Science.gov

Sample records for arenaviruses provide broad

  1. Arenaviruses,

    DTIC Science & Technology

    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.

    PubMed

    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].

    PubMed

    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

    PubMed Central

    Urata, Shuzo; de la Torre, Juan Carlos

    2011-01-01

    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. PMID:22312335

  5. Pathogenesis of arenavirus hemorrhagic fevers.

    PubMed

    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

    PubMed Central

    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. PMID:27076139

  7. Reverse Genetics Approaches to Control Arenavirus.

    PubMed

    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.

  8. Development of Recombinant Arenavirus-Based Vaccines.

    PubMed

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

    2017-01-01

    The development of arenavirus reverse genetics has provided 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. These advances in arenavirus genetics have also facilitated screens to identify anti-arenaviral drugs and the pursuit of novel strategies to generate live-attenuated arenavirus vaccine candidates. Moreover, the generation of tri-segmented (r3) arenaviruses expressing foreign genes of interest (GOI) has opened the possibility of implementing live-attenuated arenaviruses-based vaccine vector approaches. In this chapter, we will summarize the implementation of plasmid-based reverse genetics techniques for the development of r3 arenaviruses expressing foreign GOI for their implementation as vaccine vectors.

  9. Novel Arenavirus, Zambia

    PubMed Central

    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. PMID:22000372

  10. Novel arenavirus, Zambia.

    PubMed

    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.

  11. Reporter-Expressing, Replicating-Competent Recombinant Arenaviruses

    PubMed Central

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

    2016-01-01

    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. PMID:27447662

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

    PubMed

    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.

  13. Arenavirus Reverse Genetics: New Approaches for the Investigation of Arenavirus Biology and Development of Antiviral Strategies

    PubMed Central

    Emonet, Sebastien E.; Urata, Shuzo; de la Torre, Juan C.

    2011-01-01

    Several arenaviruses, chiefly Lassa virus, cause hemorrhagic fever disease in humans and pose a significant public health problem 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 development of novel antiviral strategies to combat pathogenic arenaviruses would be facilitated by a detailed understanding of the arenavirus molecular and cell biology. To this end, the development of reverse genetics systems for several arenaviruses has provided investigators with novel and powerful approaches to dissect the functions of arenavirus proteins and their interactions with host factors required to complete each of the steps of the virus life cycle, as well as to cause disease. PMID:21324503

  14. Arenavirus genetic diversity and its biological implications.

    PubMed

    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.

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

    PubMed

    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.

  16. Envelope glycoprotein of arenaviruses.

    PubMed

    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.

  17. Arenavirus Quasispecies and Their Biological Implications.

    PubMed

    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

  18. Enhanced Methanol Production in Plants Provides Broad Spectrum Insect Resistance

    PubMed Central

    Dixit, Sameer; Upadhyay, Santosh Kumar; Singh, Harpal; Sidhu, Om Prakash; Verma, Praveen Chandra; K, Chandrashekar

    2013-01-01

    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. PMID:24223989

  19. A systems biology starter kit for arenaviruses.

    PubMed

    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.

    PubMed

    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. Synthetic Peptide Vaccines for the Control of Arenavirus Infections.

    DTIC Science & Technology

    1983-09-01

    as a model system for work on other arenaviruses (Machupo, Junin, Lassa ). The experimental approach involves transcribing arenavirus RNA segments into...the technology developed here, on LCMV and using RNA from Machupo, Junin and Lassa Fever viruses provided by inves- tigators at Fort Detrick, we will be...able to develop similar reagents for the control of Machupo, Junin and Lassa Fever virus infections. Specific peptide vaccines developed from these

  2. Zoonotic aspects of arenavirus infections.

    PubMed

    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.

  3. Inhibition of Arenavirus by A3, a Pyrimidine Biosynthesis Inhibitor

    PubMed Central

    Ortiz-Riaño, Emilio; Ngo, Nhi; Devito, Stefanie; Eggink, Dirk; Munger, Joshua; Shaw, Megan L.

    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. PMID:24198417

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

    PubMed

    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.

  5. Arenaviruses. Genes, proteins, and expression

    SciTech Connect

    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.

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

    PubMed

    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

  7. Highly Pathogenic New World and Old World Human Arenaviruses Induce Distinct Interferon Responses in Human Cells

    PubMed Central

    Huang, Cheng; Kolokoltsova, Olga A.; Yun, Nadezhda E.; Seregin, Alexey V.; Ronca, Shannon; Koma, Takaaki

    2015-01-01

    cytokines in severe and fatal cases. Arenaviruses initially target macrophages and dendritic cells, which are potent IFN/cytokine-producers. In human macrophages, JUNV reportedly does not trigger IFN responses. We here demonstrated that JUNV activated IFN responses in human dendritic cells. MACV, another highly pathogenic NW arenavirus, also activated IFN responses. LASV did not induce detectable IFN responses, in spite of higher replication levels, and blocked the MACV-triggered IFN response in a coinfection assay. Although these viruses are highly pathogenic to humans, our study highlights distinct innate immune responses to infections with the NW arenaviruses JUNV and MACV and to infection with the OW arenavirus LASV and provides important insights into the virus-host interaction and pathogenesis. PMID:25926656

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

    PubMed

    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.

  9. A Multivalent and Cross-Protective Vaccine Strategy against Arenaviruses Associated with Human Disease

    PubMed Central

    Kotturi, Maya F.; Botten, Jason; Sidney, John; Bui, Huynh-Hoa; Giancola, Lori; Maybeno, Matt; Babin, Josie; Oseroff, Carla; Pasquetto, Valerie; Greenbaum, Jason A.; Peters, Bjoern; Ting, Joey; Do, Danh; Vang, Lo; Alexander, Jeff; Grey, Howard; Buchmeier, Michael J.; Sette, Alessandro

    2009-01-01

    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. PMID:20019801

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

    PubMed

    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.

  11. Reverse genetics approaches to combat pathogenic arenaviruses

    PubMed Central

    de la Torre, Juan C.

    2008-01-01

    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. PMID:18782590

  12. Reverse genetics approaches to combat pathogenic arenaviruses.

    PubMed

    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.

  13. Demographic Differences in Willingness to Provide Broad and Narrow Consent for Biobank Research

    PubMed Central

    Erby, Lori A.H.; Bollinger, Juli; Tetteyfio, Eva; Ricks-Santi, Luisel J.; Kaufman, David

    2015-01-01

    Purpose: This study examined acceptability of two biobank consent models and evaluated the impact of beliefs about privacy and genetic safeguards on acceptance. Methods: U.S. adults surveyed online in English and Spanish were randomly assigned to one of two scenarios examining acceptance of broad consent (n=1528), or narrow consent (n=1533). Results: Overall, willingness to provide broad (76%) and narrow (74%) consents were similar. African Americans were as likely as white non-Hispanics to accept narrow consent (72% vs. 77%, p=0.35) but significantly less likely to accept broad consent (69% vs. 81%, p=0.004). Education, insurance, and blood donation history were also related to acceptance. Adjusting for beliefs about privacy and policy protections (Genetic Information Nondiscrimination Act, GINA), the effects of the variables were reduced. Respondents who drew comfort from GINA were more likely to support both consent (both p<0.001); those who believed it is impossible to maintain privacy were less likely to find both broad (p=0.04) and narrow models acceptable (p=0.02). Conclusions: Choice of consent model matters when engaging diverse populations in biobank research. Beliefs underlying concerns about privacy and genetic protections should be considered when constructing biobank protocols. PMID:25825819

  14. Cell entry by human pathogenic arenaviruses.

    PubMed

    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.

  15. The role of the vascular endothelium in arenavirus haemorrhagic fevers.

    PubMed

    Kunz, Stefan

    2009-12-01

    Viral haemorrhagic fevers (VHF) caused by arenaviruses are among the most devastating emerging human diseases. The most important pathogen among the arenaviruses is Lassa virus (LASV), the causative agent of Lassa fever that is endemic to West Africa. On the South American continent, the New World arenavirus Junin virus (JUNV), Machupo (MACV), Guanarito (GTOV), and Sabia virus (SABV) have emerged as causative agents of severe VHFs. Clinical and experimental studies on arenavirus VHF have revealed a crucial role of the endothelium in their pathogenesis. However, in contrast to other VHFs, haemorrhages are not a salient feature of Lassa fever and fatal cases do not show overt destruction of vascular tissue. The functional alteration of the vascular endothelium that precede shock and death in fatal Lassa fever may be due to more subtle direct or indirect effects of the virus on endothelial cells. Haemorrhagic disease manifestations and vascular involvement are more pronounced in the VHF caused by the South American haemorrhagic fever viruses. Recent studies on JUNV revealed perturbation of specific endothelial cell function, including expression of cell adhesion molecules, coagulation factors, and vasoactive mediators as a consequence of productive viral infection. These studies provided first possible links to some of the vascular abnormalities observed in patients, however, their relevance in vivo remains to be investigated.

  16. T Cell Responses to Arenavirus Infections.

    DTIC Science & Technology

    1991-11-01

    FIELD GROUP SUB-GROUP T cells; Arenaviruses ; Hemorrhagic fevers, Lassa fever, 06 13 LCMV Lassa fever virus; Synthetic peptides; Vaccine; I Recombinant...virus-specific effector T cells and that some of the T cell determinants they recognize are conserved among O.W. arenaviruses . For example, Jahrling...specific T cells were not represented by these peptides. fl4AM17.817073 (MFBM24) CONCLUSIONS Our knowledge of the immune response to arenaviruses is

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

    PubMed

    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.

  18. Ribavirin can be mutagenic for arenaviruses.

    PubMed

    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.

  19. Arenavirus reverse genetics for vaccine development.

    PubMed

    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.

  20. Development of Live-Attenuated Arenavirus Vaccines Based on Codon Deoptimization

    PubMed Central

    Cheng, Benson Yee Hin; Ortiz-Riaño, Emilio; Nogales, Aitor

    2015-01-01

    ABSTRACT Arenaviruses have a significant impact on public health and pose a credible biodefense threat, but the development of safe and effective arenavirus vaccines has remained elusive, and currently, no Food and Drug Administration (FDA)-licensed arenavirus vaccines are available. Here, we explored the use of a codon deoptimization (CD)-based approach as a novel strategy to develop live-attenuated arenavirus vaccines. We recoded the nucleoprotein (NP) of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) with the least frequently used codons in mammalian cells, which caused lower LCMV NP expression levels in transfected cells that correlated with decreased NP activity in cell-based functional assays. We used reverse-genetics approaches to rescue a battery of recombinant LCMVs (rLCMVs) encoding CD NPs (rLCMV/NPCD) that showed attenuated growth kinetics in vitro. Moreover, experiments using the well-characterized mouse model of LCMV infection revealed that rLCMV/NPCD1 and rLCMV/NPCD2 were highly attenuated in vivo but, upon a single immunization, conferred complete protection against a subsequent lethal challenge with wild-type (WT) recombinant LCMV (rLCMV/WT). Both rLCMV/NPCD1 and rLCMV/NPCD2 were genetically and phenotypically stable during serial passages in FDA vaccine-approved Vero cells. These results provide proof of concept of the safety, efficacy, and stability of a CD-based approach for developing live-attenuated vaccine candidates against human-pathogenic arenaviruses. IMPORTANCE Several arenaviruses cause severe hemorrhagic fever in humans and pose a credible bioterrorism threat. Currently, no FDA-licensed vaccines are available to combat arenavirus infections, while antiarenaviral therapy is limited to the off-label use of ribavirin, which is only partially effective and is associated with side effects. Here, we describe the generation of recombinant versions of the prototypic arenavirus LCMV encoding codon-deoptimized viral

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

    PubMed

    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

  2. Widespread Recombination, Reassortment, and Transmission of Unbalanced Compound Viral Genotypes in Natural Arenavirus Infections

    PubMed Central

    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.

    2015-01-01

    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

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

    PubMed

    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.

  4. Synthetic Peptide Vaccines for the Control of Arenavirus Infections.

    DTIC Science & Technology

    1987-07-31

    identification of antigenic determinants conserved among arenaviruses 5 C. Molecular cloning of LCMV and comparison with other arenaviruses 7 D. In vivo...amino acids of the GP-2 which contains one such conserved 4 antigenic site. 2) Molecular cloning of LCMV and comparison with other arenaviruses. LCMV...C. Molecular cloning of LCMV and comparison with other arenaviruses During the previous year we have completed and extended our nucleotide sequencing

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

    PubMed

    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.

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

    PubMed Central

    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.

    2015-01-01

    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. PMID:26079174

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

    PubMed

    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.

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

    SciTech Connect

    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.

  9. Identification and Mechanism of Action of a Novel Small-Molecule Inhibitor of Arenavirus Multiplication

    PubMed Central

    Ngo, Nhi; Cubitt, Beatrice; Iwasaki, Masaharu

    2015-01-01

    antiarenaviral therapy being limited to the off-label use of ribavirin that is only partially effective. Here we describe a novel recombinant LCMV and its use to develop a cell-based assay suitable for HTS to rapidly identify inhibitors arenavirus multiplication. The concepts and experimental strategies we describe in this work provide the bases for the rapid identification and characterization of novel anti-HFA therapeutics. PMID:26292327

  10. Identification, Characterization, and In Vitro Culture of Highly Divergent Arenaviruses from Boa Constrictors and Annulated Tree Boas: Candidate Etiological Agents for Snake Inclusion Body Disease

    PubMed Central

    Stenglein, Mark D.; Sanders, Chris; Kistler, Amy L.; Ruby, J. Graham; Franco, Jessica Y.; Reavill, Drury R.; Dunker, Freeland; DeRisi, Joseph L.

    2012-01-01

    ABSTRACT Inclusion body disease (IBD) is an infectious fatal disease of snakes typified by behavioral abnormalities, wasting, and secondary infections. At a histopathological level, the disease is identified by the presence of large eosinophilic cytoplasmic inclusions in multiple tissues. To date, no virus or other pathogen has been definitively characterized or associated with the disease. Using a metagenomic approach to search for candidate etiologic agents in snakes with confirmed IBD, we identified and de novo assembled the complete genomic sequences of two viruses related to arenaviruses, and a third arenavirus-like sequence was discovered by screening an additional set of samples. A continuous boa constrictor cell line was established and used to propagate and isolate one of the viruses in culture. Viral nucleoprotein was localized and concentrated within large cytoplasmic inclusions in infected cells in culture and tissues from diseased snakes. In total, viral RNA was detected in 6/8 confirmed IBD cases and 0/18 controls. These viruses have a typical arenavirus genome organization but are highly divergent, belonging to a lineage separate from that of the Old and New World arenaviruses. Furthermore, these viruses encode envelope glycoproteins that are more similar to those of filoviruses than to those of other arenaviruses. These findings implicate these viruses as candidate etiologic agents of IBD. The presence of arenaviruses outside mammals reveals that these viruses infect an unexpectedly broad range of species and represent a new reservoir of potential human pathogens. PMID:22893382

  11. Molecular mechanism of arenavirus assembly and budding.

    PubMed

    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.

  12. Molecular Mechanism of Arenavirus Assembly and Budding

    PubMed Central

    Urata, Shuzo; Yasuda, Jiro

    2012-01-01

    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. PMID:23202453

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

    PubMed

    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.

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

    PubMed

    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.

  15. Synthetic Vaccines for the Control of Arenavirus Infections.

    DTIC Science & Technology

    1991-10-22

    World (Pichinde and Tacaribe) viruses and unifies the model of glycoprotein processing for all of the arenaviruses . Before this demonstration it was...at these structures we sought evidence of conservation among known GP-C sequences for various arenaviruses . Examining the hairpin loop, membrane...have established that we can purify native GP-l molecules from Old and New World arenaviruses by salt stripping and sucrose gradient centrifugation

  16. Sensitivity of Selected Arenaviruses to a Human Interferon.

    DTIC Science & Technology

    1979-02-25

    A97 3 5U~ ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FR-ETC F/6 6/5 I SENSITIVITY OF SELECTED ARENAVIRUSES TO A HUMAN INTERFERON. (U) U FEB 79...TYPEOF REPORT & PERIOD COVERED Sensitivity of Selected Arenaviruses to a Human Interim - Interferon - / - 6. PERFORMING ORG. REPORT NUMBER 7. AUTHOR a...Human interferon, interferon sensitivity, human interferon bioassay, BS-C-l cells, Detroit 532 cells, Arenaviruses , vesicular stomatitis virus. O

  17. Synthetic Peptide Vaccines for the Control of Arenavirus Infections

    DTIC Science & Technology

    1989-08-29

    AESTRACT (Continue on reverse if necessary and identify by block numer) Arenaviruses are endemic on both the African and South American continents and...currently available. we are using genetic cloning ’methods to develop an effective vaccine against arenaviruses . De-,elopmental studies have been carried out...rapid development and evaluation of vaccines iaainst th--e pathogenic arenaviruses Lassa, J~unin, and IMachupo. U.sing techniques of peptide and

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

    PubMed

    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.

  19. T Cell Responses to Arenavirus Infections

    DTIC Science & Technology

    1989-05-10

    Lassa virus causes Lassa fever (2, 3), whereas in Argentina and Bolivia, Junin and Machupo viruses cause Argentinian hemorrhagic fever (reviewed in...Hemorrhagic fever ; Lassa fever ; 06 13 LCMV; Lassa virus ; Synthetic peptide; Immunity; Vaccine; , I Recombinant vaccinia virus 19. ABSTRACT (Continue on...reverse if necessarv and idntifv hv hlnr n,,rnhorl ’Experimental evidence suggests that immunity to the Old World arenavirus ,

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed Central

    Vela, Eric

    2012-01-01

    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. PMID:23170184

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

    PubMed

    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.

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

    PubMed Central

    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. PMID:26266264

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

    PubMed

    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.

  8. Arenavirus Variations Due to Host-Specific Adaptation

    PubMed Central

    Zapata, Juan C.; Salvato, Maria S.

    2013-01-01

    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. PMID:23344562

  9. Arenavirus variations due to host-specific adaptation.

    PubMed

    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.

  10. Mapping the complete glycoproteome of virion-derived HIV-1 gp120 provides insights into broadly neutralizing antibody binding

    PubMed Central

    Panico, Maria; Bouché, Laura; Binet, Daniel; O’Connor, Michael-John; Rahman, Dinah; Pang, Poh-Choo; Canis, Kevin; North, Simon J.; Desrosiers, Ronald C.; Chertova, Elena; Keele, Brandon F.; Bess, Julian W.; Lifson, Jeffrey D.; Haslam, Stuart M.; Dell, Anne; Morris, Howard R.

    2016-01-01

    The surface envelope glycoprotein (SU) of Human immunodeficiency virus type 1 (HIV-1), gp120SU plays an essential role in virus binding to target CD4+ T-cells and is a major vaccine target. Gp120 has remarkably high levels of N-linked glycosylation and there is considerable evidence that this “glycan shield” can help protect the virus from antibody-mediated neutralization. In recent years, however, it has become clear that gp120 glycosylation can also be included in the targets of recognition by some of the most potent broadly neutralizing antibodies. Knowing the site-specific glycosylation of gp120 can facilitate the rational design of glycopeptide antigens for HIV vaccine development. While most prior studies have focused on glycan analysis of recombinant forms of gp120, here we report the first systematic glycosylation site analysis of gp120 derived from virions produced by infected T lymphoid cells and show that a single site is exclusively substituted with complex glycans. These results should help guide the design of vaccine immunogens. PMID:27604319

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

    PubMed

    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.

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

    PubMed Central

    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.

    2015-01-01

    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. PMID:26587982

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed Central

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

    2013-01-01

    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. PMID:23864502

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

    PubMed

    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.

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

    PubMed

    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.

  18. Multifunctional Nature of the Arenavirus RING Finger Protein Z

    PubMed Central

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

    2012-01-01

    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. PMID:23202512

  19. Arenavirus Nucleoproteins Prevent Activation of Nuclear Factor Kappa B

    PubMed Central

    Rodrigo, W. W. Shanaka I.; Ortiz-Riaño, Emilio; Pythoud, Christelle; Kunz, Stefan

    2012-01-01

    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. PMID:22623788

  20. Sodium Hydrogen Exchangers Contribute to Arenavirus Cell Entry

    PubMed Central

    Iwasaki, Masaharu; Ngo, Nhi

    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. PMID:24173224

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

    PubMed

    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.

  2. Sodium hydrogen exchangers contribute to arenavirus cell entry.

    PubMed

    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.

  3. Differential Inhibition of Type I Interferon Induction by Arenavirus Nucleoproteins▿

    PubMed Central

    Martínez-Sobrido, Luis; Giannakas, Panagiotis; Cubitt, Beatrice; García-Sastre, Adolfo; de la Torre, Juan Carlos

    2007-01-01

    We have documented that the nucleoprotein (NP) of the prototypic arenavirus lymphocytic choriomeningitis virus is an antagonist of the type I interferon response. In this study we tested the ability of NPs encoded by representative arenavirus species from both Old World and New World antigenic groups to inhibit production of interferon. We found that, with the exception of Tacaribe virus (TCRV), all NPs tested inhibited activation of beta interferon and interferon regulatory factor 3 (IRF-3)-dependent promoters, as well as the nuclear translocation of IRF-3. Consistent with this observation, TCRV-infected cells also failed to inhibit interferon production. PMID:17804508

  4. Arenavirus evasion of host anti-viral responses.

    PubMed

    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.

  5. Arenavirus chemotherapy—retrospect and prospect

    PubMed Central

    Pfau, C. J.

    1975-01-01

    Two groups of compounds, identifiable by structural similarity, have been found to interfere with the in vitro replication of arenaviruses. All 4 members of the benzimidazole group contain dipolar fused benzene and 5-membered nitrogen-containing rings and share potential chelating ability through the different bidentate structures formed with their side-chains. The biological activity of one of these compounds, metisazone, has been shown to depend on the presence of divalent metals of the first transition series, Cu++ being the most effective. Furthermore, whereas metisazone inactivates cell-free virus, two other members of the group, HBB and 1,2-bis(5-methoxy-1H-benzimidazol-2-yl)-1,2-ethanediol, act intracellularly. The site of action of the fourth member, SKF 30097, is not known. Using murine lymphocytic choriomeningitis infections as an in vivo model, the bisbenzimidazole derivative has been found to increase life-span without interfering with virus replication. Medication with SKF 30097 or metisazone and copper (2+) sulfate did not significantly or reproducibly change the expected day of death of the animals. The amantadine compounds of the second group have unusual symmetric structures with a 10-carbon cage. The parent compound acts intracellularly, while the site of action of an octachloro derivative is not known. Medication with the parent compound, but not the derivative, shortened the interval between LCM infection and death of the mouse. Tissue culture and animal screening of the many available derivatives in these two groups may uncover compounds more efficacious than those already examined. PMID:1085227

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

    PubMed

    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.

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

    PubMed Central

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

    2013-01-01

    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 as well as 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. PMID:24075870

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

    PubMed

    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.

  9. Development of Infectious Clones for Virulent and Avirulent Pichinde Viruses: a Model Virus To Study Arenavirus-Induced Hemorrhagic Fevers ▿ †

    PubMed Central

    Lan, Shuiyun; McLay Schelde, Lisa; Wang, Jialong; Kumar, Naveen; Ly, Hinh; Liang, Yuying

    2009-01-01

    Several arenaviruses can cause hemorrhagic fever diseases (VHFs) in humans, the pathogenic mechanism of which is poorly understood due to their virulent nature and the lack of molecular clones. A safe, convenient, and economical small animal model of arenavirus hemorrhagic fever is based on guinea pigs infected by the arenavirus Pichinde (PICV). PICV does not cause disease in humans, but an adapted strain of PICV (P18) causes a disease in guinea pigs that mimics arenavirus hemorrhagic fever in humans in many aspects, while a low-passaged strain (P2) remains avirulent in infected animals. In order to identify the virulence determinants within the PICV genome, we developed the molecular clones for both the avirulent P2 and virulent P18 viruses. Recombinant viruses were generated by transfecting plasmids that contain the antigenomic L and S RNA segments of PICV under the control of the T7 promoter into BSRT7-5 cells, which constitutively express T7 RNA polymerase. By analyzing viral growth kinetics in vitro and virulence in vivo, we show that the recombinant viruses accurately recapitulate the replication and virulence natures of their respective parental viruses. Both parental and recombinant virulent viruses led to high levels of viremia and titers in different organs of the infected animals, whereas the avirulent viruses were effectively controlled and cleared by the hosts. These novel infectious clones for the PICV provide essential tools to identify the virulence factors that are responsible for the severe VHF-like disease in infected animals. PMID:19386714

  10. Co-circulation of Clade C New World Arenaviruses: New geographic distribution and host species.

    PubMed

    Fernandes, Jorlan; de Oliveira, Renata Carvalho; Guterres, Alexandro; de Carvalho Serra, Fabiana; Bonvicino, Cibele Rodrigues; D'Andrea, Paulo Sergio; Cunha, Rivaldo Venâncio; Levis, Silvana; de Lemos, Elba Regina Sampaio

    2015-07-01

    Clade C, of the New World Arenaviruses, is composed of only the Latino and Oliveros viruses and, besides the geographic range of their rodent reservoirs, the distribution of these viruses has been restricted to Bolivia and Argentina. In this study, the genetic detection and phylogenetic analysis of the complete S segment sequences of sympatric arenaviruses from Brazil revealed a new geographic distribution of clade C arenaviruses, as well as the association of Oliveros virus with a new rodent reservoir.

  11. Computational and Functional Analysis of the Virus-Receptor Interface Reveals Host Range Trade-Offs in New World Arenaviruses

    PubMed Central

    Kerr, Scott A.; Jackson, Eleisha L.; Lungu, Oana I.; Meyer, Austin G.; Demogines, Ann; Ellington, Andrew D.; Georgiou, George

    2015-01-01

    ABSTRACT Animal viruses frequently cause zoonotic disease in humans. As these viruses are highly diverse, evaluating the threat that they pose remains a major challenge, and efficient approaches are needed to rapidly predict virus-host compatibility. Here, we develop a combined computational and experimental approach to assess the compatibility of New World arenaviruses, endemic in rodents, with the host TfR1 entry receptors of different potential new host species. Using signatures of positive selection, we identify a small motif on rodent TfR1 that conveys species specificity to the entry of viruses into cells. However, we show that mutations in this region affect the entry of each arenavirus differently. For example, a human single nucleotide polymorphism (SNP) in this region, L212V, makes human TfR1 a weaker receptor for one arenavirus, Machupo virus, but a stronger receptor for two other arenaviruses, Junin and Sabia viruses. Collectively, these findings set the stage for potential evolutionary trade-offs, where natural selection for resistance to one virus may make humans or rodents susceptible to other arenavirus species. Given the complexity of this host-virus interplay, we propose a computational method to predict these interactions, based on homology modeling and computational docking of the virus-receptor protein-protein interaction. We demonstrate the utility of this model for Machupo virus, for which a suitable cocrystal structural template exists. Our model effectively predicts whether the TfR1 receptors of different species will be functional receptors for Machupo virus entry. Approaches such at this could provide a first step toward computationally predicting the “host jumping” potential of a virus into a new host species. IMPORTANCE We demonstrate how evolutionary trade-offs may exist in the dynamic evolutionary interplay between viruses and their hosts, where natural selection for resistance to one virus could make humans or rodents susceptible

  12. Human and Host Species Transferrin Receptor 1 Use by North American Arenaviruses

    PubMed Central

    Zong, Min; Fofana, Isabel

    2014-01-01

    ABSTRACT At least five New World (NW) arenaviruses cause hemorrhagic fevers in South America. These pathogenic clade B viruses, as well as nonpathogenic arenaviruses of the same clade, use transferrin receptor 1 (TfR1) of their host species to enter cells. Pathogenic viruses are distinguished from closely related nonpathogenic ones by their additional ability to utilize human TfR1 (hTfR1). Here, we investigate the receptor usage of North American arenaviruses, whose entry proteins share greatest similarity with those of the clade B viruses. We show that all six North American arenaviruses investigated utilize host species TfR1 orthologs and present evidence consistent with arenavirus-mediated selection pressure on the TfR1 of the North American arenavirus host species. Notably, one of these viruses, AV96010151, closely related to the prototype Whitewater Arroyo virus (WWAV), entered cells using hTfR1, consistent with a role for a WWAV-like virus in three fatal human infections whose causative agent has not been identified. In addition, modest changes were sufficient to convert hTfR1 into a functional receptor for most of these viruses, suggesting that a minor alteration in virus entry protein may allow these viruses to use hTfR1. Our data establish TfR1 as a cellular receptor for North American arenaviruses, highlight an “arms race” between these viruses and their host species, support the association of North American arenavirus with fatal human infections, and suggest that these viruses have a higher potential to emerge and cause human diseases than has previously been appreciated. IMPORTANCE hTfR1 use is a key determinant for a NW arenavirus to cause hemorrhagic fevers in humans. All known pathogenic NW arenaviruses are transmitted in South America by their host rodents. North American arenaviruses are generally considered nonpathogenic, but some of these viruses have been tentatively implicated in human fatalities. We show that these North American

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

    PubMed

    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.

  14. Antigen and Genome Detection of Arenavirus, Bunyavirus, and Filovirus Infections

    DTIC Science & Technology

    1993-02-01

    The specific aims of this project were to develop detection systems for recognizing and quanitating antigens and genomes of hemorrhagic fever viruses ...and to use these detection systems to investigate the pathogenesis of these viruses in animal models. These were to be accomplished using existing...antibodies and nucleic acid probes supplied by the MRDC as well as virus infected tissues or cell cultures. Pichinde virus , an arenavirus non

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

    PubMed

    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.

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

    PubMed

    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.

  17. Arenavirus Infection Induces Discrete Cytosolic Structures for RNA Replication

    PubMed Central

    Baird, Nicholas L.; York, Joanne

    2012-01-01

    Arenaviruses are responsible for acute hemorrhagic fevers with high mortality and pose significant threats to public health and biodefense. These enveloped negative-sense RNA viruses replicate in the cell cytoplasm and express four proteins. To better understand how these proteins insinuate themselves into cellular processes to orchestrate productive viral replication, we have identified and characterized novel cytosolic structures involved in arenavirus replication and transcription. In cells infected with the nonpathogenic Tacaribe virus or the attenuated Candid#1 strain of Junín virus, we find that newly synthesized viral RNAs localize to cytosolic puncta containing the nucleoprotein (N) of the virus. Density gradient centrifugation studies reveal that these replication-transcription complexes (RTCs) are associated with cellular membranes and contain full-length genomic- and antigenomic-sense RNAs. Viral mRNAs segregate at a higher buoyant density and are likewise scant in immunopurified RTCs, consistent with their translation on bulk cellular ribosomes. In addition, confocal microscopy analysis reveals that RTCs contain the lipid phosphatidylinositol-4-phosphate and proteins involved in cellular mRNA metabolism, including the large and small ribosomal subunit proteins L10a and S6, the stress granule protein G3BP1, and a subset of translation initiation factors. Elucidating the structure and function of RTCs will enhance our understanding of virus-cell interactions that promote arenavirus replication and mitigate against host cell immunity. This knowledge may lead to novel intervention strategies to limit viral virulence and pathogenesis. PMID:22875974

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

    SciTech Connect

    Li, Kun; Lin, Xian-Dan; Wang, Wen; Shi, Mang; Guo, Wen-Ping; Zhang, Xiao-He; Xing, Jian-Guang; 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.

  19. Single-Dose Vaccination of a Recombinant Parainfluenza Virus 5 Expressing NP from H5N1 Virus Provides Broad Immunity against Influenza A Viruses

    PubMed Central

    Li, Zhuo; Gabbard, Jon D.; Mooney, Alaina; Gao, Xiudan; Chen, Zhenhai; Place, Ryan J.; Tompkins, S. Mark

    2013-01-01

    Influenza viruses often evade host immunity via antigenic drift and shift despite previous influenza virus infection and/or vaccination. Vaccines that match circulating virus strains are needed for optimal protection. Development of a universal influenza virus vaccine providing broadly cross-protective immunity will be of great importance. The nucleoprotein (NP) of influenza A virus is highly conserved among all strains of influenza A viruses and has been explored as an antigen for developing a universal influenza virus vaccine. In this work, we generated a recombinant parainfluenza virus 5 (PIV5) containing NP from H5N1 (A/Vietnam/1203/2004), a highly pathogenic avian influenza (HPAI) virus, between HN and L (PIV5-NP-HN/L) and tested its efficacy. PIV5-NP-HN/L induced humoral and T cell responses in mice. A single inoculation of PIV5-NP-HN/L provided complete protection against lethal heterosubtypic H1N1 challenge and 50% protection against lethal H5N1 HPAI virus challenge. To improve efficacy, NP was inserted into different locations within the PIV5 genome. Recombinant PIV5 containing NP between F and SH (PIV5-NP-F/SH) or between SH and HN (PIV5-NP-SH/HN) provided better protection against H5N1 HPAI virus challenge than did PIV5-NP-HN/L. These results suggest that PIV5 expressing NP from H5N1 has the potential to be utilized as a universal influenza virus vaccine. PMID:23514880

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

    PubMed

    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.

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

    PubMed

    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.

  2. Isolation, Identification, and Characterization of Novel Arenaviruses, the Etiological Agents of Boid Inclusion Body Disease

    PubMed Central

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

    2013-01-01

    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. PMID:23926354

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

    PubMed

    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.

  4. Novel Arenavirus Entry Inhibitors Discovered by Using a Minigenome Rescue System for High-Throughput Drug Screening

    PubMed Central

    Rathbun, Jessica Y.; Droniou, Magali E.; Damoiseaux, Robert; Haworth, Kevin G.; Henley, Jill E.; Exline, Colin M.; Choe, Hyeryun

    2015-01-01

    ABSTRACT Certain members of the Arenaviridae family are category A agents capable of causing severe hemorrhagic fevers in humans. Specific antiviral treatments do not exist, and the only commonly used drug, ribavirin, has limited efficacy and can cause severe side effects. The discovery and development of new antivirals are inhibited by the biohazardous nature of the viruses, making them a relatively poorly understood group of human pathogens. We therefore adapted a reverse-genetics minigenome (MG) rescue system based on Junin virus, the causative agent of Argentine hemorrhagic fever, for high-throughput screening (HTS). The MG rescue system recapitulates all stages of the virus life cycle and enables screening of small-molecule libraries under biosafety containment level 2 (BSL2) conditions. The HTS resulted in the identification of four candidate compounds with potent activity against a broad panel of arenaviruses, three of which were completely novel. The target for all 4 compounds was the stage of viral entry, which positions the compounds as potentially important leads for future development. IMPORTANCE The arenavirus family includes several members that are highly pathogenic, causing acute viral hemorrhagic fevers with high mortality rates. No specific effective treatments exist, and although a vaccine is available for Junin virus, the causative agent of Argentine hemorrhagic fever, it is licensed for use only in areas where Argentine hemorrhagic fever is endemic. For these reasons, it is important to identify specific compounds that could be developed as antivirals against these deadly viruses. PMID:26041296

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

    PubMed

    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.

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

    PubMed Central

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

    1994-01-01

    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. Images Figure 6 Figure 7 PMID:8030751

  7. The High Degree of Sequence Plasticity of the Arenavirus Noncoding Intergenic Region (IGR) Enables the Use of a Nonviral Universal Synthetic IGR To Attenuate Arenaviruses

    PubMed Central

    Iwasaki, Masaharu; Cubitt, Beatrice; Sullivan, Brian M.

    2016-01-01

    ABSTRACT Hemorrhagic fever arenaviruses (HFAs) pose important public health problems in regions where they are endemic. Concerns about human-pathogenic arenaviruses are exacerbated because of the lack of FDA-licensed arenavirus vaccines and because current antiarenaviral therapy is limited to an off-label use of ribavirin that is only partially effective. We have recently shown that the noncoding intergenic region (IGR) present in each arenavirus genome segment, the S and L segments (S-IGR and L-IGR, respectively), plays important roles in the control of virus protein expression and that this knowledge could be harnessed for the development of live-attenuated vaccine strains to combat HFAs. In this study, we further investigated the sequence plasticity of the arenavirus IGR. We demonstrate that recombinants of the prototypic arenavirus lymphocytic choriomeningitis virus (rLCMVs), whose S-IGRs were replaced by the S-IGR of Lassa virus (LASV) or an entirely nonviral S-IGR-like sequence (Ssyn), are viable, indicating that the function of S-IGR tolerates a high degree of sequence plasticity. In addition, rLCMVs whose L-IGRs were replaced by Ssyn or S-IGRs of the very distantly related reptarenavirus Golden Gate virus (GGV) were viable and severely attenuated in vivo but able to elicit protective immunity against a lethal challenge with wild-type LCMV. Our findings indicate that replacement of L-IGR by a nonviral Ssyn could serve as a universal molecular determinant of arenavirus attenuation. IMPORTANCE Hemorrhagic fever arenaviruses (HFAs) cause high rates of morbidity and mortality and pose important public health problems in regions where they are endemic. Implementation of live-attenuated vaccines (LAVs) will represent a major step to combat HFAs. Here we document that the arenavirus noncoding intergenic region (IGR) has a high degree of plasticity compatible with virus viability. This observation led us to generate recombinant LCMVs containing nonviral synthetic

  8. Innate and adaptive immune control of genetically engineered live-attenuated arenavirus vaccine prototypes.

    PubMed

    Pinschewer, Daniel D; Flatz, Lukas; Steinborn, Ralf; Horvath, Edit; Fernandez, Marylise; Lutz, Hans; Suter, Mark; Bergthaler, Andreas

    2010-09-01

    Arenaviruses such as Lassa virus (LASV) cause significant morbidity and mortality in endemic areas. Using a glycoprotein (GP) exchange strategy, we have recently developed live-attenuated arenavirus vaccine prototypes (rLCMV/VSVG) based on lymphocytic choriomeningitis virus (LCMV), a close relative of LASV. rLCMV/VSVG induced long-term CD8(+) T cell immunity against wild-type virus challenge and exhibited a stably attenuated phenotype in vivo. Here we elucidated the innate and adaptive immune requirements for the control of rLCMV/VSVG. Infection of RAG(-/-) mice resulted in persisting viral RNA in blood but not in overt viremia. The latter was only found in mice lacking both RAG and IFN type I receptor. Conversely, absence of IFN type II signaling or NK cells on an RAG-deficient background had only minor effects on vaccine virus load or none at all. rLCMV/VSVG infection of wild-type mice induced less type I IFN than did wild-type LCMV, and type I as well as type II IFNs were dispensable for the induction of virus-specific memory CD8 T cells and virus-neutralizing antibodies by rLCMV/VSVG. In conclusion, the adaptive immune systems are essential for elimination of rLCMV/VSVG, and type I but not type II IFN plays a major contributive role in lowering rLCMV/VSVG loads in vivo, attesting to the attenuation profile of the vaccine. Nevertheless, IFNs are not required for the induction of potent vaccine responses. These results provide a better understanding of the immunobiology of rLCMV/VSVG and will contribute to the further development of GP exchange vaccines for combating arenaviral hemorrhagic fevers.

  9. Virion RNA species of the arenaviruses Pichinde, Tacaribe, and Tamiami.

    PubMed Central

    Vezza, A C; Clewley, J P; Gard, G P; Abraham, N Z; Compans, R W; Bishop, D H

    1978-01-01

    The principal RNA species isolated from labeled preparations of the arenavirus Pichinde usually include a large viral RNA species L (apparent molecular weight = 3.2 X 10(6)), and a smaller viral RNA species S (apparent molecular weight = 1.6 X 10(6)). In addition, either little or considerable quantities of 28S rRNA as well as 18S rRNA can also be obtained in virus extracts, depending on the virus stock and growth conditions used to generate virus preparations. Similar RNA species have been identified in RNA extracted from Tacaribe and Tamiami arenavirus preparations. Oligonucleotide fingerprint analyses have confirmed the host ribosomal origin of the 28S and 18S species. Such analyses have also indicated that the Pichinde viral L and S RNA species each contain unique nucleotide sequences. Viral RNA preparations isolated by conventional phenol-sodium dodecyl sulfate extraction often have much of their L and S RNA species in the form of aggregates as visualized by either electron microscopy or oligonucleotide fingerprinting of material recovered from the top of gels (run by using undenatured RNA preparations). Circular and linear RNA forms have also been seen in electron micrographs of undenatured RNA preparations, although denatured viral RNA preparations have yielded mostly linear RNA species with few RNA aggregates or circular forms. Images PMID:660722

  10. Crystal structure of the prefusion surface glycoprotein of the prototypic arenavirus LCMV

    PubMed Central

    Sullivan, Brian M.; Legrand, Pierre; Zandonatti, Michelle A.; Robinson, James E.; Garry, Robert F.; Rey, Félix A.; Oldstone, Michael B.; Saphire, Erica Ollmann

    2016-01-01

    Arenaviruses exist worldwide and can cause hemorrhagic fever and neurologic disease. A single glycoprotein is expressed on the viral surface that mediates entry into target cells. This glycoprotein, termed GPC, contains a membrane-associated signal peptide, a receptor-binding subunit termed GP1 and a fusion-mediating subunit termed GP2. Although GPC is a critical target of antibodies and vaccines, the structure of the metastable GP1-GP2 prefusion complex has remained elusive for all arenaviruses. Here we describe the crystal structure of the fully glycosylated, prefusion GP1-GP2 complex of the prototypic arenavirus LCMV at 3.5Å. This structure reveals the conformational changes that the arenavirus glycoprotein must undergo to cause fusion, and illustrates the fusion regions and potential oligomeric states. PMID:27111888

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

    PubMed Central

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

    PubMed

    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.

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

    PubMed

    Gowen, Brian B; Ennis, Jane; Russell, Andrew; Sefing, Eric J; Wong, Min-Hui; Turner, Jeffrey

    2011-01-01

    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.

  14. The 2010 Broad Prize

    ERIC Educational Resources Information Center

    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…

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

  18. Novel Arenavirus Sequences in Hylomyscus sp. and Mus (Nannomys) setulosus from Côte d'Ivoire: Implications for Evolution of Arenaviruses in Africa

    PubMed Central

    Kouassi, Stéphane K.; Fichet-Calvet, Elisabeth; Becker-Ziaja, Beate; Rieger, Toni; Ölschläger, 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. PMID:21695269

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

    PubMed

    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.

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

    PubMed Central

    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

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

    SciTech Connect

    Abraham, Jonathan; Corbett, Kevin D.; Farzan, Michael; Choe, Hyeryun; Harrison, Stephen C.

    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.

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

    PubMed Central

    Meyer, Bjoern

    2016-01-01

    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. PMID:26865707

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

    PubMed Central

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

    2016-01-01

    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 dcument 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. PMID:27855284

  4. Advax™, a polysaccharide adjuvant derived from delta inulin, provides improved influenza vaccine protection through broad-based enhancement of adaptive immune responses

    PubMed Central

    Honda-Okubo, Yoshikazu; Saade, Fadi; Petrovsky, Nikolai

    2012-01-01

    Advax™ adjuvant is derived from inulin, a natural plant-derived polysaccharide that when crystallized in the delta polymorphic form, becomes immunologically active. This study was performed to assess the ability of Advax™ adjuvant to enhance influenza vaccine immunogenicity and protection. Mice were immunized with influenza vaccine alone or combined with Advax™ adjuvant. Immuno-phenotyping of the anti-influenza response was performed including antibody isotypes, B-cell ELISPOT, CD4 and CD8 T-cell proliferation, influenza-stimulated cytokine secretion, DTH skin tests and challenge with live influenza virus. Advax™ adjuvant increased neutralizing antibody and memory B-cell responses to influenza. It similarly enhanced CD4 and CD8 T-cell proliferation and increased influenza-stimulated IL-2, IFN-γ, IL-5, IL-6, and GM-CSF responses. This translated into enhanced protection against mortality and morbidity in mice. Advax™ adjuvant provided significant antigen dose-sparing compared to influenza antigen alone. Protection could be transferred from mice that had received Advax™-adjuvanted vaccine to naïve mice by immune serum. Enhanced humoral and T-cell responses induced by Advax™-formulated vaccine were sustained 12 months post-immunization. Advax™ adjuvant had low reactogenicity and no adverse events were identified. This suggests Advax™ adjuvant could be a useful influenza vaccine adjuvant. PMID:22728225

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

    PubMed

    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.

  6. Genome Comparison of Virulent and Avirulent Strains of the Arenavirus Pichinde

    PubMed Central

    Lan, Shuiyun; McLay, Lisa; Aronson, Judy; Ly, Hinh; Liang, Yuying

    2008-01-01

    A virulent (P18) strain of the Pichinde arenavirus produces a disease in guinea pigs that somewhat mimics human Lassa fever, whereas an avirulent (P2) strain of this virus is attenuated in infected animals. It has been speculated that the composition of viral genomes may confer the degree of virulence in an infected host; the complete sequence of the viral genomes, however, is not known. Here, we provide for the first time genomic sequences of both S and L segments for both the P2 and P18 strains. Sequence comparisons identify three mutations in the GP1 subunit of the viral glycoprotein, one in the nucleoprotein NP, and five in the viral RNA polymerase L protein. These mutations, alone or in combination, may contribute to the acquired virulence of Pichinde infection in animals. The 3 amino acid changes in the variable region of the GP1 glycoprotein subunit may affect viral entry by altering its receptor-binding activity. While NP has previously been shown to modulate the host immune responses to viral infection, we found that the R374K change in this protein does not affect the NP function in suppressing interferon-β expression. Four out of the five amino acid changes in the L protein occur in a small region of the protein that may contribute to viral virulence by enhancing its function on viral genomic RNA synthesis. PMID:18506572

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

    PubMed

    Bergthaler, Andreas; Gerber, Nicolas U; Merkler, Doron; Horvath, Edit; de la Torre, Juan Carlos; Pinschewer, Daniel D

    2006-06-01

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

    PubMed

    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.

  9. General Molecular Strategy for Development of Arenavirus Live-Attenuated Vaccines

    PubMed Central

    Iwasaki, Masaharu; Ngo, Nhi; Cubitt, Beatrice; Teijaro, John R.

    2015-01-01

    ABSTRACT Hemorrhagic fever arenaviruses (HFA) pose important public health problems in regions where they are endemic. Thus, Lassa virus (LASV) infects several hundred thousand individuals yearly in West Africa, causing a large number of Lassa fever cases associated with high morbidity and mortality. Concerns about human-pathogenic arenaviruses are exacerbated because of the lack of FDA-licensed arenavirus vaccines and because current antiarenaviral therapy is limited to an off-label use of ribavirin that is only partially effective. The Mopeia virus (MOPV)/LASV reassortant (ML29) is a LASV candidate live-attenuated vaccine (LAV) that has shown promising results in animal models. Nevertheless, the mechanism of ML29 attenuation remains unknown, which raises concerns about the phenotypic stability of ML29 in response to additional mutations. Development of LAVs based on well-defined molecular mechanisms of attenuation will represent a major step in combatting HFA. We used the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) to develop a general molecular strategy for arenavirus attenuation. Our approach involved replacement of the noncoding intergenic region (IGR) of the L genome segment with the IGR of the S genome segment to generate a recombinant LCMV, rLCMV(IGR/S-S), that was highly attenuated in vivo but induced protection against a lethal challenge with wild-type LCMV. Attenuation of rLCMV(IGR/S-S) was associated with a stable reorganization of the control of viral gene expression. This strategy can facilitate the rapid development of LAVs with the antigenic composition of the parental HFA and a mechanism of attenuation that minimizes concerns about increased virulence that could be caused by genetic changes in the LAV. IMPORTANCE Hemorrhagic fever arenaviruses (HFA) cause high morbidity and mortality, and pose important public health problems in the regions where they are endemic. Implementation of live-attenuated vaccines (LAV) will represent a

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

    PubMed Central

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

    2013-01-01

    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. PMID:23337384

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

    PubMed

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

    PubMed

    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.

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

    PubMed

    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.

  14. Vaccination Strategies against Highly Pathogenic Arenaviruses: The Next Steps toward Clinical Trials

    PubMed Central

    Ölschläger, 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. PMID:23592977

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed Central

    Shao, Junjie; Liang, Yuying; Ly, Hinh

    2015-01-01

    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. PMID:26011826

  19. Novel Mechanism of Arenavirus-Induced Liver Pathology

    PubMed Central

    Beier, Juliane I.; Jokinen, Jenny D.; Holz, Gretchen E.; Whang, Patrick S.; Martin, Amah M.; Warner, Nikole L.; Arteel, Gavin E.; Lukashevich, Igor S.

    2015-01-01

    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 development of new

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

    PubMed Central

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

    2010-01-01

    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 which

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed Central

    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

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

    PubMed

    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.

  5. Hantavirus and Arenavirus Antibodies in Persons with Occupational Rodent Exposure, North America

    PubMed Central

    Milazzo, Mary Louise; Armstrong, Lori R.; Childs, James E.; Rollin, Pierre E.; Khabbaz, Rima; Peters, C.J.; Ksiazek, Thomas G.

    2007-01-01

    Rodents are the principal hosts of Sin Nombre virus, 4 other hantaviruses known to cause hantavirus pulmonary syndrome in North America, and the 3 North American arenaviruses. Serum samples from 757 persons who had worked with rodents in North America and handled neotomine or sigmodontine rodents were tested for antibodies against Sin Nombre virus, Whitewater Arroyo virus, Guanarito virus, and lymphocytic choriomeningitis virus. Antibodies against Sin Nombre virus were found in 4 persons, against Whitewater Arroyo virus or Guanarito virus in 2 persons, and against lymphocytic choriomeningitis virus in none. These results suggest that risk for infection with hantaviruses or arenaviruses usually is low in persons whose occupations entail close physical contact with neotomine or sigmodontine rodents in North America. PMID:17553266

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

  9. Targeting of Arenavirus RNA Synthesis by a Carboxamide-Derivatized Aromatic Disulfide with Virucidal Activity

    PubMed Central

    Sepúlveda, Claudia S.; García, Cybele C.; Levingston Macleod, Jesica M.

    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. PMID:24278404

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

    PubMed Central

    McLay, Lisa; Liang, Yuying

    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. PMID:24068704

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

    SciTech Connect

    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.

  12. Differential Contributions of Tacaribe Arenavirus Nucleoprotein N-Terminal and C-Terminal Residues to Nucleocapsid Functional Activity

    PubMed Central

    D'Antuono, Alejandra; Loureiro, Maria Eugenia; Foscaldi, Sabrina; Marino-Buslje, Cristina

    2014-01-01

    ABSTRACT The arenavirus nucleoprotein (NP) is the main protein component of viral nucleocapsids and is strictly required for viral genome replication mediated by the L polymerase. Homo-oligomerization of NP is presumed to play an important role in nucleocapsid assembly, albeit the underlying mechanism and the relevance of NP-NP interaction in nucleocapsid activity are still poorly understood. Here, we evaluate the contribution of the New World Tacaribe virus (TCRV) NP self-interaction to nucleocapsid functional activity. We show that alanine substitution of N-terminal residues predicted to be available for NP-NP interaction strongly affected NP self-association, as determined by coimmunoprecipitation assays, produced a drastic inhibition of transcription and replication of a TCRV minigenome RNA, and impaired NP binding to RNA. Mutagenesis and functional analysis also revealed that, while dispensable for NP self-interaction, key amino acids at the C-terminal domain were essential for RNA synthesis. Furthermore, mutations at these C-terminal residues rendered NP unable to bind RNA both in vivo and in vitro but had no effect on the interaction with the L polymerase. In addition, while all oligomerization-defective variants tested exhibited unaltered capacities to sustain NP-L interaction, NP deletion mutants were fully incompetent to bind L, suggesting that, whereas NP self-association is dispensable, the integrity of both the N-terminal and C-terminal domains is required for binding the L polymerase. Overall, our results suggest that NP self-interaction mediated by the N-terminal domain may play a critical role in TCRV nucleocapsid assembly and activity and that the C-terminal domain of NP is implicated in RNA binding. IMPORTANCE The mechanism of arenavirus functional nucleocapsid assembly is still poorly understood. No detailed information is available on the nucleocapsid structure, and the regions of full-length NP involved in binding to viral RNA remain to be

  13. A Molecular Sensor To Characterize Arenavirus Envelope Glycoprotein Cleavage by Subtilisin Kexin Isozyme 1/Site 1 Protease

    PubMed Central

    Oppliger, Joel; da Palma, Joel Ramos; Burri, Dominique J.; Khatib, Abdel-Majid; Spiropoulou, Christina F.

    2015-01-01

    ABSTRACT Arenaviruses are emerging viruses including several causative agents of severe hemorrhagic fevers in humans. The advent of next-generation sequencing technology has greatly accelerated the discovery of novel arenavirus species. However, for many of these viruses, only genetic information is available, and their zoonotic disease potential remains unknown. During the arenavirus life cycle, processing of the viral envelope glycoprotein precursor (GPC) by the cellular subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P) is crucial for productive infection. The ability of newly emerging arenaviruses to hijack human SKI-1/S1P appears, therefore, to be a requirement for efficient zoonotic transmission and human disease potential. Here we implement a newly developed cell-based molecular sensor for SKI-1/S1P to characterize the processing of arenavirus GPC-derived target sequences by human SKI-1/S1P in a quantitative manner. We show that only nine amino acids flanking the putative cleavage site are necessary and sufficient to accurately recapitulate the efficiency and subcellular location of arenavirus GPC processing. In a proof of concept, our sensor correctly predicts efficient processing of the GPC of the newly emergent pathogenic Lujo virus by human SKI-1/S1P and defines the exact cleavage site. Lastly, we employed our sensor to show efficient GPC processing of a panel of pathogenic and nonpathogenic New World arenaviruses, suggesting that GPC cleavage represents no barrier for zoonotic transmission of these pathogens. Our SKI-1/S1P sensor thus represents a rapid and robust test system for assessment of the processing of putative cleavage sites derived from the GPCs of newly discovered arenavirus by the SKI-1/S1P of humans or any other species, based solely on sequence information. IMPORTANCE Arenaviruses are important emerging human pathogens that can cause severe hemorrhagic fevers with high mortality in humans. A crucial step in productive arenavirus

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

    PubMed

    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.

  15. [Neutralization test for lymphocytic choriomeningitis virus for distinguishing between two arenavirus infections in Argentina].

    PubMed

    Ambrosio, A M; Riera, L; Saavedra, M C; Sottosanti, J J

    2001-01-01

    The active coexistence of two pathogenic arenaviruses, Junin (JUNV) and lymphocytic choriomeningitis (LCMV), in the same region of Argentina, has been known since the early 70's, and records of clinical and subclinical human infections by one and/or the other agent have been continuously produced for the last 25 years. Anti-LCMV antibody is currently searched only by indirect immunofluorescence, a test that shows cross reactions among a number of arenaviruses yielding, in the cases of LCMV and JUNV consecutive infections, a concomitant seroconversion for both viruses, as an inconclusive diagnostic result. In contrast, neutralization (NT) tests reveal arenavirus antibodies directed to unique epitopes on these virus envelopes, thus allowing to disclose the sequence in the cases of consecutive infections. In this paper, the characteristics of neutralization (NT) test for LCMV in cell cultures are described, as well as its performance in the field diagnosis of LCMV human infections. The native LCMV strain Cba An 13065 was inoculated on L-929 cell (ATCC CCL 1), and procedures were followed to perform a constant virus-variable serum NT test. Final points of sera titrations were expressed as the maximal serum dilution that yielded 75% of pfu inhibition. This NT test was assayed on paired serum samples of 36 patients with confirmed Argentine hemorrhagic fever (AHF) (a disease caused by JUNV), who had had a known previous contact with LCMV through IFI. The use of this one test led to confusing diagnosis of the disease due to concomitant seroconversion for JUNV and LCMV. By using NT test, it was shown that: some of them were possibly not infected by LCMV, and that 30/36 cases (83.3%) had a pre-existing level of LCMV antibody, with titers in the range of 5 to 640, remaining unchanged 60 days after the clinical AHF. This shows that NT antibodies to LCMV are not influenced by the outcome of the immune response to JUNV, thus confirming the efficiency of NT test as identificator

  16. Effective Oral Favipiravir (T-705) Therapy Initiated after the Onset of Clinical Disease in a Model of Arenavirus Hemorrhagic Fever

    PubMed Central

    Mendenhall, Michelle; Russell, Andrew; Smee, Donald F.; Hall, Jeffery O.; Skirpstunas, Ramona; Furuta, Yousuke; Gowen, Brian B.

    2011-01-01

    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 LD50 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 same species based

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

    PubMed

    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.

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

    PubMed Central

    Leski, Tomasz A.; Lin, Baochuan; Malanoski, Anthony P.; Wang, Zheng; Long, Nina C.; Meador, Carolyn E.; Barrows, Brian; Ibrahim, Sofi; Hardick, Justin P.; Aitichou, Mohamed; Schnur, Joel M.; Tibbetts, Clark; Stenger, David A.

    2009-01-01

    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 104 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 available from

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

    PubMed

    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.

  20. Isolation of Tacaribe Virus, a Caribbean Arenavirus, from Host-Seeking Amblyomma americanum Ticks in Florida

    PubMed Central

    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. PMID:25536075

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

    PubMed

    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.

  2. Receptor binding and cell entry of Old World arenaviruses reveal novel aspects of virus-host interaction.

    PubMed

    Kunz, Stefan

    2009-05-10

    Ten years ago, the first cellular receptor for the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) and the highly pathogenic Lassa virus (LASV) was identified as alpha-dystroglycan (alpha-DG), a versatile receptor for proteins of the extracellular matrix (ECM). Biochemical analysis of the interaction of alpha-DG with arenaviruses and ECM proteins revealed a strikingly similar mechanism of receptor recognition that critically depends on specific sugar modification on alpha-DG involving a novel class of putative glycosyltransferase, the LARGE proteins. Interestingly, recent genome-wide detection and characterization of positive selection in human populations revealed evidence for positive selection of a locus within the LARGE gene in populations from Western Africa, where LASV is endemic. While most enveloped viruses that enter the host cell in a pH-dependent manner use clathrin-mediated endocytosis, recent studies revealed that the Old World arenaviruses LCMV and LASV enter the host cell predominantly via a novel and unusual endocytotic pathway independent of clathrin, caveolin, dynamin, and actin. Upon internalization, the virus is rapidly delivered to endosomes via an unusual route of vesicular trafficking that is largely independent of the small GTPases Rab5 and Rab7. Since infection of cells with LCMV and LASV depends on DG, this unusual endocytotic pathway could be related to normal cellular trafficking of the DG complex. Alternatively, engagement of arenavirus particles may target DG for an endocytotic pathway not normally used in uninfected cells thereby inducing an entry route specifically tailored to the pathogen's needs.

  3. Mucosal arenavirus infection of primates can protect them from lethal hemorrhagic fever.

    PubMed

    Rodas, Juan D; Lukashevich, Igor S; Zapata, Juan C; Cairo, Cristiana; Tikhonov, Ilia; Djavani, Mahmoud; Pauza, C David; Salvato, Maria S

    2004-03-01

    Arenaviruses are transmitted from rodents to human beings by blood or mucosal exposure. The most devastating arenavirus in terms of human disease is Lassa fever virus, causing up to 300,000 annual infections in West Africa. We used a model for Lassa fever in which Rhesus macaques were infected with a related virus, lymphocytic choriomeningitis virus (LCMV). Our goals were to determine the outcome of infection after mucosal inoculation and later lethal challenge, to characterize protective immune responses, and to test cross-protection between a virulent (LCMV-WE) and an avirulent (LCMV-ARM) strain of virus. Although intravenous infections in the monkey model were uniformly lethal, intragastric infections recapitulated the spectrum of clinical outcomes seen in human exposure to Lassa fever virus: death, recovery from disease, and most often, subclinical infection. Plaque neutralization, ELISA, lymphocyte proliferation, and chromium-release assays were used to monitor humoral and cellular immune responses. Cross protection between the two strains was observed. The three out of seven monkeys that experienced protection were also the three with the strongest cell-mediated immunity.

  4. Identification of Virulence Determinants within the L Genomic Segment of the Pichinde Arenavirus

    PubMed Central

    McLay, Lisa; Lan, Shuiyun; Ansari, Aftab

    2013-01-01

    Several arenaviruses are responsible for causing viral hemorrhagic fevers (VHF) in humans. Lassa virus (LASV), the causative agent of Lassa fever, is a biosafety level 4 (BSL4) pathogen that requires handling in BSL4 facilities. In contrast, the Pichinde arenavirus (PICV) is a BSL2 pathogen that can cause hemorrhagic fever-like symptoms in guinea pigs that resemble those observed in human Lassa fever. Comparative sequence analysis of the avirulent P2 strain of PICV and the virulent P18 strain shows a high degree of sequence homology in the bisegmented genome between the two strains despite the polarized clinical outcomes noted for the infected animals. Using reverse genetics systems that we have recently developed, we have mapped the sequence changes in the large (L) segment of the PICV genome that are responsible for the heightened virulence phenotype of the P18 strain. By monitoring the degree of disease severity and lethality caused by the different mutant viruses, we have identified specific residues located within the viral L polymerase gene encoded on the L segment essential for mediating disease pathogenesis. Through quantitative reverse transcription-PCR (RT-PCR) analysis, we have confirmed that the same set of residues is responsible for the increased viral replicative potential of the P18 strain and its heightened disease severity in vivo. Our laboratory findings serve to reinforce field observations that a high level of viremia often correlates with severe disease outcomes in LASV-infected patients. PMID:23552411

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

    SciTech Connect

    Garcia, C.C.; Topisirovic, I.; Djavani, M.; Borden, K.L.B.; Damonte, E.B.; Salvato, M.S.

    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.

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

    PubMed

    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.

  7. The Broad Way

    ERIC Educational Resources Information Center

    Butler, Kevin

    2008-01-01

    In the world of corporate philanthropy, there are those who give to educational causes, and this article describes one such philanthropist, Eli Broad, who shares his take on schools in America. Broad is in a category unto himself not only because of the amount of money he has given--more than $280 million since 1999--but also for his unique…

  8. Arenavirus Stable Signal Peptide Is the Keystone Subunit for Glycoprotein Complex Organization

    PubMed Central

    Bederka, Lydia H.; Bonhomme, Cyrille J.; Ling, Emily L.

    2014-01-01

    ABSTRACT The rodent arenavirus glycoprotein complex encodes a stable signal peptide (SSP) that is an essential structural component of mature virions. The SSP, GP1, and GP2 subunits of the trimeric glycoprotein complex noncovalently interact to stud the surface of virions and initiate arenavirus infectivity. Nascent glycoprotein production undergoes two proteolytic cleavage events: first within the endoplasmic reticulum (ER) to cleave SSP from the remaining precursor GP1/2 (glycoprotein complex [GPC]) glycoprotein and second within the Golgi stacks by the cellular SKI-1/S1P for GP1/2 processing to yield GP1 and GP2 subunits. Cleaved SSP is not degraded but retained as an essential glycoprotein subunit. Here, we defined functions of the 58-amino-acid lymphocytic choriomeningitis virus (LCMV) SSP in regard to glycoprotein complex processing and maturation. Using molecular biology techniques, confocal microscopy, and flow cytometry, we detected SSP at the plasma membrane of transfected cells. Further, we identified a sorting signal (FLLL) near the carboxyl terminus of SSP that is required for glycoprotein maturation and trafficking. In the absence of SSP, the glycoprotein accumulated within the ER and was unable to undergo processing by SKI-1/S1P. Mutation of this highly conserved FLLL motif showed impaired glycoprotein processing and secretory pathway trafficking, as well as defective surface expression and pH-dependent membrane fusion. Immunoprecipitation of SSP confirmed an interaction between the signal peptide and the GP2 subunit; however, mutations within this FLLL motif disrupted the association of the GP1 subunit with the remaining glycoprotein complex. PMID:25352624

  9. The N-Terminal Domain of the Arenavirus L Protein Is an RNA Endonuclease Essential in mRNA Transcription

    PubMed Central

    Morin, Benjamin; Coutard, Bruno; Lelke, Michaela; Ferron, François; Kerber, Romy; Jamal, Saïd; Frangeul, Antoine; Baronti, Cécile; Charrel, Rémi; de Lamballerie, Xavier; Vonrhein, Clemens; Lescar, Julien; Bricogne, Gérard; Günther, Stephan; Canard, Bruno

    2010-01-01

    Arenaviridae synthesize viral mRNAs using short capped primers presumably acquired from cellular transcripts by a ‘cap-snatching’ mechanism. Here, we report the crystal structure and functional characterization of the N-terminal 196 residues (NL1) of the L protein from the prototypic arenavirus: lymphocytic choriomeningitis virus. The NL1 domain is able to bind and cleave RNA. The 2.13 Å resolution crystal structure of NL1 reveals a type II endonuclease α/β architecture similar to the N-terminal end of the influenza virus PA protein. Superimposition of both structures, mutagenesis and reverse genetics studies reveal a unique spatial arrangement of key active site residues related to the PD…(D/E)XK type II endonuclease signature sequence. We show that this endonuclease domain is conserved and active across the virus families Arenaviridae, Bunyaviridae and Orthomyxoviridae and propose that the arenavirus NL1 domain is the Arenaviridae cap-snatching endonuclease. PMID:20862324

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

    PubMed

    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.

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

    PubMed Central

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

    2015-01-01

    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. PMID:26022445

  12. Identification of Two Functional Domains within the Arenavirus Nucleoprotein▿

    PubMed Central

    Levingston Macleod, Jesica M.; D'Antuono, Alejandra; Loureiro, Maria Eugenia; Casabona, Juan Cruz; Gomez, Guillermo A.; Lopez, Nora

    2011-01-01

    Tacaribe virus (TCRV) belongs to the Arenaviridae family. Its bisegmented negative-stranded RNA genome encodes the nucleoprotein (N), the precursor of the envelope glycoproteins, the polymerase (L), and a RING finger matrix (Z) protein. The 570-amino-acid N protein binds to viral RNA, forming nucleocapsids, which are the template for transcription and replication by the viral polymerase. We have previously shown that the interaction between N and Z is required for assembly of infectious virus-like particles (VLPs) (J. C. Casabona et al., J. Virol. 83:7029-7039, 2009). Here, we examine the functional organization of TCRV N protein. A series of deletions and point mutations were introduced into the N-coding sequence, and the ability of the mutants to sustain heterotypic (N-Z) or homotypic (N-N) interactions was analyzed. We found that N protein displays two functional domains. By using coimmunoprecipitation studies, VLP incorporation assays, and double immunofluorescence staining, the carboxy-terminal region of N was found to be required for N-Z interaction and also necessary for incorporation of N protein into VLPs. Moreover, further analysis of this region showed that the integrity of a putative zinc-finger motif, as well as its amino-flanking sequence (residues 461 to 489), are critical for Z binding and N incorporation into VLPs. In addition, we provide evidence of an essential role of the amino-terminal region of N protein for N-N interaction. In this regard, using reciprocal coimmunoprecipitation analysis, we identified a 28-residue region predicted to form a coiled-coil domain (residues 92 to 119) as a newly recognized molecular determinant of N homotypic interactions. PMID:21159858

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

    PubMed

    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.

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

    PubMed

    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.

  15. Genetic analysis of heptad-repeat regions in the G2 fusion subunit of the Junin arenavirus envelope glycoprotein

    SciTech Connect

    York, Joanne . E-mail: joanne.york@umontana.edu; Agnihothram, Sudhakar S. . E-mail: sudhakar.agnihothram@umontana.edu; Romanowski, Victor . E-mail: victor@biol.unlp.edu.ar; Nunberg, Jack H. . E-mail: jack.nunberg@umontana.edu

    2005-12-20

    The G2 fusion subunit of the Junin virus envelope glycoprotein GP-C contains two hydrophobic heptad-repeat regions that are postulated to form a six-helix bundle structure required for the membrane fusion activity of Class I viral fusion proteins. We have investigated the role of these heptad-repeat regions and, specifically, the importance of the putative interhelical a and d position sidechains by using alanine-scanning mutagenesis. All the mutant glycoproteins were expressed and transported to the cell surface. Proteolytic maturation at the subtilisin kexin isozyme-1/site-1-protease (SKI-1/S1P) cleavage site was observed in all but two of the mutants. Among the adequately cleaved mutant glycoproteins, four positions in the N-terminal region (I333, L336, L347 and L350) and two positions in the C-terminal region (R392 and W395) were shown to be important determinants of cell-cell fusion. Taken together, our results indicate that {alpha}-helical coiled-coil structures are likely critical in promoting arenavirus membrane fusion. These findings support the inclusion of the arenavirus GP-C among the Class I viral fusion proteins and suggest pharmacologic and immunologic strategies for targeting arenavirus infection and hemorrhagic fever.

  16. Broad Bandwidth Telecommunications Systems.

    ERIC Educational Resources Information Center

    Sodolski, John

    Broad bandwidth transmission systems have been around for years. They include microwave, assorted cable systems, and recently, satellites. With the exception of some privately owned systems, broadband services have been furnished by the common carriers. Recently, a new element has been added--Cable Antenna Television (CATV) distribution systems.…

  17. The Broad Foundations, 2006

    ERIC Educational Resources Information Center

    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…

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

    PubMed Central

    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

  19. Broad-band beam buncher

    DOEpatents

    Goldberg, David A.; Flood, William S.; Arthur, Allan A.; Voelker, Ferdinand

    1986-01-01

    A broad-band beam buncher is disclosed, comprising an evacuated housing, an electron gun therein for producing an electron beam, a buncher cavity having entrance and exit openings through which the beam is directed, grids across such openings, a source providing a positive DC voltage between the cavity and the electron gun, a drift tube through which the electron beam travels in passing through such cavity, grids across the ends of such drift tube, gaps being provided between the drift tube grids and the entrance and exit grids, a modulator for supplying an ultrahigh frequency modulating signal to the drift tube for producing velocity modulation of the electrons in the beam, a drift space in the housing through which the velocity modulated electron beam travels and in which the beam is bunched, and a discharge opening from such drift tube and having a grid across such opening through which the bunched electron beam is discharged into an accelerator or the like. The buncher cavity and the drift tube may be arranged to constitute an extension of a coaxial transmission line which is employed to deliver the modulating signal from a signal source. The extended transmission line may be terminated in its characteristic impedance to afford a broad-band response and the device as a whole designed to effect broad-band beam coupling, so as to minimize variations of the output across the response band.

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

    PubMed

    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.

  1. Broad band waveguide spectrometer

    DOEpatents

    Goldman, Don S.

    1995-01-01

    A spectrometer for analyzing a sample of material utilizing a broad band source of electromagnetic radiation and a detector. The spectrometer employs a waveguide possessing an entry and an exit for the electromagnetic radiation emanating from the source. The waveguide further includes a surface between the entry and exit portions which permits interaction between the electromagnetic radiation passing through the wave guide and a sample material. A tapered portion forms a part of the entry of the wave guide and couples the electromagnetic radiation emanating from the source to the waveguide. The electromagnetic radiation passing from the exit of the waveguide is captured and directed to a detector for analysis.

  2. Broad host range plasmids.

    PubMed

    Jain, Aayushi; Srivastava, Preeti

    2013-11-01

    Plasmids are and will remain important cloning vehicles for biotechnology. They have also been associated with the spread of a number of diseases and therefore are a subject of environmental concern. With the advent of sequencing technologies, the database of plasmids is increasing. It will be of immense importance to identify the various bacterial hosts in which the plasmid can replicate. The present review article describes the features that confer broad host range to the plasmids, the molecular basis of plasmid host range evolution, and applications in recombinant DNA technology and environment.

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

    PubMed Central

    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

  4. Uncovering Viral Protein-Protein Interactions and their Role in Arenavirus Life Cycle

    PubMed Central

    Loureiro, Maria Eugenia; D’Antuono, Alejandra; Levingston Macleod, Jesica M.; López, Nora

    2012-01-01

    The Arenaviridae family includes widely distributed pathogens that cause severe hemorrhagic fever in humans. Replication and packaging of their single-stranded RNA genome involve RNA recognition by viral proteins and a number of key protein-protein interactions. Viral RNA synthesis is directed by the virus-encoded RNA dependent-RNA polymerase (L protein) and requires viral RNA encapsidation by the Nucleoprotein. In addition to the role that the interaction between L and the Nucleoprotein may have in the replication process, polymerase activity appears to be modulated by the association between L and the small multifunctional Z protein. Z is also a structural component of the virions that plays an essential role in viral morphogenesis. Indeed, interaction of the Z protein with the Nucleoprotein is critical for genome packaging. Furthermore, current evidence suggests that binding between Z and the viral envelope glycoprotein complex is required for virion infectivity, and that Z homo-oligomerization is an essential step for particle assembly and budding. Efforts to understand the molecular basis of arenavirus life cycle have revealed important details on these viral protein-protein interactions that will be reviewed in this article. PMID:23170177

  5. Broad-band beam buncher

    DOEpatents

    Goldberg, D.A.; Flood, W.S.; Arthur, A.A.; Voelker, F.

    1984-03-20

    A broad-band beam bunther is disclosed, comprising an evacuated housing, an electron gun therein for producing an electron beam, a buncher cavity having entrance and exit openings through which the beam is directed, grids across such openings, a source providing a positive DC voltage between the cavity and the electron gun, a drift tube through which the electron beam travels in passing through such cavity, grids across the ends of such drift tube, gaps being provided between the drift tube grids and the entrance and exit grids, a modulator for supplying an ultrahigh frequency modulating signal to the drift tube for producing velocity modulation of the electrons in the beam, a drift space in the housing through which the velocity modulated electron beam travels and in which the beam is bunched, and a discharge opening from such drift tube and having a grid across such opening through which the bunched electron beam is discharged into an accelerator or the like. The buncher cavity and the drift tube may be arranged to constitute an extension of a coaxial transmission line which is employed to deliver the modulating signal from a signal source. The extended transmission line may be terminated in its characteristic impedance to afford a broad-

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

    PubMed

    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.

  7. Molecular Determinants of Arenavirus Z Protein Homo-Oligomerization and L Polymerase Binding▿

    PubMed Central

    Loureiro, Maria Eugenia; Wilda, Maximiliano; Levingston Macleod, Jesica M.; D'Antuono, Alejandra; Foscaldi, Sabrina; Buslje, Cristina Marino; Lopez, Nora

    2011-01-01

    The arenavirus Z is a zinc-binding RING protein that has been implicated in multiple functions during the viral life cycle. These roles of Z involve interactions with viral and cellular proteins that remain incompletely understood. In this regard, Z inhibits viral RNA transcription and replication through direct interaction with the viral L polymerase. Here, we defined the L-binding domain of Tacaribe virus (TCRV) Z protein and the structural requirements mediating Z homo-oligomerization. By using site-directed mutagenesis, coimmunoprecipitation, and functional assays, we showed that residues R37, N39, W44, L50, and Y57, located around the zinc coordination site I, play a critical role in the Z-L interaction. We also found that Z protein from either TCRV or the pathogenic Junin virus (JUNV) self-associates into oligomeric forms in mammalian cells. Importantly, mutation of the myristoylation site, the strictly conserved residue G at position 2, severely impaired the ability of both TCRV Z and JUNV Z to self-interact as well as their capacity to accumulate at the plasma membrane, strongly suggesting that Z homo-oligomerization is associated with its myristoylation and cell membrane targeting. In contrast, disruption of the RING structure or substitution of W44 or N39, which are critical for L protein recognition, did not affect Z self-binding. Overall, the data presented here indicate that homo-oligomerization is not a requirement for Z-L interaction or Z-mediated polymerase activity inhibition. PMID:21957305

  8. Failure to prove arenavirus infection among the small mammals from an endemic area of Korean hemorrhagic nephrosonephritis.

    PubMed

    Okuno, T; Casals, J; Kim, K H; Walton, D W; Shin, H K

    1976-08-01

    In the light of recent knowledge on a complex of diseases caused by a new group of viruses, arenaviruses, virological studies largely directed toward small field mammals were undertaken during 1973-1974 aiming at etiological clarification of Korean hemorrhagic nephrosonephritis (KHNN). Specimens were collected in an endemic area of KHNN located north to northeast of Seoul. Virus isolation tests with 299 urine specimens and 131 mite pools recovered from small mammals and 14 acute stage sera from typical cases yielded negative results. Complement-fixation (CF) tests failed to detect antibodies against the antigens of Congo, lymphocytic choriomeningitis (LCM), Tacaribe, and Pichinde viruses among 366 small mammal sera. In addition, CF tests of 59 of the above sera against Apoi and Lassa virus antigens were negative. The results do not support the likelihood of an arenavirus being transmitted among Korean small field mammals, the overwhelming majority of which were Apodemus agrarius. A hypothesis that KHNN is caused by a virus of small field mammal origin was not proved within the technical limit of relatively unsophisticated methods employed herein.

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

    SciTech Connect

    Burri, Dominique J.; Pasquato, Antonella; Ramos da Palma, Joel; Igonet, Sebastien; Oldstone, Michael B.A.; Kunz, Stefan

    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.

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

    PubMed Central

    Haist, Kelsey; Ziegler, Christopher; Botten, Jason

    2015-01-01

    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. PMID:25978311

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

    PubMed Central

    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

  12. An attenuated Lassa vaccine in SIV-infected rhesus macaques does not persist or cause arenavirus disease but does elicit Lassa virus-specific immunity

    PubMed Central

    2013-01-01

    Background Lassa hemorrhagic fever (LHF) is a rodent-borne viral disease that can be fatal for human beings. In this study, an attenuated Lassa vaccine candidate, ML29, was tested in SIV-infected rhesus macaques for its ability to elicit immune responses without instigating signs pathognomonic for arenavirus disease. ML29 is a reassortant between Lassa and Mopeia viruses that causes a transient infection in non-human primates and confers sterilizing protection from lethal Lassa viral challenge. However, since the LHF endemic area of West Africa also has high HIV seroprevalence, it is important to determine whether vaccination could be safe in the context of HIV infection. Results SIV-infected and uninfected rhesus macaques were vaccinated with the ML29 virus and monitored for specific humoral and cellular immune responses, as well as for classical and non-classical signs of arenavirus disease. Classical disease signs included viremia, rash, respiratory distress, malaise, high liver enzyme levels, and virus invasion of the central nervous system. Non-classical signs, derived from profiling the blood transcriptome of virulent and non-virulent arenavirus infections, included increased expression of interferon-stimulated genes (ISG) and decreased expression of COX2, IL-1β, coagulation intermediates and nuclear receptors needed for stress signaling. All vaccinated monkeys showed ML29-specific antibody responses and ML29-specific cell-mediated immunity. Conclusion SIV-infected and uninfected rhesus macaques responded similarly to ML29 vaccination, and none developed chronic arenavirus infection. Importantly, none of the macaques developed signs, classical or non-classical, of arenavirus disease. PMID:23402317

  13. The Broad Foundations, 2008

    ERIC Educational Resources Information Center

    Broad Foundation, 2008

    2008-01-01

    This 2008 foundation report provides an opportunity to look back and ahead as the organization reviews what has been accomplished and identifies challenges to be tackled in the future in the areas of education, scientific and medical research, and the arts. Grant making from the perspective of grantees is presented in each area. [This document was…

  14. Broad spectrum solar cell

    DOEpatents

    Walukiewicz, Wladyslaw; Yu, Kin Man; Wu, Junqiao; Schaff, William J.

    2007-05-15

    An alloy having a large band gap range is used in a multijunction solar cell to enhance utilization of the solar energy spectrum. In one embodiment, the alloy is In.sub.1-xGa.sub.xN having an energy bandgap range of approximately 0.7 eV to 3.4 eV, providing a good match to the solar energy spectrum. Multiple junctions having different bandgaps are stacked to form a solar cell. Each junction may have different bandgaps (realized by varying the alloy composition), and therefore be responsive to different parts of the spectrum. The junctions are stacked in such a manner that some bands of light pass through upper junctions to lower junctions that are responsive to such bands.

  15. Antibodies to Tacaribe Serocomplex Viruses (Family Arenaviridae, Genus Arenavirus) in Cricetid Rodents from New Mexico, Texas, and Mexico

    PubMed Central

    Milazzo, Mary L.; Barragán-Gomez, Artemio; Hanson, John Delton; Estrada-Franco, Jose G.; Arellano, Elizabeth; González-Cózatl, Francisco X.; Fernández-Salas, Ildefonso; Ramirez-Aguilar, Francisco; Rogers, Duke S.; Bradley, Robert D.

    2010-01-01

    Abstract Blood samples from 4893 cricetid rodents were tested for antibody (immunoglobulin G) to Whitewater Arroyo virus and Amaparí virus to extend our knowledge of the natural host range and geographical distribution of Tacaribe serocomplex viruses in North America. Antibodies to arenaviruses were found in northern pygmy mice (Baiomys taylori), woodrats (Neotoma spp.), northern grasshopper mice (Onychomys leucogaster), oryzomys (Oryzomys spp.), deermice (Megadontomys nelsoni and Peromyscus spp.), harvest mice (Reithrodontomys spp.), and cotton rats (Sigmodon spp.) captured in New Mexico, Texas, or Mexico. Comparison of endpoint antibody titers to Whitewater Arroyo virus and Amaparí virus in individual blood samples indicated that the Tacaribe complex viruses enzootic in Texas and Mexico are antigenically diverse. PMID:20795917

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

    PubMed

    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.

  17. Novel approaches in anti-arenaviral drug development

    SciTech Connect

    Lee, Andrew M.; Pasquato, Antonella; Kunz, Stefan

    2011-03-15

    Hemorrhagic fevers caused by arenaviruses are among the most devastating emerging human diseases. Considering the number of individuals affected, the current lack of a licensed vaccine, and the limited therapeutic options, arenaviruses are arguably among the most neglected tropical pathogens and the development of efficacious anti-arenaviral drugs is of high priority. Over the past years significant efforts have been undertaken to identify novel potent inhibitors of arenavirus infection. High throughput screening of small molecule libraries employing pseudotype platforms led to the discovery of several potent and broadly active inhibitors of arenavirus cell entry that are effective against the major hemorrhagic arenaviruses. Mechanistic studies revealed that these novel entry inhibitors block arenavirus membrane fusion and provided novel insights into the unusual mechanism of this process. The success of these approaches highlights the power of small molecule screens in antiviral drug discovery and establishes arenavirus membrane fusion as a robust drug target. These broad screenings have been complemented by strategies targeting cellular factors involved in productive arenavirus infection. Approaches targeting the cellular protease implicated in maturation of the fusion-active viral envelope glycoprotein identified the proteolytic processing of the arenavirus glycoprotein precursor as a novel and promising target for anti-arenaviral strategies.

  18. Broad-spectrum antiviral agents

    PubMed Central

    Zhu, Jun-Da; Meng, Wen; Wang, Xiao-Jia; Wang, Hwa-Chain R.

    2015-01-01

    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. PMID:26052325

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

    PubMed

    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.

  20. Passive Broad-Spectrum Influenza Immunoprophylaxis

    PubMed Central

    Berry, Cassandra M.; Penhale, William J.; Sangster, Mark Y.

    2014-01-01

    Influenza is a perennial problem affecting millions of people annually with the everpresent threat of devastating pandemics. Active prophylaxis by vaccination against influenza virus is currently the main countermeasure supplemented with antivirals. However, disadvantages of this strategy include the impact of antigenic drift, necessitating constant updating of vaccine strain composition, and emerging antiviral drug resistance. The development of other options for influenza prophylaxis, particularly with broad acting agents able to provide protection in the period between the onset of a pandemic and the development of a strain specific vaccine, is of great interest. Exploitation of broad-spectrum mediators could provide barricade protection in the early critical phase of influenza virus outbreaks. Passive immunity has the potential to provide immediate antiviral effects, inhibiting virus replication, reducing virus shedding, and thereby protecting vulnerable populations in the event of an impending influenza pandemic. Here, we review passive broad-spectrum influenza prophylaxis options with a focus on harnessing natural host defenses, including interferons and antibodies. PMID:25328697

  1. Cochlear microphonic broad tuning curves

    NASA Astrophysics Data System (ADS)

    Ayat, Mohammad; Teal, Paul D.; Searchfield, Grant D.; Razali, Najwani

    2015-12-01

    It is known that the cochlear microphonic voltage exhibits much broader tuning than does the basilar membrane motion. The most commonly used explanation for this is that when an electrode is inserted at a particular point inside the scala media, the microphonic potentials of neighbouring hair cells have different phases, leading to cancelation at the electrodes location. In situ recording of functioning outer hair cells (OHCs) for investigating this hypothesis is exceptionally difficult. Therefore, to investigate the discrepancy between the tuning curves of the basilar membrane and those of the cochlear microphonic, and the effect of phase cancellation of adjacent hair cells on the broadness of the cochlear microphonic tuning curves, we use an electromechanical model of the cochlea to devise an experiment. We explore the effect of adjacent hair cells (i.e., longitudinal phase cancellation) on the broadness of the cochlear microphonic tuning curves in different locations. The results of the experiment indicate that active longitudinal coupling (i.e., coupling with active adjacent outer hair cells) only slightly changes the broadness of the CM tuning curves. The results also demonstrate that there is a π phase difference between the potentials produced by the hair bundle and the soma near the place associated with the characteristic frequency based on place-frequency maps (i.e., the best place). We suggest that the transversal phase cancellation (caused by the phase difference between the hair bundle and the soma) plays a far more important role than longitudinal phase cancellation in the broadness of the cochlear microphonic tuning curves. Moreover, by increasing the modelled longitudinal resistance resulting the cochlear microphonic curves exhibiting sharper tuning. The results of the simulations suggest that the passive network of the organ of Corti determines the phase difference between the hair bundle and soma, and hence determines the sharpness of the

  2. The Signal Peptide of the Junín Arenavirus Envelope Glycoprotein Is Myristoylated and Forms an Essential Subunit of the Mature G1-G2 Complex

    PubMed Central

    York, Joanne; Romanowski, Victor; Lu, Min; Nunberg, Jack H.

    2004-01-01

    Arenaviruses comprise a diverse family of rodent-borne viruses that are responsible for recurring and emerging outbreaks of viral hemorrhagic fevers worldwide. The Junín virus, a member of the New World arenaviruses, is endemic to the pampas grasslands of Argentina and is the etiologic agent of Argentine hemorrhagic fever. In this study, we have analyzed the assembly and function of the Junín virus envelope glycoproteins. The mature envelope glycoprotein complex is proteolytically processed from the GP-C precursor polypeptide and consists of three noncovalently associated subunits, G1, G2, and a stable 58-amino-acid signal peptide. This tripartite organization is found both on virions of the attenuated Candid 1 strain and in cells expressing the pathogenic MC2 strain GP-C gene. Replacement of the Junín virus GP-C signal peptide with that of human CD4 has little effect on glycoprotein assembly while abolishing the ability of the G1-G2 complex to mediate pH-dependent cell-cell fusion. In addition, we demonstrate that the Junín virus GP-C signal peptide subunit is myristoylated at its N-terminal glycine. Alanine substitution for the modified glycine residue in the GP-C signal peptide does not affect formation of the tripartite envelope glycoprotein complex but markedly reduces its membrane fusion activity. In contrast to the classical view that signal peptides act primarily in targeting nascent polypeptides to the endoplasmic reticulum, we suggest that the signal peptide of the arenavirus GP-C may serve additional functions in envelope glycoprotein structure and trafficking. PMID:15367645

  3. Broad-Application Test Reactor

    SciTech Connect

    Motloch, C.G.

    1992-05-01

    This report is about a new, safe, and operationally efficient DOE reactor of nuclear research and testing proposed for the early to mid- 21st Century. Dubbed the Broad-Application Test Reactor (BATR), the proposed facility incorporates a multiple-application, multiple-mission design to support DOE programs such as naval reactors and space power and propulsion, as well as research in medical, science, isotope, and electronics arenas. DOE research reactors are aging, and implementing major replacement projects requires long lead times. Primary design drivers include safety, low risk, minimum operation cost, mission flexibility, waste minimization, and long life. Scientists and engineers at the Idaho National Engineering Laboratory are evaluating possible fuel forms, structural materials, reactor geometries, coolants, and moderators.

  4. Ghost imaging with broad distance

    NASA Astrophysics Data System (ADS)

    Duan, De-Yang; Zhang, Lu; Du, Shao-Jiang; Xia, Yun-Jie

    2015-10-01

    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. Project supported by the National Natural Science Foundation of China (Grant Nos. 61178012, 11204156, 11304179, and 11247240), the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant Nos. 20133705110001 and 20123705120002), the Scientific Research Foundation for Outstanding Young Scientists of Shandong Province, China (Grant No. BS2013DX034), and the Natural Science Foundation of Shandong Province, China (Grant No. ZR2012FQ024).

  5. Broadly tunable picosecond ir source

    DOEpatents

    Campillo, A.J.; Hyer, R.C.; Shapiro, S.L.

    1980-04-23

    A picosecond traveling-wave parametric device capable of controlled spectral bandwidth and wavelength in the infrared is reported. Intense 1.064 ..mu..m picosecond pulses (1) pass through a 4.5 cm long LiNbO/sub 3/ optical parametric oscillator crystal (2) set at its degeneracy angle. A broad band emerges, and a simple grating (3) and mirror (4) arrangement is used to inject a selected narrow-band into a 2 cm long LiNbO/sub 3/ optical parametric amplifier crystal (5) along a second pump line. Typical input energies at 1.064 ..mu..m along both pump lines are 6 to 8 mJ for the oscillator and 10 mJ for the amplifier. This yields 1 mJ of tunable output in the range 1.98 to 2.38 ..mu..m which when down-converted in a 1 cm long CdSe crystal mixer (6) gives 2 ..mu..J of tunable radiation over the 14.8 to 18.5 ..mu..m region. The bandwidth and wavelength of both the 2 and 16 ..mu..m radiation output are controlled solely by the diffraction grating.

  6. Broadly tunable picosecond IR source

    DOEpatents

    Campillo, Anthony J.; Hyer, Ronald C.; Shapiro, Stanley J.

    1982-01-01

    A picosecond traveling-wave parametric device capable of controlled spectral bandwidth and wavelength in the infrared is reported. Intense 1.064 .mu.m picosecond pulses (1) pass through a 4.5 cm long LiNbO.sub.3 optical parametric oscillator crystal (2) set at its degeneracy angle. A broad band emerges, and a simple grating (3) and mirror (4) arrangement is used to inject a selected narrow-band into a 2 cm long LiNbO.sub.3 optical parametric amplifier crystal (5) along a second pump line. Typical input energies at 1.064 .mu.m along both pump lines are 6-8 mJ for the oscillator and 10 mJ for the amplifier. This yields 1 mJ of tunable output in the range 1.98 to 2.38 .mu.m which when down-converted in a 1 cm long CdSe crystal mixer (6) gives 2 .mu.J of tunable radiation over the 14.8 to 18.5 .mu.m region. The bandwidth and wavelength of both the 2 and 16 .mu.m radiation output are controlled solely by the diffraction grating.

  7. 76 FR 34087 - Broad Stakeholder Survey

    Federal Register 2010, 2011, 2012, 2013, 2014

    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...

  8. Mapping of the Tacaribe Arenavirus Z-Protein Binding Sites on the L Protein Identified both Amino Acids within the Putative Polymerase Domain and a Region at the N Terminus of L That Are Critically Involved in Binding▿

    PubMed Central

    Wilda, Maximiliano; Lopez, Nora; Casabona, Juan Cruz; Franze-Fernandez, Maria T.

    2008-01-01

    Tacaribe virus (TacV) is the prototype of the New World group of arenaviruses. The TacV genome encodes four proteins: the nucleoprotein (N), the glycoprotein precursor, the polymerase (L), and a RING finger protein (Z). Using a reverse genetics system, we demonstrated that TacV N and L are sufficient to drive transcription and replication mediated by TacV-like RNAs and that Z is a powerful inhibitor of these processes (Lopez et al., J. Virol. 65:12241-12251, 2001). More recently, we provided the first evidence of an interaction between Z and L and showed that Z's inhibitory activity was dependent on its ability to bind to L (Jácamo et al., J. Virol. 77:10383-10393, 2003). In the present study, we mapped the TacV Z-binding sites on the 2,210-amino-acid L polymerase. To that end, we performed deletion analysis and point mutations of L and studied the Z-L interaction by coimmunoprecipitation with specific sera. We found that the C-terminal region of L was not essential for the interaction and identified two noncontiguous regions that were critical for binding: one at the N-terminus of L between residues 156 and 292 and a second one in the polymerase domain (domain III). The importance of domain III in binding was revealed by substitutions in D1188 and H1189 within motif A and in each residue of the conserved SDD sequence (residues 1328, 1329, and 1330) within motif C. Our results showed that of the substituted residues, only H1189 and D1329 appeared to be critically involved in binding Z. PMID:18799569

  9. Jupiter's Temperatures--Broad Latitude

    NASA Technical Reports Server (NTRS)

    1997-01-01

    This is one of the highest resolution images ever recorded of Jupiter's temperature field. It was obtained by NASA's Galileo mission, with its Photopolarimeter-Radiometer (PPR) experiment, during the seventh of its 10 orbits around Jupiter to date. This map, shown in the left panel, indicates the forces powering Jovian winds, and differentiates between areas of strongest upwelling and downwelling winds in the upper part of the atmosphere. A Hubble Space Telescope Planetary Camera color composite of this same region, taken within 10 hours of the PPR map, is shown in the right panel for the same region, as a reference to the visual clouds. An outline of the region mapped by the PPR is also shown.

    This atmospheric observation covered a broad latitude region, and it shows that the visually dark regions generally have warmer temperatures than the visually light ones, indicating that they are regions of downwelling, dry air which clear out cloud condensate particles. The 'little red spot' at the northernmost part of this image is colder than its surroundings, consistent with it being a region of upwelling and cooling gas. The smaller spots to its southeast (lower right) and other lighter spots in the HST image are all colder than their surroundings, consistent with regions of upwelling and cooling gas. The northern half of the brightest band in the map is brighter than the southern half, and it reveals some detailed structure, down to the 1900- kilometer (1200-mile) resolution of the PPR, which is not always readily correlated with variations of the visual cloud field.

    One surprise of this temperature map involved temperatures near the dark blue-gray feature in the map, an area like the one into which the Probe descended. While large regions of downwelling wind heat the local area elsewhere in Jupiter, this region of vigorous downwelling appears close to being thermally neutral. The drying, downwelling winds may be deeper in the atmosphere than sensed by the PPR

  10. Broad Prize: Do the Successes Spread?

    ERIC Educational Resources Information Center

    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…

  11. Broad Academy's Growing Reach Draws Scrutiny

    ERIC Educational Resources Information Center

    Samuels, Christina A.

    2011-01-01

    Billionaire businessman Eli Broad, one of the country's most active philanthropists, founded the "Broad Superintendents Academy" in 2002 with an extraordinarily optimistic goal: Find leaders from both inside and outside education, train them, and have them occupying the superintendencies in a third of the 75 largest school districts--all in just…

  12. Academic Ranking of World Universities by Broad Subject Fields

    ERIC Educational Resources Information Center

    Cheng, Ying; Liu, Nian Cai

    2007-01-01

    Upon numerous requests to provide ranking of world universities by broad subject fields/schools/colleges and by subject fields/programs/departments, the authors present the ranking methodologies and problems that arose from the research by the Institute of Higher Education, Shanghai Jiao Tong University on the Academic Ranking of World…

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

    PubMed

    Fricton, J R; Okeson, J P

    2000-07-01

    The emerging field of orofacial pain is being considered by the American Dental Association for full status as a new dental specialty to improve the care for these patients. The broad support among dentists for this initiative stems from an awareness of the benefits the field can provide for dentists and their patients.

  14. Broad-spectrum antibiotics in Norwegian hospitals.

    PubMed

    Holen, Øyunn; Alberg, Torunn; Blix, Hege Salvesen; Smith, Ingrid; Neteland, Marion Iren; Eriksen, Hanne Merete

    2017-03-01

    BACKGROUND One of the objectives in the action plan to reduce antimicrobial resistance in the health services in Norway is to reduce the use of broad-spectrum antibiotics in Norwegian hospitals. This study describes the use of certain broad-spectrum antibiotics mentioned in the action plan in Norwegian hospitals, and assesses prescribing practices in relation to the Norwegian guidelines for antibiotic use in hospitals.MATERIAL AND METHOD Data were analysed from a nationwide non-identifiable point prevalence survey in May 2016 where all systemic use of antibiotics was recorded.RESULTS Broad-spectrum antibiotics accounted for 33 % of all antibiotics prescribed. Altogether 84 % of all broad-spectrum antibiotics were prescribed as treatment, 8 % were for prophylactic use, and 8 % were classified as other/unknown. Lower respiratory tract infections were the most frequent indication for treatment with broad-spectrum antibiotics, involving 30 % of all broad-spectrum treatment.INTERPRETATION This point prevalence survey in Norwegian hospitals in spring 2016 indicates a possibility for reducing the use of broad-spectrum antibiotics in the treatment of lower respiratory tract infections and for prophylactic use. Reduction of healthcare-associated infections may also contribute.

  15. Polarization and Broad Absorption Lines in Quasars

    NASA Astrophysics Data System (ADS)

    Antonucci, Robert

    1990-12-01

    OI 287 is a unique extragalactic source. It appears to take one property from each class of object. It is either some kind of missing link, or a new type of activity. Because of the high optical polarization, OI 287 has been classified with the blazars. However, every other blazar is variable in optical flux, polarization, and polarization angle., while OI 287 is constant at V=17, P=8%, and theta=145 degrees. Also, every other blazar has a radio source dominated by an intense flat-spectrum core, while OI 287 has an upper limit of 2% of the total 20cm flux in the core. The only group of quasars which ever shows even moderate (2-5%) constant optical polarization is the broad absorption line (BAL) objects, e.g. PHL 5200 and H1413+113. Among the BAL quasars, PHL 5200 and H1413+113 have exceptionally smooth deep, attached absorption lines, and also the highest polarization. We want to know whether OI 287 is a BAL quasar. It would be the first definite radio loud example. If it is a BAL quasar then the high polarization is really related to (and perhaps the key to) the BAL phenomenon, and we can use the techniques of spectropolarimetry to help unlock the BAL geometry. The UV spectral shape would also provide help determining the cause of polarization.

  16. Influenza virus antigenicity and broadly neutralizing epitopes.

    PubMed

    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.

  17. Broad Area Cooler Concepts for Cryogenic Propellant Tanks

    NASA Technical Reports Server (NTRS)

    Christie, R. J.; Tomsik, T. M.; Elchert, J. P.; Guzik, M. C.

    2011-01-01

    Numerous studies and ground tests have shown that broad area cooling (also known as distributed cooling) can reduce or eliminate cryogenic propellant boil-off and enable long duration storage in space. Various combinations of cryocoolers, circulators, heat exchangers and other hardware could be used to build the system. In this study, several configurations of broad area cooling systems were compared by weighing hardware combinations, input power requirements, component availability, and Technical Readiness Level (TRL). The preferred system has a high TRL and can be scaled up to provide cooling capacities on the order of 150W at 90K

  18. Broad area search for regions and objects of interest

    SciTech Connect

    Skurikhin, Alexei N; Pope, Paul A

    2011-01-12

    A quad chart provides an overview on the on-going project 'Broad Area Search for Regions and Objects of Interest' funded by the DOE Office of Nonproliferation and Verification Research and Development. Specifically, the quad chart shows: (1) Project title 'Broad Area Search for Regions and Objects of Interest'; (2) PI and Co-investigators; (3) Concept Panel outlining the project's approach built upon front-end scale-space image analysis; (4) Technical Challenges posed by the project, such as robustness, non-conformities, disparate spatial configuration and weak correlation between presence of objects of interest and low-level description of the surrounding geospatial background; and (5) Planned Accomplishment.

  19. Formation of broad Balmer wings in symbiotic stars

    NASA Astrophysics Data System (ADS)

    Chang, Seok-Jun; Heo, Jeong-Eun; Hong, Chae-Lin; Lee, Hee-Won

    2016-07-01

    Symbiotic stars are binary systems composed of a hot white dwarf and a mass losing giant. In addition to many prominent emission lines symbiotic stars exhibit Raman scattered O VI features at 6825 and 7088 Å. Another notable feature present in the spectra of many symbiotics is the broad wings around Balmer lines. Astrophysical mechanisms that can produce broad wings include Thomson scattering by free electrons and Raman scattering of Ly,β and higher series by neutral hydrogen. In this poster presentation we produce broad wings around Hα and H,β adopting a Monte Carlo techinique in order to make a quantitative comparison of these two mechanisms. Thomson wings are characterized by the exponential cutoff given by the termal width whereas the Raman wings are dependent on the column density and continuum shape in the far UV region. A brief discussion is provided.

  20. Arctic Change Information for a Broad Audience

    NASA Astrophysics Data System (ADS)

    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. Does Broad-Band Seismometer Clip?

    NASA Astrophysics Data System (ADS)

    Tunc, S.; Tunc, B.; Caka, D.; Ada, S.; Rademacher, H.

    2012-12-01

    Any measurement system's dynamic range in decibel (dB), can be defined as proportion of maximum and minimum amplitude (Amax and Amin) which can be measured by the system. Dynamic range defines limitation of the system. Maximum dynamic range, caused by an earthquake with magnitude around 9 is known approximately 220dB in the world. Although the analog feed-back broad-band seismic sensors have 160 dB dynamic range seems to be enough to record most of the earthquakes, these sensors may clip (saturation), when the ground shaking caused by seismic waves is strong enough. Many institutions use broad-band seismometer in Turkey. Because of the clipping of the broad-band seismometers, there were some problems on location and magnitude of the Van Earthquake which occurred October, 23, 2011. To avoid the clipping problem proposed that, relevant sensors choose or install accelerometer simultaneously with the broad-band sensor to the recording system at the seismic stations. In this study, giving information on why the broad-band seismometers clipping, clearing up the general and wrong understanding is "broad-band seismometers do not clip".

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

    PubMed

    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.

  3. Broad-Spectrum Solution-Processed Photovoltaics

    NASA Astrophysics Data System (ADS)

    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

  4. 21. Providence & Worchester RR: Freight house. Providence, Providence Co., ...

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

    21. Providence & Worchester RR: Freight house. Providence, Providence Co., RI. Sec. 4119, mp 185.66 (See HAER no. RI-3 for further documentation on this site.) - Northeast Railroad Corridor, Amtrak route between CT & MA state lines, Providence, Providence County, RI

  5. Visual attention spreads broadly but selects information locally

    PubMed Central

    Shioiri, Satoshi; Honjyo, Hajime; Kashiwase, Yoshiyuki; Matsumiya, Kazumichi; Kuriki, Ichiro

    2016-01-01

    Visual attention spreads over a range around the focus as the spotlight metaphor describes. Spatial spread of attentional enhancement and local selection/inhibition are crucial factors determining the profile of the spatial attention. Enhancement and ignorance/suppression are opposite effects of attention, and appeared to be mutually exclusive. Yet, no unified view of the factors has been provided despite their necessity for understanding the functions of spatial attention. This report provides electroencephalographic and behavioral evidence for the attentional spread at an early stage and selection/inhibition at a later stage of visual processing. Steady state visual evoked potential showed broad spatial tuning whereas the P3 component of the event related potential showed local selection or inhibition of the adjacent areas. Based on these results, we propose a two-stage model of spatial attention with broad spread at an early stage and local selection at a later stage. PMID:27759056

  6. DIVA defense: Broad protection for salmonella suppression

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A live, attenuated Salmonella enterica serovar Typhimurium vaccine was developed to confer broad protection against multiple Salmonella serovars to prevent disease and reduce pathogen colonization and shedding. Two vaccine trials were performed in swine to determine the protection afforded by the va...

  7. The GREGOR Broad-Band Imager

    NASA Astrophysics Data System (ADS)

    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.

  8. BSO--Broad System of Ordering.

    ERIC Educational Resources Information Center

    Lloyd, Geoffrey

    The Broad System of Ordering (BSO), a subject-indication coding and ordering scheme developed to meet the requirements of the UNISIST program for an international switching mechanism between information systems using diverse indexing/retrieval languages is described. The scope and purpose of the BSO, its development and testing, a schematic…

  9. Project Broad Jump: A Leap Into Learning

    ERIC Educational Resources Information Center

    Fleming, Douglas

    1972-01-01

    Project Broad Jump is a New York-based education program for some 600 youngsters from urban areas, in the third through tenth grades. The basic concept of the program is that academic opportunities are not accessible to many inner-city youth, whereas Head Start and Follow Through help pre-third graders, and Upward Bound helps high school students.…

  10. Teaching the Broad, Interdisciplinary Impact of Evolution

    ERIC Educational Resources Information Center

    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,…

  11. Education and Broad Concepts of Agency

    ERIC Educational Resources Information Center

    Winch, Christopher

    2014-01-01

    Drawing on recent debates about the relationship between propositional and practical knowledge, this article is concerned with broad concepts of agency. Specifically, it is concerned with agency that involves the forming and putting into effect of intentions over relatively extended periods, particularly in work contexts (called, for want of a…

  12. The RING Domain and the L79 Residue of Z Protein Are Involved in both the Rescue of Nucleocapsids and the Incorporation of Glycoproteins into Infectious Chimeric Arenavirus-Like Particles ▿

    PubMed Central

    Casabona, Juan Cruz; Levingston Macleod, Jesica M.; Loureiro, Maria Eugenia; Gomez, Guillermo A.; Lopez, Nora

    2009-01-01

    Arenaviruses, such as Tacaribe virus (TacV) and its closely related pathogenic Junin virus (JunV), are enveloped viruses with a bipartite negative-sense RNA genome that encodes the nucleocapsid protein (N), the precursor of the envelope glycoprotein complex (GP), the polymerase (L), and a RING finger protein (Z), which is the driving force of arenavirus budding. We have established a plasmid-based system which allowed the successful packaging of TacV-like nucleocapsids along with Z and GP of JunV into infectious virus-like particles (VLPs). By coexpressing different combinations of the system components, followed by biochemical analysis of the VLPs, the requirements for the assembly of both N and GP into particles were defined. We found that coexpression of N with Z protein in the absence of minigenome and other viral proteins was sufficient to recruit N within lipid-enveloped Z-containing VLPs. In addition, whereas GP was not required for the incorporation of N, coexpression of N substantially enhanced the ratio of GP to Z into VLPs. Disruption of the RING structure or mutation of residue L79 to alanine within Z protein, although it had no effect on Z self-budding, severely impaired VLP infectivity. These mutations drastically altered intracellular Z-N interactions and the incorporation of both N and GP into VLPs. Our results support the conclusion that the interaction between Z and N is required for assembly of both the nucleocapsids and the glycoproteins into infectious arenavirus budding particles. PMID:19420075

  13. Broadly Neutralizing Antibodies for HIV Eradication.

    PubMed

    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.

  14. Broad Absorption Line Quasars and Galaxy Evolution

    NASA Astrophysics Data System (ADS)

    Wills, B. J.

    2009-12-01

    Luminous QSOs are signposts to galaxy evolution. Local supermassive black holes are the faded relics of quasars in their heyday at redshifts ˜2. Relationships between the masses of these local supermassive black holes and their host galaxy bulges reveal an intimate link, fundamental to galaxy evolution: the newly evolving galaxy fuels the seed black hole through its accretion disk and by loss of angular momentum and energy in the form of outflowing winds. As the central engine approaches Eddington luminosities, winds drive away dusty gas, revealing a luminous QSO and halting star formation in the galaxy bulge. Relativistic winds are manifested in powerful radio jets in ˜10% of quasars, and sub-relativistic winds are revealed by broad blueshifted absorption troughs in the “broad absorption line” (BAL) quasars. Historically, BALs avoid powerful radio quasars. Here we examine the BALs to investigate this inverse connection.

  15. Broad-spectrum antivirals against viral fusion

    PubMed Central

    Vigant, Frederic; Santos, Nuno C.; Lee, Benhur

    2015-01-01

    Effective antivirals have been developed against specific viruses, such as HIV, Hepatitis C virus and influenza virus. This ‘one bug–one drug’ approach to antiviral drug development can be successful, but it may be inadequate for responding to an increasing diversity of viruses that cause significant diseases in humans. The majority of viral pathogens that cause emerging and re-emerging infectious diseases are membrane-enveloped viruses, which require the fusion of viral and cell membranes for virus entry. Therefore, antivirals that target the membrane fusion process represent new paradigms for broad-spectrum antiviral discovery. In this Review, we discuss the mechanisms responsible for the fusion between virus and cell membranes and explore how broad-spectrum antivirals target this process to prevent virus entry. PMID:26075364

  16. 8. The entire south face of the Broad Street bridge ...

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

    8. The entire south face of the Broad Street bridge as seen from the flood levy in front of Central High School. - Broad Street Bridge, Spanning Scioto River at U.S. Route 40 (Broad Street), Columbus, Franklin County, OH

  17. Relativistic redshifts in quasar broad lines

    SciTech Connect

    Tremaine, Scott; Shen, Yue; Liu, Xin; Loeb, Abraham E-mail: yshen@obs.carnegiescience.edu E-mail: aloeb@cfa.harvard.edu

    2014-10-10

    The broad emission lines commonly seen in quasar spectra have velocity widths of a few percent of the speed of light, so special- and general-relativistic effects have a significant influence on the line profile. We have determined the redshift of the broad Hβ line in the quasar rest frame (determined from the core component of the [O III] line) for over 20,000 quasars from the Sloan Digital Sky Survey Data Release 7 quasar catalog. The mean redshift as a function of line width is approximately consistent with the relativistic redshift that is expected if the line originates in a randomly oriented Keplerian disk that is obscured when the inclination of the disk to the line of sight exceeds ∼30°-45°, consistent with simple active galactic nucleus unification schemes. This result also implies that the net line-of-sight inflow/outflow velocities in the broad-line region are much less than the Keplerian velocity when averaged over a large sample of quasars with a given line width.

  18. Widespread Synchronous Volcanism Reveals a Broad Galapagos Hotspot Melting Anomaly

    NASA Astrophysics Data System (ADS)

    O'Connor, J. M.; Stoffers, P.; Wijbrans, J. R.; Worthington, T. J.

    2004-12-01

    The massive aseismic ridges and associated seamounts dominating the morphology of the Panama Basin, eastern Central Pacific, have long been attributed to a Galapagos hotspot melting anomaly linked to a deep-seated mantle plume. Although these structures can provide information about the origin of hotspots and existence, or otherwise, of mantle plumes very little is known about their volcanic histories due to a lack of direct age and geochemical information. We report here 74 whole rock and 2 plagioclase 40Ar/39Ar ages for rocks dredged from 53 locations during the first systematic sampling of the Cocos, Carnegie, Coiba and Malpelo aseismic ridges and associated seamounts (F.S. SONNE PAGANINI expedition). In addition we also report ages for DSDP drill sites on Cocos, Carnegie and Coiba ridges and 7 Cocos Island subaerial samples. The distribution of new, and published ages for the Galapagos Archipelago-platform and NE end of the Cocos Ridge, show a general trend of increasing age with distance from the Galapagos Archipelago. A more dominant trend however is one of aseismic ridge-seamount formation in a progression of broad zones of synchronous, often overlapping volcanism created at discrete intervals. Broad zones of coeval Cocos and Carnegie volcanism once formed much larger regions of synchronous volcanism that have been split apart by the complex history of seafloor spreading associated with the Cocos-Nazca spreading center. We link these broad regions of synchronous volcanism to a correspondingly large hotspot melting anomaly. The present day, as yet unfragmented, zone of synchronous volcanism associated with this proposed broad hotspot is marked by the extensive region of recent volcanism extending across the Nazca and Cocos plates encompassing the Galapagos Archipelago-Platform and the Cocos Ridge as far north as Cocos Island. The complex tectonic history of the Cocos-Nazca spreading-center has controlled how the broad zones of synchronous, often overlapping

  19. Broad spectrum antibiotic compounds and use thereof

    DOEpatents

    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.

  20. Broad-band acoustic Doppler current profiler

    USGS Publications Warehouse

    Cobb, E.D.

    1993-01-01

    The broad-band acoustic Doppler current profiler is an instrument that determines velocity based on the Doppler principle by reflecting acoustic signals off sediment particles in the water. The instrument is capable of measuring velocity magnitude and direction throughout a water column and of measuring water depth. It is also capable of bottom tracking and can, therefore, keep track of its own relative position as it is moved across a channel. Discharge measurements can be made quickly and, based on limited tests, accurately with this instrument. ?? 1993.

  1. Terconazole - a new broad-spectrum antifungal.

    PubMed

    Van Cutsem, J; Van Gerven, F; Zaman, R; Janssen, P A

    1983-01-01

    Terconazole, a new triazole ketal, is found to be highly active in vitro on a wide range of yeasts and mycelium-forming fungi. The in vitro activity depends largely on the medium used. In vitro it is a potent antifungal agent in preventing the morphogenetic transformation of the yeast into the (pseudo-)mycelium form of Candida albicans. In vivo terconazole is highly active in topical treatment of various experimental models of dermatophytosis and candidosis. It also possesses moderate oral broad-spectrum activity. No side effects were observed.

  2. Broad Line Radio Galaxies with NuSTAR

    NASA Astrophysics Data System (ADS)

    Lohfink, A.; Ogle, P.; Matt, G.; Lanz, L.; Madejski, G.; Reynolds, C.; Walton, D.; Harrison, F.

    2014-07-01

    The formation of relativistic jets is an open question in AGN physics. Despite significant observational efforts it is still unclear why some AGN show strong radio jets while others do not. Of particular interest to answer this question are broad line radio galaxies, which do show a strong jet but otherwise show an X-ray spectrum similar to their radio-quiet kin. While studies of the standard X-ray band (0.5-10 keV) have not yielded any significant insights, the newly launched X-ray mission NuSTAR offers the possibility to also study the hard X-ray spectra of these sources. In combination with coordinated XMM-Newton and Suzaku observations this provides the best broad-band X-ray spectra of broad line radio galaxies to-date. In this talk I will discuss the first results from the NuSTAR Radio Galaxy program and their implications for our understanding of jet formation.

  3. Duelling winds: a model for broad-line regions.

    NASA Astrophysics Data System (ADS)

    Smith, M. D.; Raine, D. J.

    A model for broad-line regions in active galactic nuclei is discussed. When the X-ray flux from a galactic nucleus Compton-heats an accretion disc a large amount of hot gas can be released in the form of a wind. This material becomes entrained into a wind blowing from the nucleus. Provided the ram pressure of the nuclear wind exceeds that of the disc wind, it will collapse into clouds. The nuclear wind accelerates small clouds to higher velocities, corresponding to observed line widths. Large clouds fall inwards. Cloud sizes, line asymmetries and variability characteristics are determined.

  4. Ptychography with broad-bandwidth radiation

    SciTech Connect

    Enders, B. Dierolf, M.; Stockmar, M.; Pfeiffer, F.; Cloetens, P.; Thibault, P.

    2014-04-28

    Ptychography, a scanning Coherent Diffractive Imaging (CDI) technique, has quickly gained momentum as a robust method to deliver quantitative images of extended specimens. A current conundrum for the development of X-ray CDI is the conflict between a need for higher flux to reach higher resolutions and the requirement to strongly filter the incident beam to satisfy the tight coherence prerequisite of the technique. Latest developments in algorithmic treatment of ptychographic data indicate that the technique is more robust than initially assumed, so that some experimental limitations can be substantially relaxed. Here, we demonstrate that ptychography can be conducted in conditions that were up to now considered insufficient, using a broad-bandwidth X-ray beam and an integrating scintillator-based detector. Our work shows the wide applicability of ptychography and paves the way to high-throughput, high-flux diffractive imaging.

  5. Spectrophotometry of six broad absorption line QSOs

    NASA Technical Reports Server (NTRS)

    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.

  6. Broad specification fuels technology program, phase 1

    NASA Technical Reports Server (NTRS)

    Lohmann, R. P.; Jeroszko, R. A.

    1982-01-01

    An experimental evaluation was conducted to assess the impact of the use of broadened properties fuels on combustor design concepts. Emphasis was placed on establishing the viability of design modifications to current combustor concepts and the use of advanced technology concepts to facilitate operation on Experimental Referee Broad Specification (ERBS) fuel while meeting exhaust emissions and performance specifications and maintaining acceptable durability. Three different combustor concepts, representative of progressively more aggressive technology levels, were evaluated. When operated on ERBS rather than Jet A fuel, a single stage combustor typical of that in the most recent versions of the JT9D-7 engine was found to produce excess carbon monoxide emissions at idle and elevated liner temperatures at high power levels that were projected to reduced liner life by 13 percent. The introduction of improved component technology, such as refined fuel injectors and advanced liner cooling concepts were shown to have the potential of enhancing the fuel flexibility of the single stage combustor.

  7. Cefadroxil, a New Broad-Spectrum Cephalosporin

    PubMed Central

    Buck, R. E.; Price, K. E.

    1977-01-01

    Cefadroxil is a new semisynthetic cephalosporin with a broad antibacterial spectrum and a high chemotherapeutic potential when administered orally. The inhibitory activity of this compound was similar to that of cephalexin and cephradine when tested against 602 clinical isolates on Mueller-Hinton medium. In the oral treatment of experimental infections of mice, cefadroxil was more effective than cephalexin against Streptococcus pyogenes, and comparably effective against Streptococcus pneumoniae, Staphylococcus aureus, and several gram-negative species. Administered orally to mice, at doses ranging from 25 to 100 mg/kg, cefadroxil attained peak concentrations in the blood similar to those of cephalexin. At a dose of 200 mg/kg, however, higher peak levels were noted with cefadroxil than with cephalexin. In regard to other properties which were investigated, the behavior of cefadroxil compared favorably to that of cephalexin. PMID:848939

  8. The Broad-Line Region Cloud Model

    NASA Astrophysics Data System (ADS)

    Dietrich, Matthias

    Generally, it is believed that the broad-emission lines are emitted by rapidly moving clouds or filaments within the BLR. The line profiles are expected to be variable on time scales of years due to redistribution of the clouds. However, observations show that profile changes can occur more rapidly than this indicating that hydrodynamical instabilities are associated with the BLR clouds themselves. Since the number of clouds is estimated to at least ~ 10^7 it is difficult to explain how stochastic events affecting individual clouds can yield detectable profile variations. Small-scale fluctuations due to as many as 4 x 10^6 clouds would be still observable in emission-line profiles taken with high spectral resolution and high S/N ratio (cf. Capriotti et al. 1981). Echelle spectra of 3C 273 and NGC 5548 will be presented. The line profiles of H\\alpha and H\\beta have been studied with high spectral resolution (\\Delta v ~ 10 km s^{-1}). The statistical variations of the residua of the H\\alpha and H\\beta line profiles will be used to test whether this is consistent with the expected statistical scatter due to the finite number of line emitting clouds. Based on these fluctuations it will be possible to derive an estimation of the total number of emission-line clouds. The results will be compared with simulations of cloud ensembles with different distributions, geometries, and numbers of individual emitters.

  9. Multimode Broad-Band Patch Antennas

    NASA Technical Reports Server (NTRS)

    Romanofsky, Robert R.

    2003-01-01

    Microstrip patch antennas of a proposed type would be tunable over broad wavelength ranges. These antennas would be attractive for use in a variety of microwave communication systems in which there are requirements for transmission and/or reception at multiple, widely separated frequencies. Prior efforts to construct tunable microstrip patch antennas have involved integration of microstrip circuitry with, variously, ferrite films with magneticfield tuning, solid-state electronic tuning devices, or piezoelectric tuning actuators. Those efforts have been somewhat successful, but have yielded tuning ranges of 20 percent and smaller much smaller than needed in typical practical cases. Like prior microstrip patch antennas (both tunable and non-tunable), the proposed antennas would have instantaneous bandwidths of about 1 percent of their nominal or resonance frequencies. However, these would be tunable over much broader frequency ranges as much as several octaves, depending on specific designs. They could be fabricated relatively simply and inexpensively by use of conventional photolithography, and without need for integration with solid-state electronic or piezoelectric control devices. An antenna as proposed (see figure) would include a microstrip patch radiating element on a thin ferroelectric film on a semiconductor substrate with a ground-plane conductor on the underside of the substrate. The ferroelectric film could be, for example, SrTiO3 with a thickness of the order of 1 or 2 micrometers.

  10. Broad-Band Activatable White-Opsin

    PubMed Central

    Batabyal, Subrata; Cervenka, Gregory; Ha, Ji Hee; Kim, Young-tae; Mohanty, Samarendra

    2015-01-01

    Currently, the use of optogenetic sensitization of retinal cells combined with activation/inhibition has the potential to be an alternative to retinal implants that would require electrodes inside every single neuron for high visual resolution. However, clinical translation of optogenetic activation for restoration of vision suffers from the drawback that the narrow spectral sensitivity of an opsin requires active stimulation by a blue laser or a light emitting diode with much higher intensities than ambient light. In order to allow an ambient light-based stimulation paradigm, we report the development of a ‘white-opsin’ that has broad spectral excitability in the visible spectrum. The cells sensitized with white-opsin showed excitability at an order of magnitude higher with white light compared to using only narrow-band light components. Further, cells sensitized with white-opsin produced a photocurrent that was five times higher than Channelrhodopsin-2 under similar photo-excitation conditions. The use of fast white-opsin may allow opsin-sensitized neurons in a degenerated retina to exhibit a higher sensitivity to ambient white light. This property, therefore, significantly lowers the activation threshold in contrast to conventional approaches that use intense narrow-band opsins and light to activate cellular stimulation. PMID:26360377

  11. Photoionisation modelling of the broad line region

    NASA Astrophysics Data System (ADS)

    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.

  12. Broad Street elevation of the competition design for the New ...

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

    Broad Street elevation of the competition design for the New Masonic Temple, Philadelphia, by architects Collins and Authenrieth, 1867 - Masonic Temple, 1 North Broad Street, Philadelphia, Philadelphia County, PA

  13. Broad spectrum anthelmintic potential of Cassia plants

    PubMed Central

    Kundu, Suman; Roy, Saptarshi; Lyndem, Larisha Mawkhleing

    2014-01-01

    Objective To study the in vitro anthelmintic efficacy of Cassia alata (C. alata), Cassia angustifolia (C. angustifolia) and Cassia occidentalis (C. occidentalis). 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. PMID:25183125

  14. 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

    SciTech Connect

    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.

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

    PubMed

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

    2017-01-01

    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.

  16. Antibiofilm Peptides: Potential as Broad-Spectrum Agents

    PubMed Central

    2016-01-01

    The treatment of bacterial diseases is facing twin threats, with increasing bacterial antibiotic resistance and relatively few novel compounds or strategies under development or entering the clinic. Bacteria frequently grow on surfaces as biofilm communities encased in a polymeric matrix. The biofilm mode of growth is associated with 65 to 80% of all clinical infections. It causes broad adaptive changes; biofilm bacteria are especially (10- to 1,000-fold) resistant to conventional antibiotics and to date no antimicrobials have been developed specifically to treat biofilms. Small synthetic peptides with broad-spectrum antibiofilm activity represent a novel approach to treat biofilm-related infections. Recent developments have provided evidence that these peptides can inhibit even developed biofilms, kill multiple bacterial species in biofilms (including the ESKAPE [Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species] pathogens), show strong synergy with several antibiotics, and act by targeting a universal stress response in bacteria. Thus, these peptides represent a promising alternative treatment to conventional antibiotics and work effectively in animal models of biofilm-associated infections. PMID:27068589

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

    PubMed

    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.

  18. Provide, provide: the economics of aging.

    PubMed

    1998-06-26

    Most older persons face two potentially serious economic problems: (a) declining earning power and (b) declining health that can be partly offset by increased utilization of health care. The decline in earning power is largely attributable to physiological changes and to obsolescence of skills and knowledge. These adverse effects are exacerbated by public and private policies that reduce the incentives of older persons to continue work and increase the cost to employers of employing older workers. The problems of earnings replacement and health care payment are usually discussed separately, but there are several reasons why they should be considered together. First, there are often tradeoffs between the two. Money is money, and for most people there is never enough to go around. This is self-evident where private funds are concerned. Low-income elderly, for instance, frequently must choose between expensive prescription drugs and an adequate diet. For middle-income elderly, the choice may be between saving on medigap insurance or forgoing an airplane trip to a grandchild's graduation. Difficult choices are also inherent in the allocation of public funds. The same tax receipts that could be used to maintain or increase retirement benefits could be used to fund additional care, and vice versa. In discussing these tradeoffs, some analysts assert that people will gladly give up other goods and services for medical care that cures illness, relieves pain, or restores function. Others believe that some people would forgo some health insurance in order to maintain access to other goods and services. A second reason for looking at the two problems together is that they pose similar questions for public policy. How much should each generation provide for its own needs in old age, and how much should be provided by the generations that follow? How much provision should be voluntary, how much compulsory? How much intra-generational redistribution is appropriate after age 65

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

    SciTech Connect

    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.

  20. Duelling winds: A model for broad-line regions

    NASA Astrophysics Data System (ADS)

    Smith, M.

    1984-10-01

    A model for broad-line regions in which the X-ray flux from a galactic nucleus Compton-heats an accretion disk, releasing a large amount of hot gas as a wind is discussed. This material becomes entrained into a wind blowing from the nucleus. Provided the ram pressure of the nuclear wind exceeds that of the disk wind, it collapses into clouds. The nuclear wind accelerates small clouds to higher velocities, corresponding to observed line widths. Large clouds fall inwards. Cloud sizes, line asymmetries and variability characteristics are determined. While large clouds can be responsible for a blueward shift of a peak of a line, the fast-moving small clouds can enhance the red wing.

  1. Discovery of potent broad spectrum antivirals derived from marine actinobacteria.

    PubMed

    Raveh, Avi; Delekta, Phillip C; Dobry, Craig J; Peng, Weiping; Schultz, Pamela J; Blakely, Pennelope K; Tai, Andrew W; Matainaho, Teatulohi; Irani, David N; Sherman, David H; Miller, David J

    2013-01-01

    Natural products provide a vast array of chemical structures to explore in the discovery of new medicines. Although secondary metabolites produced by microbes have been developed to treat a variety of diseases, including bacterial and fungal infections, to date there has been limited investigation of natural products with antiviral activity. In this report, we used a phenotypic cell-based replicon assay coupled with an iterative biochemical fractionation process to identify, purify, and characterize antiviral compounds produced by marine microbes. We isolated a compound from Streptomyces kaviengensis, a novel actinomycetes isolated from marine sediments obtained off the coast of New Ireland, Papua New Guinea, which we identified as antimycin A1a. This compound displays potent activity against western equine encephalitis virus in cultured cells with half-maximal inhibitory concentrations of less than 4 nM and a selectivity index of greater than 550. Our efforts also revealed that several antimycin A analogues display antiviral activity, and mechanism of action studies confirmed that these Streptomyces-derived secondary metabolites function by inhibiting the cellular mitochondrial electron transport chain, thereby suppressing de novo pyrimidine synthesis. Furthermore, we found that antimycin A functions as a broad spectrum agent with activity against a wide range of RNA viruses in cultured cells, including members of the Togaviridae, Flaviviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families. Finally, we demonstrate that antimycin A reduces central nervous system viral titers, improves clinical disease severity, and enhances survival in mice given a lethal challenge with western equine encephalitis virus. Our results provide conclusive validation for using natural product resources derived from marine microbes as source material for antiviral drug discovery, and they indicate that host mitochondrial electron transport is a viable target for the

  2. Discovery of Potent Broad Spectrum Antivirals Derived from Marine Actinobacteria

    PubMed Central

    Raveh, Avi; Delekta, Phillip C.; Dobry, Craig J.; Peng, Weiping; Schultz, Pamela J.; Blakely, Pennelope K.; Tai, Andrew W.; Matainaho, Teatulohi; Irani, David N.; Sherman, David H.; Miller, David J.

    2013-01-01

    Natural products provide a vast array of chemical structures to explore in the discovery of new medicines. Although secondary metabolites produced by microbes have been developed to treat a variety of diseases, including bacterial and fungal infections, to date there has been limited investigation of natural products with antiviral activity. In this report, we used a phenotypic cell-based replicon assay coupled with an iterative biochemical fractionation process to identify, purify, and characterize antiviral compounds produced by marine microbes. We isolated a compound from Streptomyces kaviengensis, a novel actinomycetes isolated from marine sediments obtained off the coast of New Ireland, Papua New Guinea, which we identified as antimycin A1a. This compound displays potent activity against western equine encephalitis virus in cultured cells with half-maximal inhibitory concentrations of less than 4 nM and a selectivity index of greater than 550. Our efforts also revealed that several antimycin A analogues display antiviral activity, and mechanism of action studies confirmed that these Streptomyces-derived secondary metabolites function by inhibiting the cellular mitochondrial electron transport chain, thereby suppressing de novo pyrimidine synthesis. Furthermore, we found that antimycin A functions as a broad spectrum agent with activity against a wide range of RNA viruses in cultured cells, including members of the Togaviridae, Flaviviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families. Finally, we demonstrate that antimycin A reduces central nervous system viral titers, improves clinical disease severity, and enhances survival in mice given a lethal challenge with western equine encephalitis virus. Our results provide conclusive validation for using natural product resources derived from marine microbes as source material for antiviral drug discovery, and they indicate that host mitochondrial electron transport is a viable target for the

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

    SciTech Connect

    Hidalgo, Paola Rodriguez; Eracleous, Michael; Charlton, Jane; Hamann, Fred; Murphy, Michael T.; Nestor, Daniel

    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.

  4. Dependent rational providers.

    PubMed

    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.

  5. Reproductive compensation in broad-nosed pipefish females

    PubMed Central

    Goncalves, Ines Braga; Mobley, Kenyon B.; Ahnesjö, Ingrid; Sagebakken, Gry; Jones, Adam G.; Kvarnemo, Charlotta

    2010-01-01

    The differential allocation hypothesis assumes that animals should weigh costs and benefits of investing into reproduction with a current mate against the expected quality of future mates, and predicts that they should invest more into reproduction when pairing with a high-quality mate. In the broad-nosed pipefish (Syngnathus typhle), males care for the embryos in a brood pouch and females compete for access to male mating partners. Both sexes prefer mating with large partners. In the present study, we show that the same female provides both large and small mating partners with eggs of similar size, weight and lipid content when mated to two males in succession. Importantly, however, eggs provided to small males (less preferred) had higher egg protein content (11% more) than those provided to large males (preferred). Thus, contrary to the differential allocation hypothesis, eggs did not contain more resources when females mated with a larger male. Instead, the pattern observed in our results is consistent with a compensatory reproductive strategy. PMID:20106851

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

    PubMed

    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.

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

    NASA Technical Reports Server (NTRS)

    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

  8. A Broad Analysis of IL1 Polymorphism and Rheumatoid Arthritis

    PubMed Central

    Johnsen, Alyssa K.; Plenge, Robert M.; Butty, Vincent; Campbell, Christopher; Dieguez-Gonzalez, Rebeca; Gomez-Reino, Juan J.; Shadick, Nancy; Weinblatt, Michael; Gonzalez, Antonio; Gregersen, Peter K.; Benoist, Christophe; Mathis, Diane

    2008-01-01

    Objective It has been suggested that polymorphisms in IL1 are correlated with severe and/or erosive rheumatoid arthritis (RA), but the implicated alleles have differed among studies. The aim of this study was to perform a broad and well-powered search for association between allelic polymorphism in IL1A and IL1B and the susceptibility to or severity of RA. Methods Key coding and regulatory regions in IL1A and IL1B were sequenced in 24 patients with RA, revealing 4 novel single-nucleotide polymorphisms (SNPs) in IL1B. These and a comprehensive set of 24 SNPs tagging most of the underlying genetic diversity were genotyped in 3 independent RA case-control sample sets and 1 longitudinal RA cohort, totaling 3,561 patients and 3,062 control subjects. Results No fully significant associations were observed. Analysis of the discovery case-control sample sets indicated a potential association of IL1B promoter region SNPs with susceptibility to RA (for RA3/A, odds ratio [OR] 1.27, P = 0.0021) or with the incidence of radiographic erosions (for RA4/C, OR 1.56, P = 0.036), but these findings were not replicated in independent case-control samples. No association with rheumatoid factor, anti-cyclic citrullinated peptide, or the Disease Activity Score in 28 joints was found. None of the associations previously observed in other studies were replicated here. Conclusion In spite of a broad and highly powered study, we observed no robust, reproducible association between IL1A/B variants and the susceptibility to or severity of RA in white individuals of European descent. Our results provide evidence that, in the majority of cases, polymorphism in IL1A and IL1B is not a major contributor to genetic susceptibility to RA. PMID:18576312

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

    PubMed Central

    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

  10. Arizona's Application Service Provider.

    ERIC Educational Resources Information Center

    Jordan, Darla

    2002-01-01

    Describes the U.S.'s first statewide K-12 application service provider (ASP). The ASP, implemented by the Arizona School Facilities Board, provides access to productivity, communications, and education software programs from any Internet-enabled device, whether in the classroom or home. (EV)

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

    NASA Astrophysics Data System (ADS)

    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.

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

    PubMed

    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

  13. Using New Media to Reach Broad Audiences

    NASA Astrophysics Data System (ADS)

    Gay, P. L.

    2008-06-01

    The International Year of Astronomy New Media Working Group (IYA NMWG) has a singular mission: To flood the Internet with ways to learn about astronomy, interact with astronomers and astronomy content, and socially network with astronomy. Within each of these areas, we seek to build lasting programs and partnerships that will continue beyond 2009. Our weapon of choice is New Media. It is often easiest to define New Media by what it is not. Television, radio, print and their online redistribution of content are not New Media. Many forms of New Media start as user provided content and content infrastructures that answer that individual's creative whim in a way that is adopted by a broader audience. Classic examples include Blogs and Podcasts. This media is typically distributed through content specific websites and RSS feeds, which allow syndication. RSS aggregators (iTunes has audio and video aggregation abilities) allow subscribers to have content delivered to their computers automatically when they connect to the Internet. RSS technology is also being used in such creative ways as allowing automatically updating Google-maps that show the location of someone with an intelligent GPS system, and in sharing 100 word microblogs from anyone (Twitters) through a single feed. In this poster, we outline how the IYA NMWG plans to use New Media to reach target primary audiences of astronomy enthusiasts, image lovers, and amateur astronomers, as well as secondary audiences, including: science fiction fans, online gamers, and skeptics.

  14. IYA: Using New Media to Reach Broad Audiences

    NASA Astrophysics Data System (ADS)

    Gay, Pamela L.; IYA New Media Working Group

    2007-12-01

    The International Year of Astronomy New Media Working Group (IYA NMWG) seeks to flood the Internet with ways to learn about astronomy and increase interaction among professionals, amateurs, and laypeople. Our primary audiences are amateur astronomers, astronomy and space enthusiasts, and image lovers, but secondary audiences include science fiction fans, online gamers, and skeptics. We aim to build lasting programs and partnerships that will continue beyond 2009. Our weapon of choice is New Media. New Media differ from traditional media (such as television, radio, and print) in their informality. Many forms of New Media start as user-provided content. New Media content-building infrastructures answer the content provider's creative whims, and New-Media content can be commented upon, shared, borrowed, adopted, edited, and re-posted by a broad audience. Classic examples of New Media include blogs and podcasts. This media is typically distributed through content-specific websites and RSS feeds, which allow individual Internet users to select preferred streams of media (including text, audio, and video) to be delivered to them automatically.

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

    ERIC Educational Resources Information Center

    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…

  16. 48 CFR 2035.71 - Broad agency announcements.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 6 2013-10-01 2013-10-01 false Broad agency announcements. 2035.71 Section 2035.71 Federal Acquisition Regulations System NUCLEAR REGULATORY COMMISSION SPECIAL CATEGORIES OF CONTRACTING RESEARCH AND DEVELOPMENT CONTRACTING 2035.71 Broad agency announcements....

  17. VIEW EASTACROSS SOUTH BROAD STREET LEFTBUILDING 28 BLACKSMITH SHOP (1885) ...

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

    VIEW EAST-ACROSS SOUTH BROAD STREET LEFT-BUILDING 28 BLACKSMITH SHOP (1885) CENTER-REAR-BUILDING 40 WIRE WAREHOUSE (1915) RIGHT-BUILDING 32 MACHINE SHOP (1890) - John A. Roebling's Sons Company & American Steel & Wire Company, South Broad, Clark, Elmer, Mott & Hudson Streets, Trenton, Mercer County, NJ

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

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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…

  20. Testing Provides Crucial Information

    ERIC Educational Resources Information Center

    Morial, Marc H.

    2015-01-01

    The National Urban League president and CEO Marc H. Morial weighs in on what he sees as the need for continued annual assessments of students, rejecting the course of opting out that has taken hold in some places across America. Assessment data provides students with the opportunity to receive personalized supports and necessary interventions to…

  1. [Providing Effective Behavior Support.

    ERIC Educational Resources Information Center

    SAIL: Technical Assistance Journal, 1996

    1996-01-01

    This theme issue addresses the provision of behavioral support for students with behavior disorders. The first article, "Providing Effective Behavior Support to All Students: Procedures and Processes" (George Sugai), summarizes the literature on the effectiveness of various interventions and offers several models for examining the…

  2. Internet Medline providers.

    PubMed

    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

  3. Second Interim Report of the Broadly-Based Community Study of Exceptional Education.

    ERIC Educational Resources Information Center

    Milwaukee Public Schools, WI. Div. of Curriculum and Instruction.

    Presented are recommendations of a Milwaukee public school study for the purpose of providing a meaningful, effective, and comprehensive educational program for exceptional students. Fourteen recommendations covering the broad policy of exceptional education include policies on integration into normal school programs, transportation, and early…

  4. Achieving Provider Engagement

    PubMed Central

    Greenfield, Geva; Pappas, Yannis; Car, Josip; Majeed, Azeem; Harris, Matthew

    2014-01-01

    The literature on integrated care is limited with respect to practical learning and experience. Although some attention has been paid to organizational processes and structures, not enough is paid to people, relationships, and the importance of these in bringing about integration. Little is known, for example, about provider engagement in the organizational change process, how to obtain and maintain it, and how it is demonstrated in the delivery of integrated care. Based on qualitative data from the evaluation of a large-scale integrated care initiative in London, United Kingdom, we explored the role of provider engagement in effective integration of services. Using thematic analysis, we identified an evolving engagement narrative with three distinct phases: enthusiasm, antipathy, and ambivalence, and argue that health care managers need to be aware of the impact of professional engagement to succeed in advancing the integrated care agenda. PMID:25212855

  5. Providing plastic zone extrusion

    DOEpatents

    Manchiraju, Venkata Kiran; Feng, Zhili; David, Stan A.; Yu, Zhenzhen

    2017-04-11

    Plastic zone extrusion may be provided. First, a compressor may generate frictional heat in stock to place the stock in a plastic zone of the stock. Then, a conveyer may receive the stock in its plastic zone from the compressor and transport the stock in its plastic zone from the compressor. Next, a die may receive the stock in its plastic zone from the conveyer and extrude the stock to form a wire.

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

    PubMed

    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.

  7. Broad activation of latent HIV-1 in vivo

    PubMed Central

    Barton, Kirston; Hiener, Bonnie; Winckelmann, Anni; Rasmussen, Thomas Aagaard; Shao, Wei; Byth, Karen; Lanfear, Robert; Solomon, Ajantha; McMahon, James; Harrington, Sean; Buzon, Maria; Lichterfeld, Mathias; Denton, Paul W.; Olesen, Rikke; Østergaard, Lars; Tolstrup, Martin; Lewin, Sharon R.; Søgaard, Ole Schmeltz; Palmer, Sarah

    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 measure of HIV-1 reservoir size. Our findings provide insights into the effects of panobinostat and vorinostat as LRAs for latent HIV-1. PMID:27605062

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

    PubMed

    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.

  9. Rainbow Vectors for Broad-Range Bacterial Fluorescence Labeling

    PubMed Central

    Barbier, Mariette; Damron, F. Heath

    2016-01-01

    Since their discovery, fluorescent proteins have been widely used to study protein function, localization or interaction, promoter activity and regulation, drug discovery or for non-invasive imaging. They have been extensively modified to improve brightness, stability, and oligomerization state. However, only a few studies have focused on understanding the dynamics of fluorescent proteins expression in bacteria. In this work, we developed a set plasmids encoding 12 fluorescent proteins for bacterial labeling to facilitate the study of pathogen-host interactions. These broad-spectrum plasmids can be used with a wide variety of Gram-negative microorganisms including Escherichia coli, Pseudomonas aeruginosa, Burkholderia cepacia, Bordetella bronchiseptica, Shigella flexneri or Klebsiella pneumoniae. For comparison, fluorescent protein expression and physical characteristics in Escherichia coli were analyzed using fluorescence microscopy, flow cytometry and in vivo imaging. Fluorescent proteins derived from the Aequorea Victoria family showed high photobleaching, while proteins form the Discosoma sp. and the Fungia coccina family were more photostable for microscopy applications. Only E2-Crimson, mCherry and mKeima were successfully detected for in vivo applications. Overall, E2-Crimson was the fastest maturing protein tested in E. coli with the best overall performance in the study parameters. This study provides a unified comparison and comprehensive characterization of fluorescent protein photostability, maturation and toxicity, and offers general recommendations on the optimal fluorescent proteins for in vitro and in vivo applications. PMID:26937640

  10. Improved PCR Amplification of Broad Spectrum GC DNA Templates.

    PubMed

    Guido, Nicholas; Starostina, Elena; Leake, Devin; Saaem, Ishtiaq

    2016-01-01

    Many applications in molecular biology can benefit from improved PCR amplification of DNA segments containing a wide range of GC content. Conventional PCR amplification of DNA sequences with regions of GC less than 30%, or higher than 70%, is complex due to secondary structures that block the DNA polymerase as well as mispriming and mis-annealing of the DNA. This complexity will often generate incomplete or nonspecific products that hamper downstream applications. In this study, we address multiplexed PCR amplification of DNA segments containing a wide range of GC content. In order to mitigate amplification complications due to high or low GC regions, we tested a combination of different PCR cycling conditions and chemical additives. To assess the fate of specific oligonucleotide (oligo) species with varying GC content in a multiplexed PCR, we developed a novel method of sequence analysis. Here we show that subcycling during the amplification process significantly improved amplification of short template pools (~200 bp), particularly when the template contained a low percent of GC. Furthermore, the combination of subcycling and 7-deaza-dGTP achieved efficient amplification of short templates ranging from 10-90% GC composition. Moreover, we found that 7-deaza-dGTP improved the amplification of longer products (~1000 bp). These methods provide an updated approach for PCR amplification of DNA segments containing a broad range of GC content.

  11. Broad Band Intra-Cavity Total Reflection Chemical Sensor

    DOEpatents

    Pipino, Andrew C. R.

    1998-11-10

    A broadband, ultrahigh-sensitivity chemical sensor is provided that allows etection through utilization of a small, extremely low-loss, monolithic optical cavity. The cavity is fabricated from highly transparent optical material in the shape of a regular polygon with one or more convex facets to form a stable resonator for ray trajectories sustained by total internal reflection. Optical radiation enters and exits the monolithic cavity by photon tunneling in which two totally reflecting surfaces are brought into close proximity. In the presence of absorbing material, the loss per pass is increased since the evanescent waves that exist exterior to the cavity at points where the circulating pulse is totally reflected, are absorbed. The decay rate of an injected pulse is determined by coupling out an infinitesimal fraction of the pulse to produce an intensity-versus-time decay curve. Since the change in the decay rate resulting from absorption is inversely proportional to the magnitude of absorption, a quantitative sensor of concentration or absorption cross-section with 1 part-per-million/pass or better sensitivity is obtained. The broadband nature of total internal reflection permits a single device to be used over a broad wavelength range. The absorption spectrum of the surrounding medium can thereby be obtained as a measurement of inverse decay time as a function of wavelength.

  12. Broad targeting of resistance to apoptosis in cancer

    PubMed Central

    Mohammad, Ramzi M.; Muqbil, Irfana; Lowe, Leroy; Yedjou, Clement; Hsu, Hsue-Yin; Lin, Liang-Tzung; Siegelin, Markus David; Fimognari, Carmela; Kumar, Nagi B.; Dou, Q. Ping; Yang, Huanjie; Samadi, Abbas K.; Russo, Gian Luigi; Spagnuolo, Carmela; Ray, Swapan K.; Chakrabarti, Mrinmay; Morre, James D.; Coley, Helen M.; Honoki, Kanya; Fujii, Hiromasa; Georgakilas, Alexandros G.; Amedei, Amedeo; Niccolai, Elena; Amin, Amr; Ashraf, S. Salman; Helferich, William G.; Yang, Xujuan; Boosani, Chandra S.; Guha, Gunjan; Bhakta, Dipita; Ciriolo, Maria Rosa; Aquilano, Katia; Chen, Sophie; Mohammed, Sulma I.; Keith, W. Nicol; Bilsland, Alan; Halicka, Dorota; Nowsheen, Somaira; Azmi, Asfar S.

    2015-01-01

    Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer. PMID:25936818

  13. Polarization and Broad Absorption Lines in Quasars-Repeat

    NASA Astrophysics Data System (ADS)

    Antonucci, Robert

    1990-12-01

    OI 287 is a unique extragalactic source. It appears to take one property from each class of object. It is either some kind of missing link, or a new type of activity. Because of the high optical polarization, OI 287 has been classified with the blazars. However, every other blazar is variable in optical flux, polarization, and polarization angle., while OI 287 is constant at V=17, P=8%, and theta=145 degrees. Also, every other blazar has a radio source dominated by an intense flat-spectrum core, while OI 287 has an upper limit of 2% of the total 20cm flux in the core. The only group of quasars which ever shows even moderate (2-5%) constant optical polarization is the broad absorption line (BAL) objects, e.g. PHL 5200 and H1413+113. Among the BAL quasars, PHL 5200 and H1413+113 have exceptionally smooth deep, attached absorption lines, and also the highest polarization. We want to know whether OI 287 is a BAL quasar. It would be the first definite radio loud example. If it is a BAL quasar then the high polarization is really related to (and perhaps the key to) the BAL phenomenon, and we can use the techniques of spectropolarimetry to help unlock the BAL geometry. The UV spectral shape would also provide help determining the cause of polarization.

  14. Rainbow Vectors for Broad-Range Bacterial Fluorescence Labeling.

    PubMed

    Barbier, Mariette; Damron, F Heath

    2016-01-01

    Since their discovery, fluorescent proteins have been widely used to study protein function, localization or interaction, promoter activity and regulation, drug discovery or for non-invasive imaging. They have been extensively modified to improve brightness, stability, and oligomerization state. However, only a few studies have focused on understanding the dynamics of fluorescent proteins expression in bacteria. In this work, we developed a set plasmids encoding 12 fluorescent proteins for bacterial labeling to facilitate the study of pathogen-host interactions. These broad-spectrum plasmids can be used with a wide variety of Gram-negative microorganisms including Escherichia coli, Pseudomonas aeruginosa, Burkholderia cepacia, Bordetella bronchiseptica, Shigella flexneri or Klebsiella pneumoniae. For comparison, fluorescent protein expression and physical characteristics in Escherichia coli were analyzed using fluorescence microscopy, flow cytometry and in vivo imaging. Fluorescent proteins derived from the Aequorea Victoria family showed high photobleaching, while proteins form the Discosoma sp. and the Fungia coccina family were more photostable for microscopy applications. Only E2-Crimson, mCherry and mKeima were successfully detected for in vivo applications. Overall, E2-Crimson was the fastest maturing protein tested in E. coli with the best overall performance in the study parameters. This study provides a unified comparison and comprehensive characterization of fluorescent protein photostability, maturation and toxicity, and offers general recommendations on the optimal fluorescent proteins for in vitro and in vivo applications.

  15. Phenomenology of Broad Emission Lines in Active Galactic Nuclei

    NASA Astrophysics Data System (ADS)

    Sulentic, J. W.; Marziani, P.; Dultzin-Hacyan, D.

    Broad emission lines hold fundamental clues about the kinematics and structure of the central regions in AGN. In this article we review the most robust line profile properties and correlations emerging from the best data available. We identify fundamental differences between the profiles of radio-quiet and radio-loud sources as well as differences between the high- and low-ionization lines, especially in the radio-quiet majority of AGN. An Eigenvector 1 correlation space involving FWHM Hβ, W(FeIIopt)/W(Hβ), and the soft X-ray spectral index provides optimal discrimination between all principal AGN types (from narrow-line Seyfert 1 to radio galaxies). Both optical and radio continuum luminosities appear to be uncorrelated with the E1 parameters. We identify two populations of radio-quiet AGN: Population A sources (with FWHM(Hβ) <~ 4000 km s-1, generally strong FeII emission and a soft X-ray excess) show almost no parameter space overlap with radio-loud sources. Population B shows optical properties largely indistinguishable from radio-loud sources, including usually weak FeII emission, FWHM(Hβ) >~ 4000 km s-1 and lack of a soft X-ray excess. There is growing evidence that a fundamental parameter underlying Eigenvector 1 may be the luminosity-to-mass ratio of the active nucleus (L/M), with source orientation playing a concomitant role.

  16. Hypoxia elicits broad and systematic changes in protein subcellular localization

    PubMed Central

    Henke, Robert Michael; Dastidar, Ranita Ghosh; Shah, Ajit; Cadinu, Daniela; Yao, Xiao; Hooda, Jagmohan

    2011-01-01

    Oxygen provides a crucial energy source in eukaryotic cells. Hence, eukaryotes ranging from yeast to humans have developed sophisticated mechanisms to respond to changes in oxygen levels. Regulation of protein localization, like protein modifications, can be an effective mechanism to control protein function and activity. However, the contribution of protein localization in oxygen signaling has not been examined on a genomewide scale. Here, we examine how hypoxia affects protein distribution on a genomewide scale in the model eukaryote, the yeast Saccharomyces cerevisiae. We demonstrate, by live cell imaging, that hypoxia alters the cellular distribution of 203 proteins in yeast. These hypoxia-redistributed proteins include an array of proteins with important functions in various organelles. Many of them are nuclear and are components of key regulatory complexes, such as transcriptional regulatory and chromatin remodeling complexes. Under hypoxia, these proteins are synthesized and retained in the cytosol. Upon reoxygenation, they relocalize effectively to their normal cellular compartments, such as the nucleus, mitochondria, endoplasmic reticulum, and cell periphery. The resumption of the normal cellular locations of many proteins can occur even when protein synthesis is inhibited. Furthermore, we show that the changes in protein distribution induced by hypoxia follow a slower trajectory than those induced by reoxygenation. These results show that the regulation of protein localization is a common and potentially dominant mechanism underlying oxygen signaling and regulation. These results may have broad implications in understanding oxygen signaling and hypoxia responses in higher eukaryotes such as humans. PMID:21753182

  17. Providing Contraception to Adolescents.

    PubMed

    Raidoo, Shandhini; Kaneshiro, Bliss

    2015-12-01

    Adolescents have high rates of unintended pregnancy and face unique reproductive health challenges. Providing confidential contraceptive services to adolescents is important in reducing the rate of unintended pregnancy. Long-acting contraception such as the intrauterine device and contraceptive implant are recommended as first-line contraceptives for adolescents because they are highly effective with few side effects. The use of barrier methods to prevent sexually transmitted infections should be encouraged. Adolescents have limited knowledge of reproductive health and contraceptive options, and their sources of information are often unreliable. Access to contraception is available through a variety of resources that continue to expand.

  18. The Provident Sea

    NASA Astrophysics Data System (ADS)

    Cushing, David H.

    1988-09-01

    The Provident Sea describes the history of fish stock management (including whales and seals). The book traces, on the basis of the original scientific material, the history of the management of "the provident sea" up to recent times when problems of over-exploitation have had dramatic effects upon stocks. The need for management arose mainly from the increasing industrialization of capture. Hence the preindustrial fisheries are covered, in particular the old cod fishery on the Grand Bank and the herring fishery in the North Sea, as an essential background to current problems. The origins of fisheries and whaling science are described, as is the development up to 1965 of the science and institution in fisheries, whaling, and sealing. In the sixties and seventies, certain major fishing nations took a heavy harvest of fish stocks using sophisticated and efficient gathering methods. This in turn led to conflict and one consequence was the "Law of the Sea" conference set up to try and resolve these issues.

  19. Providers target industrial areas

    SciTech Connect

    Vames, S.

    1997-06-11

    Energy customers in California are negotiating new deals now that the California Public Utilities Commission has dropped its plan to gradually phase in energy deregulation. The commission has set January 1, 1998 as the date when most energy consumers in the state will be free to choose their providers. Deals currently under negotiation are mostly long-term electrical supply contracts with entire cities. Initially, the cities most likely to enter such contracts are those that wish to use the prospect of cheap energy to keep existing industry and lure new industry. One such deal has been set in South San Francisco, and industrial suburb of San Francisco with several fine chemicals and biotechnology firms. The city has signed a five-year contract with FirstPoint (Portland, OR) to provide energy and related services for residents, businesses, and industry. But while residential and small business customers expect to see only a 10% drop in their overall bills, industrial customers foresee larger savings because of discounts to large energy users offered by FirstPoint and the city.

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

    PubMed Central

    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

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

    PubMed

    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.

  2. SDSS 0956+5128: A BROAD-LINE QUASAR WITH EXTREME VELOCITY OFFSETS

    SciTech Connect

    Steinhardt, Charles L.; Schramm, Malte; Silverman, John D.; Alexandroff, Rachael; Pattarakijwanich, Petchara; Strauss, Michael A.; Capak, Peter; Civano, Francesca; Elvis, Martin; Masters, Dan; Mobasher, Bahram

    2012-11-01

    We report on the discovery of a Type 1 quasar, SDSS 0956+5128, with a surprising combination of extreme velocity offsets. SDSS 0956+5128 is a broad-lined quasar exhibiting emission lines at three substantially different redshifts: a systemic redshift of z {approx} 0.714 based on narrow emission lines, a broad Mg II emission line centered 1200 km s{sup -1} bluer than the systemic velocity, at z {approx} 0.707, and broad H{alpha} and H{beta} emission lines centered at z {approx} 0.690. The Balmer line peaks are 4100 km s{sup -1} bluer than the systemic redshift. There are no previously known objects with such an extreme difference between broad Mg II and broad Balmer emission. The two most promising explanations are either an extreme disk emitter or a high-velocity black hole recoil. However, neither explanation appears able to explain all of the observed features of SDSS 0956+5128, so the object may provide a challenge to our general understanding of quasar physics.

  3. What Drives the Outflows in Broad Absorption Line QSOs?

    NASA Technical Reports Server (NTRS)

    Begelman, Mitchell C.

    1997-01-01

    We have made progress in the areas related to the propulsion and confinement of gas responsible for broad absorption troughts in QSOs: Radiative Acceleration in BALQSOs; The "Ghost" of Lyman (alpha); and Magnetic Confinement of Absorbing Gas.

  4. What HERA May Provide?

    SciTech Connect

    Jung, Hannes; De Roeck, Albert; Bartels, Jochen; Behnke, Olaf; Blumlein, Johannes; Brodsky, Stanley; Cooper-Sarkar, Amanda; Deak, Michal; Devenish, Robin; Diehl, Markus; Gehrmann, Thomas; Grindhammer, Guenter; Gustafson, Gosta; Khoze, Valery; Knutsson, Albert; Klein, Max; Krauss, Frank; Kutak, Krzysztof; Laenen, Eric; Lonnblad, Leif; 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.

  5. Quality Control on the IBERARRY broad-band seismic network

    NASA Astrophysics Data System (ADS)

    Diaz, J.; Liguerzana, S.; Villaseñor, A.; Carbonell, R.

    2008-12-01

    Systematic quality control of the seismic recordings acquired by the IBERARRAY broad-band seismic network is carried out. As part of the standard quality control procedure of the raw seismic data, the background noise power spectral density (PSD) is regularly estimated for all the stations of the IberArray portable seismic network and is statistically analyzed to compute probability density functions (PDFs) using the PQLX software package. These PDFs provide a useful tool for managing the network, as they allow to identify stations with unacceptable high noise levels in the frequency band of interest as well as temporal changes of the noise level that may indicate the convenience of changing the location of some sites. At long periods (20-120s), the vertical components usually lie 15db above the NLNM of Peterson (1993). The horizontal components are much noisier in this frequency range, often depassing the NHNM for the longest periods. At microseismic frequencies (0.05 - 0.3 Hz), the noise level is very similar between all the stations, while at high frequencies (> 1 Hz), the main contribution seems to arise from the cultural noise and therefore produces significant variations between the stations. Among the different features observed in the PDF curves, we can highlight the day/night differences in the mean noise level, specially significant for high frequencies, the importance of the local site effects, illustrated by two stations located less than 100 km away but lying in very different terrains and the observation of noise variations related to weather conditions in the microseismic band.

  6. Broadly tunable, longitudinally diode-pumped Alexandrite laser

    NASA Astrophysics Data System (ADS)

    Strotkamp, M.; Witte, U.; Munk, A.; Hartung, A.; Gausmann, S.; Hengesbach, S.; Traub, M.; Hoffmann, H.-D.; Hoeffner, J.; Jungbluth, B.

    2014-02-01

    We present design and first performance data of a broadly tunable Alexandrite laser longitudinally pumped by a newly developed high brightness single emitter diode laser module with output in the red spectral range. Replacing the flashlamps, which are usually used for pumping Alexandrite, will increase the efficiency and maintenance interval of the laser. The pump module is designed as an optical stack of seven single-emitter laser diodes. We selected an optomechanical concept for the tight overlay of the radiation using a minimal number of optical components for collimation, e.g. a FAC and a SAC lens, and focusing. The module provides optical output power of more than 14 W (peak pulse output in the focus) with a beam quality of M2 = 41 in the fast axis and M2 = 39 in the slow axis. The Alexandrite crystal is pumped from one end at a repetition rate of 35 Hz and 200μs long pump pulses. The temperature of the laser crystal can be tuned to between 30 °C and 190 °C using a thermostat. The diode-pumped Alexandrite laser reaches a maximum optical-optical efficiency of 20 % and a slope efficiency of more than 30 % in fundamental-mode operation (M2 < 1.10). When a Findlay-Clay analysis with four different output couplers is conducted, the round-trip loss of the cavity is determined to be around 1 %. The wavelength is tunable to between 755 and 788 nm via crystal temperature or between 745 and 805 nm via an additional Brewster prism.

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

    PubMed

    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.

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

    PubMed Central

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

    2016-01-01

    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. PMID:27869733

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

    NASA Technical Reports Server (NTRS)

    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.

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

    PubMed

    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.

  11. Ultrafast pulsed laser utilizing broad bandwidth laser glass

    DOEpatents

    Payne, Stephen A.; Hayden, Joseph S.

    1997-01-01

    An ultrafast laser uses a Nd-doped phosphate laser glass characterized by a particularly broad emission bandwidth to generate the shortest possible output pulses. The laser glass is composed primarily of P.sub.2 O.sub.5, Al.sub.2 O.sub.3 and MgO, and possesses physical and thermal properties that are compatible with standard melting and manufacturing methods. The broad bandwidth laser glass can be used in modelocked oscillators as well as in amplifier modules.

  12. Ultra high vacuum broad band high power microwave window

    DOEpatents

    Nguyen-Tuong, V.; Dylla, H.F. III

    1997-11-04

    An improved high vacuum microwave window has been developed that utilizes high density polyethylene coated on two sides with SiOx, SiNx, or a combination of the two. The resultant low dielectric and low loss tangent window creates a low outgassing, low permeation seal through which broad band, high power microwave energy may be passed. No matching device is necessary and the sealing technique is simple. The features of the window are broad band transmission, ultra-high vacuum compatibility with a simple sealing technique, low voltage standing wave ratio, high power transmission and low cost. 5 figs.

  13. Ultra high vacuum broad band high power microwave window

    DOEpatents

    Nguyen-Tuong, Viet; Dylla, III, Henry Frederick

    1997-01-01

    An improved high vacuum microwave window has been developed that utilizes high density polyethylene coated on two sides with SiOx, SiNx, or a combination of the two. The resultant low dielectric and low loss tangent window creates a low outgassing, low permeation seal through which broad band, high power microwave energy may be passed. No matching device is necessary and the sealing technique is simple. The features of the window are broad band transmission, ultra-high vacuum compatibility with a simple sealing technique, low voltage standing wave ratio, high power transmission and low cost.

  14. Femtosecond soliton source with fast and broad spectral tunability.

    PubMed

    Masip, Martin E; Rieznik, A A; König, Pablo G; Grosz, Diego F; Bragas, Andrea V; Martinez, Oscar E

    2009-03-15

    We present a complete set of measurements and numerical simulations of a femtosecond soliton source with fast and broad spectral tunability and nearly constant pulse width and average power. Solitons generated in a photonic crystal fiber, at the low-power coupling regime, can be tuned in a broad range of wavelengths, from 850 to 1200 nm using the input power as the control parameter. These solitons keep almost constant time duration (approximately 40 fs) and spectral widths (approximately 20 nm) over the entire measured spectra regardless of input power. Our numerical simulations agree well with measurements and predict a wide working wavelength range and robustness to input parameters.

  15. Ultrafast pulsed laser utilizing broad bandwidth laser glass

    DOEpatents

    Payne, S.A.; Hayden, J.S.

    1997-09-02

    An ultrafast laser uses a Nd-doped phosphate laser glass characterized by a particularly broad emission bandwidth to generate the shortest possible output pulses. The laser glass is composed primarily of P{sub 2}O{sub 5}, Al{sub 2}O{sub 3} and MgO, and possesses physical and thermal properties that are compatible with standard melting and manufacturing methods. The broad bandwidth laser glass can be used in modelocked oscillators as well as in amplifier modules. 7 figs.

  16. Fluorescence-based Broad Dynamic Range Viscosity Probes.

    PubMed

    Dragan, Anatoliy; Graham, August E; Geddes, Chris D

    2014-03-01

    We introduce two new fluorescent viscosity probes, SYBR Green (SG) and PicoGreen (PG), that we have studied over a broad range of viscosity and in collagen solutions. In water, both dyes have low quantum yields and excited state lifetimes, while in viscous solvents or in complex with DNA both parameters dramatically (300-1000-fold) increase. We show that in log-log scale the dependence of the dyes' quantum yield vs. viscosity is linear, the slope of which is sensitive to temperature. Application of SG and PG, as a fluorescence-based broad dynamic range viscosity probes, to the life sciences is discussed.

  17. Time Variable Broad Line Emission in NGC 4203: Evidence for Stellar Contrails

    NASA Astrophysics Data System (ADS)

    Devereux, Nicholas A.

    2012-01-01

    Dual epoch spectroscopy of the lenticular galaxy, NGC 4203, obtained with the Hubble Space Telescope has revealed that the double-peaked component of the broad Hα emission line is time variable, increasing by a factor of 2.2 in brightness between 1999 and 2010. Modeling the gas distribution responsible for the double-peaked profiles indicates that a ring is a more appropriate description than a disk and most likely represents the contrail of a red supergiant star that is being tidally disrupted at a distance of 1500 AU from the central black hole. There is also a bright core of broad Hα line emission that is not time variable and identified with a large scale inflow from an outer radius 1 pc. If the gas number density is ≥ 106 cm-3, as suggested by the absence of similarly broad [O I] and [O III] emission lines, then the steady state inflow rate is 2 × 10-2 M⊙/yr which exceeds the inflow requirement to explain the X-ray luminosity in terms of radiatively inefficient accretion by a factor of 6. The central AGN is unable to sustain ionization of the broad line region, the discrepancy is particularly acute in 2010 when the broad Hα emission line is dominated by the contrail of the in-falling supergiant star. However, ram pressure shock ionization produced by the interaction of the in-falling supergiant with the ambient interstellar medium may help alleviate the ionizing deficit by generating a mechanical source of ionization supplementing the photoionization provided by the AGN. Support for Program number HST AR-11752.01-A was provided by NASA through a grant from the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, incorporated, under NASA contract NAS5-26555.

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

    PubMed

    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.

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

    PubMed

    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.

  20. A wide-angle and polarization insensitive infrared broad band metamaterial absorber

    NASA Astrophysics Data System (ADS)

    Xie, Ting; Chen, Zhong; Ma, Rongyi; Zhong, Min

    2017-01-01

    In this paper, we present the design and experimental demonstration of a broad single-band metamaterial absorber composed of a simple two-dimensional periodic silver-SiO2-silver sandwich array. The experimental results show that a near-perfect absorption band with a bandwidth of approximately 0.4 μm in the THz region is obtained, which is in reasonable agreement with the simulated results. The calculated electric field intensity distributions indicate that the broad absorption band is achieved by plasmonic hybridization of two plasmon resonances: one originates from outward coupling between adjacent unit cells and the other arises from inward coupling between the two sub-structures. The effects of the structural parameters and the SiO2 layer thickness on the broad absorption band are investigated experimentally. The effect of the angle of incidence on the broad absorption band is also investigated experimentally and the absorption band remains high at large angles of incidence (60°), which thus provides more efficient absorption of obliquely incident beams.

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

    PubMed Central

    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

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

    SciTech Connect

    Runco, Jordan N.; Cosens, Maren; Bennert, Vardha N.; Scott, Bryan; Komossa, S.; Malkan, Matthew A.; Treu, Tommaso; Lazarova, Mariana S.; Auger, Matthew W.; Park, Daeseong E-mail: mcosens@calpoly.edu E-mail: malkan@astro.ucla.edu E-mail: lazarovam2@unk.edu E-mail: daeseongpark@kasi.re.kr

    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.

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

    NASA Technical Reports Server (NTRS)

    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.

  4. 48 CFR 35.016 - Broad agency announcement.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... CATEGORIES OF CONTRACTING RESEARCH AND DEVELOPMENT CONTRACTING 35.016 Broad agency announcement. (a) General... Scientific Review (see 6.102(d)(2)) for the acquisition of basic and applied research and that part of... the state-of-the-art or increasing knowledge or understanding rather than focusing on a...

  5. It's Up to Us! Broad Form Deeds in Kentucky.

    ERIC Educational Resources Information Center

    Zuercher, Melanie A., Ed.

    This adult literacy curriculum best serves groups of students, but is also effective for one-on-one tutoring methods. The material covers the history of broad form deeds in Kentucky (instruments with which coal rights, but not the farmlands above the coal, were sold to mining companies) and includes four personal narratives of Kentucky residents…

  6. CHICKEN COOP AND BROAD LEAF MAPLE, LOOKING NORTHEAST. Three chicken ...

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

    CHICKEN COOP AND BROAD LEAF MAPLE, LOOKING NORTHEAST. Three chicken coops on the farm were used by both chickens and turkeys. The yards around the buildings were once fenced in to give the poultry brooding space. - Kineth Farm, Chicken Coop, 19162 STATE ROUTE 20, Coupeville, Island County, WA

  7. 48 CFR 35.016 - Broad agency announcement.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    .... This paragraph prescribes procedures for the use of the broad agency announcement (BAA) with Peer or... system or hardware solution. The BAA technique shall only be used when meaningful proposals with varying technical/scientific approaches can be reasonably anticipated. (b) The BAA, together with any...

  8. 48 CFR 35.016 - Broad agency announcement.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    .... This paragraph prescribes procedures for the use of the broad agency announcement (BAA) with Peer or... development not related to the development of a specific system or hardware procurement. BAA's may be used by... system or hardware solution. The BAA technique shall only be used when meaningful proposals with...

  9. Numerical Models of Broad Bandwidth Nanosecond Optical Parametric Oscillators

    SciTech Connect

    Bowers, M.S.; Gehr, R.J.; Smith, A.V.

    1998-10-14

    We describe results from three new methods of numerically modeling broad-bandwidth, nanosecond OPO's in the plane-wave approximate ion. They account for differences in group velocities among the three mixing waves, and also include a qutt~ttun noise model.

  10. Thinking Broadly: Financing Strategies for Comprehensive Child and Family Initiatives.

    ERIC Educational Resources Information Center

    Hayes, Cheryl D.

    In the current tight fiscal environment, it is critical for state and community leaders to think broadly and systematically about how to finance important education, family, and child services, and community development initiatives. This guide presents a conceptual framework for financing child and family services and community building and…

  11. Optimizing technology investments: a broad mission model approach

    NASA Technical Reports Server (NTRS)

    Shishko, R.

    2003-01-01

    A long-standing problem in NASA is how to allocate scarce technology development resources across advanced technologies in order to best support a large set of future potential missions. Within NASA, two orthogonal paradigms have received attention in recent years: the real-options approach and the broad mission model approach. This paper focuses on the latter.

  12. Expanding Opportunities for Urban Minorities: Housing's Role, Broadly Defined.

    ERIC Educational Resources Information Center

    Schermer, George; And Others

    Recognizing the broad range of social and economic limitations associated with residential segregation, the Ford and Rockefeller Foundations initiated a research program to define the extent of these problems and to advance strategies for dealing with them. The initial phase of the project commissioned research papers which were reviewed and…

  13. Red and Blue Shifted Broad Lines in High Luminosity QSOs

    NASA Astrophysics Data System (ADS)

    McIntosh, D. H.; Rieke, M. J.; Rix, H.-W.; Foltz, C. B.; Weymann, R. J.; Chaffee, F. H.

    1998-05-01

    We have observed a sample of 25 high luminosity QSOs, in the range 2.0 ≲ z ≲ 2.5, at 1.6micron with the near-infrared spectrograph FSPEC on the Multiple Mirror Telescope. We have measured the systemic redshift z_sys by direct detection of the strong [O 3]lambda5007 line emitted from the narrow-line-region. We have found that the broad Hβ lines, from the same spectra, have a systematic mean red shift of 530+/-80 km s(-1) with respect to systemic. From data in the literature, we have found that the high ionization, rest-frame ultraviolet broad lines C 4lambda1549 and Lyalpha are systematically blue shifted ~ 1500 km s(-1) and ~ 1000 km s(-1) , respectively, from systemic. Therefore, estimating the ionizing flux from the inter-galactic-medium J_ν() IGM via the Proximity Effect, using redshift measurements from these two broad line species, results in an over-estimation of J_ν() IGM by factors of 2.5-4.0. Furthermore, related calculations of the lower limit for the density of baryons Omega_b will be over-estimated by factors of 1.6-2.0. However, the low ionization broad line Mg 2lambda2798 is within 100 km s(-1) of systemic, and thus would be the line of choice for determining the true redshift of distant (z>1) QSOs without near-infrared spectroscopy.

  14. The Broad Autism Phenotype. Findings from an Epidemiological Survey

    ERIC Educational Resources Information Center

    Micali, N.; Chakrabarti, S.; Fombonne, E.

    2004-01-01

    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…

  15. Mathematical Development: The Role of Broad Cognitive Processes

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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…

  17. Effects of broad frequency vibration on cultured osteoblasts

    NASA Technical Reports Server (NTRS)

    Tanaka, Shigeo M.; Li, Jiliang; Duncan, Randall L.; Yokota, Hiroki; Burr, David B.; Turner, Charles H.

    2003-01-01

    Bone is subjected in vivo to both high amplitude, low frequency strain, incurred by locomotion, and to low amplitude, broad frequency strain. The biological effects of low amplitude, broad frequency strain are poorly understood. To evaluate the effects of low amplitude strains ranging in frequency from 0 to 50 Hz on osteoblastic function, we seeded MC3T3-E1 cells into collagen gels and applied the following loading protocols for 3 min per day for either 3 or 7 days: (1) sinusoidal strain at 3 Hz, with 0-3000 microstrain peak-to-peak followed by 0.33 s resting time, (2) "broad frequency vibration" of low amplitude strain (standard deviation of 300 microstrain) including frequency components from 0 to 50 Hz, and (3) sinusoidal strain combined with broad frequency vibration (S + V). The cells were harvested on day 4 or 8. We found that the S + V stimulation significantly repressed cell proliferation by day 8. Osteocalcin mRNA was up-regulated 2.6-fold after 7 days of S + V stimulation, and MMP-9 mRNA was elevated 1.3-fold after 3 days of vibration alone. Sinusoidal stimulation alone did not affect the cell responses. No differences due to loading were observed in alkaline phosphatase activity and in mRNA levels of type I collagen, osteopontin, connexin 43, MMPs-1A, -3, -13. These results suggest that osteoblasts are more sensitive to low amplitude, broad frequency strain, and this kind of strain could sensitize osteoblasts to high amplitude, low frequency strain. This suggestion implies a potential contribution of stochastic resonance to the mechanical sensitivity of osteoblasts. Copyright 2002 Elsevier Science Ltd.

  18. 27. Yards north of Branch Avenue Bridge. Providence, Providence Co., ...

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

    27. Yards north of Branch Avenue Bridge. Providence, Providence Co., RI. Sec. 4116, mp 186.25. - Northeast Railroad Corridor, Amtrak route between CT & MA state lines, Providence, Providence County, RI

  19. 28. Yards north of Branch Avenue Bridge. Providence, Providence Co., ...

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

    28. Yards north of Branch Avenue Bridge. Providence, Providence Co., RI. Sec. 4116, mp 186.25. - Northeast Railroad Corridor, Amtrak route between CT & MA state lines, Providence, Providence County, RI

  20. Comparison of PA imaging by narrow beam scanning and one-shot broad beam excitation

    NASA Astrophysics Data System (ADS)

    Xia, Jinjun; Wei, Chen-Wei; Huang, Lingyun; Pelivanov, I. M.; O'Donnell, Matthew

    2011-03-01

    Current systems designed for deep photoacoustic (PA) imaging typically use a low repetition rate, high power pulsed laser to provide a ns-scale pulse illuminating a large tissue volume. Acoustic signals recorded on each laser firing can be used to reconstruct a complete 2-D (3-D) image of sources of heat release within that region. Using broad-beam excitation, the maximum frame rate of the imaging system is restricted by the pulse repetition rate of the laser. An alternate illumination approach is proposed based on fast scanning by a low energy (~ 1 mJ) high repetition rate (up to a few kHz) narrow laser beam (~1 mm) along the tissue surface over a region of interest. A final PA image is produced from the summation of individual PA images reconstructed at each laser beam position. This concept can take advantage of high repetition rate fiber lasers to create PA images with much higher frame rates than current systems, enabling true real-time integration of photoacoustics with ultrasound imaging. As an initial proof of concept, we compare conventional broad beam illumination to a scanned beam approach in a simple model system. Two transparent teflon tubes with diameters of 1.6 mm and 0.8 mm were filled with ink having an absorption coefficient of 5 cm-1. These tubes were buried inside chicken breast tissue acting as an optical scattering medium. They were separated by 3 mm or 10 mm to test spatial and contrast resolution for the two scan formats. The excitation wavelength was 700 nm. The excitation source is a traditional OPO pumped by a Q-switched Nd:YAG laser with doubler. Photoacoustic images were reconstructed using signals from a small, scanned PVDF transducer acting as an acoustic array. Two different illumination schemes were compared: one was 15 mm x 10 mm in cross section and acted as the broad beam; the other was 5 mm x 2 mm in cross section (15 times smaller than the broad beam case) and was scanned over an area equivalent to broad beam illumination

  1. Interpretation of broad-band seismograms from central Aleutian earthquakes.

    USGS Publications Warehouse

    Engdahl, E.R.; Kind, R.

    1986-01-01

    Broad-band Graefenberg (GRF) array data from 11 moderate-size shallow-depth earthquakes in the central Aleutians have been used to study the effects of focal depth and structure across the arc on observed waveforms. The theoretical results, primarily phase arrival times, suggest that arc structure is responsible for many of the complicated features seen on vertical-component summation seismograms simulated with different instrument responses from the broad-band array data. Except for one trench event, all the earthquakes studied occurred along the plate interface zone, had similar thrust focal mechanisms, and differed only in depth. As a result, the effects of depth phases on observed GRF waveforms across the arc were found to be systematically related to the increase in focal depth along the shallow-dipping seismic zone. -from Authors

  2. The precipitation synthesis of broad-spectrum UV absorber nanoceria

    NASA Astrophysics Data System (ADS)

    Nurhasanah, Iis; Sutanto, Heri; Puspaningrum, Nurul Wahyu

    2013-09-01

    In this paper the possibility of nanoceria as broad-spectrum UV absorber was evaluated. Nanoceria were synthesized by precipitation process from cerium nitrate solution and ammonium hydroxide as precipitant agent. Isopropanol was mixed with water as solvent to prevent hard agglomeration. The structure of resulting nanoceria was characterized by x-ray diffractometer (XRD). The transparency in the visible light and efficiency of protection in UV A region were studied using ultraviolet-visible (UV - Vis) spectrophotometer. The results show that nanoceria possess good tranparency in visible light and high UV light absorption. The critical absorption wavelenght of 368 nm was obtained which is desirable for excellent broad-spectrum protection absorbers. Moreover, analysis of photodegradation nanoceria to methylene blue solution shows poor photocatalytic activity. It indicates that nanoceria suitable for used as UV absorber in personal care products.

  3. Experimental evaluation of combustor concepts for burning broad property fuels

    NASA Technical Reports Server (NTRS)

    Kasper, J. M.; Ekstedt, E. E.; Dodds, W. J.; Shayeson, M. W.

    1980-01-01

    A baseline CF6-50 combustor and three advanced combustor designs were evaluated to determine the effects of combustor design on operational characteristics using broad property fuels. Three fuels were used in each test: Jet A, a broad property 13% hydrogen fuel, and a 12% hydrogen fuel blend. Testing was performed in a sector rig at true cruise and simulated takeoff conditions for the CF6-50 engine cycle. The advanced combustors (all double annular, lean dome designs) generally exhibited lower metal temperatures, exhaust emissions, and carbon buildup than the baseline CF6-50 combustor. The sensitivities of emissions and metal temperatures to fuel hydrogen content were also generally lower for the advanced designs. The most promising advanced design used premixing tubes in the main stage. This design was chosen for additional testing in which fuel/air ratio, reference velocity, and fuel flow split were varied.

  4. The precipitation synthesis of broad-spectrum UV absorber nanoceria

    SciTech Connect

    Nurhasanah, Iis; Sutanto, Heri; Puspaningrum, Nurul Wahyu

    2013-09-09

    In this paper the possibility of nanoceria as broad-spectrum UV absorber was evaluated. Nanoceria were synthesized by precipitation process from cerium nitrate solution and ammonium hydroxide as precipitant agent. Isopropanol was mixed with water as solvent to prevent hard agglomeration. The structure of resulting nanoceria was characterized by x-ray diffractometer (XRD). The transparency in the visible light and efficiency of protection in UV A region were studied using ultraviolet-visible (UV - Vis) spectrophotometer. The results show that nanoceria possess good tranparency in visible light and high UV light absorption. The critical absorption wavelenght of 368 nm was obtained which is desirable for excellent broad-spectrum protection absorbers. Moreover, analysis of photodegradation nanoceria to methylene blue solution shows poor photocatalytic activity. It indicates that nanoceria suitable for used as UV absorber in personal care products.

  5. Broad Consent For Research With Biological Samples: Workshop Conclusions

    PubMed Central

    Grady, Christine; Eckstein, Lisa; Berkman, Ben; Brock, Dan; Cook-Deegan, Robert; Fullerton, Stephanie M.; Greely, Hank; Hansson, Mats G.; Hull, Sara; Kim, Scott; Lo, Bernie; Pentz, Rebecca; Rodriguez, Laura; Weil, Carol; Wilfond, Benjamin S.; Wendler, David

    2016-01-01

    Different types of consent are used to obtain human biospecimens for future research. This variation has resulted in confusion regarding what research is permitted, inadvertent constraints on future research, and research proceeding without consent. The NIH Clinical Center’s Department of Bioethics held a workshop to consider the ethical acceptability of addressing these concerns by using broad consent for future research on stored biospecimens. Multiple bioethics scholars, who have written on these issues, discussed the reasons for consent, the range of consent strategies, gaps in our understanding, and concluded with a proposal for broad initial consent coupled with oversight and, when feasible, ongoing provision of information to donors. The manuscript describes areas of agreement as well as areas that need more research and dialogue. Given recent proposed changes to the Common Rule, and new guidance regarding storing and sharing data and samples, this is an important and timely topic. PMID:26305750

  6. Lateral modes of broad area semiconductor lasers - Theory and experiment

    NASA Technical Reports Server (NTRS)

    Lang, Robert J.; Larsson, Anders G.; Cody, Jeffrey G.

    1991-01-01

    Calculations of the lateral modes of an ideal broad area laser, including the nonlinear interaction between the carriers and the optical field, are made. The results include periodically modulated near fields and single- and double-lobed far fields similar to those previously measured. The unsaturable losses are higher and quantum efficiencies are lower than those determined from plane-wave approximations. Broad area InGaAs-GaAlAs-GaAs quantum-well lasers were fabricated and measured and found to closely agree with the theory in near, far, and spectrally resolved near fields. An occultation experiment on the far field confirms previously predicted unstable resonatorlike modes with V-shaped fronts.

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

    SciTech Connect

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

    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.

  8. Broad Absorption Line Quasar catalogues with Supervised Neural Networks

    SciTech Connect

    Scaringi, Simone; Knigge, Christian; Cottis, Christopher E.; Goad, Michael R.

    2008-12-05

    We have applied a Learning Vector Quantization (LVQ) algorithm to SDSS DR5 quasar spectra in order to create a large catalogue of broad absorption line quasars (BALQSOs). We first discuss the problems with BALQSO catalogues constructed using the conventional balnicity and/or absorption indices (BI and AI), and then describe the supervised LVQ network we have trained to recognise BALQSOs. The resulting BALQSO catalogue should be substantially more robust and complete than BI-or AI-based ones.

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

    NASA Astrophysics Data System (ADS)

    Zachoval, Zbyněk; Roušar, Ladislav

    2015-05-01

    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.

  10. Very Broad Band VHF/UHF Omnidirectional Antenna Design Study

    DTIC Science & Technology

    1989-12-01

    antennas, is unsuitable for the given appli- cation because its pattern is bi- directional and produces a broad lobe perpendicular to both sides of the...starting point for the new design. The objective was to modify the LPDA to fit the A/V and concurrently achieve a nearly omni- directional radiation pattern...has been included in this review. In particular, many conformal designs including microstrip patch, stripline, slot, and cavity antennas have been

  11. Broad band variability of SS433: accretion disk at work?

    NASA Astrophysics Data System (ADS)

    Revnivtsev, M.; Fabrika, S.; Abolmasov, P.; Postnov, K.; Bikmaev, I.; Burenin, R.; Pavlinsky, M.; Sunyaev, R.; Khamitov, I.; Sakhibullin, N.

    2006-02-01

    We present broad band power spectra of variations of SS433 in radio, optical and X-ray spectral bands. We show that at frequencies lower than 10-5 Hz the source demonstrates the same variability pattern in all these bands. The broad band power spectrum can be fitted by one power law down to frequencies 10-7 Hz with flattening afterwards. Such a flattening means that on time scales longer than 107 s the source variability becomes uncorrelated. This naturally leads to the appearance of quasi-poissonian flares in the source light curve, which have been regularly observed in radio and optical spectral bands. The radio flux power spectrum appears to have a second break at Fourier frequencies ˜ 10-5 Hz which can be caused by the smearing of the intrinsic radio variability on timescale of the light-crossing time of the radio emitting region. We find a correlation of the radio and optical fluxes of SS433 and the radio flux is delayed by about ˜ 2 days with respect to the optical one. Power spectra of optical and X-ray variabilities continue with the same power law from 10-7 Hz up to 0.01{-}0.05 Hz. The broad band power spectrum of SS433 can be interpreted in terms of self-similar accretion rate modulations in the accretion disk proposed by Lyubarskii (1997, MNRAS, 292, 679) and elaborated by Churazov et al. (2001, MNRAS, 321, 759). We discuss a viscous time-scale in the accretion disk of SS433 with reference to the observed broad band power spectrum.

  12. Broad Halpha Wing Formation in the Planetary Nebula IC 4997.

    PubMed

    Lee; Hyung

    2000-02-10

    The young and compact planetary nebula IC 4997 is known to exhibit very broad wings with a width exceeding 5000 km s-1 around Halpha. We propose that the broad wings are formed through Rayleigh-Raman scattering that involves atomic hydrogen, by which Lybeta photons with a velocity width of a few 102 km s-1 are converted to optical photons and fill the Halpha broad wing region. The conversion efficiency reaches 0.6 near the line center, where the scattering optical depth is much larger than 1, and rapidly decreases in the far wings. Assuming that close to the central star there exists an unresolved inner compact core of high density, nH approximately 109-1010 cm-3, we use the photoionization code "CLOUDY" to show that sufficient Lybeta photons for scattering are produced. Using a top-hat-incident profile for the Lybeta flux and a scattering region with a H i column density NHi=2x1020 cm-2 and a substantial covering factor, we perform a profile-fitting analysis in order to obtain a satisfactory fit to the observed flux. We briefly discuss the astrophysical implications of the Rayleigh-Raman processes in planetary nebulae and other emission objects.

  13. Delayering of Microelectronic Devices Using an Adjustable Broad-Beam Ion Source

    NASA Astrophysics Data System (ADS)

    Robins, A. C.; Cerchiara, R. R.; Fischione, P. E.; Boccabella, M. F.; Matesa, J. M.; Marsh, L. M.; Zhang, Z.

    2013-11-01

    Analysis of the integrated circuits of a microelectronic device depends on delayering. Focused ion beam (FIB) or broad ion beam (BIB) milling are effective complementary methods of delayering. FIB provides higher removal rates, but is limited in the effective area that can be revealed per unit time, while BIB provides lower removal rates, but has the advantage with respect to the size of the field of view produced. Microstructural features and the appearance of defects were identified and tracked for two model systems: Cu vias and Cu TSVs (through-silicon vias).

  14. Broadly tunable dual-wavelength light source for coherent anti-Stokes Raman scattering microscopy.

    PubMed

    Ganikhanov, Feruz; Carrasco, Silvia; Sunney Xie, X; Katz, Mordechai; Seitz, Wolfgang; Kopf, Daniel

    2006-05-01

    The signal and idler beams from a picosecond, synchronously pumped optical parametric oscillator (OPO) provide the two colors necessary for coherent anti-Stokes Raman scattering (CARS) microscopy. The OPO provides a continuously tunable frequency difference between the two beams over a broad range of Raman shifts (100-3700 cm(-1)) by varying the temperature of a single nonlinear crystal. The near-infrared output (900-1300 nm) allows for deep penetration into thick samples and reduced nonlinear photodamage. Applications of this light source to in vivo cell and ex vivo tissue imaging are demonstrated.

  15. Stapled HIV-1 Peptides Recapitulate Antigenic Structures and Engage Broadly Neutralizing Antibodies

    PubMed Central

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

    2014-01-01

    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. PMID:25420104

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

    SciTech Connect

    Ryskamp, J.M.; 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.

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

    SciTech Connect

    Ryskamp, J.M.; 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.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed Central

    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

  2. Spatial evolution of filaments in broad area diode laser amplifiers

    NASA Astrophysics Data System (ADS)

    Lang, Robert J.; Mehuys, David; Hardy, Amos; Dzurko, Ken M.; Welch, David F.

    1993-03-01

    We report a numerical model that demonstrates the evolution of a uniform array of filaments from random fluctuations in the input of a single-pass semiconductor laser amplifier. We also report the first direct experimental observation of the spatial evolution of filaments in a broad area active grating semiconductor laser amplifier. The observed filamentation shows good agreement with the numerical model. This agreement suggests that such filaments may result from the unstable growth of microscopic fluctuations in the input and/or nonuniformities within the amplifier.

  3. Earthquake response considerations of broad liquid storage tanks

    NASA Astrophysics Data System (ADS)

    Cambra, F. J.

    1982-11-01

    The influences of tank geometry and foundation stiffness variation on the simulated seismic structural response of a model broad tank are discussed. An empirical method for describing tank bottom plate uplift geometry is proposed which recognizes radial catenary force and foundation stiffness. Axial symmetric lift, static tilt and dynamic shaking table tests were performed in the University of California, Berkeley, earthquake simulator laboratory. A structural geometric survey of a 63 ft - 10 inches tall by 289 ft - 6 inches diameter crude oil storage tank was conducted to establish a comparative base by which to evaluate the model tank eccentricities.

  4. Frequency narrowing of a 25 W broad area diode laser

    NASA Astrophysics Data System (ADS)

    Sell, J. F.; Miller, W.; Wright, D.; Zhdanov, B. V.; Knize, R. J.

    2009-02-01

    We report on the spectral narrowing of a high powered (25 W) broad area diode laser using an external cavity with a holographic diffraction grating. In a Littman-Metcalf configuration, the external cavity is able to reduce the linewidth of the diode laser to primarily a single longitudinal mode (1.8 MHz) for output powers of ≤10 W at 852 nm. Many physics applications could benefit from such high powered, narrow linewidth lasers; however both the frequency stability and the spatial profile of the output beam show room for improvement.

  5. Redshifted and Blueshifted Broad Lines in Luminous Quasars

    NASA Astrophysics Data System (ADS)

    McIntosh, D. H.; Rix, H.-W.; Rieke, M. J.; Foltz, C. B.

    1999-06-01

    We have observed a sample of 22 luminous quasars, in the range 2.0<~z<~2.5, at 1.6 μm with the near-infrared (NIR) spectrograph FSPEC on the Multiple Mirror Telescope. Our sample contains 13 radio-loud and nine radio-quiet objects. We have measured the systemic redshifts zsys directly from the strong [O III] λ5007 line emitted from the narrow-line region. From the same spectra, we have found that the nonresonance broad Hβ lines have a systematic mean redward shift of 520+/-80 km s-1 with respect to systemic. Such a shift was not found in our identical analysis of the low-redshift sample of Boroson & Green. The amplitude of this redshift is comparable to half the expected gravitational redshift and transverse Doppler effects and is consistent with a correlation between redshift differences and quasar luminosity. From data in the literature, we confirm that the high-ionization rest-frame ultraviolet broad lines are blueshifted ~550-1050 km s-1 from systemic and that these velocity shifts systematically increase with ionization potential. Our results allow us to quantify the known bias in estimating the ionizing flux from the intergalactic medium JIGMν via the proximity effect. Using redshift measurements commonly determined from strong broad-line species, like Lyα or C IV λ1549, results in an overestimation of JIGMν by factors of ~1.9-2.3. Similarly, corresponding lower limits on the density of baryons Ωb will be overestimated by factors of ~1.4-1.5. However, the low-ionization Mg II λ2798 broad line is within ~50 km s-1 of systemic and thus would be the line of choice for determining the true redshift of 1.03.1 objects using NIR spectroscopy. Observations reported here were obtained at the Multiple Mirror Telescope Observatory, a facility operated jointly by the University of Arizona and the Smithsonian Institution.

  6. 4. Looking east towards the Broad Street Bridge at Fall ...

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

    4. Looking east towards the Broad Street Bridge at Fall No. 2. A dam extended from the rock abutment, visible on the left, to a point just above Monadnock Mill No. 1, the right border in the photo. Water entered a canal on the south side of the dam, an area under the 1 1/2 story wood structure, and then flowed into Mill No. 1 where it powered a breast wheel. The long 3-story building was the Cloth Room Building/Old Bleach House. - Claremont Village Industrial District, Between B, Claremont, Sullivan County, NH

  7. Low-noise cryogenically cooled broad-band microwave preamplifiers

    NASA Astrophysics Data System (ADS)

    Leskovar, B.

    1987-04-01

    The present noise performance, bandwidth capability and gain stability of low-noise cryogenically cooled broad-band preamplifiers are summarized and reviewed in the 150 MHz to 4 GHz frequency range. Stability factor of Gallium Arsenide Field-Effect transistors as a function of frequency and ambient temperature is presented and discussed. Also, other performance data, such as gain nonuniformity, phase shift as a function of frequency, and voltage standing-wave ratio, of several low-noise wide-band preamplifiers of interest for research instrumentation systems are presented.

  8. Assessment of autonomic response by broad-band respiration

    NASA Technical Reports Server (NTRS)

    Berger, R. D.; Saul, J. P.; Cohen, R. J.

    1989-01-01

    We present a technique for introducing broad-band respiratory perturbations so that the response characteristics of the autonomic nervous system can be determined noninvasively over a wide range of physiologically relevant frequencies. A subject's respiratory bandwidth was broadened by breathing on cue to a sequence of audible tones spaced by Poisson intervals. The transfer function between the respiratory input and the resulting instantaneous heart rate was then computed using spectral analysis techniques. Results using this method are comparable to those found using traditional techniques, but are obtained with an economy of data collection.

  9. Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus.

    PubMed

    Giang, Erick; Dorner, Marcus; Prentoe, Jannick C; Dreux, Marlène; Evans, Matthew J; Bukh, Jens; Rice, Charles M; Ploss, Alexander; Burton, Dennis R; Law, Mansun

    2012-04-17

    Hepatitis C virus (HCV) infects ∼2% of the world's population. It is estimated that there are more than 500,000 new infections annually in Egypt, the country with the highest HCV prevalence. An effective vaccine would help control this expanding global health burden. HCV is highly variable, and an effective vaccine should target conserved T- and B-cell epitopes of the virus. Conserved B-cell epitopes overlapping the CD81 receptor-binding site (CD81bs) on the E2 viral envelope glycoprotein have been reported previously and provide promising vaccine targets. In this study, we isolated 73 human mAbs 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 CD81bs 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 to HCV.

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

    PubMed

    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.

  11. Ray-based geoacoustic inversion for high frequency broad band data

    NASA Astrophysics Data System (ADS)

    Siderius, Martin; Hursky, Paul; Porter, Michael

    2003-04-01

    One of the difficulties in making reliable acoustic propagation predictions in shallow water is the lack of good information about the seabed type. In recent years, matched field processing- (MFP-) based geoacoustic inversion has been shown as a practical technique for estimating properties of the seabed. The MFP inversion method compares measured acoustic fields to those generated using an acoustic propagation model. Often, thousands of forward model calculations are required to find a set of seabed parameters that correlate well with the measured data. The large number of forward model calculations is computationally demanding and this is made worse when matching at higher frequencies or over broad band data. Ray-based propagation modeling relieves some of the computational burden since the calculation time is fairly insensitive to frequency and is inherently broad band. Further, the ray arrival amplitudes and delays are well suited for interpolation and this allows the seabed parameter search space to be explored using just a few ray trace calculations. The broad band nature of the modeled data provides flexibility in choosing correlation functions and this allows for more robust inversions. In this presentation, techniques using ray-based propagation modeling will be applied to the geoacoustic inversion problem.

  12. A Broad 22 Micron Emission Feature in the Carina Nebula H ii Region.

    PubMed

    Chan; Onaka

    2000-04-10

    We report the detection of a broad 22 µm emission feature in the Carina Nebula H ii region by the Infrared Space Observatory (ISO) short-wavelength spectrometer. The feature shape is similar to that of the 22 µm emission feature of newly synthesized dust observed in the Cassiopeia A supernova remnant. This finding suggests that both of the features are arising from the same carrier and that supernovae are probably the dominant production sources of this new interstellar grain. A similar broad emission dust feature is also found in the spectra of two starburst galaxies from the ISO archival data. This new dust grain could be an abundant component of interstellar grains and can be used to trace the supernova rate or star formation rate in external galaxies. The existence of the broad 22 µm emission feature complicates the dust model for starburst galaxies and must be taken into account correctly in the derivation of dust color temperature. Mg protosilicate has been suggested as the carrier of the 22 µm emission dust feature observed in Cassiopeia A. The present results provide useful information in studies on the chemical composition and emission mechanism of the carrier.

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

    SciTech Connect

    Kubota-Koketsu, Ritsuko; Mizuta, Hiroyuki; Oshita, Masatoshi; Ideno, Shoji; Yunoki, Mikihiro; Kuhara, Motoki; Yamamoto, Naomasa; Okuno, Yoshinobu; Ikuta, Kazuyoshi

    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.

  14. Broad-scale patterns of abundance of non-indigenous soft-bottom invertebrates in Denmark

    NASA Astrophysics Data System (ADS)

    Thomsen, Mads S.; Wernberg, Thomas; Silliman, Brian R.; Josefson, Alf B.

    2009-06-01

    Quantifying the broad-scale distribution and abundance of non-indigenous species (NIS) is necessary to provide accurate estimations on impacts of invasions, to prioritize research, and to guide national management. Sediment grab-sampling is a standardized method for monitoring marine benthos. In Denmark, ~45,000 grab-samples were collected from 1970 to 2005. Using these samples, we compared densities of NIS and native species among 27 broad spatio-temporal groupings. Eight known NIS and one ‘cryptogenic species’ (the polychaete Neanthes succinea) were found in the samples. Most were present in low abundance, but the bivalve Mya arenaria, likely introduced by the vikings from North America, was particularly abundant. M. arenaria was found in ca. 20% of all samples and was among the 10 most common species in all of Denmark. M. arenaria’s high abundance, high filtration capacity and importance in food-web interactions, suggest that this species has dramatically impacted shallow coastal ecosystems in Denmark. The polychaete Marenzelleria viridis, the gastropod Potamopyrgus antipodarum and N. succinea were also widespread and abundant, and they too are likely to have had broad-scale impacts. In conclusion, 28% of grab-samples collected in Denmark over 35 years were affected by some degree of NIS or cryptogenic species, suggesting that centuries of human-mediated transfer of organisms has had a profound impact on the ecology of soft-bottom systems in Denmark.

  15. Broad Surveys of DNA Viral Diversity Obtained through Viral Metagenomics of Mosquitoes

    PubMed Central

    Ng, Terry Fei Fan; Willner, Dana L.; Lim, Yan Wei; Schmieder, Robert; Chau, Betty; Nilsson, Christina; Anthony, Simon; Ruan, Yijun; Rohwer, Forest; Breitbart, Mya

    2011-01-01

    Viruses are the most abundant and diverse genetic entities on Earth; however, broad surveys of viral diversity are hindered by the lack of a universal assay for viruses and the inability to sample a sufficient number of individual hosts. This study utilized vector-enabled metagenomics (VEM) to provide a snapshot of the diversity of DNA viruses present in three mosquito samples from San Diego, California. The majority of the sequences were novel, suggesting that the viral community in mosquitoes, as well as the animal and plant hosts they feed on, is highly diverse and largely uncharacterized. Each mosquito sample contained a distinct viral community. The mosquito viromes contained sequences related to a broad range of animal, plant, insect and bacterial viruses. Animal viruses identified included anelloviruses, circoviruses, herpesviruses, poxviruses, and papillomaviruses, which mosquitoes may have obtained from vertebrate hosts during blood feeding. Notably, sequences related to human papillomaviruses were identified in one of the mosquito samples. Sequences similar to plant viruses were identified in all mosquito viromes, which were potentially acquired through feeding on plant nectar. Numerous bacteriophages and insect viruses were also detected, including a novel densovirus likely infecting Culex erythrothorax. Through sampling insect vectors, VEM enables broad survey of viral diversity and has significantly increased our knowledge of the DNA viruses present in mosquitoes. PMID:21674005

  16. THE LICK AGN MONITORING PROJECT: ALTERNATE ROUTES TO A BROAD-LINE REGION RADIUS

    SciTech Connect

    Greene, Jenny E.; Hood, Carol E.; Barth, Aaron J.; Bentz, Misty C.; Walsh, Jonelle L.; Bennert, Vardha N.; Treu, Tommaso; Filippenko, Alexei V.; Gates, Elinor; Malkan, Matthew A.; Woo, Jong-Hak

    2010-11-01

    It is now possible to estimate black hole (BH) masses across cosmic time, using broad emission lines in active galaxies. This technique informs our views of how galaxies and their central BHs coevolve. Unfortunately, there are many outstanding uncertainties associated with these 'virial' mass estimates. One of these comes from using the accretion luminosity to infer a size for the broad-line region (BLR). Incorporating the new sample of low-luminosity active galaxies from our recent monitoring campaign at Lick Observatory, we recalibrate the radius-luminosity relation with tracers of the accretion luminosity other than the optical continuum. We find that the radius of the BLR scales as the square root of the X-ray and H{beta} luminosities, in agreement with recent optical studies. On the other hand, the scaling appears to be marginally steeper with narrow-line luminosities. This is consistent with a previously observed decrease in the ratio of narrow-line to X-ray luminosity with increasing total luminosity. The radius of the BLR correlates most tightly with H{beta} luminosity, while the X-ray and narrow-line relations both have comparable scatter of a factor of 2. These correlations provide useful alternative virial BH masses in objects with no detectable optical/UV continuum emission, such as high-redshift galaxies with broad emission lines, radio-loud objects, or local active galaxies with galaxy-dominated continua.

  17. The Size, Structure and Ionization of the Broad Line Region in NGC 3227

    NASA Astrophysics Data System (ADS)

    Devereux, Nicholas A.

    2013-01-01

    Hubble Space Telescope spectroscopy of the Seyfert 1.5 galaxy, NGC 3227, confirms previous reports that the broad Hα emission line flux is time variable, decreasing by a modest ~ 11% between 1999 and 2000 in response to a corresponding ~ 37% decrease in the underlying continuum. Modeling the gas distribution responsible for the broad Hα, Hβ and Hγ emission lines favors a spherically symmetric inflow as opposed to a thin disk. Adopting a central black hole mass of 7.6 x 106 M⊙, determined from prior reverberation mapping, leads to the following dimensions for the size of the region emitting the broad Hα line; an outer radius ~ 90 l.d and an inner radius ~ 3 l.d. Thus, the previously determined reverberation size for the broad line region (BLR) consistently coincides with the inner radius of a much larger volume of ionized gas. However, the perceived size of the BLR is an illusion, a consequence of the fact that the emitting region is ionization bounded at the outer radius and diminished by Doppler broadening at the inner radius. The actual dimensions of the inflow remain to be determined. Nevertheless, the steady state mass inflow rate is estimated to be ~10-2 M⊙/yr which is sufficient to explain the X-ray luminosity of the AGN in terms of radiatively inefficient accretion. Collectively, the results challenge many preconceived notions concerning the nature of BLRs in active galactic nuclei. Support for Program number HST-AR-11752.01-A was provided by NASA through a grant from the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Incorporated, under NASA contract NAS5-26555.

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

    NASA Astrophysics Data System (ADS)

    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.

  19. The Occasional Case Against Broad Dissemination and Implementation

    PubMed Central

    Comer, Jonathan S.; Barlow, David H.

    2014-01-01

    Mental illness imposes a staggering public health burden in the United States. Although the past 40 years have witnessed tremendous advances in the identification of evidence-based practices (EBPs) in psychological treatments, gaps persist between treatment in experimental settings and services available in the community. In response, considerable attention and large financial commitments have focused in recent years on broad dissemination and implementation efforts designed to improve the quality of psychological services delivered by a variety of generalist practitioners across practice settings. Increasingly, under the influence of the Patient Protection and Affordable Care Act, it is envisioned that these generalists will practice in integrated primary care settings. These advances hold enormous potential, and yet, given the tremendous diversity of mental health problems and human suffering, broad dissemination and implementation efforts to generalists alone may not be sufficient to adequately address the burden of mental illness. Some EBPs may prove too complex for universal dissemination, and the time and expense required for quality dissemination and implementation preclude large-scale training in the treatment of low base rate disorders. As dissemination and implementation efforts work to ensure a quality generalist mental health care workforce, herein we highlight the vital need for available specialty care in the delivery of psychological treatments. Given traditional barriers that interfere with the accessibility of specialty care, we propose the transformative potential of a specialty behavioral telehealth care workforce, transacting with the generalist practitioner workforce to collectively ensure the highest quality and timely delivery of needed treatments to affected individuals. PMID:23915401

  20. RBC broad-crested weirs for circular sewers and pipes

    NASA Astrophysics Data System (ADS)

    Clemmens, A. J.; Bos, M. G.; Replogle, J. A.

    1984-02-01

    In recent years, significant advancements have been made in the practical application of long-throated flumes and broad-crested weirs for flow measurements in irrigation canals. The modified RBC (Replogle-Bos-Clemmens) broad-crested weir has many advantages over related open-channel flow devices. These include high accuracy and reliability for a wide variety of shapes, low head-loss requirements which are predictable, and relatively simple inexpensive construction. In this paper we have extended the application of these weirs to circular pipes flowing partially full. The theoretical equations are presented for ideal flow from which approximate ratings can be obtained to within a reasonable accuracy with an empirical discharge coefficient, However, a mathematical model is available which accurately predicts these ratings by directly accounting for the effects of friction. The ratings for a wide variety of shapes and sizes of these weirs were computed with the model and fit to an empirical equation. The constants for this equation are plotted graphically for easy use. The resulting ratings should be well within ±3%. Design examples are given which show how to select the flume dimensions for maintaining free-flowing conditions (modular flow) and for minimizing sediment deposition. Once constructed, the rating for a given flume can be determined even when not constructed as planned.

  1. Arbidol as a broad-spectrum antiviral: an update.

    PubMed

    Blaising, Julie; Polyak, Stephen J; Pécheur, Eve-Isabelle

    2014-07-01

    Arbidol (ARB) is a Russian-made small indole-derivative molecule, licensed in Russia and China for prophylaxis and treatment of influenza and other respiratory viral infections. It also demonstrates inhibitory activity against other viruses, enveloped or not, responsible for emerging or globally prevalent infectious diseases such as hepatitis B and C, gastroenteritis, hemorrhagic fevers or encephalitis. In this review, we will explore the possibility and pertinence of ARB as a broad-spectrum antiviral, after a careful examination of its physico-chemical properties, pharmacokinetics, toxicity, and molecular mechanisms of action. Recent studies suggest that ARB's dual interactions with membranes and aromatic amino acids in proteins may be central to its broad-spectrum antiviral activity. This could impact on the virus itself, and/or on cellular functions or critical steps in virus-cell interactions, thereby positioning ARB as both a direct-acting antiviral (DAA) and a host-targeting agent (HTA). In the context of recent studies in animals and humans, we will discuss the prospective clinical use of ARB in various viral infections.

  2. The broad-lined Type Ic supernova 2003jd

    NASA Astrophysics Data System (ADS)

    Valenti, S.; Benetti, S.; Cappellaro, E.; Patat, F.; Mazzali, P.; Turatto, M.; Hurley, K.; Maeda, K.; Gal-Yam, A.; Foley, R. J.; Filippenko, A. V.; Pastorello, A.; Challis, P.; Frontera, F.; Harutyunyan, A.; Iye, M.; Kawabata, K.; Kirshner, R. P.; Li, W.; Lipkin, Y. M.; Matheson, T.; Nomoto, K.; Ofek, E. O.; Ohyama, Y.; Pian, E.; Poznanski, D.; Salvo, M.; Sauer, D. N.; Schmidt, B. P.; Soderberg, A.; Zampieri, L.

    2008-02-01

    The results of a worldwide coordinated observational campaign on the broad-lined Type Ic supernova (SN Ic) 2003jd are presented. In total, 74 photometric data points and 26 spectra were collected using 11 different telescopes. SN 2003jd is one of the most luminous SN Ic ever observed. A comparison with other Type Ic supernovae (SNe Ic) confirms that SN 2003jd represents an intermediate case between broad-line events (2002ap, 2006aj) and highly energetic SNe (1997ef, 1998bw, 2003dh, 2003lw), with an ejected mass of Mej = 3.0 +/- 1Msolar and a kinetic energy of Ek(tot) = 7+3-2 × 1051erg. SN 2003jd is similar to SN 1998bw in terms of overall luminosity, but it is closer to SNe 2006aj and 2002ap in terms of light-curve shape and spectral evolution. The comparison with other SNe Ic suggests that the V-band light curves of SNe Ic can be partially homogenized by introducing a time-stretch factor. Finally, because of the similarity of SN 2003jd to the SN 2006aj/XRF 060218 event, we discuss the possible connection of SN 2003jd with a gamma-ray burst (GRB). E-mail: svalenti@eso.org Based on observations at ESO-Paranal, Prog. 074.D-0161A.

  3. Discrimination of ionic species from broad-beam ion sources

    NASA Technical Reports Server (NTRS)

    Anderson, J. R.

    1993-01-01

    The performance of a broad-beam, three-grid, ion extraction system incorporating radio frequency (RF) mass discrimination was investigated experimentally. This testing demonstrated that the system, based on a modified single-stage Bennett mass spectrometer, can discriminate between ionic species having about a 2-to-1 mass ratio while producing a broad-beam of ions with low kinetic energy (less than 15 eV). Testing was conducted using either argon and krypton ions or atomic and diatomic oxygen ions. A simple one-dimensional model, which ignores magnetic field and space-charge effects, was developed to predict the species separation capabilities as well as the kinetic energies of the extracted ions. The experimental results correlated well with the model predictions. This RF mass discrimination system can be used in applications where both atomic and diatomic ions are produced, but a beam of only one of the species is desired. An example of such an application is a 5 eV atomic oxygen source. This source would produce a beam of atomic oxygen with 5 eV kinetic energy, which would be directed onto a material specimen, to simulate the interaction between the surface of a satellite and the rarefied atmosphere encountered in low-Earth orbit.

  4. Broad Specification Fuels Combustion Technology Program, Phase 2

    NASA Technical Reports Server (NTRS)

    Lohmann, R. P.; Jeroszko, R. A.; Kennedy, J. B.

    1990-01-01

    An experimental evaluation of two advanced technology combustor concepts was conducted to evolve and assess their capability for operation on broadened properties fuels. The concepts were based on the results of Phase 1 of the Broad Specification Fuel Combustor Technology Program which indicated that combustors with variable geometry or staged combustion zones had a flexibility of operation that could facilitate operation on these fuels. Emphasis in defining these concepts included the use of single pipe as opposed to duplex or staged fuels systems to avoid the risk of coking associated with the reduction in thermal stability expected in broadened properties fuels. The first concept was a variable geometry combustor in which the airflow into the primary zone could be altered through valves on the front while the second was an outgrowth of the staged Vorbix combustor, evolved under the NASA/P&W ECCP and EEE programs incorporating simplified fuel and air introduction. The results of the investigation, which involved the use of Experimental Referee Broad Specification (ERBS) fuel, indicated that in the form initially conceived, both of these combustor concepts were deficient in performance relative to many of the program goals for performance emissions. However, variations of both combustors were evaluated that incorporated features to simulate conceptual enhancement to demonstrate the long range potential of the combustor. In both cases, significant improvements relative to the program goals were observed.

  5. Radiation pressure confinement - IV. Application to broad absorption line outflows

    NASA Astrophysics Data System (ADS)

    Baskin, Alexei; Laor, Ari; Stern, Jonathan

    2014-12-01

    A fraction of quasars present broad absorption lines, produced by outflowing gas with typical velocities of 3000-10 000 km s-1. 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 1022 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, and can be used to test the validity of RPC as a solution for the overionization problem. The ionization structure of the outflow implies that if the outflow is radiatively driven, then broad absorption line quasars should have L/L_Eddgtrsim 0.1.

  6. Communicating Science Broadly: An NSF Point of View

    NASA Astrophysics Data System (ADS)

    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.

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

    NASA Astrophysics Data System (ADS)

    Al-Kaisey, Mahdi T.; Alwan, Abdul-Kader H.; Mohammad, Manal H.; Saeed, Amjed 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.

  8. Spectral decomposition of broad-line agns and host galaxies

    SciTech Connect

    Vanden Berk, Daniel E.; Shen, Jiajian; Yip, Ching-Wa; Schneider, Donald P.; Connolly, Andrew J.; Burton, Ross E.; Jester, Sebastian; Hall, Patrick B.; Szalay, Alex S.; Brinkmann, John; /Apache Point Observ.

    2005-09-01

    Using an eigenspectrum decomposition technique, we separate the host galaxy from the broad line active galactic nucleus (AGN) in a set of 4666 spectra from the Sloan Digital Sky Survey (SDSS), from redshifts near zero up to about 0.75. The decomposition technique uses separate sets of galaxy and quasar eigenspectra to efficiently and reliably separate the AGN and host spectroscopic components. The technique accurately reproduces the host galaxy spectrum, its contributing fraction, and its classification. We show how the accuracy of the decomposition depends upon S/N, host galaxy fraction, and the galaxy class. Based on the eigencoefficients, the sample of SDSS broad-line AGN host galaxies spans a wide range of spectral types, but the distribution differs significantly from inactive galaxies. In particular, post-starburst activity appears to be much more common among AGN host galaxies. The luminosities of the hosts are much higher than expected for normal early-type galaxies, and their colors become increasingly bluer than early-type galaxies with increasing host luminosity. Most of the AGNs with detected hosts are emitting at between 1% and 10% of their estimated Eddington luminosities, but the sensitivity of the technique usually does not extend to the Eddington limit. There are mild correlations among the AGN and host galaxy eigencoefficients, possibly indicating a link between recent star formation and the onset of AGN activity. The catalog of spectral reconstruction parameters is available as an electronic table.

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

    PubMed Central

    2010-01-01

    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. PMID:20163710

  10. A COMPREHENSIVE NONPOINT SOURCE FIELD STUDY FOR SEDIMENT, NUTRIENTS, AND PATHOGENS IN THE SOUTH FORK BROAD RIVER WATERSHED IN NORTHEAST GEORGIA

    EPA Science Inventory

    This technical report provides a description of the field project design, quality control, the sampling protocols and analysis methodology used, and standard operating procedures for the South Fork Broad River Watershed (SFBR) Total Maximum Daily Load (TMDL) project. This watersh...

  11. Guide to Building a Broad-Based Coalition: Supporting the Development and Sustainability of a System of Pathways

    ERIC Educational Resources Information Center

    ConnectEd: The California Center for College and Career, 2010

    2010-01-01

    As communities across California commit to developing systems of high school pathways that will engage students in school and prepare them to succeed in postsecondary opportunities and contribute to a vital regional economy, many are realizing the importance of providing "broad-based support" for this work. Students need a choice of…

  12. The broad Hα, [O III] line wings in stellar supercluster A of NGC 2363 and the turbulent mixing layer hypothesis

    NASA Astrophysics Data System (ADS)

    Binette, L.; Drissen, L.; Ubeda, L.; Raga, A. C.; Robert, C.; Krongold, Y.

    2009-06-01

    Context: Supercluster A in the extragalactic H ii region NGC 2363 is remarkable for the hypersonic gas seen as faint extended broad emission lines with a full-width zero intensity of 7000 km s-1. Aims: We explore the possibility that the observed broad profiles are the result of the interaction of a high-velocity cluster wind with dense photoionized clumps. Methods: The geometry considered is that of near static photoionized condensations at the surface of which turbulent mixing layers arise as a result of the interaction with the hot wind. The approximative treatment of turbulence was carried out using the mixing length approach of Cantó & Raga. The code mappings ic was used to derive the mean quantities describing the flow and to compute the line emissivities within the turbulent layers. The velocity projection in three dimensions of the line sources was carried out analytically. Results: A fast entraining wind of up to ≈ 4300 km s-1 appears to be required to reproduce the faint wings of the broad Hα and [O iii] profiles. A slower wind of 3500 km s-1, however, can still reproduce the bulk of the broad component and does provide a better fit than an ad hoc Gaussian profile. Conclusions: Radial acceleration in 3D (away from supercluster A) of the emission gas provides a reasonable first-order fit to the broad line component. No broad component is predicted for the [N ii] and [S ii] lines, as observed. The wind velocity required is uncomfortably high and alternative processes that would provide comparable constant acceleration of the emission gas up to 4000 km s-1 might have to be considered.

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

    NASA Technical Reports Server (NTRS)

    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.

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

    PubMed

    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.

  15. [Development of the biological preparation enatin with broad-range antimicrobial action].

    PubMed

    Romanovskaia, T V; Kolomiets, E I; Zdor, N A; Lobanok, A G

    2002-01-01

    Physiological and biochemical traits of epiphytic spore forming bacteria Bacillus pumilis BIM V-263 were examined. The nutrient medium and conditions for submerged cultivation of the strain were selected. The growth dynamics and antagonistic activity during cultivation in a laboratory fermenter ANKUM-2M were studied. The results provide grounds for development of the biological preparation Enatin with broad-range antimicrobial effect. The plant-protective and growth-stimulating effect of Enatin was examined in laboratory and field experiments. The preparation holds promise as means for biological control of crop pathogens.

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

    DOEpatents

    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.

  17. An Intrinsic Baldwin Effect in the H Beta Broad Emission Line in the Spectrum of NGC 5548

    NASA Technical Reports Server (NTRS)

    Gilbert, Karoline M.; Peterson, Bradley M.

    2003-01-01

    We investigate the possibility of an intrinsic Baldwin effect (i.e., nonlinear emission-line response to continuum variations) in the broad HP emission line of the active galaxy NGC 5548 using crosscorrelation techniques to remove light-travel time effects from the data. We find a nonlinear relationship between the HP emission line and continuum fluxes that is in good agreement with theoretical predictions. We suggest that similar analysis of multiple lines might provide a useful diagnostic of physical conditions in the broad-line region.

  18. Fault protection of broad-area laser diodes

    NASA Astrophysics Data System (ADS)

    Jacob, J. H.; Petr, R.; Jaspan, M. A.; Swartz, S. D.; Knapczyk, M. T.; Flusberg, A. M.; Chin, A. K.; Smilanski, I.

    2009-02-01

    Detailed reliability studies of high-power, CW, broad-area, GaAs-based laser- diodes were performed. Optical and electrical transients occurring prior to device failure by catastrophic optical-damage (COD) were observed. These transients were correlated with COD formation as observed in laser diodes with an optical window in the n-side electrode. In addition, custom electronics were designed to fault-protect the laser diodes during aging tests, i.e. each time a transient (fault) was detected, the operating current was temporarily cut off within 4μs of fault detection. The lifetime of fault-protected 808-nm laser-diode bars operated at a constant current of 120A (~130W) and 35°C exceeded similar unprotected devices by factors of 2.

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

    PubMed

    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.

  20. Spontaneous pattern formation in broad-area lasers

    NASA Astrophysics Data System (ADS)

    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.

  1. Modeling of optical wireless scattering communication channels over broad spectra.

    PubMed

    Liu, Weihao; Zou, Difan; Xu, Zhengyuan

    2015-03-01

    The air molecules and suspended aerosols help to build non-line-of-sight (NLOS) optical scattering communication links using carriers from near infrared to visible light and ultraviolet bands. This paper proposes channel models over such broad spectra. Wavelength dependent Rayleigh and Mie scattering and absorption coefficients of particles are analytically obtained first. They are applied to the ray tracing based Monte Carlo method, which models the photon scattering angle from the scatterer and propagation distance between two consecutive scatterers. Communication link path loss is studied under different operation conditions, including visibility, particle density, wavelength, and communication range. It is observed that optimum communication performances exist across the wavelength under specific atmospheric conditions. Infrared, visible light and ultraviolet bands show their respective features as conditions vary.

  2. Genetically Engineered Broad-Spectrum Disease Resistance in Tomato

    NASA Astrophysics Data System (ADS)

    Oldroyd, Giles E. D.; Staskawicz, Brian J.

    1998-08-01

    Resistance in tomato to the bacterial pathogen Pseudomonas syringae pathovar tomato requires Pto and Prf. Mutations that eliminate Prf show a loss of both Pto resistance and sensitivity to the organophosphate insecticide fenthion, suggesting that Prf controls both phenotypes. Herein, we report that the overexpression of Prf leads to enhanced resistance to a number of normally virulent bacterial and viral pathogens and leads to increased sensitivity to fenthion. These plants express levels of salicylic acid comparable to plants induced for systemic acquired resistance (SAR) and constitutively express pathogenesis related genes. These results suggest that the overexpression of Prf activates the Pto and Fen pathways in a pathogen-independent manner and leads to the activation of SAR. Transgene-induced SAR has implications for the generation of broad spectrum disease resistance in agricultural crop plants.

  3. Mucin biopolymers as broad-spectrum antiviral agents

    PubMed Central

    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

  4. Specialty fibers for broad spectra of wavelength and power

    NASA Astrophysics Data System (ADS)

    Artyushenko, Viacheslav; Wojciechowski, Cezar; Ingram, Jim; Kononenko, Vitaly; Lobachev, Vladimir; Sakharova, Tatjana; Ludczak, Jacek; Grzebieniak, Andrzej; Wojciechowski, Zdzislaw

    2005-09-01

    Review of the latest development in production and advanced applications of specialty fibre optics includes specialty silica fibers and IR-fibers drawn from chalcogenide glasses and extruded from crystal solutions of Silver Halides. Transmission range of these 3 types of fibers spans 0.2 to 18μm, while the power of radiation they may deliver varies from microwatts for sensing applications to several kilowatts - when silica fibers are assembled, for example, in high power cables for laser technology applications. Various probes and bundles assembled from specialty fibers are used for remote sensing of IR-emission, temperature, mechanical stress and for process-spectroscopy in very broad range - from 0.2 to 18μm.

  5. Towards HIV-1 remission: potential roles for broadly neutralizing antibodies

    PubMed Central

    Halper-Stromberg, Ariel; Nussenzweig, Michel C.

    2016-01-01

    Current antiretroviral drug therapies do not cure HIV-1 because they do not eliminate a pool of long-lived cells harboring immunologically silent but replication-competent proviruses — termed the latent reservoir. Eliminating this reservoir and stimulating the immune response to control infection in the absence of therapy remain important but unsolved goals of HIV-1 cure research. Recently discovered broadly neutralizing antibodies (bNAbs) exhibit remarkable breadth and potency in their ability to neutralize HIV-1 in vitro, and recent studies have demonstrated new therapeutic applications for passively administered bNAbs in vivo. This Review discusses the roles bNAbs might play in HIV-1 treatment regimens, including prevention, therapy, and cure. PMID:26752643

  6. SPECTROSCOPY OF BROAD-LINE BLAZARS FROM 1LAC

    SciTech Connect

    Shaw, Michael S.; Romani, Roger W.; Healey, Stephen E.; Michelson, Peter F.; Readhead, Anthony C. S.; Richards, Joseph L.; Max-Moerbeck, Walter; King, Oliver G.

    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.

  7. A broad band imager for the European Solar Telescope

    NASA Astrophysics Data System (ADS)

    Munari, Matteo; Scuderi, Salvatore; Cecconi, Massimo

    2012-09-01

    We report on the results of the conceptual design study of a broad band imager for the European Solar Telescope (EST), a joint project of several European research institutes to design and realize a 4-m class solar telescope. The EST broad band imager is an imaging instrument whose function is to obtain diffraction limited images over the full field of view of EST at multiple wavelengths and high frame rate. Its scientific objective is the study of fundamental astrophysical processes at their intrinsic scales in the Sun's atmosphere. The optical layout foresee two observational modes: a maximum field of view mode and a high resolution mode. The imager will have a 2'x2' corrected field of view in the first mode and an angular resolution better than 0.04" at 500nm in the latter mode. The imager will cover a wavelength range spanning from 390nm to 900nm through a number of filters with bandpasses between 0.05nm and 0.5nm. The selected optical layout is an all refractive design. To optimize optical performances and throughput there will be two arms working simultaneously: a blue arm (covering the 380nm - 500nm range) and a red arm (600nm - 900nm). The blue arm will have two channels while the red arm only one. Each channel will be divided in three subchannels: one will host narrow band filters for chromospheric observations, another one, in focus wide band filters used as reference for speckle reconstruction and photospheric observations, and the last one, out of focus wide band filters for phase diversity reconstruction of photospheric observations.

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

    SciTech Connect

    Zhang, Shaohua; Zhou, Hongyan; Wang, Huiyuan; Wang, Tinggui; Xing, Feijun; Jiang, Peng; Zhang, Kai E-mail: whywang@mail.ustc.edu.cn

    2014-05-01

    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 is refined by our new algorithm. Correlations of outflow velocity and strength with a hot dust indicator (β{sub NIR}) and other quasar physical parameters—such as an Eddington ratio, luminosity, and a UV continuum slope—are explored in order to figure out which parameters drive outflows. Here β{sub NIR} is the near-infrared continuum slope, which is a good indicator of the amount of hot dust emission relative to the accretion disk emission. We confirm previous findings that outflow properties moderately or weakly depend on the Eddington ratio, UV slope, and luminosity. For the first time, we report moderate and significant correlations of outflow strength and velocity with β{sub NIR} in BAL quasars. It is consistent with the behavior of blueshifted broad emission lines in non-BAL quasars. The statistical analysis and composite spectra study both reveal that outflow strength and velocity are more strongly correlated with β{sub NIR} than the Eddington ratio, luminosity, and UV slope. In particular, the composites show that the entire C IV absorption profile shifts blueward and broadens as β{sub NIR} increases, while the Eddington ratio and UV slope only affect the high and low velocity part of outflows, respectively. We discuss several potential processes and suggest that the dusty outflow scenario, i.e., that dust is intrinsic to outflows and may contribute to the outflow acceleration, is most likely.

  9. Alpha horizontal stent delivery for coil embolization of a broad-necked large basilar apex aneurysm: a case report

    PubMed Central

    Ohshima, Tomotaka; Nagakura, Masamune; Nishizawa, Toshihisa; Kato, Kyozo

    2015-01-01

    ABSTRACT Here we describe a novel technique for single stent horizontal reconstruction and coil embolization for a broad-necked large basilar artery (BA) apex aneurysm. A previously healthy 77-year-old woman presented with a broad-necked large BA apex aneurysm. Due to difficulty accessing the right posterior cerebral artery (PCA), we abandoned the Y-stent technique. Instead, we decided to navigate the stent through the BA to the left PCA making a loop of the stent delivery catheter inside the aneurysm in an "alpha" fashion. The procedure outcome was excellent without any complications. Alpha horizontal stent delivery via an antegrade approach for coil embolization of broad-necked large BA apex aneurysms may provide an effective therapeutic alternative, if other techniques are not feasible. PMID:26663945

  10. Support Net for Frontline Providers

    DTIC Science & Technology

    2016-03-01

    2-0153 TITLE: SupportNet for Frontline Behavioral Health Providers PRINCIPAL INVESTIGATOR: Dr. Charles Benight CONTRACTING ORGANIZATION: Regents...military behavioral health providers who are continually exposed to extensive traumatic material on an on-going basis. Job burnout and STS potentially...readiness for soldiers. SupportNet aimed to assess the level of secondary trauma and job burnout among military behavioral health providers and to

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

    PubMed

    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.

  12. Family Day Care Provider Handbook

    ERIC Educational Resources Information Center

    New York State Office of Children and Family Services, 2006

    2006-01-01

    Family day care providers are responsible for creating a high-quality program where children have opportunities to grow, learn and thrive. Part of providing high-quality child care includes complying with the family day care regulations from the New York State Office of Children and Family Services (OCFS). This Handbook will help day care…

  13. Choosing a primary care provider

    MedlinePlus

    Family doctor - how to choose one; Primary care provider - how to choose one; Doctor - how to choose a family doctor ... A PCP is your main health care provider in non-emergency ... and teach healthy lifestyle choices Identify and treat common ...

  14. HMO partnering: the provider dilemma.

    PubMed

    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.

  15. Incentives and provider payment methods.

    PubMed

    Barnum, H; Kutzin, J; Saxenian, H

    1995-01-01

    The mode of payment creates powerful incentives affecting provider behavior and the efficiency, equity and quality outcomes of health finance reforms. This article examines provider incentives as well as administrative costs, and institutional conditions for successful implementation associated with provider payment alternatives. The alternatives considered are budget reforms, capitation, fee-for-service, and case-based reimbursement. We conclude that competition, whether through a regulated private sector or within a public system, has the potential to improve the performance of any payment method. All methods generate both adverse and beneficial incentives. Systems with mixed forms of provider payment can provide tradeoffs to offset the disadvantages of individual modes. Low-income countries should avoid complex payment systems requiring higher levels of institutional development.

  16. The Characteristics of Broad and Narrow Focal Zone Lithotripters

    NASA Astrophysics Data System (ADS)

    Pishchalnikov, Yuri A.; McAteer, James A.; VonDerHaar, R. Jason; Pishchalnikova, Irina V.; Williams, James C.

    2008-09-01

    The focal width of a lithotripter is a measure of the diameter of its focal zone, the region where acoustic pressures are at least half the maximum positive pressure generated at a given power level. Different lithotripters have different focal widths. The Dornier HM3, for example, has a focal width of ˜10-12 mm and for many years this was the widest focal zone among clinical machines. Electromagnetic lithotripters tend to have narrower focal zones, in the range of ˜4-6 mm. Recent studies suggesting that focal width plays an important role in stone breakage prompted this assessment of two electromagnetic lithotripters. Acoustical mapping using a fiber optic probe hydrophone (FOPH-500) and breakage of U-30 gypsum model stones were used to compare a conventional lithotripter (Dornier DoLi-50) and a broad focal zone device (XiXin XX-ES). FOPH mapping characterized the focal width of the DoLi to be about 5mm and that of the XX-ES to be much wider (˜18 mm). For stone breakage experiments the DoLi was fired at power level 3 (mid-range) and the XX-ES was operated at the recommended clinical setting of 9.3 kV. Both lithotripters were fired at 60 SW/min. U-30 model stones held in a 2mm mesh basket were positioned at the clinical target point on the acoustic axis and at 5mm steps laterally, and the number of SW's to complete fragmentation was counted. Breakage on-axis was similar for the two machines (DoLi 676±105 SW's versus XX-ES 644±123 SW's, p>0.6), but at 15mm the DoLi required nearly twice the number of SW's as the XX-ES (DoLi 3006±780 SW's versus 1726±972 SW's, p<0.006). This demonstrates that a broad focal zone lithotripter is more effective in breaking stones off axis and supports the idea that focal width is an important feature, likely to be relevant in the clinical setting where respiratory motion may limit the effectiveness of narrow focal zone machines.

  17. Utilization of human DC-SIGN and L-SIGN for entry and infection of host cells by the New World arenavirus, Junín virus

    PubMed Central

    Belouzard, Sandrine; Cordo, Sandra M.; Candurra, Nélida A.; Whittaker, Gary R.

    2014-01-01

    The target cell tropism of enveloped viruses is regulated by interactions between viral proteins and cellular receptors determining susceptibility at a host cell, tissue or species level. However, a number of additional cell-surface moieties can also bind viral envelope glycoproteins and could act as capture receptors, serving as attachment factors to concentrate virus particles on the cell surface, or to disseminate the virus infection to target organs or susceptible cells within the host. Here, we used Junín virus (JUNV) or JUNV glycoprotein complex (GPC)-pseudotyped particles to study their ability to be internalized by the human C-type lectins hDC- or hL-SIGN. Our results provide evidence that hDC- and hL-SIGN can mediate the entry of Junín virus into cells, and may play an important role in virus infection and dissemination in the host. PMID:24183720

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

    PubMed Central

    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

  19. Aerosol Absorption Retrievals from the PACE Broad Spectrum Ocean Color Instrument (OCI)

    NASA Technical Reports Server (NTRS)

    Mattoo, Shana; Remer, Lorraine A.; Levy, Robert C.; Gupta, Pawan; Ahmad, Ziauddin; Martins, J. Vanderlei; Lima, Adriana Rocha; Torres, Omar

    2016-01-01

    The PACE (Pre-­Aerosol, Clouds and ocean Ecosystem) mission, anticipated for launch in the early 2020s, is designed to characterize oceanic and atmospheric properties. The primary instrument on-­-board will be a moderate resolution (approximately 1 km nadir) radiometer, called the Ocean Color Instrument (OCI). OCI will provide high spectral resolution (5 nm) from the UV to NIR (350 - 800 nm), with additional spectral bands in the NIR and SWIR. The OCI itself is an excellent instrument for atmospheric objectives, providing measurements across a broad spectral range that in essence combines the capabilities of MODIS and OMI, but with the UV channels from OMI to be available at moderate resolution. (Image credit: PACE Science Definition Team Report). Objective: Can we make use of the UV-­SWIR measurements to derive information about aerosol absorption when aerosol loading is high?

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

    NASA Astrophysics Data System (ADS)

    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.

  1. Broad-Spectrum Biofilm Inhibition by Kingella kingae Exopolysaccharide▿

    PubMed Central

    Bendaoud, Meriem; Vinogradov, Evgeny; Balashova, Nataliya V.; Kadouri, Daniel E.; Kachlany, Scott C.; Kaplan, Jeffrey B.

    2011-01-01

    Cell-free extracts prepared from Kingella kingae colony biofilms were found to inhibit biofilm formation by Aggregatibacter actinomycetemcomitans, Klebsiella pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Candida albicans, and K. kingae. The extracts evidently inhibited biofilm formation by modifying the physicochemical properties of the cell surface, the biofilm matrix, and the substrate. Chemical and biochemical analyses indicated that the biofilm inhibition activity in the K. kingae extract was due to polysaccharide. Structural analyses showed that the extract contained two major polysaccharides. One was a linear polysaccharide with the structure →6)-α-d-GlcNAcp-(1→5)-β-d-OclAp-(2→, which was identical to a capsular polysaccharide produced by Actinobacillus pleuropneumoniae serotype 5. The second was a novel linear polysaccharide, designated PAM galactan, with the structure →3)-β-d-Galf-(1→6)-β-d-Galf-(1→. Purified PAM galactan exhibited broad-spectrum biofilm inhibition activity. A cluster of three K. kingae genes encoding UDP-galactopyranose mutase (ugm) and two putative galactofuranosyl transferases was sufficient for the synthesis of PAM galactan in Escherichia coli. PAM galactan is one of a growing number of bacterial polysaccharides that exhibit antibiofilm activity. The biological roles and potential technological applications of these molecules remain unknown. PMID:21602333

  2. Antibodies against HLA-DP recognize broadly expressed epitopes.

    PubMed

    Simmons, Daimon P; Kafetzi, Maria L; Wood, Isabelle; Macaskill, Peter C; Milford, Edgar L; Guleria, Indira

    2016-12-01

    HLA matching and avoidance of pre-transplant donor-specific antibodies are important in selection of donors for solid organ transplant. Solid phase testing with single antigen beads allows resolution of antibody reactivity to the level of the allele. Single antigen bead testing results at a large transplant center were reviewed to identify selective reactivity patterns of anti-HLA antibodies. Many HLA-DP antibodies were identified in the context of other HLA antibodies, but some sera had antibodies against only HLA-DP. B cell flow crossmatch testing was positive for 2 out of 9 sera with HLA-DP antibodies. Many patterns of reactivity corresponded to epitopes in hypervariable regions C and F of DPB1, but some matched epitopes in other regions or DPA1. Through analysis of single antigen bead testing from a large number of patients, we report that anti-HLA-DP antibodies predominantly recognize broadly cross-reactive epitopes. The United Network for Organ Sharing has mandated HLA-DP typing on all deceased kidney donors, and HLA-DP epitopes should be considered as the major antigens for avoidance of pre-transplant donor-specific antibodies.

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

    PubMed Central

    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

  4. Broad specificity of human phosphoglycerate kinase for antiviral nucleoside analogs.

    PubMed

    Gallois-Montbrun, Sarah; Faraj, Abdesslem; Seclaman, Edward; Sommadossi, Jean-Pierre; Deville-Bonne, Dominique; Véron, Michel

    2004-11-01

    Nucleoside analogs used in antiviral therapies need to be phosphorylated to their tri-phospho counterparts in order to be active on their cellular target. Human phosphoglycerate kinase (hPGK) was recently reported to participate in the last step of phosphorylation of cytidine L-nucleotide derivatives [Krishnan PGE, Lam W, Dutschman GE, Grill SP, Cheng YC. Novel role of 3-phosphoglycerate kinase, a glycolytic enzyme, in the activation of L-nucleoside analogs, a new class of anticancer and antiviral agents. J Biol Chem 2003;278:36726-32]. In the present work, we extended the enzymatic study of human PGK specificity to purine and pyrimidine nucleotide derivatives in both D- and L-configuration. Human PGK demonstrated catalytic efficiencies in the 10(4)-10(5)M(-1)s(-1) range for purine ribo-, deoxyribo- and dideoxyribonucleotide derivatives, either in D- or L-configuration. In contrast, it was poorly active with natural pyrimidine D-nucleotides (less than 10(3)M(-1)s(-1)). Pyrimidine L-enantiomers, which are promising therapeutic analogs against B hepatitis, were 2-25 times better substrates than their D-counterparts. The broad specificity of substrate of human PGK suggests that this enzyme may be involved in the cellular activation of several antiviral nucleoside analogs including dideoxyinosine, acyclovir, L-2'-deoxycytosine and L-2'-deoxythymidine.

  5. Broad band imager for the European Solar Telescope

    NASA Astrophysics Data System (ADS)

    Munari, Matteo; Scuderi, Salvo; Cecconi, Massimo

    2010-07-01

    The European Solar Telescope (EST) is a joint project of several European research institutes to design and realize a 4-m class solar telescope. The EST broad band imager is an imaging instrument whose function is to obtain diffraction limited images over the full field of view of EST at multiple wavelengths and high frame rate. Its scientific objective is the study of fundamental astrophysical processes at their intrinsic scales in the Sun's atmosphere. The current layout foresee two observation modes: a maximum field of view mode and a high resolution mode. The imager will have a 2'x2' corrected field of view in the first mode and an angular resolution better than 0.04" at 500nm in the latter mode. The imager will cover a wavelength range spanning from 390nm to 900nm through a number of filters with bandpasses between 0.05nm and 0.5nm. To optimize optical performances and throughput there will be two arms working simultaneously: a blue arm (covering the 380nm - 500nm range) and a red arm (600nm - 900nm). The blue arm will have two channels while the red arm only one. Each channel will be divided in three subchannels: one will host narrow band filters for chromospheric observations, another one, in focus wide band filters used as reference for speckle reconstruction and photospheric observations, and the last one, out of focus wide band filters for phase diversity reconstruction of photospheric observations.

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

    PubMed

    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.

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

    PubMed

    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.

  8. Series-fed circularly polarized microstrip antennas with broad bandwidth

    NASA Astrophysics Data System (ADS)

    Mao, Shau-Gang; Chen, Shiou-Li; Yeh, Jen-Chun; Lin, Tien-Min

    2007-08-01

    A new series-fed circularly polarized antenna (SFCPA) in microstrip configuration, which consists of a traveling-wave-type crank-line antenna (CLA) and a resonant-type square-ring slot antenna (SRSA), is developed. Unlike the conventional crank-line (CL) antenna array with an open end or a resistive load, the proposed SFCPA uses the SRSA at the termination of the CLA and thus exhibits not only a broad circularly polarized (CP) bandwidth but also a large antenna gain. The characteristics of the SFCPA, including the leaky-wave radiation and the circular polarization, are examined in terms of the dispersion diagram and the current distribution. The SFCPA with the two-cell CLA and the terminated SRSA is fabricated and measured to demonstrate the 10-dB return loss and 3-dB axial ratio (AR) bandwidths of 34.3% and 30.5%, respectively. The frequency-scanning radiation patterns with a 5-7 dBi antenna gain are also presented in the operating band.

  9. A Broad Set of Chromatin Factors Influences Splicing

    PubMed Central

    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

  10. Microchip green laser sources: broad range of possibilities

    NASA Astrophysics Data System (ADS)

    Essaian, Stepan; Khaydarov, John; Slavov, Slav; Ter-Mikirtychev, Vartan; Gabrielyan, Gevorg; Keroopyan, Meruzhan; Soghomonyan, Suren

    2012-02-01

    Spectralus presents its progress in development of miniature, highly efficient, and versatile diode-pumped solid-state (DPSS) green laser source, based on a monolithic cavity microchip laser platform. The use of periodically poled MgO-doped Lithium Niobate (PPMgOLN) as the nonlinear frequency doubler together with gain material Nd3+:YVO4 allows obtaining a significant increase in the overall efficiency of the green microchip laser in comparison with other compact green laser source architectures with comparable output power. Originally, this laser source was designed to be part of the miniature and efficient RGB light source for microdisplay-based (LCOS, DLP or similar) mobile projector devices. Recently, we have extended range of operations for our original laser platform. In particular, we demonstrate the following: high peak power (>500mW), high average power (>200mW), broad temperature range of operation (-30°C - 60°C), and low noise CW operation (<0.5% RMS).

  11. Are Black Hole Masses from broad emission lines reliable

    NASA Astrophysics Data System (ADS)

    Mejia-Restrepo, Julian; Trakhtenbrot, B.; Lira, P.; Netzert, H.; Capellupo, D.

    2015-09-01

    For a proper understanding of AGNs we requires accurate estimates of the central Black Hole Mass (MBH). Here we discuss the comparison of single-epoch (SE) MBH estimators based on low ionization (Hα, Hβ, and MgII) and high ionization (CIV) broad emission lines. We use a sample of 39 unobscured AGNs at z=1.55 selected to cover a large range in MBH (2.0dex) and L/Ledd (2.5dex) and observed by X-shooter. We corroborate that low ionization lines can generally be safely used for virial MBH estimations. We found that the FWHM(MgII) is in general about 30% narrower than the FWHM of Hβ and Hα. However, high accretion rate objects show FWHM(MgII) similar or even broader than FWHM(Hβ) indicating that MgII is not suitable for MBH estimation in these objects. We confirm the systematic uncertainties associated with the use of the high ionization CIV line basically because its dynamics is highly affected by the accretion rate that induces radiation-driven winds.

  12. Characteristics of a broad band and thin ferrite absorbing wall

    NASA Astrophysics Data System (ADS)

    Kotsuka, Youji

    The author proposes a method of reducing the thickness of a ferrite absorbing wall and controlling the matching frequency characteristics by applying a DC magnetic field, HDC, perpendicularly to the microwave magnetic field. The matching characteristics of this method are investigated in detail on the basis of experimental data. The thickness reduction of the absorbing is first discussed from the standpoint of scalar permeability. Based upon these investigations, a thinned ferrite absorbing wall has been designed on a trial basis. The synthetic wave-absorbing material consists of a ferrite disk backed with a samarium-cobalt magnetic material generating a static magnetic field. Fairly good VSWR (voltage standing wave ratio) characteristics below 1.2 have been obtained with a total thickness of 3.8 mm in the frequency range from VHF to UHF. As an application of these characteristics, by controlling both the ferrite thickness and DC magnetic field simultaneously, it has been clarified that the matching frequency characteristics are easily exchanged in the broad frequency region.

  13. Elimination of HIV-1-infected cells by broadly neutralizing antibodies

    PubMed Central

    Bruel, Timothée; Guivel-Benhassine, Florence; Amraoui, Sonia; Malbec, Marine; Richard, Léa; Bourdic, Katia; Donahue, Daniel Aaron; Lorin, Valérie; Casartelli, Nicoletta; Noël, Nicolas; Lambotte, Olivier; Mouquet, Hugo; Schwartz, Olivier

    2016-01-01

    The Fc region of HIV-1 Env-specific broadly neutralizing antibodies (bNAbs) is required for suppressing viraemia, through mechanisms which remain poorly understood. Here, we identify bNAbs that exert antibody-dependent cellular cytotoxicity (ADCC) in cell culture and kill HIV-1-infected lymphocytes through natural killer (NK) engagement. These antibodies target the CD4-binding site, the glycans/V3 and V1/V2 loops on gp120, or the gp41 moiety. The landscape of Env epitope exposure at the surface and the sensitivity of infected cells to ADCC vary considerably between viral strains. Efficient ADCC requires sustained cell surface binding of bNAbs to Env, and combining bNAbs allows a potent killing activity. Furthermore, reactivated infected cells from HIV-positive individuals expose heterogeneous Env epitope patterns, with levels that are often but not always sufficient to trigger killing by bNAbs. Our study delineates the parameters controlling ADCC activity of bNAbs, and supports the use of the most potent antibodies to clear the viral reservoir. PMID:26936020

  14. The genome organization of the broad bean necrosis virus (BBNV).

    PubMed

    Lu, X; Yamamoto, S; Tanaka, M; Hibi, T; Namba, S

    1998-01-01

    The genome of the broad bean necrosis virus Oita-isolate (BBNV-O) [RNA1 (6.0 kb), RNA2 (2.8 kb) and RNA3 (2.4 kb)] was cloned and sequenced. Computer analysis indicates that methyltransferase, helicase and RNA-dependent RNA polymerase (RdRp) motifs are present in RNA1. The viral capsid protein (CP) cistron is located at the 5' terminal end of RNA2 and the Mr of CP (20 K) is close to that determined by SDS-PAGE analysis. An ochre codon (UAA) in the CP cistron is thought to be partially suppressed to produce a large readthrough protein. RNA3 possesses typical motifs of triple gene block proteins, which are also reported in several other plant viruses. The furovirus genome organization and phylogenetic analysis using RdRp and CP amino acid sequences suggest that BBNV is closely related to potato mop-top virus (PMTV), but is relatively distantly related to other furoviruses. The data also suggest that the genus Furovirus should be separated into several genera: the prototypical genus Furovirus, which excludes the following viruses: the PMTV group including BBNV; the beet necrotic yellow vein virus (BNYVV) group; and the peanut clump virus (PCV) group.

  15. The reconfiguration of broad leaves in strong winds and currents

    NASA Astrophysics Data System (ADS)

    Miller, Laura; Hoover, Alex; Marzuola, Jeremy

    2015-11-01

    Flexible plants, fungi, and sessile animals are thought to reconfigure in the wind and water to reduce the drag forces that act upon them. In strong winds, for example, leaves roll up into cone shapes that reduce flutter and drag when compared to paper cut-outs with similar shape and flexibility. 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 two-dimensional leaf in a three-dimensional flow will passively allow roll up and reduce drag and flutter. In this project, we use computational fluid dynamics and particle image velocimetry to determine how leaves roll up into drag reducing shapes in extreme conditions. Force and flow measurements are taken on real broad leaves and simplified physical models. Corresponding numerical simulations using the immersed boundary method are used to understand which features of the flexible leaves result in proper reconfiguration and drag reduction.

  16. The Physical Nature of Polar Broad Absorption Line Quasars

    NASA Technical Reports Server (NTRS)

    Ghost, Kajal; Punsly, Brian

    2007-01-01

    It has been shown based on radio variability arguments that some BALQSOs (broad absorption line quasars) are viewed along the polar axis (o rthogonal to accretion disk) in the recent article of Zhou et a. Thes e arguments are based on the brightness temperature, T(sub b) exceedi ng 10(exp 12) K which leads to the well-known inverse Compton catastr ophe unless the radio jet is relativistic and is viewed along its axi s. In this letter, we expand the Zhou et al sample of polar BALQSOs u sing their techniques applied to SDSS DR5. In the process, we clarify a mistake in their calculation of brightness temperature. The expanded sample of high T(sub b) BALQSOS, has an inordinately large fraction of LoBALQSOs (low ionization BALQSOs). We consider this an important clue to understanding the nature of the polar BALQSOs. This is expec ted in the polar BALQSO analytical/numerical models of Punsly that pr edicted that LoBALQSOs occur when the line of sight is very close to the polar axis, where the outflow density is the highest.

  17. Convergence of broad-scale migration strategies in terrestrial birds

    PubMed Central

    La Sorte, Frank A.; Fink, Daniel; Hochachka, Wesley M.; Kelling, Steve

    2016-01-01

    Migration is a common strategy used by birds that breed in seasonal environments. Selection for greater migration efficiency is likely to be stronger for terrestrial species whose migration strategies require non-stop transoceanic crossings. If multiple species use the same transoceanic flyway, then we expect the migration strategies of these species to converge geographically towards the most optimal solution. We test this by examining population-level migration trajectories within the Western Hemisphere for 118 migratory species using occurrence information from eBird. Geographical convergence of migration strategies was evident within specific terrestrial regions where geomorphological features such as mountains or isthmuses constrained overland migration. Convergence was also evident for transoceanic migrants that crossed the Gulf of Mexico or Atlantic Ocean. Here, annual population-level movements were characterized by clockwise looped trajectories, which resulted in faster but more circuitous journeys in the spring and more direct journeys in the autumn. These findings suggest that the unique constraints and requirements associated with transoceanic migration have promoted the spatial convergence of migration strategies. The combination of seasonal atmospheric and environmental conditions that has facilitated the use of similar broad-scale migration strategies may be especially prone to disruption under climate and land-use change. PMID:26791618

  18. Two photon absorption in high power broad area laser diodes

    NASA Astrophysics Data System (ADS)

    Dogan, Mehmet; Michael, Christopher P.; Zheng, Yan; Zhu, Lin; Jacob, Jonah H.

    2014-03-01

    Recent advances in thermal management and improvements in fabrication and facet passivation enabled extracting unprecedented optical powers from laser diodes (LDs). However, even in the absence of thermal roll-over or catastrophic optical damage (COD), the maximum achievable power is limited by optical non-linear effects. Due to its non-linear nature, two-photon absorption (TPA) becomes one of the dominant factors that limit efficient extraction of laser power from LDs. In this paper, theoretical and experimental analysis of TPA in high-power broad area laser diodes (BALD) is presented. A phenomenological optical extraction model that incorporates TPA explains the reduction in optical extraction efficiency at high intensities in BALD bars with 100μm-wide emitters. The model includes two contributions associated with TPA: the straightforward absorption of laser photons and the subsequent single photon absorption by the holes and electrons generated by the TPA process. TPA is a fundamental limitation since it is inherent to the LD semiconductor material. Therefore scaling the LDs to high power requires designs that reduce the optical intensity by increasing the mode size.

  19. Convergence of broad-scale migration strategies in terrestrial birds.

    PubMed

    La Sorte, Frank A; Fink, Daniel; Hochachka, Wesley M; Kelling, Steve

    2016-01-27

    Migration is a common strategy used by birds that breed in seasonal environments. Selection for greater migration efficiency is likely to be stronger for terrestrial species whose migration strategies require non-stop transoceanic crossings. If multiple species use the same transoceanic flyway, then we expect the migration strategies of these species to converge geographically towards the most optimal solution. We test this by examining population-level migration trajectories within the Western Hemisphere for 118 migratory species using occurrence information from eBird. Geographical convergence of migration strategies was evident within specific terrestrial regions where geomorphological features such as mountains or isthmuses constrained overland migration. Convergence was also evident for transoceanic migrants that crossed the Gulf of Mexico or Atlantic Ocean. Here, annual population-level movements were characterized by clockwise looped trajectories, which resulted in faster but more circuitous journeys in the spring and more direct journeys in the autumn. These findings suggest that the unique constraints and requirements associated with transoceanic migration have promoted the spatial convergence of migration strategies. The combination of seasonal atmospheric and environmental conditions that has facilitated the use of similar broad-scale migration strategies may be especially prone to disruption under climate and land-use change.

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

    NASA Astrophysics Data System (ADS)

    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.

  1. Broad-beam, high current, metal ion implantation facility

    SciTech Connect

    Brown, I.G.; Dickinson, M.R.; Galvin, J.E.; Godechot, X.; MacGill, R.A.

    1990-07-01

    We have developed a high current metal ion implantation facility with which high current beams of virtually all the solid metals of the Periodic Table can be produced. The facility makes use of a metal vapor vacuum arc ion source which is operated in a pulsed mode, with pulse width 0.25 ms and repetition rate up to 100 pps. Beam extraction voltage is up to 100 kV, corresponding to an ion energy of up to several hundred keV because of the ion charge state multiplicity; beam current is up to several Amperes peak and around 10 mA time averaged delivered onto target. Implantation is done in a broad-beam mode, with a direct line-of-sight from ion source to target. Here we describe the facility and some of the implants that have been carried out using it, including the seeding' of silicon wafers prior to CVD with titanium, palladium or tungsten, the formation of buried iridium silicide layers, and actinide (uranium and thorium) doping of III-V compounds. 16 refs., 6 figs.

  2. Anticandidal activities of terconazole, a broad-spectrum antimycotic.

    PubMed

    Tolman, E L; Isaacson, D M; Rosenthale, M E; McGuire, J L; Van Cutsem, J; Borgers, M; Van den Bossche, H

    1986-06-01

    Terconazole is a new triazole ketal derivative with broad-spectrum in vitro and in vivo antifungal activities. This study further characterizes the effects of terconazole in vitro on yeast cell growth, viability, and morphology. Terconazole inhibited the growth of Candida albicans ATCC 44859 in a concentration-related manner, but with modest effects noted at levels from 10(-8) to 10(-5) M when the yeast was grown on media favoring the cell form. The inhibitory potency of terconazole on yeast cell viability varied with the strain and species of Candida tested. The susceptibility of C. albicans ATCC 44859 to terconazole was markedly enhanced when the yeast was grown on Eagle minimum essential medium, which favors mycelium formation. The effects of terconazole on the morphology of yeast cells (grown on Eagle minimum essential medium) were shown by phase-contrast and electron microscopy. There is a progression of changes, from loss of mycelia formation at 10(-8) M terconazole through complete necrosis at 10(-4) M.

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

    PubMed

    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.

  4. VERY LARGE TELESCOPE SPECTROPOLARIMETRY OF BROAD ABSORPTION LINE QSOs

    SciTech Connect

    DiPompeo, M. A.; Brotherton, M. S.; De Breuck, C.

    2011-03-15

    We present spectropolarimetry of 19 confirmed and four possible bright, southern broad absorption line (BAL) quasars from the European Southern Observatory Very Large Telescope. A wide range of redshifts is covered in the sample (from 0.9 to 3.4), and both low- and high-ionization quasars are represented, as well as radio-loud and radio-quiet BALQSOs. We continue to confirm previously established spectropolarimetric properties of BALQSOs, including the generally rising continuum polarization with shorter wavelengths and comparatively large fraction with high broadband polarization (6 of 19 with polarizations >2%). Emission lines are polarized less than or similar to the continuum, except in a few unusual cases, and absorption troughs tend to have higher polarizations. A search for correlations between polarization properties has been done, identifying two significant or marginally significant correlations. These are an increase in continuum polarization with decreasing optical luminosity (increasing absolute B magnitude) and decreasing C IV emission-line polarization with increased continuum polarization.

  5. Broad-lined Supernova 2016coi with a Helium Envelope

    NASA Astrophysics Data System (ADS)

    Yamanaka, Masayuki; Nakaoka, Tatsuya; Tanaka, Masaomi; Maeda, Keiichi; Honda, Satoshi; Hanayama, Hidekazu; Morokuma, Tomoki; Imai, Masataka; Kinugasa, Kenzo; Murata, Katsuhiro L.; Nishimori, Takefumi; Hashimoto, Osamu; Gima, Hirotaka; Hosoya, Kensuke; Ito, Ayano; Karita, Mayu; Kawabata, Miho; Morihana, Kumiko; Morikawa, Yuto; Murakami, Kotone; Nagayama, Takahiro; Ono, Tatsuharu; Onozato, Hiroki; Sarugaku, Yuki; Sato, Mitsuteru; Suzuki, Daisuke; Takahashi, Jun; Takayama, Masaki; Yaguchi, Hijiri; Akitaya, Hiroshi; Asakura, Yuichiro; Kawabata, Koji S.; Kuroda, Daisuke; Nogami, Daisaku; Oasa, Yumiko; Omodaka, Toshihiro; Saito, Yoshihiko; Sekiguchi, Kazuhiro; Tominaga, Nozomu; Uemura, Makoto; Watanabe, Makoto

    2017-03-01

    We present the early-phase spectra and the light curves of the broad-lined (BL) supernova (SN) 2016coi from t = 7 to 67 days after the estimated explosion date. This SN was initially reported as a BL Type SN Ic (SN Ic-BL). However, we found that spectra up to t = 12 days exhibited the He i λ5876, λ6678, and λ7065 absorption lines. We show that the smoothed and blueshifted spectra of normal SNe Ib are remarkably similar to the observed spectrum of SN 2016coi. The line velocities of SN 2016coi were similar to those of SNe Ic-BL and significantly faster than those of SNe Ib. Analyses of the line velocity and light curve suggest that the kinetic energy and the total ejecta mass of SN 2016coi are similar to those of SNe Ic-BL. Together with BL SNe 2009bb and 2012ap, for which the detection of He i was also reported, these SNe could be transitional objects between SNe Ic-BL and SNe Ib, and be classified as BL Type “Ib” SNe (SNe “Ib”-BL). Our work demonstrates the diversity of the outermost layer in BL SNe, which should be related to the variety of the evolutionary paths.

  6. Axial flow fan broad-band noise and prediction

    NASA Astrophysics Data System (ADS)

    Carolus, Thomas; Schneider, Marc; Reese, Hauke

    2007-02-01

    Two prediction methods for broad-band noise of low-pressure axial fans are investigated. Emphasis is put on the interaction noise due to ingested turbulence. The numerical large eddy simulation (LES) is applied to predict the unsteady blade forces due to grid generated highly turbulent inflow; the blade forces are then fed into an analytical two-dimensional acoustic ducted source model. A simple semi-empirical noise prediction model (SEM) is utilized for indicative comparison. Finally, to obtain a database for detailed verification, the turbulence statistics for a variety of different inflow configurations are determined experimentally using hot wire anemometry and a correlation analysis. In the limits of the necessary assumptions the SEM predicts the noise spectra and the overall sound power surprisingly well without any further tuning of parameters; the influence of the fan operating point and the nature of the inflow is obtained. Naturally, the predicted spectra appear unrealistically "smooth", since the empirical input data are averaged and modeled in the frequency domain. By way of contrast the LES yields the fluctuating forces on the blades in the time domain. Details of the source characteristics and their origin are obtained rather clearly. The predicted effects of the ingested turbulence on the fluctuating blade forces and the fan noise compare favorably with experiments. However, the choice of the numerical grid size determines the maximal resolvable frequency and the computational cost. As contrasted with the SEM, the cost for the LES-based method are immense.

  7. Extension of the Bgl Broad Group Cross Section Library

    NASA Astrophysics Data System (ADS)

    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.

  8. Multijunction organic photovoltaics with a broad spectral response.

    PubMed

    Macko, Jill A; Lunt, Richard R; Osedach, Timothy P; Brown, Patrick R; Barr, Miles C; Gleason, Karen K; Bulovic, Vladimir

    2012-11-14

    We demonstrate series-integrated multijunction organic photovoltaics fabricated monolithically by vapor-deposition in a transposed subcell order with the near-infrared-absorbing subcell in front of the green-absorbing subcell. This transposed subcell order is enabled by the highly complementary absorption spectra of a near-infrared-absorbing visibly-transparent subcell and a visible-absorbing subcell and motivated by the non-spatially-uniform optical intensity in nanoscale photovoltaics. The subcell order and thicknesses are optimized via transfer-matrix formalism and short-circuit current simulations. An efficient charge recombination zone consisting of layers of BCP/Ag/MoOx leads to negligible voltage and series-resistance losses. Under 1-sun illumination the multijunction solar cells exhibit a power conversion efficiency of 5.5 ± 0.2% with an FF of 0.685 ± 0.002 and a V(OC) of 1.65 ± 0.02 V, corresponding to the sum of the V(OC) of the component subcells. These devices exhibit a broad spectral response (in the wavelength range of 350 nm to 850 nm) but are limited by subcell external quantum efficiencies between 20% and 30% over the photoactive spectrum.

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

    PubMed

    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. Active infrared hyperspectral imaging system using a broadly tunable optical parametric oscillator

    NASA Astrophysics Data System (ADS)

    Malcolm, G. P. A.; Maker, G. T.; Robertson, G.; Dunn, M. H.; Stothard, D. J. M.

    2009-09-01

    The in situ identification and spatial location of gases, discrete liquid droplets and residues on surfaces is a technically challenging problem. Active Infrared (IR) hyperspectral imaging is a powerful technique that combines real-time imaging and optical spectroscopy for "standoff" detection of suspected chemical substances, including chemical warfare agents, toxic industrial chemicals, explosives and narcotics. An active IR hyperspectral imaging system requires a coherent, broadly tunable IR light source of high spectral purity, in order to detect a broad range of target substances. In this paper we outline a compact and power-efficient IR illumination source with high stability, efficiency, tuning range and spectral purity based upon an optical parametric oscillator (OPO). The fusion of established OPO technology with novel diode-pumped laser technology and electro-mechanical scanning has enabled a broadly applicable imaging system. This system is capable of hyperspectral imaging at both Near-IR (1.3 - 1.9 μm) and Mid-IR (2.3 - 4.6 μm) wavelengths simultaneously with a line width of < 3 cm-1. System size and complexity are minimised by using a dual InGaAs/InSb single element detector, and images are acquired by raster scanning the coaxial signal and idler beams simultaneously, at ranges up to 20 m. Reflection, absorption and scatter of incident radiation by chemical targets and their surroundings provide a method for spatial location, and characteristic spectra obtained from each sample can be used to identify targets uniquely. To date, we have recognized liquids in sample sizes as small 20 μl-and gases with sensitivity as high as 10ppm.m-at detection standoff distances > 10 m.

  11. Broad host range plasmids can invade an unexpectedly diverse fraction of a soil bacterial community

    PubMed Central

    Klümper, Uli; Riber, Leise; Dechesne, Arnaud; Sannazzarro, Analia; Hansen, Lars H; Sørensen, Søren J; Smets, Barth F

    2015-01-01

    Conjugal plasmids can provide microbes with full complements of new genes and constitute potent vehicles for horizontal gene transfer. Conjugal plasmid transfer is deemed responsible for the rapid spread of antibiotic resistance among microbes. While broad host range plasmids are known to transfer to diverse hosts in pure culture, the extent of their ability to transfer in the complex bacterial communities present in most habitats has not been comprehensively studied. Here, we isolated and characterized transconjugants with a degree of sensitivity not previously realized to investigate the transfer range of IncP- and IncPromA-type broad host range plasmids from three proteobacterial donors to a soil bacterial community. We identified transfer to many different recipients belonging to 11 different bacterial phyla. The prevalence of transconjugants belonging to diverse Gram-positive Firmicutes and Actinobacteria suggests that inter-Gram plasmid transfer of IncP-1 and IncPromA-type plasmids is a frequent phenomenon. While the plasmid receiving fractions of the community were both plasmid- and donor- dependent, we identified a core super-permissive fraction that could take up different plasmids from diverse donor strains. This fraction, comprising 80% of the identified transconjugants, thus has the potential to dominate IncP- and IncPromA-type plasmid transfer in soil. Our results demonstrate that these broad host range plasmids have a hitherto unrecognized potential to transfer readily to very diverse bacteria and can, therefore, directly connect large proportions of the soil bacterial gene pool. This finding reinforces the evolutionary and medical significances of these plasmids. PMID:25333461

  12. Comprehensive panel of real-time TaqMan polymerase chain reaction assays for detection and absolute quantification of filoviruses, arenaviruses, and New World hantaviruses.

    PubMed

    Trombley, Adrienne R; Wachter, Leslie; Garrison, Jeffrey; Buckley-Beason, Valerie A; Jahrling, Jordan; Hensley, Lisa E; Schoepp, Randal J; Norwood, David A; Goba, Augustine; Fair, Joseph N; Kulesh, David A

    2010-05-01

    Viral hemorrhagic fever is caused by a diverse group of single-stranded, negative-sense or positive-sense RNA viruses belonging to the families Filoviridae (Ebola and Marburg), Arenaviridae (Lassa, Junin, Machupo, Sabia, and Guanarito), and Bunyaviridae (hantavirus). Disease characteristics in these families mark each with the potential to be used as a biological threat agent. Because other diseases have similar clinical symptoms, specific laboratory diagnostic tests are necessary to provide the differential diagnosis during outbreaks and for instituting acceptable quarantine procedures. We designed 48 TaqMan-based polymerase chain reaction (PCR) assays for specific and absolute quantitative detection of multiple hemorrhagic fever viruses. Forty-six assays were determined to be virus-specific, and two were designated as pan assays for Marburg virus. The limit of detection for the assays ranged from 10 to 0.001 plaque-forming units (PFU)/PCR. Although these real-time hemorrhagic fever virus assays are qualitative (presence of target), they are also quantitative (measure a single DNA/RNA target sequence in an unknown sample and express the final results as an absolute value (e.g., viral load, PFUs, or copies/mL) on the basis of concentration of standard samples and can be used in viral load, vaccine, and antiviral drug studies.

  13. Ability to develop broadly neutralizing HIV-1 antibodies is not restricted by the germline Ig gene repertoire.

    PubMed

    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.

  14. Broad Street elevation of James H. Windrim and George Summers’s ...

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

    Broad Street elevation of James H. Windrim and George Summers’s neoclassical competition design for the New Masonic Temple, Philadelphia, 1867 - Masonic Temple, 1 North Broad Street, Philadelphia, Philadelphia County, PA

  15. 33 CFR 334.475 - Brickyard Creek and tributaries and the Broad River at Beaufort, SC.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...°. (9) (Laurel Bay Military Family Housing Area, Broad River). That section of the Broad River, beginning on the western shoreline of Laurel Bay Military Family Housing Area boundary line, at latitude...

  16. 33 CFR 334.475 - Brickyard Creek and tributaries and the Broad River at Beaufort, SC.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...°. (9) (Laurel Bay Military Family Housing Area, Broad River). That section of the Broad River, beginning on the western shoreline of Laurel Bay Military Family Housing Area boundary line, at latitude...

  17. 33 CFR 334.475 - Brickyard Creek and tributaries and the Broad River at Beaufort, SC.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...°. (9) (Laurel Bay Military Family Housing Area, Broad River). That section of the Broad River, beginning on the western shoreline of Laurel Bay Military Family Housing Area boundary line, at latitude...

  18. 33 CFR 334.475 - Brickyard Creek and tributaries and the Broad River at Beaufort, SC.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...°. (9) (Laurel Bay Military Family Housing Area, Broad River). That section of the Broad River, beginning on the western shoreline of Laurel Bay Military Family Housing Area boundary line, at latitude...

  19. 33 CFR 334.475 - Brickyard Creek and tributaries and the Broad River at Beaufort, SC.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...°. (9) (Laurel Bay Military Family Housing Area, Broad River). That section of the Broad River, beginning on the western shoreline of Laurel Bay Military Family Housing Area boundary line, at latitude...

  20. Impact of broad-specification fuels on future jet aircraft. [engine components and performance

    NASA Technical Reports Server (NTRS)

    Grobman, J. S.

    1978-01-01

    The effects that broad specification fuels have on airframe and engine components were discussed along with the improvements in component technology required to use broad specification fuels without sacrificing performance, reliability, maintainability, or safety.

  1. Ecosystem services provided by waterbirds.

    PubMed

    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.

  2. Ancillary Services Provided from DER

    SciTech Connect

    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.

  3. Sensor Network Provides Environmental Data

    NASA Technical Reports Server (NTRS)

    2007-01-01

    The National Biocomputation Center, a joint partnership between the Stanford University School of Medicine's Department of Surgery and NASA's Ames Research Center, is the test bed for much of NASA's research in telemedicine, the remote delivery of medical care. In early 2005, researchers at the National Biocomputation Center formed a spinoff company, Intelesense Technologies, to use the telemedicine sensors to provide integrated global monitoring systems. Intelesense uses the systems to better understand how environments and people are linked, monitor and protect natural resources, predict and adapt to environmental changes, provide for sustainable development, reduce the costs and impacts of natural disasters, and provide an effective and intelligent response to such disasters. Current projects range from protecting the environment to tracking emerging infectious diseases like avian influenza (bird flu) and helping people from around the world connect and interact with each other to better understand their environment and themselves.

  4. Broad targeting of angiogenesis for cancer prevention and therapy

    PubMed Central

    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.

    2015-01-01

    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

  5. Broad targeting of angiogenesis for cancer prevention and therapy.

    PubMed

    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

  6. BeppoSAX broad-band observations of Gamma Cassiopeiae

    NASA Astrophysics Data System (ADS)

    Owens, A.; Oosterbroek, T.; Parmar, A. N.; Schulz, R.; Stüwe, J. A.; Haberl, F.

    1999-08-01

    We report broad-band X-ray measurements of the Be star gamma Cassiopeiae by the BeppoSAX X-ray astronomy satellite. The observations took place on 1998 July, 18-23. The 0.1-200 keV X-ray spectrum is reasonably well fit by an optically thin thermal plasma model of temperature 12.5+/-0.6 keV with significant residuals around 0.3 keV and 1 keV. The former is interpreted as the variable soft component reported by ROSAT, although there is no evidence for variability at the 5% level. For a blackbody interpretation, the fitted temperature is 100+/- (320) 13 eV, in agreement with the ROSAT value of 200+/- 10 eV. However, a MEKAL interpretation gives a significantly lower temperature of (48+/-11 eV). The fitted abundances are about half solar values, in agreement with previous measurements. At higher energies, the spectrum does not require non-thermal components and the observation of a line at 6.8 keV supports the ASCA interpretation of the source as an accreting white dwarf. Assuming a source distance of 188 pc, the bolometric luminosity in the 2-10 keV band is 6x10(32) ergs s(-1) . Simultaneous optical measurements by the Wendelstein Observatory near Munich, indicate that the source continues to be in a late but rather normal Be phase, with no obvious signs of a transition to the Be-shell phase. The measured magnitudes at B, V and R wavelengths of 2.18+/-0.06, 2.23+/-0.02 and 2.36+/-0.03, respectively, confirm this.

  7. Sensitive radioimmunoassay for the broad-spectrum antiviral agent ribavirin.

    PubMed

    Austin, R K; Trefts, P E; Hintz, M; Connor, J D; Kagnoff, M F

    1983-11-01

    Ribavirin, 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxyamide (Virazole; Viratek, Inc., Covina, Calif.), has a broad spectrum of antiviral activity. However, the study of the absorption, metabolism, and excretion of this compound has been limited by the lack of an appropriate assay for ribavirin and its metabolites. Since ribavirin has definite potential for therapeutic use, we developed a radioimmunoassay to measure ribavirin levels in clinical specimens. To prepare an effective immunogen, ribavirin was monosuccinylated and coupled to ovalbumin. The competitive binding radioimmunoassay, in which tritium-labeled ribavirin and rabbit antiribavirin serum were used, was quantitative for ribavirin at concentrations of 1 pmol/100 microliter in urine or plasma samples. The rabbit antibody cross-reacted with the major metabolite of ribavirin, 1,2,4-triazole-3-carboxamide, at a low level (2 to 5%) which did not interfere with ribavirin binding until concentrations of 1,2,4-triazole-3-carboxamide 10- to 100-fold higher than ribavirin were present in mock samples, a condition not present in biological specimens. We used the ribavirin radioimmunoassay to determine the ribavirin concentration in mouse plasma after intraperitoneal administration, in the sera of adults from Sierra Leone after oral or intravenous administration for treatment of suspected Lassa fever, and in the sera of children in the United States after small-particle aerosol administration. Our experience with the radioimmunoassay indicates that it is sensitive, accurate, and reproducible. The assay will permit studies leading to a better understanding of the pharmacology and pharmacokinetics of this potentially useful antiviral drug.

  8. Directed abstraction: Encouraging broad, personal generalizations following a success experience.

    PubMed

    Zunick, Peter V; Fazio, Russell H; Vasey, Michael W

    2015-07-01

    People with negative self-views may fail to generalize appropriately from success experiences (e.g., Wood, Heimpel, Newby-Clark, & Ross, 2005). We drew on theories regarding self-views (Swann, Griffin, Predmore, & Gaines, 1987) and abstraction (Semin & Fiedler, 1991), as well as past linguistic framing work (e.g., Marigold, Holmes, & Ross, 2007, 2010; Salancik, 1974), to create a new technique to encourage people with negative self-views to generalize broadly from a success experience to the self-concept. We call this technique directed abstraction. In Experiment 1, participants with negative self-views who completed a directed abstraction writing task following success feedback regarding a novel laboratory task generalized more from that success, reporting higher ability levels and greater expectations of future success in the relevant domain. In Experiment 2, directed abstraction produced similar results (including more positive self-related affect, e.g., pride) after participants recalled a past public speaking success. In Experiment 3, participants high in fear of public speaking gave two speeches in a context designed to be challenging yet also to elicit successful performances. Directed abstraction helped these participants generalize from their success to beliefs about their abilities, expectations about the future, and confidence as a speaker. In Experiment 4, directed abstraction following success on a verbal task increased persistence in the face of failure on a subsequent verbal task. We discuss implications for understanding how and when people generalize from a success, compare directed abstraction to existing interventions, and suggest practical applications for this influence technique.

  9. A Broad Specificity Nucleoside Kinase from Thermoplasma acidophilum

    PubMed Central

    Elkin, Sarah R.; Kumar, Abhinav; Price, Carol W.; Columbus, Linda

    2012-01-01

    The crystal structure of Ta0880, determined at 1.91 A resolution, from Thermoplasma acidophilum revealed a dimer with each monomer composed of an α/β /α sandwich domain and a smaller lid domain. The overall fold belongs to the PfkB family of carbohydrate kinases (a family member of the Ribokinase clan) which include ribokinases, 1-phosphofructokinases, 6-phosphofructo-2-kinase, inosine/guanosine kinases, frutokinases, adenosine kinases, and many more. Based on its general fold, Ta0880 had been annotated as a ribokinase-like protein. Using a coupled pyruvate kinase/lactate dehydrogenase assay, the activity of Ta0880 was assessed against a variety of ribokinase/pfkB-like family substrates; activity was not observed for ribose, fructose-1-phosphate, or fructose-6-phosphate. Based on structural similarity with nucleoside kinases (NK) from Methanocaldococcus jannaschii (MjNK, PDB 2C49 and 2C4E) and Burkholderia thailandensis (BtNK, PDB 3B1O), nucleoside kinase activity was investigated. Ta0880 (TaNK) was confirmed to have nucleoside kinase activity with an apparent KM for guanosine of 0.21 μM and catalytic efficiency of 345,000 M−1 s−1. These three NKs have significantly different substrate, phosphate donor, and cation specificities and comparisons of specificity and structure identified residues likely responsible for the nucleoside substrate selectivity. Phylogenetic analysis identified three clusters within the PfkB family and indicates that TaNK represents a new sub-family with broad nucleoside specificities. PMID:23161756

  10. EVIDENCE FOR PHOTOIONIZATION-DRIVEN BROAD ABSORPTION LINE VARIABILITY

    SciTech Connect

    Wang, Tinggui; Yang, Chenwei; Wang, Huiyuan; Ferland, Gary

    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.

  11. WINNERSS - Reaching a broad audience from an academic institution

    NASA Astrophysics Data System (ADS)

    Limaye, S. S.; Pertzborn, R. A.

    2001-12-01

    "Wisconsin Idea National Network - Education and Research in Space Sciences: Our Home in the Universe" is a Thematic Outreach Program from the University of Wisconsin-Madison. WINNERSS addresses the main current and future research topics in space sciences - origins of the universe, beginning(s) of life in the universe, the abitability of our home planet. These themes have origins in what we have learned in the age of space exploration and bring together the diverse disciplines of physics, astronomy, astrophysics, geology and geophysics, chemistry, atmospheric science, oceanography, astrobiology - or collectively, the space sciences. This has come about through evolution of our knowledge and our understanding of the role of different processes that have shaped our environment. These include the asteroid impacts on the earth and in our solar system, the discovery of possible microbial of life in Martian rocks that came to earth as meteorites, the discovery of planetary systems around other stars. At the same time, there has been a significant evolution in our knowledge and understanding of the universe and the fragility of the environment on our home planet. The sustainability and global environment are highlighted by global change processes such as weather extremes, "ozone hole", and concerns about the global warming illustrated by events such as the break-up of Antarctic icebergs the size of Rhode sland. Following the long tradition of the Wisconsin Idea, WINNERSS will strive to highlight research in these and related topics through Informal Science Education, K-12 programs and teacher development in space sciences. Broad geographic reach is enabled through the alumni clubs and the UW-Madison Speakers Bureau. WINNERSS is funded by the Wisconin Idea Program of the University of Wisconsin and is being implemented in collaboration with the Wisconsin Alumni Association, and the following components of the University of Wisconsin-Madison: the Graduate School, College

  12. A broad specificity nucleoside kinase from Thermoplasma acidophilum.

    PubMed

    Elkin, Sarah R; Kumar, Abhinav; Price, Carol W; Columbus, Linda

    2013-04-01

    The crystal structure of Ta0880, determined at 1.91 Å resolution, from Thermoplasma acidophilum revealed a dimer with each monomer composed of an α/β/α sandwich domain and a smaller lid domain. The overall fold belongs to the PfkB family of carbohydrate kinases (a family member of the Ribokinase clan) which include ribokinases, 1-phosphofructokinases, 6-phosphofructo-2-kinase, inosine/guanosine kinases, fructokinases, adenosine kinases, and many more. Based on its general fold, Ta0880 had been annotated as a ribokinase-like protein. Using a coupled pyruvate kinase/lactate dehydrogenase assay, the activity of Ta0880 was assessed against a variety of ribokinase/pfkB-like family substrates; activity was not observed for ribose, fructose-1-phosphate, or fructose-6-phosphate. Based on structural similarity with nucleoside kinases (NK) from Methanocaldococcus jannaschii (MjNK, PDB 2C49, and 2C4E) and Burkholderia thailandensis (BtNK, PDB 3B1O), nucleoside kinase activity was investigated. Ta0880 (TaNK) was confirmed to have nucleoside kinase activity with an apparent KM for guanosine of 0.21 μM and catalytic efficiency of 345,000 M(-1) s(-1) . These three NKs have significantly different substrate, phosphate donor, and cation specificities and comparisons of specificity and structure identified residues likely responsible for the nucleoside substrate selectivity. Phylogenetic analysis identified three clusters within the PfkB family and indicates that TaNK is a member of a new sub-family with broad nucleoside specificities. Proteins 2013. © 2012 Wiley Periodicals, Inc.

  13. A single amino acid deletion in the matrix protein of porcine reproductive and respiratory syndrome virus confers resistance to a polyclonal swine antibody with broadly neutralizing activity.

    PubMed

    Trible, Benjamin R; Popescu, Luca N; Monday, Nicholas; Calvert, Jay G; Rowland, Raymond R R

    2015-06-01

    Assessment of virus neutralization (VN) activity in 176 pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV) identified one pig with broadly neutralizing activity. A Tyr-10 deletion in the matrix protein provided escape from broad neutralization without affecting homologous neutralizing activity. The role of the Tyr-10 deletion was confirmed through an infectious clone with a Tyr-10 deletion. The results demonstrate differences in the properties and specificities of VN responses elicited during PRRSV infection.

  14. Broadly neutralizing epitopes in the Plasmodium vivax vaccine candidate Duffy Binding Protein

    DOE PAGES

    Chen, Edwin; Salinas, Nichole D.; Huang, Yining; ...

    2016-05-18

    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 motifsmore » 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. In conclusion, 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.« less

  15. Broadly neutralizing epitopes in the Plasmodium vivax vaccine candidate Duffy Binding Protein

    SciTech Connect

    Chen, Edwin; Salinas, Nichole D.; Huang, Yining; Ntumngia, Francis; Plasencia, Manolo D.; Gross, Michael L.; Adams, John H.; Tolia, Niraj Harish

    2016-05-18

    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. In conclusion, 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.

  16. Broad-band soft x-ray diagnostic instruments at the LLNL Novette laser facility

    SciTech Connect

    Tirsell, K.G.; Lee, P.H.Y.; Nilson, D.G.; Medecki, H.

    1983-09-15

    Complementary broad-band instruments have been developed to measure time dependent, absolute soft x-ray spectra at the Lawrence Livermore National Laboratory (LLNL) Nd glass laser irradiation facilities. Absolute flux measurements of x rays emitted from laser-produced plasmas are important for understanding laser absorption and energy transport. We will describe two new 10-channel XRD systems that have been installed at the LLNL Novette facility for use in the 0.15- to 1.5-keV range. Since XRD channel time response is limited by available oscilloscope performance to 120 ps, a soft x-ray streak camera has been developed for better time resolution (20 ps) and greater dynamic range (approx.10/sup 3/) in the same x-ray energy region. Using suitable filters, grazing incidence mirrors, and a gold or cesium-iodide transmission cathode, this streak camera instrument has been installed at Novette to provide one broad and four relatively narrow channels. It can also be used in a single channel, spatially discriminating mode by means of pinhole imaging. The complementary nature of these instruments has been enhanced by locating them in close proximity and matching their channel energy responses. As an example of the use of these instruments, we present results from Novette 2..omega..(0.53 ..mu..m) gold disk irradiations at 1 ns and 10/sup 14/ to 10/sup 15/ W/cm/sup 2/.

  17. Broad-stripe single longitudinal mode laser based on metal slots

    NASA Astrophysics Data System (ADS)

    Jia, Peng; Qin, Li; Chen, Yongyi; Zhang, Jianwei; Zhang, Jian; Zhang, Xing; Zeng, Yugang; Shan, Xiaonan; Ning, Yongqiang; Wang, Lijun

    2016-04-01

    Single-longitudinal-mode end-emitting laser with 10 periods of metal slots at around 956 nm has been fabricated. 100 μm wide broad-stripe and ten periods of 9.5 μm periodicity metal slots are defined by i-line lithography and dry etching. Experimentally, continuous-wave power of 213 mW has achieved, at a slope efficiency of 520 mW/A, having a 3 dB spectrum width of less than 0.04 nm at 900 mA, and operating in a stable single longitudinal mode with the side-mode suppression ratio (SMSR) of 42 dB. We prove that metal slots introduce sufficient loss into the cavity to filter out the wanted mode, and is more efficient on our chip structure than traditional slot laser. This paper provides a new method for the realizing high power broad-stripe (~100 μm) laser and array with single longitudinal mode operation.

  18. Broadly neutralizing alphavirus antibodies bind an epitope on E2 and inhibit entry and egress

    PubMed Central

    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.

    2015-01-01

    SUMMARY 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. PMID:26553503

  19. A LAIR-1 insertion generates broadly reactive antibodies against malaria variant antigens

    PubMed Central

    Abdi, Abdirahman; Perez, Mathilde Foglierini; Geiger, Roger; Tully, Claire Maria; Jarrossay, David; Maina Ndungu, Francis; Wambua, Juliana; Bejon, Philip; Fregni, Chiara Silacci; Fernandez-Rodriguez, Blanca; Barbieri, Sonia; Bianchi, Siro; Marsh, Kevin; Thathy, Vandana; Corti, Davide; Sallusto, Federica

    2016-01-01

    Plasmodium falciparum antigens expressed on the surface of infected erythrocytes are important targets of naturally acquired immunity against malaria, but their high number and variability provide the pathogen with a powerful means of escape from host antibodies1–4. Although broadly reactive antibodies against these antigens could be useful as therapeutics and in vaccine design, their identification has proven elusive. Here, we report the isolation of human monoclonal antibodies that recognize erythrocytes infected by different P. falciparum isolates and opsonize these cells by binding to members of the RIFIN family. These antibodies acquired broad reactivity through a novel mechanism of insertion of a large DNA fragment between the V and DJ segments. The insert, which is both necessary and sufficient for binding to RIFINs, encodes the entire 100 amino acid collagen-binding domain of LAIR-1, an Ig superfamily inhibitory receptor encoded on chromosome 19. In each of the two donors studied, the antibodies are produced by a single expanded B cell clone and carry distinct somatic mutations in the LAIR-1 domain that abolish binding to collagen and increase binding to infected erythrocytes. These findings illustrate, with a biologically relevant example, a novel mechanism of antibody diversification by interchromosomal DNA transposition and demonstrate the existence of conserved epitopes that may be suitable candidates for the development of a malaria vaccine. PMID:26700814

  20. Broadly neutralizing epitopes in the Plasmodium vivax vaccine candidate Duffy Binding Protein.

    PubMed

    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.

  1. Roles of glycans in interactions between gp120 and HIV broadly neutralizing antibodies.

    PubMed

    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.

  2. Broadly Neutralizing Alphavirus Antibodies Bind an Epitope on E2 and Inhibit Entry and Egress.

    PubMed

    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.

  3. Broad target chemical screening approach used as tool for rapid assessment of groundwater quality.

    PubMed

    ter Laak, Thomas L; Puijker, Leo M; van Leerdam, Jan A; Raat, Klaasjan J; Kolkman, Annemieke; de Voogt, Pim; van Wezel, Annemarie P

    2012-06-15

    The chemical water quality is often assessed by screening for a limited set of target chemicals. This 'conventional' target analysis approach inevitably misses chemicals present in the samples. In this study a 'broad' target screening approach for water quality assessment using high resolution and accurate mass spectrometry (HR MS) was applied to detect a wide variety of organic chemicals in 42 groundwater samples. In this approach, both known and unidentified chemicals observed in previous samples define the training set for the analysis of future samples and, additionally, new samples can be used to extend the training set. Nearly 400 chemicals were observed in the samples, of which 82 were known and more than 313 are of unknown identity. The obtained results were interpreted in relation to the source characteristics and land use. Groundwater that was affected by landfills showed the highest total MS response (ion counts) and most individual chemicals and was therefore considered most contaminated. Furthermore, river bank filtrated water was generally more contaminated than phreatic groundwater and groundwater from (semi)confined aquifers was most pristine. Additionally, industrial chemicals were more frequently observed in river bank filtrated water and pesticides were more frequently observed in water originating from rural areas. The 'broad' target screening approach for both known and unidentified chemicals does provide more information on the over-all water quality than 'conventional' target analysis.

  4. Characterisation of Host Growth after Infection with a Broad-Range Freshwater Cyanopodophage

    PubMed Central

    Watkins, Siobhan C.; Smith, James R.; Hayes, Paul K.; Watts, Joy E. M.

    2014-01-01

    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. PMID:24489900

  5. Polarization-Controlled Broad Color Palette Based on an Ultrathin One-Dimensional Resonant Grating Structure

    NASA Astrophysics Data System (ADS)

    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.

  6. Polarization-Controlled Broad Color Palette Based on an Ultrathin One-Dimensional Resonant Grating Structure

    PubMed Central

    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. PMID:28067264

  7. The National Occupational Research Agenda: a model of broad stakeholder input into priority setting.

    PubMed Central

    Rosenstock, L; Olenec, C; Wagner, G R

    1998-01-01

    OBJECTIVES: No single organization has the resources necessary to conduct occupational safety and health research to adequately serve the needs of workers in the United States. The National Institute for Occupational Safety and Health (NIOSH) undertook the task of setting research priorities in response to a broadly perceived need to systematically address those topics most pressing and most likely to yield gains to workers and to the nation. METHODS: NIOSH and its public and private partners used a consensus-building process to set priorities for the next decade for occupational safety and health research--the National Occupational Research Agenda. RESULTS: The process resulted in the identification of 21 research priorities grouped into 3 categories: disease and injury, work environment and workforce, and research tools and approaches. CONCLUSIONS: Although the field of occupational safety and health is often contentious and adversarial, these research priorities reflect a remarkable degree of concurrence among a broad range of stakeholders who provided input into a clearly defined and open process. PMID:9518963

  8. A LAIR1 insertion generates broadly reactive antibodies against malaria variant antigens.

    PubMed

    Tan, Joshua; Pieper, Kathrin; Piccoli, Luca; Abdi, Abdirahman; Foglierini, Mathilde; Geiger, Roger; Tully, Claire Maria; Jarrossay, David; Ndungu, Francis Maina; Wambua, Juliana; Bejon, Philip; Fregni, Chiara Silacci; Fernandez-Rodriguez, Blanca; Barbieri, Sonia; Bianchi, Siro; Marsh, Kevin; Thathy, Vandana; Corti, Davide; Sallusto, Federica; Bull, Peter; Lanzavecchia, Antonio

    2016-01-07

    Plasmodium falciparum antigens expressed on the surface of infected erythrocytes are important targets of naturally acquired immunity against malaria, but their high number and variability provide the pathogen with a powerful means of escape from host antibodies. Although broadly reactive antibodies against these antigens could be useful as therapeutics and in vaccine design, their identification has proven elusive. Here we report the isolation of human monoclonal antibodies that recognize erythrocytes infected by different P. falciparum isolates and opsonize these cells by binding to members of the RIFIN family. These antibodies acquired broad reactivity through a novel mechanism of insertion of a large DNA fragment between the V and DJ segments. The insert, which is both necessary and sufficient for binding to RIFINs, encodes the entire 98 amino acid collagen-binding domain of LAIR1, an immunoglobulin superfamily inhibitory receptor encoded on chromosome 19. In each of the two donors studied, the antibodies are produced by a single expanded B-cell clone and carry distinct somatic mutations in the LAIR1 domain that abolish binding to collagen and increase binding to infected erythrocytes. These findings illustrate, with a biologically relevant example, a novel mechanism of antibody diversification by interchromosomal DNA transposition and demonstrate the existence of conserved epitopes that may be suitable candidates for the development of a malaria vaccine.

  9. FirebrowseR: an R client to the Broad Institute’s Firehose Pipeline

    PubMed Central

    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

  10. A tunable, linac based, intense, broad-band THz source forpump-probe experiments

    SciTech Connect

    Schmerge, J.; Adolphsen, C.; Corbett, J.; Dolgashev, V.; Durr, H.; Fazio, M.; Fisher, A.; Frisch, J.; Gaffney, K.; Guehr, M.; Hastings, J.; Hettel, B.; Hoffmann, M.; Hogan, M.; Holtkamp, N.; Huang, X.; Huang, Z.; Kirchmann, P.; LaRue, J.; Limborg, C.; Lindenberg, A.; Loos, H.; Maxwell, T.; Nilsson, A.; Raubenheimer, T.; Reis, D.; Ross, M.; Shen, Z. -X.; Stupakov, G.; Tantawi, S.; Tian, K.; Wu, Z.; Xiang, D.; Yakimenko, V.

    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.

  11. Uptake of perfluoroalkyl acids in the leaves of coniferous and deciduous broad-leaved trees.

    PubMed

    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.

  12. Design of wide bandwidth pyramidal microwave absorbers using ferrite composites with broad magnetic loss spectra

    NASA Astrophysics Data System (ADS)

    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.

  13. Twitter for travel medicine providers.

    PubMed

    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.

  14. Mentor Program Provides STEM Options

    ERIC Educational Resources Information Center

    Abdul-alim, Jamaal

    2011-01-01

    The ACE Mentor Program provides early career exposure, mentoring, and scholarships to high school students in an attempt to encourage them to enter one of the three fields that make up the ACE acronym: (1) architecture; (2) construction; and (3) engineering. Founded in 1993 by longtime engineering consultant Charles Thornton, the program is…

  15. Ecosystem services provided by bats.

    PubMed

    Kunz, Thomas H; Braun de Torrez, Elizabeth; Bauer, Dana; Lobova, Tatyana; Fleming, Theodore H

    2011-03-01

    Ecosystem services are the benefits obtained from the environment that increase human well-being. Economic valuation is conducted by measuring the human welfare gains or losses that result from changes in the provision of ecosystem services. Bats have long been postulated to play important roles in arthropod suppression, seed dispersal, and pollination; however, only recently have these ecosystem services begun to be thoroughly evaluated. Here, we review the available literature on the ecological and economic impact of ecosystem services provided by bats. We describe dietary preferences, foraging behaviors, adaptations, and phylogenetic histories of insectivorous, frugivorous, and nectarivorous bats worldwide in the context of their respective ecosystem services. For each trophic ensemble, we discuss the consequences of these ecological interactions on both natural and agricultural systems. Throughout this review, we highlight the research needed to fully determine the ecosystem services in question. Finally, we provide a comprehensive overview of economic valuation of ecosystem services. Unfortunately, few studies estimating the economic value of ecosystem services provided by bats have been conducted to date; however, we outline a framework that could be used in future studies to more fully address this question. Consumptive goods provided by bats, such as food and guano, are often exchanged in markets where the market price indicates an economic value. Nonmarket valuation methods can be used to estimate the economic value of nonconsumptive services, including inputs to agricultural production and recreational activities. Information on the ecological and economic value of ecosystem services provided by bats can be used to inform decisions regarding where and when to protect or restore bat populations and associated habitats, as well as to improve public perception of bats.

  16. Some comments on providing broadband light to users

    SciTech Connect

    Benson, S.

    1997-12-01

    Though the free-electron laser gain medium is inherently broadband and several labs have demonstrated wavelength tuning over a range of several octaves, it is quite challenging to deliver such a broad bandwidth to users. The challenge arises from providing high quality, high power light, transporting the light to the users, and providing diagnostics to the user over a very large wavelength range. This paper summarizes some of the issues which must be considered and discusses some of the solutions which user facilities around the world have used to address the problems.

  17. Broad-range real time PCR and DNA sequencing for the diagnosis of bacterial meningitis.

    PubMed

    Deutch, Susanna; Pedersen, Lisbeth N; Pødenphant, Lone; Olesen, Rikke; Schmidt, Michael B; Møller, Jens K; Ostergaard, Lars

    2006-01-01

    Rapid aetiological diagnosis of bacterial meningitis is crucial for the early targeting of antimicrobial and adjuvant therapy. Broad-range polymerase chain reaction (PCR) targeting the 16S rRNA gene allows aetiological diagnosis of bacterial meningitis when applied to cerebrospinal fluid (CSF). We assessed the additional diagnostic effect of applying a novel broad-range real time PCR and subsequent DNA sequencing to culture, microscopy, and broad-range conventional PCR on CSF in patients with suspected bacterial meningitis. Broad-range conventional PCR and broad-range real time PCR with subsequent DNA sequencing were applied to 206 CSF specimens collected consecutively from 203 patients aged 6 d to 86 y. Patients' charts were reviewed for clinical information. 17 pathogens were identified by PCR and DNA sequencing or culture. Three specimens were negative by culture but positive by broad-range real time PCR. Three specimens were positive by culture but negative by broad-range real time PCR. Compared with culture, the sensitivity of broad-range real time PCR was 86%, and the specificity 98%. Conventional PCR resulted in a sensitivity of 64% and specificity of 98%. Broad-range real time PCR was generally comparable to culture of CSF and may be a useful supplement, particularly when antimicrobial therapy has been administered. Broad-range real time PCR was more sensitive than broad-range conventional PCR and microscopy.

  18. Privileged phosphine-based metal-organic frameworks for broad-scope asymmetric catalysis.

    PubMed

    Falkowski, Joseph M; Sawano, Takahiro; Zhang, Teng; Tsun, Galen; Chen, Yuan; Lockard, Jenny V; Lin, Wenbin

    2014-04-09

    A robust and porous Zr metal-organic framework (MOF) based on a BINAP-derived dicarboxylate linker, BINAP-MOF, was synthesized and post-synthetically metalated with Ru and Rh complexes to afford highly enantioselective catalysts for important organic transformations. The Rh-functionalized MOF is not only highly enantioselective (up to >99% ee) but also 3 times as active as the homogeneous control. XAFS studies revealed that the Ru-functionalized MOF contains Ru-BINAP precatalysts with the same coordination environment as the homogeneous Ru complex. The post-synthetically metalated BINAP-MOFs provide a versatile family of single-site solid catalysts for catalyzing a broad scope of asymmetric organic transformations, including addition of aryl and alkyl groups to α,β-unsaturated ketones and hydrogenation of substituted alkene and carbonyl compounds.

  19. Broadband and Broad-angle Polarization-independent Metasurface for Radar Cross Section Reduction

    NASA Astrophysics Data System (ADS)

    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.

  20. Note: A simple broad bandwidth undersampling frequency-domain digital diffuse optical spectroscopy system

    NASA Astrophysics Data System (ADS)

    Jung, Justin; Istfan, Raeef; Roblyer, Darren

    2014-07-01

    Near-Infrared frequency-domain technologies, such as Diffuse Optical Spectroscopy (DOS), have demonstrated growing potential in a number of clinical applications. The broader dissemination of this technology is limited by the complexity and cost of instrumentation. We present here a simple system constructed with off-the-shelf components that utilizes undersampling for digital frequency-domain dDOS measurements. Broadband RF sweeps (50-300 MHz) were digitally sampled at 25 MSPS; amplitude, phase, and optical property extractions were within 5% of network analyzer derived values. The use of undersampling for broad bandwidth dDOS provides a significant reduction in complexity, power consumption, and cost compared with high-speed ADCs and analog techniques.