: National Protection and Programs Directorate, DHS. ACTION: 60-day... comments concerning the Broad Stakeholder Survey. DATES: Comments are encouraged and will be accepted until.... The Broad Stakeholder Survey is designed to gather stakeholder feedback on the effectiveness of...

  14. 78 FR 20119 - Broad Stakeholder Survey

    Science.gov (United States)

    2013-04-03

    ... SECURITY Broad Stakeholder Survey AGENCY: National Protection and Programs Directorate, DHS. ACTION: 30-day... soliciting comments concerning the Broad Stakeholder Survey. DHS previously published this ICR in the Federal... responders across the Nation. The Broad Stakeholder Survey is designed to gather stakeholder feedback on...

  15. 77 FR 50144 - Broad Stakeholder Survey

    Science.gov (United States)

    2012-08-20

    ... SECURITY Broad Stakeholder Survey AGENCY: National Protection and Programs Directorate, DHS. ACTION: 60-day... comments concerning the Broad Stakeholder Survey. DATES: Comments are encouraged and will be accepted until... across the Nation. The Broad Stakeholder Survey is designed to gather stakeholder feedback on...

  16. Identification and specificity of broadly neutralizing antibodies against HIV

    OpenAIRE

    McCoy, Laura E.; Burton, Dennis R.

    2017-01-01

    Summary Beginning in 2009, studies of the humoral responses of HIV‐positive individuals have led to the identification of scores, if not hundreds, of antibodies that are both broadly reactive and potently neutralizing. This development has provided renewed impetus toward an HIV vaccine and led directly to the development of novel immunogens. Advances in identification of donors with the most potent and broad anti‐HIV serum neutralizing responses were crucial in this effort. Equally, developme...

  17. Magnetohydrodynamic stability of broad line region clouds

    CERN Document Server

    Krause, Martin; Burkert, Andreas

    2012-01-01

    Hydrodynamic stability has been a longstanding issue for the cloud model of the broad line region in active galactic nuclei. We argue that the clouds may be gravitationally bound to the supermassive black hole. If true, stabilisation by thermal pressure alone becomes even more difficult. We further argue that if magnetic fields should be present in such clouds at a level that could affect the stability properties, they need to be strong enough to compete with the radiation pressure on the cloud. This would imply magnetic field values of a few Gauss for a sample of Active Galactic Nuclei we draw from the literature. We then investigate the effect of several magnetic configurations on cloud stability in axi-symmetric magnetohydrodynamic simulations. For a purely azimuthal magnetic field which provides the dominant pressure support, the cloud first gets compressed by the opposing radiative and gravitational forces. The pressure inside the cloud then increases, and it expands vertically. Kelvin-Helmholtz and colu...

  18. Broad Prize: Do the Successes Spread?

    Science.gov (United States)

    Samuels, Christina A.

    2011-01-01

    When the Broad Prize for Urban Education was created in 2002, billionaire philanthropist Eli Broad said he hoped the awards, in addition to rewarding high-performing school districts, would foster healthy competition; boost the prestige of urban education, long viewed as dysfunctional; and showcase best practices. Over the 10 years the prize has…

  19. Influenza virus antigenicity and broadly neutralizing epitopes.

    Science.gov (United States)

    Air, Gillian M

    2015-04-01

    A vaccine formulation that would be effective against all strains of influenza virus has long been a goal of vaccine developers, but antibodies after infection or vaccination were seen to be strain specific and there was little evidence of cross-reactive antibodies that neutralized across subtypes. Recently a number of broadly neutralizing monoclonal antibodies have been characterized. This review describes the different classes of broadly neutralizing antibodies and discusses the potential of their therapeutic use or for design of immunogens that induce a high proportion of broadly neutralizing antibodies.

  20. Arctic Change Information for a Broad Audience

    Science.gov (United States)

    Soreide, N. N.; Overland, J. E.; Calder, J.

    2002-12-01

    Demonstrable environmental changes have occurred in the Arctic over the past three decades. NOAA's Arctic Theme Page is a rich resource web site focused on high latitude studies and the Arctic, with links to widely distributed data and information focused on the Arctic. Included is a collection of essays on relevant topics by experts in Arctic research. The website has proven useful to a wide audience, including scientists, students, teachers, decision makers and the general public, as indicated through recognition by USA Today, Science magazine, etc. (http://www.arctic.noaa.gov) Working jointly with NSF and the University of Washington's Polar Science Center as part of the Study of Environmental Arctic Change (SEARCH) program, NOAA has developed a website for access to pan-Arctic time series spanning diverse data types including climate indices, atmospheric, oceanic, sea ice, terrestrial, biological and fisheries. Modest analysis functions and more detailed analysis results are provided. (http://www.unaami.noaa.gov/). This paper will describe development of an Artic Change Detection status website to provide a direct and comprehensive view of previous and ongoing change in the Arctic for a broad climate community. For example, composite metrics are developed using principal component analysis based on 86 multivariate pan-Arctic time series for seven data types. Two of these metrics can be interpreted as a regime change/trend component and an interdecadal component. Changes can also be visually observed through tracking of 28 separate biophysical indicators. Results will be presented in the form of a web site with relevant, easily understood, value-added knowledge backed by peer review from Arctic scientists and scientific journals.

  1. Bid Optimization in Broad-Match Ad auctions

    CERN Document Server

    Even-dar, Eyal; Mirrokni, Vahab; Muthukrishnan, S; Nadav, Uri

    2009-01-01

    Ad auctions in sponsored search support ``broad match'' that allows an advertiser to target a large number of queries while bidding only on a limited number. While giving more expressiveness to advertisers, this feature makes it challenging to optimize bids to maximize their returns: choosing to bid on a query as a broad match because it provides high profit results in one bidding for related queries which may yield low or even negative profits. We abstract and study the complexity of the {\\em bid optimization problem} which is to determine an advertiser's bids on a subset of keywords (possibly using broad match) so that her profit is maximized. In the query language model when the advertiser is allowed to bid on all queries as broad match, we present an linear programming (LP)-based polynomial-time algorithm that gets the optimal profit. In the model in which an advertiser can only bid on keywords, ie., a subset of keywords as an exact or broad match, we show that this problem is not approximable within any ...

  2. Measuring Prevention More Broadly, An Empirical...

    Data.gov (United States)

    U.S. Department of Health & Human Services — Measuring Prevention More Broadly, An Empirical Assessment of CHIPRA Core Measures Differences in CHIP design and structure, across states and over time, may limit...

  3. OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins.

    Science.gov (United States)

    Harder, Edward; Damm, Wolfgang; Maple, Jon; Wu, Chuanjie; Reboul, Mark; Xiang, Jin Yu; Wang, Lingle; Lupyan, Dmitry; Dahlgren, Markus K; Knight, Jennifer L; Kaus, Joseph W; Cerutti, David S; Krilov, Goran; Jorgensen, William L; Abel, Robert; Friesner, Richard A

    2016-01-12

    The parametrization and validation of the OPLS3 force field for small molecules and proteins are reported. Enhancements with respect to the previous version (OPLS2.1) include the addition of off-atom charge sites to represent halogen bonding and aryl nitrogen lone pairs as well as a complete refit of peptide dihedral parameters to better model the native structure of proteins. To adequately cover medicinal chemical space, OPLS3 employs over an order of magnitude more reference data and associated parameter types relative to other commonly used small molecule force fields (e.g., MMFF and OPLS_2005). As a consequence, OPLS3 achieves a high level of accuracy across performance benchmarks that assess small molecule conformational propensities and solvation. The newly fitted peptide dihedrals lead to significant improvements in the representation of secondary structure elements in simulated peptides and native structure stability over a number of proteins. Together, the improvements made to both the small molecule and protein force field lead to a high level of accuracy in predicting protein-ligand binding measured over a wide range of targets and ligands (less than 1 kcal/mol RMS error) representing a 30% improvement over earlier variants of the OPLS force field.

  4. Giant Broad Line Regions in Dwarf Seyferts

    CERN Document Server

    Devereux, Nick

    2015-01-01

    High angular resolution spectroscopy obtained with the Hubble Space Telescope (HST) has revealed a remarkable population of galaxies hosting dwarf Seyfert nuclei with an unusually large broad-line region (BLR). These objects are remarkable for two reasons. Firstly, the size of the BLR can, in some cases, rival those seen in the most luminous quasars. Secondly, the size of the BLR is not correlated with the central continuum luminosity, an observation that distinguishes them from their reverberating counterparts. Collectively, these early results suggest that non-reverberating dwarf Seyferts are a heterogeneous group and not simply scaled versions of each other. Careful inspection reveals broad H Balmer emission lines with single peaks, double peaks, and a combination of the two, suggesting that the broad emission lines are produced in kinematically distinct regions centered on the black hole (BH). Because the gravitational field strength is already known for these objects, by virtue of knowing their BH mass, ...

  5. Broad-Spectrum Solution-Processed Photovoltaics

    Science.gov (United States)

    Ip, Alexander Halley

    High global demand for energy coupled with dwindling fossil fuel supply has driven the development of sustainable energy sources such as solar photovoltaics. Emerging solar technologies aim for low-cost, solution-processable materials which would allow wide deployment. Colloidal quantum dots (CQDs) are such a materials system which exhibits the ability to absorb across the entire solar spectrum, including in the infrared where many technologies cannot harvest photons. However, due to their nanocrystalline nature, CQDs are susceptible to surface-associated electronic traps which greatly inhibit performance. In this thesis, surface engineering of CQDs is presented through a combined ligand approach which improves the passivation of surface trap states. A metal halide treatment is found to passivate quantum dot surfaces in solution, while bifunctional organic ligands produce a dense film in solid state. This approach reduced midgap trap states fivefold compared with conventional passivation strategies and led to solar cells with a record certified 7.0% power conversion efficiency. The effect of this process on the electronic structure is studied through photoelectron spectroscopy. It is found that while the halide provides deep trap passivation, the nature of the metal cation on the CQD surface affects the density of band tail states. This effect is explored further through a wide survey of materials, and it is found that the coordination ability of the metal cation is responsible for the suppression of shallow traps. With this understanding of CQD surface passivation, broad spectral usage is then explored through a study of visible-absorbing organolead halide perovskite materials as well as narrow-bandgap CQD solar cells. Control over growth conditions and modification of electrode interfaces resulted in efficient perovskite devices with effective usages of visible photons. For infrared-absorbing CQDs, it is found that, in addition to providing surface trap

  6. Inclination of Broad Line Region in Narrow Line and Broad Line Seyfert 1 Galaxies

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    The sizes of the Broad Line Region (BLR) of some Seyfert 1 galax-ies and nearby quasars can be determined by the reverberation mapping method.Combining with the observed FWHM of Hβ emission line and assuming that themotion of BLR clouds is virialized, the black hole masses of these objects have beenestimated. However, this method strongly depends on the poorly-understood geom-etry and inclination of the BLR. On the other hand, a tight correlation between theblack hole mass and the bulge velocity dispersion was recently found for both activeand nearby inactive galaxies. This may provide another method, independent of theBLR geometry, for estimating the black hole mass. Using this method for estimatingthe black hole mass and combining with the measured BLR size and FWHM of Hβemission line, we derived the BLR inclination angles for 20 Seyfert I galaxies underthe assumption that the BLR is disk-like. The derived inclination angles agree wellwith those derived previously by fitting the UV continuum and Hβ emission lineprofiles. Adopting a relation between the FWHMs of [OⅢ]λ5007 forbidden line andthe stellar velocity dispersion, we also estimated the BLR inclinations for 50 nar-row line Seyfert 1 galaxies (NLSls). We found that the inclinations of broad LineSeyfert 1 galaxies (BLS1s) are systematically greater than those of NLS1s, whichseldom exceed 30. This may be an important factor that leads to the differencesbetween NLS1s and BLS1s if the BLR of NLS1s is really disk-like.

  7. Modelling Demand for Broad Money in Australia

    OpenAIRE

    Abbas Valadkhani

    2002-01-01

    The existence of a stable demand for money is very important for the conduct of monetary policy. It is argued that previous work on the demand for money in Australia has not been very satisfactory in a number of ways. This paper examines the long- and short-run determinants of the demand for broad money employing the Johansen cointegration technique and a short-run dynamic model. Using quarterly data for the period 1976:3-2002:2, this paper finds, inter alia, that the demand for broad money i...

  8. Teaching the Broad, Interdisciplinary Impact of Evolution

    Science.gov (United States)

    Benson, David; Atlas, Pierre; Haberski, Raymond; Higgs, Jamie; Kiley, Patrick; Maxwell, Michael, Jr.; Mirola, William; Norton, Jamey

    2009-01-01

    As perhaps the most encompassing idea in biology, evolution has impacted not only science, but other academic disciplines as well. The broad, interdisciplinary impact of evolution was the theme of a course taught at Marian College, Indianapolis, Indiana in 2002, 2004, and 2006. Using a strategy that could be readily adopted at other institutions,…

  9. The GREGOR Broad-Band Imager

    Science.gov (United States)

    von der Lühe, O.; Volkmer, R.; Kentischer, T. J.; Geißler, R.

    2012-11-01

    The design and characteristics of the Broad-Band Imager (BBI) of GREGOR are described. BBI covers the visible spectral range with two cameras simultaneously for a large field and with critical sampling at 390 nm, and it includes a mode for observing the pupil in a Foucault configuration. Samples of first-light observations are shown.

  10. Testing and Validation of High Density Resequencing Microarray for Broad Range Biothreat Agents Detection

    Science.gov (United States)

    2009-08-11

    on the chip. In the remaining five cases (Marburg Musoke, Lassa Acar, two Sandfly fever viruses: Sicilian and Punta Toro as well as Hantaan virus), the...types, such as closely related strains of filoviruses of the Ebola Zaire group, or the Machupo and Lassa arenaviruses. Furthermore, each RPM-TEI... Lassa viruses is described in supporting methods Text S1. Primer selection To simplify primer design and multiplex PCR optimization, four independent

  11. Broadly Neutralizing Antibodies for HIV Eradication.

    Science.gov (United States)

    Stephenson, Kathryn E; Barouch, Dan H

    2016-02-01

    Passive transfer of antibodies has long been considered a potential treatment modality for infectious diseases, including HIV. Early efforts to use antibodies to suppress HIV replication, however, were largely unsuccessful, as the antibodies that were studied neutralized only a relatively narrow spectrum of viral strains and were not very potent. Recent advances have led to the discovery of a large portfolio of human monoclonal antibodies that are broadly neutralizing across many HIV-1 subtypes and are also substantially more potent. These antibodies target multiple different epitopes on the HIV envelope, thus allowing for the development of antibody combinations. In this review, we discuss the application of broadly neutralizing antibodies (bNAbs) for HIV treatment and HIV eradication strategies. We highlight bNAbs that target key epitopes, such as the CD4 binding site and the V2/V3-glycan-dependent sites, and we discuss several bNAbs that are currently in the clinical development pipeline.

  12. Multiple and broad frequency response Gunn diodes

    Science.gov (United States)

    Pilgrim, N. J.; Macpherson, R. F.; Khalid, A.; Dunn, G. M.; Cumming, D. R. S.

    2009-10-01

    Gunn diodes, operating in transit time mode, are usually thought of as incapable of generating power at multiple frequencies or over a broad frequency range. In this paper, we report experimental results showing that these diodes can generate power at several frequencies and, using Monte Carlo simulations of both planar and vertical devices, we offer an explanation of how this unusual behaviour may come into being and suggest possible applications for this novel device.

  13. To Broad-Match or Not to Broad-Match : An Auctioneer's Dilemma ?

    CERN Document Server

    Singh, Sudhir Kumar

    2008-01-01

    We initiate the study of an interesting aspect of sponsored search advertising, namely the consequences of broad match-a feature where an ad of an advertiser can be mapped to a broader range of relevant queries, and not necessarily to the particular keyword(s) that ad is associated with. Starting with a very natural setting for strategies available to the advertisers, and via a careful look through algorithmic and complexity theoretic glasses, we first propose a solution concept called broad match equilibrium(BME) for the game originating from the strategic behavior of advertisers as they try to optimize their budget allocation across various keywords. Next, we consider two broad match scenarios based on factors such as information asymmetry between advertisers and the auctioneer, and the extent of auctioneer's control on the budget splitting. In the first scenario, the advertisers have the full information about broad match and relevant parameters, and can reapportion their own budgets to utilize the extra i...

  14. Crx broadly modulates the pineal transcriptome

    DEFF Research Database (Denmark)

    Rovsing, Louise; Clokie, Samuel; Bustos, Diego M;

    2011-01-01

    Cone-rod homeobox (Crx) encodes Crx, a transcription factor expressed selectively in retinal photoreceptors and pinealocytes, the major cell type of the pineal gland. In this study, the influence of Crx on the mammalian pineal gland was studied by light and electron microscopy and by use......-regulation of 745 genes (p pineal glands of wild......-type animals; only eight of these were also day/night expressed in the Crx-/- pineal gland. However, in the Crx-/- pineal gland 41 genes exhibited differential night/day expression that was not seen in wild-type animals. These findings indicate that Crx broadly modulates the pineal transcriptome and also...

  15. Broad spectrum antibiotic compounds and use thereof

    Energy Technology Data Exchange (ETDEWEB)

    Koglin, Alexander; Strieker, Matthias

    2016-07-05

    The discovery of a non-ribosomal peptide synthetase (NRPS) gene cluster in the genome of Clostridium thermocellum that produces a secondary metabolite that is assembled outside of the host membrane is described. Also described is the identification of homologous NRPS gene clusters from several additional microorganisms. The secondary metabolites produced by the NRPS gene clusters exhibit broad spectrum antibiotic activity. Thus, antibiotic compounds produced by the NRPS gene clusters, and analogs thereof, their use for inhibiting bacterial growth, and methods of making the antibiotic compounds are described.

  16. A Simple Disk Wind Model for Broad Absorption Line Quasars

    CERN Document Server

    Higginbottom, N; Long, K S; Sim, S A; Matthews, J H

    2013-01-01

    Approximately 20% of quasi-stellar objects (QSOs) exhibit broad, blue-shifted absorption lines in their ultraviolet spectra. Such features provide clear evidence for significant outflows from these systems, most likely in the form of accretion disk winds. These winds may represent the "quasar" mode of feedback that is often invoked in galaxy formation/evolution models, and they are also key to unification scenarios for active galactic nuclei (AGN) and QSOs. To test these ideas, we construct a simple benchmark model of an equatorial, biconical accretion disk wind in a QSO and use a Monte Carlo ionization/radiative transfer code to calculate the ultraviolet spectra as a function of viewing angle. We find that for plausible outflow parameters, sightlines looking directly into the wind cone do produce broad, blue-shifted absorption features in the transitions typically seen in broad absorption line QSOs. However, our benchmark model is intrinsically X-ray weak in order to prevent overionization of the outflow, an...

  17. XMM-Newton and Broad Iron Lines

    CERN Document Server

    Fabian, A C

    2007-01-01

    Iron line emission is common in the X-ray spectra of accreting black holes. When the line emission is broad or variable then it is likely to originate from close to the black hole. X-ray irradiation of the accretion flow by the power-law X-ray continuum produces the X-ray 'reflection' spectrum which includes the iron line. The shape and variability of the iron lines and reflection can be used as a diagnostic of the radius, velocity and nature of the flow. The inner radius of the dense flow corresponds to the innermost stable circular orbit and thus can be used to determine the spin of the black hole. Studies of broad iron lines and reflection spectra offer much promise for understanding how the inner parts of accretion flows (and outflows) around black holes operate. There remains great potential for XMM-Newton to continue to make significant progress in this work. The need for high quality spectra and thus for long exposure times is paramount.

  18. Trails, RS2477, B-Roads83, Published in 2006, Duchesne County.

    Data.gov (United States)

    NSGIC GIS Inventory (aka Ramona) — This Trails, RS2477 dataset, was produced all or in part from Other information as of 2006. It is described as 'B-Roads83'. Data by this publisher are often provided...

  19. Trails, RS2477, B-Roads83, Published in 2008, Duchesne County.

    Data.gov (United States)

    NSGIC GIS Inventory (aka Ramona) — This Trails, RS2477 dataset, was produced all or in part from Other information as of 2008. It is described as 'B-Roads83'. Data by this publisher are often provided...

  20. Broad-band acoustic hyperbolic metamaterial

    CERN Document Server

    Shen, Chen; Sui, Ni; Wang, Wenqi; Cummer, Steven A; Jing, Yun

    2015-01-01

    Acoustic metamaterials (AMMs) are engineered materials, made from subwavelength structures, that exhibit useful or unusual constitutive properties. There has been intense research interest in AMMs since its first realization in 2000 by Liu et al. A number of functionalities and applications have been proposed and achieved using AMMs. Hyperbolic metamaterials are one of the most important types of metamaterials due to their extreme anisotropy and numerous possible applications, including negative refraction, backward waves, spatial filtering, and subwavelength imaging. Although the importance of acoustic hyperbolic metamaterials (AHMMs) as a tool for achieving full control of acoustic waves is substantial, the realization of a broad-band and truly hyperbolic AMM has not been reported so far. Here, we demonstrate the design and experimental characterization of a broadband AHMM that operates between 1.0 kHz and 2.5 kHz.

  1. Spectrophotometry of six broad absorption line QSOs

    Science.gov (United States)

    Junkkarinen, Vesa T.; Burbidge, E. Margaret; Smith, Harding E.

    1987-01-01

    Spectrophotometric observations of six broad absorption-line QSOs (BALQSOs) are presented. The continua and emission lines are compared with those in the spectra of QSOs without BALs. A statistically significant difference is found in the emission-line intensity ratio for (N V 1240-A)/(C IV 1549-A). The median value of (N V)/(C IV) for the BALQSOs is two to three times the median for QSOs without BALs. The absorption features of the BALQSOs are described, and the column densities and limits on the ionization structure of the BAL region are discussed. If the dominant ionization mechanism is photoionization, then it is likely that either the ionizing spectrum is steep or the abundances are considerably different from solar. Collisional ionization may be a significant factor, but it cannot totally dominate the ionization rate.

  2. A simple disc wind model for broad absorption line quasars

    Science.gov (United States)

    Higginbottom, N.; Knigge, C.; Long, K. S.; Sim, S. A.; Matthews, J. H.

    2013-12-01

    Approximately 20 per cent of quasi-stellar objects (QSOs) exhibit broad, blue-shifted absorption lines in their ultraviolet spectra. Such features provide clear evidence for significant outflows from these systems, most likely in the form of accretion disc winds. These winds may represent the `quasar' mode of feedback that is often invoked in galaxy formation/evolution models, and they are also key to unification scenarios for active galactic nuclei (AGN) and QSOs. To test these ideas, we construct a simple benchmark model of an equatorial, biconical accretion disc wind in a QSO and use a Monte Carlo ionization/radiative transfer code to calculate the ultraviolet spectra as a function of viewing angle. We find that for plausible outflow parameters, sightlines looking directly into the wind cone do produce broad, blue-shifted absorption features in the transitions typically seen in broad absorption line (BAL) QSOs. However, our benchmark model is intrinsically X-ray weak in order to prevent overionization of the outflow, and the wind does not yet produce collisionally excited line emission at the level observed in non-BAL QSOs. As a first step towards addressing these shortcomings, we discuss the sensitivity of our results to changes in the assumed X-ray luminosity and mass-loss rate, Ṁwind. In the context of our adopted geometry, Ṁwind ˜ Ṁacc is required in order to produce significant BAL features. The kinetic luminosity and momentum carried by such outflows would be sufficient to provide significant feedback.

  3. Seven broad absorption line quasars with excess broad band absorption near 2250

    CERN Document Server

    Zhang, Shaohua; Jiang, Peng; Zhou, Hongyan; Ma, Jingzhe; Brandt, W N; York, Donald G; Noterdaeme, P; Schneider, Donald P

    2014-01-01

    We report the discovery of excess broad band absorption near 2250 A (EBBA) in the spectra of seven broad absorption line (BAL) quasars. By comparing with the statistical results from the control quasar sample, the significance for the detections are all above the > 4{\\sigma} level, with five above > 5{\\sigma}. The detections have also been verified by several other independent methods. The EBBAs present broader and weaker bumps at smaller wavenumbers than the Milky Way, and similar to the Large Magellanic Cloud. The EBBA bump may be related to the 2175 A bump seen in the Local Group and may be a counterpart of the 2175 A bump under different conditions in the early Universe. Furthermore, five objects in this sample show low-ionization broad absorption lines (LoBALs), such as Mg II and Al III, in addition to the high-ionization broad absorption lines (HiBALs) of C IV and Si IV. The fraction of LoBALs in our sample, ~70%, is surprisingly high compared to that of general BAL quasars, ~10%. Although the origin of...

  4. Photoionisation modelling of the broad line region

    Science.gov (United States)

    King, Anthea

    2016-08-01

    Two of the most fundamental questions regarding the broad line region (BLR) are "what is its structure?" and "how is it moving?" Baldwin et al. (1995) showed that by summing over an ensemble of clouds at differing densities and distances from the ionising source we can easily and naturally produce a spectrum similar to what is observed for AGN. This approach is called the `locally optimally emitting clouds' (LOC) model. This approach can also explain the well-observed stratification of emission lines in the BLR (e.g. Clavel et al. 1991, Peterson et al. 1991, Kollatschny et al. 2001) and `breathing' of BLR with changes in the continuum luminosity (Netzer & Mor 1990, Peterson et al. 2014) and is therefore a generally accepted model of the BLR. However, LOC predictions require some assumptions to be made about the distribution of the clouds within the BLR. By comparing photoionization predictions, for a distribution of cloud properties, with observed spectra we can infer something about the structure of the BLR and distribution of clouds. I use existing reverberation mapping data to constrain the structure of the BLR by observing how individual line strengths and ratios of different lines change in high and low luminosity states. I will present my initial constraints and discuss the challenges associated with the method.

  5. Validation, automatic generation and use of broad phonetic transcriptions

    NARCIS (Netherlands)

    Bael, Cristophe Patrick Jan Van

    2007-01-01

    Broad phonetic transcriptions represent the pronunciation of words as strings of characters from specifically designed symbol sets. In everyday life, broad phonetic transcriptions are often used as aids to pronounce (foreign) words. In addition, broad phonetic transcriptions are often used for lingu

  6. Broad spectrum anthelmintic potential of Cassia plants

    Institute of Scientific and Technical Information of China (English)

    Suman Kundu; Saptarshi Roy; Larisha Mawkhleing Lyndem

    2014-01-01

    Objective: To study the in vitro anthelmintic efficacy of Cassia alata (C. alata), Cassia(C. angustifolia) and Cassia occidentalis (C. occidentalis). angustifolia Methods: Crude ethanol extract from leaves of the three plants were prepared in rotary evaporator and different concentrations (10, 20 and 40 mg/mL) of leaf extracts were used for treatment on different representatives of helminthes (Heterakis gallinarum, Raillietina tetragona and Catatropis sp.) from domestic fowl (Gallus gallus domesticus). Loss of motility and death were monitored frequently.Results: C. alata showed early paralysis in all worms treated followed by C. angustifolia. C. occidentalis in combination with C. alata together caused early paralysis in all treated worms than the combination of C. alata with C. angustfolia. While Heterakis gallinarum in control survived for (81.33±2.07) h, treated worms lost their motility at (5.71±0.10) h, (6.60±0.86) h and (13.95±0.43) h with C. angustifolia, C. alata and C. occidentalis respectively at a concentration of 40 mg/mL which showed better efficacy than albendazole. Catatropis sp. survival period was (26.49±1.38) h in control, but with plant treatment, it lost its motility in just (0.57±0.08) h, (1.00±0.12) h and (1.47±0.40) h at 40 mg/mL concentration of C. alata, C. angustifolia and C. occidentalis respectively.Raillietina tetragona on the other hand became paralysed at (1.68±0.27) h, (2.95±0.29) h and (4.13±0.31) h with above concentrations treated with three plants respectively, however in control it survived up to (81.93±4.71) h.Conclusions:This present study indicated broad spectrum vermifugal activity of all plants tested.

  7. Interim Report on SNP analysis and forensic microarray probe design for South American hemorrhagic fever viruses, tick-borne encephalitis virus, henipaviruses, Old World Arenaviruses, filoviruses, Crimean-Congo hemorrhagic fever viruses, Rift Valley fever

    Energy Technology Data Exchange (ETDEWEB)

    Jaing, C; Gardner, S

    2012-06-05

    The goal of this project is to develop forensic genotyping assays for select agent viruses, enhancing the current capabilities for the viral bioforensics and law enforcement community. We used a multipronged approach combining bioinformatics analysis, PCR-enriched samples, microarrays and TaqMan assays to develop high resolution and cost effective genotyping methods for strain level forensic discrimination of viruses. We have leveraged substantial experience and efficiency gained through year 1 on software development, SNP discovery, TaqMan signature design and phylogenetic signature mapping to scale up the development of forensics signatures in year 2. In this report, we have summarized the whole genome wide SNP analysis and microarray probe design for forensics characterization of South American hemorrhagic fever viruses, tick-borne encephalitis viruses and henipaviruses, Old World Arenaviruses, filoviruses, Crimean-Congo hemorrhagic fever virus, Rift Valley fever virus and Japanese encephalitis virus.

  8. The response of rodents to scent marks: four broad hypotheses.

    Science.gov (United States)

    Ferkin, Michael H

    2015-02-01

    This article is part of a Special Issue "Chemosignals and Reproduction". Many terrestrial mammals must be able to distinguish between the myriad of scent marks they encounter in order for them to facilitate or deter direct interactions with their scent donors. I review studies that examine how rodents, mainly meadow voles (Microtus pennsylvanicus), respond when they encounter the scent marks of conspecifics and heterospecifics, and how context, as well as the age and condition of senders and receivers, affect their responses. The review uses four broad hypotheses to discuss the response of rodents to scent marks. The four hypotheses are as follows: 1) Scent marks convey accurate information to the receiver about the sender's state and phenotype and genotype. 2) Scent marks are individually distinct. 3) The response of receivers to scent marks is flexible and would be modulated by the cognitive abilities of receivers. 4) Receivers respond to the information contained or conveyed by the scent mark in a manner that will increase their survival and fitness. The studies cited in this review show that scent marks signal accurate information about the sender's phenotype, genotype, and condition, which receivers use to distinguish among the scent marks of different conspecifics and heterospecifics, and by doing so, receivers tailor their response accordingly to increase their survival and fitness. Thus, the four broad hypotheses may serve as guide to increase our understanding of the response of receivers to scent marks and provide a conceptual framework for future research and the development of additional hypotheses.

  9. Therapy Provider Phase Information

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Therapy Provider Phase Information dataset is a tool for providers to search by their National Provider Identifier (NPI) number to determine their phase for...

  10. Naked eye visibility of Sirius in broad daylight.

    Science.gov (United States)

    Können, Gunther P; Tinbergen, Jaap; Stammes, Piet

    2015-02-01

    Sirius was spotted with the naked eye at broad daylight by looking along the finder of a 1 m telescope on La Palma Observatory at a 2370 m height. Sun elevation was 73°; Sirius was nearly straight under the Sun at 37° elevation. The sky radiance, although not recorded directly, could be determined from the simultaneously obtained high-precision wavelength-dependent sky polarization data near Sirius. This was done by fitting the polarization data with the doubling-adding KNMI (DAK) radiative transfer model, which provided the values of the surface albedo and of the aerosol optical thickness required for determining the absolute sky radiance. Our analysis implies that Sirius, when positioned overhead, can be a daytime naked eye object from sea level even if its culmination occurs at solar noon. It also suggests that the second-brightest star (Canopus), if positioned overhead, could be perceptible even at solar noon.

  11. Method for detection and imaging over a broad spectral range

    Science.gov (United States)

    Yefremenko, Volodymyr; Gordiyenko, Eduard; Pishko, legal representative, Olga; Novosad, Valentyn; Pishko, deceased; Vitalii

    2007-09-25

    A method of controlling the coordinate sensitivity in a superconducting microbolometer employs localized light, heating or magnetic field effects to form normal or mixed state regions on a superconducting film and to control the spatial location. Electron beam lithography and wet chemical etching were applied as pattern transfer processes in epitaxial Y--Ba--Cu--O films. Two different sensor designs were tested: (i) a 3 millimeter long and 40 micrometer wide stripe and (ii) a 1.25 millimeters long, and 50 micron wide meandering-like structure. Scanning the laser beam along the stripe leads to physical displacement of the sensitive area, and, therefore, may be used as a basis for imaging over a broad spectral range. Forming the superconducting film as a meandering structure provides the equivalent of a two-dimensional detector array. Advantages of this approach are simplicity of detector fabrication, and simplicity of the read-out process requiring only two electrical terminals.

  12. Robust linear regression with broad distributions of errors

    CERN Document Server

    Postnikov, Eugene B

    2015-01-01

    We consider the problem of linear fitting of noisy data in the case of broad (say $\\alpha$-stable) distributions of random impacts ("noise"), which can lack even the first moment. This situation, common in statistical physics of small systems, in Earth sciences, in network science or in econophysics, does not allow for application of conventional Gaussian maximum-likelihood estimators resulting in usual least-squares fits. Such fits lead to large deviations of fitted parameters from their true values due to the presence of outliers. The approaches discussed here aim onto the minimization of the width of the distribution of residua. The corresponding width of the distribution can either be defined via the interquantile distance of the corresponding distributions or via the scale parameter in its characteristic function. The methods provide the robust regression even in the case of short samples with large outliers, and are equivalent to the normal least squares fit for the Gaussian noises. Our discussion is il...

  13. DISCOVERY OF THE TRANSITION OF A MINI-BROAD ABSORPTION LINE INTO A BROAD ABSORPTION LINE IN THE SDSS QUASAR J115122.14+020426.3

    Energy Technology Data Exchange (ETDEWEB)

    Hidalgo, Paola Rodriguez; Eracleous, Michael; Charlton, Jane [Department of Astronomy and Astrophysics, Pennsylvania State University, 525 Davey Lab, University Park, PA 16802 (United States); Hamann, Fred [Department of Astronomy, University of Florida, Gainesville, FL 32611 (United States); Murphy, Michael T. [Center for Astrophysics and Supercomputing, Swinburne University of Technology, P.O. Box 218, Hawthorn, Victoria 3122 (Australia); Nestor, Daniel [Department of Physics and Astronomy, University of California, 430 Portola Plaza, Box 951547, Los Angeles, CA 90095 (United States)

    2013-09-20

    We present the detection of a rare case of dramatic strengthening in the UV absorption profiles in the spectrum of the quasar J115122.14+020426.3 between observations {approx}2.86 yr apart in the quasar rest frame. A spectrum obtained in 2001 by the Sloan Digital Sky Survey shows a C IV ''mini-broad'' absorption line (FWHM = 1220 km s{sup -1}) with a maximum blueshift velocity of {approx}9520 km s{sup -1}, while a later spectrum from the Very Large Telescope shows a significantly broader and stronger absorption line, with a maximum blueshift velocity of {approx}12, 240 km s{sup -1} that qualifies as a broad absorption line. A similar variability pattern is observed in two additional systems at lower blueshifted velocities and in the Ly{alpha} and N V transitions as well. One of the absorption systems appears to be resolved and shows evidence for partial covering of the quasar continuum source (C{sub f} {approx} 0.65), indicating a transverse absorber size of, at least, {approx}6 Multiplication-Sign 10{sup 16} cm. In contrast, a cluster of narrower C IV lines appears to originate in gas that fully covers the continuum and broad emission line sources. There is no evidence for changes in the centroid velocity of the absorption troughs. This case suggests that at least some of the absorbers that produce ''mini-broad'' and broad absorption lines in quasar spectra do not belong to intrinsically separate classes. Here, the ''mini-broad'' absorption line is most likely interpreted as an intermediate phase before the appearance of a broad absorption line due to their similar velocities. While the current observations do not provide enough constraints to discern among the possible causes for this variability, future monitoring of multiple transitions at high resolution will help achieve this goal.

  14. The characteristic of power flow in broad band dynamic vibration absorber

    Institute of Scientific and Technical Information of China (English)

    WANG Minqing; SHENG Meiping; SUN Jincai; LIU Yi

    2002-01-01

    DVA (dynamic vibration absorber) is good for restrain of the resonance vibration in low frequency, especially under the condition that there are only one mode or two modes in a frequency band. It seems rather difficult to control the resonance vibration of elastic structures in high frequency, since usually there are so many modes in high frequency band. The broad band DVA is brought forward to reduce the resonance vibration of elastic structures. The broad band DVA is designed on the basis of the characteristic of power flow in structure in this paper.The broad band DVA is effective on absorbing the resonance vibration power flow of the mostimportant modes. The ability of absorbing vibration for the broad band DVA is analyzed indetail. The results obtained in this paper provide a basis for the optimization design of thebroad band DVA and the optimization positions on structures.

  15. Dependent rational providers.

    Science.gov (United States)

    Brothers, Kyle B

    2011-04-01

    Provider claims to conscientious objection have generated a great deal of heated debate in recent years. However, the conflicts that arise when providers make claims to the "conscience" are only a subset of the more fundamental challenges that arise in health care practice when patients and providers come into conflict. In this piece, the author provides an account of patient-provider conflict from within the moral tradition of St. Thomas Aquinas. He argues that the practice of health care providers should be understood as a form of practical reasoning and that this practical reasoning must necessarily incorporate both "moral" and "professional" commitments. In order to understand how the practical reasoning of provider should account for the needs and commitments of the patient and vice versa, he explores the account of dependence provided by Alasdair MacIntyre in his book Dependent Rational Animals. MacIntyre argues that St. Thomas' account of practical reasoning should be extended and adapted to account for the embodied vulnerability of all humans. In light of this insight, providers must view patients not only as the subjects of their moral reflection but also as fellow humans upon whom the provider depends for feedback on the effectiveness and relevance of her practical reasoning. The author argues that this account precludes responsive providers from adopting either moral or professional conclusions on the appropriateness of interventions outside the individual circumstances that arise in particular situations. The adoption of this orientation toward patients will neither eradicate provider-patient conflict nor compel providers to perform interventions to which they object. But this account does require that providers attend meaningfully to the suffering of patients and seek feedback on whether their intervention has effectively addressed that suffering.

  16. Energy degeneracies from Broad Histogram Method and Wang-Landau Sampling

    CERN Document Server

    Lima, Alexandre Pereira; Girardi, Daniel

    2016-01-01

    In this work, we present a comparative study of the accuracy provided by the Wang-Landau sampling and the Broad Histogram method to estimate de density of states of the two dimensional Ising ferromagnet. The microcanonical averages used to describe the thermodynamic behaviour and to use the Broad Histogram method were obtained using the single spin-flip Wang-Landau sampling, attempting to convergence issues and accuracy improvements. We compare the results provided by both techniques with the exact ones for thermodynamic properties and critical exponents. Our results, within the Wang-Landau sampling, reveal that the Broad Histogram approach provides a better description of the density of states for all cases analysed.

  17. On the Operational Meaning of Broad-Spectrum Philosophy Methodology

    Directory of Open Access Journals (Sweden)

    Miao Yi

    2012-06-01

    Full Text Available This study analyze the Broad-spectrum Philosophy Methodology on the operational meaning, and discusses three relatively primary methods of Broad-spectrum Philosophy Methodologies. The methodology of Broad-spectrum philosophy cannot pursuit of accuracy of numerical sense, but it pursuits of the exact nature of the research questions, the accuracy of the sense of set theory and sums up the experience which we solve problems in real life and make it up to the generalized quantization and procedural level and thus the methodology of Broad-spectrum philosophy has a general guide and it is a broad operations research. We gets the results that along with deep exploration and development of Broad-spectrum Philosophy Methodology, its function as generalized operation research can be more powerful.

  18. Cross-reactive broadly neutralizing antibodies: timing is everything

    OpenAIRE

    Euler, Zelda; Schuitemaker, Hanneke

    2012-01-01

    The recent surge of research into new broadly neutralizing antibodies in HIV-1 infection has recharged the field of HIV-1 vaccinology. In this review we discuss the currently known broadly neutralizing antibodies and focus on factors that may shape these antibodies in natural infection. We further discuss the role of these antibodies in the clinical course of the infection and consider immunological obstacles in inducing broadly neutralizing antibodies with a vaccine.

  19. Cross-reactive broadly neutralizing antibodies: timing is everything.

    Science.gov (United States)

    Euler, Zelda; Schuitemaker, Hanneke

    2012-01-01

    The recent surge of research into new broadly neutralizing antibodies in HIV-1 infection has recharged the field of HIV-1 vaccinology. In this review we discuss the currently known broadly neutralizing antibodies and focus on factors that may shape these antibodies in natural infection. We further discuss the role of these antibodies in the clinical course of the infection and consider immunological obstacles in inducing broadly neutralizing antibodies with a vaccine.

  20. Ultra-Broad-Band Optical Parametric Amplifier or Oscillator

    Science.gov (United States)

    Strekalov, Dmitry; Matsko, Andrey; Savchenkov, Anatolly; Maleki, Lute

    2009-01-01

    A concept for an ultra-broad-band optical parametric amplifier or oscillator has emerged as a by-product of a theoretical study in fundamental quantum optics. The study was originally intended to address the question of whether the two-photon temporal correlation function of light [in particular, light produced by spontaneous parametric down conversion (SPDC)] can be considerably narrower than the inverse of the spectral width (bandwidth) of the light. The answer to the question was found to be negative. More specifically, on the basis of the universal integral relations between the quantum two-photon temporal correlation and the classical spectrum of light, it was found that the lower limit of two-photon correlation time is set approximately by the inverse of the bandwidth. The mathematical solution for the minimum two-photon correlation time also provides the minimum relative frequency dispersion of the down-converted light components; in turn, the minimum relative frequency dispersion translates to the maximum bandwidth, which is important for the design of an ultra-broad-band optical parametric oscillator or amplifier. In the study, results of an analysis of the general integral relations were applied in the case of an optically nonlinear, frequency-dispersive crystal in which SPDC produces collinear photons. Equations were found for the crystal orientation and pump wavelength, specific for each parametric-down-converting crystal, that eliminate the relative frequency dispersion of collinear degenerate (equal-frequency) signal and idler components up to the fourth order in the frequency-detuning parameter

  1. Broad epitope coverage of a human in vitro antibody library

    Science.gov (United States)

    Sivasubramanian, Arvind; Lynaugh, Heather; Yu, Yao; Miles, Adam; Eckman, Josh; Schutz, Kevin; Piffath, Crystal; Boland, Nadthakarn; Durand, Stéphanie; Boland, Todd; Vásquez, Maximiliano; Xu, Yingda; Abdiche, Yasmina

    2017-01-01

    ABSTRACT Successful discovery of therapeutic antibodies hinges on the identification of appropriate affinity binders targeting a diversity of molecular epitopes presented by the antigen. Antibody campaigns that yield such broad “epitope coverage” increase the likelihood of identifying candidates with the desired biological functions. Accordingly, epitope binning assays are employed in the early discovery stages to partition antibodies into epitope families or “bins” and prioritize leads for further characterization and optimization. The collaborative program described here, which used hen egg white lysozyme (HEL) as a model antigen, combined 3 key capabilities: 1) access to a diverse panel of antibodies selected from a human in vitro antibody library; 2) application of state-of-the-art high-throughput epitope binning; and 3) analysis and interpretation of the epitope binning data with reference to an exhaustive set of published antibody:HEL co-crystal structures. Binning experiments on a large merged panel of antibodies containing clones from the library and the literature revealed that the inferred epitopes for the library clones overlapped with, and extended beyond, the known structural epitopes. Our analysis revealed that nearly the entire solvent-exposed surface of HEL is antigenic, as has been proposed for protein antigens in general. The data further demonstrated that synthetic antibody repertoires provide as wide epitope coverage as those obtained from animal immunizations. The work highlights molecular insights contributed by increasingly higher-throughput binning methods and their broad utility to guide the discovery of therapeutic antibodies representing a diverse set of functional epitopes. PMID:27748644

  2. Extracting fundamental transverse mode operation in broad area quantum cascade lasers

    Science.gov (United States)

    Kaspi, R.; Luong, S.; Yang, C.; Lu, C.; Newell, T. C.; Bate, T.

    2016-11-01

    Power scaling in broad area quantum cascade lasers results in the operation of high order transverse modes with a far-field profile consisting of two lobes propagating at large angles relative to the optical axis. We report a method of suppressing the high order transverse modes that can extract the fundamental mode and provide emission along the optical axis. By generating a lateral constriction in the waveguide in the form of short trenches defined by the focused ion beam milling technique, we report broad area devices in which most of the power is contained in a near diffraction-limited beam that provides high brightness.

  3. Broad support evident for the emerging specialty of orofacial pain.

    Science.gov (United States)

    Talley, R L; Fricton, J R; Okeson, J P

    2000-01-01

    The emerging field of Orofacial Pain is being considered by the American Dental Association for full status as a new dental specialty. Many recent advances in the neuroscience of orofacial pain have lead to treatments by orofacial pain dentists that provide significant relief for patients with chronic orofacial pain disorders. However, access to this care has been limited leaving many patients to continue to suffer. Subsequently, recent efforts to improve this by developing the field into a specialty have shown broad support among dentists and increased awareness of the benefits this field can provide for dentists and their patients. A recent survey of 805 individuals in the general population who reported having a persistent pain disorder revealed that more than four out of 10 people have yet to find adequate relief, saying their pain is out of control-despite having the pain for more than 5 years and switching doctors at least once. "This survey suggests that there are millions of people living with severe uncontrolled pain," says Russell Portenoy, MD, President of the American Pain Society. "This is a great tragedy. Although not everyone can be helped, it is very likely that most of these patients could benefit if provided with state-of-the-art therapies and improved access to pain specialists when needed." (1). Development of the field of Orofacial Pain into a dental specialty has been motivated primarily by this issue; patients with complex chronic orofacial pain disorders have not been historically treated well by any discipline of health care. Recent studies of chronic orofacial pain patients have found that these patients have a high number of previous clinicians and have endured many years with pain prior to seeing an orofacial pain dentist (2) (Fig. 1). Complex pain patients and the clinicians who see them are often confused about whom they should consult for relief of the painful disorder. Treatment for these patients within the existing structure of

  4. Assessing Eli Broad's Assault on Public School System Leadership

    Science.gov (United States)

    English, Fenwick W.; Crowder, Zan

    2012-01-01

    Eli Broad's approach to reforming urban public education does not recognize his own self-interest in promoting changes within such educational systems, a classic problem of misrecognition. The Broad agenda is an assault on the notion of the mission of public education as a service instead of a for-profit enterprise concerned with making money for…

  5. Social Cognition, Social Skill, and the Broad Autism Phenotype

    Science.gov (United States)

    Sasson, Noah J.; Nowlin, Rachel B.; Pinkham, Amy E.

    2013-01-01

    Social-cognitive deficits differentiate parents with the "broad autism phenotype" from non-broad autism phenotype parents more robustly than other neuropsychological features of autism, suggesting that this domain may be particularly informative for identifying genetic and brain processes associated with the phenotype. The current study…

  6. Broadly protective influenza vaccines: Redirecting the antibody response through adjuvation

    NARCIS (Netherlands)

    Cox, F.

    2016-01-01

    Influenza virus infections are responsible for significant morbidity worldwide and current vaccines have limited coverage, therefore it remains a high priority to develop broadly protective vaccines. With the discovery of broadly neutralizing antibodies (bnAbs) against influenza these vaccines becam

  7. Boot Camp for Education CEOs: The Broad Foundation Superintendents Academy

    Science.gov (United States)

    Jehlen, Alain

    2012-01-01

    The Broad Foundation Superintendents Academy is the most prominent and most controversial training institute for school chiefs. The Academy is the flagship program of the Eli and Edythe Broad Foundation, the smallest of a triumvirate of corporate foundations that are at the heart of the billionaire campaign to remake public education in the image…

  8. Provider of Services File

    Data.gov (United States)

    U.S. Department of Health & Human Services — The POS file consists of two data files, one for CLIA labs and one for 18 other provider types. The file names are CLIA and OTHER. If downloading the file, note it...

  9. What HERA may provide?

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Hannes [DESY, Hamburg (Germany); De Roeck, Albert [CERN, Genf (Switzerland); Bartles, Jochen [Univ. Hamburg (DE). Institut fuer Theoretische Physik II] (and others)

    2008-09-15

    More than 100 people participated in a discussion session at the DIS08 workshop on the topic What HERA may provide. A summary of the discussion with a structured outlook and list of desirable measurements and theory calculations is given. (orig.)

  10. Internet Medline providers.

    Science.gov (United States)

    Vine, D L; Coady, T R

    1998-01-01

    Each database in this review has features that will appeal to some users. Each provides a credible interface to information available within the Medline database. The major differences are pricing and interface design. In this context, features that cost more and might seem trivial to the occasional searcher may actually save time and money when used by the professional. Internet Grateful Med is free, but Ms. Coady and I agree the availability of only three ANDable search fields is a major functional limitation. PubMed is also free but much more powerful. The command line interface that permits very sophisticated searches requires a commitment that casual users will find intimidating. Ms. Coady did not believe the feedback currently provided during a search was sufficient for sustained professional use. Paper Chase and Knowledge Finder are mature, modestly priced Medline search services. Paper Chase provides a menu-driven interface that is very easy to use, yet permits the user to search virtually all of Medline's data fields. Knowledge Finder emphasizes the use of natural language queries but fully supports more traditional search strategies. The impact of the tradeoff between fuzzy and Boolean strategies offered by Knowledge Finder is unclear and beyond the scope of this review. Additional software must be downloaded to use all of Knowledge Finders' features. Other providers required no software beyond the basic Internet browser, and this requirement prevented Ms. Coady from evaluating Knowledge Finder. Ovid and Silver Platter offer well-designed interfaces that simplify the construction of complex queries. These are clearly services designed for professional users. While pricing eliminates these for casual use, it should be emphasized that Medline citation access is only a portion of the service provided by these high-end vendors. Finally, we should comment that each of the vendors and government-sponsored services provided prompt and useful feedback to e

  11. Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo

    DEFF Research Database (Denmark)

    Erbayraktar, Serhat; Grasso, Giovanni; Sfacteria, Alessandra;

    2003-01-01

    importantly, asialoEPO exhibits a broad spectrum of neuroprotective activities, as demonstrated in models of cerebral ischemia, spinal cord compression, and sciatic nerve crush. These data suggest that nonerythropoietic variants of rhEPO can cross the blood-brain barrier and provide neuroprotection....

  12. Building Service Provider Capabilities

    DEFF Research Database (Denmark)

    Brandl, Kristin; Jaura, Manya; Ørberg Jensen, Peter D.

    In this paper we study whether and how the interaction between clients and the service providers contributes to the development of capabilities in service provider firms. In situations where such a contribution occurs, we analyze how different types of activities in the production process...... of the services, such as sequential or reciprocal task activities, influence the development of different types of capabilities. We study five cases of offshore-outsourced knowledge-intensive business services that are distinguished according to their reciprocal or sequential task activities in their production...... process. We find that clients influence the development of human capital capabilities and management capabilities in reciprocally produced services. While in sequential produced services clients influence the development of organizational capital capabilities and management capital capabilities....

  13. Biodiversity inhibits parasites: Broad evidence for the dilution effect.

    Science.gov (United States)

    Civitello, David J; Cohen, Jeremy; Fatima, Hiba; Halstead, Neal T; Liriano, Josue; McMahon, Taegan A; Ortega, C Nicole; Sauer, Erin Louise; Sehgal, Tanya; Young, Suzanne; Rohr, Jason R

    2015-07-14

    Infectious diseases of humans, wildlife, and domesticated species are increasing worldwide, driving the need to understand the mechanisms that shape outbreaks. Simultaneously, human activities are drastically reducing biodiversity. These concurrent patterns have prompted repeated suggestions that biodiversity and disease are linked. For example, the dilution effect hypothesis posits that these patterns are causally related; diverse host communities inhibit the spread of parasites via several mechanisms, such as by regulating populations of susceptible hosts or interfering with parasite transmission. However, the generality of the dilution effect hypothesis remains controversial, especially for zoonotic diseases of humans. Here we provide broad evidence that host diversity inhibits parasite abundance using a meta-analysis of 202 effect sizes on 61 parasite species. The magnitude of these effects was independent of host density, study design, and type and specialization of parasites, indicating that dilution was robust across all ecological contexts examined. However, the magnitude of dilution was more closely related to the frequency, rather than density, of focal host species. Importantly, observational studies overwhelmingly documented dilution effects, and there was also significant evidence for dilution effects of zoonotic parasites of humans. Thus, dilution effects occur commonly in nature, and they may modulate human disease risk. A second analysis identified similar effects of diversity in plant-herbivore systems. Thus, although there can be exceptions, our results indicate that biodiversity generally decreases parasitism and herbivory. Consequently, anthropogenic declines in biodiversity could increase human and wildlife diseases and decrease crop and forest production.

  14. Broad electrical tuning of graphene-loaded plasmonic antennas.

    Science.gov (United States)

    Yao, Yu; Kats, Mikhail A; Genevet, Patrice; Yu, Nanfang; Song, Yi; Kong, Jing; Capasso, Federico

    2013-03-13

    Plasmonic antennas enable the conversion of light from free space into subwavelength volumes and vice versa, which facilitates the manipulation of light at the nanoscale. Dynamic control of the properties of antennas is desirable for many applications, including biochemical sensors, reconfigurable meta-surfaces and compact optoelectronic devices. The combination of metallic structures and graphene, which has gate-voltage dependent optical properties, is emerging as a possible platform for electrically controlled plasmonic devices. In this paper, we demonstrate in situ control of antennas using graphene as an electrically tunable load in the nanoscale antenna gap. In our experiments, we demonstrate electrical tuning of graphene-loaded antennas over a broad wavelength range of 650 nm (∼140 cm(-1), ∼10% of the resonance frequency) in the mid-infrared (MIR) region. We propose an equivalent circuit model to quantitatively analyze the tuning behavior of graphene-loaded antenna pairs and derive an analytical expression for the tuning range of resonant wavelength. In a separate experiment, we used doubly resonant antenna arrays to achieve MIR optical intensity modulation with maximum modulation depth of more than 30% and bandwidth of 600 nm (∼100 cm(-1), 8% of the resonance frequency). This study shows that combining graphene with metallic nanostructures provides a route to electrically tunable optical and optoelectronic devices.

  15. Ultra-broad bandwidth parametric amplification at degeneracy.

    Science.gov (United States)

    Limpert, J; Aguergaray, C; Montant, S; Manek-Hönninger, I; Petit, S; Descamps, D; Cormier, E; Salin, F

    2005-09-19

    We report on a novel approach of ultra-broad bandwidth parametric amplification around degeneracy. A bandwidth of up to 400 nm centered around 800 nm is amplified in a BBO crystal by using chirped pump pulses with a bandwitdth as broad as 10 nm. A supercontinuum signal is generated in a microstructured fiber, having to first order a quadratic chirp, which is necessary to ensure temporal overlap of the interacting waves over this broad bandwidth. Furthermore, we discuss the potential of this approach for an octave-spanning parametric amplification.

  16. Characterization of non-host resistance in broad bean to the wheat stripe rust pathogen

    Directory of Open Access Journals (Sweden)

    Cheng Yulin

    2012-06-01

    Full Text Available Abstract Background Non-host resistance (NHR confers plant species immunity against the majority of microbial pathogens and represents the most robust and durable form of plant resistance in nature. As one of the main genera of rust fungi with economic and biological importance, Puccinia infects almost all cereals but is unable to cause diseases on legumes. Little is known about the mechanism of this kind of effective defense in legumes to these non-host pathogens. Results In this study, the basis of NHR in broad bean (Vicia faba L. against the wheat stripe rust pathogen, Puccinia striiformis f. sp. tritici (Pst, was characterized. No visible symptoms were observed on broad bean leaves inoculated with Pst. Microscopic observations showed that successful location of stomata and haustoria formation were significantly reduced in Pst infection of broad bean. Attempted infection induced the formation of papillae, cell wall thickening, production of reactive oxygen species, callose deposition and accumulation of phenolic compounds in plant cell walls. The few Pst haustoria that did form in broad bean cells were encased in reactive oxygen and callose materials and those cells elicited cell death. Furthermore, a total of seven defense-related genes were identified and found to be up-regulated during the Pst infection. Conclusions The results indicate that NHR in broad bean against Pst results from a continuum of layered defenses, including basic incompatibility, structural and chemical strengthening of cell wall, posthaustorial hypersensitive response and induction of several defense-related genes, demonstrating the multi-layered feature of NHR. This work also provides useful information for further determination of resistance mechanisms in broad bean to rust fungi, especially the adapted important broad bean rust pathogen, Uromyces viciae-fabae, because of strong similarity and association between NHR of plants to unadapted pathogens and basal

  17. Providing Compassion through Flow

    Directory of Open Access Journals (Sweden)

    Lydia Royeen

    2015-07-01

    Full Text Available Meg Kral, MS, OTR/L, CLT, is the cover artist for the Summer 2015 issue of The Open Journal of Occupational Therapy. Her untitled piece of art is an oil painting and is a re-creation of a photograph taken while on vacation. Meg is currently supervisor of outpatient services at Rush University Medical Center. She is lymphedema certified and has a specific interest in breast cancer lymphedema. Art and occupational therapy serve similar purposes for Meg: both provide a sense of flow. She values the outcomes, whether it is a piece of art or improved functional status

  18. The FRII Broad Line Seyfert 1 Galaxy: PKSJ 1037-2705

    CERN Document Server

    Punsly, Brian; Tingay, Steven; Gutierrez, Carlos M; Rasmussen, Jesper; Colbert, Ed

    2008-01-01

    In this article, we demonstrate that PKSJ 1037-2705 has a weak accretion flow luminosity, well below the Seyfert1/QSO dividing line, weak broad emission lines (BELs) and moderately powerful FRII extended radio emission. It is one of the few documented examples of a broad-line object in which the time averaged jet kinetic luminosity, $\\bar{Q}$, is larger than the total thermal luminosity (IR to X-ray) of the accretion flow, $L_{bol}$. The blazar nucleus dominates the optical and near ultraviolet emission and is a strong source of hard X-rays. The strong blazar emission indicates that the relativistic radio jet is presently active. The implication is that even weakly accreting AGN can create powerful jets. Kinetically dominated ($\\bar{Q}>L_{bol}$) broad-line objects provide important constraints on the relationship between the accretion flow and the jet production mechanism.

  19. Broad-Scale Genetic Diversity of Cannabis for Forensic Applications

    Science.gov (United States)

    Dufresnes, Christophe; Jan, Catherine; Bienert, Friederike; Goudet, Jérôme; Fumagalli, Luca

    2017-01-01

    Cannabis (hemp and marijuana) is an iconic yet controversial crop. On the one hand, it represents a growing market for pharmaceutical and agricultural sectors. On the other hand, plants synthesizing the psychoactive THC produce the most widespread illicit drug in the world. Yet, the difficulty to reliably distinguish between Cannabis varieties based on morphological or biochemical criteria impedes the development of promising industrial programs and hinders the fight against narcotrafficking. Genetics offers an appropriate alternative to characterize drug vs. non-drug Cannabis. However, forensic applications require rapid and affordable genotyping of informative and reliable molecular markers for which a broad-scale reference database, representing both intra- and inter-variety variation, is available. Here we provide such a resource for Cannabis, by genotyping 13 microsatellite loci (STRs) in 1 324 samples selected specifically for fibre (24 hemp varieties) and drug (15 marijuana varieties) production. We showed that these loci are sufficient to capture most of the genome-wide diversity patterns recently revealed by NGS data. We recovered strong genetic structure between marijuana and hemp and demonstrated that anonymous samples can be confidently assigned to either plant types. Fibres appear genetically homogeneous whereas drugs show low (often clonal) diversity within varieties, but very high genetic differentiation between them, likely resulting from breeding practices. Based on an additional test dataset including samples from 41 local police seizures, we showed that the genetic signature of marijuana cultivars could be used to trace crime scene evidence. To date, our study provides the most comprehensive genetic resource for Cannabis forensics worldwide. PMID:28107530

  20. Broad-Scale Genetic Diversity of Cannabis for Forensic Applications.

    Science.gov (United States)

    Dufresnes, Christophe; Jan, Catherine; Bienert, Friederike; Goudet, Jérôme; Fumagalli, Luca

    2017-01-01

    Cannabis (hemp and marijuana) is an iconic yet controversial crop. On the one hand, it represents a growing market for pharmaceutical and agricultural sectors. On the other hand, plants synthesizing the psychoactive THC produce the most widespread illicit drug in the world. Yet, the difficulty to reliably distinguish between Cannabis varieties based on morphological or biochemical criteria impedes the development of promising industrial programs and hinders the fight against narcotrafficking. Genetics offers an appropriate alternative to characterize drug vs. non-drug Cannabis. However, forensic applications require rapid and affordable genotyping of informative and reliable molecular markers for which a broad-scale reference database, representing both intra- and inter-variety variation, is available. Here we provide such a resource for Cannabis, by genotyping 13 microsatellite loci (STRs) in 1 324 samples selected specifically for fibre (24 hemp varieties) and drug (15 marijuana varieties) production. We showed that these loci are sufficient to capture most of the genome-wide diversity patterns recently revealed by NGS data. We recovered strong genetic structure between marijuana and hemp and demonstrated that anonymous samples can be confidently assigned to either plant types. Fibres appear genetically homogeneous whereas drugs show low (often clonal) diversity within varieties, but very high genetic differentiation between them, likely resulting from breeding practices. Based on an additional test dataset including samples from 41 local police seizures, we showed that the genetic signature of marijuana cultivars could be used to trace crime scene evidence. To date, our study provides the most comprehensive genetic resource for Cannabis forensics worldwide.

  1. AGN Broad Line Regions Scale with Bolometric Luminosity

    CERN Document Server

    Trippe, Sascha

    2015-01-01

    The masses of supermassive black holes in active galactic nuclei (AGN) can be derived spectroscopically via virial mass estimators based on selected broad optical/ultraviolet emission lines. These estimates commonly use the line width as a proxy for the gas speed and the monochromatic continuum luminosity as a proxy for the radius of the broad line region. However, if the size of the broad line region scales with bolometric rather than monochromatic AGN luminosity, mass estimates based on different emission lines will show a systematic discrepancy which is a function of the color of the AGN continuum. This has actually been observed in mass estimates based on H-alpha / H-beta and C IV lines, indicating that AGN broad line regions indeed scale with bolometric luminosity. Given that this effect seems to have been overlooked as yet, currently used single-epoch mass estimates are likely to be biased.

  2. Broad Spectrum Sanitizing Wipes with Food Additives Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Microcide proposes to develop novel multipurpose non-toxic sanitizing wipes that are aqueous based, have shelf life of 3-5 years, have broad spectrum microbicidal...

  3. Clues to Quasar Broad Line Region Geometry and Kinematics

    DEFF Research Database (Denmark)

    Vestergaard, Marianne; Wilkes, B. J.; Barthel, P. D.

    2000-01-01

    width to show significant inverse correlations with the fractional radio core-flux density, R, the radio axis inclination indicator. Highly inclined systems have broader line wings, consistent with a high-velocity field perpendicular to the radio axis. By contrast, the narrow line-core shows...... and with an accretion disk-wind emitting the broad lines. A spherical distribution of randomly orbiting broad-line clouds and a polar high-ionization outflow are ruled out....

  4. Cavity Enhanced Optical Vernier Spectroscopy, Broad Band, High Resolution, High Sensitivity

    CERN Document Server

    Gohle, Christoph; Schliesser, Albert; Udem, Thomas; Hänsch, Theodor W

    2007-01-01

    A femtosecond frequency comb provides a vast number of equidistantly spaced narrow band laser modes that can be simultaneously tuned and frequency calibrated with 15 digits accuracy. Our Vernier spectrometer utilizes all of theses modes in a massively parallel manner to rapidly record both absorption and dispersion spectra with a sensitivity that is provided by a high finesse broad band optical resonator and a resolution that is only limited by the frequency comb line width while keeping the required setup simple.

  5. Packaging and Performance of 980nm Broad Area Semiconductor Lasers

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    High power broad area semiconductor lasers have found increasing applications in pumping of solid state laser systems and fiber amplifiers, frequency doubling, medical systems and material processing.Packaging including the assembly design, process and thermal management, has a significant impact on the optical performance and reliability of a high power broad area laser. In this paper, we introduce the package structures and assembling process of 980nm broad area lasers and report the performances including output power, thermal behavior and far fields.We will report two types of high power broad area laser assemblies.One is a microchannel liquid cooled assembly and the other is a conduction cooled CT-mount assembly. Optical powers of 15W and 10W were achieved from a 980nm broad area laser with a 120 μ m stripe width in a microchannel liquid cooled assembly and conduction cooled CT-mount assembly, respectively.Furthermore,a high power of 6.5W out of fiber was demonstrated from a pigtailed, fully packaged butterfly-type module without TEC (Thermoelectric cooler).The measurement results showed that thermal management is the key in not only improving output power, but also significantly improving beam divergence and far field distribution.The results also showed that the die attach solder can significant impact the reliability of high power broad area lasers and that indium solder is not suitable for high power laser applications due to electromigration at high current densities and high temperatures.

  6. Standardization of an ELISA test using a recombinant nucleoprotein from the Junin virus as the antigen and serological screening for arenavirus among the population of Nova Xavantina, State of Mato Grosso Padronização de um teste de ELISA utilizando a nucleoproteína recombinante de vírus Junin como antígeno e triagem sorológica para Arenavírus na população de Nova Xavantina, Estado do Mato Grosso

    Directory of Open Access Journals (Sweden)

    Alex Martins Machado

    2010-06-01

    Full Text Available INTRODUCTION: Arenavirus hemorrhagic fever is a severe emerging disease. METHODS: Considering that the levels of antibodies against arenavirus in the Brazilian population are completely unknown, we have standardized an ELISA test for detecting IgG antibodies using a recombinant nucleoprotein from the Junin virus as the antigen. This protein was obtained by inserting the gene of the Junin virus nucleoprotein into the genome of Autographa californica nucleopolyhedrovirus, using the Bac-to-Bac baculovirus expression system. This recombinant baculovirus was used to infect S. frugiperda cells (SF9. RESULTS: The infection resulted in synthesis of high concentrations of recombinant protein. This protein was detected on 12.5% polyacrylamide gel and by means of Western blot. Using the standardized ELISA test, 343 samples from the population of Nova Xavantina were analyzed. We observed that 1.4% of the serum samples (five samples presented antibody titers against arenavirus. CONCLUSIONS: These results show the population studied may present exposure to arenavirus infection.INTRODUÇÃO: A febre hemorrágica por Arenavirus é uma severa doença emergente. MÉTODOS: Considerando que os níveis de anticorpos contra Arenavirus na população brasileira é totalmente desconhecido, nos padronizamos um teste de ELISA para detecção de anticorpos IgG usando uma nucleoproteína recombinante do vírus Junin como antígeno. Esta proteína foi obtida pela inserção do gene da nucleoproteína do vírus Junin no genoma do vírus Autographa californica nucleopolyhedrovirus, utilizando o sistema de expressão em Baculovírus, Bac-To-Bac. Este baculovirus recombinante foi utilizado para infecção de células de S. frugiperda (Sf9. RESULTADOS: A infecção resultou na produção de altas concentrações de proteína recombinante. Esta proteína foi detectada em gel de poliacrilamida 12,5%, e em Western blot. Utilizando o teste de ELISA padronizado, foram analizadas 343

  7. What HERA May Provide?

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Hannes; /DESY; De Roeck, Albert; /CERN; Bartels, Jochen; /Hamburg U., Inst. Theor. Phys. II; Behnke, Olaf; Blumlein, Johannes; /DESY; Brodsky, Stanley; /SLAC /Durham U., IPPP; Cooper-Sarkar, Amanda; /Oxford U.; Deak, Michal; /DESY; Devenish, Robin; /Oxford U.; Diehl, Markus; /DESY; Gehrmann, Thomas; /Zurich U.; Grindhammer, Guenter; /Munich, Max Planck Inst.; Gustafson, Gosta; /CERN /Lund U., Dept. Theor. Phys.; Khoze, Valery; /Durham U., IPPP; Knutsson, Albert; /DESY; Klein, Max; /Liverpool U.; Krauss, Frank; /Durham U., IPPP; Kutak, Krzysztof; /DESY; Laenen, Eric; /NIKHEF, Amsterdam; Lonnblad, Leif; /Lund U., Dept. Theor. Phys.; Motyka, Leszek; /Hamburg U., Inst. Theor. Phys. II /Birmingham U. /Southern Methodist U. /DESY /Piemonte Orientale U., Novara /CERN /Paris, LPTHE /Hamburg U. /Penn State U.

    2011-11-10

    More than 100 people participated in a discussion session at the DIS08 workshop on the topic What HERA may provide. A summary of the discussion with a structured outlook and list of desirable measurements and theory calculations is given. The HERA accelerator and the HERA experiments H1, HERMES and ZEUS stopped running in the end of June 2007. This was after 15 years of very successful operation since the first collisions in 1992. A total luminosity of {approx} 500 pb{sup -1} has been accumulated by each of the collider experiments H1 and ZEUS. During the years the increasingly better understood and upgraded detectors and HERA accelerator have contributed significantly to this success. The physics program remains in full swing and plenty of new results were presented at DIS08 which are approaching the anticipated final precision, fulfilling and exceeding the physics plans and the previsions of the upgrade program. Most of the analyses presented at DIS08 were still based on the so called HERA I data sample, i.e. data taken until 2000, before the shutdown for the luminosity upgrade. This sample has an integrated luminosity of {approx} 100 pb{sup -1}, and the four times larger statistics sample from HERA II is still in the process of being analyzed.

  8. Spatiotemporal exploratory models for broad-scale survey data.

    Science.gov (United States)

    Fink, Daniel; Hochachka, Wesley M; Zuckerberg, Benjamin; Winkler, David W; Shaby, Ben; Munson, M Arthur; Hooker, Giles; Riedewald, Mirek; Sheldon, Daniel; Kelling, Steve

    2010-12-01

    The distributions of animal populations change and evolve through time. Migratory species exploit different habitats at different times of the year. Biotic and abiotic features that determine where a species lives vary due to natural and anthropogenic factors. This spatiotemporal variation needs to be accounted for in any modeling of species' distributions. In this paper we introduce a semiparametric model that provides a flexible framework for analyzing dynamic patterns of species occurrence and abundance from broad-scale survey data. The spatiotemporal exploratory model (STEM) adds essential spatiotemporal structure to existing techniques for developing species distribution models through a simple parametric structure without requiring a detailed understanding of the underlying dynamic processes. STEMs use a multi-scale strategy to differentiate between local and global-scale spatiotemporal structure. A user-specified species distribution model accounts for spatial and temporal patterning at the local level. These local patterns are then allowed to "scale up" via ensemble averaging to larger scales. This makes STEMs especially well suited for exploring distributional dynamics arising from a variety of processes. Using data from eBird, an online citizen science bird-monitoring project, we demonstrate that monthly changes in distribution of a migratory species, the Tree Swallow (Tachycineta bicolor), can be more accurately described with a STEM than a conventional bagged decision tree model in which spatiotemporal structure has not been imposed. We also demonstrate that there is no loss of model predictive power when a STEM is used to describe a spatiotemporal distribution with very little spatiotemporal variation; the distribution of a nonmigratory species, the Northern Cardinal (Cardinalis cardinalis).

  9. Characteristics of doripenem: a new broad-spectrum antibiotic

    Directory of Open Access Journals (Sweden)

    Francisco Alvarez-Lerma

    2009-05-01

    Full Text Available Francisco Alvarez-Lerma1, Santiago Grau2, Olivia Ferrández21Intensive Care Unit, 2Pharmacy Department, Hospital Del Mar, Barcelona, SpainAbstract: Doripenem (S-4661 is a new parenteral antibiotic from the carbapenem class; similarly to imipenem and meropenem, it has a broad-spectrum activity against Gram-positive, Gram-negative, and anaerobic bacteria. It is active against multiresistant Gram-negative bacilli such as extended-spectrum beta-lactamase-producing (ESBL Gram-negative Enterobacteriaceae and nonfermentative Gram-negative bacilli including some strains of Pseudomonas aeruginosa that are resistant to other carbapenems. Doripenem’s chemical structure is similar to that of meropenem (substitution of one sulfamoxil-aminomethyl chain for the dimethyl-carboxyl chain, and has one 1-beta-methyl chain which provides resistance to dehydropeptidase-I enzyme. The clinical trials conducted so far have focused on the treatment of severe infections such as complicated intra-abdominal infections, complicated urinary tract infections and pyelonephritis, nosocomial pneumonia, and ventilator-associated pneumonia. Given its activity profile and the results from the clinical trials, this antibiotic may be used for empirical treatment of multibacterial infections produced by potentially multiresistant Gram-negative bacilli. In 2007, the US Food and Drug Administration approved the use of doripenem for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. The European Medicines Agency has approved the use of doripenem for the same indications in addition to nosocomial pneumonia regardless of whether it is ventilator-associated or not.Keywords: doripenem, antimicrobial activity, clinical efficacy, pharmacokinetics, tolerability

  10. Antiviral Therapy by HIV-1 Broadly Neutralizing and Inhibitory Antibodies

    Directory of Open Access Journals (Sweden)

    Zhiqing Zhang

    2016-11-01

    Full Text Available Human immunodeficiency virus type 1 (HIV-1 infection causes acquired immune deficiency syndrome (AIDS, a global epidemic for more than three decades. HIV-1 replication is primarily controlled through antiretroviral therapy (ART but this treatment does not cure HIV-1 infection. Furthermore, there is increasing viral resistance to ART, and side effects associated with long-term therapy. Consequently, there is a need of alternative candidates for HIV-1 prevention and therapy. Recent advances have discovered multiple broadly neutralizing antibodies against HIV-1. In this review, we describe the key epitopes on the HIV-1 Env protein and the reciprocal broadly neutralizing antibodies, and discuss the ongoing clinical trials of broadly neutralizing and inhibitory antibody therapy as well as antibody combinations, bispecific antibodies, and methods that improve therapeutic efficacy by combining broadly neutralizing antibodies (bNAbs with latency reversing agents. Compared with ART, HIV-1 therapeutics that incorporate these broadly neutralizing and inhibitory antibodies offer the advantage of decreasing virus load and clearing infected cells, which is a promising prospect in HIV-1 prevention and treatment.

  11. Antiviral Therapy by HIV-1 Broadly Neutralizing and Inhibitory Antibodies.

    Science.gov (United States)

    Zhang, Zhiqing; Li, Shaowei; Gu, Ying; Xia, Ningshao

    2016-11-18

    Human immunodeficiency virus type 1 (HIV-1) infection causes acquired immune deficiency syndrome (AIDS), a global epidemic for more than three decades. HIV-1 replication is primarily controlled through antiretroviral therapy (ART) but this treatment does not cure HIV-1 infection. Furthermore, there is increasing viral resistance to ART, and side effects associated with long-term therapy. Consequently, there is a need of alternative candidates for HIV-1 prevention and therapy. Recent advances have discovered multiple broadly neutralizing antibodies against HIV-1. In this review, we describe the key epitopes on the HIV-1 Env protein and the reciprocal broadly neutralizing antibodies, and discuss the ongoing clinical trials of broadly neutralizing and inhibitory antibody therapy as well as antibody combinations, bispecific antibodies, and methods that improve therapeutic efficacy by combining broadly neutralizing antibodies (bNAbs) with latency reversing agents. Compared with ART, HIV-1 therapeutics that incorporate these broadly neutralizing and inhibitory antibodies offer the advantage of decreasing virus load and clearing infected cells, which is a promising prospect in HIV-1 prevention and treatment.

  12. PG 1411 + 442 - The nearest broad absorption line quasar

    Science.gov (United States)

    Malkan, Matthew A.; Green, Richard F.; Hutchings, John B.

    1987-01-01

    IUE observations reveal strong, moderately broad absorption troughs in the blue wings of the C IV and N V emission lines of the quasar PG 1411 + 442. No absorption from weakly ionized gas is detected. The emission-line strengths and overall shape of the ultraviolet/optical/near-infrared/far-infrared continuum of the new broad absorption line quasar are within the range normally measured in quasars. Its redshift is low enough to allow the morphology of the host galaxy to be studied in deep broad-band and intermediate-band CCD images. The galaxy appears to be a large spiral with a very long arm or tail. The inclination angle is 57 deg, which rules out the possibility that the line of sight to the nucleus intersects a large path length in a galactic disk.

  13. Folded cavity angled-grating broad-area lasers.

    Science.gov (United States)

    Zhao, Yunsong; Zhu, Lin

    2013-10-01

    The angled-grating broad-area laser is a promising candidate for high power, high brightness diode laser source. The key point in the design is the angled gratings which can simultaneously support the unique snake-like zigzag lasing mode and eliminate the direct Fabry-Perot (FP) feedback. Unlike a conventional laser waveguide mode, the phase front of the zigzag mode periodically changes along the propagation direction. By use of the mirror symmetry of the zigzag mode, we propose and demonstrate the folded cavity angled-grating broad-area lasers. One benefit of this design is to reduce the required wafer space compared to a regular angled-grating broad-area laser, especially in a long cavity laser for high power operation. Experimental results show that the folded cavity laser exhibits good beam quality in far field with a slightly larger threshold and smaller slope efficiency due to the additional interface loss.

  14. Surface Roughness Effects on Discharge Coefficient of Broad Crested Weir

    Directory of Open Access Journals (Sweden)

    Shaker A. Jalil

    2014-06-01

    Full Text Available The aim of this study is to investigate the effects of surface roughness sizes on the discharge coefficient for a broad crested weirs. For this purpose, three models having different lengths of broad crested weirs were tested in a horizontal flume. In each model, the surface was roughed four times. Experimental results of all models showed that the logical negative effect of roughness increased on the discharge (Q for different values of length. The performance of broad crested weir improved with decrease ratio of roughness to the weir height (Ks/P and with the increase of the total Head to the Length (H/L. An empirical equation was obtained to estimate the variation of discharge coefficient Cd in terms total head to length ratio, with total head to roughness ratio.

  15. Broad ligament pregnancy a diagnostic dilemma: a case report

    Directory of Open Access Journals (Sweden)

    Amit Gupta

    2016-07-01

    Full Text Available Broad ligament pregnancy is one of the rarest forms of ectopic pregnancy with high risk of maternal mortality. Although ultrasonography is usually helpful in making the diagnosis but it is mostly established during laparotomy. 34 year old G2P1 with previous caesarean section reported at 8th month of pregnancy with inability to perceive foetal movements. Ultrasonography confirmed intrauterine fetal demise. Patient was taken for caesarean section after failed induction. Intraoperative diagnosis of broad ligament pregnancy was made and broad ligament along with fetus, sac, fallopian tube and ovary was excised. Post-operative period was uneventful. [Int J Reprod Contracept Obstet Gynecol 2016; 5(7.000: 2478-2480

  16. New connections: Cell to cell HIV-1 transmission, resistance to broadly neutralizing antibodies, and an envelope sorting motif.

    Science.gov (United States)

    Smith, S Abigail; Derdeyn, Cynthia A

    2017-03-01

    HIV-1 infection from cell to cell may provide an efficient mode of viral spread in vivo and could therefore present a significant challenge for preventative or therapeutic strategies based on broadly neutralizing antibodies. Indeed, Li et al show that the potency and magnitude of multiple HIV-1 broadly neutralizing antibody classes are decreased during cell to cell infection in a context dependent manner. A functional motif in gp41 appears to contribute to this differential susceptibility by modulating exposure of neutralization epitopes.

  17. Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-120 interface

    OpenAIRE

    Huang, Jinghe; Kang, Byong H; Pancera, Marie; Lee, Jeong Hyun; Tong, Tommy; Feng, Yu; Georgiev, Ivelin S.; Chuang, Gwo-Yu; Druz, Aliaksandr; Doria-Rose, Nicole A.; Laub, Leo; Sliepen, Kwinten; van Gils, Marit J.; de la Peña, Alba Torrents; Derking, Ronald

    2014-01-01

    The isolation of human monoclonal antibodies (mAbs) is providing important insights regarding the specificities that underlie broad neutralization of HIV-1 (reviewed in 1 ). Here we report a broad and extremely potent HIV-specific mAb, termed 35O22, which binds novel HIV-1 envelope glycoprotein (Env) epitope. 35O22 neutralized 62% of 181 pseudoviruses with an IC50

  18. Novel water-based antiseptic lotion demonstrates rapid, broad-spectrum kill compared with alcohol antiseptic.

    Science.gov (United States)

    Czerwinski, Steven E; Cozean, Jesse; Cozean, Colette

    2014-01-01

    A novel alcohol-based antiseptic and a novel water-based antiseptic lotion, both with a synergistic combination of antimicrobial ingredients containing 0.2% benzethonium chloride, were evaluated using the standard time-kill method against 25 FDA-specified challenge microorganisms. The purpose of the testing was to determine whether a non-alcohol product could have equivalent rapid and broad-spectrum kill to a traditional alcohol sanitizer. Both the alcohol- and water-based products showed rapid and broad-spectrum antimicrobial activity. The average 15-s kill was 99.999% of the challenge organism for the alcohol-based antiseptic and 99.971% for the water-based antiseptic. The alcohol-based product demonstrated 100% of peak efficacy (60s) within the first 15s, whereas the water-based product showed 99.97%. The novel alcohol-based antiseptic reduced concentrations of 100% of organisms by 99.999%, whereas the water-based antiseptic lotion showed the same reduction for 96% of organisms. A novel water-based antiseptic product demonstrated equivalent rapid, broad-spectrum antimicrobial activity to an alcohol-based sanitizer and provided additional benefits of reduced irritation, persistent effect, and greater efficacy against common viruses. The combination of rapid, broad-spectrum immediate kill and persistent efficacy against pathogens may have significant clinical benefit in limiting the spread of disease.

  19. Molecular evolution of broadly neutralizing Llama antibodies to the CD4-binding site of HIV-1.

    Directory of Open Access Journals (Sweden)

    Laura E McCoy

    2014-12-01

    Full Text Available To date, no immunization of humans or animals has elicited broadly neutralizing sera able to prevent HIV-1 transmission; however, elicitation of broad and potent heavy chain only antibodies (HCAb has previously been reported in llamas. In this study, the anti-HIV immune responses in immunized llamas were studied via deep sequencing analysis using broadly neutralizing monoclonal HCAbs as a guides. Distinct neutralizing antibody lineages were identified in each animal, including two defined by novel antibodies (as variable regions called VHH identified by robotic screening of over 6000 clones. The combined application of five VHH against viruses from clades A, B, C and CRF_AG resulted in neutralization as potent as any of the VHH individually and a predicted 100% coverage with a median IC50 of 0.17 µg/ml for the panel of 60 viruses tested. Molecular analysis of the VHH repertoires of two sets of immunized animals showed that each neutralizing lineage was only observed following immunization, demonstrating that they were elicited de novo. Our results show that immunization can induce potent and broadly neutralizing antibodies in llamas with features similar to human antibodies and provide a framework to analyze the effectiveness of immunization protocols.

  20. Molecular Evolution of Broadly Neutralizing Llama Antibodies to the CD4-Binding Site of HIV-1

    Science.gov (United States)

    McCoy, Laura E.; Rutten, Lucy; Frampton, Dan; Anderson, Ian; Granger, Luke; Bashford-Rogers, Rachael; Dekkers, Gillian; Strokappe, Nika M.; Seaman, Michael S.; Koh, Willie; Grippo, Vanina; Kliche, Alexander; Verrips, Theo; Kellam, Paul; Fassati, Ariberto; Weiss, Robin A.

    2014-01-01

    To date, no immunization of humans or animals has elicited broadly neutralizing sera able to prevent HIV-1 transmission; however, elicitation of broad and potent heavy chain only antibodies (HCAb) has previously been reported in llamas. In this study, the anti-HIV immune responses in immunized llamas were studied via deep sequencing analysis using broadly neutralizing monoclonal HCAbs as a guides. Distinct neutralizing antibody lineages were identified in each animal, including two defined by novel antibodies (as variable regions called VHH) identified by robotic screening of over 6000 clones. The combined application of five VHH against viruses from clades A, B, C and CRF_AG resulted in neutralization as potent as any of the VHH individually and a predicted 100% coverage with a median IC50 of 0.17 µg/ml for the panel of 60 viruses tested. Molecular analysis of the VHH repertoires of two sets of immunized animals showed that each neutralizing lineage was only observed following immunization, demonstrating that they were elicited de novo. Our results show that immunization can induce potent and broadly neutralizing antibodies in llamas with features similar to human antibodies and provide a framework to analyze the effectiveness of immunization protocols. PMID:25522326

  1. Molecular evolution of broadly neutralizing Llama antibodies to the CD4-binding site of HIV-1.

    Science.gov (United States)

    McCoy, Laura E; Rutten, Lucy; Frampton, Dan; Anderson, Ian; Granger, Luke; Bashford-Rogers, Rachael; Dekkers, Gillian; Strokappe, Nika M; Seaman, Michael S; Koh, Willie; Grippo, Vanina; Kliche, Alexander; Verrips, Theo; Kellam, Paul; Fassati, Ariberto; Weiss, Robin A

    2014-12-01

    To date, no immunization of humans or animals has elicited broadly neutralizing sera able to prevent HIV-1 transmission; however, elicitation of broad and potent heavy chain only antibodies (HCAb) has previously been reported in llamas. In this study, the anti-HIV immune responses in immunized llamas were studied via deep sequencing analysis using broadly neutralizing monoclonal HCAbs as a guides. Distinct neutralizing antibody lineages were identified in each animal, including two defined by novel antibodies (as variable regions called VHH) identified by robotic screening of over 6000 clones. The combined application of five VHH against viruses from clades A, B, C and CRF_AG resulted in neutralization as potent as any of the VHH individually and a predicted 100% coverage with a median IC50 of 0.17 µg/ml for the panel of 60 viruses tested. Molecular analysis of the VHH repertoires of two sets of immunized animals showed that each neutralizing lineage was only observed following immunization, demonstrating that they were elicited de novo. Our results show that immunization can induce potent and broadly neutralizing antibodies in llamas with features similar to human antibodies and provide a framework to analyze the effectiveness of immunization protocols.

  2. Influenza A HA's conserved epitopes and broadly neutralizing antibodies: a prediction method.

    Science.gov (United States)

    Ren, Jing; Ellis, John; Li, Jinyan

    2014-10-01

    A conserved epitope is an epitope retained by multiple strains of influenza as the key target of a broadly neutralizing antibody. Identification of conserved epitopes is of strong interest to help design broad-spectrum vaccines against influenza. Conservation score measures the evolutionary conservation of an amino acid position in a protein based on the phylogenetic relationships observed amongst homologous sequences. Here, Average Amino Acid Conservation Score (AAACS) is proposed as a method to identify HA's conserved epitopes. Our analysis shows that there is a clear distinction between conserved epitopes and nonconserved epitopes in terms of AAACS. This method also provides an excellent classification performance on an independent dataset. In contrast, alignment-based comparison methods do not work well for this problem, because conserved epitopes to the same broadly neutralizing antibody are usually not identical or similar. Location-based methods are not successful either, because conserved epitopes are located at both the less-conserved globular head (HA1) and the more-conserved stem (HA2). As a case study, two conserved epitopes on HA are predicted for the influenza A virus H7N9: One should match the broadly neutralizing antibodies CR9114 or FI6v3, while the other is new and requires validation by wet-lab experiments.

  3. BROAD Hβ EMISSION-LINE VARIABILITY IN A SAMPLE OF 102 LOCAL ACTIVE GALAXIES

    Energy Technology Data Exchange (ETDEWEB)

    Runco, Jordan N.; Cosens, Maren; Bennert, Vardha N.; Scott, Bryan [Physics Department, California Polytechnic State University, San Luis Obispo CA 93407 (United States); Komossa, S. [Max-Planck-Institut für Radioastronomie, Auf dem Hügel 69, D-53121, Bonn (Germany); Malkan, Matthew A.; Treu, Tommaso [Department of Physics, University of California, Los Angeles, CA 90095 (United States); Lazarova, Mariana S. [Department of Physics and Physical Science, University of Nebraska Kearney, Kearney, NE 68849 (United States); Auger, Matthew W. [Institute of Astronomy, Madingley Road, Cambridge CB3 0HA (United Kingdom); Park, Daeseong, E-mail: jrunco@calpoly.edu, E-mail: mcosens@calpoly.edu, E-mail: vbennert@calpoly.edu, E-mail: malkan@astro.ucla.edu, E-mail: tt@physics.ucsb.edu, E-mail: lazarovam2@unk.edu, E-mail: mauger@ast.cam.ac.uk, E-mail: daeseongpark@kasi.re.kr [Korea Astronomy and Space Science Institute, Daejeon, 34055 (Korea, Republic of)

    2016-04-10

    A sample of 102 local (0.02 ≤ z ≤ 0.1) Seyfert galaxies with black hole masses M{sub BH} > 10{sup 7}M{sub ⊙} was selected from the Sloan Digital Sky Survey (SDSS) and observed using the Keck 10 m telescope to study the scaling relations between M{sub BH} and host galaxy properties. We study profile changes of the broad Hβ emission line within the three to nine year time frame between the two sets of spectra. The variability of the broad Hβ emission line is of particular interest, not only because it is used to estimate M{sub BH}, but also because its strength and width are used to classify Seyfert galaxies into different types. At least some form of broad-line variability (in either width or flux) is observed in the majority (∼66%) of the objects, resulting in a Seyfert-type change for ∼38% of the objects, likely driven by variable accretion and/or obscuration. The broad Hβ line virtually disappears in 3/102 (∼3%) extreme cases. We discuss potential causes for these changing look active galactic nuclei. While similar dramatic transitions have previously been reported in the literature, either on a case-by-case basis or in larger samples focusing on quasars at higher redshifts, our study provides statistical information on the frequency of Hβ line variability in a sample of low-redshift Seyfert galaxies.

  4. Estimating the Broad-Sense Heritability of Early Growth of Cowpea

    OpenAIRE

    Xu, Nicole W.; Xu, Shizhong; Ehlers, Jeff

    2009-01-01

    Cowpea is an important tropical crop. It provides a large proportion of the food resource for the African human population and their livestock. The yield and quality of cowpea have been dramatically improved through traditional breeding strategies for the past few decades. However, reports of heritability estimates for early growth of cowpea are rare. We designed a simple experiment to estimate the broad-sense heritability of early growth. We randomly selected 15 cowpea varieties among a tota...

  5. Silver Nanoparticles with Broad Multiband Linear Optical Absorption

    KAUST Repository

    Bakr, Osman M.

    2009-07-06

    A simple one-pot method produces silver nanoparticles coated with aryl thiols that show intense, broad nonplasmonic optical properties. The synthesis works with many aryl-thiol capping ligands, including water-soluble 4-mercaptobenzoic acid. The nanoparticles produced show linear absorption that is broader, stronger, and more structured than most conventional organic and inorganic dyes.

  6. Broad Band Photometric Reverberation Mapping of NGC 4395

    CERN Document Server

    Edri, Haim; Chelouche, Doron; Kaspi, Shai; Behar, Ehud

    2012-01-01

    We present results of broad band photometric reverberation mapping (RM) to measure the radius of the broad line region, and subsequently the black hole mass (M$_{\\rm BH}$), in the nearby, low luminosity active galactic nuclei (AGN) NGC 4395. Using the Wise Observatory's 1m telescope equipped with the SDSS g$'$, r$'$ and i$'$ broad band filters, we monitored NGC 4395 for 9 consecutive nights and obtained 3 light curves each with over 250 data points. The g$'$ and r$'$ bands include time variable contributions from H$\\beta$ and H$\\alpha$ (respectively) plus continuum. The i$'$ band is free of broad lines and covers exclusively continuum. We show that by looking for a peak in the difference between the cross-correlation and the auto-correlation functions for all combinations of filters, we can get a reliable estimate of the time lag necessary to compute M$_{\\rm BH}$. We measure the time lag for H$\\alpha$ to be $3.6 \\pm 0.8 $ hours, comparable to previous studies using the line resolved spectroscopic RM method. W...

  7. Mathematical Development: The Role of Broad Cognitive Processes

    Science.gov (United States)

    Calderón-Tena, Carlos O.

    2016-01-01

    This study investigated the role of broad cognitive processes in the development of mathematics skills among children and adolescents. Four hundred and forty-seven students (age mean [M] = 10.23 years, 73% boys and 27% girls) from an elementary school district in the US southwest participated. Structural equation modelling tests indicated that…

  8. PRINCIPAR An Efficient, Broad-coverage, Principle-based Parser

    CERN Document Server

    Lin, D

    1994-01-01

    We present an efficient, broad-coverage, principle-based parser for English. The parser has been implemented in C++ and runs on SUN Sparcstations with X-windows. It contains a lexicon with over 90,000 entries, constructed automatically by applying a set of extraction and conversion rules to entries from machine readable dictionaries.

  9. Model Invariance across Genders of the Broad Autism Phenotype Questionnaire

    Science.gov (United States)

    Broderick, Neill; Wade, Jordan L.; Meyer, J. Patrick; Hull, Michael; Reeve, Ronald E.

    2015-01-01

    ASD is one of the most heritable neuropsychiatric disorders, though comprehensive genetic liability remains elusive. To facilitate genetic research, researchers employ the concept of the broad autism phenotype (BAP), a milder presentation of traits in undiagnosed relatives. Research suggests that the BAP Questionnaire (BAPQ) demonstrates…

  10. Broad-band hard X-ray reflectors

    DEFF Research Database (Denmark)

    Joensen, K.D.; Gorenstein, P.; Hoghoj, P.;

    1997-01-01

    Interest in optics for hard X-ray broad-band application is growing. In this paper, we compare the hard X-ray (20-100 keV) reflectivity obtained with an energy-dispersive reflectometer, of a standard commercial gold thin-film with that of a 600 bilayer W/Si X-ray supermirror. The reflectivity of ...

  11. Broad-Band Spectroscopy of Hercules X-1 with Suzaku

    Science.gov (United States)

    Asami, Fumi; Enoto, Teruaki; Iwakiri, Wataru; Yamada, Shin'ya; Tamagawa, Toru; Mihara, Tatehiro; Nagase, Fumiaki

    2014-01-01

    Hercules X-1 was observed with Suzaku in the main-on state from 2005 to 2010. The 0.4- 100 keV wide-band spectra obtained in four observations showed a broad hump around 4-9 keV in addition to narrow Fe lines at 6.4 and 6.7 keV. The hump was seen in all the four observations regardless of the selection of the continuum models. Thus it is considered a stable and intrinsic spectral feature in Her X-1. The broad hump lacked a sharp structure like an absorption edge. Thus it was represented by two different spectral models: an ionized partial covering or an additional broad line at 6.5 keV. The former required a persistently existing ionized absorber, whose origin was unclear. In the latter case, the Gaussian fitting of the 6.5-keV line needs a large width of sigma = 1.0-1.5 keV and a large equivalent width of 400-900 eV. If the broad line originates from Fe fluorescence of accreting matter, its large width may be explained by the Doppler broadening in the accretion flow. However, the large equivalent width may be inconsistent with a simple accretion geometry.

  12. Broad spectral range synchronized flat-top arrayed waveguide grating

    NARCIS (Netherlands)

    Akca, B. Imran; Doerr, Christopher R.; Pollnau, Markus; Ridder, de René M.

    2012-01-01

    A broad-band Mach-Zehnder-interferometer-synchronized flat-top arrayed waveguide grating is presented with a 0.5-dB bandwidth of 12 nm over 90 nm of spectral range and a central excess loss value of -0.5 dB.

  13. Broad-band spectrophotometry of HAT-P-32 b

    DEFF Research Database (Denmark)

    Mallonn, M.; Bernt, I.; Herrero, E.

    2016-01-01

    Multicolour broad-band transit observations offer the opportunity to characterize the atmosphere of an extrasolar planet with small- to medium-sized telescopes. One of the most favourable targets is the hot Jupiter HAT-P-32 b. We combined 21 new transit observations of this planet with 36 previou...

  14. VLPs displaying a single L2 epitope induce broadly cross-neutralizing antibodies against human papillomavirus.

    Directory of Open Access Journals (Sweden)

    Ebenezer Tumban

    Full Text Available BACKGROUND: Virus-like Particles (VLPs display can be used to increase the immunogenicity of heterologous antigens. Here, we report the use of a bacteriophage MS2-based VLP display platform to develop a monovalent vaccine targeting a broadly neutralizing epitope in the minor capsid protein human papillomavirus (HPV that provides broad protection from diverse HPV types in a mouse pseudovirus infection model. METHODOLOGY/PRINCIPAL FINDINGS: Peptides spanning a previously described cross-neutralizing epitope from HPV type 16 were genetically inserted at the N-terminus of MS2 bacteriophage coat protein. Three of the four recombinant L2-coat proteins assembled into VLPs. L2-VLPs elicited high-titer anti-L2 antibodies in mice, similar to recombinant VLPs that we had previously made in which the L2 peptide was displayed on a surface-exposed loop on VLPs of a related bacteriophage, PP7. Somewhat surprisingly, L2-MS2 VLPs elicited antibodies that were much more broadly cross-reactive with L2 peptides from diverse HPV isolates than L2-PP7 VLPs. Similarly, mice immunized with L2-MS2 VLPs were protected from genital and cutaneous infection by highly diverse HPV pseudovirus types. CONCLUSION/SIGNIFICANCE: We show that peptides can be displayed in a highly immunogenic fashion at the N-terminus of MS2 coat protein VLPs. A VLP-based vaccine targeting HPV L2 elicits broadly cross-reactive and cross-protective antibodies to heterologous HPV types. L2-VLPs could serve as the basis of a broadly protective second generation HPV vaccine.

  15. Permissiveness of soil microbial communities towards broad host range plasmids

    DEFF Research Database (Denmark)

    Klümper, Uli

    larger than previously assumed. I was able to show abundant plasmid transfer from the Gram negative donor strains to a wide diversity of Gram positive soil bacteria, formerly thought to constitute distinct clusters of gene transfer. Moreover, among the observed transconjugants, I identified a core super...... environmental factors that modulate plasmid transfer in soil microbial communities. In order to attain these goals, I developed a high-throughput method that enabled me to evaluate the permissiveness of bacterial communities towards introduced plasmids. This new approach is based on the introduction...... fraction of soil the bacteria (up to 1 in 10,000) were able to take up any of these broad host range conjugal plasmids. The transconjugal pools comprised 11 bacterial phyla. This finding indicates that the realized transfer range of broad host range plasmids in environmental microbial communities is much...

  16. 30 GHz monitoring of broad absorption line (BAL) quasars

    CERN Document Server

    Ceglowski, Maciej; Pazderska, Bogna; Gawronski, Marcin

    2014-01-01

    Broad absorption line (BAL) quasars have been studied for over thirty years. Yet it is still unclear why and when we observe broad absorption lines in quasars. Is this phenomenon caused by geometry or is it connected with the evolution process? Variability of the BAL quasars, if present, can give us information about their orientation, namely it can indicate whether they are oriented more pole-on. Using the Torun 32-metre dish equipped with the One Centimetre Receiver Array (OCRA) we have started a monitoring campaign of a sample of compact radio-loud BAL quasars. This 30 GHz variability monitoring program supplements the high-resolution interferometric observations of these objects we have carried out with the EVN and VLBA.

  17. Flow characteristics at trapezoidal broad-crested side weir

    Directory of Open Access Journals (Sweden)

    Říha Jaromír

    2015-06-01

    Full Text Available Broad-crested side weirs have been the subject of numerous hydraulic studies; however, the flow field at the weir crest and in front of the weir in the approach channel still has not been fully described. Also, the discharge coefficient of broad-crested side weirs, whether slightly inclined towards the stream or lateral, still has yet to be clearly determined. Experimental research was carried out to describe the flow characteristics at low Froude numbers in the approach flow channel for various combinations of in- and overflow discharges. Three side weir types with different oblique angles were studied. Their flow characteristics and discharge coefficients were analyzed and assessed based on the results obtained from extensive measurements performed on a hydraulic model. The empirical relation between the angle of side weir obliqueness, Froude numbers in the up- and downstream channels, and the coefficient of obliqueness was derived.

  18. Evolution of Broad-line Emission from Active Galactic Nuclei

    CERN Document Server

    Elitzur, Moshe; Trump, Jonathan R

    2013-01-01

    Apart from viewing-dependent obscuration, intrinsic broad-line emission from active galactic nuclei (AGNs) follows an evolutionary sequence: Type $1 \\to 1.2/1.5 \\to 1.8/1.9 \\to 2$ as the accretion rate onto the central black hole is decreasing. This spectral evolution is controlled, at least in part, by the parameter $L_{\\rm bol}/M^{2/3}$, where $L_{\\rm bol}$ is the AGN bolometric luminosity and $M$ is the black hole mass. Both this dependence and the double-peaked profiles that emerge along the sequence arise naturally in the disk-wind scenario for the AGN broad-line region.

  19. Diverse Broad Line Region Kinematic Signatures From Reverberation Mapping

    CERN Document Server

    Denney, K D; Pogge, R W; Adair, A; Atlee, D W; Au-Yong, K; Bentz, M C; Bird, J C; Brokofsky, D J; Chisholm, E; Comins, M L; Dietrich, M; Doroshenko, V T; Eastman, J D; Efimov, Y S; Ewald, S; Ferbey, S; Gaskell, C M; Hedrick, C H; Jackson, K; Klimanov, S A; Klimek, E S; Kruse, A K; Ladéroute, A; Lamb, J B; Leighly, K; Minezaki, T; Nazarov, S V; Onken, C A; Petersen, E A; Peterson, P; Poindexter, S; Sakata, Y; Schlesinger, K J; Sergeev, S G; Skolski, N; Stieglitz, L; Tobin, J J; Unterborn, C; Vestergaard, M; Watkins, A E; Watson, L C; Yoshii, Y

    2009-01-01

    A detailed analysis of the data from a high sampling rate, multi-month reverberation mapping campaign, undertaken primarily at MDM Observatory with supporting observations from telescopes around the world, reveals that the Hbeta emission region within the broad line regions (BLRs) of several nearby AGNs exhibit a variety of kinematic behaviors. While the primary goal of this campaign was to obtain either new or improved Hbeta reverberation lag measurements for several relatively low luminosity AGNs (presented in a separate work), we were also able to unambiguously reconstruct velocity-resolved reverberation signals from a subset of our targets. Through high cadence spectroscopic monitoring of the optical continuum and broad Hbeta emission line variations observed in the nuclear regions of NGC 3227, NGC 3516, and NGC 5548, we clearly see evidence for outflowing, infalling, and virialized BLR gas motions, respectively.

  20. The broad autism phenotype: findings from an epidemiological survey.

    Science.gov (United States)

    Micali, N; Chakrabarti, S; Fombonne, E

    2004-03-01

    This study aimed to determine if relatives of children with autism and less severe pervasive developmental disorders (PDDs) have higher rates of various components of the broad autistic phenotype. Psychiatric and medical disorders were investigated. Parents of children with PDDs were selected from an epidemiological survey and compared with parents of control children with non-autistic developmental problems. Rates of abnormalities and disorders were compared in relatives of 79 cases and 61 controls. Medical and autoimmune disorders in both groups were endorsed by few relatives. Specific developmental disorders were commoner in parents of controls. Depression and anxiety were significantly more prevalent in mothers of children with PDDs. Significantly more PDD children had at least one first-degree relative with anxiety and one second-degree relative with OCD. PDDs were commoner in first-degree relatives. The implications of the findings for the definition of the broad phenotype of autism are discussed.

  1. Structural basis of hepatitis C virus neutralization by broadly neutralizing antibody HCV1

    Energy Technology Data Exchange (ETDEWEB)

    Kong, Leopold; Giang, Erick; Robbins, Justin B.; Stanfield, Robyn L.; Burton, Dennis R.; Wilson, Ian A.; Law, Mansun (Scripps)

    2012-10-29

    Hepatitis C virus (HCV) infects more than 2% of the global population and is a leading cause of liver cirrhosis, hepatocellular carcinoma, and end-stage liver diseases. Circulating HCV is genetically diverse, and therefore a broadly effective vaccine must target conserved T- and B-cell epitopes of the virus. Human mAb HCV1 has broad neutralizing activity against HCV isolates from at least four major genotypes and protects in the chimpanzee model from primary HCV challenge. The antibody targets a conserved antigenic site (residues 412-423) on the virus E2 envelope glycoprotein. Two crystal structures of HCV1 Fab in complex with an epitope peptide at 1.8-{angstrom} resolution reveal that the epitope is a {beta}-hairpin displaying a hydrophilic face and a hydrophobic face on opposing sides of the hairpin. The antibody predominantly interacts with E2 residues Leu{sup 413} and Trp{sup 420} on the hydrophobic face of the epitope, thus providing an explanation for how HCV isolates bearing mutations at Asn{sup 415} on the same binding face escape neutralization by this antibody. The results provide structural information for a neutralizing epitope on the HCV E2 glycoprotein and should help guide rational design of HCV immunogens to elicit similar broadly neutralizing antibodies through vaccination.

  2. Broad-Band Molecular Polarization in White Dwarfs

    Science.gov (United States)

    Berdyugina, S. V.; Berdyugin, A. V.; Piirola, V.; Shapiro, A.

    2007-09-01

    We present novel calculations of broad-band polarization due to the molecular Paschen--Back effect in a strong magnetic field. Based on that, we analyze new spectropolarimetric observations of the cool magnetic helium-rich white dwarf G 99-37 which shows strongly polarized molecular bands in its spectrum. Combining the polarimetric observations with our model calculations for the CH bands at 4300 Å, we deduce a magnetic field of 8 MG on this unique magnetic white dwarf.

  3. Flow structure in front of the broad-crested weir

    Directory of Open Access Journals (Sweden)

    Zachoval Zbyněk

    2015-01-01

    Full Text Available The paper deals with research focused on description of flow structure in front of broad-crested weir. Based on experimental measurement, the flow structure in front of the weir (the recirculation zone of flow and tornado vortices and flow structure on the weir crest has been described. The determined flow character has been simulated using numerical model and based on comparing results the suitable model of turbulence has been recommended.

  4. Broad Money Demand and Monetary Policy in Tunisia

    OpenAIRE

    Volker Treichel

    1997-01-01

    The development of empirical foundations to the conduct of monetary policy in Tunisia is the central concern of this paper. Finding stable money demand functions, it broadly corroborates the choice of monetary aggregates as intermediate targets of monetary policy by the Tunisian Central Bank. It finds, however, a lower income elasticity than the one currently applied by the Central Bank and proposes a different methodology for defining monetary growth targets. The paper also finds that both i...

  5. The broad spectrum revisited: Evidence from plant remains

    OpenAIRE

    Weiss, Ehud; Wetterstrom, Wilma; Nadel, Dani; Bar-Yosef, Ofer

    2004-01-01

    The beginning of agriculture is one of the most important developments in human history, with enormous consequences that paved the way for settled life and complex society. Much of the research on the origins of agriculture over the last 40 years has been guided by Flannery's [Flannery, K. V. (1969) in The Domestication and Exploitation of Plants and Animals, eds. Ucko, P. J. & Dimbleby, G. W. (Duckworth, London), pp. 73–100] “broad spectrum revolution” (BSR) hypothesis, which posits that the...

  6. Broad spectrum antiangiogenic treatment for ocular neovascular diseases.

    Directory of Open Access Journals (Sweden)

    Ofra Benny

    Full Text Available UNLABELLED: Pathological neovascularization is a hallmark of late stage neovascular (wet age-related macular degeneration (AMD and the leading cause of blindness in people over the age of 50 in the western world. The treatments focus on suppression of choroidal neovascularization (CNV, while current approved therapies are limited to inhibiting vascular endothelial growth factor (VEGF exclusively. However, this treatment does not address the underlying cause of AMD, and the loss of VEGF's neuroprotective can be a potential side effect. Therapy which targets the key processes in AMD, the pathological neovascularization, vessel leakage and inflammation could bring a major shift in the approach to disease treatment and prevention. In this study we have demonstrated the efficacy of such broad spectrum antiangiogenic therapy on mouse model of AMD. METHODS AND FINDINGS: Lodamin, a polymeric formulation of TNP-470, is a potent broad-spectrum antiangiogenic drug. Lodamin significantly reduced key processes involved in AMD progression as demonstrated in mice and rats. Its suppressive effects on angiogenesis, vascular leakage and inflammation were studied in a wide array of assays including; a Matrigel, delayed-type hypersensitivity (DTH, Miles assay, laser-induced CNV and corneal micropocket assay. Lodamin significantly suppressed the secretion of various pro-inflammatory cytokines in the CNV lesion including monocyte chemotactic protein-1 (MCP-1/Ccl2. Importantly, Lodamin was found to regress established CNV lesions, unlike soluble fms-like tyrosine kinase-1 (sFlk-1. The drug was found to be safe in mice and have little toxicity as demonstrated by electroretinography (ERG assessing retinal and by histology. CONCLUSIONS: Lodamin, a polymer formulation of TNP-470, was identified as a first in its class, broad-spectrum antiangiogenic drug that can be administered orally or locally to treat corneal and retinal neovascularization. Several unique properties

  7. FTIR Spectroscopic Study of Broad Bean 3iseased Leaves

    Institute of Scientific and Technical Information of China (English)

    2012-01-01

    [Objective] The aim was to indentify diseased leaves of broad bean by vibra- tional spectroscopy. [Method] In this paper, broad bean rust, fusarium rhizome rot, broad bean zonate spot, yellow leaf curl virus and normal leaves were studied using Fourier transform infrared spectroscopy combined with chemometrics. [Result] The spectra of the samples were similar, only with minor differences in absorption inten- sity of several peaks. Second derivative analyses show that the significant difference of all samples was in the range of 1 200-700 cm2. The data in the range of 1 200- 700 cm' were selected to evaluate correlation coefficients, hierarchical cluster analy- sis (HCA) and principal component analysis (PCA). Results showed that the correla- tion coefficients are larger than 0.928 not only between the healthy leaves, but also between the same diseased leaves. The values between healthy and diseased leaves, and among diseased leaves, are all declined. HCA and PCA yielded about 73.3% and 82.2% accuracy, respectively. [Conclusion] This study demonstrated that FTIR techniques might be used to detect crop diseases.

  8. Safety requirements, facility user needs, and reactor concepts for a new Broad Application Test Reactor

    Energy Technology Data Exchange (ETDEWEB)

    Ryskamp, J.M. [ed.; Liebenthal, J.L.; Denison, A.B.; Fletcher, C.D.

    1992-07-01

    This report describes the EG&G Laboratory Directed Research and Development Program (LDRD) Broad Application Test Reactor (BATR) Project that was conducted in fiscal year 1991. The scope of this project was divided into three phases: a project process definition phase, a requirements development phase, and a preconceptual reactor design and evaluation phase. Multidisciplinary teams of experts conducted each phase. This report presents the need for a new test reactor, the project process definition, a set of current and projected regulatory compliance and safety requirements, a set of facility user needs for a broad range of projected testing missions, and descriptions of reactor concepts capable of meeting these requirements. This information can be applied to strategic planning to provide the Department of Energy with management options.

  9. Safety requirements, facility user needs, and reactor concepts for a new Broad Application Test Reactor

    Energy Technology Data Exchange (ETDEWEB)

    Ryskamp, J.M. (ed.); Liebenthal, J.L.; Denison, A.B.; Fletcher, C.D.

    1992-07-01

    This report describes the EG G Laboratory Directed Research and Development Program (LDRD) Broad Application Test Reactor (BATR) Project that was conducted in fiscal year 1991. The scope of this project was divided into three phases: a project process definition phase, a requirements development phase, and a preconceptual reactor design and evaluation phase. Multidisciplinary teams of experts conducted each phase. This report presents the need for a new test reactor, the project process definition, a set of current and projected regulatory compliance and safety requirements, a set of facility user needs for a broad range of projected testing missions, and descriptions of reactor concepts capable of meeting these requirements. This information can be applied to strategic planning to provide the Department of Energy with management options.

  10. Stapled HIV-1 peptides recapitulate antigenic structures and engage broadly neutralizing antibodies.

    Science.gov (United States)

    Bird, Gregory H; Irimia, Adriana; Ofek, Gilad; Kwong, Peter D; Wilson, Ian A; Walensky, Loren D

    2014-12-01

    Hydrocarbon stapling can restore bioactive α-helical structure to natural peptides, yielding research tools and prototype therapeutics to dissect and target protein interactions. Here we explore the capacity of peptide stapling to generate high-fidelity, protease-resistant mimics of antigenic structures for vaccine development. HIV-1 has been refractory to vaccine technologies thus far, although select human antibodies can broadly neutralize HIV-1 by targeting sequences of the gp41 juxtamembrane fusion apparatus. To develop candidate HIV-1 immunogens, we generated and characterized stabilized α-helices of the membrane-proximal external region (SAH-MPER) of gp41. SAH-MPER peptides were remarkably protease resistant and bound to the broadly neutralizing 4E10 and 10E8 antibodies with high affinity, recapitulating the structure of the MPER epitope when differentially engaged by the two anti-HIV Fabs. Thus, stapled peptides may provide a new opportunity to develop chemically stabilized antigens for vaccination.

  11. Broadly Neutralizing Antibodies Against HIV: New Insights to Inform Vaccine Design.

    Science.gov (United States)

    Sadanand, Saheli; Suscovich, Todd J; Alter, Galit

    2016-01-01

    HIV-1 poses immense immunological challenges to the humoral immune response because of its ability to shield itself and replicate and evolve rapidly. Although most currently licensed vaccines provide protection via the induction of antibodies (Abs) that can directly block infection ( 1 ), 30 years of HIV-1 vaccine research has failed to successfully elicit such Abs against globally relevant HIV strains. However, mounting evidence suggests that these broadly neutralizing antibodies (bNAbs) do emerge naturally in a significant fraction of infected subjects, albeit after years of infection, indicating that these responses can be selected naturally by the immune response but take long periods of time to evolve. We review the basic structural characteristics of broadly neutralizing antibodies and how they recognize the virus, and we discuss new vaccination strategies that aim to mimic natural evolution to guide B cells to produce protective Abs against HIV-1.

  12. The Discussion about Truth Viewpoint and its Significance on the View of Broad-Spectrum Philosophy

    Directory of Open Access Journals (Sweden)

    Facheng Shang

    2012-11-01

    Full Text Available In this study, we have a discussion about truth viewpoint and its significance on the view of Broad-spectrum Philosophy, which inherit and develop the truth of Marxist philosophy Broad-spectrum. Philosophy provides a unique perspective; it introduces the concept of observocontrol mode, which regards the truth as an image in the equivalence class. By changing the observocontrol mode, it reveals “Multilobe” of the truth of the same objective. To answer the question on "how to test the truth", it constructs the procedures and criteria to knowledge the truth. These researches have an important revelation on the enrichment and development of the study of Marxism truth theory.

  13. Broad-Spectrum Antibiotic Treatment and Subsequent Childhood Type 1 Diabetes

    DEFF Research Database (Denmark)

    Clausen, Tine D; Bergholt, Thomas; Bouaziz, Olivier

    2016-01-01

    of childhood type 1 diabetes and the potential effect-modification by mode of delivery. MATERIALS AND METHODS: A Danish nationwide cohort study including all singletons born during 1997-2010. End of follow-up by December 2012. Four national registers provided information on antibiotic redemptions, outcome...... and confounders. Redemptions of antibiotic prescriptions during the first two years of life was classified into narrow-spectrum or broad-spectrum antibiotics. Children were followed from age two to fourteen, both inclusive. The risk of type 1 diabetes with onset before the age of 15 years was assessed by Cox...... regression. A total of 858,201 singletons contributed 5,906,069 person-years, during which 1,503 children developed type 1 diabetes. RESULTS: Redemption of broad-spectrum antibiotics during the first two years of life was associated with an increased rate of type 1 diabetes during the following 13 years...

  14. Internet Provider Facilities, Published in Not Provided, US Army.

    Data.gov (United States)

    NSGIC GIS Inventory (aka Ramona) — This Internet Provider Facilities dataset as of Not Provided. Data by this publisher are often provided in Not Applicable coordinate system; in a Not Applicable...

  15. Broadly neutralizing anti-influenza antibodies require Fc receptor engagement for in vivo protection.

    Science.gov (United States)

    DiLillo, David J; Palese, Peter; Wilson, Patrick C; Ravetch, Jeffrey V

    2016-02-01

    In vivo protection by antimicrobial neutralizing Abs can require the contribution of effector functions mediated by Fc-Fcγ receptor (Fc-FcγR) interactions for optimal efficacy. In influenza, broadly neutralizing anti-hemagglutinin (anti-HA) stalk mAbs require Fc-FcγR interactions to mediate in vivo protection, but strain-specific anti-HA head mAbs do not. Whether this rule applies only to anti-stalk Abs or is applicable to any broadly neutralizing Ab (bNAb) against influenza is unknown. Here, we characterized the contribution of Fc-FcγR interactions during in vivo protection for a panel of 13 anti-HA mAbs, including bNAbs and non-neutralizing Abs, against both the stalk and head domains. All classes of broadly binding anti-HA mAbs required Fc-FcγR interactions to provide protection in vivo, including those mAbs that bind the HA head and those that do not neutralize virus in vitro. Further, a broadly neutralizing anti-neuraminidase (anti-NA) mAb also required FcγRs to provide protection in vivo, but a strain-specific anti-NA mAb did not. Thus, these findings suggest that the breadth of reactivity of anti-influenza Abs, regardless of their epitope, necessitates interactions with FcγRs on effector cell populations to mediate in vivo protection. These findings will guide the design of antiviral Ab therapeutics and inform vaccine design to elicit Abs with optimal binding properties and effector functions.

  16. Broad-Spectrum Antibiotic Treatment and Subsequent Childhood Type 1 Diabetes: A Nationwide Danish Cohort Study

    Science.gov (United States)

    Bergholt, Thomas; Bouaziz, Olivier; Arpi, Magnus; Eriksson, Frank; Rasmussen, Steen; Keiding, Niels; Løkkegaard, Ellen C.

    2016-01-01

    Background Studies link antibiotic treatment and delivery by cesarean section with increased risk of chronic diseases through changes of the gut-microbiota. We aimed to evaluate the association of broad-spectrum antibiotic treatment during the first two years of life with subsequent onset of childhood type 1 diabetes and the potential effect-modification by mode of delivery. Materials and Methods A Danish nationwide cohort study including all singletons born during 1997–2010. End of follow-up by December 2012. Four national registers provided information on antibiotic redemptions, outcome and confounders. Redemptions of antibiotic prescriptions during the first two years of life was classified into narrow-spectrum or broad-spectrum antibiotics. Children were followed from age two to fourteen, both inclusive. The risk of type 1 diabetes with onset before the age of 15 years was assessed by Cox regression. A total of 858,201 singletons contributed 5,906,069 person-years, during which 1,503 children developed type 1 diabetes. Results Redemption of broad-spectrum antibiotics during the first two years of life was associated with an increased rate of type 1 diabetes during the following 13 years of life (HR 1.13; 95% CI 1.02 to 1.25), however, the rate was modified by mode of delivery. Broad-spectrum antibiotics were associated with an increased rate of type 1 diabetes in children delivered by either intrapartum cesarean section (HR 1.70; 95% CI 1.15 to 2.51) or prelabor cesarean section (HR 1.63; 95% CI 1.11 to 2.39), but not in vaginally delivered children. Number needed to harm was 433 and 562, respectively. The association with broad-spectrum antibiotics was not modified by parity, genetic predisposition or maternal redemption of antibiotics during pregnancy or lactation. Conclusions Redemption of broad-spectrum antibiotics during infancy is associated with an increased risk of childhood type 1 diabetes in children delivered by cesarean section. PMID:27560963

  17. New focal plane detector system for the broad range spectrometer

    Energy Technology Data Exchange (ETDEWEB)

    Sjoreen, T.P.

    1984-01-01

    A focal plane detector system consisting of a vertical drift chamber, parallel plate avalanche counters, and an ionization chamber with segmented anodes has been installed in the Broad Range Spectrometer at the Holifield Facility at Oak Ridge. The system, which has been designed for use with light-heavy ions with energies ranging from 10 to 25 MeV/amu, has a position resolution of approx. 0.1 mm, a scattering angle resolution of approx. 3 mrad, and a mass resolution of approx. 1/60.

  18. VLBA imaging of radio-loud Broad Absorption Line QSOs

    CERN Document Server

    Montenegro-Montes, F M; Benn, C R; Carballo, R; Dallacasa, D; González-Serrano, J I; Holt, J; Jiménez-Luján, F

    2009-01-01

    Broad Absorption Line Quasars (BAL QSOs) have been found to be associated with extremely compact radio sources. These reduced dimensions can be either due to projection effects or these objects might actually be intrinsically small. Exploring these two hypotheses is important to understand the nature and origin of the BAL phenomenon because orientation effects are an important discriminant between the different models proposed to explain this phenomenon. In this work we present VLBA observations of 5 BAL QSOs and discuss their pc-scale morphology.

  19. Broad-band photometric evolution of star clusters

    OpenAIRE

    Girardi, Leo

    2001-01-01

    I briefly introduce a database of models that describe the evolution of star clusters in several broad-band photometric systems. Models are based on the latest Padova stellar evolutionary tracks - now including the alpha-enhanced case and improved AGB models - and a revised library of synthetic spectra from model atmospheres. As of today, we have revised isochrones in Johnson-Cousins-Glass, HST/WFPC2, HST/NICMOS, Thuan-Gunn, and Washington systems. Several other filter sets are included in a ...

  20. Evidence of the Link between Broad Emission Line Regions and Accretion Disks in Active Galactic Nuclei

    Institute of Scientific and Technical Information of China (English)

    Yun Xu; Xin-Wu Cao

    2007-01-01

    There is observational evidence that broad-line regions (BLRs) exist in most active galactic nuclei (AGNs), but their origin is still unclear. One scenario is that the BLRs originate from winds accelerated from the hot coronae of the disks, and the winds are suppressed when the black hole is accreting at low rates. This model predicts a relation between (m) ((m) = (M)/(M)Edd) and the FWHM of broad emission lines. We estimate the central black hole masses for a sample of bright AGNs by using their broad Hβ line-widths and optical luminosities. The dimensionless accretion rates (m) = (M)/(M)Edd are derived from the optical continuum luminosities by using two different models: using an empirical relation between the bolometric luminosity Lbol and the optical luminosity ((m) = Lbol/LEdd, a fixed radiative efficiency is adopted); and calculating the optical spectra of accretion disks as a function of (m). We find a significant correlation between the derived (m) and the observed line width of Hβ,FWHM∝ (m)-0.37, which almost overlaps the disk-corona model calculations, if the viscosity α≈ 0.1 - 0.2 is adopted. Our results provide strong evidence for the physical link between the BLRs and accretion disks in AGNs.

  1. In-air broad beam ionoluminescence microscopy as a tool for rocks and stone artworks characterisation.

    Science.gov (United States)

    Lo Giudice, Alessandro; Re, Alessandro; Angelici, Debora; Calusi, Silvia; Gelli, Nicla; Giuntini, Lorenzo; Massi, Mirko; Pratesi, Giovanni

    2012-07-01

    Broad beam ionoluminescence (IL) microscopy is a promising technique for the non-destructive characterisation of rocks and stone objects. Luminescence imaging by means of broad ion beams has been sporadically used by other authors but, to our knowledge, its potential has not yet been fully investigated, neither in geological science nor in other fields. The in-air broad beam IL microscope was developed and installed at the INFN-LABEC external microbeam in Florence. Similar to the cathodoluminescence (CL) microscope, the apparatus exploits a CCD colour camera collecting images (few square millimetres wide, with ~10-μm spatial resolution) of the luminescence emitted by the sample hit by a defocused megaelectron volt (MeV) proton beam. The main differences with the well-established and widespread CL are the possibility of working in air (no sampling or conductive coatings required) and the possibility of combining the analysis with microbeam analysis, such as, for example, μ-IL and μ-PIXE (particle-induced X-ray emission). To show the potential of the technique, IL images of thin sections of lapis lazuli are compared with those obtained by means of an in-vacuum cold CL. An application to the study of stone artworks is also reported. This technique and apparatus will provide a valuable help for interdisciplinary applications, e.g. in geological sciences and in the cultural heritage field.

  2. Broad neutralizing human monoclonal antibodies against influenza virus from vaccinated healthy donors

    Energy Technology Data Exchange (ETDEWEB)

    Kubota-Koketsu, Ritsuko; Mizuta, Hiroyuki [Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871 (Japan); Oshita, Masatoshi; Ideno, Shoji [Osaka Research Laboratory, Benesis Corporation, Yodogawa-ku, Osaka 532-6505 (Japan); Yunoki, Mikihiro [Osaka Research Laboratory, Benesis Corporation, Yodogawa-ku, Osaka 532-6505 (Japan); Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871 (Japan); Kuhara, Motoki [Ina Laboratory, Medical and Biological Laboratories Corporation, Ltd., Ina, Nagano 396-0002 (Japan); Yamamoto, Naomasa [Department of Biochemistry, School of Pharmaceutical Sciences, Ohu University, Koriyama, Fukushima 963-8611 (Japan); Okuno, Yoshinobu [Kanonji Institute, The Research Foundation for Microbial Diseases of Osaka University, Kanonji, Kagawa 768-0061 (Japan); Ikuta, Kazuyoshi, E-mail: ikuta@biken.osaka-u.ac.jp [Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871 (Japan)

    2009-09-11

    Human monoclonal antibodies (HuMAbs) prepared from patients with viral infections could provide information on human epitopes important for the development of vaccines as well as potential therapeutic applications. Through the fusion of peripheral blood mononuclear cells from a total of five influenza-vaccinated volunteers, with newly developed murine-human chimera fusion partner cells, named SPYMEG, we obtained 10 hybridoma clones stably producing anti-influenza virus antibodies: one for influenza A H1N1, four for influenza A H3N2 and five for influenza B. Surprisingly, most of the HuMAbs showed broad reactivity within subtype and four (two for H3N2 and two for B) showed broad neutralizing ability. Importantly, epitope mapping revealed that the two broad neutralizing antibodies to H3N2 derived from different donors recognized the same epitope located underneath the receptor-binding site of the hemagglutinin globular region that is highly conserved among H3N2 strains.

  3. Multivalent dendritic molecules as broad spectrum bacteria agglutination agents.

    Science.gov (United States)

    Xiao, Shuzhang; Abu-Esba, Lica; Turkyilmaz, Serhan; White, Alexander G; Smith, Bradley D

    2013-01-01

    This study reports the first set of synthetic molecules that act as broad spectrum agglutination agents and thus are complementary to the specific targeting of antibodies. The molecules have dendritic architecture and contain multiple copies of zinc(II)-dipicolylamine (ZnDPA) units that have selective affinity for the bacterial cell envelope. A series of molecular structures were evaluated, with the number of appended ZnDPA units ranging from four to thirty-two. Agglutination assays showed that the multivalent probes rapidly cross-linked ten different strains of bacteria, regardless of Gram-type and cell morphology. Fluorescence microscopy studies using probes with four ZnDPA units indicated a high selectivity for bacteria agglutination in the presence of mammalian cells and no measurable effect on the health of the cells. The high bacterial selectivity was confirmed by conducting in vivo optical imaging studies of a mouse leg infection model. The results suggest that multivalent ZnDPA molecular probes with dendritic structures have great promise as selective, broad spectrum bacterial agglutination agents for infection imaging and theranostic applications.

  4. Broad Ly alpha Emission from Three Nearby BL Lacertae Objects

    CERN Document Server

    Stocke, John T; Perlman, Eric S

    2011-01-01

    We present far-UV HST/COS spectra of four nearby BL Lac Objects. BL Lac spectra are dominated by a smooth, power-law continuum which arises in a relativistic jet. However, the spectra are not necessarily featureless; weak, broad- and/or narrow-line emission is sometimes seen in high-quality optical spectra. We present detections of Lya emission in HST/COS spectra of Mrk421 (z=0.030) and PKS2005-489 (z=0.071) as well as an archival HST/GHRS observation of Mrk501 (z=0.0337). Archival HST/STIS observations of PKS2155-304 (z=0.116) show no Lya emission to a very low upper limit. Using the assumption that the broad-line region (BLR) clouds are asymmetrically placed around the AGN, we use these measured Lya emission features to constrain either the relativistic Gamma values for the ionizing continuum produced by the jet (in the ionization-bounded case) or the mass of warm gas (in the density-bounded case). While realistic Gamma values can be obtained for all four cases, the values for Mrk421 and PKS2155-304 are hig...

  5. Broad spectrum microarray for fingerprint-based bacterial species identification

    Directory of Open Access Journals (Sweden)

    Frey Jürg E

    2010-02-01

    Full Text Available Abstract Background Microarrays are powerful tools for DNA-based molecular diagnostics and identification of pathogens. Most target a limited range of organisms and are based on only one or a very few genes for specific identification. Such microarrays are limited to organisms for which specific probes are available, and often have difficulty discriminating closely related taxa. We have developed an alternative broad-spectrum microarray that employs hybridisation fingerprints generated by high-density anonymous markers distributed over the entire genome for identification based on comparison to a reference database. Results A high-density microarray carrying 95,000 unique 13-mer probes was designed. Optimized methods were developed to deliver reproducible hybridisation patterns that enabled confident discrimination of bacteria at the species, subspecies, and strain levels. High correlation coefficients were achieved between replicates. A sub-selection of 12,071 probes, determined by ANOVA and class prediction analysis, enabled the discrimination of all samples in our panel. Mismatch probe hybridisation was observed but was found to have no effect on the discriminatory capacity of our system. Conclusions These results indicate the potential of our genome chip for reliable identification of a wide range of bacterial taxa at the subspecies level without laborious prior sequencing and probe design. With its high resolution capacity, our proof-of-principle chip demonstrates great potential as a tool for molecular diagnostics of broad taxonomic groups.

  6. Peculiar Broad Absorption Line Quasars found in DPOSS

    CERN Document Server

    Brunner, R J; Djorgovski, S G; Gal, R R; Mahabal, A A; Lopes, P A A; De Carvalho, R R; Odewahn, S C; Castro, S; Thompson, D; Chaffee, F; Darling, J; Desai, V; Brunner, Robert J.; Hall, Patrick B.

    2003-01-01

    With the recent release of large (i.e., > hundred million objects), well-calibrated photometric surveys, such as DPOSS, 2MASS, and SDSS, spectroscopic identification of important targets is no longer a simple issue. In order to enhance the returns from a spectroscopic survey, candidate sources are often preferentially selected to be of interest, such as brown dwarfs or high redshift quasars. This approach, while useful for targeted projects, risks missing new or unusual species. We have, as a result, taken the alternative path of spectroscopically identifying interesting sources with the sole criterion being that they are in low density areas of the g - r and r - i color-space defined by the DPOSS survey. In this paper, we present three peculiar broad absorption line quasars that were discovered during this spectroscopic survey, demonstrating the efficacy of this approach. PSS J0052+2405 is an Iron LoBAL quasar at a redshift z = 2.4512 with very broad absorption from many species. PSS J0141+3334 is a reddened...

  7. Outflow and hot dust emission in broad absorption line quasars

    CERN Document Server

    Zhang, Shaohua; Wang, Tinggui; Xing, Feijun; Zhang, Kai; Zhou, Hongyan; Jiang, Peng

    2014-01-01

    We have investigated a sample of 2099 broad absorption line (BAL) quasars with z=1.7-2.2 built from the Sloan Digital Sky Survey Data Release Seven and the Wide-field Infrared Survey. This sample is collected from two BAL quasar samples in the literature, and refined by our new algorithm. Correlations of outflow velocity and strength with hot dust indicator (beta_NIR) and other quasar physical parameters, such as Eddington ratio, luminosity and UV continuum slope, are explored in order to figure out which parameters drive outflows. Here beta_NIR is the near-infrared continuum slope, a good indicator of the amount of hot dust emission relative to accretion disk emission. We confirm previous findings that outflow properties moderately or weakly depends on Eddington ratio, UV slope and luminosity. For the first time, we report moderate and significant correlations of outflow strength and velocity with beta_NIR in BAL quasars. It is consistent with the behavior of blueshifted broad emission lines in non-BAL quasa...

  8. A prism based magnifying hyperlens with broad-band imaging

    Science.gov (United States)

    Habib, Md. Samiul; Stefani, Alessio; Atakaramians, Shaghik; Fleming, Simon C.; Argyros, Alexander; Kuhlmey, Boris T.

    2017-03-01

    Magnification in metamaterial hyperlenses has been demonstrated using curved geometries or tapered devices, at frequencies ranging from the microwave to the ultraviolet spectrum. One of the main issues of such hyperlenses is the difficulty in manufacturing. In this letter, we numerically and experimentally study a wire medium prism as an imaging device at THz frequencies. We characterize the transmission of the image of two sub-wavelength apertures, observing that our device is capable of resolving the apertures and producing a two-fold magnified image at the output. The hyperlens shows strong frequency dependent artefacts, a priori limiting the use of the device for broad-band imaging. We identify the main source of image aberration as the reflections supported by the wire medium and also show that even the weaker reflections severely affect the imaging quality. In order to correct for the reflections, we devise a filtering technique equivalent to spatially variable time gating so that ultra-broad band imaging is achieved.

  9. Broad-spectrum antimicrobial polycarbonate hydrogels with fast degradability.

    Science.gov (United States)

    Pascual, Ana; Tan, Jeremy P K; Yuen, Alex; Chan, Julian M W; Coady, Daniel J; Mecerreyes, David; Hedrick, James L; Yang, Yi Yan; Sardon, Haritz

    2015-04-13

    In this study, a new family of broad-spectrum antimicrobial polycarbonate hydrogels has been successfully synthesized and characterized. Tertiary amine-containing eight-membered monofunctional and difunctional cyclic carbonates were synthesized, and chemically cross-linked polycarbonate hydrogels were obtained by copolymerizing these monomers with a poly(ethylene glycol)-based bifunctional initiator via organocatalyzed ring-opening polymerization using 1,8-diazabicyclo[5.4.0]undec-7-ene catalyst. The gels were quaternized using methyl iodide to confer antimicrobial properties. Stable hydrogels were obtained only when the bifunctional monomer concentration was equal to or higher than 12 mol %. In vitro antimicrobial studies revealed that all quaternized hydrogels exhibited broad-spectrum antimicrobial activity against Staphylococcus aureus (Gram-positive), Escherichia coli (Gram-negative), Pseudomonas aeruginosa (Gram-negative), and Candida albicans (fungus), while the antimicrobial activity of the nonquaternized hydrogels was negligible. Moreover, the gels showed fast degradation at room temperature (4-6 days), which makes them ideal candidates for wound healing and implantable biomaterials.

  10. More Is Better: Selecting for Broad Host Range Bacteriophages.

    Science.gov (United States)

    Ross, Alexa; Ward, Samantha; Hyman, Paul

    2016-01-01

    Bacteriophages are viruses that infect bacteria. In this perspective, we discuss several aspects of a characteristic feature of bacteriophages, their host range. Each phage has its own particular host range, the range of bacteria that it can infect. While some phages can only infect one or a few bacterial strains, other phages can infect many species or even bacteria from different genera. Different methods for determining host range may give different results, reflecting the multiple mechanisms bacteria have to resist phage infection and reflecting the different steps of infection each method depends on. This makes defining host range difficult. Another difficulty in describing host range arises from the inconsistent use of the words "narrow" and especially "broad" when describing the breadth of the host range. Nearly all bacteriophages have been isolated using a single host strain of bacteria. While this procedure is fairly standard, it may more likely produce narrow rather than broad host range phage. Our results and those of others suggest that using multiple host strains during isolation can more reliably produce broader host range phages. This challenges the common belief that most bacteriophages have a narrow host range. We highlight the implications of this for several areas that are affected by host range including horizontal gene transfer and phage therapy.

  11. The UV-Optical Albedo of Broad Emission Line Clouds

    CERN Document Server

    Korista, K T; Korista, Kirk; Ferland, Gary

    1997-01-01

    We explore the effective UV-optical albedos of a variety of types of broad emission line clouds, as well as their possible effects on the observed spectra of AGN. An important albedo source in moderately ionized ionization-bounded clouds is that due to neutral hydrogen: Rayleigh scattering of continuum photons off the extreme damping wings of Lya. The photons resulting from this scattering mechanism may contribute significantly to the Lya emission line, especially in the very broad wings. In addition, line photons emitted near 1200 Angstroms (e.g., N V 1240) that stream toward the neutral portion of the cloud may be reflected off this Rayleigh scattering mirror, so that they preferentially escape from the illuminated face. Inclusion of this effect can alter predicted emission line strengths and profiles. In more highly-ionized ionization-bounded clouds, Thompson scattering dominates the UV-optical albedo, but this albedo is lessened by the hydrogen gas opacity. These clouds are most reflective on the long wav...

  12. Effect of gamma irradiation on antinutritional factors in broad bean

    Energy Technology Data Exchange (ETDEWEB)

    Al-Kaisey, M.T. E-mail: istd@uruklink.net; Alwan, A.-K.H.; Mohammad, M.H.; Saeed, A.H

    2003-06-01

    The effect of gamma irradiation on the level of antinutritional factors (trypsin inhibitor (TI), phytic acid and oligosaccharides) of broad bean was investigated. The seeds were subjected to gamma irradiation at 0, 2.5, 5, 7.5 and 10 kGy, respectively using cobalt-60 gamma radiation with a dose rate 2.37 kGy/h. TI activity was reduced by 4.5%, 6.7%, 8.5% and 9.2% at 2.5, 5, 7.5 and 10 kGy, respectively. Meanwhile, irradiation at 10.2, 12.3, 15.4 and 18.2 kGy reduced the phytic acid content. The flatulence causing oligosaccharides were decreased as the radiation dose increased. The chemical composition (protein, oil, ash and total carbohydrates) of the tested seeds was determined. Gamma radiation seems to be a good procedure to improve the quality of broad bean from the nutritional point of view.

  13. Communicating Science Broadly: An NSF Point of View

    Science.gov (United States)

    Leinen, M. S.

    2006-12-01

    In the view of NSF, communicating about both the process of doing science and about scientific results are of paramount importance. But those of us in the agency are not the ones who do the science or generate the results. Thus, our policy is to encourage the community we fund to communicate their results as broadly as possible. Why does NSF feel so strongly about communicating scientific results? First, science only moves forward when there is free and open debate about scientific results through public mechanisms in which there is an opportunity for thorough analysis (e.g. scientific literature, professional meetings and workshops). Second, the research we support is done for the good of the public and should be communicated to the public. Third, scientific results are critical to many important decision-making processes and policy-making processes. Democracies thrive when an informed public is engaged, so communicating science broadly to the lay public is important. Why does NSF feel so strongly about communicating about the process of science? Science is a habit of mind; an orderly process for testing ideas. But many do not understand how science is done, the difference between fact and conjecture, why speculation, hypotheses and theory are critical to progress, or why the culture of constructive criticism is essential to progress. Without this context, science can be misunderstood as magic, opinion, or argument. Thus the efforts that we fund to enhance scientific education and outreach are critical to having discourse about scientific results.

  14. Broad Spectrum Respiratory Pathogen Analysis of Throat Swabs from Military Recruits Reveals Interference Between Rhinoviruses and Adenoviruses

    Science.gov (United States)

    2010-03-09

    components of the respiratory microflora . The technology has been success- fully demonstrated to identify a broad range of pathogens (including bacteria...available, approximately 20 recruits meeting the FRI case definition ( oral temperature of >=38°C and cough or a sore throat, or provider-diagnosed pneumonia

  15. Spatiospectral and picosecond spatiotemporal properties of a broad area operating channeled-substrate-planar laser array

    Science.gov (United States)

    Yu, NU; Defreez, Richard K.; Bossert, David J.; Wilson, Geoffrey A.; Elliott, Richard A.

    1991-01-01

    Spatiospectral and spatiotemporal properties of an eight-element channeled-substrate-planar laser array are investigated in both CW and pulsed operating conditions. The closely spaced CSP array with strong optical coupling between array elements is characterized by a broad area laserlike operation determined by its spatial mode spectra. The spatiotemporal evolution of the near and far field exhibits complex dynamic behavior in the picosecond to nanosecond domain. Operating parameters for the laser device have been experimentally determined. These results provide important information for the evaluation of the dynamic behavior of coherent semiconductor laser arrays.

  16. Standarized radiological hazard analysis for a broad based operational safety program

    Energy Technology Data Exchange (ETDEWEB)

    Wadman, W.W. III; Andrews, L.L.

    1992-01-01

    The Radiological hazard Analysis (RHA) Manual provides a methodology and detailed guidance for systematic analysis of radiological hazards over a broad spectrum of program functions, housed in a wide variety of facilities. Radiological programs at LANL include: research and experimentation; routine materials operations; production; non-destructive examination or testing; isotope and machine produced radiations; chemistry; and metallurgy. The RHA permits uniform evaluation of hazard types over a range of several orders of magnitude of hazard severity. The results are used to estimate risk, evaluate types and level or resource allocations, identify deficiencies, and plan corrective actions for safe working environments. 2 refs.

  17. Virological features associated with the development of broadly neutralizing antibodies to HIV-1.

    Science.gov (United States)

    Moore, Penny L; Williamson, Carolyn; Morris, Lynn

    2015-04-01

    The development of a preventative HIV-1 vaccine remains a global public health priority. This will likely require the elicitation of broadly neutralizing antibodies (bNAbs) able to block infection by diverse viral strains from across the world. Understanding the pathway to neutralization breadth in HIV-1 infected humans will provide insights into how bNAb lineages arise, a process that probably involves a combination of host and viral factors. Here, we focus on the role of viral characteristics and evolution in shaping bNAbs during HIV-1 infection, and describe how these findings may be translated into novel vaccine strategies.

  18. V-shaped resonators for addition of broad-area laser diode arrays

    Science.gov (United States)

    Liu, Bo; Liu, Yun; Braiman, Yehuda Y.

    2012-12-25

    A system and method for addition of broad-area semiconductor laser diode arrays are described. The system can include an array of laser diodes, a V-shaped external cavity, and grating systems to provide feedback for phase-locking of the laser diode array. A V-shaped mirror used to couple the laser diode emissions along two optical paths can be a V-shaped prism mirror, a V-shaped stepped mirror or include multiple V-shaped micro-mirrors. The V-shaped external cavity can be a ring cavity. The system can include an external injection laser to further improve coherence and phase-locking.

  19. Spatially nondegenerate four-wave mixing in a broad area semiconductor laser: Modeling

    DEFF Research Database (Denmark)

    Jensen, Søren Blaaberg; Tromborg, Bjarne; Petersen, P. M.

    coupled equations for the field components in the cavity and a rate equation is used to describe the carrier density of the semiconductor material. The interference pattern of the four field components inside the cavity induces a periodic spatial modulation of the carrier density and thus of the complex......We present a numerical model of spatially nondegenerate four-wave mixing in a bulk broad area semiconductor laser with an external reflector and a spatial filter. The external reflector provides a feedback with an off-aixs direction of propagation. Such a configuration has experimentally been seen...

  20. Evidence for Photoionization Driven Broad Absorption Line Variability

    CERN Document Server

    Wang, Tinggui; Wang, Huiyuan; Ferland, Gary

    2015-01-01

    We present a qualitative analysis of the variability of quasar broad absorption lines using the large multi-epoch spectroscopic dataset of the Sloan Digital Sky Survey Data Release 10. We confirm that variations of absorption lines are highly coordinated among different components of the same ion or the same absorption component of different ions for C IV, Si IV and N V. Furthermore, we show that the equivalent widths of the lines decrease or increase statistically when the continuum brightens or dims. This is further supported by the synchronized variations of emission and absorption line equivalent width, when the well established intrinsic Baldwin effect for emission lines is taken into account. We find that the emergence of an absorption component is usually accompanying with dimming of the continuum while the disappearance of an absorption line component with brightening of the continuum. This suggests that the emergence or disappearance of a C IV absorption component is only the extreme case, when the i...

  1. Mucin biopolymers as broad-spectrum antiviral agents

    Science.gov (United States)

    Lieleg, Oliver; Lieleg, Corinna; Bloom, Jesse; Buck, Christopher B.; Ribbeck, Katharina

    2012-01-01

    Mucus is a porous biopolymer matrix that coats all wet epithelia in the human body and serves as the first line of defense against many pathogenic bacteria and viruses. However, under certain conditions viruses are able to penetrate this infection barrier, which compromises the protective function of native mucus. Here, we find that isolated porcine gastric mucin polymers, key structural components of native mucus, can protect an underlying cell layer from infection by small viruses such as human papillomavirus (HPV), Merkel cell polyomavirus (MCV), or a strain of influenza A virus. Single particle analysis of virus mobility inside the mucin barrier reveals that this shielding effect is in part based on a retardation of virus diffusion inside the biopolymer matrix. Our findings suggest that purified mucins may be used as a broad-range antiviral supplement to personal hygiene products, baby formula or lubricants to support our immune system. PMID:22475261

  2. Broad Iron Lines in AGN and X-ray Binaries

    CERN Document Server

    Fabian, A C

    2004-01-01

    Several AGN and black hole X-ray binaries show a clear very broad iron line which is strong evidence that the black holes are rapidly spinning. Detailed analysis of these objects shows that the emission line is not significantly affected by absorption and that the source variability is principally due to variation in amplitude of a power-law. Underlying this is a much less variable, relativistically-smeared, reflection-dominated, component which carries the imprint of strong gravity at a few gravitational radii. The strong gravitational light bending in these regions then explains the power-law variability as due to changes in height of the primary X-ray source above the disc. The reflection component, in particular its variability and the profile of the iron line, enables us to study the innermost regions around an accreting, spinning, black hole.

  3. Clinical evaluation of clotrimazole. A broad-spectrum antifungal agent.

    Science.gov (United States)

    Spiekermann, P H; Young, M D

    1976-03-01

    The efficacy and safety of the broad-spectrum, topically applied antifungal agent clotrimazole were evaluated in two double-blind, multicentric trials. Ten investigators reported on a total of 1,361 cases in which a 1% solution or a 1% cream formulation was compared with its respective vehicle. Clotrimazole was therapeutically effective, as confirmed by mycological cure (negative microscopy and culture) and clinical improvement, in tinea pedis, tinea cruris, tinea corporis, pityriasis versicolor, and cutaneous candidasis. Furthermore, species identification established the efficacy of clotrimazole against Trichophyton rubrum, T mentagrophytes, Epidermophyton floccosum, Microsporum canis, Malassezia furfur (Pityrosporum orbiculare), and Candida albicans. Safety was demonstrated by the low incidence of possibly drug-related adverse experiences, namely, 19 (2.7%) of 699 patients who were treated with clotrimazole, of whom four (0.6%) discontinued treatment.

  4. The Broad Line Radio Galaxy J2114+820

    CERN Document Server

    Lara, L; Cotton, W D; Feretti, L; Giovannini, G; Marcaide, J M; Venturi, T

    1998-01-01

    In the frame of the study of a new sample of large angular size radio galaxies selected from the NRAO VLA Sky Survey, we have made radio observations of J2114+820, a low power radio galaxy with an angular size of 6'. Its radio structure basically consists of a prominent core, a jet directed in north-west direction and two extended S-shaped lobes. We have also observed the optical counterpart of J2114+820, a bright elliptical galaxy with a strong unresolved central component. The optical spectrum shows broad emission lines. This fact, together with its low radio power and FR-I type morphology, renders J2114+820 a non-trivial object from the point of view of the current unification schemes of radio loud active galactic nuclei.

  5. Spontaneous pattern formation in broad-area lasers

    Science.gov (United States)

    Krents, Anton; Anchikov, Dmitry; Molevich, Nonna; Pakhomov, Anton

    2016-10-01

    The paper studies the spontaneous formation of nonlinear optical patterns in broad area lasers. Spatiotemporal transverse dynamics of the laser is described by the Maxwell-Bloch equations (MBE). The instability of the steady-state solution leads to pattern formation. Two different types of instabilities were observed analytically (Hopf and wave). 2D numerical simulation of the MBE with the random initial conditions has been performed using a split-step Fourier method and periodic boundary conditions. Hopf instability leads to homogeneous oscillations, spatiotemporal chaos and spiral waves. In the case of wave instability, the direct numerical simulation showed that space-time (periodic, quasi-periodic, or chaotic) modulation of the uniform profile is observed. The characteristic sizes of excited patterns are in good agreement with analytical predictions. The nonlinear interaction of four travelling waves forms a square optical vortex lattice similar to the vortex lattices observed in superconductors and Bose Einstein condensate.

  6. Broadly neutralizing antibodies: An approach to control HIV-1 infection.

    Science.gov (United States)

    Yaseen, Mahmoud Mohammad; Yaseen, Mohammad Mahmoud; Alqudah, Mohammad Ali

    2017-01-02

    Although available antiretroviral therapy (ART) has changed human immunodeficiency virus (HIV)-1 infection to a non-fatal chronic disease, the economic burden of lifelong therapy, severe adverse ART effects, daily ART adherence, and emergence of ART-resistant HIV-1 mutants require prospecting for alternative therapeutic modalities. Indeed, a growing body of evidence suggests that broadly neutralizing anti-HIV-1 antibodies (BNAbs) may offer one such feasible alternative. To evaluate their therapeutic potential in established HIV-1 infection, we sought to address recent advances in pre-clinical and clinical investigations in this area of HIV-1 research. In addition, we addressed the obstacles that may impede the success of such immunotherapeutic approach, suggested strategic solutions, and briefly compared this approach with the currently used ART to open new insights for potential future passive immunotherapy for HIV-1 infection.

  7. Engineering broadly neutralizing antibodies for HIV prevention and therapy.

    Science.gov (United States)

    Hua, Casey K; Ackerman, Margaret E

    2016-08-01

    A combination of advances spanning from isolation to delivery of potent HIV-specific antibodies has begun to revolutionize understandings of antibody-mediated antiviral activity. As a result, the set of broadly neutralizing and highly protective antibodies has grown in number, diversity, potency, and breadth of viral recognition and neutralization. These antibodies are now being further enhanced by rational engineering of their anti-HIV activities and coupled to cutting edge gene delivery and strategies to optimize their pharmacokinetics and biodistribution. As a result, the prospects for clinical use of HIV-specific antibodies to treat, clear, and prevent HIV infection are gaining momentum. Here we discuss the diverse methods whereby antibodies are being optimized for neutralization potency and breadth, biodistribution, pharmacokinetics, and effector function with the aim of revolutionizing HIV treatment and prevention options.

  8. SPECTROSCOPY OF BROAD-LINE BLAZARS FROM 1LAC

    Energy Technology Data Exchange (ETDEWEB)

    Shaw, Michael S.; Romani, Roger W.; Healey, Stephen E.; Michelson, Peter F. [Department of Physics/KIPAC, Stanford University, Stanford, CA 94305 (United States); Cotter, Garret; Potter, William J. [Department of Astrophysics, University of Oxford, Oxford OX1 3RH (United Kingdom); Readhead, Anthony C. S.; Richards, Joseph L.; Max-Moerbeck, Walter; King, Oliver G. [Department of Astronomy, California Institute of Technology, Pasadena, CA 91125 (United States)

    2012-03-20

    We report on optical spectroscopy of 165 flat spectrum radio quasars (FSRQs) in the Fermi 1LAC sample, which have helped allow a nearly complete study of this population. Fermi FSRQs show significant evidence for non-thermal emission even in the optical; the degree depends on the {gamma}-ray hardness. They also have smaller virial estimates of hole mass than the optical quasar sample. This appears to be largely due to a preferred (axial) view of the {gamma}-ray FSRQ and non-isotropic (H/R {approx} 0.4) distribution of broad-line velocities. Even after correction for this bias, the Fermi FSRQs show higher mean Eddington ratios than the optical population. A comparison of optical spectral properties with Owens Valley Radio Observatory radio flare activity shows no strong correlation.

  9. Broad activation of latent HIV-1 in vivo

    DEFF Research Database (Denmark)

    Barton, Kirston; Hiener, Bonnie; Winckelmann, Anni;

    2016-01-01

    The 'shock and kill' approach to cure human immunodeficiency virus (HIV) includes transcriptional induction of latent HIV-1 proviruses using latency-reversing agents (LRAs) with targeted immunotherapy to purge infected cells. The administration of LRAs (panobinostat or vorinostat) to HIV-1-infected...... individuals on antiretroviral therapy induces a significant increase in cell-associated unspliced (CA-US) HIV-1 RNA from CD4(+) T cells. However, it is important to discern whether the increases in CA-US HIV-1 RNA are due to limited or broad activation of HIV-1 proviruses. Here we use single-genome sequencing...... to find that the RNA transcripts observed following LRA administration are genetically diverse, indicating activation of transcription from an extensive range of proviruses. Defective sequences are more frequently found in CA HIV-1 RNA than in HIV-1 DNA, which has implications for developing an accurate...

  10. Broad band invisibility cloak made of normal dielectric multilayer

    CERN Document Server

    Xu, Xiaofei; Xiong, Shuai; Fan, Jinlong; Zhao, Jun-Ming; Jiang, Tian

    2011-01-01

    We present the design, fabrication and performance test of a quasi three-dimensional carpet cloak made of normal dielectric in the microwave regime. Taking advantage of a simple linear coordinate transformation we design a carpet cloak with homogeneous anisotropic medium and then practically realize the device with multilayer of alternating normal dielectric slabs based on the effective medium theory. As a proof-of-concept example, we fabricate the carpet cloak with multilayer of FR4 dielectric slabs with air spacing. The performance of the fabricated design is verified through full-wave numerical simulation and measurement of the far-field scattering electromagnetic waves in a microwave anechoic chamber. Experimental results have demonstrated pronounced cloaking effect in a very broad band from 8 GHz to 18 GHz (whole X and Ku band) due to the low loss, non-dispersive feature of the multilayer dielectric structure.

  11. Rufinamide: a novel broad-spectrum antiepileptic drug.

    Science.gov (United States)

    Wheless, James W; Vazquez, Blanca

    2010-01-01

    The last 20 years have witnessed a tremendous explosion in the number of antiepileptic drugs (AEDs) as well as the introduction of AEDS developed for specific epilepsy syndromes. The study of the efficacy and side effect profile of AEDs for unique epilepsy syndromes has allowed neurologists to utilize evidence-based medicine when treating patients. In late 2008, the Food and Drug Administration approved rufinamide for adjunctive use in the treatment of seizures associated with Lennox-Gastaut syndrome. This unique chemical compound is also the first new AED to reach the market in the United States having a pediatric indication prior to approval for adults. Rufinamide appears to have a broad spectrum of efficacy, is well tolerated, and may be rapidly initiated--properties that will likely extend its use outside of Lennox-Gastaut syndrome.

  12. Characterisation of a Broad Energy Germanium (BEGe) detector

    Energy Technology Data Exchange (ETDEWEB)

    Barrientos, D., E-mail: diego_barrientos@usal.es [Laboratorio de Radiaciones Ionizantes, University of Salamanca (Spain); Boston, A.J.; Boston, H.C. [Nuclear Physics Group, University of Liverpool (United Kingdom); Quintana, B.; Sagrado, I.C. [Laboratorio de Radiaciones Ionizantes, University of Salamanca (Spain); Unsworth, C.; Moon, S.; Cresswell, J.R. [Nuclear Physics Group, University of Liverpool (United Kingdom)

    2011-08-21

    Characterisation of Germanium detectors used for gamma-ray tracking or medical imaging is one of the current goals in the Nuclear physics community. Good knowledge of detector response to different gamma radiations is needed for this purpose. In order to develop this task, Pulse Shape Analysis (PSA) techniques have been developed for different detector geometries or setups. In this work, we present the results of the application of PSA for a Canberra Broad Energy Germanium (BEGe) detector. This detector was scanned across its front and bottom face using a fully digital data acquisition system; allowing to record detector charge pulse shapes from well defined positions with collimated sources of {sup 241}Am, {sup 22}Na and {sup 137}Cs. With the study of the data acquired, characteristics of the inner detector geometry like crystal limits or positions of contact and isolate can be found, as well as the direction of the axes for the Germanium crystal.

  13. Broad spectrum moderators and advanced reflector filters using 208Pb

    DEFF Research Database (Denmark)

    Schönfeldt, Troels; Batkov, K.; Klinkby, Esben Bryndt

    2015-01-01

    thermalizing property of 208Pb to design a broad spectrum moderator, i.e. a moderator which emits thermal and cold neutrons from the same position. Using 208Pb as a reflector filter material is shown to be slightly less efficient than a conventional beryllium reflector filter. However, when surrounding...... the reflector filter by a cold moderator it is possible to regain the neutrons with wavelengths below the Bragg edge, which are suppressed in the beryllium reflector filter. In both the beryllium and lead case surrounding the reflector filter with a cold moderator increases the cold brightness significantly......Cold and thermal neutrons used in neutrons scattering experiments are produced in nuclear reactors and spallation sources. The neutrons are cooled to thermal or cold temperatures in thermal and cold moderators, respectively. The present study shows that it is possible to exploit the poor...

  14. The Nature of Partial Covering in Broad Absorption Line Quasars

    Science.gov (United States)

    Leighly, Karen

    2012-10-01

    Ejected gas is seen as broad absorption lines in 20% of quasars. It has been known for 15 years that prominent lines such as CIV are usually saturated but not black because the absorbing gas only partially covers the continuum emission region. Therefore, column densities estimated from these lines are only lower limits. Accurate column densities can be obtained from rare ions that have two or more transitions from the same lower level, so that the optical depth and covering fraction can be solved for simultanously. Suitable lines are hard to find, so such measurements are rare. We have found that metastable helium is particularly useful for these measurements. Yet despite these advances, partial covering remains a just a parameter and its physical nature is not understood.We propose a unique experiment to constrain the physical nature of partial covering. We will compare the covering fraction measured from PV {a doublet in the far UV} with that measured from metastable HeI {optical and IR}. The ions creating these lines are relatively rare, and they present similar opacity over a wide range of gas parameters. But due to their wide wavelength separation, these lines probe dramatically different regions of the continuum source, the temperature-dependent accretion disk. So we expect different covering fraction behavior for different partial covering scenarios. This experiment is relevant for understanding the geometry and clumpiness of the outflow, and the results may impact our understanding of the global covering fraction, a parameter critical for determining the outflow kinetic luminosity, and thereby estimating feedback efficiency for broad absorption line outflows.

  15. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus.

    Science.gov (United States)

    Liao, Hua-Xin; Lynch, Rebecca; Zhou, Tongqing; Gao, Feng; Alam, S Munir; Boyd, Scott D; Fire, Andrew Z; Roskin, Krishna M; Schramm, Chaim A; Zhang, Zhenhai; Zhu, Jiang; Shapiro, Lawrence; Mullikin, James C; Gnanakaran, S; Hraber, Peter; Wiehe, Kevin; Kelsoe, Garnett; Yang, Guang; Xia, Shi-Mao; Montefiori, David C; Parks, Robert; Lloyd, Krissey E; Scearce, Richard M; Soderberg, Kelly A; Cohen, Myron; Kamanga, Gift; Louder, Mark K; Tran, Lillian M; Chen, Yue; Cai, Fangping; Chen, Sheri; Moquin, Stephanie; Du, Xiulian; Joyce, M Gordon; Srivatsan, Sanjay; Zhang, Baoshan; Zheng, Anqi; Shaw, George M; Hahn, Beatrice H; Kepler, Thomas B; Korber, Bette T M; Kwong, Peter D; Mascola, John R; Haynes, Barton F

    2013-04-25

    Current human immunodeficiency virus-1 (HIV-1) vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in approximately 20% of HIV-1-infected individuals, and details of their generation could provide a blueprint for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection. The mature antibody, CH103, neutralized approximately 55% of HIV-1 isolates, and its co-crystal structure with the HIV-1 envelope protein gp120 revealed a new loop-based mechanism of CD4-binding-site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the unmutated common ancestor of the CH103 lineage avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data determine the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies, and provide insights into strategies to elicit similar antibodies by vaccination.

  16. Virilization of the Broad Line Region in Active Galactic Nuclei - connection between shifts and widths of broad emission lines

    CERN Document Server

    Jonic, Sanja; Ilic, Dragana; Popovic, Luka C

    2016-01-01

    We investigate the virilization of the emission lines Hbeta and Mg II in the sample of 287 Type 1 Active Galactic Nuclei taken from the Sloan Digital Sky Survey database. We explore the connections between the intrinsic line shifts and full widths at different levels of maximal intensity. We found that: (i) Hbeta seems to be a good virial estimator of black hole masses, and an intrinsic redshift of Hbeta is dominantly caused by the gravitational effect, (ii) there is an anti-correlation between the redshift and width of the wings of the Mg II line, (iii) the broad Mg II line can be used as virial estimator only at 50% of the maximal intensity, while the widths and intrinsic shifts of the line wings can not be used for this purpose.

  17. HMO partnering: the provider dilemma.

    Science.gov (United States)

    Ayers, J; Benson, L; Bonhag, R

    1996-10-01

    While the growth of HMOs has slowed patient visits to doctors, it also has created a deluge of press clippings. On July 16, 1996, three articles on the subject appeared in the Wall Street Journal, front section. The headlines painted a vivid picture of the forces acting on HMOs and providers alike (Figure 1). The articles portended more change for healthcare. The "shake-out," a term applied to industries in serious transformation, brings shedding of excess capacity and loss of jobs and income. Providers, in particular, find themselves in a difficult dilemma. They must not only cut costs as reimbursement drops, but also retain patients with good outcomes and high quality service. Patient retention means keeping the individual patient from switching to another provider and keeping the insurer's group of patients as an authorized provider for that insurer. The relationship between provider and HMO lies at the heart of the provider dilemma. The HMO structure, which shifts financial risk for care, is quickly setting the standard, for healthcare pricing, medical standards, and management practices. Understanding and responding to HMO needs are vital to competitive advantage and survival. The article discusses the inherent dilemma of HMO and provider partnering and suggests provider responses.

  18. Babesiosis for Health Care Providers

    Centers for Disease Control (CDC) Podcasts

    2012-04-25

    This podcast will educate health care providers on diagnosing babesiosis and providing patients at risk with tick bite prevention messages.  Created: 4/25/2012 by Center for Global Health, Division of Parasitic Diseases and Malaria.   Date Released: 4/25/2012.

  19. Broad-scale patterns of late jurassic dinosaur paleoecology.

    Directory of Open Access Journals (Sweden)

    Christopher R Noto

    Full Text Available BACKGROUND: There have been numerous studies on dinosaur biogeographic distribution patterns. However, these distribution data have not yet been applied to ecological questions. Ecological studies of dinosaurs have tended to focus on reconstructing individual taxa, usually through comparisons to modern analogs. Fewer studies have sought to determine if the ecological structure of fossil assemblages is preserved and, if so, how dinosaur communities varied. Climate is a major component driving differences between communities. If the ecological structure of a fossil locality is preserved, we expect that dinosaur assemblages from similar environments will share a similar ecological structure. METHODOLOGY/PRINCIPAL FINDINGS: This study applies Ecological Structure Analysis (ESA to a dataset of 100+ dinosaur taxa arranged into twelve composite fossil assemblages from around the world. Each assemblage was assigned a climate zone (biome based on its location. Dinosaur taxa were placed into ecomorphological categories. The proportion of each category creates an ecological profile for the assemblage, which were compared using cluster and principal components analyses. Assemblages grouped according to biome, with most coming from arid or semi-arid/seasonal climates. Differences between assemblages are tied to the proportion of large high-browsing vs. small ground-foraging herbivores, which separates arid from semi-arid and moister environments, respectively. However, the effects of historical, taphonomic, and other environmental factors are still evident. CONCLUSIONS/SIGNIFICANCE: This study is the first to show that the general ecological structure of Late Jurassic dinosaur assemblages is preserved at large scales and can be assessed quantitatively. Despite a broad similarity of climatic conditions, a degree of ecological variation is observed between assemblages, from arid to moist. Taxonomic differences between Asia and the other regions demonstrate at

  20. Analysis of mammalian gene function through broad based phenotypic screens across a consortium of mouse clinics

    Science.gov (United States)

    Adams, David J; Adams, Niels C; Adler, Thure; Aguilar-Pimentel, Antonio; Ali-Hadji, Dalila; Amann, Gregory; André, Philippe; Atkins, Sarah; Auburtin, Aurelie; Ayadi, Abdel; Becker, Julien; Becker, Lore; Bedu, Elodie; Bekeredjian, Raffi; Birling, Marie-Christine; Blake, Andrew; Bottomley, Joanna; Bowl, Mike; Brault, Véronique; Busch, Dirk H; Bussell, James N; Calzada-Wack, Julia; Cater, Heather; Champy, Marie-France; Charles, Philippe; Chevalier, Claire; Chiani, Francesco; Codner, Gemma F; Combe, Roy; Cox, Roger; Dalloneau, Emilie; Dierich, André; Di Fenza, Armida; Doe, Brendan; Duchon, Arnaud; Eickelberg, Oliver; Esapa, Chris T; El Fertak, Lahcen; Feigel, Tanja; Emelyanova, Irina; Estabel, Jeanne; Favor, Jack; Flenniken, Ann; Gambadoro, Alessia; Garrett, Lilian; Gates, Hilary; Gerdin, Anna-Karin; Gkoutos, George; Greenaway, Simon; Glasl, Lisa; Goetz, Patrice; Da Cruz, Isabelle Goncalves; Götz, Alexander; Graw, Jochen; Guimond, Alain; Hans, Wolfgang; Hicks, Geoff; Hölter, Sabine M; Höfler, Heinz; Hancock, John M; Hoehndorf, Robert; Hough, Tertius; Houghton, Richard; Hurt, Anja; Ivandic, Boris; Jacobs, Hughes; Jacquot, Sylvie; Jones, Nora; Karp, Natasha A; Katus, Hugo A; Kitchen, Sharon; Klein-Rodewald, Tanja; Klingenspor, Martin; Klopstock, Thomas; Lalanne, Valerie; Leblanc, Sophie; Lengger, Christoph; le Marchand, Elise; Ludwig, Tonia; Lux, Aline; McKerlie, Colin; Maier, Holger; Mandel, Jean-Louis; Marschall, Susan; Mark, Manuel; Melvin, David G; Meziane, Hamid; Micklich, Kateryna; Mittelhauser, Christophe; Monassier, Laurent; Moulaert, David; Muller, Stéphanie; Naton, Beatrix; Neff, Frauke; Nolan, Patrick M; Nutter, Lauryl MJ; Ollert, Markus; Pavlovic, Guillaume; Pellegata, Natalia S; Peter, Emilie; Petit-Demoulière, Benoit; Pickard, Amanda; Podrini, Christine; Potter, Paul; Pouilly, Laurent; Puk, Oliver; Richardson, David; Rousseau, Stephane; Quintanilla-Fend, Leticia; Quwailid, Mohamed M; Racz, Ildiko; Rathkolb, Birgit; Riet, Fabrice; Rossant, Janet; Roux, Michel; Rozman, Jan; Ryder, Ed; Salisbury, Jennifer; Santos, Luis; Schäble, Karl-Heinz; Schiller, Evelyn; Schrewe, Anja; Schulz, Holger; Steinkamp, Ralf; Simon, Michelle; Stewart, Michelle; Stöger, Claudia; Stöger, Tobias; Sun, Minxuan; Sunter, David; Teboul, Lydia; Tilly, Isabelle; Tocchini-Valentini, Glauco P; Tost, Monica; Treise, Irina; Vasseur, Laurent; Velot, Emilie; Vogt-Weisenhorn, Daniela; Wagner, Christelle; Walling, Alison; Weber, Bruno; Wendling, Olivia; Westerberg, Henrik; Willershäuser, Monja; Wolf, Eckhard; Wolter, Anne; Wood, Joe; Wurst, Wolfgang; Yildirim, Ali Önder; Zeh, Ramona; Zimmer, Andreas; Zimprich, Annemarie

    2015-01-01

    The function of the majority of genes in the mouse and human genomes remains unknown. The mouse ES cell knockout resource provides a basis for characterisation of relationships between gene and phenotype. The EUMODIC consortium developed and validated robust methodologies for broad-based phenotyping of knockouts through a pipeline comprising 20 disease-orientated platforms. We developed novel statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no prior functional annotation. We captured data from over 27,000 mice finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. Novel phenotypes were uncovered for many genes with unknown function providing a powerful basis for hypothesis generation and further investigation in diverse systems. PMID:26214591

  1. Nonlinear effects in photoionization over a broad photon-energy range within the TDCIS scheme

    Science.gov (United States)

    Karamatskou, Antonia

    2017-01-01

    The present tutorial provides an overview of the time-dependent configuration interaction singles scheme applied to nonlinear ionization over a broad photon-energy range. The efficient propagation of the wave function and the calculation of photoelectron spectra within this approach are described and demonstrated in various applications. Above-threshold ionization of argon and xenon in the extreme ultraviolet energy range is investigated as an example. A particular focus is put on the xenon 4d giant dipole resonance and the information that nonlinear ionization can provide about resonance substructure. Furthermore, above-threshold ionization is studied in the x-ray regime and the intensity regime, at which multiphoton ionization starts to play a role at hard x-ray photon energies, is identified.

  2. Transient Broad Specular Reflections from Titan's North Pole

    Science.gov (United States)

    Dhingra, Rajani D.; Barnes, Jason W.

    2016-10-01

    In 2014, Cassini observed rough patches or transient broad specular reflections on one of Titan's seas, Punga Mare. These observations were made by the Visual and Infrared Mapping Spectrometer (VIMS). The rough patches were interpreted to be waves on the surface of the hydrocarbon sea with slopes of 60 ± 10. Although long anticipated, this was an important observation since there was no detection of waves in the initial flybys of north polar lakes and seas until the northern summer approached.We have analyzed several recent VIMS flybys of Titan's north pole looking for these rough surfaces. Our observations are classified as clouds, mudflats, specular reflections, or waves based on VIMS color composites. We observe waves in at least two seas at the north pole, Ligeia Mare and Kraken Mare. In addition, we also observe specular reflections from the shoreline or land, indicating the wet sidewalk effect or mudflat in other flybys. Wet sidewalk observations indicate a recent rainfall event causing diffuse specular reflection.These new observations help us understand more about the weather conditions and sea-wind interaction generating waves on the seas.

  3. Broad-band study with Suzaku of the magnetar class

    CERN Document Server

    Enoto, Teruaki; Makishima, Kazuo; Rea, Nanda; Hurley, Kevein; Shibata, Shinpei

    2010-01-01

    Broad-band (0.8-70 keV) spectra of the persistent X-ray emission from 9 magnetars were obtained with Suzaku, including 3 objects in apparent outburst. The soft X-ray component was detected from all of them, with a typical blackbody temperature of kT ~ 0.5 keV, while the hard-tail component, dominating above ~10 keV, was detected at ~1 mCrab intensity from 7 of them. Therefore, the spectrum composed of a soft emission and a hard-tail component may be considered to be a common property of magnetars, both in their active and quiescent states. Wide-band spectral analyses revealed that the hard-tail component has a 1-60 keV flux, Fh, comparable to or even higher than that carried by the 1-60 keV soft component, Fs. The hardness ratio of these objects, defined as xi=Fh/Fs, was found to be tightly anti-correlated with their characteristic age tau as xi=(3.3+/-0.3)x(tau/1 kyr)^(-0.67+/-0.04) with a correlation coefficient of -0.989, over the range from xi~10 to xi~0.1. Magnetars in outburst states were found to lie o...

  4. HAMLET - A protein-lipid complex with broad tumoricidal activity.

    Science.gov (United States)

    Ho, James C S; Nadeem, Aftab; Svanborg, Catharina

    2017-01-15

    HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) is a tumoricidal protein-lipid complex with broad effects against cancer cells of different origin. The therapeutic potential is emphasized by a high degree of specificity for tumor tissue. Here we review early studies of HAMLET, in collaboration with the Orrenius laboratory, and some key features of the subsequent development of the HAMLET project. The early studies focused on the apoptotic response that accompanies death in HAMLET treated tumor cells and the role of mitochondria in this process. In subsequent studies, we have identified a sequence of interactions that starts with the membrane integration of HAMLET and the activation of ion fluxes followed by HAMLET internalization, progressive inhibition of MAPK kinases and GTPases and sorting of HAMLET to different cellular compartments, including the nuclei. Therapeutic efficacy of HAMLET has been demonstrated in animal models of glioblastoma, bladder cancer and intestinal cancer. In clinical studies, HAMLET has been shown to target skin papillomas and bladder cancers. The findings identify HAMLET as a new drug candidate with promising selectivity for cancer cells and a strong therapeutic potential.

  5. Broad Absorption Line Variability in Radio-Loud Quasars

    CERN Document Server

    Welling, C A; Brandt, W N; Capellupo, D M; Gibson, R R

    2014-01-01

    We investigate C IV broad absorption line (BAL) variability within a sample of 46 radio-loud quasars (RLQs), selected from SDSS/FIRST data to include both core-dominated (39) and lobe-dominated (7) objects. The sample consists primarily of high-ionization BAL quasars, and a substantial fraction have large BAL velocities or equivalent widths; their radio luminosities and radio-loudness values span ~2.5 orders of magnitude. We have obtained 34 new Hobby-Eberly Telescope (HET) spectra of 28 BAL RLQs to compare to earlier SDSS data, and we also incorporate archival coverage (primarily dual-epoch SDSS) for a total set of 78 pairs of equivalent width measurements for 46 BAL RLQs, probing rest-frame timescales of ~80-6000 d (median 500 d). In general, only modest changes in the depths of segments of absorption troughs are observed, akin to those seen in prior studies of BAL RQQs. Also similar to previous findings for RQQs, the RLQs studied here are more likely to display BAL variability on longer rest-frame timescal...

  6. Variability in Low Ionization Broad Absorption Line Outflows

    CERN Document Server

    Vivek, M; Petitjean, P; Mohan, V; Mahabal, A; Samui, S

    2014-01-01

    We present results of our time variability studies of Mg II and Al III absorption lines in a sample of 22 Low Ionization Broad Absorption Line QSOs (LoBAL QSOs) at 0.2 = 1 year) absorption line variability is seen in 8 cases (36% systems) while only 4 of them (i.e 18% systems) show variability over short time-scales (i.e < 1 year). We notice a tendency of highly variable LoBAL QSOs to have high ejection velocity, low equivalent width and low redshift. The detection rate of variability in LoBAL QSOs showing Fe fine-structure lines (FeLoBAL QSOs) is less than that seen in non-Fe LoBAL QSOs. Absorption line variability is more frequently detected in QSOs having continuum dominated by Fe emission lines compared to rest of the QSOs. Confirming these trends with a bigger sample will give vital clues for understanding the physical distinction between different BAL QSO sub-classes. We correlate the absorption line variability with various parameters derived from continuum light curves and find no clear correlation...

  7. A Variable PV Broad Absorption Line and Quasar Outflow Energetics

    CERN Document Server

    Capellupo, Daniel M; Barlow, Tom A

    2014-01-01

    Broad absorption lines (BALs) in quasar spectra identify high velocity outflows that might exist in all quasars and could play a major role in feedback to galaxy evolution. The viability of BAL outflows as a feedback mechanism depends on their kinetic energies, as derived from the outflow velocities, column densities, and distances from the central quasar. We estimate these quantities for the quasar, Q1413+1143 (redshift $z_e = 2.56$), aided by the first detection of PV $\\lambda\\lambda$1118,1128 BAL variability in a quasar. In particular, PV absorption at velocities where the CIV trough does not reach zero intensity implies that the CIV BAL is saturated and the absorber only partially covers the background continuum source (with characteristic size 22.3 (cm^-2). Variability in the PV and saturated CIV BALs strongly disfavors changes in the ionization as the cause of the BAL variability, but supports models with high-column density BAL clouds moving across our lines of sight. The observed variability time of ...

  8. Transient C IV Broad Absorption Lines in radio detected QSOs

    CERN Document Server

    Vivek, M; Gupta, N

    2015-01-01

    We study the transient (i.e. emerging or disappearing) C IV broad absorption line (BAL) components in 50 radio detected QSOs using multi-epoch spectra available in Sloan Digital Sky Survey DR10. We report the detectionof 6 BALQSOs having at least one distinct transient C IV absorption component. Based on the structure function analysis of optical light curves, we suggest that the transient absorption is unlikely to be triggered by continuum variations. Transient absorption components usually have low C IV equivalent widths ( 10000 \\kms) and typically occur over rest-frame timescales > 800 days. The detection rate of transient C IV absorption seen in our sample is higher than that reported in the literature. Using a control sample of QSOs, we show that this difference is most likely due to the longer monitoring time-scale of sources in our sample while the effect of small number statistics cannot be ignored. Thus, in order to establish the role played by radio jets in driving the BAL outflows, we need a larger...

  9. 5-Alkyloxytryptamines are membrane-targeting, broad-spectrum antibiotics.

    Science.gov (United States)

    Faulkner, Katherine C; Hurley, Katherine A; Weibel, Douglas B

    2016-11-15

    Antibiotic adjuvant therapy represents an exciting opportunity to enhance the activity of clinical antibiotics by co-dosing with a secondary small molecule. Successful adjuvants decrease the concentration of antibiotics used to defeat bacteria, increase activity (in some cases introducing activity against organisms that are drug resistant), and reduce the frequency at which drug-resistant bacteria emerge. We report that 5-alkyloxytryptamines are a new class of broad-spectrum antibacterial agents with exciting activity as antibiotic adjuvants. We synthesized 5-alkyloxytryptamine analogs and found that an alkyl chain length of 6-12 carbons and a primary ammonium group are necessary for the antibacterial activity of the compounds, and an alkyl chain length of 6-10 carbons increased the membrane permeability of Gram-positive and Gram-negative bacteria. Although several of the most potent analogs also have activity against the membranes of human embryonic kidney cells, we demonstrate that below the minimum inhibitory concentration (MIC)-where mammalian cell toxicity is low-these compounds may be successfully used as adjuvants for chloramphenicol, tetracycline, ciprofloxacin, and rifampicin against clinical strains of Salmonella typhimurium, Acinetobacter baumannii and Staphylococcus aureus, reducing MIC values by as much as several logs.

  10. The broad Fe K line profile in NGC 4151

    CERN Document Server

    Wang, J; Wang, T; Wang, Junxian.; Zhou, Youyuan.; Wang, Tinggui.

    1999-01-01

    We present an analysis of the Fe K line profile of NGC 4151 by using long ASCA observation data obtained in May 1995. The unprecedented good data quality, which is much better in the energy band around 6.4 keV than that of the famous 4.2-day ASCA observation of MCG -6-30-15 in July 1994, offers a unique opportunity to study the details of Fe K line profile. Apart from those characteristics already noticed in earlier ASCA observations on this object (Yaqoob et al. 1995): a broad and skewed profile, with a strong peak at about 6.4 keV and a large red wing extending to $\\sim$4 - 5 keV, which is remarkably similar to that of MCG -6-30-15, we also find a weak blue wing extending to about 8 keV, thanks to the good quality of the data. When fitted by a relativistic accretion disk line plus a narrow core at 6.4 keV, the data constrain the accretion disk to be nearly face-on, contrary to the edge-on geometry inferred from optical and UV observations. However, the extended blue wing can not be well fitted even after we...

  11. Discovery of a fast, broad, transient outflow in NGC 985

    CERN Document Server

    Ebrero, J; Kaastra, J S; Ely, J C

    2016-01-01

    We observed the Seyfert 1 galaxy NGC 985 on multiple occasions to search for variability in its UV and X-ray absorption features in order to establish their location and physical properties. We use XMM-Newton to obtain X-ray spectra using the EPIC-pn camera, and the Cosmic Origins Spectrograph (COS) on the Hubble Space Telescope (HST) to obtain UV spectra. Our observations are simultaneous and span timescales of days to years. We find that the soft X-ray obscuration that absorbed the low energy continuum of NGC 985 in August 2013 diminished greatly by January 2015. The total X-ray column density decreased from 2.1 x 10^22 cm^-2 to ~6 x 10^21 cm^-2. We also detect broad, fast UV absorption lines in COS spectra obtained during the 2013 obscuration event. Lines of C III*, Ly alpha, Si IV and C IV with outflow velocities of -5970 km/s and a full-width at half-maximum of 1420 km/s are prominent in the 2013 spectrum, but have disappeared in all but Ly alpha in the 2015 spectra. The ionization state and the column d...

  12. A Broad Set of Chromatin Factors Influences Splicing

    Science.gov (United States)

    Allemand, Eric; Myers, Michael P.; Garcia-Bernardo, Jose; Harel-Bellan, Annick; Krainer, Adrian R.; Muchardt, Christian

    2016-01-01

    Several studies propose an influence of chromatin on pre-mRNA splicing, but it is still unclear how widespread and how direct this phenomenon is. We find here that when assembled in vivo, the U2 snRNP co-purifies with a subset of chromatin-proteins, including histones and remodeling complexes like SWI/SNF. Yet, an unbiased RNAi screen revealed that the outcome of splicing is influenced by a much larger variety of chromatin factors not all associating with the spliceosome. The availability of this broad range of chromatin factors impacting splicing further unveiled their very context specific effect, resulting in either inclusion or skipping, depending on the exon under scrutiny. Finally, a direct assessment of the impact of chromatin on splicing using an in vitro co-transcriptional splicing assay with pre-mRNAs transcribed from a nucleosomal template, demonstrated that chromatin impacts nascent pre-mRNP in their competence for splicing. Altogether, our data show that numerous chromatin factors associated or not with the spliceosome can affect the outcome of splicing, possibly as a function of the local chromatin environment that by default interferes with the efficiency of splicing. PMID:27662573

  13. Clustering Measurements of broad-line AGNs: Review and Future

    CERN Document Server

    Krumpe, Mirko; Coil, Alison L

    2013-01-01

    Despite substantial effort, the precise physical processes that lead to the growth of super-massive black holes in the centers of galaxies are still not well understood. These phases of black hole growth are thought to be of key importance in understanding galaxy evolution. Forthcoming missions such as eROSITA, HETDEX, eBOSS, BigBOSS, LSST, and Pan-STARRS will compile by far the largest ever Active Galactic Nuclei (AGNs) catalogs which will allow us to measure the spatial distribution of AGNs in the universe with unprecedented accuracy. For the first time, AGN clustering measurements will reach a level of precision that will not only allow for an alternative approach to answering open questions in AGN/galaxy co-evolution but will open a new frontier, allowing us to precisely determine cosmological parameters. This paper reviews the large-scale clustering measurements of broad line AGNs. We summarize how clustering is measured and which constraints can be derived from AGN clustering measurements, we discuss re...

  14. Defining Key Features of the Broad Autism Phenotype

    Science.gov (United States)

    Losh, Molly; Childress, Debra; Lam, Kristen; Piven, Joseph

    2009-01-01

    This study examined the frequency of personality, language, and social-behavioral characteristics believed to comprise the broad autism phenotype (BAP), across families differing in genetic liability to autism. We hypothesized that within this unique sample comprised of multiple-incidence autism families (MIAF), single-incidence autism families (SIAF), and control Down syndrome families (DWNS), a graded expression would be observed for the principal characteristics conferring genetic susceptibility to autism, in which such features would express most profoundly among parents from MIAFs, less strongly among SIAFs, and least of all among comparison parents from DWNS families, who should display population base rates. Analyses detected linear expression of traits in line with hypotheses, and further suggested differential intrafamilial expression across family types. In the vast majority of MIAFs both parents displayed BAP characteristics, whereas within SIAFs, it was equally likely that one, both, or neither parent show BAP features. The significance of these findings is discussed in relation to etiologic mechanisms in autism and relevance to molecular genetic studies. PMID:17948871

  15. Oxygen consumption of rats with broad intestinal resection

    Directory of Open Access Journals (Sweden)

    Luz J.

    2000-01-01

    Full Text Available The study was performed to investigate possible alterations in oxygen consumption in an animal model with broad intestinal resection. Oxygen consumption and the thermal effect of a short meal were measured in rats subjected to short bowel syndrome. Four groups of rats were used. Group I was the control group, group II was sham operated, group III was submitted to 80% jejunum-ileum resection, and group IV was submitted to 80% jejunum-ileum resection with colon interposition. Ninety days after surgery, oxygen consumption was measured over a period of 6 h with the animals fasted overnight. The thermal effect of feeding was determined in another session of oxygen consumption measurement in animals fasted for 12 h. A 12-kcal meal was then introduced into the animal chamber and oxygen consumption was measured for a further 4 h. No differences in fasting oxygen consumption or in the thermal effect of the meal were detected among the groups studied. It is concluded that short bowel syndrome does not affect the overall energy expenditure of rats.

  16. Extension of the Bgl Broad Group Cross Section Library

    Science.gov (United States)

    Kirilova, Desislava; Belousov, Sergey; Ilieva, Krassimira

    2009-08-01

    The broad group cross-section libraries BUGLE and BGL are applied for reactor shielding calculation using the DOORS package based on discrete ordinates method and multigroup approximation of the neutron cross-sections. BUGLE and BGL libraries are problem oriented for PWR or VVER type of reactors respectively. They had been generated by collapsing the problem independent fine group library VITAMIN-B6 applying PWR and VVER one-dimensional radial model of the reactor middle plane using the SCALE software package. The surveillance assemblies (SA) of VVER-1000/320 are located on the baffle above the reactor core upper edge in a region where geometry and materials differ from those of the middle plane and the neutron field gradient is very high which would result in a different neutron spectrum. That is why the application of the fore-mentioned libraries for the neutron fluence calculation in the region of SA could lead to an additional inaccuracy. This was the main reason to study the necessity for an extension of the BGL library with cross-sections appropriate for the SA region. Comparative analysis of the neutron spectra of the SA region calculated by the VITAMIN-B6 and BGL libraries using the two-dimensional code DORT have been done with purpose to evaluate the BGL applicability for SA calculation.

  17. A study of tachyon dynamics for broad classes of potentials

    Energy Technology Data Exchange (ETDEWEB)

    Quiros, Israel [Division de Ciencias e Ingenieria de la Universidad de Guanajuato, AP 150, 37150, Leon, Guanajuato (Mexico); Gonzalez, Tame [Departamento de Fisica, Universidad Central de Las Villas, 54830 Santa Clara (Cuba); Gonzalez, Dania; Napoles, Yunelsy [Departamento de Matematica, Universidad Central de Las Villas, 54830 Santa Clara (Cuba); GarcIa-Salcedo, Ricardo [Centro de Investigacion en Ciencia Aplicada y Tecnologia Avanzada-Legaria del IPN, Mexico DF (Mexico); Moreno, Claudia, E-mail: iquiros@Fisica.ugto.m, E-mail: tame@uclv.edu.c, E-mail: dgm@uclv.edu.c, E-mail: yna@uclv.edu.c, E-mail: rigarcias@ipn.m, E-mail: claudia.moreno@cucei.udg.m [Departamento de Fisica y Matematicas, Centro Universitario de Ciencias Exactas e IngenierIas, Av. Revolucion 1500 SR, Universidad de Guadalajara, 44430 Guadalajara, Jalisco (Mexico)

    2010-11-07

    We investigate in detail the asymptotic properties of tachyon cosmology for a broad class of self-interaction potentials. The present approach relies on an appropriate re-definition of the tachyon field, which, in conjunction with a method formerly applied in the bibliography in a different context allows us to generalize the dynamical systems study of tachyon cosmology to a wider class of self-interaction potentials beyond the (inverse) square-law one. It is revealed that independent of the functional form of the potential, the matter-dominated solution and the ultra-relativistic (also matter-dominated) solution are always associated with equilibrium points in the phase space of the tachyon models. The latter is always the past attractor, while the former is a saddle critical point. For inverse power-law potentials V{proportional_to}{phi}{sup -2{lambda}} the late-time attractor is always the de Sitter solution, while for sinh-like potentials V{proportional_to}sinh {sup -{alpha}}({lambda}{sup {phi}}), depending on the region of parameter space, the late-time attractor can be either the inflationary tachyon-dominated solution or the matter-scaling (also inflationary) phase. In general, for most part of known quintessential potentials, the late-time dynamics will be associated either with de Sitter inflation, or with matter-scaling, or with scalar field-dominated solutions.

  18. Recognition determinants of broadly neutralizing human antibodies against dengue viruses.

    Science.gov (United States)

    Rouvinski, Alexander; Guardado-Calvo, Pablo; Barba-Spaeth, Giovanna; Duquerroy, Stéphane; Vaney, Marie-Christine; Kikuti, Carlos M; Navarro Sanchez, M Erika; Dejnirattisai, Wanwisa; Wongwiwat, Wiyada; Haouz, Ahmed; Girard-Blanc, Christine; Petres, Stéphane; Shepard, William E; Desprès, Philippe; Arenzana-Seisdedos, Fernando; Dussart, Philippe; Mongkolsapaya, Juthathip; Screaton, Gavin R; Rey, Félix A

    2015-04-02

    Dengue disease is caused by four different flavivirus serotypes, which infect 390 million people yearly with 25% symptomatic cases and for which no licensed vaccine is available. Recent phase III vaccine trials showed partial protection, and in particular no protection for dengue virus serotype 2 (refs 3, 4). Structural studies so far have characterized only epitopes recognized by serotype-specific human antibodies. We recently isolated human antibodies potently neutralizing all four dengue virus serotypes. Here we describe the X-ray structures of four of these broadly neutralizing antibodies in complex with the envelope glycoprotein E from dengue virus serotype 2, revealing that the recognition determinants are at a serotype-invariant site at the E-dimer interface, including the exposed main chain of the E fusion loop and the two conserved glycan chains. This 'E-dimer-dependent epitope' is also the binding site for the viral glycoprotein prM during virus maturation in the secretory pathway of the infected cell, explaining its conservation across serotypes and highlighting an Achilles' heel of the virus with respect to antibody neutralization. These findings will be instrumental for devising novel immunogens to protect simultaneously against all four serotypes of dengue virus.

  19. HIV-1 envelope glycoprotein immunogens to induce broadly neutralizing antibodies.

    Science.gov (United States)

    Sliepen, Kwinten; Sanders, Rogier W

    2016-01-01

    The long pursuit for a vaccine against human immunodeficiency virus 1 (HIV-1) has recently been boosted by a number of exciting developments. An HIV-1 subunit vaccine ideally should elicit potent broadly neutralizing antibodies (bNAbs), but raising bNAbs by vaccination has proved extremely difficult because of the characteristics of the HIV-1 envelope glycoprotein complex (Env). However, the isolation of bNAbs from HIV-1-infected patients demonstrates that the human humoral immune system is capable of making such antibodies. Therefore, a focus of HIV-1 vaccinology is the elicitation of bNAbs by engineered immunogens and by using vaccination strategies aimed at mimicking the bNAb maturation pathways in HIV-infected patients. Important clues can also be taken from the successful subunit vaccines against hepatitis B virus and human papillomavirus. Here, we review the different types of HIV-1 immunogens and vaccination strategies that are being explored in the search for an HIV-1 vaccine that induces bNAbs.

  20. A broad area electrospray generated by a piezoelectric transformer

    Science.gov (United States)

    Ramshani, Zeinab; Johnson, Michael J.; Atashbar, Massood Z.; Go, David B.

    2016-07-01

    Electrosprays are typically formed by the application of a high (kilovolt) voltage to the flow exiting a small diameter capillary, and they have been used in applications ranging from material synthesis to spray coating because of the finely controlled plume of micron-sized droplets they produce. In this work, we report a similar but distinct spray directly off the surface of a piezoelectric transformer. Using a paper wick to deliver liquid to the surface of the piezoelectric crystal, a continuous, broad area spray is generated from the wick in contact with the transformer surface, only requiring input voltages on the order of 20 Vamp. Systematic variation of critical parameters indicate that this piezoelectric transformer-generated spray is similar to a conventional electrospray, with the spray current exhibiting a non-linear dependence on the solution conductivity, but distinct, as the spray exhibits little dependence on the solution surface tension. This innovative spray could potentially lead to uniform, large area spray coverage from a single device for a wide variety of applications.

  1. Radiation pressure confinement - IV. Application to broad absorption line outflows

    CERN Document Server

    Baskin, Alexei; Stern, Jonathan

    2014-01-01

    A fraction of quasars present broad absorption lines, produced by outflowing gas with typical velocities of 3000 - 10,000 km/s. If the outflowing gas fills a significant fraction of the volume where it resides, then it will be highly ionized by the quasar due to its low density, and will not produce the observed UV absorption. The suggestion that the outflow is shielded from the ionizing radiation was excluded by recent observations. The remaining solution is a dense outflow with a filling factor $f<10^{-3}$. What produces such a small $f$? Here we point out that radiation pressure confinement (RPC) inevitably leads to gas compression and the formation of dense thin gas sheets/filaments, with a large gradient in density and ionization along the line of sight. The total column of ionized dustless gas is a few times $10^{22}$ cm$^{-2}$, consistent with the observed X-ray absorption and detectable P V absorption. The predicted maximal columns of various ions show a small dependence on the system parameters, a...

  2. More Is Better: Selecting for Broad Host Range Bacteriophages

    Science.gov (United States)

    Ross, Alexa; Ward, Samantha; Hyman, Paul

    2016-01-01

    Bacteriophages are viruses that infect bacteria. In this perspective, we discuss several aspects of a characteristic feature of bacteriophages, their host range. Each phage has its own particular host range, the range of bacteria that it can infect. While some phages can only infect one or a few bacterial strains, other phages can infect many species or even bacteria from different genera. Different methods for determining host range may give different results, reflecting the multiple mechanisms bacteria have to resist phage infection and reflecting the different steps of infection each method depends on. This makes defining host range difficult. Another difficulty in describing host range arises from the inconsistent use of the words “narrow” and especially “broad” when describing the breadth of the host range. Nearly all bacteriophages have been isolated using a single host strain of bacteria. While this procedure is fairly standard, it may more likely produce narrow rather than broad host range phage. Our results and those of others suggest that using multiple host strains during isolation can more reliably produce broader host range phages. This challenges the common belief that most bacteriophages have a narrow host range. We highlight the implications of this for several areas that are affected by host range including horizontal gene transfer and phage therapy. PMID:27660623

  3. TERRAIN, PROVIDENCE COUNTY, RHODE ISLAND

    Data.gov (United States)

    Federal Emergency Management Agency, Department of Homeland Security — The Providence AOI consists of the costal portion of the county, and meshes up seamlessly with the Kent county AOI directly south. Ground Control is collected...

  4. Medicare Referring Provider DMEPOS PUF

    Data.gov (United States)

    U.S. Department of Health & Human Services — This dataset, which is part of CMSs Medicare Provider Utilization and Payment Data, details information on Durable Medical Equipment, Prosthetics, Orthotics and...

  5. Locally Optimally Emitting Clouds and the Variable Broad Emission Line Spectrum of NGC 5548

    Science.gov (United States)

    Korista, Kirk T.; Goad, Michael R.

    2000-06-01

    In recent work Baldwin et al. proposed that in the geometrically extended broad-line regions (BLRs) of quasars and active galactic nuclei, a range in line-emitting gas properties (e.g., density, column density) might exist at each radius and showed that under these conditions the broad emission line spectra of these objects may be dominated by selection effects introduced by the atomic physics and general radiative transfer within the large pool of line-emitting entities. In this picture, the light we see originates in a vast amalgam of emitters but is dominated by those emitters best able to reprocess the incident continuum into a particular emission line. We test this ``locally optimally emitting clouds'' (LOC) model against the extensive spectroscopic database of the Seyfert 1 galaxy NGC 5548. The time-averaged, integrated-light UV broad emission line spectrum from the 1993 Hubble Space Telescope (HST) monitoring campaign is reproduced via the optimization of three global geometric parameters: the outer radius, the index controlling the radial cloud covering fraction of the continuum source, and the integrated cloud covering fraction. We make an ad hoc selection from the range of successful models, and for a simple spherical BLR geometry we simulate the emission-line light curves for the 1989 IUE and 1993 HST campaigns, using the respective observed UV continuum light curves as drivers. We find good agreement between the predicted and observed light curves and lags-a demonstration of the LOC picture's viability as a means to understanding the BLR environment. Finally, we discuss the next step in developing the LOC picture, which involves the marriage of echo-mapping techniques with spectral simulation grids such as those presented here, using the constraints provided by a high-quality, temporally well-sampled spectroscopic data set.

  6. Radiation pressure confinement - III. The origin of the broad ionization distribution in AGN outflows

    Science.gov (United States)

    Stern, Jonathan; Behar, Ehud; Laor, Ari; Baskin, Alexei; Holczer, Tomer

    2014-12-01

    The winds of ionized gas driven by active galactic nuclei (AGN) can be studied through absorption lines in their X-ray spectra. A recurring feature of these outflows is their broad ionization distribution, including essentially all ionization levels (e.g., Fe0+ to Fe25+). This characteristic feature can be quantified with the absorption measure distribution (AMD), defined as the distribution of column density with ionization parameter |dN/d log ξ|. Observed AMDs extend over 0.1 ≲ ξ ≲ 104 (cgs), and are remarkably similar in different objects. Power-law fits (|dN/d log ξ| ≈ N1ξa) yield N1 = 3 × 1021 cm- 2 ± 0.4 dex and a = 0-0.4. What is the source of this broad ionization distribution, and what sets the small range of observed N1 and a? A common interpretation is a multiphase outflow, with a wide range of gas densities in a uniform gas pressure medium. However, the incident radiation pressure leads to a gas pressure gradient in the photoionized gas, and therefore to a broad range of ionization states within a single slab. We show that this compression of the gas by the radiation pressure leads to an AMD with |dN/d log ξ| = 8 × 1021 ξ0.03 cm-2, remarkably similar to that observed. The calculated values of N1 and a depend weakly on the gas metallicity, the ionizing spectral slope, the distance from the nucleus, the ambient density, and the total absorber column. Thus, radiation pressure compression (RPC) of the photoionized gas provides a natural explanation for the observed AMD. RPC predicts that the gas pressure increases with decreasing ionization, which can be used to test the validity of RPC in ionized AGN outflows.

  7. Lodging Update: Providence, Rhode Island

    Directory of Open Access Journals (Sweden)

    Ragel Roginsky

    2013-04-01

    Full Text Available Each quarter, Pinnacle Advisory Group prepares an analysis of the New England lodging industry, which provides a regional summary and then focuses in depth on a particular market. These reviews look at recent and proposed supply changes, factors affecting demand and growth rates, and the effects of interactions between such supply and demand trends. In this issue, the authors spotlight the lodging market in Providence, Rhode Island.

  8. Ability to develop broadly neutralizing HIV-1 antibodies is not restricted by the germline Ig gene repertoire.

    Science.gov (United States)

    Scheepers, Cathrine; Shrestha, Ram K; Lambson, Bronwen E; Jackson, Katherine J L; Wright, Imogen A; Naicker, Dshanta; Goosen, Mark; Berrie, Leigh; Ismail, Arshad; Garrett, Nigel; Abdool Karim, Quarraisha; Abdool Karim, Salim S; Moore, Penny L; Travers, Simon A; Morris, Lynn

    2015-05-01

    The human Ig repertoire is vast, producing billions of unique Abs from a limited number of germline Ig genes. The IgH V region (IGHV) is central to Ag binding and consists of 48 functional genes. In this study, we analyzed whether HIV-1-infected individuals who develop broadly neutralizing Abs show a distinctive germline IGHV profile. Using both 454 and Illumina technologies, we sequenced the IGHV repertoire of 28 HIV-infected South African women from the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 002 and 004 cohorts, 13 of whom developed broadly neutralizing Abs. Of the 259 IGHV alleles identified in this study, approximately half were not found in the International Immunogenetics Database (IMGT). This included 85 entirely novel alleles and 38 alleles that matched rearranged sequences in non-IMGT databases. Analysis of the rearranged H chain V region genes of mAbs isolated from seven of these women, as well as previously isolated broadly neutralizing Abs from other donors, provided evidence that at least eight novel or non-IMGT alleles contributed to functional Abs. Importantly, we found that, despite a wide range in the number of IGHV alleles in each individual, including alleles used by known broadly neutralizing Abs, there were no significant differences in germline IGHV repertoires between individuals who do and do not develop broadly neutralizing Abs. This study reports novel IGHV repertoires and highlights the importance of a fully comprehensive Ig database for germline gene usage prediction. Furthermore, these data suggest a lack of genetic bias in broadly neutralizing Ab development in HIV-1 infection, with positive implications for HIV vaccine design.

  9. Ancillary Services Provided from DER

    Energy Technology Data Exchange (ETDEWEB)

    Campbell, J.B.

    2005-12-21

    Distributed energy resources (DER) are quickly making their way to industry primarily as backup generation. They are effective at starting and then producing full-load power within a few seconds. The distribution system is aging and transmission system development has not kept up with the growth in load and generation. The nation's transmission system is stressed with heavy power flows over long distances, and many areas are experiencing problems in providing the power quality needed to satisfy customers. Thus, a new market for DER is beginning to emerge. DER can alleviate the burden on the distribution system by providing ancillary services while providing a cost adjustment for the DER owner. This report describes 10 types of ancillary services that distributed generation (DG) can provide to the distribution system. Of these 10 services the feasibility, control strategy, effectiveness, and cost benefits are all analyzed as in the context of a future utility-power market. In this market, services will be provided at a local level that will benefit the customer, the distribution utility, and the transmission company.

  10. Ecosystem services provided by waterbirds.

    Science.gov (United States)

    Green, Andy J; Elmberg, Johan

    2014-02-01

    Ecosystem services are ecosystem processes that directly or indirectly benefit human well-being. There has been much recent literature identifying different services and the communities and species that provide them. This is a vital first step towards management and maintenance of these services. In this review, we specifically address the waterbirds, which play key functional roles in many aquatic ecosystems, including as predators, herbivores and vectors of seeds, invertebrates and nutrients, although these roles have often been overlooked. Waterbirds can maintain the diversity of other organisms, control pests, be effective bioindicators of ecological conditions, and act as sentinels of potential disease outbreaks. They also provide important provisioning (meat, feathers, eggs, etc.) and cultural services to both indigenous and westernized societies. We identify key gaps in the understanding of ecosystem services provided by waterbirds and areas for future research required to clarify their functional role in ecosystems and the services they provide. We consider how the economic value of these services could be calculated, giving some examples. Such valuation will provide powerful arguments for waterbird conservation.

  11. Broad targeting of angiogenesis for cancer prevention and therapy.

    Science.gov (United States)

    Wang, Zongwei; Dabrosin, Charlotta; Yin, Xin; Fuster, Mark M; Arreola, Alexandra; Rathmell, W Kimryn; Generali, Daniele; Nagaraju, Ganji P; El-Rayes, Bassel; Ribatti, Domenico; Chen, Yi Charlie; Honoki, Kanya; Fujii, Hiromasa; Georgakilas, Alexandros G; Nowsheen, Somaira; Amedei, Amedeo; Niccolai, Elena; Amin, Amr; Ashraf, S Salman; Helferich, Bill; Yang, Xujuan; Guha, Gunjan; Bhakta, Dipita; Ciriolo, Maria Rosa; Aquilano, Katia; Chen, Sophie; Halicka, Dorota; Mohammed, Sulma I; Azmi, Asfar S; Bilsland, Alan; Keith, W Nicol; Jensen, Lasse D

    2015-12-01

    Deregulation of angiogenesis--the growth of new blood vessels from an existing vasculature--is a main driving force in many severe human diseases including cancer. As such, tumor angiogenesis is important for delivering oxygen and nutrients to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding "the most important target" may, however, prove a very challenging approach as the tumor environment is highly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the "Halifax Project" within the "Getting to know cancer" framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the

  12. Anisotropy in broad component of H$\\alpha$ line in the magnetospheric device RT-1

    CERN Document Server

    Kawazura, Yohei; Yoshida, Zensho; Nishiura, Masaki; Nogami, Tomoaki; Kashyap, Ankur; Yano, Yoshihisa; Saitoh, Haruhiko; Yamasaki, Miyuri; Mushiake, Toshiki; Nakatsuka, Masataka

    2016-01-01

    Temperature anisotropy in broad component of H$\\alpha$ line was found in the ring trap 1 (RT-1) device by Doppler spectroscopy. Since hot hydrogen neutrals emitting a broad component are mainly produced by charge exchange between neutrals and protons, the anisotropy in the broad component is the evidence of proton temperature anisotropy generated by betatron acceleration.

  13. Alternative food promotes broad mite control on chilli pepper plants

    NARCIS (Netherlands)

    Duarte, M.V.A.; Venzon, M.; de S. Bittencourt, M.C.; Rodríguez-Cruz, F.A.; Pallini, A.; Janssen, A.

    2015-01-01

    Many omnivorous arthropods are important natural enemies because they can feed on plant-provided pollen and several prey species, and thus persist in crops even in the absence of the target pest. Hence, populations of these predators can be established in a crop by providing alternative food, thus i

  14. EVIDENCE FOR PHOTOIONIZATION-DRIVEN BROAD ABSORPTION LINE VARIABILITY

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Tinggui; Yang, Chenwei; Wang, Huiyuan [CAS Key Laboratory for Research in Galaxies and Cosmology, Department of Astronomy, University of Science and Technology of China, Hefei, Anhui 230026 (China); Ferland, Gary, E-mail: twang@ustc.edu.cn [Department of Physics and Astronomy, University of Kentucky, Lexington, KY 40506 (United States)

    2015-12-01

    We present a qualitative analysis of the variability of quasar broad absorption lines using the large multi-epoch spectroscopic data set of the Sloan Digital Sky Survey Data Release 10. We confirm that variations of absorption lines are highly coordinated among different components of the same ion or the same absorption component of different ions for C iv, Si iv, and N v. Furthermore, we show that the equivalent widths (EWs) of the lines decrease or increase statistically when the continuum brightens or dims. This is further supported by the synchronized variations of emission and absorption-line EWs when the well-established intrinsic Baldwin effect for emission lines is taken into account. We find that the emergence of an absorption component is usually accompanied by the dimming of the continuum while the disappearance of an absorption-line component is accompanied by the brightening of the continuum. This suggests that the emergence or disappearance of a C iv absorption component is only the extreme case, when the ionic column density is very sensitive to continuum variations or the continuum variability the amplitude is larger. These results support the idea that absorption-line variability is driven mainly by changes in the gas ionization in response to continuum variations, that the line-absorbing gas is highly ionized, and in some extreme cases, too highly ionized to be detected in UV absorption lines. Due to uncertainties in the spectroscopic flux calibration, we cannot quantify the fraction of quasars with asynchronized continuum and absorption-line variations.

  15. Galactose as Broad Ligand for Multiple Tumor Imaging and Therapy.

    Science.gov (United States)

    Ma, Yuxiang; Chen, Haiyan; Su, Shanyuhan; Wang, Tong; Zhang, Congying; Fida, Guissi; Cui, Sisi; Zhao, Juan; Gu, Yueqing

    2015-01-01

    Galactose residues could be specifically recognized by the asialoglycoprotein receptor (ASGPR) which is highly exhibited on liver tissues. However, ASGPR has not been widely investigated on different tumor cell lines except for hepatoma carcinoma cells, which motivates us to investigate the possibility of galactose serving as a board tumor ligand. In this study, a galactose (Gal)-based probe conjugated with fluorescence dye MPA (Gal-MPA) was constructed for the evaluation of tumor affinities/targeted ability on different tumor cell lines. In the vitro cell study, it was indicated that the fluorescence probe Gal-MPA displayed higher cell affinity to tumor cells (HepG2, MCF-7 and A549) than that of the normal liver cells l02. In the vivo dynamic study of Gal-MPA in tumor-bearing mice (HepG2, MCF-7, A549, HCT116, U87, MDA-MB-231 and S180), it was shown that its high tumor targeted ability with the maximal tumor/normal tissue ratio reached up to 6.8. Meanwhile, the fast tumor-targeted ability within 2 hours and long retention on tumor site up to 120 hours were observed. Our results demonstrated that galactose should be a promising broad ligand for multiple tumor imaging and targeted therapy. Subsequently, Gal was covalently conjugated to doxorubicin (DOX) to form prodrug Gal-DOX for tumor targeted therapy. The therapeutic results of Gal-DOX than DOX being better suggested that galactosylated prodrugs might have the prospective potential in tumor targeted therapy.

  16. FirebrowseR: an R client to the Broad Institute’s Firehose Pipeline

    Science.gov (United States)

    Deng, Mario; Brägelmann, Johannes; Kryukov, Ivan; Saraiva-Agostinho, Nuno; Perner, Sven

    2017-01-01

    With its Firebrowse service (http://firebrowse.org/) the Broad Institute is making large-scale multi-platform omics data analysis results publicly available through a Representational State Transfer (REST) Application Programmable Interface (API). Querying this database through an API client from an arbitrary programming environment is an essential task, allowing other developers and researchers to focus on their analysis and avoid data wrangling. Hence, as a first result, we developed a workflow to automatically generate, test and deploy such clients for rapid response to API changes. Its underlying infrastructure, a combination of free and publicly available web services, facilitates the development of API clients. It decouples changes in server software from the client software by reacting to changes in the RESTful service and removing direct dependencies on a specific implementation of an API. As a second result, FirebrowseR, an R client to the Broad Institute’s RESTful Firehose Pipeline, is provided as a working example, which is built by the means of the presented workflow. The package’s features are demonstrated by an example analysis of cancer gene expression data. Database URL: https://github.com/mariodeng/ PMID:28062517

  17. Broad Balmer line emission and cosmic ray acceleration efficiency in supernova remnant shocks

    CERN Document Server

    Morlino, G; Bandiera, R; Amato, E

    2013-01-01

    Balmer emission may be a powerful diagnostic tool to test the paradigm of cosmic ray (CR) acceleration in young supernova remnant (SNR) shocks. The width of the broad Balmer line is a direct indicator of the downstream plasma temperature. In case of efficient particle acceleration an appreciable fraction of the total kinetic energy of the plasma is channeled into CRs, therefore the downstream temperature decreases and so does the broad Balmer line width. This width also depends on the level of thermal equilibration between ions and neutral hydrogen atoms in the downstream. Since in general in young SNR shocks only a few charge exchange (CE) reactions occur before ionization, equilibration between ions and neutrals is not reached, and a kinetic description of the neutrals is required in order to properly compute Balmer emission. We provide a method for the calculation of Balmer emission using a self-consistent description of the shock structure in the presence of neutrals and CRs. We use a recently developed s...

  18. Polarization-Controlled Broad Color Palette Based on an Ultrathin One-Dimensional Resonant Grating Structure

    Science.gov (United States)

    Koirala, Ishwor; Shrestha, Vivek Raj; Park, Chul-Soon; Lee, Sang-Shin; Choi, Duk-Yong

    2017-01-01

    Highly efficient polarization-tuned structural color filters, which are based on a one- dimensional resonant aluminum grating that is integrated with a silicon nitride waveguide, are proposed and demonstrated to feature a broad color palette. For such a metallic grating structure, transmissive color filtering is only feasible for the incident transverse-magnetic (TM) polarization due to its high reflection regarding the transverse-electric (TE) case; however, polarization-tuned customized colors can be efficiently achieved by optimizing the structural parameters like the duty ratio of the metallic grating. For the fabricated color filters, the transmission peaks, which are imputed to the resonance between the incident light and the guided modes that are supported by the dielectric waveguide, provided efficiencies as high as 90% and 70% for the TM and TE polarizations, respectively, as intended. Through the tailoring of the polarization, a group of filters with different grating periods were successfully exploited to produce a broad color palette spanning the entire visible band. Lastly, a nanoscale alphabetic pattern featuring a flexible combination of colorations was practically constructed via an arrangement of horizontal and vertical gratings.

  19. Broad-scale Population Genetics of the Host Sea Anemone, Heteractis magnifica

    KAUST Repository

    Emms, Madeleine

    2015-12-01

    Broad-scale population genetics can reveal population structure across an organism’s entire range, which can enable us to determine the most efficient population-wide management strategy depending on levels of connectivity. Genetic variation and differences in genetic diversity on small-scales have been reported in anemones, but nothing is known about their broad-scale population structure, including that of “host” anemone species, which are increasingly being targeted in the aquarium trade. In this study, microsatellite markers were used as a tool to determine the population structure of a sessile, host anemone species, Heteractis magnifica, across the Indo-Pacific region. In addition, two rDNA markers were used to identify Symbiodinium from the samples, and phylogenetic analyses were used to measure diversity and geographic distribution of Symbiodinium across the region. Significant population structure was identified in H. magnifica across the Indo-Pacific, with at least three genetic breaks, possibly the result of factors such as geographic distance, geographic isolation and environmental variation. Symbiodinium associations were also affected by environmental variation and supported the geographic isolation of some regions. These results suggests that management of H. magnifica must be implemented on a local scale, due to the lack of connectivity between clusters. This study also provides further evidence for the combined effects of geographic distance and environmental distance in explaining genetic variance.

  20. Characterisation of host growth after infection with a broad-range freshwater cyanopodophage.

    Directory of Open Access Journals (Sweden)

    Siobhan C Watkins

    Full Text Available Freshwater cyanophages are poorly characterised in comparison to their marine counterparts, however, the level of genetic diversity that exists in freshwater cyanophage communities is likely to exceed that found in marine environments, due to the habitat heterogeneity within freshwater systems. Many cyanophages are specialists, infecting a single host species or strain; however, some are less fastidious and infect a number of different host genotypes within the same species or even hosts from different genera. Few instances of host growth characterisation after infection by broad host-range phages have been described. Here we provide an initial characterisation of interactions between a cyanophage isolated from a freshwater fishing lake in the south of England and its hosts. Designated ΦMHI42, the phage is able to infect isolates from two genera of freshwater cyanobacteria, Planktothrix and Microcystis. Transmission Electron Microscopy and Atomic Force Microscopy indicate that ΦMHI42 is a member of the Podoviridae, albeit with a larger than expected capsid. The kinetics of host growth after infection with ΦMHI42 differed across host genera, species and strains in a way that was not related to the growth rate of the uninfected host. To our knowledge, this is the first characterisation of the growth of cyanobacteria in the presence of a broad host-range freshwater cyanophage.

  1. Interpreting broad emission-line variations II: Tensions between luminosity, characteristic size and responsivity

    CERN Document Server

    Goad, Michael R

    2015-01-01

    We investigate the variability behaviour of the broad Hb emission-line to driving continuum variations in the best-studied AGN NGC 5548. For a particular choice of BLR geometry, Hb surface emissivity based on photoionization models, and using a scaled version of the 13 yr optical continuum light curve as a proxy for the driving ionizing continuum, we explore several key factors that determine the broad emission line luminosity L, characteristic size R(RW), and variability amplitude (i.e., responsivity) eta, as well as the interplay between them. For fixed boundary models which extend as far as the hot-dust the predicted delays for Hb are on average too long. However, the predicted variability amplitude of Hb provides a remarkably good match to observations except during low continuum states. We suggest that the continuum flux variations which drive the redistribution in Hb surface emissivity F(r) do not on their own lead to large enough changes in R(RW) or eta(eff). We thus investigate dust-bounded BLRs for w...

  2. Uptake of perfluoroalkyl acids in the leaves of coniferous and deciduous broad-leaved trees.

    Science.gov (United States)

    Zhang, Huanhuan; Liu, Wei; He, Xin; Wang, Yu; Zhang, Qian

    2015-07-01

    Analytical methods for determining perfluoroalkyl acids (PFAAs) in leaves were developed to quantify a suite of analytes in both coniferous and deciduous broad-leaved trees. Sodium hydroxide-methanol and solid-phase extraction was selected as the extracting and cleanup strategy for PFAA analysis. Ten perfluorocarboxylic acids (PFCAs) and 4 perfluorosulfonic acids (PFSAs) were monitored in 7 kinds of leaves grown in the urban areas of Dalian, China. The results show that coniferous tree leaves take up more PFAAs than broad-leaved tree leaves, with the highest amount of 150 ng/g in pine needles. Leaf PFCA levels were much higher than PFSAs level. Short carbon-chain PFCAs with 3 to 6 perfluorinated carbons account for approximately 40% to 80% of the total leaf PFAAs, where uptake decreased with increasing carbon chain length. Temporal observation of leaf PFAAs revealed no significant variation of concentrations in the leaves over a weekly interval and the absence of significant seasonal change in pine needles and sophora. The present study provides some evidence for the accumulation of PFAAs in leaves, which is valuable for understanding their environmental behavior and the development of alternative bioindicator.

  3. Design of wide bandwidth pyramidal microwave absorbers using ferrite composites with broad magnetic loss spectra

    Science.gov (United States)

    Park, Myung-Jun; Kim, Sung-Soo

    2016-09-01

    Wide bandwidth microwave absorbers with a pyramidal shape and a significantly reduced thickness can be designed using high lossy ferrite materials with broad magnetic loss spectra. The microwave absorbing properties of pyramidal cone absorbers are analyzed using the transmission line approximation, which provides the reflection loss as a function of the material parameters and absorber geometry. Three types of ferrite materials (NiZn spinel ferrite, Co2Z hexaferrite, and RuCoM hexaferrite) are used as the absorbent fillers in a rubber matrix. Among these, Co2Z ferrite is the most suitable material for wide bandwidth pyramidal absorbers, due to its broad magnetic loss spectrum in the GHz frequency range. The optimal geometry of the pyramidal absorber is also determined using the transmission line theory. With the reduced total height of the pyramidal absorber (approximately 60 mm), a wide bandwidth (1.5-18 GHz with respect to the -20 dB reflection loss) can be realized. The proposed absorbers have a thickness advantage over the classical pyramidal ohmic absorbers; thus, they are suitable for small and semi-anechoic chambers.

  4. Broadly Neutralizing Alphavirus Antibodies Bind an Epitope on E2 and Inhibit Entry and Egress.

    Science.gov (United States)

    Fox, Julie M; Long, Feng; Edeling, Melissa A; Lin, Hueylie; van Duijl-Richter, Mareike K S; Fong, Rachel H; Kahle, Kristen M; Smit, Jolanda M; Jin, Jing; Simmons, Graham; Doranz, Benjamin J; Crowe, James E; Fremont, Daved H; Rossmann, Michael G; Diamond, Michael S

    2015-11-19

    We screened a panel of mouse and human monoclonal antibodies (MAbs) against chikungunya virus and identified several with inhibitory activity against multiple alphaviruses. Passive transfer of broadly neutralizing MAbs protected mice against infection by chikungunya, Mayaro, and O'nyong'nyong alphaviruses. Using alanine-scanning mutagenesis, loss-of-function recombinant proteins and viruses, and multiple functional assays, we determined that broadly neutralizing MAbs block multiple steps in the viral lifecycle, including entry and egress, and bind to a conserved epitope on the B domain of the E2 glycoprotein. A 16 Å resolution cryo-electron microscopy structure of a Fab fragment bound to CHIKV E2 B domain provided an explanation for its neutralizing activity. Binding to the B domain was associated with repositioning of the A domain of E2 that enabled cross-linking of neighboring spikes. Our results suggest that B domain antigenic determinants could be targeted for vaccine or antibody therapeutic development against multiple alphaviruses of global concern.

  5. Roles of glycans in interactions between gp120 and HIV broadly neutralizing antibodies.

    Science.gov (United States)

    Qi, Yifei; Jo, Sunhwan; Im, Wonpil

    2016-03-01

    Many novel broadly neutralizing antibodies against human immunodeficiency virus (HIV) have been identified during the past decade, providing promising templates for the development of an effective HIV-1 vaccine. Structural studies reveal that the epitopes of some of these antibodies involve one or more crucial glycans, without which the binding is completely abolished. In this study, we have investigated the critical roles of glycans in interactions between HIV-1 gp120 and two broadly neutralizing antibodies PG9 (targeting V1/V2) and PGT128 (targeting V3) that are able to neutralize more than 70% of HIV-1 isolates. We have performed molecular dynamics simulations of a number of systems including antibody-gp120 complex with and without glycans, antibody, gp120 with and without glycans, and glycan-only systems. The simulation results show that the complex structures are stabilized by the glycans, and the multivalent interactions between the antibody and gp120 promote cooperativities to further enhance the binding. In the free gp120, the glycans increase the flexibility of the V1/V2 and V3 loops, which likely increases the entropy cost of the antibody recognition. However, the antibodies are able to bind the flexible interface by recognizing the preexisting glycan conformation, and penetrating the glycan shield with flexible complementarity determining region loops that sample the bound conformations occasionally.

  6. Broadly neutralizing epitopes in the Plasmodium vivax vaccine candidate Duffy Binding Protein.

    Science.gov (United States)

    Chen, Edwin; Salinas, Nichole D; Huang, Yining; Ntumngia, Francis; Plasencia, Manolo D; Gross, Michael L; Adams, John H; Tolia, Niraj Harish

    2016-05-31

    Plasmodium vivax Duffy Binding Protein (PvDBP) is the most promising vaccine candidate for P. vivax malaria. The polymorphic nature of PvDBP induces strain-specific immune responses, however, and the epitopes of broadly neutralizing antibodies are unknown. These features hamper the rational design of potent DBP-based vaccines and necessitate the identification of globally conserved epitopes. Using X-ray crystallography, small-angle X-ray scattering, hydrogen-deuterium exchange mass spectrometry, and mutational mapping, we have defined epitopes for three inhibitory mAbs (mAbs 2D10, 2H2, and 2C6) and one noninhibitory mAb (3D10) that engage DBP. These studies expand the currently known inhibitory epitope repertoire by establishing protective motifs in subdomain three outside the receptor-binding and dimerization residues of DBP, and introduce globally conserved protective targets. All of the epitopes are highly conserved among DBP alleles. The identification of broadly conserved epitopes of inhibitory antibodies provides critical motifs that should be retained in the next generation of potent vaccines for P. vivax malaria.

  7. A tunable, linac based, intense, broad-band THz source forpump-probe experiments

    Energy Technology Data Exchange (ETDEWEB)

    Schmerge, J. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Adolphsen, C. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Corbett, J. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Dolgashev, V. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Durr, H. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Fazio, M. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Fisher, A. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Frisch, J. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Gaffney, K. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Guehr, M. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Hastings, J. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Hettel, B. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Hoffmann, M. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Hogan, M. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Holtkamp, N. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Huang, X. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Huang, Z. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Kirchmann, P. [SLAC National Accelerator Lab., Menlo Park, CA (United States); LaRue, J. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Limborg, C. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Lindenberg, A. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Loos, H. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Maxwell, T. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Nilsson, A. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Raubenheimer, T. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Reis, D. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Ross, M. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Shen, Z. -X. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Stupakov, G. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Tantawi, S. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Tian, K. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Wu, Z. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Xiang, D. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Yakimenko, V. [SLAC National Accelerator Lab., Menlo Park, CA (United States)

    2015-02-02

    We propose an intense THz source with tunable frequency and bandwidth that can directly interact with the degrees of freedom that determine the properties of materials and thus provides a new tool for controlling and directing these ultrafast processes as well as aiding synthesis of new materials with new functional properties. This THz source will broadly impact our understanding of dynamical processes in matter at the atomic-scale and in real time. Established optical pumping schemes using femtosecond visible frequency laser pulses for excitation are extended into the THz frequency regime thereby enabling resonant excitation of bonds in correlated solid state materials (phonon pumping), to drive low energy electronic excitations, to trigger surface chemistry reactions, and to all-optically bias a material with ultrashort electric fields or magnetic fields. A linac-based THz source can supply stand-alone experiments with peak intensities two orders of magnitude stronger than existing laser-based sources, but when coupled with atomic-scale sensitive femtosecond x-ray probes it opens a new frontier in ultrafast science with broad applications to correlated materials, interfacial and liquid phase chemistry, and materials in extreme conditions.

  8. Twitter for travel medicine providers.

    Science.gov (United States)

    Mills, Deborah J; Kohl, Sarah E

    2016-03-01

    Travel medicine practitioners, perhaps more so than medical practitioners working in other areas of medicine, require a constant flow of information to stay up-to-date, and provide best practice information and care to their patients. Many travel medicine providers are unaware of the popularity and potential of the Twitter platform. Twitter use among our travellers, as well as by physicians and health providers, is growing exponentially. There is a rapidly expanding body of published literature on this information tool. This review provides a brief overview of the ways Twitter is being used by health practitioners, the advantages that are peculiar to Twitter as a platform of social media, and how the interested practitioner can get started. Some key points about the dark side of Twitter are highlighted, as well as the potential benefits of using Twitter as a way to disseminate accurate medical information to the public. This article will help readers develop an increased understanding of Twitter as a tool for extracting useful facts and insights from the ever increasing volume of health information.

  9. Broad-Band EUV Multilayer Coatings For Solar Physics Project

    Data.gov (United States)

    National Aeronautics and Space Administration — We propose to develop and commercialize a new class of aperiodic multilayer coating that is designed to provide high normal-incidence reflectance over a wide...

  10. Comparative Study of Carbon Storage and Allocation Characteristics of Mature Evergreen Broad-leaved Forest

    Institute of Scientific and Technical Information of China (English)

    Zhangquan; ZENG; Canming; ZHANGY; Yandong; NIU; Xiquan; LI; Zijian; WU; Jia; LUO

    2014-01-01

    Evergreen broad-leaved forest is an important forest type in China.This paper analyzes the allocation characteristics of vegetation and soil carbon pool of evergreen broad-leaved forest,to understand the current status of research on the carbon storage of evergreen broadleaved forest as well as shortcomings.In the context of global climate change,it is necessary to carry out the long-term research of evergreen broad-leaved forest,in order to grasp the formation mechanism of evergreen broad-leaved forest productivity,and the impact of climate change on the carbon sequestration function of evergreen broad-leaved forest ecosystem.

  11. Service Provider DevOps

    OpenAIRE

    John, Wolfgang; Marchetto, Guido; Németh, Felicián; Sköldström, Pontus; Steinert, Rebecca; Meirosu, Catalin; Papafili, Ioanna; Pentikousis, Kostas

    2017-01-01

    Although there is consensus that software defined networking and network functions virtualization overhaul service provisioning and deployment, the community still lacks a definite answer on how carrier-grade operations praxis needs to evolve. This article presents what lies beyond the first evolutionary steps in network management, identifies the challenges in service verification, observability, and troubleshooting, and explains how to address them using our Service Provider DevOps (SP-DevO...

  12. Systematization, description and territory of the middle and rostral cerebral arteries in broad-snouted caimans (Caiman latirostris)

    OpenAIRE

    2010-01-01

    Background: Information on the arterial vascularization of the broad-snouted caimans’ brain (Caiman latirostris), a specie from the Brazilian fauna, is inexistent and the literature consulted yielded only one description about the development of embryonic circulation and post-birth cerebrovascular alterations in the brain of three caymans. The objective of this study was to describe and systematize the cerebral arterial vascularization of this reptile, by providing a standard irrigation model...

  13. Solar Atmospheric Magnetic Energy Coupling: Broad Plasma Conditions and Temperature Scales

    CERN Document Server

    Orange, N Brice; Gendre, Bruce; Morris, David C; Oluseyi, Hakeem M

    2016-01-01

    Solar variability investigations that include its magnetic energy coupling are paramount to solving many key solar/stellar physics problems. Particularly understanding the temporal variability of magnetic energy redistribution and heating processes. Using three years of observations from the {\\it Solar Dynamics Observatory's} Atmospheric Imaging Assembly and Heliosemic Magnetic Imager, radiative and magnetic fluxes were measured from coronal hole, quiet Sun, active regions, active region cores (i.e., inter moss), and at full-disk scales, respectively. We present, and mathematically describe, their coupling of radiative fluxes, across broad temperature gradients, to the available photospheric magnetic energy. A comparison of the common linear relationship of radiative to magnetic coupling is performed against our extended broken power-law description, which reveals a potential entanglement of thermodynamic and magnetic energy contributions in existing literature. As such, our work provides an improved approach...

  14. Honing a harder-hitting hammerhead improves broadly neutralizing antibody breadth and potency.

    Science.gov (United States)

    Lewis, George K

    2015-06-01

    While current HIV-1 therapies have greatly improved the quality and duration of life for infected individuals, a vaccine to prevent transmission of the virus is lacking. Broadly neutralizing monoclonal antibodies (bnmAbs) with the capacity to neutralize multiple HIV-1 variants have been isolated from HIV-1-infected individuals, and there has been a great effort to investigate how these bnmAbs arise, due their potential for HIV-1 vaccination. In this issue of the JCI, Willis and colleagues apply a computational approach to design variants of the bnmAb PG9 in an attempt to enhance potency and neutralization breadth. One of these variants was able to target multiple PG9-resistant strains, as the result of stabilization of the long heavy chain complementarity determining region 3 (HCDR3). The results of this study provide important insight and a unique approach to optimizing HIV-1 bnmABs.

  15. Synergistic effect of broad-spectrum Sunscreens and antihistamines in the control of idiopathic solar urticaria

    DEFF Research Database (Denmark)

    Faurschou, A.; Wulf, Hans Chr.

    2008-01-01

    Background: It can be difficult to provide patients with idiopathic solar urticaria adequate protection from sunlight. In a nonrandomized controlled trial, we used a standardized phototest procedure to determine the effects of using sunscreen and antihistamine to control idiopathic solar urticaria....... The patients were then treated with a high-protection, broad-spectrum sunscreen and a nonsedative antihistamine alone and in combination and underwent similar phototesting. The use of sunscreen allowed the patients to tolerate much higher doses of UV radiation (32-38 times the MUD on untreated skin......). Antihistamine use did not increase the patients' MUD but did suppress wheal formation and itch, and only immediate erythema sharply located in the irradiated areas occurred. The combination of sunscreen and antihistamine acted synergistically and increased the tolerance to UV radiation markedly (80-267 times...

  16. Broadband and Broad-angle Polarization-independent Metasurface for Radar Cross Section Reduction

    Science.gov (United States)

    Sun, Hengyi; Gu, Changqing; Chen, Xinlei; Li, Zhuo; Liu, Liangliang; Xu, Bingzheng; Zhou, Zicheng

    2017-01-01

    In this work, a broadband and broad-angle polarization-independent random coding metasurface structure is proposed for radar cross section (RCS) reduction. An efficient genetic algorithm is utilized to obtain the optimal layout of the unit cells of the metasurface to get a uniform backscattering under normal incidence. Excellent agreement between the simulation and experimental results show that the proposed metasurface structure can significantly reduce the radar cross section more than 10 dB from 17 GHz to 42 GHz when the angle of incident waves varies from 10° to 50°. The proposed coding metasurface provides an efficient scheme to reduce the scattering of the electromagnetic waves.

  17. Development of a neutron detector with broad dynamic range and multi-hit capability

    Science.gov (United States)

    Pawelczak, Iwona; Toke, Jan; Tsai, Yun-Tse; Udo Schröder, W.

    2007-10-01

    A new type of Gd-loaded plastic neutron detector with a broad dynamic range (from thermal to MeV range) and multi-hit capability has been designed and subjected to series of tests. The device consists of a stack of alternating plastic scintillator (Saint Gobain BC-408) slabs and thin radiator films (PDMS -- SYLGARD 184) loaded with 0.5% of Gd per weight, viewed by a photomultiplier tube. The scintillator functions as neutron moderator, provides a prompt integrated neutron energy signal, and detects delayed n capture by Gd nuclei via associated capture γ-rays. The design, Monte Carlo simulations carried out with an extended code DENIS(E), as well as first measurements with the detector will be discussed.

  18. Immune Pathways in Atopic Dermatitis, and Definition of Biomarkers through Broad and Targeted Therapeutics.

    Science.gov (United States)

    Mansouri, Yasaman; Guttman-Yassky, Emma

    2015-04-29

    Atopic dermatitis (AD) is the most common inflammatory skin disease. Recent research findings have provided an insight into the complex pathogenic mechanisms involved in this disease. Despite a rising prevalence, effective and safe therapeutics for patients with moderate-to-severe AD are still lacking. Biomarkers of lesional, nonlesional skin, and blood have been developed for baseline as well as after treatment with broad and specific treatments (i.e., cyclosporine A and dupilumab). These biomarkers will help with the development of novel targeted therapeutics and assessment of disease reversal, with the promise of a more personalized treatment approach. Since AD involves more than one subtype (i.e., intrinsic/extrinsic, pediatric/adult, etc.), these molecular fingerprints needs to be validated in all subpopulations with AD.

  19. 11th International Conference On Broad-Band Wireless Computing, Communication and Applications

    CERN Document Server

    Xhafa, Fatos; Yim, Kangbin

    2017-01-01

    The success of all-IP networking and wireless technology has changed the ways of living the people around the world. The progress of electronic integration and wireless communications is going to pave the way to offer people the access to the wireless networks on the fly, based on which all electronic devices will be able to exchange the information with each other in ubiquitous way whenever necessary. The aim of the volume is to provide latest research findings, innovative research results, methods and development techniques from both theoretical and practical perspectives related to the emerging areas of broadband and wireless computing. This proceedings volume presents the results of the 11th International Conference on Broad-Band Wireless Computing, Communication And Applications (BWCCA-2016), held November 5-7, 2016, at Soonchunhyang University, Asan, Korea. .

  20. The protein invasion: a broad review on the origin of the translational system.

    Science.gov (United States)

    Morgens, David W

    2013-10-01

    Translation, coded peptide synthesis, arguably exists at the heart of modern cellular life. By orchestrating an incredibly complex interaction between tRNAs, mRNAs, aaRSs, the ribosome, and numerous other small molecules, the translational system allows the interpretation of data in the form of DNA to create massively complex proteins which control and enact almost every cellular function. A natural question then, is how did this system evolve? Here we present a broad review of the existing theories of the last two decades on the origin of the translational system. We attempt to synthesize the wide variety of ideas as well as organize them into modular components, addressing the evolution of the peptide-RNA interaction, tRNA, mRNA, the ribosome, and the first proteins separately. We hope to provide both a comprehensive overview of the literature as well as a framework for future discussions and novel theories.

  1. Peracetic acid treatment generates potent inactivated oral vaccines from a broad range of culturable bacterial species

    Directory of Open Access Journals (Sweden)

    Kathrin eMoor

    2016-02-01

    Full Text Available Our mucosal surfaces are the main sites of non-vector-borne pathogen entry, as well as the main interface with our commensal microbiota. We are still only beginning to understand how mucosal adaptive immunity interacts with commensal and pathogenic microbes to influence factors such as infectivity, phenotypic diversity and within-host evolution. This is in part due to difficulties in generating specific mucosal adaptive immune responses without disrupting the mucosal microbial ecosystem itself. Here we present a very simple tool to generate inactivated mucosal vaccines from a broad range of culturable bacteria. Oral gavage of 1010 peracetic acid-inactivated bacteria induces high-titer specific intestinal IgA in the absence of any measurable inflammation or species invasion. As a proof of principal, we demonstrate that this technique is sufficient to provide fully protective immunity in the murine model of invasive non-typhoidal Salmonellosis, even in the face of severe innate immune deficiency.

  2. A broadly tunable autocorrelator for ultra-short, ultra-high power infrared optical pulses

    Energy Technology Data Exchange (ETDEWEB)

    Szarmes, E.B.; Madey, J.M.J. [Duke Univ., Durham, NC (United States)

    1995-12-31

    We describe the design of a crossed-beam, optical autocorrelator that uses an uncoated, birefringent beamsplitter to split a linearly polarized incident pulse into two orthogonally polarized pulses, and a Type II, SHG crystal to generate the intensity autocorrelation function. The uncoated beamsplitter accommodates extremely broad tunability while precluding any temporal distortion of ultrashort optical pulses at the dielectric interface, and the specific design provides efficient operation between 1 {mu}m and 4 {mu}m. Furthermore, the use of Type II SHG completely eliminates any single-beam doubling, so the autocorrelator can be operated at very shallow crossed-beam angles without generating a background pedestal. The autocorrelator has been constructed and installed in the Mark III laboratory at Duke University as a broadband diagnostic for ongoing compression experiments on the chirped-pulse FEL.

  3. The broad view of nuclear technology for aerospace

    Energy Technology Data Exchange (ETDEWEB)

    Buden, D. (Center for Nuclear Engineering and Technology, Idaho National Engineering Laboratory, P.O. Box 1625, Idaho Falls, Idaho 83415-2516 (US)); Angelo, J.A. Jr. (Science Applications International Corp., 700 South Babcock Street, Suite 300, Melbourne, Florida 32901 (US))

    1991-01-01

    Nuclear technologies can directly support advanced space initiatives. For near-Earth missions, nuclear technology can be used to power air traffic control, communications and manufacturing platforms, provide emergency power for manned platforms, provide power for maneuvering units, move asteroids for mining, measure the natural radiation environment, provide radiation protection instruments, and design radiation hardened robotic systems. For the Lunar and Mars surfaces, nuclear technology can be used for base stationary, mobile, and emergency power, energy storage, process heat, nuclear thermal and electric rocket propulsion, excavation and underground engineering, water and sewage treatment and sterilization, food processing and preservation, mineral exploration, self-luminous systems, radiation protection instrumentation, radiation environmental warning systems, and habitat shielding design. Outer planet missions can make use of nuclear technology for power and propulsion. Programs need to be initiated to ensure the full beneficial use of nuclear technologies in advanced space missions.

  4. Immunology and Pathology of Arenavirus Infections

    Science.gov (United States)

    1991-01-31

    0011 were euthanatized by exsanguination by cardiac puncture under ketamine/ xylazine anesthesia. Macrophage culture: Resident peritoneal macrophages were...infection as well. This dichotomy points out the danger of extrapolating from in vitro observations to derive pathogenetic hypotheses. It is tempting to

  5. Intergroup Dialogue: Education for a Broad Conception of Civic Engagement

    Science.gov (United States)

    Gurin, Patricia; Nagda, Biren A.; Sorensen, Nicholas

    2011-01-01

    Intergroup dialogue provides what students need in order to relate and collaborate across differences, something they have to do in community projects that usually involve interactions across racial, social class, religious, and geographical divides. In this article, the authors demonstrate the efficacy of intergroup dialogue, drawing from a…

  6. Wind Turbine Providing Grid Support

    DEFF Research Database (Denmark)

    2011-01-01

    A variable speed wind turbine is arranged to provide additional electrical power to counteract non-periodic disturbances in an electrical grid. A controller monitors events indicating a need to increase the electrical output power from the wind turbine to the electrical grid. The controller...... is arranged to control the wind turbine as follows: after an indicating event has been detected, the wind turbine enters an overproduction period in which the electrical output power is increased, wherein the additional electrical output power is taken from kinetic energy stored in the rotor and without...... changing the operation of the wind turbine to a more efficient working point.; When the rotational speed of the rotor reaches a minimum value, the wind turbine enters a recovery period to re-accelerate the rotor to the nominal rotational speed while further contributing to the stability of the electrical...

  7. Providing Southern Perspectives on CSR

    DEFF Research Database (Denmark)

    Jeppesen, Søren; Kothuis, Bas

    The article seeks to contribute to the SMEs and CSR literature in developing countries by providing; a) a ‘Southern’ SME perspective, which includes the voices of managers and workers, b) a perspective of CSR, which opens up to informal CSR practices that SMEs undertake, and c) an analysis...... of the key institutional issues affecting the CSR practices of SMEs. It presents perceptions of CSR practices among 21 SMEs in the garment industry in South Africa, based on 40 interviews with managers and 19 interviews with workers through the use of qualitative and quantitative interview frameworks....... It highlights a high degree of similarities between managers and workers, though knowledge of (cognitive level) the concept ‘CSR’ differ considerably. Informal practices are widespread and of key importance to the SMEs, expressed by managers and workers alike. History, industry and manager-workers relations...

  8. Using of Automatic Metadata Providing

    Directory of Open Access Journals (Sweden)

    P. Šimek

    2013-12-01

    Full Text Available The paper deals with the necessity of systemic solution for metadata providing by local archives into central repositories and its subsequent implementatiton by the Department of Information Technologies, Faculty of Economics and Management, Czech University of Life Sciences in Prague, for the needs of the agrarian WWW AGRIS portal. The system supports the OAI-PMH (Open Archive Initiative – Protocol for Metadata Harvesting protocol, several metadata formats and thesauri and meets the quality requirements: functionality, high level of reliability, applicability, sustainability and transferability. The SW application for the OAI-PMH requests’ servicing is run in the setting of the WWW Apache server using an efficient PHP framework Nette and database dibi layer.

  9. Broadly absorbing metalloporphyrin-based multichromophoric arrays for triplet harvesting

    Energy Technology Data Exchange (ETDEWEB)

    Thompson, Mark E.; Whited, Matthew T.; Djurovich, Peter I.

    2016-09-20

    The present disclosure relates to multichromophoric assemblies comprising metalloporphyrin scaffolds. The present disclosure also relates, in part, to methods for generating electric-field-stabilized geminate polaron pairs comprising applying electric fields to the multichromophoric assemblies described herein, or alternatively, directly to the metalloporphyrins provided by the present disclosure. The present disclosure further relates, in part, to multichromophoric assemblies comprising metalloporphyrin scaffolds, which exhibit enhanced energy transfer properties.

  10. Learning from the 2009 H1N1 pandemic: prospects for more broadly effective influenza vaccines

    Institute of Scientific and Technical Information of China (English)

    Ethan C. Settembre; Philip R. Dormitzer; Rino Rappuoli

    2011-01-01

    Calls to develop a universal influenza vaccine have increased in the wake of the 2009 H1 N1 influenza pandemic. This demand comes at a time when analyses of the human antibody repertoire, informed by structures of complexes between broadly neutralizing antibodies and influenza hemagglutinin, have revealed the target of a class of broadly neutralizing antibodies. Recent studies suggest a path forward to more broadly protective influenza vaccines.%@@ Calls to develop a universal influenza vaccine have increased in the wake of the 2009 H1 N1 influenza pandemic.This demand comes at a time when analyses of the human antibody repertoire, informed by structures of complexes between broadly neutralizing antibodies and influenza hemagglutinin, have revealed the target of a class of broadly neutralizing antibodies.Recent studies suggest a path forward to more broadly protective influenza vaccines.

  11. Free space optical networks for ultra-broad band services

    CERN Document Server

    Kartalopoulos, Stamatios V

    2011-01-01

    "Free Space Optical Network is a next generation communication network which uses optical waves instead of microwaves, potentially offering faster communication with ultra band width, meaning more complex communication services can be simultaneously offered. This book describes the network concepts in simple language starting with point-to-point free space optics basics and discusses networking, interoperability with existing communication network, and security. An ideal resource for communication professionals just entering the free space optical communication field and graduate students majoring in optical communications"--Provided by publisher.

  12. A computationally optimized broadly reactive H5 hemagglutinin vaccine provides protection against homologous and heterologous H5N1 highly pathogenic avian influenza virus infection in chickens

    Science.gov (United States)

    Since its emergence in 1996 in China, H5N1 highly pathogenic avian influenza (HPAI) virus has continuously evolved into different genetic clades that have created challenges to maintaining antigenically relevant H5N1 vaccine seeds. Therefore, a universal (multi-hemagglutinin [HA] subtype) or more c...

  13. A combination of functionally different plant traits provides a means to quantitatively predict a broad range of species assemblages in NW Europe

    NARCIS (Netherlands)

    Douma, J.C.; Aerts, R.; Witte, J.P.M.; Bekker, R.M.; Kunzmann, D.; Metselaar, K.; Bodegom, van P.M.

    2012-01-01

    Assembly theory predicts that filtering processes will select species by their attributes to build a community. Some filters increase functional similarity among species, while others lead to dissimilarity. Assuming converging processes to be dominant within habitats, we tested in this study whether

  14. Broad phylogenomic sampling and the sister lineage of land plants.

    Directory of Open Access Journals (Sweden)

    Ruth E Timme

    Full Text Available The tremendous diversity of land plants all descended from a single charophyte green alga that colonized the land somewhere between 430 and 470 million years ago. Six orders of charophyte green algae, in addition to embryophytes, comprise the Streptophyta s.l. Previous studies have focused on reconstructing the phylogeny of organisms tied to this key colonization event, but wildly conflicting results have sparked a contentious debate over which lineage gave rise to land plants. The dominant view has been that 'stoneworts,' or Charales, are the sister lineage, but an alternative hypothesis supports the Zygnematales (often referred to as "pond scum" as the sister lineage. In this paper, we provide a well-supported, 160-nuclear-gene phylogenomic analysis supporting the Zygnematales as the closest living relative to land plants. Our study makes two key contributions to the field: 1 the use of an unbiased method to collect a large set of orthologs from deeply diverging species and 2 the use of these data in determining the sister lineage to land plants. We anticipate this updated phylogeny not only will hugely impact lesson plans in introductory biology courses, but also will provide a solid phylogenetic tree for future green-lineage research, whether it be related to plants or green algae.

  15. Ion-exchanged Er3+/Yb3+ co-doped waveguide amplifiers longitudinally pumped by broad area lasers.

    Science.gov (United States)

    Donzella, V; Toccafondo, V; Faralli, S; Di Pasquale, F; Cassagnettes, C; Barbier, D; Figueroa, H Hernandez

    2010-06-07

    A multimode pumping scheme for Er(3+)/Yb(3+) co-doped waveguide amplifiers based on broad area lasers at around 980 nm is presented. The proposed amplifier is fabricated by ion-exchange (IE) technique on silicate and phosphate glasses. The highly efficient energy transfer from Yb(3+) to Er(3+) ions, combined with the use of low cost and high power broad area laser, allows the realization of high performance and cost-effective integrated amplifiers. The structure has been designed and numerically studied using a 3D finite element modelling tool, and over 3 dB/cm small signal gain has been predicted for an optimized amplifier. Preliminary characterization of an amplifier structure provides a first experimental evidence of the novel multimode longitudinal pumping.

  16. Sublingual immunization with M2-based vaccine induces broad protective immunity against influenza.

    Directory of Open Access Journals (Sweden)

    Byoung-Shik Shim

    Full Text Available BACKGROUND: The ectodomain of matrix protein 2 (M2e of influenza A virus is a rationale target antigen candidate for the development of a universal vaccine against influenza as M2e undergoes little sequence variation amongst human influenza A strains. Vaccine-induced M2e-specific antibodies (Abs have been shown to display significant cross-protective activity in animal models. M2e-based vaccine constructs have been shown to be more protective when administered by the intranasal (i.n. route than after parenteral injection. However, i.n. administration of vaccines poses rare but serious safety issues associated with retrograde passage of inhaled antigens and adjuvants through the olfactory epithelium. In this study, we examined whether the sublingual (s.l. route could serve as a safe and effective alternative mucosal delivery route for administering a prototype M2e-based vaccine. The mechanism whereby s.l. immunization with M2e vaccine candidate induces broad protection against infection with different influenza virus subtypes was explored. METHODS AND RESULTS: A recombinant M2 protein with three tandem copies of the M2e (3M2eC was expressed in Escherichia coli. Parenteral immunizations of mice with 3M2eC induced high levels of M2e-specific serum Abs but failed to provide complete protection against lethal challenge with influenza virus. In contrast, s.l. immunization with 3M2eC was superior for inducing protection in mice. In the latter animals, protection was associated with specific Ab responses in the lungs. CONCLUSIONS: The results demonstrate that s.l. immunization with 3M2eC vaccine induced airway mucosal immune responses along with broad cross-protective immunity to influenza. These findings may contribute to the understanding of the M2-based vaccine approach to control epidemic and pandemic influenza infections.

  17. Characterization of FGFR1 Locus in sqNSCLC Reveals a Broad and Heterogeneous Amplicon.

    Directory of Open Access Journals (Sweden)

    Claire Rooney

    Full Text Available FGFR1 amplification occurs in ~20% of sqNSCLC and trials with FGFR inhibitors have selected FGFR1 amplified patients by FISH. Lung cancer cell lines were profiled for sensitivity to AZD4547, a potent, selective inhibitor of FGFRs 1-3. Sensitivity to FGFR inhibition was associated with but not wholly predicted by increased FGFR1 gene copy number. Additional biomarker assays evaluating expression of FGFRs and correlation between amplification and expression in clinical tissues are therefore warranted. We validated nanoString for mRNA expression analysis of 194 genes, including FGFRs, from clinical tumour tissue. In a panel of sqNSCLC tumours 14.4% (13/90 were FGFR1 amplified by FISH. Although mean FGFR1 expression was significantly higher in amplified samples, there was significant overlap in the range of expression levels between the amplified and non-amplified cohorts with several non-amplified samples expressing FGFR1 to levels equivalent to amplified samples. Statistical analysis revealed increased expression of FGFR1 neighboring genes on the 8p12 amplicon (BAG4, LSM1 and WHSC1L1 in FGFR1 amplified tumours, suggesting a broad rather than focal amplicon and raises the potential for codependencies. High resolution aCGH analysis of pre-clinical and clinical samples supported the presence of a broad and heterogeneous amplicon around the FGFR1 locus. In conclusion, the range of FGFR1 expression levels in both FGFR1 amplified and non-amplified NSCLC tissues, together with the breadth and intra-patient heterogeneity of the 8p amplicon highlights the need for gene expression analysis of clinical samples to inform the understanding of determinants of response to FGFR inhibitors. In this respect the nanoString platform provides an attractive option for RNA analysis of FFPE clinical samples.

  18. REVERBERATION AND PHOTOIONIZATION ESTIMATES OF THE BROAD-LINE REGION RADIUS IN LOW-z QUASARS

    Energy Technology Data Exchange (ETDEWEB)

    Negrete, C. Alenka [Instituto Nacional de Astrofisica, Optica y Electronica (Mexico); Dultzin, Deborah [Instituto de Astronomia, Universidad Nacional Autonoma de Mexico (Mexico); Marziani, Paola [INAF, Astronomical Observatory of Padova, I-35122 Padova (Italy); Sulentic, Jack W., E-mail: cnegrete@inaoep.mx, E-mail: deborah@astro.unam.mx, E-mail: paola.marziani@oapd.inaf.it, E-mail: sulentic@iaa.es [Instituto de Astrofisica de Andalucia, E-18008 Granada (Spain)

    2013-07-01

    Black hole mass estimation in quasars, especially at high redshift, involves the use of single-epoch spectra with signal-to-noise ratio and resolution that permit accurate measurement of the width of a broad line assumed to be a reliable virial estimator. Coupled with an estimate of the radius of the broad-line region (BLR) this yields the black hole mass M{sub BH}. The radius of the BLR may be inferred from an extrapolation of the correlation between source luminosity and reverberation-derived r{sub BLR} measures (the so-called Kaspi relation involving about 60 low-z sources). We are exploring a different method for estimating r{sub BLR} directly from inferred physical conditions in the BLR of each source. We report here on a comparison of r{sub BLR} estimates that come from our method and from reverberation mapping. Our ''photoionization'' method employs diagnostic line intensity ratios in the rest-frame range 1400-2000 A (Al III {lambda}1860/Si III] {lambda}1892, C IV {lambda}1549/Al III {lambda}1860) that enable derivation of the product of density and ionization parameter with the BLR distance derived from the definition of the ionization parameter. We find good agreement between our estimates of the density, ionization parameter, and r{sub BLR} and those from reverberation mapping. We suggest empirical corrections to improve the agreement between individual photoionization-derived r{sub BLR} values and those obtained from reverberation mapping. The results in this paper can be exploited to estimate M{sub BH} for large samples of high-z quasars using an appropriate virial broadening estimator. We show that the width of the UV intermediate emission lines are consistent with the width of H{beta}, thereby providing a reliable virial broadening estimator that can be measured in large samples of high-z quasars.

  19. On Mencius’Broad View of Life%论孟子的大生命观

    Institute of Scientific and Technical Information of China (English)

    董甲河

    2014-01-01

    Mencius’broad view of life holds that destiny is the origin of life,while body and mind constitute the structure of life,and the mind is more important than the body.Mencius put life into question from destiny to Mind,and put forward the methods of cultivating Mind,cultivating Qi to return the origin of life,and ultimately reach the state of knowing the Mind and destiny.Mencius provides a Confucian model of lifestyle,and points out a fair and square road for the Confucians.However,from a practical utility point of view,Mencius’broad view of life is only suitable for superior wise people and can not fully carry out in reality.%孟子的大生命观认为天命是生命的本源,身心是生命的结构,心比身更重要。孟子把生命的问题由天道转化为心性问题,提出养心、养气等心性方法,回归生命的本源,最终可以达到尽心知性知天的生命境界。孟子规定了儒者生命之道的模式,为儒者安身立命指出了一条正大光明之路。然而,从现实效用来看,孟子的大生命观模式只适合于上智之人,不能在现实中完全开展。

  20. Correlation between radio and broad-line emissions in radio-loud quasars

    CERN Document Server

    Cao, X; Cao, Xinwu

    1999-01-01

    Radio emission is a good indicator of the jet power of radio-loud quasars, while the emission in broad-line can well represent the accretion disc radiation in quasars. We compile a sample of all sources of which the broad-line fluxes are available from 1 Jy, S4 and S5 radio source catalogues. A correlation between radio and broad-line emission for this sample of radio-loud quasars is presented, which is in favour of a close link between the accretion processes and the relativistic jets. The BL Lac objects seem to follow the statistical behaviour of the quasars, but with fainter broad-line emission.

  1. Pinellia ternata agglutinin expression in chloroplasts confers broad spectrum resistance against aphid, whitefly, Lepidopteran insects, bacterial and viral pathogens.

    Science.gov (United States)

    Jin, Shuangxia; Zhang, Xianlong; Daniell, Henry

    2012-04-01

    Broad spectrum protection against different insects and pathogens requires multigene engineering. However, such broad spectrum protection against biotic stress is provided by a single protein in some medicinal plants. Therefore, tobacco chloroplasts were transformed with the agglutinin gene from Pinellia ternata (pta), a widely cultivated Chinese medicinal herb. Pinellia ternata agglutinin (PTA) was expressed up to 9.2% of total soluble protein in mature leaves. Purified PTA showed similar hemagglutination activity as snowdrop lectin. Artificial diet with purified PTA from transplastomic plants showed marked and broad insecticidal activity. In planta bioassays conducted with T0 or T1 generation PTA lines showed that the growth of aphid Myzus persicae (Sulzer) was reduced by 89%-92% when compared with untransformed (UT) plants. Similarly, the larval survival and total population of whitefly (Bemisia tabaci) on transplastomic lines were reduced by 91%-93% when compared with UT plants. This is indeed the first report of lectin controlling whitefly infestation. When transplastomic PTA leaves were fed to corn earworm (Helicoverpa zea), tobacco budworm (Heliothis virescens) or the beet armyworm (spodoptera exigua), 100% mortality was observed against all these three insects. In planta bioassays revealed Erwinia population to be 10,000-fold higher in control than in PTA lines. Similar results were observed with tobacco mosaic virus (TMV) challenge. Therefore, broad spectrum resistance to homopteran (sap-sucking), Lepidopteran insects as well as anti-bacterial or anti-viral activity observed in PTA lines provides a new option to engineer protection against biotic stress by hyper-expression of an unique protein that is naturally present in a medicinal plant.

  2. A broad distribution of the alternative oxidase in microsporidian parasites.

    Directory of Open Access Journals (Sweden)

    Bryony A P Williams

    2010-02-01

    Full Text Available Microsporidia are a group of obligate intracellular parasitic eukaryotes that were considered to be amitochondriate until the recent discovery of highly reduced mitochondrial organelles called mitosomes. Analysis of the complete genome of Encephalitozoon cuniculi revealed a highly reduced set of proteins in the organelle, mostly related to the assembly of iron-sulphur clusters. Oxidative phosphorylation and the Krebs cycle proteins were absent, in keeping with the notion that the microsporidia and their mitosomes are anaerobic, as is the case for other mitosome bearing eukaryotes, such as Giardia. Here we provide evidence opening the possibility that mitosomes in a number of microsporidian lineages are not completely anaerobic. Specifically, we have identified and characterized a gene encoding the alternative oxidase (AOX, a typically mitochondrial terminal oxidase in eukaryotes, in the genomes of several distantly related microsporidian species, even though this gene is absent from the complete genome of E. cuniculi. In order to confirm that these genes encode functional proteins, AOX genes from both A. locustae and T. hominis were over-expressed in E. coli and AOX activity measured spectrophotometrically using ubiquinol-1 (UQ-1 as substrate. Both A. locustae and T. hominis AOX proteins reduced UQ-1 in a cyanide and antimycin-resistant manner that was sensitive to ascofuranone, a potent inhibitor of the trypanosomal AOX. The physiological role of AOX microsporidia may be to reoxidise reducing equivalents produced by glycolysis, in a manner comparable to that observed in trypanosomes.

  3. Providing Data Access for Interdisciplinary Research

    Science.gov (United States)

    Hooper, R. P.; Couch, A.

    2012-12-01

    Developing an interdisciplinary understanding of human and environmental interactions with water requires access to a variety of data kinds collected by various organizations. The CUAHSI Hydrologic Information System (HIS) is a standards-based, services-oriented architecture designed for time-series data. Such data represents an important type of data in water studies. Through the efforts of HIS, a standard transmission language, WaterML2, has been adopted by the Open Geospatial Consortium and is under consideration by the World Meteorologic Organization as an international standards. Web services have also been developed to retrieve data and metadata. HIS is completed with a metadata catalog, hosted by San Diego Supercomputing Center, which indexes more than 20 million time series provided from over 90 different services. This catalog is supported through a hierarchically organized controlled vocabulary that is open for community input and mediation. Data publishers include federal agencies, universities, state agencies, and non-profit organizations such as watershed associations. Accessing data from such a broad spectrum of sources through a uniform service standard promises to truly transform the way in which hydrologic research is done. CUAHSI HIS is a large-scale prototype at this time, but a proposal is under consideration by the National Science Foundation to operationalize HIS through a data facility, tentatively called the CUAHSI Water Data Center. Establishing HIS is an important step to enable research into human-environment interactions with water, but it is only one step. Other data structures will need to be made accessible and interoperable to support this research. Some data—such as two-dimensional GIS coverages—already have widely used standards for transmission and sharing. The US Federal government has long operated a clearinghouse for federal geographic data that is now being augmented with other services such as ArcGIS OnLine. Other data

  4. Personal glucose meters for detection and quantification of a broad range of analytes

    Science.gov (United States)

    Lu, Yi; Xiang, Yu

    2015-02-03

    A general methodology for the development of highly sensitive and selective sensors that can achieve portable, low-cost and quantitative detection of a broad range of targets using only a personal glucose meter (PGM) is disclosed. The method uses recognition molecules that are specific for a target agent, enzymes that can convert an enzyme substrate into glucose, and PGM. Also provided are sensors, which can include a solid support to which is attached a recognition molecule that permits detection of a target agent, wherein the recognition molecule specifically binds to the target agent in the presence of the target agent but not significantly to other agents as well as an enzyme that can catalyze the conversion of a substance into glucose, wherein the enzyme is attached directly or indirectly to the recognition molecule, and wherein in the presence of the target agent the enzyme can convert the substance into glucose. The disclosed sensors can be part of a lateral flow device. Methods of using such sensors for detecting target agents are also provided.

  5. Multifarious roles of intrinsic disorder in proteins illustrate its broad impact on plant biology.

    Science.gov (United States)

    Sun, Xiaolin; Rikkerink, Erik H A; Jones, William T; Uversky, Vladimir N

    2013-01-01

    Intrinsically disordered proteins (IDPs) are highly abundant in eukaryotic proteomes. Plant IDPs play critical roles in plant biology and often act as integrators of signals from multiple plant regulatory and environmental inputs. Binding promiscuity and plasticity allow IDPs to interact with multiple partners in protein interaction networks and provide important functional advantages in molecular recognition through transient protein-protein interactions. Short interaction-prone segments within IDPs, termed molecular recognition features, represent potential binding sites that can undergo disorder-to-order transition upon binding to their partners. In this review, we summarize the evidence for the importance of IDPs in plant biology and evaluate the functions associated with intrinsic disorder in five different types of plant protein families experimentally confirmed as IDPs. Functional studies of these proteins illustrate the broad impact of disorder on many areas of plant biology, including abiotic stress, transcriptional regulation, light perception, and development. Based on the roles of disorder in the protein-protein interactions, we propose various modes of action for plant IDPs that may provide insight for future experimental approaches aimed at understanding the molecular basis of protein function within important plant pathways.

  6. Broad-Bandwidth FPGA-Based Digital Polyphase Spectrometer

    Science.gov (United States)

    Jamot, Robert F.; Monroe, Ryan M.

    2012-01-01

    With present concern for ecological sustainability ever increasing, it is desirable to model the composition of Earth s upper atmosphere accurately with regards to certain helpful and harmful chemicals, such as greenhouse gases and ozone. The microwave limb sounder (MLS) is an instrument designed to map the global day-to-day concentrations of key atmospheric constituents continuously. One important component in MLS is the spectrometer, which processes the raw data provided by the receivers into frequency-domain information that cannot only be transmitted more efficiently, but also processed directly once received. The present-generation spectrometer is fully analog. The goal is to include a fully digital spectrometer in the next-generation sensor. In a digital spectrometer, incoming analog data must be converted into a digital format, processed through a Fourier transform, and finally accumulated to reduce the impact of input noise. While the final design will be placed on an application specific integrated circuit (ASIC), the building of these chips is prohibitively expensive. To that end, this design was constructed on a field-programmable gate array (FPGA). A family of state-of-the-art digital Fourier transform spectrometers has been developed, with a combination of high bandwidth and fine resolution. Analog signals consisting of radiation emitted by constituents in planetary atmospheres or galactic sources are downconverted and subsequently digitized by a pair of interleaved analog-to-digital converters (ADCs). This 6-Gsps (gigasample per second) digital representation of the analog signal is then processed through an FPGA-based streaming fast Fourier transform (FFT). Digital spectrometers have many advantages over previously used analog spectrometers, especially in terms of accuracy and resolution, both of which are particularly important for the type of scientific questions to be addressed with next-generation radiometers.

  7. Severely calcified leiomyoma of broad ligament in a postmenopausal woman: Report of a rare case

    OpenAIRE

    Subrata Pal; Sajeeb Mondal; Palash Kr Mondal; Gargi Raychaudhuri; Rajashree Pradhan; Suparna Banerjee

    2016-01-01

    Calcified broad ligament leiomyoma is a rare benign lesion in postmenopausal age group. It causes diagnostic confusion with solid calcified adnexal mass and large bladder calculi at the pelvic region. Clinical and radiological diagnoses were confirmed by histopathology of the hysterectomy specimen. We hereby present a case of heavily calcified broad ligament fibroid in a postmenopausal woman.

  8. Severely calcified leiomyoma of broad ligament in a postmenopausal woman: Report of a rare case

    Directory of Open Access Journals (Sweden)

    Subrata Pal

    2016-01-01

    Full Text Available Calcified broad ligament leiomyoma is a rare benign lesion in postmenopausal age group. It causes diagnostic confusion with solid calcified adnexal mass and large bladder calculi at the pelvic region. Clinical and radiological diagnoses were confirmed by histopathology of the hysterectomy specimen. We hereby present a case of heavily calcified broad ligament fibroid in a postmenopausal woman.

  9. Public Entrepreneurs and the Adoption of Broad-Based Merit Aid beyond the Southeastern United States

    Science.gov (United States)

    Ingle, William Kyle; Petroff, Ruth Ann

    2013-01-01

    The concentration of broad-based merit aid adoption in the southeastern United States has been well noted in the literature. However, there are states that have adopted broad-based merit aid programs outside of the Southeast. Guided by multiple theoretical frameworks, including innovation diffusion theory (e.g., Gray, 1973, 1994; Rogers, 2003),…

  10. 33 CFR 110.27 - Lynn Harbor in Broad Sound, Mass.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Lynn Harbor in Broad Sound, Mass. 110.27 Section 110.27 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY ANCHORAGES ANCHORAGE REGULATIONS Special Anchorage Areas § 110.27 Lynn Harbor in Broad Sound, Mass. North...

  11. 78 FR 38161 - Endangered and Threatened Wildlife and Plants; Listing One Distinct Population Segment of Broad...

    Science.gov (United States)

    2013-06-25

    ... originating in Argentina, if certain conditions are met prior to exportation to the United States. DATES: This... broad- snouted caiman in Argentina from endangered to threatened in the List of Endangered and...) of the broad- snouted caiman (Caiman latirostris): A DPS in Argentina and a DPS encompassing...

  12. Sex Differences and Within-Family Associations in the Broad Autism Phenotype

    Science.gov (United States)

    Klusek, Jessica; Losh, Molly; Martin, Gary E.

    2014-01-01

    While there is a strong sex bias in the presentation of autism, it is unknown whether this bias is also present in subclinical manifestations of autism among relatives, or the broad autism phenotype. This study examined this question and investigated patterns of co-occurrence of broad autism phenotype traits within families of individuals with…

  13. Expression of the Broad Autism Phenotype in Simplex Autism Families from the Simons Simplex Collection

    Science.gov (United States)

    Davidson, Julie; Goin-Kochel, Robin P.; Green-Snyder, Lee Anne; Hundley, Rachel J.; Warren, Zachary; Peters, Sarika U.

    2014-01-01

    The broad autism phenotype (BAP) refers to the phenotypic expression of an underlying genetic liability to autism, manifest in non-autistic relatives. This study examined the relationship among the "Broad Autism Phenotype Questionnaire" (BAPQ), "Social Responsiveness Scale: Adult Research Version" (SRS:ARV), and "Family…

  14. A broad-band microseismometer for planetary operations

    Science.gov (United States)

    Banerdt, W. B.; Vanzandt, T.; Kaiser, W. J.; Kenny, T. W.

    1993-06-01

    There has recently been renewed interest in the development of instrumentation for making measurements on the surface of Mars. This is due to the Mars Environmental Survey (MESUR) Mission, for which approximately 16 small, long-lived (2-10 years), relatively inexpensive surface stations will be deployed in a planet-wide network. This will allow the investigation of processes (such as seismology and meteorology) which require the simultaneous measurement of phenomena at many widely spaced locations on the surface over a considerable length of time. Due to the large number of vehicles involved, the mass, power, and cost of the payload will be severely constrained. A seismometer has been identified as one of the highest priority instruments in the MESUR straw-man payload. The requirements for an effective seismic experiment on Mars place a number of constraints on any viable sensor design. First, a large number of sensors must be deployed in a long-lived global network in order to be able to locate many events reliably, provide good spatial sampling of the interior, and increase the probability of seismic detection in the event of localized seismicity and/or high attenuation. From a practical standpoint, this means that individual surface stations will necessarily be constrained in terms of cost, mass, and power. Landing and thermal control systems will probably be simple, in order to minimize cost, resulting in large impact accelerations and wide daily and seasonal thermal swings. The level of seismic noise will determine the maximum usable sensitivity for seismometer. Unfortunately, the ambient seismic noise level for Mars is not well known. However lunar seismic noise levels are several orders of magnitude below that of the Earth. Sensitivities on the order of 10(exp -11)g over a bandwidth of .04 to 20 Hz are thought to be necessary to fulfill the science objectives for a seimometer placed on the Martian surface. Silicon micromachined sensor technology offers

  15. Broad-band X-ray emission and the reality of the broad iron line from the neutron star-white dwarf X-ray binary 4U 1820-30

    Science.gov (United States)

    Mondal, Aditya S.; Dewangan, G. C.; Pahari, M.; Misra, R.; Kembhavi, A. K.; Raychaudhuri, B.

    2016-09-01

    Broad relativistic iron lines from neutron star X-ray binaries are important probes of the inner accretion disc. The X-ray reflection features can be weakened due to strong magnetic fields or very low iron abundances such as is possible in X-ray binaries with low mass, first generation stars as companions. Here, we investigate the reality of the broad iron line detected earlier from the neutron-star low-mass X-ray binary 4U 1820-30 with a degenerate helium dwarf companion. We perform a comprehensive, systematic broad-band spectral study of the atoll source using Suzaku and simultaneous NuSTAR and Swift observations. We have used different continuum models involving accretion disc emission, thermal blackbody and thermal Comptonization of either disc or blackbody photons. The Suzaku data show positive and negative residuals in the region of Fe K band. These features are well described by two absorption edges at 7.67 ± 0.14 keV and 6.93 ± 0.07 keV or partial covering photoionized absorption or by blurred reflection. Though, the simultaneous Swift and NuSTAR data do not clearly reveal the emission or absorption features, the data are consistent with the presence of either absorption or emission features. Thus, the absorption based models provide an alternative to the broad iron line or reflection model. The absorption features may arise in winds from the inner accretion disc. The broad-band spectra appear to disfavour continuum models in which the blackbody emission from the neutron-star surface provides the seed photons for thermal Comptonization. Our results suggest emission from a thin accretion disc (kTdisc ˜ 1 keV), Comptonization of disc photons in a boundary layer most likely covering a large fraction of the neutron-star surface and innermost parts of the accretion disc, and blackbody emission (kTbb ˜ 2 keV) from the polar regions.

  16. Broad T-cell receptor repertoire in T-lymphocytes derived from human induced pluripotent stem cells.

    Directory of Open Access Journals (Sweden)

    Chia-Wei Chang

    Full Text Available Human induced pluripotent stem cells (hiPSCs have enormous potential for the treatment of inherited and acquired disorders. Recently, antigen-specific T lymphocytes derived from hiPSCs have been reported. However, T lymphocyte populations with broad T cell receptor (TCR diversity have not been generated. We report that hiPSCs derived from skin biopsy are capable of producing T lymphocyte populations with a broad TCR repertoire. In vitro T cell differentiation follows a similar developmental program as observed in vivo, indicated by sequential expression of CD7, intracellular CD3 and surface CD3. The γδ TCR locus is rearranged first and is followed by rearrangement of the αβ locus. Both γδ and αβ T cells display a diverse TCR repertoire. Upon activation, the cells express CD25, CD69, cytokines (TNF-α, IFN-γ, IL-2 and cytolytic proteins (Perforin and Granzyme-B. These results suggest that most, if not all, mechanisms required to generate functional T cells with a broad TCR repertoire are intact in our in vitro differentiation protocol. These data provide a foundation for production of patient-specific T cells for the treatment of acquired or inherited immune disorders and for cancer immunotherapy.

  17. Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies.

    Science.gov (United States)

    McGuire, Andrew T; Hoot, Sam; Dreyer, Anita M; Lippy, Adriana; Stuart, Andrew; Cohen, Kristen W; Jardine, Joseph; Menis, Sergey; Scheid, Johannes F; West, Anthony P; Schief, William R; Stamatatos, Leonidas

    2013-04-08

    Broadly neutralizing antibodies (bnAbs) against HIV are believed to be a critical component of the protective responses elicited by an effective HIV vaccine. Neutralizing antibodies against the evolutionarily conserved CD4-binding site (CD4-BS) on the HIV envelope glycoprotein (Env) are capable of inhibiting infection of diverse HIV strains, and have been isolated from HIV-infected individuals. Despite the presence of anti-CD4-BS broadly neutralizing antibody (bnAb) epitopes on recombinant Env, Env immunization has so far failed to elicit such antibodies. Here, we show that Env immunogens fail to engage the germline-reverted forms of known bnAbs that target the CD4-BS. However, we found that the elimination of a conserved glycosylation site located in Loop D and two glycosylation sites located in variable region 5 of Env allows Env-binding to, and activation of, B cells expressing the germline-reverted BCRs of two potent broadly neutralizing antibodies, VRC01 and NIH45-46. Our results offer a possible explanation as to why Env immunogens have been ineffective in stimulating the production of such bNAbs. Importantly, they provide key information as to how such immunogens can be engineered to initiate the process of antibody-affinity maturation against one of the most conserved Env regions.

  18. Design of broad angular phase retarders for the complete polarization analysis of extreme ultraviolet radiation

    Science.gov (United States)

    Lin, Cheng-You; Chen, Shu-Jing; Chen, Zhao-Yang; Ding, Ying-Chun

    2015-11-01

    A method of designing broad angular phase retarders in the extreme ultraviolet (EUV) region is presented. The design is based on a standard Levenberg-Marquardt algorithm combined with a common merit function. Using this method, a series of broad angular EUV phase retarders were designed using aperiodic Mo/Si multilayers. At photon energy of 90 eV, broad angular phase retarders with 30°, 60°, and 90° phase retardations have been realized in the angular range of 39°-51°. By analyzing and comparing the performances of the designed broad angular phase retarders, we found that the Mo/Si multilayer with more layers could obtain higher phase retardation in broader angular range when used to design the broad angular phase retarder. Broad angular phase retarders possess lower sensitivity toward changing incident angle compared with the traditional phase retarders designed with transmission periodic multilayers, and can be used for the polarization control of broad angular EUV sources. Project supported by the Fundamental Research Funds for the Central Universities, China (Grant Nos. JD1517, ZY1349, and 2652014012).

  19. Dependence of the broad Fe K$\\alpha$ line on the physical parameters of AGN

    CERN Document Server

    Liu, Zhu; Lu, Youjun; Carrera, Francisco J; Falocco, Serena; Dong, Xiao-Bo

    2016-01-01

    In this paper, the dependence of the broad Fe K$\\alpha$ line on the physical parameters of AGN, such as the black hole mass $M_{BH}$, accretion rate (equivalently represented by Eddington ratio $\\lambda_{Edd}$), and optical classification, is investigated by applying the X-ray spectra stacking method to a large sample of AGN which have well measured optical parameters. A broad line feature is detected ($>3\\sigma$) in the stacked spectra of the high $\\lambda_{Edd}$ sub-sample ($\\log\\lambda_{Edd}>-0.9$). The profile of the broad line can be well fitted with relativistic broad line model, with the line energy consistent with highly ionized Fe K$\\alpha$ line (i.e. Fe xxvi). A model consisting of multiple narrow lines cannot be ruled out, however. We found hints that the Fe K line becomes broader as the $\\lambda_{Edd}$ increases. No broad line feature is shown in the sub-sample of broad-line Seyfert 1 (BLS1) galaxies and in the full sample, while a broad line might be present, though at low significance, in the su...

  20. Change in Species Diversity during Recovering Process of Evergreen Broad-leaved Fo rest

    Institute of Scientific and Technical Information of China (English)

    WenYuanguang; LiuShirong; ChenFang; HeTatping; LiangHongwen

    2005-01-01

    Evergreen broad-leaved forest is one of the most important vegetation types in China. Because of the human activities, evergreen broad-leaved forest has been destroyed extensively, leading to degraded ecosystem. It is urgent to conserve and restore these natural forests in China.tn this paper, the tendency and rate of species diversity restoration of the evergreen broad-lea ved forest in Darning Mountain has been studied. The main results are as follows:(a) in subtropical mid-mountain area, species diversity in degraded evergreen broad-leaved forest can be restored. Through analyzing b diversity index of communities in different time and space, it was found that the species composition of communities tend to be the same as that in the zonal evergreen broad-leaved forest. (b) The restoration rate of evergreen broad-leaved forest was very fast. Planting Chinese fir after clear-cutting and controlled burning of the forest 178 species appeared in a 60Om2, sample area after 20 years"" natural recovering. Among these species, 58 were tree layer and the height of community reached 18m, The survey suggested that it would take only 20 years for the degraded forest to develop into community composed of light demanding broad-leaved pioneer trees and rain-tolerance broad-leaved trees, and it need another 40-80 years to reach the stage consisting of min-tulerance evergreen broad-leaved trees, (c) Species number increased quickly at the early stage (2-20 years) during vegetation recovering process toward the climax, and decreased at the min-stage (50-60 years ), then maintained a relatively stable level at the late-stage (over 150 years).

  1. ISO observations and models of galaxies with Hidden Broad Line Regions

    CERN Document Server

    Efstathiou, A

    2005-01-01

    In this paper we present ISO mid-infrared spectrophotometry and far-infrared photometry of galaxies with Hidden Broad Line Regions (HBLR). We also present radiative transfer models of their spectral energy distributions which enable us to separate the contributions from the dusty disc of the AGN and the dusty starbursts. We find that the combination of tapered discs (discs whose thickness increases with distance from the central source in the inner part but stays constant in the outer part) and starbursts provide good fits to the data. The tapered discs dominate in the mid-infrared part of the spectrum and the starbursts in the far-infrared. After correcting the AGN luminosity for anisotropic emission we find that the ratio of the AGN luminosity to the starburst luminosity, L(AGN)/L(SB), ranges from about unity for IRAS14454-4343 to about 13 for IRAS01475-0740. Our results suggest that the warm IRAS colours of HBLR are due to the relatively high L(AGN)/L(SB). Our fits are consistent with the unified model and...

  2. The impact of JWST broad-band filter choice on photometric redshift estimation

    CERN Document Server

    Bisigello, L; Colina, L; Fèvre, O Le; Nørgaard-Nielsen, H U; Pérez-González, P G; Pye, J; van der Werf, P; Ilbert, O; Grogin, N; Koekemoer, A

    2016-01-01

    The determination of galaxy redshifts in James Webb Space Telescope (JWST)'s blank-field surveys will mostly rely on photometric estimates, based on the data provided by JWST's Near-Infrared Camera (NIRCam) at 0.6-5.0 {\\mu}m and Mid Infrared Instrument (MIRI) at {\\lambda}>5.0 {\\mu}m. In this work we analyse the impact of choosing different combinations of NIRCam and MIRI broad-band filters (F070W to F770W), as well as having ancillary data at {\\lambda}=10, but the zphot quality significantly degrades at S/N<=5. Adding MIRI photometry with one magnitude brighter depth than the NIRCam depth allows for a redshift recovery of 83-99%, depending on SED type, and its effect is particularly noteworthy for galaxies with nebular emission. The vast majority of NIRCam galaxies with [F150W]=29 AB mag at z=7-10 will be detected with MIRI at [F560W, F770W]<28 mag if these sources are at least mildly evolved or have spectra with emission lines boosting the mid-infrared fluxes.

  3. Spatially Resolving the Kinematics of the <100 {\\mu}as Quasar Broad Line Region using Spectroastrometry

    CERN Document Server

    Stern, Jonathan; Pott, Jörg-Uwe

    2015-01-01

    The broad line region (BLR) of luminous active galactic nuclei (AGN) is a prominent observational signature of the accretion flow around supermassive black holes, which can be used to measure their masses (M_BH) over cosmic history. Due to the <100 {\\mu}as angular size of the BLR, current direct constraints on BLR kinematics are limited to those provided by reverberation mapping studies, which are most efficiently carried out on low-luminosity L and low-redshift z AGN. We analyze the possibility to measure the BLR size and study its kinematic structure using spectroastrometry, whereby one measures the spatial position centroid of emission line photons as a function of velocity. We calculate the expected spectroastrometric signal of a rotation-dominated BLR for various assumptions about the ratio of random to rotational motions, and the radial distribution of the BLR gas. We show that for hyper-luminous quasars at z < 2.5, the size of the low-ionization BLR can already be constrained with existing telesc...

  4. Broad-Scale Environmental Conditions Responsible for Post-Fire Vegetation Dynamics

    Directory of Open Access Journals (Sweden)

    Stuart E. Marsh

    2010-11-01

    Full Text Available Ecosystem response to disturbance is influenced by environmental conditions at a number of scales. Changes in climate have altered fire regimes across the western United States, and have also likely altered spatio-temporal patterns of post-fire vegetation regeneration. Fire occurrence data and a vegetation index (NDVI derived from the NOAA Advanced Very High Resolution Radiometer (AVHRR were used to monitor post-fire vegetation from 1989 to 2007. We first investigated differences in post-fire rates of vegetation regeneration between ecoregions. We then related precipitation, temperature, and elevation records at four temporal scales to rates of post-fire vegetation regeneration to ascertain the influence of climate on post-fire vegetation dynamics. We found that broad-scale climate factors are an important influence on post-fire vegetation regeneration. Most notably, higher rates of post-fire regeneration occurred with warmer minimum temperatures. Increases in precipitation also resulted in higher rates of post-fire vegetation growth. While explanatory power was slight, multiple statistical approaches provided evidence for real ecological drivers of post-fire regeneration that should be investigated further at finer scales. The sensitivity of post-disturbance vegetation dynamics to climatic drivers has important ramifications for the management of ecosystems under changing climatic conditions. Shifts in temperature and precipitation regimes are likely to result in changes in post-disturbance dynamics, which could represent important feedbacks into the global climate system.

  5. Host-Pathogen Coevolution and the Emergence of Broadly Neutralizing Antibodies in Chronic Infections.

    Science.gov (United States)

    Nourmohammad, Armita; Otwinowski, Jakub; Plotkin, Joshua B

    2016-07-01

    The vertebrate adaptive immune system provides a flexible and diverse set of molecules to neutralize pathogens. Yet, viruses such as HIV can cause chronic infections by evolving as quickly as the adaptive immune system, forming an evolutionary arms race. Here we introduce a mathematical framework to study the coevolutionary dynamics between antibodies and antigens within a host. We focus on changes in the binding interactions between the antibody and antigen populations, which result from the underlying stochastic evolution of genotype frequencies driven by mutation, selection, and drift. We identify the critical viral and immune parameters that determine the distribution of antibody-antigen binding affinities. We also identify definitive signatures of coevolution that measure the reciprocal response between antibodies and viruses, and we introduce experimentally measurable quantities that quantify the extent of adaptation during continual coevolution of the two opposing populations. Using this analytical framework, we infer rates of viral and immune adaptation based on time-shifted neutralization assays in two HIV-infected patients. Finally, we analyze competition between clonal lineages of antibodies and characterize the fate of a given lineage in terms of the state of the antibody and viral populations. In particular, we derive the conditions that favor the emergence of broadly neutralizing antibodies, which may have relevance to vaccine design against HIV.

  6. Host-Pathogen Coevolution and the Emergence of Broadly Neutralizing Antibodies in Chronic Infections.

    Directory of Open Access Journals (Sweden)

    Armita Nourmohammad

    2016-07-01

    Full Text Available The vertebrate adaptive immune system provides a flexible and diverse set of molecules to neutralize pathogens. Yet, viruses such as HIV can cause chronic infections by evolving as quickly as the adaptive immune system, forming an evolutionary arms race. Here we introduce a mathematical framework to study the coevolutionary dynamics between antibodies and antigens within a host. We focus on changes in the binding interactions between the antibody and antigen populations, which result from the underlying stochastic evolution of genotype frequencies driven by mutation, selection, and drift. We identify the critical viral and immune parameters that determine the distribution of antibody-antigen binding affinities. We also identify definitive signatures of coevolution that measure the reciprocal response between antibodies and viruses, and we introduce experimentally measurable quantities that quantify the extent of adaptation during continual coevolution of the two opposing populations. Using this analytical framework, we infer rates of viral and immune adaptation based on time-shifted neutralization assays in two HIV-infected patients. Finally, we analyze competition between clonal lineages of antibodies and characterize the fate of a given lineage in terms of the state of the antibody and viral populations. In particular, we derive the conditions that favor the emergence of broadly neutralizing antibodies, which may have relevance to vaccine design against HIV.

  7. Emotion regulation in broadly defined anorexia nervosa: association with negative affective memory bias.

    Science.gov (United States)

    Manuel, Amy; Wade, Tracey D

    2013-08-01

    Theoretical models in anorexia nervosa (AN) implicate difficulties with emotion regulation as a maintaining factor. To date little is known about how different factors might maintain these difficulties. Forty eight women were recruited, 24 receiving treatment for AN (called broadly defined AN) and 24 healthy controls. Self-report measures of difficulties with emotion regulation and current depression were used in addition to computerized tasks which provided measures of social attentional bias and anger-threat bias, as well negative affective memory and recognition bias. Compared to controls, women with AN had significantly higher levels of difficulties with emotion regulation, depression, and negative affective memory bias, as well as lower bias for anger-threat. Simultaneous examination of the two variables that met pre-conditions for mediation of the relationship between group membership and difficulties with emotion regulation (anger-threat bias and negative affective memory) indicated negative affective memory bias to be a mediator, accounting for around one-third of the total effect a diagnosis of AN has on difficulties with emotion regulation. The association of these variables with AN may indicate shared risk factors with depression, and the variety of therapeutic approaches found to be effective with depression may be useful to further incorporate into treatments for AN.

  8. High-performance broad-band spectroscopy for breast cancer risk assessment

    Science.gov (United States)

    Pawluczyk, Olga; Blackmore, Kristina; Dick, Samantha; Lilge, Lothar

    2005-09-01

    Medical diagnostics and screening are becoming increasingly demanding applications for spectroscopy. Although for many years the demand was satisfied with traditional spectrometers, analysis of complex biological samples has created a need for instruments capable of detecting small differences between samples. One such application is the measurement of absorbance of broad spectrum illumination by breast tissue, in order to quantify the breast tissue density. Studies have shown that breast cancer risk is closely associated with the measurement of radiographic breast density measurement. Using signal attenuation in transillumination spectroscopy in the 550-1100nm spectral range to measure breast density, has the potential to reduce the frequency of ionizing radiation, or making the test accessible to younger women; lower the cost and make the procedure more comfortable for the patient. In order to determine breast density, small spectral variances over a total attenuation of up to 8 OD have to be detected with the spectrophotometer. For this, a high performance system has been developed. The system uses Volume Phase Holographic (VPH) transmission grating, a 2D detector array for simultaneous registration of the whole spectrum with high signal to noise ratio, dedicated optical system specifically optimized for spectroscopic applications and many other improvements. The signal to noise ratio exceeding 50,000 for a single data acquisition eliminates the need for nitrogen cooled detectors and provides sufficient information to predict breast tissue density. Current studies employing transillumination breast spectroscopy (TIBS) relating to breast cancer risk assessment and monitoring are described.

  9. Toward broad-band x-ray detected ferromagnetic resonance in longitudinal geometry

    Energy Technology Data Exchange (ETDEWEB)

    Ollefs, K. [Fakultät für Physik, Universität Duisburg-Essen, Lotharstr. 1, 47057 Duisburg (Germany); European Synchrotron Radiation Facility (ESRF), CS 40220, 38043 Grenoble Cedex (France); Meckenstock, R.; Spoddig, D.; Römer, F. M.; Hassel, Ch.; Schöppner, Ch.; Farle, M. [Fakultät für Physik, Universität Duisburg-Essen, Lotharstr. 1, 47057 Duisburg (Germany); Ney, V.; Ney, A., E-mail: andreas.ney@jku.at [Fakultät für Physik, Universität Duisburg-Essen, Lotharstr. 1, 47057 Duisburg (Germany); Institut für Halbleiter-und Festkörperphysik, Johannes Kepler Universität, Altenberger Str. 69, 4040 Linz (Austria)

    2015-06-14

    An ultrahigh-vacuum-compatible setup for broad-band X-ray detected ferromagnetic resonance (XFMR) in longitudinal geometry is introduced which relies on a low-power, continuous-wave excitation of the ferromagnetic sample. A simultaneous detection of the conventional ferromagnetic resonance via measuring the reflected microwave power and the XFMR signal of the X-ray absorption is possible. First experiments on the Fe and Co L{sub 3}-edges of a permalloy film covered with Co nanostripes as well as the Fe and Ni K-edges of a permalloy film are presented and discussed. Two different XFMR signals are found, one of which is independent of the photon energy and therefore does not provide element-selective information. The other much weaker signal is element-selective, and the dynamic magnetic properties could be detected for Fe and Co separately. The dependence of the latter XFMR signal on the photon helicity of the synchrotron light is found to be distinct from the usual x-ray magnetic circular dichroism effect.

  10. Screening of recombinant glycosyltransferases reveals the broad acceptor specificity of stevia UGT-76G1.

    Science.gov (United States)

    Dewitte, Griet; Walmagh, Maarten; Diricks, Margo; Lepak, Alexander; Gutmann, Alexander; Nidetzky, Bernd; Desmet, Tom

    2016-09-10

    UDP-glycosyltransferases (UGTs) are a promising class of biocatalysts that offer a sustainable alternative for chemical glycosylation of natural products. In this study, we aimed to characterize plant-derived UGTs from the GT-1 family with an emphasis on their acceptor promiscuity and their potential application in glycosylation processes. Recombinant expression in E. coli provided sufficient amounts of enzyme for the in-depth characterization of the salicylic acid UGT from Capsella rubella (UGT-SACr) and the stevia UGT from Stevia rebaudiana (UGT-76G1Sr). The latter was found to have a remarkably broad specificity with activities on a wide diversity of structures, from aliphatic and branched alcohols, over small phenolics to larger flavonoids, terpenoids and even higher glycoside compounds. As an example for its industrial potential, the glycosylation of curcumin was thoroughly evaluated. Under optimized conditions, 96% of curcumin was converted within 24h into the corresponding curcumin β-glycosides. In addition, the reaction was performed in a coupled system with sucrose synthase from Glycine max, to enable the cost-efficient (re)generation of UDP-Glc from sucrose as abundant and renewable resource.

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

    Science.gov (United States)

    Leviyang, Sivan; Ganusov, Vitaly V

    2015-10-01

    Recent studies have highlighted the ability of HIV to escape from cytotoxic T lymphocyte (CTL) responses that concurrently target multiple viral epitopes. Yet, the viral dynamics involved in such escape are incompletely understood. Previous analyses have made several strong assumptions regarding HIV escape from CTL responses such as independent or non-concurrent escape from individual CTL responses. Using experimental data from evolution of HIV half genomes in four patients we observe concurrent viral escape from multiple CTL responses during early infection (first 100 days of infection), providing confirmation of a recent result found in a study of one HIV-infected patient. We show that current methods of estimating CTL escape rates, based on the assumption of independent escapes, are biased and perform poorly when CTL escape proceeds concurrently at multiple epitopes. We propose a new method for analyzing longitudinal sequence data to estimate the rate of CTL escape across multiple epitopes; this method involves few parameters and performs well in simulation studies. By applying our novel method to experimental data, we find that concurrent multiple escapes occur at rates between 0.03 and 0.4 day(-1), a relatively broad range that reflects uncertainty due to sparse sampling and wide ranges of parameter values. However, we show that concurrent escape at rates 0.1-0.2 day(-1) across multiple epitopes is consistent with our patient datasets.

  12. Gravitational Microlensing of a Reverberating Quasar Broad Line Region - I. Method and Qualitative Results

    CERN Document Server

    Garsden, H; Lewis, G F

    2011-01-01

    The kinematics and morphology of the broad emission line region (BELR) of quasars are the subject of significant debate. The two leading methods for constraining BELR properties are microlensing and reverberation mapping. Here we combine these two methods with a study of the microlensing behaviour of the BELR in Q2237+0305, as a change in continuum emission (a "flare") passes through it. Beginning with some generic models of the BELR - sphere, bicones, disk - we slice in velocity and time to produce brightness profiles of the BELR over the duration of the flare. These are numerically microlensed to determine whether microlensing of reverberation mapping provides new information about the properties of BELRs. We describe our method and show images of the models as they are flaring, and the unlensed and lensed spectra that are produced. Qualitative results and a discussion of the spectra are given in this paper, highlighting some effects that could be observed. Our conclusion is that the influence of microlensi...

  13. The Tully-Fisher Relation and Its Residuals for a Broadly Selected Sample of Galaxies

    CERN Document Server

    Pizagno, J; Weinberg, D H; Rix, H W; Pogge, R W; Grebel, E K; Harbeck, D; Blanton, M; Brinkmann, J; Gunn, J E; Pizagno, James; Prada, Francisco; Weinberg, David H.; Rix, Hans-Walter; Pogge, Richard W.; Grebel, Eva K.; Harbeck, Daniel; Blanton, Michael; Gunn, James E.

    2006-01-01

    We measure the relation between galaxy luminosity and disk circular velocity (the Tully-Fisher [TF] relation), in the g, r, i, and z-bands, for a broadly selected sample of galaxies from the Sloan Digital Sky Survey, with the goal of providing well defined observational constraints for theoretical models of galaxy formation. The input sample of 234 galaxies has a roughly flat distribution of absolute magnitudes in the range -18.5 > Mr > -22, and our only morphological selection is an axis-ratio cut b/a < 0.6 to allow accurate inclination corrections. Long-slit spectroscopy yields usable H-alpha rotation curves for 170 galaxies. Observational errors, including distance errors due to peculiar velocities, are small compared to the intrinsic scatter of the TF relation. The slope of the forward TF relation steepens from -5.4 +/- 0.2 mag/log(km/s) in the g-band to -6.4 +/- 0.2 mag/log(km/s) in the z-band. The intrinsic scatter is approximately 0.4 mag in all bands. The scatter is not dominated by rare outliers o...

  14. Immunologic characteristics of HIV-infected individuals who make broadly neutralizing antibodies.

    Science.gov (United States)

    Borrow, Persephone; Moody, M Anthony

    2017-01-01

    Induction of broadly neutralizing antibodies (bnAbs) capable of inhibiting infection with diverse variants of human immunodeficiency virus type 1 (HIV-1) is a key, as-yet-unachieved goal of prophylactic HIV-1 vaccine strategies. However, some HIV-infected individuals develop bnAbs after approximately 2-4 years of infection, enabling analysis of features of these antibodies and the immunological environment that enables their induction. Distinct subsets of CD4(+) T cells play opposing roles in the regulation of humoral responses: T follicular helper (Tfh) cells support germinal center formation and provide help for affinity maturation and the development of memory B cells and plasma cells, while regulatory CD4(+) (Treg) cells including T follicular regulatory (Tfr) cells inhibit the germinal center reaction to limit autoantibody production. BnAbs exhibit high somatic mutation frequencies, long third heavy-chain complementarity determining regions, and/or autoreactivity, suggesting that bnAb generation is likely to be highly dependent on the activity of CD4(+) Tfh cells, and may be constrained by host tolerance controls. This review discusses what is known about the immunological environment during HIV-1 infection, in particular alterations in CD4(+) Tfh, Treg, and Tfr populations and autoantibody generation, and how this is related to bnAb development, and considers the implications for HIV-1 vaccine design.

  15. Ontogeny-based immunogens for the induction of V2-directed HIV broadly neutralizing antibodies.

    Science.gov (United States)

    Moore, Penny L; Gorman, Jason; Doria-Rose, Nicole A; Morris, Lynn

    2017-01-01

    The development of a preventative HIV vaccine able to elicit broadly neutralizing antibodies (bNAbs) remains a major challenge. Antibodies that recognize the V2 region at the apex of the HIV envelope trimer are among the most common bNAb specificities during chronic infection and many exhibit remarkable breadth and potency. Understanding the developmental pathway of these antibodies has provided insights into their precursors, and the viral strains that engage them, as well as defined how such antibodies mature to acquire breadth. V2-apex bNAbs are derived from rare precursors with long anionic CDR H3s that are often deleted in the B cell repertoire. However, longitudinal studies suggest that once engaged, these precursors contain many of the structural elements required for neutralization, and can rapidly acquire breadth through moderate levels of somatic hypermutation in response to emerging viral variants. These commonalities in the precursors and mechanism of neutralization have enabled the identification of viral strains that show enhanced reactivity for V2 precursors from multiple donors, and may form the basis of germline targeting approaches. In parallel, new structural insights into the HIV trimer, the target of these quaternary antibodies, has created invaluable new opportunities for ontogeny-based immunogens designed to select for rare V2-bNAb precursors, and drive them toward breadth.

  16. Streptolysin S of Streptococcus anginosus exhibits broad-range hemolytic activity.

    Science.gov (United States)

    Asam, Daniela; Mauerer, Stefanie; Spellerberg, Barbara

    2015-04-01

    Streptococcus anginosus is a commensal of mucous membranes and an emerging human pathogen. Some strains, including the type strain, display a prominent β-hemolytic phenotype. A gene cluster (sag), encoding a variant of streptolysin S (SLS) has recently been identified as the genetic background for β-hemolysin production in S. anginosus. In this study, we further characterized the hemolytic and cytolytic activity of the S. anginosus hemolysin in comparison with other streptococcal hemolysins. The results indicate that SLS of S. anginosus is a broad-range hemolysin able to lyse erythrocytes of different species, including horse, bovine, rabbit and even chicken. The hemolytic activity is temperature dependent, and a down-regulation of the hemolysin expression is induced in the presence of high glucose levels. Survival assays indicate that in contrast to other streptococcal species, S. anginosus does not require SLS for survival in the presence of human granulocytes. Cross-complementation studies using the sagB and sagD genes of Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis demonstrated functional similarities to the S. anginosus SLS. Nevertheless, distinct differences to other streptolysin S variants were noted and provide further insights into the molecular mechanisms of SLS pathogen host interactions.

  17. Agricultural Set-aside Programs and Grassland Birds: Insights from Broad-scale Population Trends

    Directory of Open Access Journals (Sweden)

    S. Riffell

    2008-10-01

    Full Text Available The Conservation Reserve Program (CRP is a voluntary set-aside program in the United States designed to amelioratesoil erosion, control crop overproduction, enhance water quality, and provide wildlife habitat by replacing crops with other forms of land cover. Because CRP includes primarily grass habitats, it has great potential to benefitdeclining North American grassland bird populations. We looked at the change in national and state population trends of grassland birds and related changes to cover-specific CRP variables (previous research grouped all CRP practices. Changes in national trends after the initiation of the CRP were inconclusive, but we observed signficant bird-CRP relations at the state level. Most bird-CRP relations were positive, except for some species associated with habitats that CRP replaced. Practice- and configuration-specific CRP variables were related to grassland bird trends, rather than a generic measure of all CRP types combined. Considering all CRP land as a single, distinct habitat type may obscure actual relations between birds and set-aside characteristics. Understanding and predictingthe effects of set-aside programs (like CRP or agri-environment schemes on grassland birds is complex and difficult. Because available broad-scale datasets are less than adequate, studies should be conducted at a variety of spatial and temporal scales.

  18. Chandra Detects Relativistic Broad Absorption Lines from APM 08279+5255

    CERN Document Server

    Chartas, G; Garmire, G P; Gallagher, S C

    2002-01-01

    We report the discovery of X-ray broad absorption lines (BALs) from the BALQSO APM 08279+5255 originating from material moving at relativistic velocities with respect to the central source. The large flux magnification by a factor of ~ 100 provided by the gravitational lens effect combined with the large redshift (z = 3.91) of the quasar have facilitated the acquisition of the first high signal-to-noise X-ray spectrum of a quasar containing X-ray BALs. Our analysis of the X-ray spectrum of APM 08279+5255 places the rest-frame energies of the two observed absorption lines at 8.1 and 9.8 keV. The detection of each of these lines is significant at the > 99.9% confidence level based on the F-test. Assuming that the absorption lines are from Fe xxv Kalpha, the implied bulk velocities of the X-ray BALs are ~ 0.2c and ~ 0.4c, respectively. The observed high bulk velocities of the X-ray BALs combined with the relatively short recombination time-scales of the X-ray absorbing gas imply that the absorbers responsible fo...

  19. Inhibition of influenza virus replication by targeting broad host cell pathways.

    Directory of Open Access Journals (Sweden)

    Isabelle Marois

    Full Text Available Antivirals that are currently used to treat influenza virus infections target components of the virus which can mutate rapidly. Consequently, there has been an increase in the number of resistant strains to one or many antivirals in recent years. Here we compared the antiviral effects of lysosomotropic alkalinizing agents (LAAs and calcium modulators (CMs, which interfere with crucial events in the influenza virus replication cycle, against avian, swine, and human viruses of different subtypes in MDCK cells. We observed that treatment with LAAs, CMs, or a combination of both, significantly inhibited viral replication. Moreover, the drugs were effective even when they were administered 8 h after infection. Finally, analysis of the expression of viral acidic polymerase (PA revealed that both drugs classes interfered with early events in the viral replication cycle. This study demonstrates that targeting broad host cellular pathways can be an efficient strategy to inhibit influenza replication. Furthermore, it provides an interesting avenue for drug development where resistance by the virus might be reduced since the virus is not targeted directly.

  20. Co-gradient variation in growth rate and development time of a broadly distributed butterfly.

    Directory of Open Access Journals (Sweden)

    Madeleine Barton

    Full Text Available Widespread species often show geographic variation in thermally-sensitive traits, providing insight into how species respond to shifts in temperature through time. Such patterns may arise from phenotypic plasticity, genetic adaptation, or their interaction. In some cases, the effects of genotype and temperature may act together to reduce, or to exacerbate, phenotypic variation in fitness-related traits across varying thermal environments. We find evidence for such interactions in life-history traits of Heteronympha merope, a butterfly distributed across a broad latitudinal gradient in south-eastern Australia. We show that body size in this butterfly is negatively related to developmental temperature in the laboratory, in accordance with the temperature-size rule, but not in the field, despite very strong temperature gradients. A common garden experiment on larval thermal responses, spanning the environmental extremes of H. merope's distribution, revealed that butterflies from low latitude (warmer climate populations have relatively fast intrinsic growth and development rates compared to those from cooler climates. These synergistic effects of genotype and temperature across the landscape (co-gradient variation are likely to accentuate phenotypic variation in these traits, and this interaction must be accounted for when predicting how H. merope will respond to temperature change through time. These results highlight the importance of understanding how variation in life-history traits may arise in response to environmental change. Without this knowledge, we may fail to detect whether organisms are tracking environmental change, and if they are, whether it is by plasticity, adaptation or both.

  1. A broad deglacial δ13C minimum event in planktonic foraminiferal records in the Okinawa Trough

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    The equatorial Pacific upwelling zone has been suspected of playing an important role in the global atmospheric CO2 changes associated with glacial-interglacial cycles.In order to assess the influencing scope of the surface water deglacial δ13C minimum in the tropical Iow-latitude Pacific,the core DGKS9603, collected from the middle Okinawa Trough, was examined for δ13C records of planktonic foraminifera N. dutertrei and G. ruber. The planktonic foraminiferal δ13C records show a clear decreasing event from 20 to 6 cal. kaBP., which is characterized by long duration of about 14 ka and amplitude shift of 0.4 × 10-3. Its minimum value occurred at 15.7 cai kaBP. The event shows fairly synchrony with the surface water deglacial δ13C minimum identiffed in the tropical Pacific and its marginal seas. Because there is no evidence in planktonic foraminiferal fauna and δ18O records for upwelling and river runoff enhancement,the broad deglacial δ13C minimum event in planktonic foraminiferal records revealed in core DGKS9603 might have been the direct influencing result of the deglacial surface water of the tropical Pacific. The identification for the event in the Okinawa Trough provides new evidence that the water evolution in the tropical low-latitude Pacific plays a key role in large regional, even global carbon cycle.

  2. A Lactobacillus plantarum esterase active on a broad range of phenolic esters.

    Science.gov (United States)

    Esteban-Torres, María; Landete, José María; Reverón, Inés; Santamaría, Laura; de las Rivas, Blanca; Muñoz, Rosario

    2015-05-01

    Lactobacillus plantarum is the lactic acid bacterial species most frequently found in the fermentation of food products of plant origin on which phenolic compounds are abundant. L. plantarum strains showed great flexibility in their ability to adapt to different environments and growth substrates. Of 28 L. plantarum strains analyzed, only cultures from 7 strains were able to hydrolyze hydroxycinnamic esters, such as methyl ferulate or methyl caffeate. As revealed by PCR, only these seven strains possessed the est_1092 gene. When the est_1092 gene was introduced into L. plantarum WCFS1 or L. lactis MG1363, their cultures acquired the ability to degrade hydroxycinnamic esters. These results support the suggestion that Est_1092 is the enzyme responsible for the degradation of hydroxycinnamic esters on the L. plantarum strains analyzed. The Est_1092 protein was recombinantly produced and biochemically characterized. Surprisingly, Est_1092 was able to hydrolyze not only hydroxycinnamic esters, since all the phenolic esters assayed were hydrolyzed. Quantitative PCR experiments revealed that the expression of est_1092 was induced in the presence of methyl ferulate, an hydroxycinnamic ester, but was inhibited on methyl gallate, an hydroxybenzoic ester. As Est_1092 is an enzyme active on a broad range of phenolic esters, simultaneously possessing feruloyl esterase and tannase activities, its presence on some L. plantarum strains provides them with additional advantages to survive and grow on plant environments.

  3. Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus

    DEFF Research Database (Denmark)

    Giang, Erick; Dorner, Marcus; Prentoe, Jannick C

    2012-01-01

    Abs recognizing five distinct antigenic regions on the virus envelope glycoprotein complex E1E2 from an HCV-immune phage-display antibody library by using an exhaustive-panning strategy. Many of these mAbs were broadly neutralizing. In particular, the mAb AR4A, recognizing a discontinuous epitope outside the CD81......bs on the E1E2 complex, has an exceptionally broad neutralizing activity toward diverse HCV genotypes and protects against heterologous HCV challenge in a small animal model. The mAb panel will be useful for the design and development of vaccine candidates to elicit broadly neutralizing antibodies...

  4. Four broad temperament dimensions: description, convergent validation correlations, and comparison with the Big Five.

    Science.gov (United States)

    Fisher, Helen E; Island, Heide D; Rich, Jonathan; Marchalik, Daniel; Brown, Lucy L

    2015-01-01

    A new temperament construct based on recent brain physiology literature has been investigated using the Fisher Temperament Inventory (FTI). Four collections of behaviors emerged, each associated with a specific neural system: the dopamine, serotonin, testosterone, and estrogen/oxytocin system. These four temperament suites have been designated: (1) Curious/Energetic, (2) Cautious/Social Norm Compliant, (3) Analytical/Tough-minded, and (4) Prosocial/Empathetic temperament dimensions. Two functional magnetic resonance imaging (fMRI) studies have suggested that the FTI can measure the influence of these neural systems. In this paper, to further the behavioral validation and characterization of the four proposed temperament dimensions, we measured correlations with five variables: (1) gender; (2) level of education; (3) religious preference; (4) political orientation; (5) the degree to which an individual regards sex as essential to a successful relationship. Subjects were 39,913 anonymous members of a US Internet dating site and 70,000+ members in six other countries. Correlations with the five variables characterize the FTI and are consistent with mechanisms using the proposed neuromodulators. We also report on an analysis between the FTI and the NEO-Five Factor Inventory, using a college sample (n = 215), which showed convergent validity. The results provide novel correlates not available in other questionnaires: religiosity, political orientation, and attitudes about sex in a relationship. Also, an Eigen analysis replicated the four clusters of co-varying items. The FTI, with its broad systems and non-pathologic factors complements existing personality questionnaires. It provides an index of some brain systems that contribute to temperament, and may be useful in psychotherapy, business, medicine, and the legal community.

  5. Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity.

    Directory of Open Access Journals (Sweden)

    Marie-Line Goulet

    Full Text Available The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between cytosolic RIG-I and viral RNA structures that contain short hairpin dsRNA and 5' triphosphate (5'ppp terminal structure. In the present study, an RNA agonist of RIG-I was synthesized in vitro and shown to stimulate RIG-I-dependent antiviral responses at concentrations in the picomolar range. In human lung epithelial A549 cells, 5'pppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, and induction of inflammatory and interferon stimulated genes - hallmarks of a fully functional antiviral response. Evaluation of the magnitude and duration of gene expression by transcriptional profiling identified a robust, sustained and diversified antiviral and inflammatory response characterized by enhanced pathogen recognition and interferon (IFN signaling. Bioinformatics analysis further identified a transcriptional signature uniquely induced by 5'pppRNA, and not by IFNα-2b, that included a constellation of IRF7 and NF-kB target genes capable of mobilizing multiple arms of the innate and adaptive immune response. Treatment of primary PBMCs or lung epithelial A549 cells with 5'pppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 5'pppRNA protected animals from a lethal challenge with H1N1 Influenza, reduced virus titers in mouse lungs and protected animals from virus-induced pneumonia. Strikingly, the RIG-I-specific transcriptional response afforded partial protection from influenza challenge, even in the absence of type I interferon signaling. This systems approach provides transcriptional, biochemical, and in vivo analysis of the antiviral efficacy of 5'pppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents.

  6. Design, fabrication and test of Load Bearing multilayer insulation to support a broad area cooled shield

    Science.gov (United States)

    Dye, S. A.; Johnson, W. L.; Plachta, D. W.; Mills, G. L.; Buchanan, L.; Kopelove, A. B.

    2014-11-01

    Improvements in cryogenic propellant storage are needed to achieve reduced or Zero Boil Off of cryopropellants, critical for long duration missions. Techniques for reducing heat leak into cryotanks include using passive multi-layer insulation (MLI) and vapor cooled or actively cooled thermal shields. Large scale shields cannot be supported by tank structural supports without heat leak through the supports. Traditional MLI also cannot support shield structural loads, and separate shield support mechanisms add significant heat leak. Quest Thermal Group and Ball Aerospace, with NASA SBIR support, have developed a novel Load Bearing multi-layer insulation (LBMLI) capable of self-supporting thermal shields and providing high thermal performance. We report on the development of LBMLI, including design, modeling and analysis, structural testing via vibe and acoustic loading, calorimeter thermal testing, and Reduced Boil-Off (RBO) testing on NASA large scale cryotanks. LBMLI uses the strength of discrete polymer spacers to control interlayer spacing and support the external load of an actively cooled shield and external MLI. Structural testing at NASA Marshall was performed to beyond maximum launch profiles without failure. LBMLI coupons were thermally tested on calorimeters, with superior performance to traditional MLI on a per layer basis. Thermal and structural tests were performed with LBMLI supporting an actively cooled shield, and comparisons are made to the performance of traditional MLI and thermal shield supports. LBMLI provided a 51% reduction in heat leak per layer over a previously tested traditional MLI with tank standoffs, a 38% reduction in mass, and was advanced to TRL5. Active thermal control using LBMLI and a broad area cooled shield offers significant advantages in total system heat flux, mass and structural robustness for future Reduced Boil-Off and Zero Boil-Off cryogenic missions with durations over a few weeks.

  7. Four broad temperament dimensions: Description, convergent validation correlations, and comparison with the Big Five

    Directory of Open Access Journals (Sweden)

    Helen eFisher

    2015-08-01

    Full Text Available A new temperament construct based on recent brain physiology literature has been investigated using the Fisher Temperament Inventory (FTI. Four collections of behaviors emerged, each associated with a specific neural system: the dopamine, serotonin, testosterone and estrogen/oxytocin system. These four temperament suites have been designated: 1 Curious/Energetic, 2 Cautious/Social Norm Compliant, 3 Analytical/Tough-minded, and 4 Prosocial/Empathetic temperament dimensions. Two functional magnetic resonance imaging (fMRI studies have suggested that the FTI can measure the influence of these neural systems. In this paper, to further the behavioral validation and characterization of the four proposed temperament dimensions, we measured correlations with five variables: 1 gender; 2 level of education; 3 religious preference; 4 political orientation; 5 the degree to which an individual regards sex as essential to a successful relationship. Subjects were 39,913 anonymous members of a US Internet dating site and 70,000+ members in six other countries. Correlations with the five variables characterize the Fisher Temperament Inventory and are consistent with mechanisms using the proposed neuromodulators. We also report on an analysis between the FTI and the NEO-Five Factor Inventory, using a college sample (n=215, which showed convergent validity. The results provide novel correlates not available in other questionnaires: religiosity, political orientation and attitudes about sex in a relationship. Also, an Eigen analysis replicated the four clusters of co-varying items. The FTI, with its broad systems and non-pathologic factors complements existing personality questionnaires. It provides an index of some brain systems that contribute to temperament, and may be useful in psychotherapy, business, medicine, and the legal community.

  8. Broad characterization of endogenous peptides in the tree shrew visual system.

    Science.gov (United States)

    Ranc, Vaclav; Petruzziello, Filomena; Kretz, Robert; Argandoña, Enrike G; Zhang, Xiaozhe; Rainer, Gregor

    2012-05-17

    Endogenous neuropeptides, acting as neurotransmitters or hormones in the brain, carry out important functions including neural plasticity, metabolism and angiogenesis. Previous neuropeptide studies have focused on peptide-rich brain regions such as the striatum or hypothalamus. Here we present an investigation of peptides in the visual system, composed of brain regions that are generally less rich in peptides, with the aim of providing the first broad overview of peptides involved in mammalian visual functions. We target three important parts of the visual system: the primary visual cortex (V1), lateral geniculate nucleus (LGN) and superior colliculus (SC). Our study is performed in the tree shrew, a close relative of primates. Using a combination of data dependent acquisition and targeted LC-MS/MS based neuropeptidomics; we identified a total of 52 peptides from the tree shrew visual system. A total of 26 peptides, for example GAV and neuropeptide K were identified in the visual system for the first time. Out of the total 52 peptides, 27 peptides with high signal-to-noise-ratio (>10) in extracted ion chromatograms (EIC) were subjected to label-free quantitation. We observed generally lower abundance of peptides in the LGN compared to V1 and SC. Consistently, a number of individual peptides showed high abundance in V1 (such as neuropeptide Y or somatostatin 28) and in SC (such as somatostatin 28 AA1-12). This study provides the first in-depth characterization of peptides in the mammalian visual system. These findings now permit the investigation of neuropeptide-regulated mechanisms of visual perception.

  9. Full term viable secondary broad ligament pregnancy – A rare case

    Directory of Open Access Journals (Sweden)

    CH. Sheethal, Dr.

    2017-01-01

    Full Text Available Broad ligament pregnancy is also known as inter ligamentous pregnancy which is a rare form of ectopic pregnancy. Very few successful live births have been reported in this condition, where such pregnancies reached term and with live birth of a baby. A case of 28 year old primigravida of 35 weeks gestation with oligoamnios was referred to our hospital. A right broad ligament pregnancy was confirmed after an ultrasound and an MRI. She was taken up for surgery and an incision was given on the anterior leaf of the broad ligament and a male live fetus was extracted. Placenta was found on the posterior leaf of the broad ligament and it was removed without any undue haemorrhage. Uterus was lying medial to the sac and was around ten weeks in size. Both mother and baby were discharged on seventh postoperative day in good health condition.

  10. Are broad optical balmer lines from central accretion disk in PG 1613+658?

    CERN Document Server

    Zhang, XueGuang

    2014-01-01

    In this letter, we report positive correlations between broad line width and broad line flux for the broad balmer lines of the long-term observed AGN PG 1613+658. Rather than the expected negative correlations under the widely accepted virialization assumption for AGN BLRs, the positive correlations indicate much different BLR structures of PG 1613+658 from the commonly considered BLR structures which are dominated by the equilibrium between radiation pressure and gas pressure. Therefore, accretion disk origin is preferred for the observed broad single-peaked optical balmer lines of PG 1613+658, because of the mainly gravity dominated disk-like BLRs with radial structures having few effects from radiation pressure.

  11. Broad emission lines variability: a window into the heart of AGN

    Science.gov (United States)

    Ilic, Dragana; Popovic, Luka C.; Shapovalova, Alla I.; Afanasiev, V. L.; Chavushyan, V. H.; Burenkov, A.; Kollatschny, W.; Kovacevic, A.

    2016-08-01

    The broad emission lines of active galactic nuclei (AGN) are known to vary both in flux and shape, and are often showing very complex line profiles. They can give us invaluable information about the kinematics and geometry of the broad line region (BLR) where these lines are originating from. The BLR is close to the supermassive black hole in AGN and may hold basic information about the formation and fueling of AGN.Here we summarize the results of the line and continuum variability of a sample of broad line AGN, obtained with the long-term optical monitoring campaign performed with telescopes of SAO (Russia), OAGH and OAN-SPM (Mexico), and Calar Alto (Spain). We monitored different type of broad line AGN (double-peaked, radio loud and radio quiet, NLSy1 and a supermassive binary black hole candidate) which show different variability characteristics that can be explained by different physical properties in BLR.

  12. Narrow line Seyfert 1 galaxies: where are the broad line regions?

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    A sample consisting of 211 narrow line Seyfert 1 galaxies (NLS1s) with high quality spectra from the Sloan Digital Sky Survey (SDSS) is selected to explore where broad line regions are in these objects. We find that the Hβ profile can be fitted well by three (narrow, intermediate and broad) Gaussian components, and the FWHM ratios of the broad to the intermediate components hold a constant of 3.0 roughly for the entire sample. If the broad components originate from the region scaled by the well-determined Hβ reverberation mapping relation, we find that the intermediate components originate from the inner edge of the torus, which is scaled by dust K-band reverberation. We find that the IC and the BC are strongly linked dynamically, but the relation of their covering factors is much more relaxed, implying that both regions are clumpy.

  13. System Realization of Broad Band Digital Beam Forming for Digital Array Radar

    Directory of Open Access Journals (Sweden)

    Wang Feng

    2013-09-01

    Full Text Available Broad band Digital Beam Forming (DBF is the key technique for the realization of Digital Array Radar (DAR. We propose the method of combination realization of the channel equalization and DBF time delay filter function by using adaptive Sample Matrix Inversion algorithm. The broad band DBF function is realized on a new DBF module based on parallel fiber optic engines and Field Program Gate Array (FPGA. Good performance is achieved when it is used to some radar products.

  14. Establishing Normative Reference Values for Standing Broad Jump among Hungarian Youth

    Science.gov (United States)

    Saint-Maurice, Pedro F.; Laurson, Kelly R.; Kaj, Mónika; Csányi, Tamás

    2015-01-01

    Purpose: The purpose of this study was to examine age and sex trends in anaerobic power assessed by a standing broad jump and to determine norm-referenced values for youth in Hungary. Method: A sample of 2,427 Hungarian youth (1,360 boys and 1,067 girls) completed the standing broad jump twice, and the highest distance score was recorded. Quantile…

  15. Microlensing Constraints on Broad Absorption and Emission Line Flows in the Quasar H1413+117

    CERN Document Server

    O'Dowd, Matthew J; Webster, Rachel L; Labrie, Kathleen; Rogers, Joshua

    2015-01-01

    We present new integral field spectroscopy of the gravitationally lensed broad absorption line (BAL) quasar H1413+117, covering the ultraviolet to visible rest-frame spectral range. We observe strong microlensing signatures in lensed image D, and we use this microlensing to simultaneously constrain both the broad emission and broad absorption line gas. By modeling the lens system over the range of probable lensing galaxy redshifts and using on a new argument based on the wavelength-independence of the broad line lensing magnifications, we determine that there is no significant broad line emission from smaller than ~20 light days. We also perform spectral decomposition to derive the intrinsic broad emission line (BEL) and continuum spectrum, subject to BAL absorption. We also reconstruct the intrinsic BAL absorption profile, whose features allow us to constrain outflow kinematics in the context of a disk-wind model. We find a very sharp, blueshifted onset of absorption of 1,500 km/s in both C IV and N V that m...

  16. Provider barriers to telemental health: obstacles overcome, obstacles remaining.

    Science.gov (United States)

    Brooks, Elizabeth; Turvey, Carolyn; Augusterfer, Eugene F

    2013-06-01

    Many providers are hesitant to use telemental health technologies. When providers are queried, various barriers are presented, such as the clinician's skepticism about the effectiveness of telemental health (TMH), viewing telehealth technologies as inconvenient, or reporting difficulties with medical reimbursement. Provider support for TMH is critical to its diffusion because clinicians often serve as the initial gatekeepers to telehealth implementation and program success. In this article, we address provider concerns in three broad domains: (1) personal barriers, (2) clinical workflow and technology barriers, and (3) licensure, credentialing, and reimbursement barriers. We found evidence that, although many barriers have been discussed in the literature for years, advancements in TMH have rapidly reduced obstacles for its use. Improvements include extensive opportunities for training, a growing evidence base supporting positive TMH outcomes, and transformations in technologies that improve provider convenience and transmission quality. Recommendations for further change are discussed within each domain. In particular, it is important to grow and disseminate data underscoring the promise and effectiveness of TMH, integrate videoconferencing capabilities into electronic medical record platforms, expand TMH reimbursement, and modify licensure standards.

  17. The effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies.

    Directory of Open Access Journals (Sweden)

    Devin Sok

    Full Text Available Broadly neutralizing HIV antibodies (bnAbs are typically highly somatically mutated, raising doubts as to whether they can be elicited by vaccination. We used 454 sequencing and designed a novel phylogenetic method to model lineage evolution of the bnAbs PGT121-134 and found a positive correlation between the level of somatic hypermutation (SHM and the development of neutralization breadth and potency. Strikingly, putative intermediates were characterized that show approximately half the mutation level of PGT121-134 but were still capable of neutralizing roughly 40-80% of PGT121-134 sensitive viruses in a 74-virus panel at median titers between 15- and 3-fold higher than PGT121-134. Such antibodies with lower levels of SHM may be more amenable to elicitation through vaccination while still providing noteworthy coverage. Binding characterization indicated a preference of inferred intermediates for native Env binding over monomeric gp120, suggesting that the PGT121-134 lineage may have been selected for binding to native Env at some point during maturation. Analysis of glycan-dependent neutralization for inferred intermediates identified additional adjacent glycans that comprise the epitope and suggests changes in glycan dependency or recognition over the course of affinity maturation for this lineage. Finally, patterns of neutralization of inferred bnAb intermediates suggest hypotheses as to how SHM may lead to potent and broad HIV neutralization and provide important clues for immunogen design.

  18. Broad-spectrum acquired resistance in barley induced by the Pseudomonas pathosystem shares transcriptional components with Arabidopsis systemic acquired resistance.

    Science.gov (United States)

    Colebrook, E H; Creissen, G; McGrann, G R D; Dreos, R; Lamb, C; Boyd, L A

    2012-05-01

    Inducible resistance responses play a central role in the defense of plants against pathogen attack. Acquired resistance (AR) is induced alongside defense toward primary attack, providing broad-spectrum protection against subsequent pathogen challenge. The localization and molecular basis of AR in cereals is poorly understood, in contrast with the well-characterized systemic acquired resistance (SAR) response in Arabidopsis. Here, we use Pseudomonas syringae as a biological inducer of AR in barley, providing a clear frame of reference to the Arabidopsis-P. syringae pathosystem. Inoculation of barley leaf tissue with the nonadapted P. syringae pv. tomato avrRpm1 (PstavrRpm1) induced an active local defense response. Furthermore, inoculation of barley with PstavrRpm1 resulted in the induction of broad-spectrum AR at a distance from the local lesion, "adjacent" AR, effective against compatible isolates of P. syringae and Magnaporthe oryzae. Global transcriptional profiling of this adjacent AR revealed similarities with the transcriptional profile of SAR in Arabidopsis, as well as transcripts previously associated with chemically induced AR in cereals, suggesting that AR in barley and SAR in Arabidopsis may be mediated by analogous pathways.

  19. Abundance and local range of broad-snouted caiman (Caiman latirostris, Alligatoridae in the northwest of Santa Catarina Island

    Directory of Open Access Journals (Sweden)

    Walfrido Moraes Tomás

    2008-12-01

    Full Text Available This is the first report on the distribution and relative abundance of the broad-snouted caiman on Santa Catarina Island. The study estimated the relative abundance of caiman along the rivers at Estação Ecológica de Carijós, in addition to evaluating the occurrence of this species in the entire area of the Ratones River plain on the northwestern portion of the island. The mean relative abundance obtained by nocturnal counts was 0.25 (±0.07 caiman/km surveyed. There was a weak correlation between the number of caimans and the air temperature. Based on interviews with the local community and nocturnal surveys of caimans in rivers and reservoirs surrounding the protected area, we concluded that the range occupied by caimans covered the entire area of the Ratones river plain, inhabiting natural habitats (rivers, mangroves, swamps as well as artificial habitats (reservoirs and water channels. Although this study provides basic information about the broad-snouted caiman population on this part of the island, it is aimed mainly at providing guidance for future research.

  20. ALP: Alternate Learning Project; Overview of a Model High School in Providence, Rhode Island.

    Science.gov (United States)

    Kenyon, Charles B.

    The Alternate Learning Project (ALP) is a community based public high school in Providence, Rhode Island. The ALP student population participates in a program offering individualized basic skills instruction, college preparatory courses, career exploration activities, and a broad arts curriculum. Throughout, the emphasis is on continuous…

  1. Diagnostics for the structure of AGNs’broad line regions with reverberation mapping data:confirmation of the two-component broad line region model

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    We re-examine the ten Reverberation Mapping(RM) sources with public data based on the two-component model of the Broad Line Region(BLR).In fitting their broad Hβ Mlines,six of them only need one Gaussian component,one of them has a double-peak profile,one has an irregular profile,and only two of them need two components,i.e.,a Very Broad Gaussian Component(VBGC) and an Inter-Mediate Gaussian Component(IMGC).The Gaussian components are assumed to come from two distinct regions in the two-component model;they are the Very Broad Line Region(VBLR) and the Inter-Mediate Line region(IMLR).The two sources with a two-component profile are Mrk 509 and NGC 4051.The time lags of the two components of both sources satisfy tIMLR/tVBLR=V 2VBLR/V 2IMLR,where tIMLR and tVBLR are the lags of the two components while VIMLR and VVBLR represent the mean gas velocities of the two regions,supporting the two-component model of the BLR of Active Galactic Nuclei(AGNs).The fact that most of these ten sources only have the VBGC confirms the assumption that RM mainly measures the radius of the VBLR;consequently,the radius obtained from the R-L relationship mainly represents the radius of VBLR.Moreover,NGC 4051,with a lag of about 5 days in the one component model,is an outlier on the R-L relationship as shown in Kaspi et al.(2005);however this problem disappears in our two-component model with lags of about 2 and 6 days for the VBGC and IMGC,respectively.

  2. Reverberation Modeling of the Broad Emission Line Region in NGC 5548

    Science.gov (United States)

    Bottorff, M. C.; Korista, K. T.; Shlosman, I.; Blandford, R. D.

    Long-term observations of broad-line region (BLR) in the Seyfert~1 galaxy NGC~5548 are analyzed and a critical comparison with the predictions of a hydromagnetically-driven outflow model of Emmering, Blandford and Shlosman is provided. This model is used to generate a time series of C~IV line profiles that have responded to a time varying continuum. We include cloud emission anisotropy, cloud obscuration, a CLOUDY-generated emissivity function and a narrow-line component which is added to the BLR component to generate the total line profiles. The model is driven with continuum input based on the monitoring campaigns of NGC~5548 reported in Clavel et al. and Korista et al., and the line strengths, profiles and lags are compared with the observations. The model is able to reproduce the basic features of CIV line variability in this active galactic nucleus, i.e., time evolution of the profile shape and strength of the C~IV emission line without varying the model parameters. The best fit model provides the effective size, the dominant geometry, the emissivity distribution and the 3D velocity field of the C~IV BLR and constrains the mass of the central black hole to about $3\\times 10^7\\ M_{\\odot}$. The inner part of the wind in NGC~5548 appears to be responsible for the anisotropically emitted CIV line, while its outer part remains dusty and molecular, thus having similar spectral characteristics to a molecular torus, although its dynamics is fundamentally different. The model predicts a differential response across the C~IV line profile, producing a red-side-first response in the relative velocity interval of $3,000-6,000 {\\rm km\\ s^{-1}}$ followed by the blue mid-wing and finally by the line core. Given that no adequate method in computing the errors for data lags and centroids exists in the literature, the {\\it data} cross-correlation function provides results which appear inconclusive, making any direct comparison with the model premature. Overall analysis

  3. Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics.

    Science.gov (United States)

    Hrabě de Angelis, Martin; Nicholson, George; Selloum, Mohammed; White, Jacqueline K; Morgan, Hugh; Ramirez-Solis, Ramiro; Sorg, Tania; Wells, Sara; Fuchs, Helmut; Fray, Martin; Adams, David J; Adams, Niels C; Adler, Thure; Aguilar-Pimentel, Antonio; Ali-Hadji, Dalila; Amann, Gregory; André, Philippe; Atkins, Sarah; Auburtin, Aurelie; Ayadi, Abdel; Becker, Julien; Becker, Lore; Bedu, Elodie; Bekeredjian, Raffi; Birling, Marie-Christine; Blake, Andrew; Bottomley, Joanna; Bowl, Michael R; Brault, Véronique; Busch, Dirk H; Bussell, James N; Calzada-Wack, Julia; Cater, Heather; Champy, Marie-France; Charles, Philippe; Chevalier, Claire; Chiani, Francesco; Codner, Gemma F; Combe, Roy; Cox, Roger; Dalloneau, Emilie; Dierich, André; Di Fenza, Armida; Doe, Brendan; Duchon, Arnaud; Eickelberg, Oliver; Esapa, Chris T; Fertak, Lahcen El; Feigel, Tanja; Emelyanova, Irina; Estabel, Jeanne; Favor, Jack; Flenniken, Ann; Gambadoro, Alessia; Garrett, Lilian; Gates, Hilary; Gerdin, Anna-Karin; Gkoutos, George; Greenaway, Simon; Glasl, Lisa; Goetz, Patrice; Da Cruz, Isabelle Goncalves; Götz, Alexander; Graw, Jochen; Guimond, Alain; Hans, Wolfgang; Hicks, Geoff; Hölter, Sabine M; Höfler, Heinz; Hancock, John M; Hoehndorf, Robert; Hough, Tertius; Houghton, Richard; Hurt, Anja; Ivandic, Boris; Jacobs, Hughes; Jacquot, Sylvie; Jones, Nora; Karp, Natasha A; Katus, Hugo A; Kitchen, Sharon; Klein-Rodewald, Tanja; Klingenspor, Martin; Klopstock, Thomas; Lalanne, Valerie; Leblanc, Sophie; Lengger, Christoph; le Marchand, Elise; Ludwig, Tonia; Lux, Aline; McKerlie, Colin; Maier, Holger; Mandel, Jean-Louis; Marschall, Susan; Mark, Manuel; Melvin, David G; Meziane, Hamid; Micklich, Kateryna; Mittelhauser, Christophe; Monassier, Laurent; Moulaert, David; Muller, Stéphanie; Naton, Beatrix; Neff, Frauke; Nolan, Patrick M; Nutter, Lauryl M J; Ollert, Markus; Pavlovic, Guillaume; Pellegata, Natalia S; Peter, Emilie; Petit-Demoulière, Benoit; Pickard, Amanda; Podrini, Christine; Potter, Paul; Pouilly, Laurent; Puk, Oliver; Richardson, David; Rousseau, Stephane; Quintanilla-Fend, Leticia; Quwailid, Mohamed M; Racz, Ildiko; Rathkolb, Birgit; Riet, Fabrice; Rossant, Janet; Roux, Michel; Rozman, Jan; Ryder, Edward; Salisbury, Jennifer; Santos, Luis; Schäble, Karl-Heinz; Schiller, Evelyn; Schrewe, Anja; Schulz, Holger; Steinkamp, Ralf; Simon, Michelle; Stewart, Michelle; Stöger, Claudia; Stöger, Tobias; Sun, Minxuan; Sunter, David; Teboul, Lydia; Tilly, Isabelle; Tocchini-Valentini, Glauco P; Tost, Monica; Treise, Irina; Vasseur, Laurent; Velot, Emilie; Vogt-Weisenhorn, Daniela; Wagner, Christelle; Walling, Alison; Wattenhofer-Donze, Marie; Weber, Bruno; Wendling, Olivia; Westerberg, Henrik; Willershäuser, Monja; Wolf, Eckhard; Wolter, Anne; Wood, Joe; Wurst, Wolfgang; Yildirim, Ali Önder; Zeh, Ramona; Zimmer, Andreas; Zimprich, Annemarie; Holmes, Chris; Steel, Karen P; Herault, Yann; Gailus-Durner, Valérie; Mallon, Ann-Marie; Brown, Steve D M

    2015-09-01

    The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.

  4. The Moderating Effects of Financial Broad-scope Trust on Consumer Knowledge, Cognitive Effort, and Financial Healthiness

    DEFF Research Database (Denmark)

    Hansen, Torben

    2017-01-01

    Substantial research results suggest the global financial crisis has negatively affected consumers' trust in financial service providers. Notably, trust not only relates to consumer trust in individual companies but also relates to the broader business context in which consumers may plan and carry...... out their financial behavior. This latter form of trust can be referred to as "broad-scope" trust (BST). BST is especially important in a society context because lack of BST may reduce financial market dynamism, competition, and productivity. Consequently, financial service providers assume...... an important social responsibility in order to develop BST. Unfortunately, not much is known about the interplay between BST and consumer financial behavior. Based on two surveys comprising 1155 bank consumers and 756 mutual fund investors, respectively, this study investigates the moderating influence of BST...

  5. Hyperactivity of the Ero1α Oxidase Elicits Endoplasmic Reticulum Stress but No Broad Antioxidant Response

    Science.gov (United States)

    Hansen, Henning Gram; Schmidt, Jonas Damgård; Søltoft, Cecilie Lützen; Ramming, Thomas; Geertz-Hansen, Henrik Marcus; Christensen, Brian; Sørensen, Esben Skipper; Juncker, Agnieszka Sierakowska; Appenzeller-Herzog, Christian; Ellgaard, Lars

    2012-01-01

    Oxidizing equivalents for the process of oxidative protein folding in the endoplasmic reticulum (ER) of mammalian cells are mainly provided by the Ero1α oxidase. The molecular mechanisms that regulate Ero1α activity in order to harness its oxidative power are quite well understood. However, the overall cellular response to oxidative stress generated by Ero1α in the lumen of the mammalian ER is poorly characterized. Here we investigate the effects of overexpressing a hyperactive mutant (C104A/C131A) of Ero1α. We show that Ero1α hyperactivity leads to hyperoxidation of the ER oxidoreductase ERp57 and induces expression of two established unfolded protein response (UPR) targets, BiP (immunoglobulin-binding protein) and HERP (homocysteine-induced ER protein). These effects could be reverted or aggravated by N-acetylcysteine and buthionine sulfoximine, respectively. Because both agents manipulate the cellular glutathione redox buffer, we conclude that the observed effects of Ero1α-C104A/C131A overexpression are likely caused by an oxidative perturbation of the ER glutathione redox buffer. In accordance, we show that Ero1α hyperactivity affects cell viability when cellular glutathione levels are compromised. Using microarray analysis, we demonstrate that the cell reacts to the oxidative challenge caused by Ero1α hyperactivity by turning on the UPR. Moreover, this analysis allowed the identification of two new targets of the mammalian UPR, CRELD1 and c18orf45. Interestingly, a broad antioxidant response was not induced. Our findings suggest that the hyperoxidation generated by Ero1α-C104A/C131A is addressed in the ER lumen and is unlikely to exert oxidative injury throughout the cell. PMID:23027870

  6. Topographic variation in aboveground biomass in a subtropical evergreen broad-leaved forest in China.

    Science.gov (United States)

    Lin, Dunmei; Lai, Jiangshan; Muller-Landau, Helene C; Mi, Xiangcheng; Ma, Keping

    2012-01-01

    The subtropical forest biome occupies about 25% of China, with species diversity only next to tropical forests. Despite the recognized importance of subtropical forest in regional carbon storage and cycling, uncertainties remain regarding the carbon storage of subtropical forests, and few studies have quantified within-site variation of biomass, making it difficult to evaluate the role of these forests in the global and regional carbon cycles. Using data for a 24-ha census plot in east China, we quantify aboveground biomass, characterize its spatial variation among different habitats, and analyse species relative contribution to the total aboveground biomass of different habitats. The average aboveground biomass was 223.0 Mg ha(-1) (bootstrapped 95% confidence intervals [217.6, 228.5]) and varied substantially among four topographically defined habitats, from 180.6 Mg ha(-1) (bootstrapped 95% CI [167.1, 195.0]) in the upper ridge to 245.9 Mg ha(-1) (bootstrapped 95% CI [238.3, 253.8]) in the lower ridge, with upper and lower valley intermediate. In consistent with our expectation, individual species contributed differently to the total aboveground biomass of different habitats, reflecting significant species habitat associations. Different species show differently in habitat preference in terms of biomass contribution. These patterns may be the consequences of ecological strategies difference among different species. Results from this study enhance our ability to evaluate the role of subtropical forests in the regional carbon cycle and provide valuable information to guide the protection and management of subtropical broad-leaved forest for carbon sequestration and carbon storage.

  7. Topographic variation in aboveground biomass in a subtropical evergreen broad-leaved forest in China.

    Directory of Open Access Journals (Sweden)

    Dunmei Lin

    Full Text Available The subtropical forest biome occupies about 25% of China, with species diversity only next to tropical forests. Despite the recognized importance of subtropical forest in regional carbon storage and cycling, uncertainties remain regarding the carbon storage of subtropical forests, and few studies have quantified within-site variation of biomass, making it difficult to evaluate the role of these forests in the global and regional carbon cycles. Using data for a 24-ha census plot in east China, we quantify aboveground biomass, characterize its spatial variation among different habitats, and analyse species relative contribution to the total aboveground biomass of different habitats. The average aboveground biomass was 223.0 Mg ha(-1 (bootstrapped 95% confidence intervals [217.6, 228.5] and varied substantially among four topographically defined habitats, from 180.6 Mg ha(-1 (bootstrapped 95% CI [167.1, 195.0] in the upper ridge to 245.9 Mg ha(-1 (bootstrapped 95% CI [238.3, 253.8] in the lower ridge, with upper and lower valley intermediate. In consistent with our expectation, individual species contributed differently to the total aboveground biomass of different habitats, reflecting significant species habitat associations. Different species show differently in habitat preference in terms of biomass contribution. These patterns may be the consequences of ecological strategies difference among different species. Results from this study enhance our ability to evaluate the role of subtropical forests in the regional carbon cycle and provide valuable information to guide the protection and management of subtropical broad-leaved forest for carbon sequestration and carbon storage.

  8. The Impact of Project-Based Climate Change Learning Experiences on Students' Broad Climate Literacy

    Science.gov (United States)

    DeWaters, J.; Powers, S. E.; Dhaniyala, S.

    2014-12-01

    Evidence-based pedagogical approaches such as project- and inquiry-based techniques have been shown to promote effective learning in science and engineering. The impact of project-based learning experiences on middle school (MS), high school (HS), and undergraduate (UG) students' climate literacy was investigated as part of a NASA Innovations in Climate Education (NICE) project. Project-based modules were developed and taught by MS and HS teachers who participated in climate change education workshops. UG students enrolled in a climate science course completed independent research projects that provided the basis for several of the HS/MS modules. All modules required students to acquire and analyze historical temperature data and future climate predictions, and apply their analysis to the solution of a societal or environmental problem related to our changing climate. Three versions of a quantitative survey were developed and used in a pre-test/post-test research design to help evaluate the project's impact on MS, HS, and UG students' climate literacy, which includes broad climate knowledge as well as affective and behavioral aspects. Content objectives were guided primarily by the 2009 document, Climate Literacy: The Essential Principles of Climate Sciences. All three groups of students made modest but statistically significant cognitive (pteacher and module content varied. The presentation will include a description of some key aspects of the project-based curricula developed and used in this research, the development and content of the climate literacy survey, and the interpretation of specific pre/post changes in participating students relative to the content of and approach used in the project-based modules.

  9. Lessons from the construction of a climate change adaptation plan: A Broads wetland case study.

    Science.gov (United States)

    Turner, R Kerry; Palmieri, Maria Giovanna; Luisetti, Tiziana

    2016-10-01

    The dynamic nature of environmental change in coastal areas means that a flexible "learning by doing" management strategy has a number of advantages. This article lays out the principles of such a strategy and then assesses an actual planning and management process focused on climate change consequences for the Broads wetland on the East coast of England. The management strategy focused on the concept of ecosystem services (stocks and flows) provided by the coastal wetland and the threats and opportunities posed to the area by sea level rise and other climate change impacts. The analysis explores the process by which an adaptive management plan has been formulated and coproduced by a combination of centralized (vertical) and stakeholder social network (horizontal) arrangements. The process values where feasible the ecosystem services under threat and prioritizes response actions. Coastal management needs a careful balance between strategic requirements imposed at a national scale and local schemes that affect regional and/or local communities and social networks. These networks aided by electronic media have allowed groups to engage more rapidly and effectively with policy proposals. However, successful deliberation is conditioned by a range of context specific factors, including the type of social networks present and their relative competitive and/or complementary characteristics. The history of consultation and dialogue between official agencies and stakeholders also plays a part in contemporary deliberation processes and the success of their outcomes. Among the issues highlighted are the multiple dimensions of nature's value; the difficulty of quantifying some ecosystem service changes, especially for cultural services; and the problem of "stakeholder fatigue" complicating engagement arrangements. Integr Environ Assess Manag 2016;12:719-725. © 2016 SETAC.

  10. Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C Infection.

    Science.gov (United States)

    Wagh, Kshitij; Bhattacharya, Tanmoy; Williamson, Carolyn; Robles, Alex; Bayne, Madeleine; Garrity, Jetta; Rist, Michael; Rademeyer, Cecilia; Yoon, Hyejin; Lapedes, Alan; Gao, Hongmei; Greene, Kelli; Louder, Mark K; Kong, Rui; Karim, Salim Abdool; Burton, Dennis R; Barouch, Dan H; Nussenzweig, Michel C; Mascola, John R; Morris, Lynn; Montefiori, David C; Korber, Bette; Seaman, Michael S

    2016-03-01

    The identification of a new generation of potent broadly neutralizing HIV-1 antibodies (bnAbs) has generated substantial interest in their potential use for the prevention and/or treatment of HIV-1 infection. While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit. We assessed the neutralizing activity of 15 bnAbs targeting four distinct epitopes of Env, including the CD4-binding site (CD4bs), the V1/V2-glycan region, the V3-glycan region, and the gp41 membrane proximal external region (MPER), against a panel of 200 acute/early clade C HIV-1 Env pseudoviruses. A mathematical model was developed that predicted neutralization by a subset of experimentally evaluated bnAb combinations with high accuracy. Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations. The most promising bnAb combinations were identified based not only on breadth and potency of neutralization, but also other relevant measures, such as the extent of complete neutralization and instantaneous inhibitory potential (IIP). By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo. These results provide a rationale for advancing bnAb combinations with the best in vitro predictors of success into clinical trials for both the prevention and treatment of HIV-1 infection.

  11. Expression of mouse beta defensin 2 in Escherichia coli and its broad-spectrum antimicrobial activity

    Directory of Open Access Journals (Sweden)

    Tianxiang Gong

    2011-09-01

    Full Text Available Mature mouse beta defensin 2 (mBD2 is a small cationic peptide with antimicrobial activity. Here we established a prokaryotic expression vector containing the cDNA of mature mBD2 fused with thioredoxin (TrxA, pET32a-mBD2. The vector was transformed into Escherichia Coli (E. coli Rosseta-gami (2 for expression fusion protein. Under the optimization of fermentation parameters: induce with 0.6 mM isopropylthiogalactoside (IPTG at 34ºC in 2×YT medium and harvest at 6 h postinduction, fusion protein TrxA-mBD2 was high expressed in the soluble fraction (>95%. After cleaved fusion protein by enterokinase, soluble mature mBD2 was achieved 6 mg/L with a volumetric productivity. Purified recombinant mBD2 demonstrated clear broad-spectrum antimicrobial activity for fungi, bacteria and virus. The MIC of antibacterial activity of against Staphylococcus aureus was 50 µg/ml. The MIC of against Candida albicans (C. albicans and Cryptococcus neoformans (C. neoformans was 12.5µg/ml and 25µg/ml, respectively. Also, the antimicrobial activity of mBD2 was effected by NaCl concentration. Additionally, mBD2 showed antiviral activity against influenza A virus (IAV, the protective rate for Madin-Darby canine kidney cells (MDCK was 93.86% at the mBD2 concentration of 100 µg/ml. These works might provide a foundation for the following research on the mBD2 as therapeutic agent for medical microbes.

  12. Development of a Memory Game to Improve Knowledge Retention in Preparation for Broad Scope Exams in an Introductory Earth Science Course

    Science.gov (United States)

    Cook, H. M.; Bilsley, N. A.

    2015-12-01

    As the demand for introductory earth science classes rises at educational institutions, large class sizes place strain on the educator's time and ability to offer extensive project-based assignments. As a result, exams covering a broad spectrum of material are more heavily weighted in students' grades. Students often struggle on the first exam, as they attempt to retain a large amount of information from several different topics, while having no exposure to the type of questions that will be asked. This frequently leads to a large dropout rate early in the academic term, or at least a sense of discouragement and stress among struggling students. To better prepare students for a broad scope exam, a review activity modelled after the traditional Milton Bradley "Memory" game was developed to remind students of what would be covered on the exam, prepare them for the style of questions that may be asked, as well as provide a fun, interactive, and educational activity. The Earth Science Memory Game was developed to have interchangeable sets to cover a broad range of topics and thus also be reusable for the duration of the course. Example games sets presented include, but are not limited to, the scientific method, minerals, rocks, topographic maps, tectonics, geologic structures, volcanoes, and weather. The Earth Science Memory Game not only provides an effective review tool to improve success rates on broad scope exams, but is also customizable by the instructor, reusable, and easily constructed by common office supplies.

  13. Insure Kids Now (IKN) (Dental Care Providers)

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Insure Kids Now (IKN) Dental Care Providers in Your State locator provides profile information for oral health providers participating in Medicaid and Children's...

  14. Targeting N-Glycan Cryptic Sugar Moieties for Broad-Spectrum Virus Neutralization: Progress in Identifying Conserved Molecular Targets in Viruses of Distinct Phylogenetic Origins

    Directory of Open Access Journals (Sweden)

    Denong Wang

    2015-03-01

    Full Text Available Identifying molecular targets for eliciting broadly virus-neutralizing antibodies is one of the key steps toward development of vaccines against emerging viral pathogens. Owing to genomic and somatic diversities among viral species, identifying protein targets for broad-spectrum virus neutralization is highly challenging even for the same virus, such as HIV-1. However, viruses rely on host glycosylation machineries to synthesize and express glycans and, thereby, may display common carbohydrate moieties. Thus, exploring glycan-binding profiles of broad-spectrum virus-neutralizing agents may provide key information to uncover the carbohydrate-based virus-neutralizing epitopes. In this study, we characterized two broadly HIV-neutralizing agents, human monoclonal antibody 2G12 and Galanthus nivalis lectin (GNA, for their viral targeting activities. Although these agents were known to be specific for oligomannosyl antigens, they differ strikingly in virus-binding activities. The former is HIV-1 specific; the latter is broadly reactive and is able to neutralize viruses of distinct phylogenetic origins, such as HIV-1, severe acute respiratory syndrome coronavirus (SARS-CoV, and human cytomegalovirus (HCMV. In carbohydrate microarray analyses, we explored the molecular basis underlying the striking differences in the spectrum of anti-virus activities of the two probes. Unlike 2G12, which is strictly specific for the high-density Man9GlcNAc2Asn (Man9-clusters, GNA recognizes a number of N-glycan cryptic sugar moieties. These include not only the known oligomannosyl antigens but also previously unrecognized tri-antennary or multi-valent GlcNAc-terminating N-glycan epitopes (Tri/m-Gn. These findings highlight the potential of N-glycan cryptic sugar moieties as conserved targets for broad-spectrum virus neutralization and suggest the GNA-model of glycan-binding warrants focused investigation.

  15. Broad Line Region Physical Conditions along the Quasar Eigenvector 1 Sequence

    CERN Document Server

    Marziani, P; Negrete, C A; Dultzin, D; Zamfir, S; Bachev, R

    2010-01-01

    [Abridged] We compare broad emission line profiles and estimate line ratios for all major emission lines between Ly-alpha and H-beta in a sample of six quasars. The sources were chosen with two criteria in mind: the existence of high quality optical and UV spectra as well as the possibility to sample the spectroscopic diversity in the 4D Eigenvector 1 context . In the latter sense each source occupies a region (bin) in the FWHM(H-beta) vs. optical FeII strength plane that is significantly different from the others. High S/N H-beta emission line profiles are used as templates for modeling the other lines (Ly-alpha, CIV 1549, HeII 1640, Al III 1860, Si III] 1892, and Mg II 2800). We can adequately model all broad lines assuming the existence of three components distinguished by blueshifted, unshifted and redshifted centroids (indicated as blue, broad and very broad component respectively). The broad component (high electron density, low ionization parameter; high column density) is present in almost all type-1 ...

  16. The Fundamental Plane of the Broad-line Region in Active Galactic Nuclei

    CERN Document Server

    Du, Pu; Hu, Chen; Ho, Luis C; Li, Yan-Rong; Bai, Jin-Ming

    2016-01-01

    Broad emission lines in active galactic nuclei (AGNs) mainly arise from gas photoionized by continuum radiation from an accretion disk around a central black hole. The shape of the broad-line profile, described by ${\\cal D}_{_{\\rm H\\beta}}={\\rm FWHM}/\\sigma_{_{\\rm H\\beta}}$, the ratio of full width at half maximum to the dispersion of broad H$\\beta$, reflects the dynamics of the broad-line region (BLR) and correlates with the dimensionless accretion rate ($\\dot{\\mathscr{M}}$) or Eddington ratio ($L_{\\rm bol}/L_{\\rm Edd}$). At the same time, $\\dot{\\mathscr{M}}$ and $L_{\\rm bol}/L_{\\rm Edd}$ correlate with ${\\cal R}_{\\rm Fe}$, the ratio of optical Fe II to H$\\beta$ line flux emission. Assembling all AGNs with reverberation mapping measurements of broad H$\\beta$, both from the literature and from new observations reported here, we find a strong bivariate correlation of the form $\\log(\\dot{\\mathscr{M}},L_{\\rm bol}/L_{\\rm Edd})=\\alpha+\\beta{\\cal D}_{_{\\rm H\\beta}}+\\gamma{\\cal R}_{\\rm Fe},$ where $\\alpha=(2.47,0.31...

  17. Constraints on the outer radius of the broad emission line region of active galactic nuclei

    CERN Document Server

    Landt, Hermine; Elvis, Martin; Karovska, Margarita

    2014-01-01

    Here we present observational evidence that the broad emission line region (BELR) of active galactic nuclei (AGN) generally has an outer boundary. This was already clear for sources with an obvious transition between the broad and narrow components of their emission lines. We show that the narrow component of the higher-order Paschen lines is absent in all sources, revealing a broad emission line profile with a broad, flat top. This indicates that the BELR is kinematically separate from the narrow emission line region. We use the virial theorem to estimate the BELR outer radius from the flat top width of the unblended profiles of the strongest Paschen lines, Pa alpha and Pa beta, and find that it scales with the ionising continuum luminosity roughly as expected from photoionisation theory. The value of the incident continuum photon flux resulting from this relationship corresponds to that required for dust sublimation. A flat-topped broad emission line profile is produced by both a spherical gas distribution ...

  18. Estimating carbon dioxide fluxes from temperate mountain grasslands using broad-band vegetation indices

    Directory of Open Access Journals (Sweden)

    G. Wohlfahrt

    2010-02-01

    Full Text Available The broad-band normalised difference vegetation index (NDVI and the simple ratio (SR were calculated from measurements of reflectance of photosynthetically active and short-wave radiation at two temperate mountain grasslands in Austria and related to the net ecosystem CO2 exchange (NEE measured concurrently by means of the eddy covariance method. There was no significant statistical difference between the relationships of midday mean NEE with narrow- and broad-band NDVI and SR, measured during and calculated for that same time window, respectively. The skill of broad-band NDVI and SR in predicting CO2 fluxes was higher for metrics dominated by gross photosynthesis and lowest for ecosystem respiration, with NEE in between. A method based on a simple light response model whose parameters were parameterised based on broad-band NDVI allowed to improve predictions of daily NEE and is suggested to hold promise for filling gaps in the NEE time series. Relationships of CO2 flux metrics with broad-band NDVI and SR however generally differed between the two studied grassland sites indicting an influence of additional factors not yet accounted for.

  19. Nesting ecology and behavior of Broad-winged Hawks in moist karst forests of Puerto Rico

    Science.gov (United States)

    Hengstenberg, D.W.; Vilella, F.J.

    2005-01-01

    The Puerto Rican Broad-winged Hawk (Buteo platypterus brunnescens) is an endemic and endangered subspecies inhabiting upland montane forests of Puerto Rico. The reproductive ecology, behavior, and nesting habitat of the Broad-winged Hawk were studied in Ri??o Abajo Forest, Puerto Rico, from 2001-02. We observed 158 courtship displays by Broad-winged Hawks. Also, we recorded 25 territorial interactions between resident Broad-winged Hawks and intruding Red-tailed Hawks (Buteo jamaicensis jamaicensis). Broad-winged Hawks displaced intruding Red-tailed Hawks from occupied territories (P = 0.009). Mayfield nest survival was 0.67 across breeding seasons (0.81 in 2001, N = 6; 0.51 in 2002, N = 4), and pairs averaged 1.1 young per nest (years combined). The birds nested in mixed species timber plantations and mature secondary forest. Nests were placed in the upper reaches of large trees emerging from the canopy. Nest tree DBH, understory stem density, and distance to karst cliff wall correctly classified (77.8%) nest sites. ?? 2005 The Raptor Research Foundation, Inc.

  20. Signature biochemical properties of broadly cross-reactive HIV-1 neutralizing antibodies in human plasma.

    Science.gov (United States)

    Sajadi, Mohammad M; Lewis, George K; Seaman, Michael S; Guan, Yongjun; Redfield, Robert R; DeVico, Anthony L

    2012-05-01

    The common properties of broadly cross-reactive HIV-1 neutralization antibodies found in certain HIV-1-infected individuals holds significant value for understanding natural and vaccine-mediated anti-HIV immunity. Recent efforts have addressed this question by deriving neutralizing monoclonal anti-envelope antibodies from memory B cell pools of selected subjects. However, it has been more difficult to identify whether broadly neutralizing antibodies circulating in plasma possess shared characteristics among individuals. To address this question, we used affinity chromatography and isoelectric focusing to fractionate plasma immunoglobulin from 10 HIV-1-infected subjects (5 subjects with broad HIV-1 neutralizing activity and 5 controls). We find that plasma neutralizing activity typically partitions into at least two subsets of antibodies. Antibodies with restricted neutralization breadth have relatively neutral isoelectric points and preferentially bind to envelope monomers and trimers versus core antigens from which variable loops and other domains have been deleted. In comparison, broadly neutralizing antibodies account for a minor fraction of the total anti-envelope response. They are consistently distinguished by more basic isoelectric points and specificity for epitopes shared by monomeric gp120, gp120 core, or CD4-induced structures. Such biochemical properties might be exploited to reliably predict or produce broad anti-HIV immunity.