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Sample records for arenaviruses provide broad

  1. [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.

  2. 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

  3. The Z Proteins of Pathogenic but Not Nonpathogenic Arenaviruses Inhibit RIG-i-Like Receptor-Dependent Interferon Production

    PubMed Central

    Xing, Junji; Ly, Hinh

    2014-01-01

    ABSTRACT Arenavirus pathogens cause a wide spectrum of diseases in humans ranging from central nervous system disease to lethal hemorrhagic fevers with few treatment options. The reason why some arenaviruses can cause severe human diseases while others cannot is unknown. We find that the Z proteins of all known pathogenic arenaviruses, lymphocytic choriomeningitis virus (LCMV) and Lassa, Junin, Machupo, Sabia, Guanarito, Chapare, Dandenong, and Lujo viruses, can inhibit retinoic acid-inducible gene 1 (RIG-i) and Melanoma Differentiation-Associated protein 5 (MDA5), in sharp contrast to those of 14 other nonpathogenic arenaviruses. Inhibition of the RIG-i-like receptors (RLRs) by pathogenic Z proteins is mediated by the protein-protein interactions of Z and RLRs, which lead to the disruption of the interactions between RLRs and mitochondrial antiviral signaling (MAVS). The Z-RLR interactive interfaces are located within the N-terminal domain (NTD) of the Z protein and the N-terminal CARD domains of RLRs. Swapping of the LCMV Z NTD into the nonpathogenic Pichinde virus (PICV) genome does not affect virus growth in Vero cells but significantly inhibits the type I interferon (IFN) responses and increases viral replication in human primary macrophages. In summary, our results show for the first time an innate immune-system-suppressive mechanism shared by the diverse pathogenic arenaviruses and thus shed important light on the pathogenic mechanism of human arenavirus pathogens. IMPORTANCE We show that all known human-pathogenic arenaviruses share an innate immune suppression mechanism that is based on viral Z protein-mediated RLR inhibition. Our report offers important insights into the potential mechanism of arenavirus pathogenesis, provides a convenient way to evaluate the pathogenic potential of known and/or emerging arenaviruses, and reveals a novel target for the development of broad-spectrum therapies to treat this group of diverse pathogens. More broadly, our

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

    PubMed

    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

  5. 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

  6. Arenavirus extinction through lethal mutagenesis.

    PubMed

    de la Torre, Juan Carlos

    2005-02-01

    Viral hemorrhagic fevers represent serious human public health problems causing devastating and often lethal disease. Several hemorrhagic fevers are caused by arenaviruses including Lassa fever virus (LFV) and the South American viral hemorrhagic fevers (SAHF). In recent years, increased air travel between Africa and other areas has led to the importation of LFV into the US, Europe, Japan, and Canada. This has raised awareness about arenaviruses as potential emerging viruses. Moreover, because of its severe morbidity and high mortality, and transmissibility from human to human, weaponized forms of LFV poses a real threat as agent of bioterrorism. No licensed vaccine is available in the US, and currently there is not efficacious therapy to treat these infections. Therefore, the importance of developing novel effective antiviral drugs to combat HF arenaviruses, for which the prototypic Arenavirus lymphocytic choriomeningitis virus (LCMV) provides us with an excellent model system. Recent findings have shown that LCMV multiplication both in cultured cells and in vivo is highly susceptible to the mutagenic agent 5-fluorouracil (FU). FU-mediated extinction of LCMV was associated with only modest increases in virus mutation frequencies, but did not significantly affect virus replication and transcription, or virus particle formation. These findings indicate that, as with other riboviruses, lethal mutagenesis is effective also against LCMV raising the possibility of using this novel antiviral strategy to combat pathogenic arenaviruses. PMID:15649566

  7. Arenaviruses other than Lassa virus.

    PubMed

    Charrel, Rémi N; de Lamballerie, Xavier

    2003-01-01

    The family Arenaviridae includes 23 viral species, of which 5 can cause viral hemorrhagic fevers with a case fatality rate of about 20%. These five viruses are Junin, Machupo, Guanarito, Sabia and Lassa virus, the manipulation of which requires biosafety level 4 facilities. They are included in the Category A Pathogen List established by the Center for Disease Control and Prevention that groups agents with the greatest potential for adverse public health impact and mass casualties whether a situation characterized by a ill-intentioned abuse of natural or engineered arenavirus would be encountered. The aims of this article are to (i) summarize the current situation; (ii) provide information to help anticipating the effects to be expected in such a situation; and to (iii) emphasize the need for fundamental research to allow the development of diagnostic, prevention and therapeutic tools as countermeasures to weaponized arenaviruses.

  8. Receptor use by pathogenic arenaviruses.

    PubMed

    Reignier, Therese; Oldenburg, Jill; Noble, Beth; Lamb, Erika; Romanowski, Victor; Buchmeier, Michael J; Cannon, Paula M

    2006-09-15

    The arenavirus family contains several important human pathogens including Lassa fever virus (LASV), lymphocytic choriomeningitis virus (LCMV) and the New World clade B viruses Junin (JUNV) and Machupo (MACV). Previously, alpha-dystroglycan (alpha-DG) was identified as a receptor recognized by LASV and certain strains of LCMV. However, other studies have suggested that alpha-DG is probably not used by the clade B viruses, and the receptor(s) for these pathogens is currently unknown. Using pseudotyped retroviral vectors displaying arenavirus glycoproteins (GPs), we are able to explore the role played by the GP in viral entry in the absence of other viral proteins. By examining the ability of the vectors to transduce DG knockout murine embryonic stem (ES) cells, we have confirmed that LASV has an absolute requirement for alpha-DG in these cells. However, the LCMV GP can still direct substantial entry into murine ES cells in the absence of alpha-DG, even when the GP from the clone 13 variant is used that has previously been reported to be highly dependent on alpha-DG for entry. We also found that neither LASV or LCMV pseudotyped vectors were able to transduce human or murine lymphocytes, presumably due to the glycosylation state of alpha-DG in these cells. In contrast, the JUNV and MACV GPs displayed broad tropism on human, murine and avian cell types, including lymphocytes, and showed no requirement for alpha-DG in murine ES cells. These findings highlight the importance of molecules other than alpha-DG for arenavirus entry. An alternate receptor is present on murine ES cells that can be used by LCMV but not by LASV, and which is not available on human or murine lymphocytes, while a distinct and widely expressed receptor(s) is used by the clade B viruses.

  9. 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.

  10. 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.

  11. 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

  12. 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. PMID:25935216

  13. 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.

  14. 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

  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. New World arenavirus clade C, but not clade A and B viruses, utilizes alpha-dystroglycan as its major receptor.

    PubMed

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

    2002-05-01

    Alpha-dystroglycan (alpha-DG) has been identified as a major receptor for lymphocytic choriomeningitis virus (LCMV) and Lassa virus, two Old World arenaviruses. The situation with New World arenaviruses is less clear: previous studies demonstrated that Oliveros virus also exhibited high-affinity binding to alpha-DG but that Guanarito virus did not. To extend these initial studies, several additional Old and New World arenaviruses were screened for entry into mouse embryonic stem cells possessing or lacking alpha-DG. In addition, representative viruses were further analyzed for direct binding to alpha-DG by means of a virus overlay protein blot assay technique. These studies indicate that Old World arenaviruses use alpha-DG as a major receptor, whereas, of the New World arenaviruses, only clade C viruses (i.e., Oliveros and Latino viruses) use alpha-DG as a major receptor. New World clade A and B arenaviruses, which include the highly pathogenic Machupo, Guanarito, Junin, and Sabia viruses, appear to use a different receptor or coreceptor for binding. Previous studies with LCMV have suggested the need for a small aliphatic amino acid at LCMV GP1 glycoprotein amino acid position 260 to allow high-affinity binding to alpha-DG. As reported herein, this requirement appears to be broadly applicable to the arenaviruses as determined by more extensive analysis of alpha-DG receptor usage and GP1 sequences of Old and New World arenaviruses. In addition, GP1 amino acid position 259 also appears to be important, since all arenaviruses showing high-affinity alpha-DG binding possess a bulky aromatic amino acid (tyrosine or phenylalanine) at this position.

  17. 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

  18. The curious case of arenavirus entry, and its inhibition.

    PubMed

    Nunberg, Jack H; York, Joanne

    2012-01-01

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

  19. Morphology and morphogenesis of arenaviruses*

    PubMed Central

    Murphy, Frederick A.; Whitfield, Sylvia G.

    1975-01-01

    Arenaviruses have unique structural characteristics; they are pleomorphic, have a mean diameter of 110-130 nm, and consist of a membranous envelope with surface projections surrounding an interior containing ribosomes and filaments. Virus particles bud from plasma membranes of infected cells and in many cases large intracytoplasmic inclusion bodies are formed. These characteristics allow generic identification, but not differentiation of individual viruses. Ultrastructural identification of virus particles and pathological processes in infected tissues of man and experimental animals is important in understanding the nature of arenaviral pathogenesis Such identification also contributes to our understanding of the mechanisms of viral shedding and transmission in reservoir host species. ImagesFig. 3Fig. 4Fig. 5Fig. 11Fig. 12Fig. 13Fig. 6Fig. 7Fig. 8Fig. 9Fig. 10Fig. 1Fig. 2Fig. 14Fig. 15Fig. 16Fig. 17 PMID:182396

  20. Genetic diversity among Bolivian arenaviruses.

    PubMed

    Cajimat, Maria N B; Milazzo, Mary Louise; Rollin, Pierre E; Nichol, Stuart T; Bowen, Michael D; Ksiazek, Thomas G; Fulhorst, Charles F

    2009-03-01

    Machupo virus and Chapare virus are members of the Tacaribe serocomplex (virus family Arenaviridae) and etiological agents of hemorrhagic fever in humans in Bolivia. The nucleotide sequences of the complete Z genes, a large fragment of the RNA-dependent RNA polymerase genes, the complete glycoprotein precursor genes, and the complete nucleocapsid protein genes of 8 strains of Machupo virus were determined to increase our knowledge of the genetic diversity among the Bolivian arenaviruses. The results of analyses of the predicted amino acid sequences of the glycoproteins of the Machupo virus strains and Chapare virus strain 200001071 indicated that immune plasma from hemorrhagic fever cases caused by Machupo virus may prove beneficial in the treatment of Bolivian hemorrhagic fever but not hemorrhagic fever caused by Chapare virus.

  1. 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

  2. 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.

  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. PMID:26769540

  4. Inhibition of Arenavirus Infection by a Glycoprotein-Derived Peptide with a Novel Mechanism

    PubMed Central

    Spence, Jennifer S.; Melnik, Lilia I.; Badani, Hussain; Wimley, William C.

    2014-01-01

    and prone to treatment failure, we identified a peptide, AVP-p, derived from the fusion glycoprotein of a nonpathogenic model arenavirus, which demonstrates antiviral activity and no acute cytotoxicity. AVP-p is unique among self-derived inhibitory peptides in that it shows broad, specific activity against pseudoviruses bearing Old and New World arenavirus glycoproteins but not against viruses from other families. Further, the peptide's mechanism of action is highly novel. Biochemical assays and cryo-electron microscopy indicate that AVP-p induces premature activation of viral fusion proteins through membrane perturbance. Peptide treatment, however, does not increase the infectivity of cell-bound virus. We hypothesize that prematurely activated virions are less fit for receptor binding and membrane fusion and that AVP-p may represent a viable therapeutic strategy for arenavirus infection. PMID:24850726

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. Novel antiviral strategies to combat human Arenavirus infections.

    PubMed

    Kunz, Stefan; de la Torre, Juan C

    2005-12-01

    Arenaviruses merit significant attention both as tractable model systems to study acute and persistent viral infections, and as clinically important human pathogens. Evidence indicates that LCMV remains present in the USA and Europe and capable of causing significant morbidity in infected individuals, likely being a neglected human pathogen. Moreover, new arenaviruses are being discovered in the Americas on the average of one every three years, with some of them causing severe hemorrhagic fever. In addition, weaponized forms of these viruses pose a real threat as agents of bioterrorism. 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. We will discuss how this new knowledge is facilitating the establishment of novel assays to identify and characterize compounds 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 bases of their ability to persist, as well as to cause severe HF (hemorrhagic fever) disease in humans. These approaches could also lead to the development of novel potent and safe Arenavirus vaccines. PMID:16375709

  10. 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

    2008-07-01

    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.

  11. Broad-scale phylogenomics provides insights into retrovirus–host evolution

    PubMed Central

    Hayward, Alexander; Grabherr, Manfred; Jern, Patric

    2013-01-01

    Genomic data provide an excellent resource to improve understanding of retrovirus evolution and the complex relationships among viruses and their hosts. In conjunction with broad-scale in silico screening of vertebrate genomes, this resource offers an opportunity to complement data on the evolution and frequency of past retroviral spread and so evaluate future risks and limitations for horizontal transmission between different host species. Here, we develop a methodology for extracting phylogenetic signal from large endogenous retrovirus (ERV) datasets by collapsing information to facilitate broad-scale phylogenomics across a wide sample of hosts. Starting with nearly 90,000 ERVs from 60 vertebrate host genomes, we construct phylogenetic hypotheses and draw inferences regarding the designation, host distribution, origin, and transmission of the Gammaretrovirus genus and associated class I ERVs. Our results uncover remarkable depths in retroviral sequence diversity, supported within a phylogenetic context. This finding suggests that current infectious exogenous retrovirus diversity may be underestimated, adding credence to the possibility that many additional exogenous retroviruses may remain to be discovered in vertebrate taxa. We demonstrate a history of frequent horizontal interorder transmissions from a rodent reservoir and suggest that rats may have acted as important overlooked facilitators of gammaretrovirus spread across diverse mammalian hosts. Together, these results demonstrate the promise of the methodology used here to analyze large ERV datasets and improve understanding of retroviral evolution and diversity for utilization in wider applications. PMID:24277832

  12. A Specific Interaction of Small Molecule Entry Inhibitors with the Envelope Glycoprotein Complex of the Junín Hemorrhagic Fever Arenavirus*

    PubMed Central

    Thomas, Celestine J.; Casquilho-Gray, Hedi E.; York, Joanne; DeCamp, Dianne L.; Dai, Dongcheng; Petrilli, Erin B.; Boger, Dale L.; Slayden, Richard A.; Amberg, Sean M.; Sprang, Stephen R.; Nunberg, Jack H.

    2011-01-01

    Arenaviruses are responsible for acute hemorrhagic fevers worldwide and are recognized to pose significant threats to public health and biodefense. Small molecule compounds have recently been discovered that inhibit arenavirus entry and protect against lethal infection in animal models. These chemically distinct inhibitors act on the tripartite envelope glycoprotein (GPC) through its unusual stable signal peptide subunit to stabilize the complex against pH-induced activation of membrane fusion in the endosome. Here, we report the production and characterization of the intact transmembrane GPC complex of Junín arenavirus and its interaction with these inhibitors. The solubilized GPC is antigenically indistinguishable from the native protein and forms a homogeneous trimer in solution. When reconstituted into a lipid bilayer, the purified complex interacts specifically with its cell-surface receptor transferrin receptor-1. We show that small molecule entry inhibitors specific to New World or Old World arenaviruses bind to the membrane-associated GPC complex in accordance with their respective species selectivities and with dissociation constants comparable with concentrations that inhibit GPC-mediated membrane fusion. Furthermore, competitive binding studies reveal that these chemically distinct inhibitors share a common binding pocket on GPC. In conjunction with previous genetic studies, these findings identify the pH-sensing interface of GPC as a highly vulnerable target for antiviral intervention. This work expands our mechanistic understanding of arenavirus entry and provides a foundation to guide the development of small molecule compounds for the treatment of arenavirus hemorrhagic fevers. PMID:21159779

  13. Replication of Boid Inclusion Body Disease-Associated Arenaviruses Is Temperature Sensitive in both Boid and Mammalian Cells

    PubMed Central

    Kipar, Anja; Korzyukov, Yegor; Bell-Sakyi, Lesley; Vapalahti, Olli; Hetzel, Udo

    2014-01-01

    ABSTRACT Boid inclusion body disease (BIDB) is a fatal disease of boid snakes, the etiology of which has only recently been revealed following the identification of several novel arenaviruses in diseased snakes. BIBD-associated arenaviruses (BIBDAV) are genetically divergent from the classical Old and New World arenaviruses and also differ substantially from each other. Even though there is convincing evidence that BIBDAV are indeed the etiological agent of BIBD, the BIBDAV reservoir hosts—if any exist besides boid snakes themselves—are not yet known. In this report, we use University of Helsinki virus (UHV; a virus that we isolated from a Boa constrictor with BIBD) to show that BIBDAV can also replicate effectively in mammalian cells, including human cells, provided they are cultured at 30°C. The infection induces the formation of cytoplasmic inclusion bodies (IB), comprised mainly of viral nucleoprotein (NP), similar to those observed in BIBD and in boid cell cultures. Transferring infected cells from 30°C to 37°C ambient temperature resulted in progressive declines in IB formation and in the amounts of viral NP and RNA, suggesting that BIBDAV growth is limited at 37°C. These observations indirectly indicate that IB formation is linked to viral replication. In addition to mammalian and reptilian cells, UHV infected arthropod (tick) cells when grown at 30°C. Even though our findings suggest that BIBDAV have a high potential to cross the species barrier, their inefficient growth at mammalian body temperatures indicates that the reservoir hosts of BIBDAV are likely species with a lower body temperature, such as snakes. IMPORTANCE The newly discovered boid inclusion body disease-associated arenaviruses (BIBDAV) of reptiles have drastically altered the phylogeny of the family Arenavirus. Prior to their discovery, known arenaviruses were considered mainly rodent-borne viruses, with each arenavirus species having its own reservoir host. BIBDAV have so far been

  14. 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

  15. Symbionts Commonly Provide Broad Spectrum Resistance to Viruses in Insects: A Comparative Analysis of Wolbachia Strains

    PubMed Central

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

    2014-01-01

    In the last decade, bacterial symbionts have been shown to play an important role in protecting hosts against pathogens. Wolbachia, a widespread symbiont in arthropods, can protect Drosophila and mosquito species against viral infections. We have investigated antiviral protection in 19 Wolbachia strains originating from 16 Drosophila species after transfer into the same genotype of Drosophila simulans. We found that approximately half of the strains protected against two RNA viruses. Given that 40% of terrestrial arthropod species are estimated to harbour Wolbachia, as many as a fifth of all arthropods species may benefit from Wolbachia-mediated protection. The level of protection against two distantly related RNA viruses – DCV and FHV – was strongly genetically correlated, which suggests that there is a single mechanism of protection with broad specificity. Furthermore, Wolbachia is making flies resistant to viruses, as increases in survival can be largely explained by reductions in viral titer. Variation in the level of antiviral protection provided by different Wolbachia strains is strongly genetically correlated to the density of the bacteria strains in host tissues. We found no support for two previously proposed mechanisms of Wolbachia-mediated protection — activation of the immune system and upregulation of the methyltransferase Dnmt2. The large variation in Wolbachia's antiviral properties highlights the need to carefully select Wolbachia strains introduced into mosquito populations to prevent the transmission of arboviruses. PMID:25233341

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

    PubMed Central

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

    2012-01-01

    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. PMID:23202505

  17. 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

  18. 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.

  19. 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

  20. 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. PMID:26587982

  1. 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

  2. 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.

  3. 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

  4. MHC basis of T cell-dependent heterologous immunity to arenaviruses.

    PubMed

    Daniels, Keith A; Hatfield, Steven D; Welsh, Raymond M; Brehm, Michael A

    2014-09-01

    Having a history of infection with one pathogen may sometimes provide a level of T cell-dependent protective heterologous immunity to another pathogen. This immunity was initially thought due to cross-reactive T cell epitopes, but recent work has suggested that such protective immunity can be initiated nonspecifically by the action of cytokines on memory T cells. We retested this concept using two small and well-defined arenaviruses, lymphocytic choriomeningitis virus (LCMV) and Pichinde virus (PV), and found that heterologous immunity in these systems was indeed linked to T cell epitopes and the major histocompatibility complex.

  5. 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.

  6. 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

  7. 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

  8. Host Cell Factors as Antiviral Targets in Arenavirus Infection

    PubMed Central

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

    2012-01-01

    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. PMID:23170173

  9. 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

  10. 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.

  11. 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.

  12. Construction of the recombinant broad-host-range plasmids providing their bacterial hosts arsenic resistance and arsenite oxidation ability.

    PubMed

    Drewniak, Lukasz; Ciezkowska, Martyna; Radlinska, Monika; Sklodowska, Aleksandra

    2015-02-20

    The plasmid pSinA of Sinorhizobium sp. M14 was used as a source of functional phenotypic modules, encoding proteins involved in arsenite oxidation and arsenic resistance, to obtain recombinant broad-host-range plasmids providing their bacterial hosts arsenic resistance and arsenite oxidative ability. An arsenite oxidation module was cloned into pBBR1MCS-2 vector yielding plasmid vector pAIO1, while an arsenic resistance module was cloned into pCM62 vector yielding plasmid pARS1. Both plasmid constructs were introduced (separately and together) into the cells of phylogenetically distant (representing Alpha-, Beta-, and Gammaproteobacteria) and physiologically diversified (unable to oxidize arsenite and susceptible/resistant to arsenite and arsenate) bacteria. Functional analysis of the modified strains showed that: (i) the plasmid pARS1 can be used for the construction of strains with an increased resistance to arsenite [up to 20mM of As(III), (ii) the presence of the plasmid pAIO1 in bacteria previously unable to oxidize As(III) to As(V), contributes to the acquisition of arsenite oxidation abilities by these cells, (iii) the highest arsenite utilization rate are observed in the culture of strains harbouring both the plasmids pAIO1 and pARS1, (iv) the strains harbouring the plasmid pAIO1 were able to grow on arsenic-contaminated mine waters (∼ 3.0 mg As L(-1)) without any supplementation.

  13. 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.

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

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

    PubMed

    Delgado, Simon; Erickson, Bobbie R; Agudo, Roberto; Blair, Patrick J; Vallejo, Efrain; Albariño, César G; Vargas, Jorge; Comer, James A; Rollin, Pierre E; Ksiazek, Thomas G; Olson, James G; Nichol, Stuart T

    2008-04-18

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

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

    PubMed

    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), gp120(SU) 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

  1. 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

  2. Activity of a phenolic dibenzylsulfide against New World arenavirus infections

    PubMed Central

    Gowen, Brian B; Jung, Kie-Hoon; Sefing, Eric J; Wong, Min-Hui; Westover, Jonna B; Smee, Donald F

    2013-01-01

    Background Junín virus (JUNV) and several other Clade B New World arenaviruses cause human disease ranging from mild febrile illness to severe viral hemorrhagic fever (HF). These viruses pose a significant threat to national security and safe and effective therapies are limited outside of Argentina, where immune plasma is the standard of care for treating JUNV infection in cases of Argentine HF. Methods An in vitro screen of the Chemtura library identified several compounds with activity against Tacaribe virus (TCRV), a Clade B arenavirus closely related to JUNV. Of these compounds, D746, a phenolic dibenzylsulfide, was further pursued for additional in vitro studies and evaluated in the AG129 mouse TCRV infection model. Results D746 was found to act during an early to intermediate stage of the TCRV replication cycle and micromolar range activity was confirmed by virus yield reduction assays with both TCRV and JUNV. Although intraperitoneal twice daily treatment regimens were found to be highly effective when started 2 hours prior to TCRV challenge in AG129 mice, post-exposure treatment initiated 3 days after infection was not efficacious. Interestingly, despite the pre-exposure treatment success, D746 did not reduce serum or tissue virus titers during the acute infection. Moreover, D746 elicited ascites fluid accumulation in mice during, as well as independent of, infection. Conclusions Our findings suggest that D746 may be altering the host response to TCRV infection in AG129 mice in a way that limits pathogenesis and thereby protects mice from otherwise lethal infection in the absence of measurable reductions in viral burden. PMID:23337126

  3. 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.

  4. 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

  5. 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

  6. 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. PMID:26865707

  7. 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

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

    PubMed

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

    2010-04-01

    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.

  9. 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.

  10. [Development and utilization of an immunoenzyme technic to diagnose arenavirus infections].

    PubMed

    Ivanov, A P; Bashkirtsev, V N; Tkachenko, E A

    1981-01-01

    The possibility of using ELISA for the detection of arenavirus antigens in different organs of infected newborn white mice as well as in the culture fluids of arenavirus-infected cell cultures was demonstrated. The sensitivity of ELISA in antigen detection 100-200 times exceeds that of the CFT, and the time of antigen detection after inoculation of animals or cell cultures is much shorter. The use of ELISA block for the detection and titration of virus-specific antibody also demonstrated high sensitivity of this method as compared with the CFT.

  11. Inhibition of multiplication of the prototypic arenavirus LCMV by valproic acid

    PubMed Central

    Vázquez-Calvo, Ángela; Martín-Acebes, Miguel A.; Sáiz, Juan-Carlos; Ngo, Nhi; Sobrino, F.; de la Torre, Juan Carlos

    2013-01-01

    Valproic acid (VPA), a short chain fatty acid commonly used for treatment of neurological disorders, has been shown to inhibit production of infectious progeny of different enveloped viruses including the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV). In this study we have investigated the mechanisms by which VPA inhibits LCMV multiplication in cultured cells. VPA reduced production of infectious LCMV progeny and virus propagation without exerting a major blockage on either viral RNA or protein synthesis, but rather affecting the cell release and specific infectivity of LCMV progeny from infected cells. Our results would support the repurposing of VPA as a candidate antiviral drug to combat arenavirus infections. PMID:23735299

  12. THE INTRACELLULAR CARGO RECEPTOR ERGIC-53 IS REQUIRED FOR THE PRODUCTION OF INFECTIOUS ARENAVIRUS, CORONAVIRUS, AND FILOVIRUS PARTICLES

    PubMed Central

    Klaus, Joseph; Eisenhauer, Philip; Russo, Joanne; Mason, Anne; 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

    2013-01-01

    SUMMARY Arenaviruses and hantaviruses cause severe and often fatal diseases in humans. 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 ERGIC-53 - a cargo receptor required for cellular 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 arenavirus particles. 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. PMID:24237698

  13. Small-Molecule Probes Targeting the Viral PPxY-Host Nedd4 Interface Block Egress of a Broad Range of RNA Viruses

    PubMed Central

    Han, Ziying; Lu, Jianhong; Liu, Yuliang; Davis, Benjamin; Lee, Michael S.; Olson, Mark A.; Ruthel, Gordon; Freedman, Bruce D.; Schnell, Matthias J.; Wrobel, Jay E.; Reitz, Allen B.

    2014-01-01

    ABSTRACT Budding of filoviruses, arenaviruses, and rhabdoviruses is facilitated by subversion of host proteins, such as Nedd4 E3 ubiquitin ligase, by viral PPxY late (L) budding domains expressed within the matrix proteins of these RNA viruses. As L domains are important for budding and are highly conserved in a wide array of RNA viruses, they represent potential broad-spectrum targets for the development of antiviral drugs. To identify potential competitive blockers, we used the known Nedd4 WW domain-PPxY interaction interface as the basis of an in silico screen. Using PPxY-dependent budding of Marburg (MARV) VP40 virus-like particles (VLPs) as our model system, we identified small-molecule hit 1 that inhibited Nedd4-PPxY interaction and PPxY-dependent budding. This lead candidate was subsequently improved with additional structure-activity relationship (SAR) analog testing which enhanced antibudding activity into the nanomolar range. Current lead compounds 4 and 5 exhibit on-target effects by specifically blocking the MARV VP40 PPxY-host Nedd4 interaction and subsequent PPxY-dependent egress of MARV VP40 VLPs. In addition, lead compounds 4 and 5 exhibited antibudding activity against Ebola and Lassa fever VLPs, as well as vesicular stomatitis and rabies viruses (VSV and RABV, respectively). These data provide target validation and suggest that inhibition of the PPxY-Nedd4 interaction can serve as the basis for the development of a novel class of broad-spectrum, host-oriented antivirals targeting viruses that depend on a functional PPxY L domain for efficient egress. IMPORTANCE There is an urgent and unmet need for the development of safe and effective therapeutics against biodefense and high-priority pathogens, including filoviruses (Ebola and Marburg) and arenaviruses (e.g., Lassa and Junin) which cause severe hemorrhagic fever syndromes with high mortality rates. We along with others have established that efficient budding of filoviruses, arenaviruses, and

  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. 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.

  16. 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

  17. Human hemorrhagic Fever causing arenaviruses: molecular mechanisms contributing to virus virulence and disease pathogenesis.

    PubMed

    Shao, Junjie; Liang, Yuying; Ly, Hinh

    2015-05-21

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

  18. Genetic Detection and Characterization of Lujo Virus, a New Hemorrhagic Fever–Associated Arenavirus from Southern Africa

    PubMed Central

    McMullan, Laura K.; Hutchison, Stephen K.; Street, Craig; Palacios, Gustavo; Khristova, Marina L.; Weyer, Jacqueline; Swanepoel, Robert; Egholm, Michael; Nichol, Stuart T.; Lipkin, W. Ian

    2009-01-01

    Lujo virus (LUJV), a new member of the family Arenaviridae and the first hemorrhagic fever–associated arenavirus from the Old World discovered in three decades, was isolated in South Africa during an outbreak of human disease characterized by nosocomial transmission and an unprecedented high case fatality rate of 80% (4/5 cases). Unbiased pyrosequencing of RNA extracts from serum and tissues of outbreak victims enabled identification and detailed phylogenetic characterization within 72 hours of sample receipt. Full genome analyses of LUJV showed it to be unique and branching off the ancestral node of the Old World arenaviruses. The virus G1 glycoprotein sequence was highly diverse and almost equidistant from that of other Old World and New World arenaviruses, consistent with a potential distinctive receptor tropism. LUJV is a novel, genetically distinct, highly pathogenic arenavirus. PMID:19478873

  19. 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.

  20. Single-dose vaccination of a recombinant parainfluenza virus 5 expressing NP from H5N1 virus provides broad immunity against influenza A viruses.

    PubMed

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

    2013-05-01

    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.

  1. 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. PMID:25549822

  2. Broad-spectrum sunscreens provide greater protection against ultraviolet-radiation-induced suppression of contact hypersensitivity to a recall antigen in humans.

    PubMed

    Damian, D L; Halliday, G M; Barnetson, R S

    1997-08-01

    This study investigates the extent to which sunscreens protect humans from ultraviolet (UV)-radiation-induced immunosuppression. In the presence of solar-simulated UV, three sunscreens with differing UVA transmission were assessed for their ability to protect the contact hypersensitivity (CHS) response to nickel of 16 nickel-allergic subjects. The sunscreens contained 2-ethylhexyl para-methoxycinnamate (cinnamate), cinnamate with oxybenzone, or cinnamate with zinc oxide, respectively. All had sun protection factors of 10 and hence inhibited UV erythema to similar extents. Volunteers were irradiated on their backs with suberythemal UV daily for 5 d after application of the sunscreens and their base lotion to different sites. Nickel-containing patches were then applied to both UV-treated sites and adjacent, unirradiated control sites. Erythema caused by nickel CHS at each site was quantitated 72 h later with a reflectance erythema meter. In comparison of the nickel reactions of irradiated and unirradiated skin, there was 35% mean immunosuppression in unprotected UV-treated skin. Significant immunosuppression also occurred at sites irradiated through the narrow-spectrum cinnamate-only sunscreen but was prevented by the two broad-spectrum sunscreens. To determine whether UV-induced suppression of the nickel response is specific for cell-mediated immunity or reflects suppression of nonspecific inflammation, a further 16 subjects were patch-tested with a skin irritant, sodium lauryl sulfate (SLS), following a sunscreen and irradiation protocol identical to that of the nickel volunteers. UV had no significant effect on SLS responses. We conclude that nickel patch testing is a valid means of assessing UV-induced immunosuppression in humans and that even with suberythemal UV, immune protection was provided only by sunscreens filtering both UVA and UVB.

  3. Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenaviruses.

    PubMed

    Radoshitzky, Sheli R; Abraham, Jonathan; Spiropoulou, Christina F; Kuhn, Jens H; Nguyen, Dan; Li, Wenhui; Nagel, Jane; Schmidt, Paul J; Nunberg, Jack H; Andrews, Nancy C; Farzan, Michael; Choe, Hyeryun

    2007-03-01

    At least five arenaviruses cause viral haemorrhagic fevers in humans. Lassa virus, an Old World arenavirus, uses the cellular receptor alpha-dystroglycan to infect cells. Machupo, Guanarito, Junin and Sabia viruses are New World haemorrhagic fever viruses that do not use alpha-dystroglycan. Here we show a specific, high-affinity association between transferrin receptor 1 (TfR1) and the entry glycoprotein (GP) of Machupo virus. Expression of human TfR1, but not human transferrin receptor 2, in hamster cell lines markedly enhanced the infection of viruses pseudotyped with the GP of Machupo, Guanarito and Junin viruses, but not with those of Lassa or lymphocytic choriomeningitis viruses. An anti-TfR1 antibody efficiently inhibited the replication of Machupo, Guanarito, Junin and Sabia viruses, but not that of Lassa virus. Iron depletion of culture medium enhanced, and iron supplementation decreased, the efficiency of infection by Junin and Machupo but not Lassa pseudoviruses. These data indicate that TfR1 is a cellular receptor for New World haemorrhagic fever arenaviruses.

  4. 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

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

    PubMed

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

    2006-02-01

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

  6. 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

  7. 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

  8. 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

  9. [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

  10. 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.

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

    PubMed

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

    2016-03-01

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

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

    PubMed Central

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

    2016-01-01

    In invertebrates, small interfering RNAs are at the vanguard of cell-autonomous antiviral immunity. In contrast, antiviral mechanisms initiated by interferon (IFN) signaling predominate in mammals. Whilst mammalian IFN-induced miRNA are known to inhibit specific viruses, it is not known whether host-directed microRNAs, downstream of IFN-signaling, have a role in mediating broad antiviral resistance. By performing an integrative, systematic, global analysis of RNA turnover utilizing 4-thiouridine labeling of newly transcribed RNA and pri/pre-miRNA in IFN-activated macrophages, we identify a new post-transcriptional viral defense mechanism mediated by miR-342-5p. On the basis of ChIP and site-directed promoter mutagenesis experiments, we find the synthesis of miR-342-5p is coupled to the antiviral IFN response via the IFN-induced transcription factor, IRF1. Strikingly, we find miR-342-5p targets mevalonate-sterol biosynthesis using a multihit mechanism suppressing the pathway at different functional levels: transcriptionally via SREBF2, post-transcriptionally via miR-33, and enzymatically via IDI1 and SC4MOL. Mass spectrometry-based lipidomics and enzymatic assays demonstrate the targeting mechanisms reduce intermediate sterol pathway metabolites and total cholesterol in macrophages. These results reveal a previously unrecognized mechanism by which IFN regulates the sterol pathway. The sterol pathway is known to be an integral part of the macrophage IFN antiviral response, and we show that miR-342-5p exerts broad antiviral effects against multiple, unrelated pathogenic viruses such Cytomegalovirus and Influenza A (H1N1). Metabolic rescue experiments confirm the specificity of these effects and demonstrate that unrelated viruses have differential mevalonate and sterol pathway requirements for their replication. This study, therefore, advances the general concept of broad antiviral defense through multihit targeting of a single host pathway. PMID:26938778

  13. T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections.

    PubMed

    Furuta, Yousuke; Takahashi, Kazumi; Shiraki, Kimiyasu; Sakamoto, Kenichi; Smee, Donald F; Barnard, Dale L; Gowen, Brian B; Julander, Justin G; Morrey, John D

    2009-06-01

    A series of pyrazinecarboxamide derivatives T-705 (favipiravir), T-1105 and T-1106 were discovered to be candidate antiviral drugs. These compounds have demonstrated good activity in treating viral infections in laboratory animals caused by various RNA viruses, including influenza virus, arenaviruses, bunyaviruses, West Nile virus (WNV), yellow fever virus (YFV), and foot-and-mouth disease virus (FMDV). Treatment has in some cases been effective when initiated up to 5-7 days after virus infection, when the animals already showed signs of illness. Studies on the mechanism of action of T-705 have shown that this compound is converted to the ribofuranosyltriphosphate derivative by host enzymes, and this metabolite selectively inhibits the influenza viral RNA-dependent RNA polymerase without cytotoxicity to mammalian cells. Interestingly, these compounds do not inhibit host DNA and RNA synthesis and inosine 5'-monophosphate dehydrogenase (IMPDH) activity. From in vivo studies using several animal models, the pyrazinecarboxamide derivatives were found to be effective in protecting animals from death, reducing viral burden, and limiting disease manifestations, even when treatment was initiated after virus inoculation. Importantly, T-705 imparts its beneficial antiviral effects without significant toxicity to the host. Prompt development of these compounds is expected to provide effective countermeasures against pandemic influenza virus and several bioweapon threats, all of which are of great global public health concern given the current paucity of highly effective broad-spectrum drugs.

  14. 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

  15. Investigation of clade B New World arenavirus tropism by using chimeric GP1 proteins.

    PubMed

    Martin, Vanessa K; Droniou-Bonzom, Magali E; Reignier, Therese; Oldenburg, Jill E; Cox, Alex U; Cannon, Paula M

    2010-01-01

    Clade B of the New World arenaviruses contains both pathogenic and nonpathogenic members, whose surface glycoproteins (GPs) are characterized by different abilities to use the human transferrin receptor type 1 (hTfR1) protein as a receptor. Using closely related pairs of pathogenic and nonpathogenic viruses, we investigated the determinants of the GP1 subunit that confer these different characteristics. We identified a central region (residues 85 to 221) in the Guanarito virus GP1 that was sufficient to interact with hTfR1, with residues 159 to 221 being essential. The recently solved structure of part of the Machupo virus GP1 suggests an explanation for these requirements.

  16. Expression of the antiapoptotic baculovirus p35 gene in tomato blocks programmed cell death and provides broad-spectrum resistance to disease

    PubMed Central

    Lincoln, James E.; Richael, Craig; Overduin, Bert; Smith, Kathy; Bostock, Richard; Gilchrist, David G.

    2002-01-01

    The sphinganine analog mycotoxin, AAL-toxin, induces a death process in plant and animal cells that shows apoptotic morphology. In nature, the AAL-toxin is the primary determinant of the Alternaria stem canker disease of tomato, thus linking apoptosis to this disease caused by Alternaria alternata f. sp. lycopersici. The product of the baculovirus p35 gene is a specific inhibitor of a class of cysteine proteases termed caspases, and naturally functions in infected insects. Transgenic tomato plants bearing the p35 gene were protected against AAL-toxin-induced death and pathogen infection. Resistance to the toxin and pathogen co-segregated with the expression of the p35 gene through the T3 generation, as did resistance to A. alternata, Colletotrichum coccodes, and Pseudomonas syringae pv. tomato. The p35 gene, stably transformed into tomato roots by Agrobacterium rhizogenes, protected roots against a 30-fold greater concentration of AAL-toxin than control roots tolerated. Transgenic expression of a p35 binding site mutant (DQMD to DRIL), inactive against animal caspases-3, did not protect against AAL-toxin. These results indicate that plants possess a protease with substrate-site specificity that is functionally equivalent to certain animal caspases. A biological conclusion is that diverse plant pathogens co-opt apoptosis during infection, and that transgenic modification of pathways regulating programmed cell death in plants is a potential strategy for engineering broad-spectrum disease resistance in plants. PMID:12403830

  17. 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…

  18. 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.

  19. Isolation of an arenavirus from a marmoset with callitrichid hepatitis and its serologic association with disease.

    PubMed Central

    Stephensen, C B; Jacob, J R; Montali, R J; Holmes, K V; Muchmore, E; Compans, R W; Arms, E D; Buchmeier, M J; Lanford, R E

    1991-01-01

    Callitrichid hepatitis (CH) is an acute, often fatal viral infection of New World primates from the family Callitrichidae. The etiologic agent of CH is unknown. We report here the isolation of an arenavirus from a common marmoset (Callithrix jacchus) with CH by using in vitro cultures of marmoset hepatocytes and Vero-E6 cells. Enveloped virions 67 to 133 nm in diameter with ribosomelike internal structures were seen in infected cultures. Immunofluorescence and Western immunoblot analysis using CH-specific antisera (principally from animals exposed to CH during zoo outbreaks) revealed three antigens in cells infected with this CH-associated virus (CHV). These antigens had the same electrophoretic mobilities on sodium dodecyl sulfate-polyacrylamide gels as did the nucleocapsid, GP2, and GPC proteins of lymphocytic choriomeningitis virus (LCMV). Monoclonal antibodies specific for these arenavirus proteins also reacted with the three CHV antigens. Conversely, the CH-specific antisera reacted with the nucleocapsid, GP2, and GPC proteins of LCMV. CHV thus appears to be a close antigenic relative of LCMV. The serologic association of CHV with several CH outbreaks implicate it as the etiologic agent of this disease. Images PMID:1712856

  20. Receptor determinants of zoonotic transmission of New World hemorrhagic fever arenaviruses.

    PubMed

    Radoshitzky, Sheli R; Kuhn, Jens H; Spiropoulou, Christina F; Albariño, César G; Nguyen, Dan P; Salazar-Bravo, Jorge; Dorfman, Tatyana; Lee, Amy S; Wang, Enxiu; Ross, Susan R; Choe, Hyeryun; Farzan, Michael

    2008-02-19

    Transferrin receptor 1 (TfR1) is a cellular receptor for the New World hemorrhagic fever arenaviruses Machupo (MACV), Junín (JUNV), and Guanarito (GTOV). Each of these viruses is specifically adapted to a distinct rodent host species, but all cause human disease. Here we compare the ability of these viruses to use various mammalian transferrin receptor 1 (TfR1) orthologs, including those of the South American rodents that serve as reservoirs for MACV, JUNV, and GTOV (Calomys callosus, Calomys musculinus, and Zygodontomys brevicauda, respectively). Retroviruses pseudotyped with MACV and JUNV but not GTOV glycoproteins (GPs) efficiently used C. callosus TfR1, whereas only JUNV GP could use C. musculinus TfR1. All three viruses efficiently used Z. brevicauda TfR1. TfR1 orthologs from related rodents, including house mouse (Mus musculus) and rat (Rattus norvegicus), did not support entry of these viruses. In contrast, these viruses efficiently used human and domestic cat TfR1 orthologs. We further show that a local region of the human TfR1 apical domain, including tyrosine 211, determined the efficiency with which MACV, JUNV, and GTOV used various TfR1 orthologs. Our data show that these New World arenaviruses are specifically adapted to the TfR1 orthologs of their respective rodent hosts and identify key commonalities between these orthologs and human TfR1 necessary for efficient transmission of these viruses to humans.

  1. Broad expression of fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase provide evidence for gluconeogenesis in human tissues other than liver and kidney.

    PubMed

    Yánez, Alejandro J; Nualart, Francisco; Droppelmann, Cristian; Bertinat, Romina; Brito, Mónica; Concha, Ilona I; Slebe, Juan C

    2003-11-01

    The importance of renal and hepatic gluconeogenesis in glucose homeostasis is well established, but the cellular localization of the key gluconeogenic enzymes liver fructose-1,6-bisphosphatase (FBPase) and cytosolic phosphoenolpyruvate carboxykinase (PEPCK) in these organs and the potential contribution of other tissues in this process has not been investigated in detail. Therefore, we analyzed the human tissue localization and cellular distribution of FBPase and PEPCK immunohistochemically. The localization analysis demonstrated that FBPase was expressed in many tissues that had not been previously reported to contain FBPase activity (e.g., prostate, ovary, suprarenal cortex, stomach, and heart). In some multicellular tissues, this enzyme was detected in specialized areas such as epithelial cells of the small intestine and prostate or lung pneumocytes II. Interestingly, FBPase was also present in pancreas and cortex cells of the adrenal gland, organs that are involved in the control of carbohydrate and lipid metabolism. Although similar results were obtained for PEPCK localization, different expression of this enzyme was observed in pancreas, adrenal gland, and pneumocytes type I. These results show that co-expression of FBPase and PEPCK occurs not only in kidney and liver, but also in a variety of organs such as the small intestine, stomach, adrenal gland, testis, and prostate which might also contribute to gluconeogenesis. Our results are consistent with published data on the expression of glucose-6-phosphatase in the human small intestine, providing evidence that this organ may play an important role in the human glucose homeostasis.

  2. 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

  3. Identification of two functional domains within the arenavirus nucleoprotein.

    PubMed

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

    2011-03-01

    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

  4. 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

  5. Identification of two functional domains within the arenavirus nucleoprotein.

    PubMed

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

    2011-03-01

    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.

  6. 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

  7. 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.

  8. Dissection of the Role of the Stable Signal Peptide of the Arenavirus Envelope Glycoprotein in Membrane Fusion

    PubMed Central

    Messina, Emily L.; York, Joanne

    2012-01-01

    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. PMID:22438561

  9. 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.

  10. Models for an arenavirus infection in a rodent population: consequences of horizontal, vertical and sexual transmission.

    PubMed

    Banerjee, Chandrani; Allen, Linda J S; Salazar-Bravo, Jorge

    2008-10-01

    Arenaviruses are associated with rodent-transmitted diseases in humans. Five arenaviruses are known to cause human illness: Lassa virus, Junin virus, Machupo virus, Guanarito virus and Sabia virus. In this investigation, we model the spread of Machupo virus in its rodent host Calomys callosus. Machupo virus infection in humans is known as Bolivian hemorrhagic fever (BHF) which has a mortality rate of approximately 5-30% [31]. Machupo virus is transmitted among rodents through horizontal (direct contact), vertical (infected mother to offspring) and sexual transmission. The immune response differs among rodents infected with Machupo virus. Either rodents develop immunity and recover (immunocompetent) or they do not develop immunity and remain infected (immunotolerant). We formulate a general deterministic model for male and female rodents consisting of eight differential equations, four for females and four for males. The four states represent susceptible, immunocompetent, immunotolerant and recovered rodents, denoted as S, I( t), I( c)and R, respectively. A unique disease-free equilibrium (DFE) is shown to exist and a basic reproduction number R( 0)is computed using the next generation matrix approach. The DFE is shown to be locally asymptotically stable if R(0) < 1and unstable if R( 0) > 1. Special cases of the general model are studied, where there is only one immune stage, either I(t) or I(c). In the first model, SI(c)R( c), it is assumed that all infected rodents are immunocompetent and recover. In the second model, SI(t), it is assumed that all infected rodents are immunotolerant. For each of these models, the basic reproduction numbers are computed and their relationship to the basic reproduction number of the general model determined. For the SI( t)model, it is shown that bistability may occur, the DFE and an enzootic equilibrium, with all rodents infectious, are locally asymptotically stable for the same set of parameter values. A simplification of the SI( t

  11. Immune response to vaccination against Argentine hemorrhagic Fever in an area where different arenaviruses coexist.

    PubMed

    Ambrosio, Ana M; Riera, Laura M; Saavedra, María Del Carmen; Sabattini, Marta S

    2006-01-01

    Neutralizing antibody (NT Ab) titers to Candid #1 (C#1) vaccine against Argentine hemorrhagic fever were studied for 2 years post-vaccination in 330 volunteers, to assess whether the kinetics and/or magnitude of this immune response is modified by previous infection with the arena viruses Junin (JUN) and lymphocytic choriomeningitis (LCM). A total of 160 volunteers received C#1, distributed as follows: without detectable pre-infection with arenaviruses (n = 54); with pre-existing antibodies to JUN (n = 55); with pre-existing antibodies to LCM (n = 51). The remaining 170 individuals received placebo. Levels of anti-JUN NT Ab displayed a trend in which titers increased with the virulence of the infecting strain, from C#1 (X = 49), through subclinical JUN infection (X = 229), vaccination following subclinical infection (X = 367) to JUN clinical infection (X =773). It was also found that the mean titer of NT Ab to C#1 did not vary significantly during 2 years of study and was: a) significantly lower than that elicited by wild strains of JUN, both clinical and subclinical infections (p < 0.01); b) significantly increased the titers of pre-existing anti-JUN Ab (p < 0.01); and c) was not modified by pre-existing anti-LCM Ab (p > 0.05). These data indicate that the immune response to C#1 boosts pre-existing immunity to JUN virus and is not changed by previous experience with LCM virus.

  12. Uncovering viral protein-protein interactions and their role in arenavirus life cycle.

    PubMed

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

    2012-09-01

    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

  13. Molecular determinants of arenavirus Z protein homo-oligomerization and L polymerase binding.

    PubMed

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

    2011-12-01

    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.

  14. 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

  15. Uncovering viral protein-protein interactions and their role in arenavirus life cycle.

    PubMed

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

    2012-09-01

    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.

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

    PubMed

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

    2016-06-01

    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

  17. 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

  18. Molecular determinants of arenavirus Z protein homo-oligomerization and L polymerase binding.

    PubMed

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

    2011-12-01

    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

  19. Vascular leak ensues a vigorous proinflammatory cytokine response to Tacaribe arenavirus infection in AG129 mice

    PubMed Central

    2013-01-01

    Background Tacaribe virus (TCRV) is a less biohazardous relative of the highly pathogenic clade B New World arenaviruses that cause viral hemorrhagic fever syndromes and require handling in maximum containment facilities not readily available to most researchers. AG129 type I and II interferon receptor knockout mice have been shown to be susceptible to TCRV infection, but the pathogenic mechanisms contributing to the lethal disease are unclear. Methods To gain insights into the pathogenesis of TCRV infection in AG129 mice, we assessed hematologic and cytokine responses during the course of infection, as well as changes in the permeability of the vascular endothelium. We also treated TCRV-challenged mice with MY-24, a compound that prevents mortality without affecting viral loads during the acute infection, and measured serum and tissue viral titers out to 40 days post-infection to determine whether the virus is ultimately cleared in recovering mice. Results We found that the development of viremia and splenomegaly precedes an elevation in white blood cells and the detection of high levels of proinflammatory mediators known to destabilize the endothelial barrier, which likely contributes to the increased vascular permeability and weight loss that was observed several days prior to when the mice generally succumb to TCRV challenge. In surviving mice treated with MY-24, viremia and liver virus titers were not cleared until 2–3 weeks post-infection, after which the mice began to recover lost weight. Remarkably, substantial viral loads were still present in the lung, spleen, brain and kidney tissues at the conclusion of the study. Conclusions Our findings suggest that vascular leak may be a contributing factor in the demise of TCRV-infected mice, as histopathologic findings are generally mild to moderate in nature, and as evidenced with MY-24 treatment, animals can survive in the face of high viral loads. PMID:23816343

  20. 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

  1. 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.

  2. 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

  3. 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

  4. 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.

  5. Infection of Type I Interferon Receptor-Deficient Mice with Various Old World Arenaviruses: A Model for Studying Virulence and Host Species Barriers

    PubMed Central

    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. PMID:23991083

  6. Sequence of the nucleocapsid protein gene of Machupo virus: close relationship with another South American pathogenic arenavirus, Junín.

    PubMed

    Griffiths, C M; Wilson, S M; Clegg, J C

    1992-01-01

    The sequence of the nucleocapsid (N) protein of Machupo virus (causative agent of Bolivian haemorrhagic fever) has been determined, and used to infer a phylogenetic relationship to other arenaviruses. The relationship of the virus to Junín and Tacaribe viruses, together with previous demonstrations of antigenic similarity and cross-protection by heterologous viruses, suggest that vaccines developed against Argentine haemorrhagic fever might also be effective against the Bolivian disease.

  7. Characterization of monoclonal antibodies to Junin virus nucleocapsid protein and application to the diagnosis of hemorrhagic fever caused by South American arenaviruses.

    PubMed

    Nakauchi, Mina; Fukushi, Shuetsu; Saijo, Masayuki; Mizutani, Tetsuya; Ure, Agustín E; Romanowski, Victor; Kurane, Ichiro; Morikawa, Shigeru

    2009-08-01

    Junin virus (JUNV), Machupo virus, Guanarito virus, Sabia virus, and Chapare virus are members of New World arenavirus clade B and are the etiological agents of viral hemorrhagic fevers that occur in South America. In this study, we produced three monoclonal antibodies (MAbs) to the recombinant nucleocapsid protein of JUNV, designated C6-9, C11-12, and E4-2. The specificity of these MAbs was examined by enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence assay, and an epitope-mapping method. Using these MAbs, we developed antigen (Ag) capture ELISA systems. We showed that by using MAb C6-9, JUNV Ag was specifically detected. On the other hand, by using MAb C11-12 or E-4-2, the Ags of all human pathogenic South American arenaviruses were detected. The combined use of these Ag capture ELISA systems in the present study may be useful for the diagnosis of acute-phase viral hemorrhagic fever due to infection by a South American arenavirus.

  8. 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…

  9. 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.

  10. 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.…

  11. 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…

  12. 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.

  13. Prospects for broadly protective influenza vaccines.

    PubMed

    Treanor, John Jay

    2015-11-27

    The development of vaccines that could provide broad protection against antigenically variant influenza viruses has long been the ultimate prize in influenza research. Recent developments have pushed us closer to this goal, and such vaccines may now be within reach. This brief review outlines the current approaches to broadly protective vaccines, and the probable hurdles and roadblocks to achieving this goal.

  14. 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.

  15. Broad spectrum bioactive sunscreens.

    PubMed

    Velasco, Maria Valéria Robles; Sarruf, Fernanda Daud; Salgado-Santos, Idalina Maria Nunes; Haroutiounian-Filho, Carlos Alberto; Kaneko, Telma Mary; Baby, André Rolim

    2008-11-01

    The development of sunscreens containing reduced concentration of chemical UV filters, even though, possessing broad spectrum effectiveness with the use of natural raw materials that improve and infer UV absorption is of great interest. Due to the structural similarities between polyphenolic compounds and organic UV filters, they might exert photoprotection activity. The objective of the present research work was to develop bioactive sunscreen delivery systems containing rutin, Passiflora incarnata L. and Plantago lanceolata extracts associated or not with organic and inorganic UV filters. UV transmission of the sunscreen delivery system films was performed by using diffuse transmittance measurements coupling to an integrating sphere. In vitro photoprotection efficacy was evaluated according to the following parameters: estimated sun protection factor (SPF); Boot's Star Rating category; UVA/UVB ratio; and critical wavelength (lambda(c)). Sunscreen delivery systems obtained SPF values ranging from 0.972+/-0.004 to 28.064+/-2.429 and bioactive compounds interacted with the UV filters positive and negatively. This behavior may be attributed to: the composition of the delivery system; the presence of inorganic UV filter and quantitative composition of the organic UV filters; and the phytochemical composition of the P. incarnata L. and P. lanceolata extracts. Among all associations of bioactive compounds and UV filters, we found that the broad spectrum sunscreen was accomplished when 1.68% (w/w) P. incarnata L. dry extract was in the presence of 7.0% (w/w) ethylhexyl methoxycinnamate, 2.0% (w/w) benzophenone-3 and 2.0% (w/w) TiO(2). It was demonstrated that this association generated estimated SPF of 20.072+/-0.906 and it has improved the protective defense against UVA radiation accompanying augmentation of the UVA/UVB ratio from 0.49 to 0.52 and lambda(c) from 364 to 368.6nm. PMID:18662760

  16. 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-

  17. 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

  18. 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…

  19. 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.

  20. Simple dynamics for broad histogram method

    NASA Astrophysics Data System (ADS)

    de Oliveira, Paulo Murilo Castro

    2002-08-01

    The purpose of this text is: (1) to clarify the foundations of the broad histogram method, stressing the conceptual differences between it and reweighting procedures in general; (2) to propose a very simple microcanonical dynamic rule, yet to be tested by theoretical grounds, which could provide a good improvement to numerical simulations.

  1. 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

  2. Differences in tropism and pH dependence for glycoproteins from the Clade B1 arenaviruses: implications for receptor usage and pathogenicity.

    PubMed

    Oldenburg, Jill; Reignier, Therese; Flanagan, Meg L; Hamilton, Genevieve A; Cannon, Paula M

    2007-07-20

    The Clade B lineage of the New World arenaviruses contains four viruses capable of causing severe hemorrhagic fevers in humans. Within this group, the B1 sub-lineage contains the pathogenic viruses Junin (JUNV) and Machupo (MACV), as well as the non-pathogenic Tacaribe virus (TCRV). In order to elucidate differences that may determine pathogenicity, we studied the entry pathways directed by the glycoproteins (GPs) from these related B1 viruses, using pseudotyped retroviral vectors and GP1 immunoadhesin constructs. Our data revealed variations in the efficiency with which different cell types could be transduced by B1 vectors, and this correlated with the ability of the immunoadhesins to bind to those cells. Interestingly, the tropism directed by the TCRV GP proved to be distinct from that of JUNV and MACV, in particular on lymphocyte cell lines. In addition, the GPs showed variations in their sensitivity to an inhibitor of endosome acidification, with the TCRV GP again being the outlier. Together these data suggest that more than one entry pathway can be used by these closely related viruses and that the ability to cause human disease may be highly dependent on receptor usage.

  3. The Broad Autism Phenotype Questionnaire

    ERIC Educational Resources Information Center

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

    2007-01-01

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

  4. 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

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

    2009-07-01

    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

  5. 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

  6. 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

  7. 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).

  8. 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.

  9. 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.

  10. Providers issue brief: alternative providers.

    PubMed

    Rothouse, M

    1999-06-29

    Access by managed care plan enrollees, scope of practice issues and fee reimbursement by Medicaid and third parties such as insurance carriers is the engine that drives legislation recognizing alternative health care providers--chiropractors, acupuncturists, physical therapists, naturopaths, massage therapists, homeopaths, and dietitians and nutritionists. PMID:11073386

  11. 77 FR 50144 - Broad Stakeholder Survey

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-20

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

  12. 78 FR 20119 - Broad Stakeholder Survey

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-03

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

  13. 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...

  14. The 2006 Broad Prize for Urban Education

    ERIC Educational Resources Information Center

    Broad Foundation, 2006

    2006-01-01

    The $1 million Broad Prize in Urban Education is the nation's largest award in K-12 public education. The Broad Prize is given annually by The Broad Foundation in the form of scholarships to urban school districts that demonstrate the greatest overall performance and improvement in student achievement while reducing achievement gaps among ethnic…

  15. 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

  16. 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.

  17. Oblique incidence for broad monoenergetic proton beams

    SciTech Connect

    Jette, David; Yuan Jiankui; Chen Weimin

    2010-11-15

    Purpose: The depth dose of a monoenergetic broad parallel proton beam has been modeled in a number of ways, but evidently not yet for oblique incidence. The purpose of this investigation is to find an accurate analytic formula for this case, which can then be used to model the depth dose of a broad beam with an initial Gaussian angular distribution. Methods: The Bortfeld model of depth dose in a broad normally incident proton beam has been extended to the case of oblique incidence. This extension uses an empirically determined Gaussian parameter {sigma}{sub x} which (roughly) characterizes the off-axis dose of a proton pencil beam. As with Bortfeld's work, the modeling is done in terms of parabolic cylinder functions. To obtain the depth dose for an initial angular distribution, the result is integrated over the angle of incidence, weighted by a Gaussian probability function. The predictions of the theory have been compared to MCNPX Monte Carlo calculations for four phantom materials (water, bone, aluminum, and copper) and for initial proton energies of 50, 100, 150, 200, and 250 MeV. Results: Comparisons of the depth dose predicted by this theory with Monte Carlo calculations have established that with very good accuracy, {sigma}{sub x} can be taken to be independent both of the depth and of the angle of incidence. As a function of initial proton range or of initial proton energy, {sigma}{sub x} has been found to obey a power law to very high accuracy. Good fits to Monte Carlo calculations have also been found for an initial Gaussian angular distribution. Conclusions: This investigation is the first step in the accurate modeling of a proton pencil beam with initial Gaussian angular distribution. It provides the longitudinal factor, with its Bragg peak buildup and sharp distal falloff. A transverse factor must still be incorporated into this theory and this will give the lateral penumbra of a collimated proton beam. Also, it will be necessary to model the dose of

  18. 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…

  19. 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--in just two…

  20. The 2007 Broad Prize for Urban Education

    ERIC Educational Resources Information Center

    Broad Foundation, 2007

    2007-01-01

    The $1 million Broad Prize in Urban Education, the nation's largest K-12 public education award given annually by The Broad Foundation, is awarded to urban school districts that demonstrate the greatest overall performance and improvement in student achievement while reducing income and ethnic achievement gaps. One hundred of the largest urban…

  1. 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…

  2. 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…

  3. Magnetohydrodynamic stability of broad line region clouds

    NASA Astrophysics Data System (ADS)

    Krause, Martin; Schartmann, Marc; Burkert, Andreas

    2012-10-01

    Hydrodynamic stability has been a longstanding issue for the cloud model of the broad line region in active galactic nuclei. We argue that the clouds may be gravitationally bound to the supermassive black hole. If true, stabilization by thermal pressure alone becomes even more difficult. We further argue that if magnetic fields are present in such clouds at a level that could affect the stability properties, they need to be strong enough to compete with the radiation pressure on the cloud. This would imply magnetic field values of a few gauss for a sample of active galactic nuclei we draw from the literature. We then investigate the effect of several magnetic configurations on cloud stability in axisymmetric magnetohydrodynamic simulations. For a purely azimuthal magnetic field which provides the dominant pressure support, the cloud first gets compressed by the opposing radiative and gravitational forces. The pressure inside the cloud then increases, and it expands vertically. Kelvin-Helmholtz and column density instabilities lead to a filamentary fragmentation of the cloud. This radiative dispersion continues until the cloud is shredded down to the resolution level. For a helical magnetic field configuration, a much more stable cloud core survives with a stationary density histogram which takes the form of a power law. Our simulated clouds develop sub-Alfvénic internal motions on the level of a few hundred km s-1.

  4. 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.

  5. 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.

  6. 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.

  7. 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. PMID:26584231

  8. 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.

  9. 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

  10. Silicon micromachined broad band light source

    NASA Technical Reports Server (NTRS)

    George, Thomas (Inventor); Jones, Eric (Inventor); Tuma, Margaret L. (Inventor); Eastwood, Michael (Inventor); Hansler, Richard (Inventor)

    2004-01-01

    A micro electromechanical system (MEMS) broad band incandescent light source includes three layers: a top transmission window layer; a middle filament mount layer; and a bottom reflector layer. A tungsten filament with a spiral geometry is positioned over a hole in the middle layer. A portion of the broad band light from the heated filament is reflective off the bottom layer. Light from the filament and the reflected light of the filament are transmitted through the transmission window. The light source may operate at temperatures of 2500 K or above. The light source may be incorporated into an on board calibrator (OBC) for a spectrometer.

  11. 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

  12. 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...

  13. Giant Broad Line Regions in Dwarf Seyferts

    NASA Astrophysics Data System (ADS)

    Devereux, Nick

    2015-12-01

    High angular resolution spectroscopy obtained with the Hubble Space Telescope (HST) has revealed a remarkable population of galaxies hosting dwarf Seyfert nuclei with an unusually large broad-line region (BLR). These objects are remarkable for two reasons. Firstly, the size of the BLR can, in some cases, rival those seen in the most luminous quasars. Secondly, the size of the BLR is not correlated with the central continuum luminosity, an observation that distinguishes them from their reverberating counterparts. Collectively, these early results suggest that non-reverberating dwarf Seyferts are a heterogeneous group, and not simply scaled versions of each other. Careful inspection reveals broad H Balmer emission lines with single peaks, double peaks, and a combination of the two, suggesting that the broad emission lines are produced in kinematically distinct regions centered on the black hole (BH). Because the gravitational field strength is already known for these objects, by virtue of knowing their BH mass, the relationship between velocity and radius may be established, given a kinematic model for the BLR gas. In this way, one can determine the inner and outer radii of the BLRs by modeling the shape of their broad emission line profiles. In the present contribution, high quality spectra obtained with the Space Telescope Imaging Spectrograph (STIS) are used to constrain the size of the BLR in the dwarf Seyfert nuclei of M81, NGC 3998, NGC 4203, NGC 3227, NGC 4051 and NGC 3516.

  14. 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,…

  15. Giant Broad Line Regions in Dwarf Seyferts

    NASA Astrophysics Data System (ADS)

    Devereux, Nicholas A.

    2016-01-01

    High angular resolution spectroscopy obtained with the Hubble Space Telescope has revealed a remarkable population of galaxies hosting dwarf Seyfert nuclei with an unusually large broad-line region (BLR). These objects are remarkable for two reasons. Firstly, the size of the BLR can, in some cases, rival those seen in the most luminous quasars. Secondly, the size of the BLR is not correlated with the central continuum luminosity, an observation that distinguishes them from their reverberating counterparts. Collectively, these early results suggest that non-reverberating dwarf Seyferts are a heterogeneous group and not simply scaled versions of each other. Careful inspection reveals broad H Balmer emission lines with single peaks, double peaks, and a combination of the two, suggesting that the broad emission lines are produced in kinematically distinct regions centered on the black hole (BH). Because the gravitational field strength is already known for these objects, by virtue of knowing their BH mass, the relationship between velocity and radius may be established, given a kinematic model for the BLR gas. In this way, one can determine the inner and outer radii of the BLRs by modeling the shape of their broad emission line profiles. In the present contribution, high quality spectra obtained with the Space Telescope Imaging Spectrograph are used to constrain the size of the BLR in the dwarf Seyfert nuclei of M81, NGC 3998, NGC 4203, NGC 3227, NGC 4051, and NGC 3516.

  16. 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…

  17. Lightweight, broad-band spectrum analyzer

    NASA Technical Reports Server (NTRS)

    Crook, G. M.

    1972-01-01

    Spectrum analyzer, utilizing techniques similar to those used to classify energy levels of nuclear particles, is incorporated into electric field detector. Primary advantage is ability to perform qualitative broad-band frequency analysis over a large dynamic amplitude range with minimum weight and electrical power requirements.

  18. 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.

  19. 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…

  20. 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

  1. 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

  2. A broad-band scalar vortex coronagraph

    NASA Astrophysics Data System (ADS)

    Errmann, R.; Minardi, S.; Pertsch, T.

    2013-10-01

    Broad-band coronagraphy with deep nulling and small inner working angle has the potential of delivering images and spectra of exoplanets and other faint objects. In recent years, many coronagraphic schemes have been proposed, the most promising being the optical vortex phase mask coronagraphs. In this paper, a new scheme of broad-band optical scalar vortex coronagraph is proposed and characterized experimentally in the laboratory. Our setup employs a pair of computer-generated phase gratings (one of them containing a singularity) to control the chromatic dispersion of phase plates and achieves a constant peak-to-peak attenuation below 1 × 10-3 over a bandwidth of 120 nm centred at 700 nm. An inner working angle of ˜λ/D is demonstrated along with a raw contrast of 11.5 mag at 2λ/D.

  3. 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.

  4. 4. A river level view of the Broad Street bridge ...

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

    4. A river level view of the Broad Street bridge and Columbus skyline from the railroad truss north of the bridge. - Broad Street Bridge, Spanning Scioto River at U.S. Route 40 (Broad Street), Columbus, Franklin County, OH

  5. Elevation of dwelling at 80 North Broad Place, SW, originally ...

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

    Elevation of dwelling at 80 North Broad Place, SW, originally built to house workers from the nearby Merrimack Mill - 80 North Broad Place, Southwest (House), 80 North Broad Place, Southwest, Huntsville, Madison County, AL

  6. 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

  7. 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.

  8. 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.

  9. Broad-Spectrum Drugs Against Viral Agents

    PubMed Central

    Christopher, Mary E.; Wong, Jonathan P.

    2008-01-01

    Development of antivirals has focused primarily on vaccines and on treatments for specific viral agents. Although effective, these approaches may be limited in situations where the etiologic agent is unknown or when the target virus has undergone mutation, recombination or reassortment. Augmentation of the innate immune response may be an effective alternative for disease amelioration. Nonspecific, broad-spectrum immune responses can be induced by double-stranded (ds)RNAs such as poly (ICLC), or oligonucleotides (ODNs) containing unmethylated deocycytidyl-deoxyguanosinyl (CpG) motifs. These may offer protection against various bacterial and viral pathogens regardless of their genetic makeup, zoonotic origin or drug resistance. PMID:19325820

  10. 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.

  11. Properties of quasar broad absorption line outflows

    NASA Astrophysics Data System (ADS)

    Capellupo, Daniel Moshin

    2012-06-01

    Broad absorption lines (BALs) in quasar spectra identify high velocity outflows that likely exist in all quasars and could play a major role in feedback to galaxy evolution. In this dissertation, I use two methods to illuminate important properties of these outflows with the goal of a better understanding of these outflow systems and ultimately of the connection between quasars and their host galaxies. The variability of BALs can help us understand the structure, evolution, and basic physical properties of the outflows. I report here on a BAL monitoring programme of a sample of 24 luminous quasars at redshifts 1.2

  12. Broadly neutralizing antibodies against influenza viruses

    PubMed Central

    Laursen, Nick S.; Wilson, Ian A.

    2014-01-01

    Despite available antivirals and vaccines, influenza infections continue to be a major cause of mortality worldwide. Vaccination generally induces an effective, but strain-specific antibody response. As the virus continually evolves, new vaccines have to be administered almost annually when a novel strain becomes dominant. Furthermore, the sporadic emerging resistance to neuraminidase inhibitors among circulating strains suggests an urgent need for new therapeutic agents. Recently, several cross-reactive antibodies have been described, which neutralize an unprecedented spectrum of influenza viruses. These broadly neutralizing antibodies generally target conserved functional regions on the major influenza surface glycoprotein hemagglutinin (HA). The characterization of their neutralization breadth and epitopes on HA could stimulate the development of new antibody-based antivirals and broader influenza vaccines. PMID:23583287

  13. 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.

  14. 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.

  15. The broad autism phenotype questionnaire: prevalence and diagnostic classification.

    PubMed

    Sasson, Noah J; Lam, Kristen S L; Childress, Debra; Parlier, Morgan; Daniels, Julie L; Piven, Joseph

    2013-04-01

    The Broad Autism Phenotype Questionnaire (BAPQ) was administered to a large community-based sample of biological parents of children with autism (PCAs) and comparison parents (CPs) (n = 1,692). Exploratory factor analysis and internal consistency parameters confirmed a robust three-factor structure of the BAPQ, corresponding to the proposed aloof, pragmatic language and rigidity subscales. Based upon the distribution of Broad Autism Phenotype (BAP) features in the general population, new normative cutoff values for BAPQ subscales were established that provide increased specificity relative to those previously reported, and thus enhance the utility of the BAPQ for diagnostically classifying the BAP. These cutoffs were also used to estimate prevalence of the BAP and its three components, with rates ranging between 14-23% for PCAs and between 5-9% for CPs. Analysis of patterns of BAP characteristics within family members revealed that BAP features were more likely to co-occur in PCAs relative to CPs. Collectively, these findings extend the utility of the BAPQ and provide additional evidence that it is an efficient and reliable tool for disaggregating the heterogeneity of autism through the identification of meaningful subgroups of parents. Autism Res 2013, 6: 134-143. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.

  16. High resolution energy analyzer for broad ion beam characterization

    SciTech Connect

    Kanarov, V.; Hayes, A.; Yevtukhov, R.; Siegfried, D.; Sferlazzo, P.

    2008-09-15

    Characterization of the ion energy distribution function (IEDF) of low energy high current density ion beams by conventional retarding field and deflection type energy analyzers is limited due to finite ion beam emittance and beam space charge spreading inside the analyzer. These deficiencies are, to a large extent, overcome with the recent development of the variable-focusing retarding field energy analyzer (RFEA), which has a cylindrical focusing electrode preceding the planar retarding grid. The principal concept of this analyzer is conversion of a divergent charged particle beam into a quasiparallel beam before analyzing it by the planar retarding field. This allows analysis of the beam particle total kinetic energy distribution with greatly improved energy resolution. Whereas this concept was first applied to analyze 5-10 keV pulsed electron beams, the present authors have adapted it to analyze the energy distribution of a low energy ({<=}1 KeV) broad ion beam. In this paper we describe the RFEA design, which was modified from the original, mainly as required by the specifics of broad ion beam energy analysis, and the device experimental characterization and modeling results. Among the modifications, an orifice electrode placed in front of the RFEA provides better spatial resolution of the broad ion beam ion optics emission region and reduces the beam plasma density in the vicinity of analyzer entry. An electron repeller grid placed in front of the RFEA collector was found critical for suppressing secondary electrons, both those incoming to the collector and those released from its surface, and improved energy spectrum measurement repeatability and accuracy. The use of finer mesh single- and double-grid retarding structures reduces the retarding grid lens effect and improves the analyzer energy resolution and accuracy of the measured spectrum mean energy. However, additional analyzer component and configuration improvements did not further change the analyzed

  17. 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.

  18. 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.

  19. Broad area optical debris impact sensor

    NASA Astrophysics Data System (ADS)

    Gauthier, L. R., Jr.; Jansen, M. E.; Meyer, J. R.

    2012-06-01

    Fiber optic sensors offer many advantages over electrical sensors for use in harsh environments. One advantage over distributed electrical sensors is the elimination of the need to route electrical power and wiring to the sensors, which, in general, improves safety and reduces power consumption. Another advantage is that the optical sensors are immune to electromagnetic interference that may be caused by radio frequency signals used for communications. Another benefit of using an optical approach for impact detectors is the implicit immunity from false detections that may otherwise be caused by unrelated mechanical shock or vibration events. Previous studies have documented the characteristics of the Optical Debris Impact Sensor (ODIS). With the ODIS, the impacts are inferred by detecting the brief triboluminescent optical pulses generated by the abrupt charge separation within a phosphor that is caused by the particle impacts. The main limitations of the ODIS are the small detection area and the limited sensitivity. This paper describes a method for extending the ODIS to accomplish broad area detection on a surface with potentially higher sensitivity. The sensing element is comprised of a stack of planar optical waveguides with phosphor-coated strips. The geometry of the design ensures optical pulses are automatically captured by the waveguides and routed to a fiber optic cable that transports the signal to a remote high-speed photodetector. Background light levels in the vicinity of the detector are filtered out by the tailored frequency response of the photodetector.

  20. Broad Ligament Hernia-Associated Bowel Obstruction

    PubMed Central

    López-Loredo, A.; León, J. F. García

    2007-01-01

    Background and Objective: We present the case of a female patient 29 years of age with antecedents of laparoscopic laser ablation for endometriosis, laparoscopic appendectomy, and umbilical hernioplasty. Methods: The patient was admitted to the hospital's emergency room for abdominal pain in the epigastrium, transfixing, irradiating to both upper quadrants and to the lumbar region, accompanied by nausea and gastrobiliary vomiting. Lipase determination was 170 mg/dL. Other laboratory findings were normal. Plain abdominal films on the patient's admission were normal, and computed tomography (CT) showed data compatible with acute pancreatitis. Without improvement during the patient's hospital stay, pain and vomiting increased in intensity and frequency. Results: New abdominal x-rays revealed dilatation of small bowel loops. Management was begun for intestinal obstruction, with intravenous hydration and placement of a nasogastric tube without a good response. At 48 hours, a diagnostic laparoscopy was performed, revealing a 3-cm internal hernia in the left broad ligament in which a 20-cm segment of terminal ileum was encased. We performed liberation of the ileal segment and closed the hernial orifice by using the laparoscopic approach. Conclusion: The patient's evolution was excellent. PMID:17651574

  1. 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

  2. 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.

  3. Human Monoclonal Antibodies Broadly Neutralizing against Influenza B Virus

    PubMed Central

    Yasugi, Mayo; Kubota-Koketsu, Ritsuko; Yamashita, Akifumi; Kawashita, Norihito; Du, Anariwa; Sasaki, Tadahiro; Nishimura, Mitsuhiro; Misaki, Ryo; Kuhara, Motoki; Boonsathorn, Naphatsawan; Fujiyama, Kazuhito; Okuno, Yoshinobu; Nakaya, Takaaki; Ikuta, Kazuyoshi

    2013-01-01

    Influenza virus has the ability to evade host immune surveillance through rapid viral genetic drift and reassortment; therefore, it remains a continuous public health threat. The development of vaccines producing broadly reactive antibodies, as well as therapeutic strategies using human neutralizing monoclonal antibodies (HuMAbs) with global reactivity, has been gathering great interest recently. Here, three hybridoma clones producing HuMAbs against influenza B virus, designated 5A7, 3A2 and 10C4, were prepared using peripheral lymphocytes from vaccinated volunteers, and were investigated for broad cross-reactive neutralizing activity. Of these HuMAbs, 3A2 and 10C4, which recognize the readily mutable 190-helix region near the receptor binding site in the hemagglutinin (HA) protein, react only with the Yamagata lineage of influenza B virus. By contrast, HuMAb 5A7 broadly neutralizes influenza B strains that were isolated from 1985 to 2006, belonging to both Yamagata and Victoria lineages. Epitope mapping revealed that 5A7 recognizes 316G, 318C and 321W near the C terminal of HA1, a highly conserved region in influenza B virus. Indeed, no mutations in the amino acid residues of the epitope region were induced, even after the virus was passaged ten times in the presence of HuMAb 5A7. Moreover, 5A7 showed significant therapeutic efficacy in mice, even when it was administered 72 hours post-infection. These results indicate that 5A7 is a promising candidate for developing therapeutics, and provide insight for the development of a universal vaccine against influenza B virus. PMID:23408886

  4. 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

  5. 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

  6. Main elevation of 3516 South Broad Place, SW. This house ...

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

    Main elevation of 3516 South Broad Place, SW. This house was used by the agent for Merrimack Mills, and now is the headquarters of Impact Ministries - 3516 South Broad Place, Southwest (House), 3516 South Broad Place, Southwest, Huntsville, Madison County, AL

  7. Structure built for Merrimack Mill at 11 North Broad Place, ...

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

    Structure built for Merrimack Mill at 11 North Broad Place, SW, originally for use at the first mill village school. It has been modified into a three-unit dwelling - 11 North Broad Place, Southwest (House), 11 North Broad Place, Southwest, Huntsville, Madison County, AL

  8. MICROLENSING OF QUASAR BROAD EMISSION LINES: CONSTRAINTS ON BROAD LINE REGION SIZE

    SciTech Connect

    Guerras, E.; Mediavilla, E.; Kochanek, C. S.; Munoz, J. A.; Falco, E.; Motta, V.

    2013-02-20

    We measure the differential microlensing of the broad emission lines between 18 quasar image pairs in 16 gravitational lenses. We find that the broad emission lines are in general weakly microlensed. The results show, at a modest level of confidence (1.8{sigma}), that high ionization lines such as C IV are more strongly microlensed than low ionization lines such as H{beta}, indicating that the high ionization line emission regions are more compact. If we statistically model the distribution of microlensing magnifications, we obtain estimates for the broad line region size of r{sub s} = 24{sup +22} {sub -15} and r{sub s} = 55{sup +150} {sub -35} lt-day (90% confidence) for the high and low ionization lines, respectively. When the samples are divided into higher and lower luminosity quasars, we find that the line emission regions of more luminous quasars are larger, with a slope consistent with the expected scaling from photoionization models. Our estimates also agree well with the results from local reveberation mapping studies.

  9. Turbulent boundary layer flow over broad-banded roughness

    NASA Astrophysics Data System (ADS)

    Pawlak, Geno; Aghsaee, Payam; Mazrouei, Saeed; Leonardi, Stefano; Rajagopalan, Krishnakumar; Kobayashi, Marcelo

    2014-11-01

    The response of the boundary layer to a regular roughness is often parameterized in terms of the length scales defining the roughness. Difficulty arises in the case of broad-banded and highly irregular roughness distributions such as over coral reefs or urban canopies where the length scale that determines the response of the boundary layer is not clear. Here we use a spectral description for roughness to create idealized two-dimensional irregular roughness profiles, using square waves as a basis function. Laboratory experiments along with Direct Numerical Simulations (DNS) are used to examine the hydrodynamic response to the broad-banded roughness and flow characteristics are related to geometric characteristics of the boundary. The simulations and experiments show that the nature of the flow over two-dimensional irregular walls can be determined as a function of the hydrodynamic origin, which, in turn, can be determined as a function of a mean cavity shape. Results are interpreted in terms of the spectral characteristics of the roughness. The contribution of the various spectral components to the total drag is analyzed for each case. The roughness spectrum influences the flow through the shape of the cavities on the wall and can provide some guidance in predicting the nature of the flow.

  10. Antibiofilm Peptides: Potential as Broad-Spectrum Agents.

    PubMed

    Pletzer, Daniel; Hancock, Robert E W

    2016-10-01

    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

  11. Geometry of Broad Line Regions of Active Galactic Nuclei

    NASA Astrophysics Data System (ADS)

    Lü, Xiao-Rong

    2008-02-01

    It has long remained an open question as to the geometry of the broad line region (BLR) in active galactic nuclei (AGNs). The reverberation mapping technique which measures the response of the broad emission lines to the ionizing continuum, when combined with multiwavelength continuum fitted by sophisticated accretion disks, provides a way of probing the BLR geometry. We analyze a sample of 35 AGNs, which have been monitored by the reverberation mapping campaign. In view of energy budget, the reverberation-based BH masses are found to be in agreement with those obtained by accretion disk models in two thirds of the present sample while the reverberation mapping methods underestimate the BH masses in about one third of objects, as also suggested by Collin et al. in a recent work. We point out that there are obviously two kinds of BLR geometry, which are strongly dependent on the Eddington ratio, and separated by the value LBol/LEdd~0.1. These results prefer a scenario of the disk and wind configuration of the BLR and identify the Eddington ratio as the physical driver regulating the wind in the BLR.

  12. Novel Broad Spectrum Inhibitors Targeting the Flavivirus Methyltransferase

    PubMed Central

    Liu, Binbin; Banavali, Nilesh K.; Jones, Susan A.; Zhang, Jing; Li, Zhong; Kramer, Laura D.; Li, Hongmin

    2015-01-01

    The flavivirus methyltransferase (MTase) is an essential enzyme that sequentially methylates the N7 and 2’-O positions of the viral RNA cap, using S-adenosyl-L-methionine (SAM) as a methyl donor. We report here that small molecule compounds, which putatively bind to the SAM-binding site of flavivirus MTase and inhibit its function, were identified by using virtual screening. In vitro methylation experiments demonstrated significant MTase inhibition by 13 of these compounds, with the most potent compound displaying sub-micromolar inhibitory activity. The most active compounds showed broad spectrum activity against the MTase proteins of multiple flaviviruses. Two of these compounds also exhibited low cytotoxicity and effectively inhibited viral replication in cell-based assays, providing further structural insight into flavivirus MTase inhibition. PMID:26098995

  13. MIPPA: First Broad Changes to Medicare Part D Plan Operations

    PubMed Central

    LeMasurier, Jean D.; Edgar, Babette

    2009-01-01

    In July 2008, as part of broad Medicare reform, Congress passed the first major legislative changes to Medicare Part D since its enactment in 2003—the Medicare Improvements for Patients and Providers Act. This new legislation has significant implications for how Part D plans can market and enroll Medicare beneficiaries. The new legislation also strengthened beneficiary protections, expanded the low-income subsidy provisions originally included in Part D, and expanded Part D coverage. These changes have significant implications for the operation of Part D plans and can affect those involved in benefit design, including specialty pharmacy coverage. This article discusses the major changes that took effect on January 1, 2009, and have immediate implications for Part D plan sponsors, including Medicare Advantage plans and stand-alone prescription drug plans. PMID:25126279

  14. Naked eye visibility of Sirius in broad daylight.

    PubMed

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

    2015-02-01

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

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

    DOEpatents

    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.

  16. 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

  17. bNAber: database of broadly neutralizing HIV antibodies.

    PubMed

    Eroshkin, Alexey M; LeBlanc, Andrew; Weekes, Dana; Post, Kai; Li, Zhanwen; Rajput, Akhil; Butera, Sal T; Burton, Dennis R; Godzik, Adam

    2014-01-01

    The discovery of broadly neutralizing antibodies (bNAbs) has provided an enormous impetus to the HIV vaccine research and to entire immunology. The bNAber database at http://bNAber.org provides open, user-friendly access to detailed data on the rapidly growing list of HIV bNAbs, including neutralization profiles, sequences and three-dimensional structures (when available). It also provides an extensive list of visualization and analysis tools, such as heatmaps to analyse neutralization data as well as structure and sequence viewers to correlate bNAbs properties with structural and sequence features of individual antibodies. The goal of the bNAber database is to enable researchers in this field to easily compare and analyse available information on bNAbs thereby supporting efforts to design an effective vaccine for HIV/AIDS. The bNAber database not only provides easy access to data that currently is scattered in the Supplementary Materials sections of individual papers, but also contributes to the development of general standards of data that have to be presented with the discovery of new bNAbs and a universal mechanism of how such data can be shared.

  18. 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.

  19. 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

  20. 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.

  1. 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

  2. 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

  3. The Neuropsychological Profile of Autism and The Broad Autism Phenotype

    PubMed Central

    Losh, Molly; Adolphs, Ralph; Poe, Michele D.; Couture, Shannon; Penn, David; Baranek, Grace T.; Piven, Joseph

    2009-01-01

    Context There now exist multiple reports of a constellation of language, personality, and social-behavioral features present among relatives that mirror the symptom domains of autism, but much milder in expression. Studies of this ‘broad autism phenotype’ (BAP) may provide a potentially important, complementary approach for detecting the genes causing autism and defining associated neural circuitry, by identifying more refined phenotypes which can be measured quantitatively in both affected and unaffected individuals, and which are tied to functioning in particular regions of the brain. Objective To gain insights into neuropsychological features that index genetic liability to autism. Design Case-control. Setting General community. Participants Thirty-eight high-functioning individuals with autism and parents of autistic individuals, both with and without the BAP (N=83), as well as control groups. Main Outcome Measures A comprehensive battery of neuropsychological tasks tapping social cognition, executive function, and global/local processing strategies (central coherence). Results Both individuals with autism and parents with the BAP differed from controls on measures of social cognition, with performance in the other two domains more similar to controls. Conclusions Data suggest that the social cognitive domain may be an important target for linking phenotype to cognitive process to brain structure in autism, and may ultimately provide insights into genes involved in autism. PMID:19414711

  4. 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.

  5. 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…

  6. 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…

  7. 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…

  8. Effects of General and Broad Cognitive Abilities on Mathematics Achievement

    ERIC Educational Resources Information Center

    Taub, Gordon E.; Keith, Timothy Z.; Floyd, Randy G.; Mcgrew, Kevin S.

    2008-01-01

    This study investigated the direct and indirect effects of general intelligence and 7 broad cognitive abilities on mathematics achievement. Structural equation modeling was used to investigate the simultaneous effects of both general and broad cognitive abilities on students' mathematics achievement. A hierarchical model of intelligence derived…

  9. 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)

  10. Glycosylation modulates arenavirus glycoprotein expression and function

    SciTech Connect

    Bonhomme, Cyrille J. Capul, Althea A. Lauron, Elvin J. Bederka, Lydia H. Knopp, Kristeene A. Buchmeier, Michael J.

    2011-01-20

    The glycoprotein of lymphocytic choriomeningitis virus (LCMV) contains nine potential N-linked glycosylation sites. We investigated the function of these N-glycosylations by using alanine-scanning mutagenesis. All the available sites were occupied on GP1 and two of three on GP2. N-linked glycan mutations at positions 87 and 97 on GP1 resulted in reduction of expression and absence of cleavage and were necessary for downstream functions, as confirmed by the loss of GP-mediated fusion activity with T87A and S97A mutants. In contrast, T234A and E379N/A381T mutants impaired GP-mediated cell fusion without altered expression or processing. Infectivity via virus-like particles required glycans and a cleaved glycoprotein. Glycosylation at the first site within GP2, not normally utilized by LCMV, exhibited increased VLP infectivity. We also confirmed the role of the N-linked glycan at position 173 in the masking of the neutralizing epitope GP-1D. Taken together, our results indicated a strong relationship between fusion and infectivity.

  11. Broad activation of latent HIV-1 in vivo.

    PubMed

    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

  12. 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

  13. 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.

  14. Broad issues to consider for library involvement in bioinformatics*

    PubMed Central

    Geer, Renata C.

    2006-01-01

    Background: The information landscape in biological and medical research has grown far beyond literature to include a wide variety of databases generated by research fields such as molecular biology and genomics. The traditional role of libraries to collect, organize, and provide access to information can expand naturally to encompass these new data domains. Methods: This paper discusses the current and potential role of libraries in bioinformatics using empirical evidence and experience from eleven years of work in user services at the National Center for Biotechnology Information. Findings: Medical and science libraries over the last decade have begun to establish educational and support programs to address the challenges users face in the effective and efficient use of a plethora of molecular biology databases and retrieval and analysis tools. As more libraries begin to establish a role in this area, the issues they face include assessment of user needs and skills, identification of existing services, development of plans for new services, recruitment and training of specialized staff, and establishment of collaborations with bioinformatics centers at their institutions. Conclusions: Increasing library involvement in bioinformatics can help address information needs of a broad range of students, researchers, and clinicians and ultimately help realize the power of bioinformatics resources in making new biological discoveries. PMID:16888662

  15. 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.

  16. Robust linear regression with broad distributions of errors

    NASA Astrophysics Data System (ADS)

    Postnikov, Eugene B.; Sokolov, Igor M.

    2015-09-01

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

  17. 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

  18. Improved PCR Amplification of Broad Spectrum GC DNA Templates

    PubMed Central

    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. PMID:27271574

  19. 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. PMID:26937640

  20. THE VIEWING ANGLES OF BROAD ABSORPTION LINE VERSUS UNABSORBED QUASARS

    SciTech Connect

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

    2012-06-10

    It was recently shown that there is a significant difference in the radio spectral index distributions of broad absorption line (BAL) quasars and unabsorbed quasars, with an overabundance of BAL quasars with steeper radio spectra. This result suggests that source orientation does play into the presence or absence of BAL features. In this paper, we provide more quantitative analysis of this result based on Monte Carlo simulations. While the relationship between viewing angle and spectral index does indeed contain a lot of scatter, the spectral index distributions are different enough to overcome that intrinsic variation. Utilizing two different models of the relationship between spectral index and viewing angle, the simulations indicate that the difference in spectral index distributions can be explained by allowing BAL quasar viewing angles to extend about 10 Degree-Sign farther from the radio jet axis than non-BAL sources, though both can be seen at small angles. These results show that orientation cannot be the only factor determining whether BAL features are present, but it does play a role.

  1. 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.

  2. Broad activation of latent HIV-1 in vivo.

    PubMed

    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

    2016-09-08

    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.

  3. 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.

  4. 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.

  5. Detection of a small shift in a broad distribution

    NASA Astrophysics Data System (ADS)

    Berg, Bernd A.

    2014-12-01

    Statistical methods for the extraction of a small shift in broad data distributions are examined by means of Monte Carlo simulations. This work was originally motivated by the CERN neutrino beam to Gran Sasso (CNGS) experiment for which the OPERA detector collaboration reported a time shift in a broad distribution with an accuracy of ±7.8 ns, while the fluctuation of the average time turns with ±23.8 ns out to be much larger. Although the physical result of a big shift has been withdrawn, statistical methods that make an identification in a broad distribution with such a small error possible remain of interest.

  6. Ultra-broad bandwidth parametric amplification at degeneracy.

    PubMed

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

    2005-09-19

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

  7. Broad Ligament Pregnancy - Success Story of a Laparoscopically Managed Case.

    PubMed

    Nayar, Jayashree; Nair, Sobha S

    2016-07-01

    Abdominal pregnancies constitute 1% of ectopic pregnancies, among which broad ligament pregnancy is a rare form. The maternal mortality rate has been reported to be as high as 20%. The diagnosis is seldom established before surgery. Laparoscopic management of broad ligament ectopic pregnancy is the ideal form of treatment in appropriately selected patients. We present the case report of successful laparoscopic treatment of a 3x3.5cm broad ligament pregnancy. A search of literature shows that ours is the 6(th) case report of such a rare ectopic pregnancy managed endoscopically successfully. PMID:27630914

  8. Microlensing of the broad line region in 17 lensed quasars

    NASA Astrophysics Data System (ADS)

    Sluse, D.; Hutsemékers, D.; Courbin, F.; Meylan, G.; Wambsganss, J.

    2012-08-01

    When an image of a strongly lensed quasar is microlensed, the different components of its spectrum are expected to be differentially magnified owing to the different sizes of the corresponding emitting region. Chromatic changes are expected to be observed in the continuum while the emission lines should be deformed as a function of the size, geometry and kinematics of the regions from which they originate. Microlensing of the emission lines has been reported only in a handful of systems so far. In this paper we search for microlensing deformations of the optical spectra of pairs of images in 17 lensed quasars with bolometric luminosities between 1044.7 - 47.4 erg/s and black hole masses 107.6 - 9.8 M⊙. This sample is composed of 13 pairs of previously unpublished spectra and four pairs of spectra from literature. Our analysis is based on a simple spectral decomposition technique which allows us to isolate the microlensed fraction of the flux independently of a detailed modeling of the quasar emission lines. Using this technique, we detect microlensing of the continuum in 85% of the systems. Among them, 80% show microlensing of the broad emission lines. Focusing on the most common emission lines in our spectra (C III] and Mg II) we detect microlensing of either the blue or the red wing, or of both wings with the same amplitude. This observation implies that the broad line region is not in general spherically symmetric. In addition, the frequent detection of microlensing of the blue and red wings independently but not simultaneously with a different amplitude, does not support existing microlensing simulations of a biconical outflow. Our analysis also provides the intrinsic flux ratio between the lensed images and the magnitude of the microlensing affecting the continuum. These two quantities are particularly relevant for the determination of the fraction of matter in clumpy form in galaxies and for the detection of dark matter substructures via the identification

  9. The Provident Principal.

    ERIC Educational Resources Information Center

    McCall, John R.

    This monograph offers leadership approaches for school principals. Discussion applies the business leadership theory of Warren Bennis and Burt Nanus to the role of the principal. Each of the booklet's three parts concludes with discussion questions. Part 1, "Visions and Values for the Provident Principal," demonstrates the importance of…

  10. 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.

  11. 10. View to northeast from near siphon structure showing broad, ...

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

    10. View to northeast from near siphon structure showing broad, U-shaped earthen banked ditch - Natomas Ditch System, Blue Ravine Segment, Juncture of Blue Ravine & Green Valley Roads, Folsom, Sacramento County, CA

  12. 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

  13. Spectropolarimetric test of the relativistic disk model for the broad emission lines of active galactic nuclei

    NASA Technical Reports Server (NTRS)

    Chen, Kaiyou; Halpern, Jules P.

    1990-01-01

    Previously, it was claimed that the broad emission lines of the radio galaxy Arp 102B can be fitted by the line profile from a simple relativistic Keplerian thin disk. It was argued that the lines originating from the relativistic accretion disk could be polarized due to electron scattering, which is likely to be the dominant opacity in the line-emitting region of Arp 102B. In the present work, the expected polarization properties of these broad emission lines are calculated. The percentage of polarization depends strongly on the inclination angle. For some angles, the red peak of the polarized, double-peaked line profile can be higher than the blue peak. This is in contrast to the total line profile, in which the blue peak is always higher than the red one. Spectropolarimetric observations could, therefore, provide an independent test of the relativistic disk model for the broad emission lines of Arp 102B and other active galactic nuclei.

  14. Recent Results from Broad-Band Intensity Mapping Measurements of Cosmic Large Scale Structure

    NASA Astrophysics Data System (ADS)

    Zemcov, Michael B.; CIBER, Herschel-SPIRE

    2016-01-01

    Intensity mapping integrates the total emission in a given spectral band over the universe's history. Tomographic measurements of cosmic structure can be performed using specific line tracers observed in narrow bands, but a wealth of information is also available from broad-band observations performed by instruments capable of capturing high-fidelity, wide-angle images of extragalactic emission. Sensitive to the continuum emission from faint and diffuse sources, these broad-band measurements provide a view on cosmic structure traced by components not readily detected in point source surveys. After accounting for measurement effects and astrophysical foregrounds, the angular power spectra of such data can be compared to predictions from models to yield powerful insights into the history of cosmic structure formation. This talk will highlight some recent measurements of large scale structure performed using broad-band intensity mapping methods that have given new insights on faint, distant, and diffuse components in the extragalactic background light.

  15. Provider panel presentations.

    PubMed

    Buckelew, Larry C; Harvey, Deborah; Mello, Joe

    2003-08-01

    To wrap up the three big items--attracting talent, the professional nurse role, and our structural disadvantages--I would offer the following take-away thoughts: We ought to do what we can to get our disproportionate share of RNs out of the health care system to work in dialysis. If we work together, we have a shot at making that happen. As an industry, we must exploit our strengths. We have to exploit the pride that comes in the services and the care that we provide. We need to create in a very visual way that difference for nurses who are considering which area of specialty to go into and where to create their careers. We, as providers, have a huge opportunity to create the right environment for our nurses. That's something we own. We have to fix it. We have to create a better place to work for nurses than any place else. We must create a more enriching place for nurses than anywhere else. That's up to us. I know a lot of us on the provider side are doing tons of things to make that happen and we need to keep driving that. We need a level playing field. We've proven the fact that we can deliver clinical outcomes with the best. Now we need help from our biggest customer to make sure we can compete for the resources that are necessary to sustain and improve those clinical outcomes on an ongoing basis. PMID:14533522

  16. 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.

  17. Provider satisfaction in army primary care clinics.

    PubMed

    Byers, V L; Mays, M Z; Mark, D D

    1999-02-01

    The job satisfaction of physicians, nurse practitioners, and physician assistants was assessed during the course of a multicenter study of Army primary care clinics. All providers in nine clinics at three medical centers who were engaged in adult or family care were invited to participate in the study. Questionnaires on job satisfaction and other practice style variables were completed by 26 physicians, 19 nurse practitioners, and 13 physician assistants (46, 76, and 41% of eligible providers, respectively). Analysis revealed a broad range of job satisfaction in the sample. However, average levels of job satisfaction were not significantly different across the three groups of primary care providers. Autonomy and collaboration were significant predictors of job satisfaction. It is clear that changes in health care systems that reduce, or appear to reduce, the primary care provider's autonomy in clinical matters are likely to reduce provider satisfaction as well. PMID:10050571

  18. 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.

  19. 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.

  20. 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.

  1. 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.

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

    PubMed

    Zhao, Yunsong; Zhu, Lin

    2013-10-01

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

  3. 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.

  4. 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. PMID:19282951

  5. 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.

  6. 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.

  7. Development of broad-spectrum antibiofilm drugs: strategies and challenges.

    PubMed

    Dharmaprakash, Akhilandeswarre; Thandavarayan, Ramamurthy; Joseph, Iype; Thomas, Sabu

    2015-01-01

    The severity of many chronic bacterial infections is mainly due to the biofilm mode of life adapted by pathogenic bacteria. The bacteria in biofilm-stage exhibit high resistance to host immune responses and antimicrobials, which complicates the treatment process and results in life threatening conditions. Most of the chronic infections are polymicrobial in nature. In order to combat the polymicrobial biofilm infections and to increase the efficiency of antimicrobials, there is an urgent need for broad-spectrum antibiofilm drugs. This review discusses the clinical needs and current status of broad-spectrum antibiofilm drugs with special emphasis on prospective strategies and hurdles in the process of new drug discovery. PMID:26059624

  8. 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.

  9. Chip scale broadly tunable laser for laser spectrometer

    NASA Astrophysics Data System (ADS)

    Chao, Tien-Hsin; Lu, Thomas; Davis, Scott R.; Anderson, Michael H.

    2016-04-01

    We are developing an innovative Tunable Laser Spectrometer (TLS) that is compact, broad tuning range (> 200 nm) enabled by an innovative chip-scale (a waveguide based architecture), non-mechanical (voltage- controlled tuning), Waveguide External-cavity Semiconductor Laser (WECSL). This WECSL based TLS, with broad tuning range, will enable the simultaneous measurement of multiple gases abundances in Martian and other planetary atmospheres, adsorbed to soil; and bound to rocks. This monolithic, robust, integrated-optic Tunable Laser Absorption Spectrometer (TLS) will operate in the near infrared and infrared spectral bands. The system architecture, principles of operation and applications of the TLS will be reported in this paper.

  10. Antibody Response to Hypervariable Region 1 Interferes with Broadly Neutralizing Antibodies to Hepatitis C Virus

    PubMed Central

    Keck, Zhen-yong; Girard-Blanc, Christine; Wang, Wenyan; Lau, Patrick; Zuiani, Adam; Rey, Felix A.; Krey, Thomas; Diamond, Michael S.

    2015-01-01

    their epitopes. This study provides insight into a new immune antagonism mechanism by which the binding of antibodies to HVR1 blocks the binding and activity of broadly neutralizing antibodies to HCV. Immunization strategies that avoid the induction of HVR1 antibodies should increase the inhibitory activity of broadly neutralizing anti-HCV antibodies elicited by candidate vaccines. PMID:26739044

  11. Workplace Learning Provider's Manual. Practical Steps for Developing Programs.

    ERIC Educational Resources Information Center

    Pacific Management and Research Associates, Sacramento, CA.

    This handbook provides a broad overview of the stages and activities to be undertaken to establish workplace learning (WPL) programs. It is designed to lead WPL service providers and employers through the process of developing a WPL program. Each chapter begins by stating the purpose and the outcomes expected upon completion. Throughout the manual…

  12. 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. PMID:25522326

  13. 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.

  14. 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.

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

    PubMed

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

    2014-01-01

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

  16. 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

  17. Broad Hβ Emission-line Variability in a Sample of 102 Local Active Galaxies

    NASA Astrophysics Data System (ADS)

    Runco, Jordan N.; Cosens, Maren; Bennert, Vardha N.; Scott, Bryan; Komossa, S.; Malkan, Matthew A.; Lazarova, Mariana S.; Auger, Matthew W.; Treu, Tommaso; Park, Daeseong

    2016-04-01

    A sample of 102 local (0.02 ≤ z ≤ 0.1) Seyfert galaxies with black hole masses MBH > 107M⊙ was selected from the Sloan Digital Sky Survey (SDSS) and observed using the Keck 10 m telescope to study the scaling relations between MBH 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 MBH, 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.

  18. Broad-Area Laser Diode With Fiber-Optic Injection

    NASA Technical Reports Server (NTRS)

    Hazel, Geoffrey; Mead, Patricia; Davis, Christopher; Cornwell, Donald

    1992-01-01

    Fiber-optic injection-locked broad-area laser diode features single-mode output via fiber-optic injection and serves as compact, rugged, high-power near-infrared source. Useful in free-space and fiber-optic communication links, as communication-receiver preamplifier, and pump source for solid-state lasers.

  19. 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…

  20. 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

  1. 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.

  2. 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.

  3. 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…

  4. 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.

  5. Self in Culture: Confusions of a Broad-Minded Constructivist.

    ERIC Educational Resources Information Center

    Kahn, Peter H., Jr.

    This essay emphasizes a need for broad-minded constructivism which posits that individuals have coherent ways of understanding their world and that these understandings are structured and hierarchically organized. The meaning behind the term "co-construction," used in psychology, anthropology, sociology, and other disciplines, is analyzed. Three…

  6. The First HeI* 10830 Broad Absorption Line Quasar

    NASA Astrophysics Data System (ADS)

    Leighly, Karen; Dietrich, M.; Barber, S.

    2010-03-01

    We report discovery of the first metastable HeI* broad absorption line quasar using SpeX on IRTF. The blue-shifted absorption profile extends in velocity space from about -1,000 to -11,000 km/s, and it shows considerable velocity structure of the order of 1,000 km/s. The maximum apparent optical depth is 0.6. Integration over the 10830 apparent optical depth profile yields a lower limit on the log HeI* column density of >14.3. Absorption is also seen in the HeI* λ3888Å line in optical spectra from SDSS and the MDM Hiltner telescope. These two transitions have the same lower level; thus, the covering fraction and optical depth can be determined. A pure partial covering model yields log HeI* column of 15.5-15.7, while a power law absorption distribution yields 16.1. These column densities are significantly larger than the lower limit because of the high ratio of the product of the wavelength and the oscillator strength (23.3). This property, plus the relatively low densities of HeI* in ionized gas, makes HeI* absorption a valuable probe of high column densities. Cloudy simulations were performed to investigate the nature of the absorber. The HeI* column density yielded a lower limit on the log ionization parameter of -0.2 and a corresponding lower limit on the log hydrogen column density of 23. The latter value is at least an order of magnitude larger than those generally obtained from BALQSOs with spectra amenable to partial covering analysis. The lack of Balmer absorption provided an upper limit on the log density of 7. The log kinetic luminosity was constrained to be between 46 and 48, corresponding to at least 0.3% to a large fraction of the bolometric luminosity. A proposed Suzaku observation may remove model degeneracy between the spectral energy distribution and ionization parameter. This work is funded by NSF AST-0707703.

  7. Introduction: human pathology within the broad scope of comparative pathology.

    PubMed

    Kaiser, H E

    1996-01-01

    of biologic integration of normal processes leading to different types of pathologic progression. A typical problem affecting man and many other fellow species is crowding. Man's pathology and the pathology of other species exhibit continued integration which is the central problem for understanding diseases where similar functions are performed by various structures, such as is the case in gaseous exchange, or differences in size and life span. The broad spectrum of comparative pathology which centers around human pathology provides a source of increased knowledge for a better understanding of diseases. The present issue is based on the two symposia organized by the International Society for the Study of Comparative Ongology during the Fifth International Conference of Anticancer Research, 17-22 October 1995, Corfu, Greece.

  8. 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.

  9. TIME VARIABLE BROAD-LINE EMISSION IN NGC 4203: EVIDENCE FOR STELLAR CONTRAILS

    SciTech Connect

    Devereux, Nick

    2011-12-10

    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 H{alpha} 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 {approx}1500 AU from the central black hole. There is also a bright core of broad H{alpha} line emission that is not time variable and identified with a large-scale inflow from an outer radius of {approx}1 pc. If the gas number density is {>=}10{sup 6} cm{sup -3}, as suggested by the absence of similarly broad [O I] and [O III] emission lines, then the steady state inflow rate is {approx} 2 Multiplication-Sign 10{sup -2} M{sub Sun} yr{sup -1}, which exceeds the inflow requirement to explain the X-ray luminosity in terms of radiatively inefficient accretion by a factor of {approx}6. The central active galactic nucleus (AGN) is unable to sustain ionization of the broad-line region; the discrepancy is particularly acute in 2010 when the broad H{alpha} emission line is dominated by the contrail of the infalling supergiant star. However, ram pressure shock ionization produced by the interaction of the infalling 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.

  10. 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

  11. 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.

  12. 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

  13. The broad-line region as supernova remnants

    NASA Astrophysics Data System (ADS)

    Tenorio-Tagle, Guillermo; Terlevich, Roberto; Franco, Jose; Melnick, Jorge

    Supernova remnants evolving in a dense medium (n about 10**7 percc) become strongly radiative while still expanding at velocities of several thousands of km/s. Radiative cooling becomes important well before the thermalization of the ejecta is completed and makes the remnant miss the Sedov adiabatic track. As a result, the shocked matter undergoes a rapid condensation behind both the leading and the reverse shocks. Two concentric, high-density, fast moving thin shells are then formed. Both cool dense shells, as well as the freely expanding ejecta, and a section of the still dynamically unperturbed interstellar gas, are irradiated and ionized by the photon field produced by the radiative shocks. The emitted spectrum has emission-line ratios similar to those observed in the broad line region of low-luminosity active galactic nuclei. Our model combines analytic and numerical hydrodynamic simulations, together with static photoionization calculations to reproduce the observed properties of these broad-line regions.

  14. 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.

  15. Learning from failures: testing broad taxonomic hypotheses about plant naturalization.

    PubMed

    Diez, Jeffrey M; Williams, Peter A; Randall, Rod P; Sullivan, Jon J; Hulme, Philip E; Duncan, Richard P

    2009-11-01

    Our understanding of broad taxonomic patterns of plant naturalizations is based entirely on observations of successful naturalizations. Omission of the failures, however, can introduce bias by conflating the probabilities of introduction and naturalization. Here, we use two comprehensive datasets of successful and failed plant naturalizations in New Zealand and Australia for a unique, flora-wide comparative test of several major invasion hypotheses. First, we show that some taxa are consistently more successful at naturalizing in these two countries, despite their environmental differences. Broad climatic origins helped to explain some of the differences in success rates in the two countries. We further show that species with native relatives were generally more successful in both countries, contrary to Darwin's naturalization hypothesis, but this effect was inconsistent among families across the two countries. Finally, we show that contrary to studies based on successful naturalizations only, islands need not be inherently more invisible than continents.

  16. Shaper-assisted phase optimization of a broad "holey" spectrum.

    PubMed

    Zhi, Miaochan; Wang, Kai; Hua, Xia; Strycker, Benjamin D; Sokolov, Alexei V

    2011-11-01

    We develop a technique for optimizing the phase of broad spectrally-separated frequency sidebands-a "holey" spectrum. We use a source of multiple-order coherent Raman sidebands, obtained by crossing femtosecond pump and Stokes beams in synthetic single-crystal diamond. We combine the sidebands into a single beam and show the phase coherence among the sidebands by investigating the interference between them in groups of three while varying one sideband phase by an acousto-optics pulse shaper. We then show how we optimize the broad "holey" spectrum by overcoming the limited temporal shaping window of the pulse shaper. We also explore how the resultant second harmonic/sum frequency generation of the full combined broadband spectrum varies as we vary different sideband phases. This step-by-step phase optimization of the "holey" spectrum can be applied to sidebands with similar structure to synthesize arbitrary optical waveforms.

  17. Broad Feshbach resonances in collisions of Dy atoms

    NASA Astrophysics Data System (ADS)

    Julienne, P.; Jachymski, K.; Maier, T.; Ferrier-Barbut, I.; Karan, H.; Schmitt, M.; Wenzel, M.; Wink, C.; Pfau, T.

    2016-05-01

    RF spectroscopy of weakly bound dimers of ultra cold bosonic Dy atoms gives evidence for the emergence of a universal s-wave halo state in a background of chaotic background resonance states. The halo state is associated with a broad magnetic Feshbach resonance. Using a coupled channels theory taking into account the short ranged van dear Waals interaction and a correction due to the strong dipole moment of Dy, we are able to extract the scattering length as a function of magnetic field tuning near two such broad resonances. These results offer prospects for tuning the interactions of Dy atoms in a regime where three-body losses are not too strong. Supported in part by the DFG, the Foundation for Polish Science International Ph. D Projects Programme, and an AFOSR MURI.

  18. 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.

  19. US and Russia broadly expand science and technology cooperation

    SciTech Connect

    Seltzer, R.

    1994-07-11

    The US and Russia agreed late last month to spur cooperation in a broad variety of science- and technology-related programs. The two countries signed agreements boosting collaboration in such areas as basic sciences and engineering, space, biomedical research, environmental protection, nuclear disarmament, energy, and geosciences during a visit to the US by Russian Prime Minister Viktor S. Chernomyrdin. The accords were signed in Washington, DC, at the third meeting of the US-Russian Joint Commission on Economic Technological Cooperation.

  20. 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

  1. 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

  2. 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. PMID:10642203

  3. 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.

  4. Broadly tunable Cr 4+-doped solid-state lasers in the near infrared and visible

    NASA Astrophysics Data System (ADS)

    Sennaroglu, Alphan

    2002-11-01

    This manuscript provides a comprehensive review of the characteristics of Cr 4+-doped solid-state lasers which produce broadly tunable coherent radiation in the near-infrared region of the electromagnetic spectrum between 1.13 and 1.63 μm. Cr 4+-doped gain media have several favorable characteristics including broad absorption bands that overlap with the operating wavelengths of several commercial pump lasers, a 4-level energy structure that allows continuous-wave as well as pulsed operation with low threshold pump powers, and the presence of broad amplification bands for the generation of ultrashort optical pulses. In addition, non-linear frequency conversion schemes can be readily employed to construct broadly tunable coherent visible sources based on Cr 4+-doped gain media. These favorable features make Cr 4+-doped lasers potentially important in many applications in optical communications, eye-safe imaging, medicine, and spectroscopy. After a description of the basic physical mechanisms that lead to broad emission in tunable solid-state lasers in general and Cr 4+-doped gain media in particular, the manuscript provides a detailed description of the operational characteristics of Cr 4+-doped lasers, including rate-equation analysis of power performance, role of thermal effects, and different mode-locking techniques for the generation of ultrashort optical pulses. Later sections focus on the work performed in the development and characterization of specific examples of Cr 4+-doped lasers. Particular attention is given to Cr 4+:forsterite and Cr 4+:YAG laser systems due to their superior power performance. Gain-switched, continuous-wave, and mode-locked operations of these lasers are described with a particular emphasis on recent developments. Studies carried out with other Cr 4+-doped lasers such as Cr 4+:Y 2SiO 5, Cr 4+-doped oxyapatite, Cr 4+-doped garnets, and Cr 4+:Ca 2GeO 4 are also described. Finally, use of non-linear conversion schemes in the generation

  5. 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

  6. 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.

  7. 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.

  8. Intrinsic performance-limiting instabilities in two-level class-B broad-area lasers

    NASA Astrophysics Data System (ADS)

    Pakhomov, A. V.; Molevich, N. E.; Krents, A. A.; Anchikov, D. A.

    2016-08-01

    The present paper is concerned with the analytical and numerical investigation of the transverse spatio-temporal instabilities in two-level broad-area lasers for the specific class-B case. We show that the two-level class-B broad-area laser tends to naturally operate in the filamentary state. This is revealed to be provided with two causes. First of them is related with the homogeneous output profile being intrinsically unstable due to the traveling-wave instability, independently from the boundary conditions. Secondly, high sensitivity to the boundaries of the pumping region was found for the commonly used top-hat-like profile leading to boundaries-induced filamentary dynamics. Spatio-temporal properties of both instability mechanisms are studied and their effects on the resulting laser dynamical behavior are analyzed.

  9. 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).

  10. 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

  11. 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

  12. Broad spectrum assessment of the epitope fluctuation--Immunogenicity hypothesis.

    PubMed

    Grosch, Jason S; Yang, Jing; Shen, Alice; Sereda, Yuriy V; Ortoleva, Peter J

    2015-11-01

    Prediction of immunogenicity is a substantial barrier in vaccine design. Here, a molecular dynamics approach to assessing the immunogenicity of nanoparticles based on structure is presented. Molecular properties of epitopes on nonenveloped viral particles are quantified via a set of metrics. One such metric, epitope fluctuation (and implied flexibility), is shown to be inversely correlated with immunogenicity for each of a broad spectrum of nonenveloped viruses. The molecular metrics and experimentally determined immunogenicities for these viruses are archived in the open-source vaccine computer-aided design database. Results indicate the promise of computer-aided vaccine design to bring greater efficiency to traditional lab-based vaccine discovery approaches.

  13. Novel approaches to increasing the brightness of broad area lasers

    NASA Astrophysics Data System (ADS)

    Crump, P.; Winterfeldt, M.; Decker, J.; Ekterai, M.; Fricke, J.; Knigge, S.; Maaßdorf, A.; Erbert, G.

    2016-03-01

    Progress in studies to increase the lateral brightness Blat of broad area lasers is reviewed. Blat=Pout/BPPlat is maximized by developing designs and technology for lowest lateral beam parameter product, BPPlat, at highest optical output power Pout. This can be achieved by limiting the number of guided lateral modes and by improving the beam quality of low-order lateral modes. Important effects to address include process and packaging induced wave-guiding, lateral carrier accumulation and the thermal lens profile. A careful selection of vertical design is also shown to be important, as are advanced techniques to filter out higher order modes.

  14. Broadly tunable quasi-phase-matching in nonlinear metamaterials

    SciTech Connect

    Rose, Alec; Smith, David R.

    2011-07-15

    The ability to tune the quasi-phase-matching (QPM) frequency is a highly desirable though lacking feature of many nonlinear devices. To this end, we consider QPM in a special class of active nonlinear metamaterials (MMs), whose properties can be controlled postfabrication. By application of a tunable, periodic perturbation in the linear susceptibility (magnetic or electric) of a MM, a single nonlinear device can be constructed to operate over an exceedingly broad bandwidth. We propose a nonlinear MM for QPM second-order harmonic generation at terahertz frequencies, predicted to have a tunable bandwidth of over 100%.

  15. 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.

  16. 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. PMID:22644153

  17. 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.

  18. Narrow- and Broad-Spectrum Antibiotic Use among U.S. Children

    PubMed Central

    Sarpong, Eric M; Miller, G Edward

    2015-01-01

    Objectives To provide updated estimates of narrow- and broad-spectrum antibiotic use among U.S. children. Data Sources Linked nationally representative data from the 2004–2010 Medical Expenditure Panel Survey Household Component and the 2000 Decennial Census. Study Design Relationships between individual-, family-, and community-level characteristics and the use of antibiotics overall and in the treatment of respiratory tract infections (RTIs) are examined using multinomial choice models. Principal Findings More than one quarter (27.3 percent) of children used at least one antibiotic each year with 12.8 percent using broad-spectrum and 18.5 percent using narrow-spectrum antibiotics. Among children with use, more than two-thirds (68.6 percent) used antibiotics to treat RTIs. Multivariate models revealed many differences across groups in antibiotic use, overall and in the treatment of RTIs. Differential use was associated with a broad range of factors related to need (e.g., age, health status), resources (e.g., insurance status, parental income, and education), race-ethnicity, and Census region. Conclusions Despite encouraging reports regarding the declining use of antibiotics, large differences in use associated with resources, race-ethnicity, and Census regions suggest a need for further improvement in the judicious and appropriate prescribing of antibiotics for U.S. children. PMID:25424240

  19. 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.

  20. Baculovirus Displaying Hemagglutinin Elicits Broad Cross-Protection against Influenza in Mice

    PubMed Central

    Seong, Baik Lin; Nguyen, Huan Huu; Chang, Jun

    2016-01-01

    The widespread influenza virus infection further emphasizes the need for novel vaccine strategies that effectively reduce the impact of epidemic as well as pandemic influenza. Conventional influenza vaccines generally induce virus neutralizing antibody responses which are specific for a few antigenically related strains within the same subtype. However, antibodies directed against the conserved stalk domain of HA could neutralize multiple subtypes of influenza virus and thus provide broad-spectrum protection. In this study, we designed and constructed a recombinant baculovirus-based vaccine, rBac-HA virus, that expresses full-length HA of pandemic H1N1 influenza virus (A/California/04/09) on the viral envelope. We demonstrated that repeated intranasal immunizations with rBac-HA virus induced HA stalk-specific antibody responses and protective immunity against homologous as well as heterosubtypic virus challenge. The adoptive transfer experiment shows that the cross-protection is conferred by the immune sera which contain HA stalk-specific antibodies. These results warrant further development of rBac-HA virus as a broad-protective vaccine against influenza. The vaccine induced protection against infection with the same subtype as well as different subtype, promising a potential universal vaccine for broad protection against different subtypes to control influenza outbreaks including pandemic. PMID:27023684

  1. 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.

  2. Training Partnerships. Linking Employers & Providers.

    ERIC Educational Resources Information Center

    Carnevale, Anthony P.; And Others

    This document summarizes research on partnerships in training. Part I describes forming linkages between employers and providers as a common business transaction and identifies services available from providers, locating a provider, criteria for selecting a provider, and how to evaluate linkage relationships. Part II describes the providers of…

  3. Large-scale clustering of broad-line Active Galactic Nuclei at low redshifts

    NASA Astrophysics Data System (ADS)

    Krumpe, Mirko; Miyaji, Takamitsu; Coil, Alison; Husemann, Bernd; Fanidakis, Nikolaos; Aceves, Hector

    2015-08-01

    In the last decade, large area surveys (e.g., SDSS, 2dF, XMM-COSMOS) significantly improved AGN clustering measurements, which now provide tight constraints on the mass of the hosting dark matter halos (as a function of AGN luminosity, type, and redshift), the environment in which super massive black hole accretion takes place, and the co-evolution of galaxies and AGN.I will report on a series of papers in which we study the large-scale clustering of broad-line optical and X-ray AGN through cross-correlation measurements with SDSS galaxies. With three independent measurements, we cover a redshift range of z=0.07-0.50. We find an X-ray luminosity dependence in the clustering amplitude of X-ray selected broad-line AGN. X-ray and optically selected broad-line AGN do not show significant differences in the clustering strengths at low redshifts. We apply Halo Occupation Distribution modeling and determined constraints on the distribution of AGN among dark matter halos as a function of their mass. At z~0.3, the AGN fraction decreases with increasing DMH mass. I will also present our newest results on the origin of the X-ray luminosity dependence of broad-line AGN clustering. The mass of supermassive black holes drives the dependence, while no dependence on L/L_EDD is found. Thus, more massive black holes reside in more massive dark matter halos. We also compare our results to state-of-the-art cosmological simulations and find good agreement.

  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. 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

  6. 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.

  7. 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.

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

    PubMed

    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

  9. 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.

  10. Sparse detector sensor: profiling experiments for broad-scale classification

    NASA Astrophysics Data System (ADS)

    Russomanno, D. J.; Yeasin, M.; Jacobs, E.; Smith, M.; Sorower, S.

    2008-04-01

    This paper presents a simple prototype sparse detector imaging sensor built using sixteen off-the-shelf, retro-reflective, infrared-sensing elements placed at five-inch intervals in a vertical configuration. Profiling experiments for broad-scale classification of objects, such as humans, humans wearing large backpacks, and humans wearing small backpacks were conducted from data acquired from the sensor. Empirical analysis on models developed using fusion of various classifiers based on a diversity measure shows over ninety percent (90.07%) accuracy (using 10-fold cross validation) in categorizing sensed data into specific classes of interest, such as, humans wearing a large backpack. The results demonstrate that shadow images of sufficient resolution can be captured by the sensor such that broad-scale classification of objects is feasible. The sensor appears to be a low-cost alternative to traditional, high-resolution imaging sensors, and, after industrial packaging, it may be a good candidate for deployment in vast geographic regions in which low-cost, unattended ground sensors with highly accurate classification algorithms are needed.

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

    PubMed

    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.

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

    PubMed

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

    2015-04-13

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

  13. 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...

  14. 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 pathways…

  15. 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.

  16. 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.

  17. Macrogeographic genetic variation in broad-snouted caiman (Caiman latirostris).

    PubMed

    Villela, Priscilla Marqui Schmidt; Coutinho, Luiz Lehmann; Piña, Carlos Ignacio; Verdade, Luciano M

    2008-12-01

    Broad-snouted caiman's (Caiman latirostris) geographic distribution comprises one of the widest latitudinal ranges among all crocodilians. In this study we analyzed the relationship between geographic distance (along the species latitudinal range) and genetic differentiation using DNA microsatellite loci developed for C. latirostris and Alligator mississippiensis. The results suggest that there is a consistent relationship between geographic distance and genetic differentiation; however, other biogeographical factors seem to be relevant. The Atlantic Chain (Serra do Mar) seems to be an effective geographic barrier, as well as the relatively narrow (< or =1.5 km) sea channel between Cardoso Island and the continent. In addition, coastal populations seem to have been well connected in recent geological time (Pleistocene 16,000 years ago) all along the eastern Brazilian coast. Further studies should focus on the São Francisco River drainage, which is still poorly known for this species. PMID:18661469

  18. SPECTROPOLARIMETRY OF RADIO-SELECTED BROAD ABSORPTION LINE QUASARS

    SciTech Connect

    DiPompeo, M. A.; Brotherton, M. S.; Becker, R. H.; Gregg, M. D.; Tran, H. D.; White, R. L.; Laurent-Muehleisen, S. A.

    2010-07-15

    We report spectropolarimetry of 30 radio-selected broad absorption line (BAL) quasars with the Keck Observatory, 25 from the sample of Becker et al. Both high- and low-ionization BAL quasars are represented, with redshifts ranging from 0.5 to 2.5. The spectropolarimetric properties of radio-selected BAL quasars are very similar to those of radio-quiet BAL quasars: a sizeable fraction (20%) shows large continuum polarization (2%-10%) usually rising toward short wavelengths; emission lines are typically less polarized than the continuum; and absorption line troughs often show large polarization jumps. There are no significant correlations between polarization properties and radio properties, including those indicative of system orientation, suggesting that BAL quasars are not simply normal quasars seen from an edge-on perspective.

  19. The generation effect: activating broad neural circuits during memory encoding.

    PubMed

    Rosner, Zachary A; Elman, Jeremy A; Shimamura, Arthur P

    2013-01-01

    The generation effect is a robust memory phenomenon in which actively producing material during encoding acts to improve later memory performance. In a functional magnetic resonance imaging (fMRI) analysis, we explored the neural basis of this effect. During encoding, participants generated synonyms from word-fragment cues (e.g., GARBAGE-W_ST_) or read other synonym pairs (e.g., GARBAGE-WASTE). Compared to simply reading target words, generating target words significantly improved later recognition memory performance. During encoding, this benefit was associated with a broad neural network that involved both prefrontal (inferior frontal gyrus, middle frontal gyrus) and posterior cortex (inferior temporal gyrus, lateral occipital cortex, parahippocampal gyrus, ventral posterior parietal cortex). These findings define the prefrontal-posterior cortical dynamics associated with the mnemonic benefits underlying the generation effect.

  20. 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

  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. Broad protection against influenza infection by vectored immunoprophylaxis in mice

    PubMed Central

    Balazs, Alejandro B.; Bloom, Jesse D.; Hong, Christin M.; Rao, Dinesh S.; Baltimore, David

    2014-01-01

    Neutralizing antibodies that target epitopes conserved among many strains of influenza virus have been recently isolated from humans. Here we demonstrate that adeno-associated viruses (AAV) encoding two such broadly neutralizing antibodies are protective against diverse influenza strains. Serum from mice that received a single intramuscular AAV injection efficiently neutralized all H1, H2 and H5 influenza strains tested. After infection with diverse strains of H1N1 influenza, treated mice showed minimal weight loss and lung inflammation. Protection lasted for at least 11 months after AAV injection. Notably, even immunodeficient and older mice were protected by this method, suggesting that expression of a monoclonal antibody alone is sufficient to protect mice from illness. If translated to humans, this prophylactic approach may be uniquely capable of protecting immunocompromised or elderly patient populations not reliably protected by existing vaccines. PMID:23728362

  3. Assessing Ground-Water Contamination Across Broad Regions

    NASA Astrophysics Data System (ADS)

    Helsel, D. R.

    2001-05-01

    Ground-water quality is measured at discrete locations, and often interpreted at local scales. However, regional patterns in ground-water quality can be used to: 1) Assess relations between water quality and broad patterns of human activities or geochemical variation; 2) Reduce monitoring costs by sampling more frequently in areas of highest concentration or vulnerability; 3) Prioritize locations for prevention efforts such as for nitrate reduction, to obtain maximum benefits for lower costs; and 4) Project water-quality conditions to unsampled locations based on a regional understanding or "model". Examples of methods for modeling and interpreting ground-water quality at regional scales are presented along with their utility for cost reduction and contamination prevention purposes.

  4. 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.

  5. An experimental characterisation of a Broad Energy Germanium detector

    NASA Astrophysics Data System (ADS)

    Harkness-Brennan, L. J.; Judson, D. S.; Boston, A. J.; Boston, H. C.; Colosimo, S. J.; Cresswell, J. R.; Nolan, P. J.; Adekola, A. S.; Colaresi, J.; Cocks, J. F. C.; Mueller, W. F.

    2014-10-01

    The spectroscopic and charge collection performance of a BE2825 Broad Energy Germanium (BEGe) detector has been experimentally investigated. The efficiency and energy resolution of the detector have been measured as a function of energy and the noise contributions to the preamplifier signal have been determined. Collimated gamma-ray sources mounted on an automated 3-axis scanning table have been used to study the variation in preamplifier signal shape with gamma-ray interaction position in the detector, so that the position-dependent charge collection process could be characterised. A suite of experimental measurements have also been undertaken to investigate the performance of the detector as a function of bias voltage and we report on anomalous behaviour observed when the detector was operating close to the depletion voltage.

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

    NASA Astrophysics Data System (ADS)

    Barrientos, D.; Boston, A. J.; Boston, H. C.; Quintana, B.; Sagrado, I. C.; Unsworth, C.; Moon, S.; Cresswell, J. R.

    2011-08-01

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

  7. New considerations on the broad-line regions of quasars

    SciTech Connect

    You, J.H.; Cheng, F.H.

    1987-11-01

    In the broad-line regions of quasars, there exist three different line emission mechanisms, i.e., the Cerenkov line and conventional line by recombination and collisional excitation. However, the Cerenkov line photon can avoid the resonance absorption because of the Cerenkov redshift and can escape easily from the deep inner part of the gas, i.e., gas appears more transparent for the Cerenkov line than for a conventional line. For an optically thick dense gas, if there are sufficient relativistic electrons, the intensity of the Cerenkov line will be dominating. Taking the quasar 3C 273 as an example, it is shown that only if N(e) is roughly 10 to the 4th to -10 to the 6th/cu cm, the calculated Cerenkov Ly-alpha luminosity is in agreement with observation. 13 references.

  8. 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.

  9. 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.

  10. 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.

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

    NASA Astrophysics Data System (ADS)

    Leighly, Karen

    2012-10-01

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

  12. Diphosphonium Ionic Liquids as Broad Spectrum Antimicrobial Agents

    PubMed Central

    O’Toole, George A.; Wathier, Michel; Zegans, Michael E.; Shanks, Robert M.Q.; Kowalski, Regis; Grinstaff, Mark W.

    2011-01-01

    Purpose One of the most disturbing trends in recent years is the growth of resistant strains of bacteria with the simultaneous dearth of new antimicrobial agents. Thus, new antimicrobial agents for use on the ocular surface are needed. Methods We synthesized a variety of ionic liquid compounds, which possess two positively charged phosphonium groups separated by ten methylene units in a “bola” type configuration. We tested these compounds for antimicrobial activity versus a variety of ocular pathogens, as well as their cytoxicity in vitro in a corneal cell line and in vivo in mice. Results The ionic liquid Di-Hex C10 demonstrated broad in vitro antimicrobial activity at the low micromolar concentrations versus Gram-negative and Gram-positive organisms, including methicillin-resistant Staphylococcus aureus strains, as well as ocular fungal pathogens. Treatment with Di-Hex C10 resulted in bacterial killing in as little as 15 minutes in vitro. Di-Hex C10 showed little cytotoxicity at 1 μM versus a corneal epithelial cell line or at 10 μM in a mouse corneal wound model. We also show that this bis-phosphonium ionic liquid structure is key, as a comparable mono phosphonium ionic liquid is cytotoxic to both bacteria and corneal epithelial cells. Conclusions Here we report the first use of dicationic bis-phosphonium ionic liquids as antimicrobial agents. Our data suggest that diphosphonium ionic liquids may represent a new class of broad-spectrum antimicrobial agents for use on the ocular surface. PMID:22236790

  13. Empirical Conversions of Broad-Band Optical and Infrared Magnitudes to Monochromatic Continuum Luminosities for Active Galactic Nuclei

    NASA Astrophysics Data System (ADS)

    Kozłowski, Sz.

    2015-09-01

    We use public data for 105,783 quasars from The Sloan Digital Sky Survey (SDSS) Data Release 7 (DR7) that include spectral monochromatic luminosities at 5100 Å, 3000 Å, and 1350 Å, and the corresponding observed broad-band ugriz, VRI (converted), JHK and WISE magnitudes, and derive broad-band-to-monochromatic luminosity ratios independent of a cosmological model. The ratios span the redshift range of z = 0.1 ÷ 4.9 and may serve as a proxy for measuring the bolometric luminosity, broad line region (BLR) radii and/or black hole masses, whenever flux-calibrated spectra are unavailable or the existing spectra have low signal-to-noise ratios. They are provided both in tabular and parametric form.

  14. The Broad Line Region in AGNs: Structure, Physics, and the f Factor

    NASA Astrophysics Data System (ADS)

    Grier, Catherine; Peterson, B. M.; Martini, P.; Pogge, R. W.; Pancoast, A.; Treu, T.; Watson, L. C.

    2014-01-01

    We present recent results in an effort to investigate the structure of the broad line region in active galactic nuclei (AGNs) using reverberation mapping data. AGNs provide our only means for exploring the black hole (BH) population outside the local universe. To measure black hole masses (MBH) in AGNs, we use the broad line region (BLR) by assuming that the motion of the emitting gas is dominated by the gravity of the BH. Virial MBH measurements can be made using the resulting Doppler-broadened emission lines: MBH = fRΔV^2/G. R is the distance of the emitting gas from the BH, ΔV is the velocity dispersion of the emitting gas, obtained from the width of the emission line, and f is a dimensionless factor that accounts for the geometry and orientation of the BLR. Because the BLR is unresolvable, the true value of f in for each object is unknown. Typically, an average virial factor f is used, calculated by assuming that AGNs follow the same MBH--σ relation as quiescent galaxies. Our inability to directly observe the structure of the BLR and is a major source of uncertainties in MBH measurements. To learn about BLR structure, we must rely on either reverberation mapping techniques or microlensing of gravitationally lensed quasars. We have been working on various aspects of this problem using high-quality reverberation-mapping data from various observing campaigns based at MDM Observatory on Kitt Peak. Results from these reverberation efforts have a broad impact on our understanding of AGN physics as well as on all MBH measurements in AGNs that provide a basis for galaxy evolution and AGN feedback models.

  15. A novel perspective on seed yield of broad bean (Vicia faba L.): differences resulting from pod characteristics.

    PubMed

    Li, Xiong; Yang, Yongping

    2014-10-31

    Broad bean (Vicia faba L.) is an important crop worldwide. An increase in seed yield would increase both the grain reserve and the profit for farmers. Previous studies on increasing broad bean seed yield have focused mainly on increases at the whole population level. Few studies have focused on the differences in plant type within populations. In this study, we classified broad bean plants into four categories based on pod type, and then evaluated the ratio of each category in field-grown broad bean populations. We analysed the seed and pod characteristics of each category, and their contributions to total seed yield. The number of seeds per pod, and the number of pods or seeds per plant differed among the four plant categories, but the seed weight was relatively uniform. There were significant differences in seed yield per plant among the four plant categories. We calculated the effects of increasing the proportion of each plant category by 10% or to 100% on seed yield, and found that seed yield could be improved by increasing the ratio of plants with the highest seed production rate. This study provides a novel perspective on estimating the seed yield of broad bean.

  16. A novel perspective on seed yield of broad bean (Vicia faba L.): differences resulting from pod characteristics

    PubMed Central

    Li, Xiong; Yang, Yongping

    2014-01-01

    Broad bean (Vicia faba L.) is an important crop worldwide. An increase in seed yield would increase both the grain reserve and the profit for farmers. Previous studies on increasing broad bean seed yield have focused mainly on increases at the whole population level. Few studies have focused on the differences in plant type within populations. In this study, we classified broad bean plants into four categories based on pod type, and then evaluated the ratio of each category in field-grown broad bean populations. We analysed the seed and pod characteristics of each category, and their contributions to total seed yield. The number of seeds per pod, and the number of pods or seeds per plant differed among the four plant categories, but the seed weight was relatively uniform. There were significant differences in seed yield per plant among the four plant categories. We calculated the effects of increasing the proportion of each plant category by 10% or to 100% on seed yield, and found that seed yield could be improved by increasing the ratio of plants with the highest seed production rate. This study provides a novel perspective on estimating the seed yield of broad bean. PMID:25358856

  17. Environmental Education Information Providers Directory.

    ERIC Educational Resources Information Center

    1999

    This report directory provides environmental education training resources and related support to education professionals. Surveys were sent to over 60 organizations asking them to self-identify as Environmental Information Providers or Environmental Education Information Providers. This report includes the list of organizations that responded and…

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

    NASA Astrophysics Data System (ADS)

    Jonić, S.; Kovačević-Dojčinović, J.; Ilić, D.; Popović, L. Č.

    2016-03-01

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

  19. Determining the composition of aqueous microdroplets with broad-band cavity enhanced Raman scattering.

    PubMed

    Symes, Rachel; Reid, Jonathan P

    2006-01-14

    We demonstrate that broad-band cavity enhanced Raman scattering (CERS) can be used to determine the composition of binary alcohol-water aerosol droplets over a wide compositional range from 10% v/v to 90% v/v. In contrast to conventional CERS using narrow-band laser excitation, the excitation is provided by a broad-band Nd:YAG pumped dye laser. A change in the spontaneous spectrum resulting from the change of the linewidth of the excitation laser permits tuning of the sensitivity range over which the droplet composition can be determined by CERS. We demonstrate that this change in sensitivity can be estimated using a simulation of the change in the sensitivity to the species in spontaneous bulk phase measurements. We further show that the compositional calibration is independent of droplet radius in the range 33-56 microm. The compositional range over which CERS is sensitive can be controlled and optimised for any particular application by exploiting the dependence of the stimulated Raman scattering on the laser linewidth and wavelength. Thus, quantitative measurements of droplet composition can be made in situ with high accuracy, providing a valuable new tool for analysing aerosol composition.

  20. Chimeric hemagglutinin influenza virus vaccine constructs elicit broadly protective stalk-specific antibodies.

    PubMed

    Krammer, Florian; Pica, Natalie; Hai, Rong; Margine, Irina; Palese, Peter

    2013-06-01

    Current influenza virus vaccine strategies stimulate immune responses toward the globular head domain of the hemagglutinin protein in order to inhibit key steps of the virus life cycle. Because this domain is highly variable across strains, new vaccine formulations are required in most years. Here we demonstrate a novel vaccine strategy that generates immunity to the highly conserved stalk domain by using chimeric hemagglutinin constructs that express unique head and stalk combinations. By repeatedly immunizing mice with constructs that expressed the same stalk but an irrelevant head, we specifically stimulated a stalk-directed response that provided broad-based heterologous and heterosubtypic immunity in mice. Notably, our vaccination scheme provides a universal vaccine approach that protects against challenge with an H5 subtype virus. Furthermore, through in vivo studies using passively transferred antibodies or depletion of CD8(+) T cells, we demonstrated the critical role that humoral mechanisms of immunity play in the protection observed. The present data suggest that a vaccine strategy based on the stalk domain of the hemagglutinin protein could be used in humans to broadly protect against a variety of influenza virus subtypes. PMID:23576508

  1. A GaAs monolithic low-noise broad-band amplifier

    NASA Astrophysics Data System (ADS)

    Archer, J. A.; Weidlich, H. P.; Pettenpaul, E.; Petz, F. A.; Huber, J.

    1981-12-01

    This paper describes the design, fabrication, and performance of GaAs monolithic low-noise broad-band amplifiers intended for broadcast receiver antenna amplifier, IF amplifier, and instrumentation applications. The process technology includes the use of Czochralski-grown semiinsulating substrates, localized implantation of ohmic and FET channel regions, and silicon nitride for passivation and MIM capacitors. The amplifiers employ shunt feedback to obtain input matching and flat broad-band response. One amplifier provides a gain of 24 dB, bandwidth of 930 MHz, and noise figure of 5.0 dB. A second amplifier provides a gain of 17 dB, bandwidth of 1400 MHz, and noise figure of 5.6 dB. Input and output VSWR's are typically less than 2:1 and the third-order intercept points are 28 and 32 dB, respectively. Improved noise figure and intercept point can be achieved by the use of external RF chokes.

  2. SUPPORT VECTOR MACHINES FOR BROAD AREA FEATURE CLASSIFICATION IN REMOTELY SENSED IMAGES

    SciTech Connect

    S. PERKINS; N. HARVEY; ET AL

    2001-03-01

    Classification of broad area features in satellite imagery is one of the most important applications of remote sensing. It is often difficult and time-consuming to develop classifiers by hand, so many researchers have turned to techniques from the fields of statistics and machine learning to automatically generate classifiers. Common techniques include maximum likelihood classifiers, neural networks and genetic algorithms. We present a new system called Afreet, which uses a recently developed machine learning paradigm called Support Vector Machines (SVMs). In contrast to other techniques, SVMs offer a solid mathematical foundation that provides a probabilistic guarantee on how well the classifier will generalize to unseen data. In addition the SVM training algorithm is guaranteed to converge to the globally optimal SVM classifier, can learn highly non-linear discrimination functions, copes extremely well with high-dimensional feature spaces (such as hype spectral data), and scales well to large problem sizes. Afreet combines an SVM with a sophisticated spatio-spectral feature construction mechanism that allows it to classify spectrally ambiguous pixels. We demonstrate the effectiveness of the system by applying Afreet to several broad area classification problems in remote sensing, and provide a comparison with conventional maximum likelihood classification.

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

    PubMed Central

    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; Kaminga, Gift; Louder, Mark K.; Tran, Lillan M.; Chen, Yue; Cai, Fangping; Chen, Sheri; Moquin, Stephanie; Du, Xiulian; Joyce, Gordon M.; 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.

    2013-01-01

    Current HIV-1 vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in ~20% of HIV-1-infected individuals, and details of their generation could provide a roadmap for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from time of infection. The mature antibody, CH103, neutralized ~55% of HIV-1 isolates, and its co-crystal structure with gp120 revealed a novel loop-based mechanism of CD4-binding site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the CH103-lineage unmutated common ancestor 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 elucidate 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 via vaccination. PMID:23552890

  4. A broad area electrospray generated by a piezoelectric transformer

    NASA Astrophysics Data System (ADS)

    Ramshani, Zeinab; Johnson, Michael J.; Atashbar, Massood Z.; Go, David B.

    2016-07-01

    Electrosprays are typically formed by the application of a high (kilovolt) voltage to the flow exiting a small diameter capillary, and they have been used in applications ranging from material synthesis to spray coating because of the finely controlled plume of micron-sized droplets they produce. In this work, we report a similar but distinct spray directly off the surface of a piezoelectric transformer. Using a paper wick to deliver liquid to the surface of the piezoelectric crystal, a continuous, broad area spray is generated from the wick in contact with the transformer surface, only requiring input voltages on the order of 20 Vamp. Systematic variation of critical parameters indicate that this piezoelectric transformer-generated spray is similar to a conventional electrospray, with the spray current exhibiting a non-linear dependence on the solution conductivity, but distinct, as the spray exhibits little dependence on the solution surface tension. This innovative spray could potentially lead to uniform, large area spray coverage from a single device for a wide variety of applications.

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

    PubMed

    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

  6. Broad-Spectrum Allosteric Inhibition of Herpesvirus Proteases

    PubMed Central

    2015-01-01

    Herpesviruses rely on a homodimeric protease for viral capsid maturation. A small molecule, DD2, previously shown to disrupt dimerization of Kaposi’s sarcoma-associated herpesvirus protease (KSHV Pr) by trapping an inactive monomeric conformation and two analogues generated through carboxylate bioisosteric replacement (compounds 2 and 3) were shown to inhibit the associated proteases of all three human herpesvirus (HHV) subfamilies (α, β, and γ). Inhibition data reveal that compound 2 has potency comparable to or better than that of DD2 against the tested proteases. Nuclear magnetic resonance spectroscopy and a new application of the kinetic analysis developed by Zhang and Poorman [Zhang, Z. Y., Poorman, R. A., et al. (1991) J. Biol. Chem. 266, 15591–15594] show DD2, compound 2, and compound 3 inhibit HHV proteases by dimer disruption. All three compounds bind the dimer interface of other HHV proteases in a manner analogous to binding of DD2 to KSHV protease. The determination and analysis of cocrystal structures of both analogues with the KSHV Pr monomer verify and elaborate on the mode of binding for this chemical scaffold, explaining a newly observed critical structure–activity relationship. These results reveal a prototypical chemical scaffold for broad-spectrum allosteric inhibition of human herpesvirus proteases and an approach for the identification of small molecules that allosterically regulate protein activity by targeting protein–protein interactions. PMID:24977643

  7. 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.

  8. Effect of Regulatory Architecture on Broad versus Narrow Sense Heritability

    PubMed Central

    Wang, Yunpeng; Vik, Jon Olav; Omholt, Stig W.; Gjuvsland, Arne B.

    2013-01-01

    Additive genetic variance (VA) and total genetic variance (VG) are core concepts in biomedical, evolutionary and production-biology genetics. What determines the large variation in reported VA/VG ratios from line-cross experiments is not well understood. Here we report how the VA/VG ratio, and thus the ratio between narrow and broad sense heritability (h2/H2), varies as a function of the regulatory architecture underlying genotype-to-phenotype (GP) maps. We studied five dynamic models (of the cAMP pathway, the glycolysis, the circadian rhythms, the cell cycle, and heart cell dynamics). We assumed genetic variation to be reflected in model parameters and extracted phenotypes summarizing the system dynamics. Even when imposing purely linear genotype to parameter maps and no environmental variation, we observed quite low VA/VG ratios. In particular, systems with positive feedback and cyclic dynamics gave more non-monotone genotype-phenotype maps and much lower VA/VG ratios than those without. The results show that some regulatory architectures consistently maintain a transparent genotype-to-phenotype relationship, whereas other architectures generate more subtle patterns. Our approach can be used to elucidate these relationships across a whole range of biological systems in a systematic fashion. PMID:23671414

  9. Broad Iron Emission from Gravitationally Lensed Quasars Observed by Chandra

    NASA Astrophysics Data System (ADS)

    Walton, D. J.; Reynolds, M. T.; Miller, J. M.; Reis, R. C.; Stern, D.; Harrison, F. A.

    2015-06-01

    Recent work has demonstrated the potential of gravitationally lensed quasars to extend measurements of black hole spin out to high redshift with the current generation of X-ray observatories. Here we present an analysis of a large sample of 27 lensed quasars in the redshift range 1.0≲ z≲ 4.5 observed with Chandra, utilizing over 1.6 Ms of total observing time, focusing on the rest-frame iron K emission from these sources. Although the X-ray signal-to-noise ratio (S/N) currently available does not permit the detection of iron emission from the inner accretion disk in individual cases in our sample, we find significant structure in the stacked residuals. In addition to the narrow core, seen almost ubiquitously in local active galactic nuclei (AGNs), we find evidence for an additional underlying broad component from the inner accretion disk, with a clear red wing to the emission profile. Based on simulations, we find the detection of this broader component to be significant at greater than the 3σ level. This implies that iron emission from the inner disk is relatively common in the population of lensed quasars, and in turn further demonstrates that, with additional observations, this population represents an opportunity to significantly extend the sample of AGN spin measurements out to high redshift.

  10. 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

  11. Application of Broad-Spectrum Resequencing Microarray for Genotyping Rhabdoviruses▿

    PubMed Central

    Dacheux, Laurent; Berthet, Nicolas; Dissard, Gabriel; Holmes, Edward C.; Delmas, Olivier; Larrous, Florence; Guigon, Ghislaine; Dickinson, Philip; Faye, Ousmane; Sall, Amadou A.; Old, Iain G.; Kong, Katherine; Kennedy, Giulia C.; Manuguerra, Jean-Claude; Cole, Stewart T.; Caro, Valérie; Gessain, Antoine; Bourhy, Hervé

    2010-01-01

    The rapid and accurate identification of pathogens is critical in the control of infectious disease. To this end, we analyzed the capacity for viral detection and identification of a newly described high-density resequencing microarray (RMA), termed PathogenID, which was designed for multiple pathogen detection using database similarity searching. We focused on one of the largest and most diverse viral families described to date, the family Rhabdoviridae. We demonstrate that this approach has the potential to identify both known and related viruses for which precise sequence information is unavailable. In particular, we demonstrate that a strategy based on consensus sequence determination for analysis of RMA output data enabled successful detection of viruses exhibiting up to 26% nucleotide divergence with the closest sequence tiled on the array. Using clinical specimens obtained from rabid patients and animals, this method also shows a high species level concordance with standard reference assays, indicating that it is amenable for the development of diagnostic assays. Finally, 12 animal rhabdoviruses which were currently unclassified, unassigned, or assigned as tentative species within the family Rhabdoviridae were successfully detected. These new data allowed an unprecedented phylogenetic analysis of 106 rhabdoviruses and further suggest that the principles and methodology developed here may be used for the broad-spectrum surveillance and the broader-scale investigation of biodiversity in the viral world. PMID:20610710

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

    NASA Astrophysics Data System (ADS)

    Quiros, Israel; Gonzalez, Tame; Gonzalez, Dania; Napoles, Yunelsy; García-Salcedo, Ricardo; Moreno, Claudia

    2010-11-01

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

  13. Defining Key Features of the Broad Autism Phenotype

    PubMed Central

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

    2009-01-01

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

  14. Preliminary design studies on the Broad Application Test Reactor

    SciTech Connect

    Terry, W.J.; Terry, W.K.; Ryskamp, J.M.; Jahshan, S.N.; Fletcher, C.D.; Moore, R.L.; Leyse, C.F.; Ottewitte, E.H.; Motloch, C.G.; Lacy, J.M.

    1992-08-01

    This report describes progress made at the Idaho National Engineering Laboratory during the first three quarters of Fiscal Year (FY) 1992 on the Laboratory-Directed Research and Development (LDRD) project to perform preliminary design studies on the Broad Application Test Reactor (BATR). This work builds on the FY-92 BATR studies, which identified anticipated mission and safety requirements for BATR and assessed a variety of reactor concepts for their potential capability to meet those requirements. The main accomplishment of the FY-92 BATR program is the development of baseline reactor configurations for the two conventional conceptual test reactors recommended in the FY-91 report. Much of the present report consists of descriptions and neutronics and thermohydraulics analyses of these baseline configurations. In addition, we considered reactor safety issues, compared the consequences of steam explosions for alternative conventional fuel types, explored a Molten Chloride Fast Reactor concept as an alternate BATR design, and examined strategies for the reduction of operating costs. Work planned for the last quarter of FY-92 is discussed, and recommendations for future work are also presented.

  15. 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

  16. Isotope incorporation in broad-snouted caimans (crocodilians)

    PubMed Central

    Caut, Stephane

    2013-01-01

    Summary The trophic ecology and migration of vertebrate species have been increasingly studied using stable isotope analysis. However, this approach requires knowledge on how dietary isotopic values are reflected in consumers' tissues. To date, this information has only been obtained for a handful of ectotherms; in particular, little is known about crocodilians. In this study, diet-tissue discrimination factors (DTDFs) and carbon and nitrogen stable isotope turnover rates were estimated for plasma, red blood cells (RBCs), and muscle obtained from broad-snouted caimans (Caiman latirostris). Individuals were fed two different control diets for 189 days. DTDFs for δ15N (Δ15N) and δ13C (Δ13C) ranged from −2.24‰ to 0.39‰ and from −0.52‰ to 1.06‰, respectively. Isotope turnover rates in tissues, expressed as half-lives, ranged from 11 to 71 days, with plasma

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

    NASA Astrophysics Data System (ADS)

    Ebrero, J.; Kriss, G. A.; Kaastra, J. S.; Ely, J. C.

    2016-02-01

    Aims: We observed the Seyfert 1 galaxy NGC 985 on several occasions to search for variability in its UV and X-ray absorption features to establish their location and physical properties. Methods: We used XMM-Newton to obtain X-ray spectra using the EPIC-pn camera, and the Cosmic Origins Spectrograph (COS) on the Hubble Space Telescope (HST) to obtain UV spectra. Our observations were simultaneous and span timescales of days to years. Results: We find that the soft X-ray obscuration that absorbed the low energy continuum of NGC 985 in August 2013 diminished greatly by January 2015. The total X-ray column density decreased from 2.1 × 1022 cm-2 to ~6 × 1021 cm-2. We also detect broad, fast UV absorption lines in COS spectra obtained during the 2013 obscuration event. Lines of C iii*, Lyα, Si iv, and C iv with outflow velocities of -5970 km s-1 and a full-width at half-maximum of 1420 km s-1 are prominent in the 2013 spectrum, but have disappeared in all but Lyα in the 2015 spectra. The ionization state and the column density of the UV absorbing gas is compatible with arising in the same gas as that causing the X-ray obscuration. The high velocity of the UV-absorbing gas suggests that the X-ray obscurer and the associated UV outflow are manifestations of an accretion disk wind.

  18. Work-related suicide in Victoria, Australia: a broad perspective.

    PubMed

    Routley, Virginia Hazel; Ozanne-Smith, Joan E

    2012-01-01

    While unintentional work-related injury is increasingly recognised as important and preventable, population studies of the full range of work related suicides have received less attention. The objective of this study is to investigate the epidemiology of work-related suicide in Victoria, July 2000-December 2007. The study draws on a database of all work-related deaths reported to the Victorian Coroner, inclusive of broadly defined work-relatedness. Inclusion criteria for work-related suicide were at least one of: suicide means was work related, work stressors were identified in police reports to the Coroners or the Coroner's finding, the suicide method involved another person's work (e.g. rail suicide, heavy vehicle) or the suicide location was a workplace. Cases still open for investigation were excluded. Of 642 work-related suicides, 55% had an association with work stressors; 32% jumped or lay in front of a train or heavy vehicle; 7% involved a work location and 6% involved work agents. Work stressor cases identified included business difficulties, recent or previous work injury, unemployment/redundancy or conflict with supervisors/colleagues (including workplace bullying). Work-related suicide is a substantial problem, for which few detailed population wide studies are available. Further research is required to understand the contribution of work stressors and effective interventions. PMID:22132703

  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. X-Ray Continua of Broad Absorption Line Quasars

    NASA Technical Reports Server (NTRS)

    Mathur, S.

    1999-01-01

    The targets for this program, PG1416-129 and LBQS 2212-1759 were known to be Broad Absorption Line Quasars (BALQSOs). BALQSOs are highly absorbed in soft X-rays. Good high energy response of Rossi-XTE made them ideal targets for observation. We observed LBQS 2212-1759 with PCA. We have now analyzed the data and found that the source was not detected. Since our target was expected to be faint, reliable estimate of background was very important. With the release of new FTOOLS (version 4.1) we were able to do so. We also analyzed a well known bright object and verified our results with the published data. This gave us confidence in the non-detection of our target LBQS 2212-1759. We are currently investigating the implications of this non-detection. Due to some scheduling problems, our second target PG1416-129 was not observed in A01. It was observed on 06/26/98. This target was detected with RXTE. We are now working on the spectral analysis with XSPEC.

  1. Breath analysis with broadly tunable quantum cascade lasers.

    PubMed

    Wörle, Katharina; Seichter, Felicia; Wilk, Andreas; Armacost, Chris; Day, Tim; Godejohann, Matthias; Wachter, Ulrich; Vogt, Josef; Radermacher, Peter; Mizaikoff, Boris

    2013-03-01

    With the availability of broadly tunable external cavity quantum cascade lasers (EC-QCLs), particularly bright mid-infrared (MIR; 3-20 μm) light sources are available offering high spectral brightness along with an analytically relevant spectral tuning range of >2 μm. Accurate isotope ratio determination of (12)CO2 and (13)CO2 in exhaled breath is of critical importance in the field of breath analysis, which may be addressed via measurements in the MIR spectral regime. Here, we combine for the first time an EC-QCL tunable across the (12)CO2/(13)CO2 spectral band with a miniaturized hollow waveguide gas cell for quantitatively determining the (12)CO2/(13)CO2 ratio within the exhaled breath of mice. Due to partially overlapping spectral features, these studies are augmented by appropriate multivariate data evaluation and calibration techniques based on partial least-squares regression along with optimized data preprocessing. Highly accurate determinations of the isotope ratio within breath samples collected from a mouse intensive care unit validated via hyphenated gas chromatography-mass spectrometry confirm the viability of IR-HWG-EC-QCL sensing techniques for isotope-selective exhaled breath analysis.

  2. 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.

  3. Rational design of a meningococcal antigen inducing broad protective immunity.

    PubMed

    Scarselli, Maria; Aricò, Beatrice; Brunelli, Brunella; Savino, Silvana; Di Marcello, Federica; Palumbo, Emmanuelle; Veggi, Daniele; Ciucchi, Laura; Cartocci, Elena; Bottomley, Matthew James; Malito, Enrico; Lo Surdo, Paola; Comanducci, Maurizio; Giuliani, Marzia Monica; Cantini, Francesca; Dragonetti, Sara; Colaprico, Annalisa; Doro, Francesco; Giannetti, Patrizia; Pallaoro, Michele; Brogioni, Barbara; Tontini, Marta; Hilleringmann, Markus; Nardi-Dei, Vincenzo; Banci, Lucia; Pizza, Mariagrazia; Rappuoli, Rino

    2011-07-13

    The sequence variability of protective antigens is a major challenge to the development of vaccines. For Neisseria meningitidis, the bacterial pathogen that causes meningitis, the amino acid sequence of the protective antigen factor H binding protein (fHBP) has more than 300 variations. These sequence differences can be classified into three distinct groups of antigenic variants that do not induce cross-protective immunity. Our goal was to generate a single antigen that would induce immunity against all known sequence variants of N. meningitidis. To achieve this, we rationally designed, expressed, and purified 54 different mutants of fHBP and tested them in mice for the induction of protective immunity. We identified and determined the crystal structure of a lead chimeric antigen that was able to induce high levels of cross-protective antibodies in mice against all variant strains tested. The new fHBP antigen had a conserved backbone that carried an engineered surface containing specificities for all three variant groups. We demonstrate that the structure-based design of multiple immunodominant antigenic surfaces on a single protein scaffold is possible and represents an effective way to create broadly protective vaccines.

  4. 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.

  5. 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

  6. 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.

  7. 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

  8. In vitro irradiation station for broad beam radiobiological experiments

    NASA Astrophysics Data System (ADS)

    Wéra, A.-C.; Riquier, H.; Heuskin, A.-C.; Michiels, C.; Lucas, S.

    2011-12-01

    The study of the interaction of charged particles with living matter is of prime importance to the fields of radiotherapy, radioprotection and space radiobiology. Particle accelerators and their associated equipment are proven to be helpful tools in performing basic science in all these fields. Indeed, they can accelerate virtually any ions to a given energy and flux and let them interact with living matter either in vivo or in vitro. In this context, the University of Namur has developed a broad beam in vitro irradiation station for use in radiobiological experiments. Cells are handled in GLP conditions and can be irradiated at various fluxes with ions ranging from hydrogen to carbon. The station is mounted on a 2 MV tandem accelerator, and the energy range can be set up in the linear energy transfer (LET) ranges that are useful for radiobiological experiments. This paper describes the current status of the hardware that has been developed, and presents results related to its performance in term of dose-rate, energy range and beam uniformity for protons, alpha particles and carbon ions. The results of clonogenic assays of A549 lung adenocarcinoma cells irradiated with protons and alpha particles are also presented and compared with literature.

  9. 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.

  10. 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.

  11. 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.

  12. 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

    2015-04-01

    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. PMID:25581790

  13. 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.

  14. 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

  15. 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.

  16. Locally Optimally Emitting Clouds and the Variable Broad Emission Line Spectrum of NGC 5548

    NASA Astrophysics Data System (ADS)

    Korista, Kirk T.; Goad, Michael R.

    2000-06-01

    In recent work Baldwin et al. proposed that in the geometrically extended broad-line regions (BLRs) of quasars and active galactic nuclei, a range in line-emitting gas properties (e.g., density, column density) might exist at each radius and showed that under these conditions the broad emission line spectra of these objects may be dominated by selection effects introduced by the atomic physics and general radiative transfer within the large pool of line-emitting entities. In this picture, the light we see originates in a vast amalgam of emitters but is dominated by those emitters best able to reprocess the incident continuum into a particular emission line. We test this ``locally optimally emitting clouds'' (LOC) model against the extensive spectroscopic database of the Seyfert 1 galaxy NGC 5548. The time-averaged, integrated-light UV broad emission line spectrum from the 1993 Hubble Space Telescope (HST) monitoring campaign is reproduced via the optimization of three global geometric parameters: the outer radius, the index controlling the radial cloud covering fraction of the continuum source, and the integrated cloud covering fraction. We make an ad hoc selection from the range of successful models, and for a simple spherical BLR geometry we simulate the emission-line light curves for the 1989 IUE and 1993 HST campaigns, using the respective observed UV continuum light curves as drivers. We find good agreement between the predicted and observed light curves and lags-a demonstration of the LOC picture's viability as a means to understanding the BLR environment. Finally, we discuss the next step in developing the LOC picture, which involves the marriage of echo-mapping techniques with spectral simulation grids such as those presented here, using the constraints provided by a high-quality, temporally well-sampled spectroscopic data set.

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

    PubMed

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

    2015-03-17

    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.

  18. 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 ...

  19. 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…

  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. 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

  2. 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. PMID:25825450

  3. Ability to develop broadly neutralizing HIV-1 antibodies is not restricted by the germline immunoglobulin gene repertoire1

    PubMed Central

    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; Karim, Quarraisha Abdool; Karim, Salim S. Abdool; Moore, Penny L.; Travers, Simon A.; Morris, Lynn

    2015-01-01

    The human immunoglobulin repertoire is vast, producing billions of unique antibodies from a limited number of germline immunoglobulin genes. The immunoglobulin heavy chain variable region (IGHV) is central to antigen binding and is comprised of 48 functional genes. Here we analyzed whether HIV-1 infected individuals who develop broadly neutralizing antibodies 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 Center for the AIDS Programme of Research in South African (CAPRISA) 002 and 004 cohorts, 13 of whom developed broadly neutralizing antibodies. 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 monoclonal antibodies isolated from 7 of the CAPRISA women and previously isolated broadly neutralizing antibodies from other donors provided evidence that at least 8 novel or non-IMGT alleles contributed to functional antibodies. Importantly, we found that despite a wide range in the number of IGHV alleles in each individual, including alleles used by known broadly neutralizing antibodies, there were no significant differences in germline IGHV repertoires between individuals who do and do not develop broadly neutralizing antibodies. This study reports novel IGHV repertoires and highlights the importance of a fully comprehensive immunoglobulin database for germline gene usage prediction. Furthermore, these data suggest a lack of genetic bias in broadly neutralizing antibody development in HIV-1 infection, with implications for HIV vaccine design. PMID:25825450

  4. 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

  5. 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

  6. Cold hardiness of the broad mite Polyphagotarsonemus latus (Acari: Tarsonemidae).

    PubMed

    Luypaert, Gil; Witters, Johan; Berkvens, Nick; Van Huylenbroeck, Johan; De Riek, Jan; De Clercq, Patrick

    2015-05-01

    The cold hardiness of the broad mite, Polyphagotarsonemus latus, a key pest in Rhododendron simsii hybrid production in northwestern Europe, was investigated in the laboratory. Survival of eggs, larvae and female adults and reproduction capacity of female P. latus were evaluated following cold exposure at 7 °C. Adult females were also exposed to temperatures of 2 and -3 °C. Further, the supercooling point and lower lethal times of adult females were determined. No eggs survived exposure to 7 °C for 17 or more days. Larval survival upon the cold treatment decreased from 53 to 13% when exposed to 7 °C for 14 and 49 days, respectively. Two-day-old adult females exposed to 7 °C for up to 42 days did not suffer significant mortality, but when returned to 25 °C their oviposition rates were lower than those of mites maintained at 25 °C. Less than 40% of females exposed for 13 days to 2 °C survived; only 20% of these females was able to reproduce upon recovery. Subzero temperatures dramatically decreased survival and reproduction capacity of adult females. The supercooling point of female adults was -16.5 °C. Median lethal times averaged 61.2 h and 9.3 days at -3 and 2 °C, respectively. In conclusion, a long term exposure (up to 6 weeks) of R. simsii plants infested with P. latus to a temperature of 7 °C, which is required for breaking dormancy of the flowers, is not expected to have detrimental effects on the survival and reproductive performance of the female mites.

  7. Predicting broad-scale occurrences of vertebrates in patchy landscapes

    USGS Publications Warehouse

    Boone, R.B.; Krohn, W.B.

    2000-01-01

    Spatially explicit landscape-scale models that predict species distributions, where patches of habitat are shown as having potential to be occupied or unoccupied, are increasingly common. To successfully use such data, one should understand how these predicted distributions are created and how their relative accuracies are assessed. Geographic ranges, defined upon observations (e.g., atlases), literature review, and expert review, are a primary data layer. A map of land cover is created, often from interpretation of satellite imagery or other remotely-sensed data. Species/habitat associations are defined based upon a literature review and expert review, describing associations for habitats derived from the cover map. Included as ancillary associations are how species relate to physical features, where appropriate, such as elevation and hydrography. The three layers of information (range, land cover, and associations) are merged, often using raster-based algebraic statements that exclude unused habitats or patches outside the range of a species. The accuracy of predictions for a suite of species is typically assessed with surveys by comparing the species predicted to occur in an area to the species observed. Omission (i.e., present in species lists but not predicted) and commission (i.e., predicted but not present in lists) errors are reported. Errors may be due to many sources. For example, ranges of species change, cover types may be misidentified, species/habitat associations may be incorrect or change, or species may be rare and unlikely to be seen in surveys and judged in-error even though the species may be present. An example is given of an appropriate use of broad-scale species predicted distributions, in which patterns and threats to Maine terrestrial vertebrate diversity are summarized.

  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. PMID:25984786

  9. 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.

  10. Evidence for Photoionization-driven Broad Absorption Line Variability

    NASA Astrophysics Data System (ADS)

    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. Galactose as Broad Ligand for Multiple Tumor Imaging and Therapy.

    PubMed

    Ma, Yuxiang; Chen, Haiyan; Su, Shanyuhan; Wang, Tong; Zhang, Congying; Fida, Guissi; Cui, Sisi; Zhao, Juan; Gu, Yueqing

    2015-01-01

    Galactose residues could be specifically recognized by the asialoglycoprotein receptor (ASGPR) which is highly exhibited on liver tissues. However, ASGPR has not been widely investigated on different tumor cell lines except for hepatoma carcinoma cells, which motivates us to investigate the possibility of galactose serving as a board tumor ligand. In this study, a galactose (Gal)-based probe conjugated with fluorescence dye MPA (Gal-MPA) was constructed for the evaluation of tumor affinities/targeted ability on different tumor cell lines. In the vitro cell study, it was indicated that the fluorescence probe Gal-MPA displayed higher cell affinity to tumor cells (HepG2, MCF-7 and A549) than that of the normal liver cells l02. In the vivo dynamic study of Gal-MPA in tumor-bearing mice (HepG2, MCF-7, A549, HCT116, U87, MDA-MB-231 and S180), it was shown that its high tumor targeted ability with the maximal tumor/normal tissue ratio reached up to 6.8. Meanwhile, the fast tumor-targeted ability within 2 hours and long retention on tumor site up to 120 hours were observed. Our results demonstrated that galactose should be a promising broad ligand for multiple tumor imaging and targeted therapy. Subsequently, Gal was covalently conjugated to doxorubicin (DOX) to form prodrug Gal-DOX for tumor targeted therapy. The therapeutic results of Gal-DOX than DOX being better suggested that galactosylated prodrugs might have the prospective potential in tumor targeted therapy.

  12. Galactose as Broad Ligand for Multiple Tumor Imaging and Therapy

    PubMed Central

    Ma, Yuxiang; Chen, Haiyan; Su, Shanyuhan; Wang, Tong; Zhang, Congying; Fida, Guissi; Cui, Sisi; Zhao, Juan; Gu, Yueqing

    2015-01-01

    Galactose residues could be specifically recognized by the asialoglycoprotein receptor (ASGPR) which is highly exhibited on liver tissues. However, ASGPR has not been widely investigated on different tumor cell lines except for hepatoma carcinoma cells, which motivates us to investigate the possibility of galactose serving as a board tumor ligand. In this study, a galactose (Gal)-based probe conjugated with fluorescence dye MPA (Gal-MPA) was constructed for the evaluation of tumor affinities/targeted ability on different tumor cell lines. In the vitro cell study, it was indicated that the fluorescence probe Gal-MPA displayed higher cell affinity to tumor cells (HepG2, MCF-7 and A549) than that of the normal liver cells l02. In the vivo dynamic study of Gal-MPA in tumor-bearing mice (HepG2, MCF-7, A549, HCT116, U87, MDA-MB-231 and S180), it was shown that its high tumor targeted ability with the maximal tumor/normal tissue ratio reached up to 6.8. Meanwhile, the fast tumor-targeted ability within 2 hours and long retention on tumor site up to 120 hours were observed. Our results demonstrated that galactose should be a promising broad ligand for multiple tumor imaging and targeted therapy. Subsequently, Gal was covalently conjugated to doxorubicin (DOX) to form prodrug Gal-DOX for tumor targeted therapy. The therapeutic results of Gal-DOX than DOX being better suggested that galactosylated prodrugs might have the prospective potential in tumor targeted therapy. PMID:26078797

  13. Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity

    PubMed Central

    Kim, Tae-Hee; Li, Fugen; Ferreiro-Neira, Isabel; Ho, Li-Lun; Luyten, Annouck; Nalapareddy, Kodandaramireddy; Long, Henry; Verzi, Michael; Shivdasani, Ramesh A.

    2014-01-01

    Cells differentiate when transcription factors (TFs) bind accessible cis-regulatory elements to establish specific gene expression programs. In differentiating embryonic stem (ES) cells, chromatin at lineage-restricted genes becomes sequentially accessible1-4, probably by virtue of “pioneer” TF activity5, but tissues may utilize other strategies in vivo. Lateral inhibition is a pervasive process in which one cell forces a different identity on its neighbors6, and it is unclear how chromatin in equipotent progenitors undergoing lateral inhibition quickly enables distinct, transiently reversible cell fates. Here we report the chromatin and transcriptional underpinnings of differentiation in mouse small intestine crypts, where Notch signaling mediates lateral inhibition to assign progenitor cells into absorptive or secretory lineages7-9. Transcript profiles in isolated LGR5+ intestinal stem cells (ISC)10 and secretory and absorptive progenitors indicated that each cell population was distinct and the progenitors specified. Nevertheless, secretory and absorptive progenitors showed comparable levels of H3K4me2 and H3K27ac histone marks and DNaseI hypersensitivity - signifying accessible, permissive chromatin - at most of the same cis-elements. Enhancers acting uniquely in progenitors were well-demarcated in LGR5+ ISC, revealing early priming of chromatin for divergent transcriptional programs, and retained active marks well after lineages were specified. On this chromatin background, ATOH1, a secretory-specific TF, controls lateral inhibition through Delta-like Notch ligand genes and also drives numerous secretory lineage genes. Depletion of ATOH1 from specified secretory cells converted them into functional enterocytes, indicating prolonged responsiveness of marked enhancers to presence or absence of a key TF. Thus, lateral inhibition and intestinal crypt lineage plasticity involve interaction of a lineage-restricted TF with broadly permissive chromatin established

  14. 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.

  15. Unveiling the X-ray/UV properties of AGN winds using Broad and mini-Broad Absorption Line Quasars

    NASA Astrophysics Data System (ADS)

    Giustini, M.

    2015-07-01

    BAL/mini-BALs are observed in the UV spectra of ˜ 20-30% of optically selected AGN as broad absorption troughs blueshifted by several thousands km/s, indicative of powerful nuclear winds. They could be representative of the average AGN if their winds cover only 20-30% of the continuum source, and/or represent an evolutionary state analogous to the high-soft state of BHB, when the jet emission is quenched and strong X-ray absorbing equatorial disk winds are virtually ubiquitous. High-quality, possibly time-resolved X-ray/UV studies are crucial to assess the global amount and 'character' of absorption in BAL/mini-BAL QSOs and to constrain the physical mechanism responsible for the launch and acceleration of their winds, therefore placing them in the broader context of AGN geometry and evolution. I will review here the known X-ray properties of BAL/mini-BAL QSOs, and present new results from a comprehensive X-ray spectral analysis of all the Palomar-Green BAL/mini-BAL QSOs with available XMM-Newton observations, for a total of 51 pointings of 14 different sources. These will include the most recent results from a high-quality simultaneous XMM/HST observational campaign on the mini-BAL QSO PG 1126-041, that unveiled with stunning details the X-ray/UV connection in action in an AGN disk wind through correlated X-ray/UV absorption variability.

  16. 32 CFR 724.203 - Broad objectives of naval discharge review.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 5 2011-07-01 2011-07-01 false Broad objectives of naval discharge review. 724... PERSONNEL NAVAL DISCHARGE REVIEW BOARD Authority/Policy for Departmental Discharge Review § 724.203 Broad objectives of naval discharge review. Naval discharge review shall have as its broad objectives: (a)...

  17. 32 CFR 724.203 - Broad objectives of naval discharge review.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 5 2010-07-01 2010-07-01 false Broad objectives of naval discharge review. 724... PERSONNEL NAVAL DISCHARGE REVIEW BOARD Authority/Policy for Departmental Discharge Review § 724.203 Broad objectives of naval discharge review. Naval discharge review shall have as its broad objectives: (a)...

  18. Sampling Broad Habitat change to assess biodiversity conservation action in Northern Ireland.

    PubMed

    Cooper, A; McCann, T; Meharg, M J

    2003-03-01

    A habitat monitoring programme, the Northern Ireland Countryside Survey, carried out by the University of Ulster for the Department of the Environment for Northern Ireland, is described. It was based on a random sample of quarter kilometer grid squares, stratified by multivariate land classification. Estimates of change in habitat area between 1987-1992 and 1998 are presented and used to assess policy-related priorities for biodiversity conservation action in widespread habitats in Northern Ireland (NI). The basis of the assessment is Broad Habitats, a classification developed as part of the United Kingdom (UK) Biodiversity Action Plan. Improved Grassland, Neutral Grassland and Bog Broad Habitats occupy the largest area of NI, which holds a large proportion of the UK Neutral Grassland and Fen Marsh and Swamp Broad Habitat resource. The greatest net area increases with time were in Improved Grassland (33%), Coniferous Woodland (12%) and Broadleaved, Mixed and Yew Woodland (9%). The greatest net area decreases were in Neutral Grassland (-32%), Arable and Horticulture (-25%), Fen, Marsh and Swamp (-19%), Bog (-8%) and Calcareous Grassland (-7%). These changes are a function of agriculture, public and private forestry, building construction and peat cutting for fuel. The Key biodiversity issue is seminatural Broad Habitat loss, in particular, Neutral Grassland and Fen, Marsh and Swamp, highlighting the lack of effective action for protecting biodiversity in the countryside as a whole. The extent to which current land use is shown to be driving change, indicates that biodiversity conservation action through implementing landscape-scale agri-environment measures could deliver major biodiversity gains. The reliable information on recent changes, provided by the Northern Ireland Countryside Survey, has been used to guide conservation planning. Future re-survey will allow the effectiveness of the conservation strategy as it applies to the countryside as a whole, to be

  19. Sampling Broad Habitat change to assess biodiversity conservation action in Northern Ireland.

    PubMed

    Cooper, A; McCann, T; Meharg, M J

    2003-03-01

    A habitat monitoring programme, the Northern Ireland Countryside Survey, carried out by the University of Ulster for the Department of the Environment for Northern Ireland, is described. It was based on a random sample of quarter kilometer grid squares, stratified by multivariate land classification. Estimates of change in habitat area between 1987-1992 and 1998 are presented and used to assess policy-related priorities for biodiversity conservation action in widespread habitats in Northern Ireland (NI). The basis of the assessment is Broad Habitats, a classification developed as part of the United Kingdom (UK) Biodiversity Action Plan. Improved Grassland, Neutral Grassland and Bog Broad Habitats occupy the largest area of NI, which holds a large proportion of the UK Neutral Grassland and Fen Marsh and Swamp Broad Habitat resource. The greatest net area increases with time were in Improved Grassland (33%), Coniferous Woodland (12%) and Broadleaved, Mixed and Yew Woodland (9%). The greatest net area decreases were in Neutral Grassland (-32%), Arable and Horticulture (-25%), Fen, Marsh and Swamp (-19%), Bog (-8%) and Calcareous Grassland (-7%). These changes are a function of agriculture, public and private forestry, building construction and peat cutting for fuel. The Key biodiversity issue is seminatural Broad Habitat loss, in particular, Neutral Grassland and Fen, Marsh and Swamp, highlighting the lack of effective action for protecting biodiversity in the countryside as a whole. The extent to which current land use is shown to be driving change, indicates that biodiversity conservation action through implementing landscape-scale agri-environment measures could deliver major biodiversity gains. The reliable information on recent changes, provided by the Northern Ireland Countryside Survey, has been used to guide conservation planning. Future re-survey will allow the effectiveness of the conservation strategy as it applies to the countryside as a whole, to be

  20. DO QUASAR BROAD-LINE VELOCITY WIDTHS ADD ANY INFORMATION TO VIRIAL BLACK HOLE MASS ESTIMATES?

    SciTech Connect

    Croom, Scott M.

    2011-08-01

    We examine how much information measured broad-line widths add to virial black hole (BH) mass estimates for flux-limited samples of quasars. We do this by comparing the BH mass estimates to those derived by randomly reassigning the quasar broad-line widths to different objects and re-calculating the BH mass. For 9000 BH masses derived from the H{beta} line we find that the distributions of original and randomized BH masses in the M{sub BH}-redshift plane and the M{sub BH}-luminosity plane are formally identical. A two-dimensional Kolmogorov-Smirnov test does not find a difference at >90% confidence. For the Mg II line (32,000 quasars) we do find very significant differences between the randomized and original BH masses, but the amplitude of the difference is still small. The difference for the C IV line (14,000 quasars) is 2{sigma}-3{sigma} and again the amplitude of the difference is small. Subdividing the data into redshift and luminosity bins we find that the median absolute difference in BH mass between the original and randomized data is 0.025, 0.01, and 0.04 dex for H{beta}, Mg II, and C IV, respectively. The maximum absolute difference is always {<=}0.1 dex. We investigate whether our results are sensitive to corrections to Mg II virial masses, such as those suggested by Onken and Kollmeier. These corrections do not influence our results, other than to reduce the significance of the difference between original and randomized BH masses to only 1{sigma}-2{sigma} for Mg II. Moreover, we demonstrate that the correlation between mass residuals and Eddington ratio discussed by Onken and Kollmeier is more directly attributable to the slope of the relation between H{beta} and Mg II line width. The implication is that the measured quasar broad-line velocity widths provide little extra information, after allowing for the mean velocity width. In this case virial estimates are equivalent to M{sub BH}{proportional_to}L{sup {alpha}}, with L/L{sub Edd

  1. Radiation safety for anesthesia providers.

    PubMed

    Phillips, Gillian; Monaghan, W Patrick

    2011-06-01

    Many modern diagnostic and surgical procedures rely heavily on the use of ionizing radiation. These procedures include computed tomography, nuclear medicine procedures, interventional radiology, and cardiac catheterization and electrophysiology procedures. Recent trends toward increased patient visits and patients with multiple challenging comorbidities have meant that anesthesia providers are increasingly required to provide services in the ancillary areas using ionizing radiation. As a result, anesthesia providers are at a greater-than-ever risk for excessive radiation doses. An overview of some of the basic principles of radiation biology, radiation physics, and radiation protection and specific guidelines related to radiation exposure and pregnancy are described. The effects of radiation exposure are cumulative and permanent, and an understanding of these principles and practices will help anesthesia providers keep their occupational exposure to a minimum. PMID:21751695

  2. Choosing Your Prenatal Care Provider

    MedlinePlus

    ... also called OB) is a doctor who has special education and training to take care of pregnant women ... midwife is a health care provider who has special education and training to take care of women of ...

  3. Concise Synthesis of Spergualin-Inspired Molecules With Broad-Spectrum Antibiotic Activity

    PubMed Central

    Assimon, Victoria A.; Shao, Hao; Garneau-Tsodikova, Sylvie

    2016-01-01

    There is a growing need to identify new, broad-spectrum antibiotics. The natural product spergualin was previously shown to have promising anti-bacterial activity and a privileged structure, but its challenging synthesis had limited further exploration. For example, syntheses of spergualin and its analogs have been reported in approximately 10 linear steps, with overall yields between 0.3 and 18%. Using the Ugi multi-component reaction, we assembled spergualin-inspired molecules in a single step, dramatically improving the overall yield (20% to 96%). Using this strategy, we generated 43 new analogs and tested them for anti-bacterial activity against two Gram-negative and four Gram-positive strains. We found that the most potent analogue, compound 6, had MIC values between 4 and 32 μg/mL against the six strains, which is a significant improvement on spergualin (MIC ∼ 6.25 to 50 μg/mL). These studies provide a concise route to a broad-spectrum antibiotic with a novel chemical scaffold. PMID:27087913

  4. 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

    2016-01-01

    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 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.

  5. 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.

  6. 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.

  7. 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. PMID:26553503

  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

    2016-01-01

    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 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. PMID:26700814

  9. 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.

  10. 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

    2016-07-01

    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.

  11. 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/.

  12. 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

  13. 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.

  14. 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.

  15. Estimating the broad-sense heritability of early growth of cowpea.

    PubMed

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

    2009-01-01

    Cowpea is an important tropical crop. It provides a large proportion of the food resource for the African human population and their livestock. The yield and quality of cowpea have been dramatically improved through traditional breeding strategies for the past few decades. However, reports of heritability estimates for early growth of cowpea are rare. We designed a simple experiment to estimate the broad-sense heritability of early growth. We randomly selected 15 cowpea varieties among a total of 5000 cowpea accessions maintained in the cowpea breeding facility at the University of California, Riverside to examine the genetic determination of early growth of cowpea (measured as the height at day five after seeding). The estimated broad-sense heritability on the individual plant basis is 0.2190. However, the corresponding estimate on the plant mean basis (average of four plants) is 0.5198, which is very high for a quantitative trait. The high heritability may explain why traditional breeding for cowpea growth is so effective. Since the design of experiment and method of data analysis are novel, this report can serve as an educational note for students in the area of quantitative genetics and plant breeding.

  16. Broad-spectrum micronutrient treatment for attention-deficit/hyperactivity disorder: rationale and evidence to date.

    PubMed

    Rucklidge, Julia J; Kaplan, Bonnie J

    2014-09-01

    Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric illness, which often co-occurs with other common psychiatric problems. Although empirical evidence supports the short-term efficacy of pharmacological and behavioural treatments, families often search for alternative treatment methods because of concerns about side effects and safety, cost and access, as well as fears about long-term exposure to psychotropic medications. This review presents the published evidence on use of broad-spectrum micronutrients to treat ADHD symptoms. This approach makes physiological sense in that nutrients are required for many critical biochemical reactions to occur, ranging from manufacturing neurotransmitters, to providing the mitochondria with essential nutrients for energy production, to assisting the gut to heal from inflammation. Multi-nutrient treatment approaches are an intriguing yet under-researched area; all but one of the trials conducted in the last decade have shown benefit for the treatment of ADHD symptoms, and the one negative trial likely used doses too low to effect change. However, the methodologies have varied widely from case-controlled studies to open-label trials to one randomized controlled trial. Sample sizes have typically been modest, although the effect sizes have tended to be medium to large. What is required now is replication, as well as investigation into the optimal ingredient range and optimal doses of nutrients. We discuss the proven and potential benefits of the broad-spectrum nutrient approach, considering the heterogeneous nature of ADHD. PMID:25056569

  17. 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.

  18. 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.

  19. 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. PMID:23786594

  20. 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.

  1. Antenna configurations provide polarization diversity

    NASA Technical Reports Server (NTRS)

    Schumacher, C. N.

    1966-01-01

    Compact back-to-back trapezoidal tooth log-periodic /TTLP/ antenna with frequency-independent characteristics is formed by reducing the angle between the two elements of a basic TTLP to zero. The back-to-back antenna, arranged in various configurations, provides monopulse operations in one or two planes and in various polarizations.

  2. 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.

  3. 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…

  4. 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. PMID:26988200

  5. 77 FR 52048 - Announcement of Test Providing Centralized Decision-Making Authority for Four CBP Centers of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-28

    ... SECURITY U.S. Customs and Border Protection Announcement of Test Providing Centralized Decision-Making...-making authority: the Electronics CEE; Pharmaceuticals, Health & Chemicals CEE; the Automotive... a general test to provide broad decision- making authority to the: Electronics CEE;...

  6. 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.

  7. The broad view of nuclear technology for aerospace

    NASA Astrophysics Data System (ADS)

    Buden, David; Angelo, Joseph A., Jr.

    1991-01-01

    Nuclear technologies can directly support advanced space initiatives. For near-Earth missions, nuclear technology can be used to power air traffic control, communications and manufacturing platforms, provide emergency power for manned platforms, provide power for maneuvering units, move asteroids for mining, measure the natural radiation environment, provide radiation protection instruments, and design radiation hardened robotic systems. For the Lunar and Mars surfaces, nuclear technology can be used for base stationary, mobile, and emergency power, energy storage, process heat, nuclear thermal and electric rocket propulsion, excavation and underground engineering, water and sewage treatment and sterilization, food processing and preservation, mineral exploration, self-luminous systems, radiation protection instrumentation, radiation environmental warning systems, and habitat shielding design. Outer planet missions can make use of nuclear technology for power and propulsion. Programs need to be initiated to ensure the full beneficial use of nuclear technologies in advanced space missions.

  8. Structure-based clustering of major histocompatibility complex (MHC) proteins for broad-based T-cell vaccine design.

    PubMed

    Tong, Joo Chuan; Tan, Tin Wee; Ranganathan, Shoba

    2014-01-01

    Structure-based clustering technique is useful for identifying superfamilies of major histocompatibility complex (MHC) proteins with similar binding specificities. The resolved MHC superfamilies play an important role in vaccine development, from discovering new targets for broad-based vaccines and therapeutics to optimizing the affinity and selectivity of hits. Here, we describe a protocol and provide a summary for grouping MHC proteins according to their structural interaction characteristics.

  9. Data-intensive science applied to broad-scale citizen science.

    PubMed

    Hochachka, Wesley M; Fink, Daniel; Hutchinson, Rebecca A; Sheldon, Daniel; Wong, Weng-Keen; Kelling, Steve

    2012-02-01

    Identifying ecological patterns across broad spatial and temporal extents requires novel approaches and methods for acquiring, integrating and modeling massive quantities of diverse data. For example, a growing number of research projects engage continent-wide networks of volunteers ('citizen-scientists') to collect species occurrence data. Although these data are information rich, they present numerous challenges in project design, implementation and analysis, which include: developing data collection tools that maximize data quantity while maintaining high standards of data quality, and applying new analytical and visualization techniques that can accurately reveal patterns in these data. Here, we describe how advances in data-intensive science provide accurate estimates in species distributions at continental scales by identifying complex environmental associations.

  10. Broad spectral domain fluorescence wavelength modulation of visible and near-infrared emissive polymersomes.

    PubMed

    Ghoroghchian, P Peter; Frail, Paul R; Susumu, Kimihiro; Park, Tae-Hong; Wu, Sophia P; Uyeda, H Tetsuo; Hammer, Daniel A; Therien, Michael J

    2005-11-01

    Incorporation of an extended family of multi[(porphinato)zinc(II)] (PZn)-based supermolecular fluorophores into the lamellar membranes of polymersomes (50 nm to 50 mum diameter polymer vesicles) gives rise to electrooptically diverse nano-to-micron (meso) scale soft materials. Studies that examine homogeneous suspensions of 100 nm diameter emissive polymersomes demonstrate fluorescence energy modulation over a broad spectral domain of the visible and near-infrared (600-900 nm). These polymersomal structures highlight that the nature of intermembranous polymer-to-fluorophore contacts depends on the position and identity of the porphyrins' phenyl ring substituents. Emissive polymersomes are shown to possess reduced spectral heterogeneity with respect to the established optical signatures of these PZn-based supermolecular fluorophores in solution; additionally, selection of fluorophore ancillary substituents predictably controls the nature of polymer-emitter noncovalent interactions to provide an important additional mechanism to further modulate the fluorescence band maxima of these meso-scale emissive vesicles.

  11. How to adapt broad-band gravitational-wave searches for r-modes

    SciTech Connect

    Owen, Benjamin J.

    2010-11-15

    Up to now there has been no search for gravitational waves from the r-modes of neutron stars in spite of the theoretical interest in the subject. Several oddities of r-modes must be addressed to obtain an observational result: The gravitational radiation field is dominated by the mass current (gravitomagnetic) quadrupole rather than the usual mass quadrupole, and the consequent difference in polarization affects detection statistics and parameter estimation. To astrophysically interpret a detection or upper limit it is necessary to convert the gravitational-wave amplitude to an r-mode amplitude. Also, it is helpful to know indirect limits on gravitational-wave emission to gauge the interest of various searches. Here I address these issues, thereby providing the ingredients to adapt broad-band searches for continuous gravitational waves to obtain r-mode results. I also show that searches of existing data can already have interesting sensitivities to r-modes.

  12. A broadly tunable autocorrelator for ultra-short, ultra-high power infrared optical pulses

    SciTech Connect

    Szarmes, E.B.; Madey, J.M.J.

    1995-12-31

    We describe the design of a crossed-beam, optical autocorrelator that uses an uncoated, birefringent beamsplitter to split a linearly polarized incident pulse into two orthogonally polarized pulses, and a Type II, SHG crystal to generate the intensity autocorrelation function. The uncoated beamsplitter accommodates extremely broad tunability while precluding any temporal distortion of ultrashort optical pulses at the dielectric interface, and the specific design provides efficient operation between 1 {mu}m and 4 {mu}m. Furthermore, the use of Type II SHG completely eliminates any single-beam doubling, so the autocorrelator can be operated at very shallow crossed-beam angles without generating a background pedestal. The autocorrelator has been constructed and installed in the Mark III laboratory at Duke University as a broadband diagnostic for ongoing compression experiments on the chirped-pulse FEL.

  13. Immune Pathways in Atopic Dermatitis, and Definition of Biomarkers through Broad and Targeted Therapeutics.

    PubMed

    Mansouri, Yasaman; Guttman-Yassky, Emma

    2015-04-29

    Atopic dermatitis (AD) is the most common inflammatory skin disease. Recent research findings have provided an insight into the complex pathogenic mechanisms involved in this disease. Despite a rising prevalence, effective and safe therapeutics for patients with moderate-to-severe AD are still lacking. Biomarkers of lesional, nonlesional skin, and blood have been developed for baseline as well as after treatment with broad and specific treatments (i.e., cyclosporine A and dupilumab). These biomarkers will help with the development of novel targeted therapeutics and assessment of disease reversal, with the promise of a more personalized treatment approach. Since AD involves more than one subtype (i.e., intrinsic/extrinsic, pediatric/adult, etc.), these molecular fingerprints needs to be validated in all subpopulations with AD.

  14. A solitary fibrous tumor in the broad ligament of the uterus.

    PubMed

    Zubor, Pavol; Kajo, Karol; Szunyogh, Norbert; Galo, Silvester; Danko, Jan

    2007-01-01

    Solitary fibrous tumor (SFT) is a rare mesenchymal tumor that occurs preferentially in the pleura. Although it has been described at some extrathoracic sites, its occurrence in the female genital tract is extremely rare. We are the first to report on an unusual case of a large (14cm in the largest diameter) SFT localized in the broad ligament of the uterus in a 50-year-old woman. The patient underwent surgical tumor extirpation and has remained well without any sign of local tumor recurrence after 6 years of follow-up. We discuss the clinical aspects, the gross macroscopic appearance, the histologic findings, and the differential diagnosis, and provide a review of the literature.

  15. Honing a harder-hitting hammerhead improves broadly neutralizing antibody breadth and potency.

    PubMed

    Lewis, George K

    2015-06-01

    While current HIV-1 therapies have greatly improved the quality and duration of life for infected individuals, a vaccine to prevent transmission of the virus is lacking. Broadly neutralizing monoclonal antibodies (bnmAbs) with the capacity to neutralize multiple HIV-1 variants have been isolated from HIV-1-infected individuals, and there has been a great effort to investigate how these bnmAbs arise, due their potential for HIV-1 vaccination. In this issue of the JCI, Willis and colleagues apply a computational approach to design variants of the bnmAb PG9 in an attempt to enhance potency and neutralization breadth. One of these variants was able to target multiple PG9-resistant strains, as the result of stabilization of the long heavy chain complementarity determining region 3 (HCDR3). The results of this study provide important insight and a unique approach to optimizing HIV-1 bnmABs.

  16. Peracetic Acid Treatment Generates Potent Inactivated Oral Vaccines from a Broad Range of Culturable Bacterial Species

    PubMed Central

    Moor, Kathrin; Wotzka, Sandra Y.; Toska, Albulena; Diard, Médéric; Hapfelmeier, Siegfried; Slack, Emma

    2016-01-01

    Our mucosal surfaces are the main sites of non-vector-borne pathogen entry, as well as the main interface with our commensal microbiota. We are still only beginning to understand how mucosal adaptive immunity interacts with commensal and pathogenic microbes to influence factors such as infectivity, phenotypic diversity, and within-host evolution. This is in part due to difficulties in generating specific mucosal adaptive immune responses without disrupting the mucosal microbial ecosystem itself. Here, we present a very simple tool to generate inactivated mucosal vaccines from a broad range of culturable bacteria. Oral gavage of 1010 peracetic acid-inactivated bacteria induces high-titer-specific intestinal IgA in the absence of any measurable inflammation or species invasion. As a proof of principle, we demonstrate that this technique is sufficient to provide fully protective immunity in the murine model of invasive non-typhoidal Salmonellosis, even in the face of severe innate immune deficiency. PMID:26904024

  17. Pacific Broad Tapeworm Adenocephalus pacificus as a Causative Agent of Globally Reemerging Diphyllobothriosis.

    PubMed

    Kuchta, Roman; Serrano-Martínez, Marcus Enrique; Scholz, Tomas

    2015-10-01

    The Pacific broad tapeworm Adenocephalus pacificus (syn. Diphyllobothrium pacificum) is the causative agent of the third most common fish-borne cestodosis among humans. Although most of the nearly 1,000 cases among humans have been reported in South America (Peru, Chile, and Ecuador), cases recently imported to Europe demonstrate the potential for spread of this tapeworm throughout the world as a result of global trade of fresh or chilled marine fish and travel or migration of humans. We provide a comprehensive survey of human cases of infection with this zoonotic parasite, summarize the history of this re-emerging disease, and identify marine fish species that may serve as a source of human infection when eaten raw or undercooked.

  18. Immune Pathways in Atopic Dermatitis, and Definition of Biomarkers through Broad and Targeted Therapeutics

    PubMed Central

    Mansouri, Yasaman; Guttman-Yassky, Emma

    2015-01-01

    Atopic dermatitis (AD) is the most common inflammatory skin disease. Recent research findings have provided an insight into the complex pathogenic mechanisms involved in this disease. Despite a rising prevalence, effective and safe therapeutics for patients with moderate-to-severe AD are still lacking. Biomarkers of lesional, nonlesional skin, and blood have been developed for baseline as well as after treatment with broad and specific treatments (i.e., cyclosporine A and dupilumab). These biomarkers will help with the development of novel targeted therapeutics and assessment of disease reversal, with the promise of a more personalized treatment approach. Since AD involves more than one subtype (i.e., intrinsic/extrinsic, pediatric/adult, etc.), these molecular fingerprints needs to be validated in all subpopulations with AD. PMID:26239452

  19. Peracetic Acid Treatment Generates Potent Inactivated Oral Vaccines from a Broad Range of Culturable Bacterial Species.

    PubMed

    Moor, Kathrin; Wotzka, Sandra Y; Toska, Albulena; Diard, Médéric; Hapfelmeier, Siegfried; Slack, Emma

    2016-01-01

    Our mucosal surfaces are the main sites of non-vector-borne pathogen entry, as well as the main interface with our commensal microbiota. We are still only beginning to understand how mucosal adaptive immunity interacts with commensal and pathogenic microbes to influence factors such as infectivity, phenotypic diversity, and within-host evolution. This is in part due to difficulties in generating specific mucosal adaptive immune responses without disrupting the mucosal microbial ecosystem itself. Here, we present a very simple tool to generate inactivated mucosal vaccines from a broad range of culturable bacteria. Oral gavage of 10(10) peracetic acid-inactivated bacteria induces high-titer-specific intestinal IgA in the absence of any measurable inflammation or species invasion. As a proof of principle, we demonstrate that this technique is sufficient to provide fully protective immunity in the murine model of invasive non-typhoidal Salmonellosis, even in the face of severe innate immune deficiency.

  20. Using high spectral resolution spectrophotometry to study broad mineral absorption features on Mars

    NASA Technical Reports Server (NTRS)

    Blaney, D. L.; Crisp, D.

    1993-01-01

    Traditionally telescopic measurements of mineralogic absorption features have been made using relatively low to moderate (R=30-300) spectral resolution. Mineralogic absorption features tend to be broad so high resolution spectroscopy (R greater than 10,000) does not provide significant additional compositional information. Low to moderate resolution spectroscopy allows an observer to obtain data over a wide wavelength range (hundreds to thousands of wavenumbers) compared to the several wavenumber intervals that are collected using high resolution spectrometers. However, spectrophotometry at high resolution has major advantages over lower resolution spectroscopy in situations that are applicable to studies of the Martian surface, i.e., at wavelengths where relatively weak surface absorption features and atmospheric gas absorption features both occur.

  1. Peracetic Acid Treatment Generates Potent Inactivated Oral Vaccines from a Broad Range of Culturable Bacterial Species.

    PubMed

    Moor, Kathrin; Wotzka, Sandra Y; Toska, Albulena; Diard, Médéric; Hapfelmeier, Siegfried; Slack, Emma

    2016-01-01

    Our mucosal surfaces are the main sites of non-vector-borne pathogen entry, as well as the main interface with our commensal microbiota. We are still only beginning to understand how mucosal adaptive immunity interacts with commensal and pathogenic microbes to influence factors such as infectivity, phenotypic diversity, and within-host evolution. This is in part due to difficulties in generating specific mucosal adaptive immune responses without disrupting the mucosal microbial ecosystem itself. Here, we present a very simple tool to generate inactivated mucosal vaccines from a broad range of culturable bacteria. Oral gavage of 10(10) peracetic acid-inactivated bacteria induces high-titer-specific intestinal IgA in the absence of any measurable inflammation or species invasion. As a proof of principle, we demonstrate that this technique is sufficient to provide fully protective immunity in the murine model of invasive non-typhoidal Salmonellosis, even in the face of severe innate immune deficiency. PMID:26904024

  2. Development of a neutron detector with broad dynamic range and multi-hit capability

    NASA Astrophysics Data System (ADS)

    Pawelczak, Iwona; Toke, Jan; Tsai, Yun-Tse; Udo Schröder, W.

    2007-10-01

    A new type of Gd-loaded plastic neutron detector with a broad dynamic range (from thermal to MeV range) and multi-hit capability has been designed and subjected to series of tests. The device consists of a stack of alternating plastic scintillator (Saint Gobain BC-408) slabs and thin radiator films (PDMS -- SYLGARD 184) loaded with 0.5% of Gd per weight, viewed by a photomultiplier tube. The scintillator functions as neutron moderator, provides a prompt integrated neutron energy signal, and detects delayed n capture by Gd nuclei via associated capture γ-rays. The design, Monte Carlo simulations carried out with an extended code DENIS(E), as well as first measurements with the detector will be discussed.

  3. Pacific Broad Tapeworm Adenocephalus pacificus as a Causative Agent of Globally Reemerging Diphyllobothriosis

    PubMed Central

    Serrano-Martínez, Marcus Enrique; Scholz, Tomas

    2015-01-01

    The Pacific broad tapeworm Adenocephalus pacificus (syn. Diphyllobothrium pacificum) is the causative agent of the third most common fish-borne cestodosis among humans. Although most of the nearly 1,000 cases among humans have been reported in South America (Peru, Chile, and Ecuador), cases recently imported to Europe demonstrate the potential for spread of this tapeworm throughout the world as a result of global trade of fresh or chilled marine fish and travel or migration of humans. We provide a comprehensive survey of human cases of infection with this zoonotic parasite, summarize the history of this re-emerging disease, and identify marine fish species that may serve as a source of human infection when eaten raw or undercooked. PMID:26402440

  4. 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.

  5. The great risk shift: a strategic road map for providers.

    PubMed

    Ringwood, William; Bosko, Tawnya

    2016-04-01

    Healthcare providers that are assessing their readiness to assume financial risk for care delivery should understand the full range of risk options available to them. Available options fall into two broad categories: episode-based risk (e.g., the Medicare BPCI initiative and CJR model, commercial insurance models, and direct-to-employer models) and population-based risk (e.g., shared savings models and professional or institutional capitation models). Providers also require a deep understanding of both internal and market-based factors that are essential for success under any risk option being contemplated. PMID:27244977

  6. Physical properties of emitting plasma near massive black holes: the Broad Line Region

    NASA Astrophysics Data System (ADS)

    Ilić, D.; Mura, G. La; Popović, L. Č.; Shapovalova, A. I.; Ciroi, S.; Chavushyan, V. H.; Rafanelli, P.; Burenkov, A. N.; Marcado, A.

    2007-04-01

    The dominant emission in Active Galactic Nuclei (AGN) spectra comes from the Broad Emission Lines (BEL) which originate in the Broad Line Region (BLR). The BLR can potentially provide a useful probe of the central part of an AGN, and consequently of the characteristics of the massive Black Hole (BH) that is assumed to be in the center of these objects. The understanding of the physics and kinematics of the BLR is crucial because of the following three reasons: (i) kinematics of the BLR is probably determined by the massive BH, with the competing effects of gravity and radiation pressure, (ii) the BLR reprocesses the UV energy emitted by the continuum source, consequently BEL can provide indirect information about the continuum source, (iii) there is indication that the physical and kinematical parameters of the BEL can be connected with the general characteristics of an AGN (e.g. mass of the BH). In order to connect the physical and kinematical parameters of the BLR, in this work we consider the intensities and widths of Balmer lines of a sample of 90 AGN from Sloan Digital Sky Survey (SDSS). Additionally, we consider the variation of the intensities and widths of Balmer lines from the BLR of NGC 5548 observed from 1996 till 2004. We apply the Boltzmann-Plot method (Popovic 2003, Popovic et al. 2006) to the Balmer line intensities and estimated the electron temperature of a typical BLR. Moreover, we discuss the possibility that the BLR is in general composed from two emitting regions: one that is closer to the BH and contributes to the BEL's wings, and another that is further from the central BH and contributes to the BEL's core.

  7. Preparing to provide MTM services.

    PubMed

    Glenn, Zandra M; Mahdavian, Soheyla L; Woodard, Todd J

    2015-02-01

    Medication Therapy Management (MTM) has been a way for pharmacist to enhance their position as an integral member of the health care team as the need for improved clinical and economic outcomes in relation to the US health care system became apparent. MTM Certificate training programs are provided by numerous organizations. Collaboration Practice Agreements (CPA) are gaining significance as the role of the pharmacist is expanding in the care of patients as part of a multidisciplinary health care team. One major hurdle that many pharmacists are faced with is receiving reimbursement for the services provided. The Medicare Modernization Act of 2003 recognized that pharmacists play an important role in the management of patient care and that pharmacists bring an expertise and knowledge that will help to identify and resolve patient medication therapy problems.

  8. Utah's Broad Voucher Plan Would Break New Ground

    ERIC Educational Resources Information Center

    McNeil, Michele

    2007-01-01

    This article reports on the provisions of a new Utah voucher plan that is hoped to embolden other states to embrace universal-voucher programs. The legislation, the product of a six-year statehouse battle, would provide every public school student who wanted one, a voucher worth $500 per year, while low-income children would receive as much as…

  9. Oral Chemotherapy Education: Using Innovation to Ensure Broad Access.

    PubMed

    Sullivan, Clare M; Dalby, Carole; Gross, Anne H; Chesnulevich, Kaitlin; Lilienfeld, Christine W; Hooper, Catherine; Rizzo, Patricia; Kochanek, Thomas

    2016-04-01

    The purpose of this article is to share one institution's intervention to improve oral chemotherapy patient education. The overall aim was to provide clinicians with a single source of educational materials that would meet a diverse group of patients' educational needs and be consistent with published guidelines.
.

  10. 75 FR 341 - FY 2010-FY 2011 Broad Agency Announcement

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-05

    ... associated with the Agency's strategic plan and mission goals, as well as to provide the general public with... proposals for special projects and programs associated with the Agency's strategic plan and mission goals... organizations, applying a systematic approach that links our strategic goals through multi-year plans to...

  11. Essential Tension: Specialization with Broad and General Training in Psychology

    ERIC Educational Resources Information Center

    Roberts, Michael C.

    2006-01-01

    The practice fields of psychology develop through specialization in training and education. The recognized specialties play a major role in developing new opportunities for professional psychology and providing quality services for the public. The essential tension comes from the balance of innovation and tradition and, in professional psychology,…

  12. Intergroup Dialogue: Education for a Broad Conception of Civic Engagement

    ERIC Educational Resources Information Center

    Gurin, Patricia; Nagda, Biren A.; Sorensen, Nicholas

    2011-01-01

    Intergroup dialogue provides what students need in order to relate and collaborate across differences, something they have to do in community projects that usually involve interactions across racial, social class, religious, and geographical divides. In this article, the authors demonstrate the efficacy of intergroup dialogue, drawing from a…

  13. Application service providers in dentistry.

    PubMed

    Schleyer, Titus

    2002-07-01

    ASP practice management systems are a new and potentially useful service for the dental profession. ASP systems have the potential to reduce the time, effort, and expense required to maintain computer-based practice management functions. ASP systems can deliver a rich array of functions at a distance, eliminate concerns about upgrades, back-ups, and server hardware, and make management of client workstations easier. The ASP industry is young, however, and its companies and products will be in constant flux. Practitioners should exercise great caution in selecting an ASP system. If the ASP model proves viable in dentistry over the long term, we can expect to see a growing number of services being delivered over the Internet. Many ASPs exist already that serve many needs of small businesses, such as accounting, personnel management, and supply ordering. Application service provider systems also have the potential to improve communication between dental care providers. The ease of exchanging selected patient information between providers may result in more patient-related information exchange than is currently the case. The quality of dental care can only benefit.

  14. Broadly absorbing metalloporphyrin-based multichromophoric arrays for triplet harvesting

    DOEpatents

    Thompson, Mark E.; Whited, Matthew T.; Djurovich, Peter I.

    2016-09-20

    The present disclosure relates to multichromophoric assemblies comprising metalloporphyrin scaffolds. The present disclosure also relates, in part, to methods for generating electric-field-stabilized geminate polaron pairs comprising applying electric fields to the multichromophoric assemblies described herein, or alternatively, directly to the metalloporphyrins provided by the present disclosure. The present disclosure further relates, in part, to multichromophoric assemblies comprising metalloporphyrin scaffolds, which exhibit enhanced energy transfer properties.

  15. A systematic literature review of individuals' perspectives on broad consent and data sharing in the United States

    PubMed Central

    Garrison, Nanibaa' A.; Sathe, Nila A.; Antommaria, Armand H. Matheny; Holm, Ingrid A.; Sanderson, Saskia C.; Smith, Maureen E.; McPheeters, Melissa L.; Clayton, Ellen W.

    2016-01-01

    Purpose: In 2011, an Advanced Notice of Proposed Rulemaking proposed that de-identified human data and specimens be included in biobanks only if patients provide consent. The National Institutes of Health Genomic Data Sharing policy went into effect in 2015, requiring broad consent from almost all research participants. Genet Med 18 7, 663–671. Methods: We conducted a systematic literature review of attitudes toward biobanking, broad consent, and data sharing. Bibliographic databases included MEDLINE, Web of Science, EthxWeb, and GenETHX. Study screening was conducted using DistillerSR. Genet Med 18 7, 663–671. Results: The final 48 studies included surveys (n = 23), focus groups (n = 8), mixed methods (n = 14), interviews (n = 1), and consent form analyses (n = 2). Study quality was characterized as good (n = 19), fair (n = 27), and poor (n = 2). Although many participants objected, broad consent was often preferred over tiered or study-specific consent, particularly when broad consent was the only option, samples were de-identified, logistics of biobanks were communicated, and privacy was addressed. Willingness for data to be shared was high, but it was lower among individuals from under-represented minorities, individuals with privacy and confidentiality concerns, and when pharmaceutical companies had access to data. Genet Med 18 7, 663–671. Conclusions: Additional research is needed to understand factors affecting willingness to give broad consent for biobank research and data sharing in order to address concerns to enhance acceptability. Genet Med 18 7, 663–671. PMID:26583683

  16. Perceptions of patient provider agreements

    PubMed Central

    Albrecht, Jennifer S.; Khokhar, Bilal; Pradel, Françoise; Campbell, Michelle; Palmer, Jacqueline; Harris, Ilene; Palumbo, Francis

    2016-01-01

    Objectives Use of patient provider agreements (PPAs) is increasing, yet there is limited evidence on the effectiveness of PPAs to prevent prescription opioid misuse and diversion, and few guidelines for providers. We conducted eight focus groups to understand patient and prescriber perceptions of PPAs. Methods We recruited 40 patients who had been asked to sign a PPA and 40 prescribers who had administered at least one PPA. We developed topic guides for the two groups based on prior literature. Focus groups were audio-recorded and transcribed verbatim. Two investigators independently performed the content analysis of the transcripts and reached consensus on recurring themes. Key findings PPA use varied according to physician specialty. General practitioners used PPAs the least but reported increasing pressure from liability insurers to use them. Many patients reported signing a PPA in the emergency room of a hospital. Prescribers and patients reported a lack of understanding among patients concerning the purpose and content of the PPA. Prescribers questioned the legal status of the PPA, while patients believed that the PPA was a legal document intended to protect prescribers. Patients and prescribers valued PPA content items differently, although both groups agreed that signing a PPA would not prevent opioid misuse. Conclusions We identified several themes concerning the administration, content, effectiveness and utility of PPAs that highlight areas of research to improve PPAs. We also describe trends requiring further investigation. Understanding content of importance to patients will facilitate the development of a patient-centred PPA. PMID:27293486

  17. Broad-spectrum identification and discrimination between biothreat agents and near-neighbor species

    NASA Astrophysics Data System (ADS)

    Malanoski, Anthony P.; Leski, Tomasz A.; Cheng, Luke; Wang, Zheng; Stenger, David A.; Lin, Baochuan

    2009-05-01

    A comprehensive resequencing microarray "Tropical and Emerging Infections (TessArray RPM-TEI 1.0 array)" has been developed to identify and distinguish between biothreat organisms of interest and genetically close related species. This array has undergone validation using an innovative approach where synthetic DNA fragments are used for organisms that it is not safe to work with outside a biosafety 3 facilities. The approach was confirmed from testing a subset of target organisms, such as Ebola viruses and Lassa viruses, at USAMRIID. Most potential biothreat organisms are actually endemic in some part of the world. Proper surveillance of biothreat agents will require some form of monitoring the evolution of the indigenous organisms under their natural environment, so when changes in the organisms occur, the diagnostic assays for these organisms can be reviewed to assure they still provide detection. Using the resequencing microarray (RPM) for detection in locations such as the Africa can support indigenous monitoring as it provides sequence information. An ongoing collaboration with Njala University aims to establish a broad-spectrum pathogen surveillance capability in the Republic of Sierra Leone, West Africa using RPM technology combined with a Geographic Information System. This has the potential to improve the public health efforts in an infected area as well as provide monitoring of the changes occurring to a biothreat organism, i.e. Lassa viruses, in its natural location.

  18. Low-power slice selective imaging of broad signals

    NASA Astrophysics Data System (ADS)

    Yang, Weiqi; Lee, Jae-Seung; Kharkov, Boris; Ilott, Andrew J.; Jerschow, Alexej

    2016-11-01

    One of the major challenges in using magnetic resonance imaging (MRI) to study immobile samples, such as solid materials or rigid tissues like bone or ligaments, is that the images appear dark due to these samples' short-lived signals. Although it is well known that narrowband signals can be excited in inhomogeneously-broadened lines, it is less well known that similar effects can be observed in dipolar-broadened systems. These long-lived signals have not been used much, mainly because their description frequently does not match intuition. While 3D imaging with these signals has previously been reported, here we focus on the demonstration of faster, 2D slice-selective imaging. The faster imaging provides more flexibility for visualizing these rigid objects. We also focus on the frequently-encountered regime wherein the maximum power achievable for rf pulses is significantly weaker than the linewidth. This regime is typically encountered in clinical MRI scans or large volume setups. When compared to UTE and conventional slice-selective spin echo methods, this technique provides better representations of the sample considered here (an eraser sample), and higher signal-to-noise ratios than spin-echo techniques in both the high and low power regimes.

  19. Broad phylogenomic sampling and the sister lineage of land plants.

    PubMed

    Timme, Ruth E; Bachvaroff, Tsvetan R; Delwiche, Charles F

    2012-01-01

    The tremendous diversity of land plants all descended from a single charophyte green alga that colonized the land somewhere between 430 and 470 million years ago. Six orders of charophyte green algae, in addition to embryophytes, comprise the Streptophyta s.l. Previous studies have focused on reconstructing the phylogeny of organisms tied to this key colonization event, but wildly conflicting results have sparked a contentious debate over which lineage gave rise to land plants. The dominant view has been that 'stoneworts,' or Charales, are the sister lineage, but an alternative hypothesis supports the Zygnematales (often referred to as "pond scum") as the sister lineage. In this paper, we provide a well-supported, 160-nuclear-gene phylogenomic analysis supporting the Zygnematales as the closest living relative to land plants. Our study makes two key contributions to the field: 1) the use of an unbiased method to collect a large set of orthologs from deeply diverging species and 2) the use of these data in determining the sister lineage to land plants. We anticipate this updated phylogeny not only will hugely impact lesson plans in introductory biology courses, but also will provide a solid phylogenetic tree for future green-lineage research, whether it be related to plants or green algae.

  20. Broad phylogenomic sampling and the sister lineage of land plants.

    PubMed

    Timme, Ruth E; Bachvaroff, Tsvetan R; Delwiche, Charles F

    2012-01-01

    The tremendous diversity of land plants all descended from a single charophyte green alga that colonized the land somewhere between 430 and 470 million years ago. Six orders of charophyte green algae, in addition to embryophytes, comprise the Streptophyta s.l. Previous studies have focused on reconstructing the phylogeny of organisms tied to this key colonization event, but wildly conflicting results have sparked a contentious debate over which lineage gave rise to land plants. The dominant view has been that 'stoneworts,' or Charales, are the sister lineage, but an alternative hypothesis supports the Zygnematales (often referred to as "pond scum") as the sister lineage. In this paper, we provide a well-supported, 160-nuclear-gene phylogenomic analysis supporting the Zygnematales as the closest living relative to land plants. Our study makes two key contributions to the field: 1) the use of an unbiased method to collect a large set of orthologs from deeply diverging species and 2) the use of these data in determining the sister lineage to land plants. We anticipate this updated phylogeny not only will hugely impact lesson plans in introductory biology courses, but also will provide a solid phylogenetic tree for future green-lineage research, whether it be related to plants or green algae. PMID:22253761

  1. The broad spectrum of preclinical radiobiology: British contributions.

    PubMed

    Denekamp, J

    1996-09-01

    British radiobiologists have often been at the forefront in taking clinical questions into the laboratory and in taking the results back into the clinic, i.e., what is nowadays labeled as Translational Research. They have published widely and have been very active in lectures, workshops, and discussions, forming an important component of the international communication web, both within the basic science aspects and in the translation from science to medicine, and back again. Major contributions have been made at the cellular and subcellular level, and at the level of multicellular structures, both normal and malignant. The common features of the response of cells to single doses in well-defined conditions have been used to interpret the much greater complexity of tissue and tumor responses treated with repeated small doses in a fractionated course, both of photons and other radiations, with and without chemical modifiers. The many contributions to the field of cell kinetics have provided the tools with which an understanding has been gained of the latency and evolution of radiation damage in different tissues. The prolonged interest in microenvironmental gradients and compensatory responses to injury have provided a framework for designing better radiotherapy schedules, and considerable spin-off to other branches of cancer therapy.

  2. X-Ray Absorbed, Broad-Lined, Red AGN and the Cosmic X-Ray Background

    NASA Technical Reports Server (NTRS)

    Mushotzky, Richard (Technical Monitor); Wilkes, Belinda

    2005-01-01

    We have obtained XMM spectra for five red, 2MASS AGN, selected from a sample observed by Chandra to be X-ray bright and to cover a range of hardness ratios. Our results confirm the presence of substantial absorbing material in three sources which have optical classifications ranging from Type 1 to Type 2, with an intrinsically flat (hard) power law continuum indicated in the other two. The presence of both X-ray absorption and broad optical emission lines with the usual strength suggests either a small (nuclear) absorber or a favored viewing angle so as to cover the X-ray source but not the broad emission line region (BELR). A soft excess is detected in all three Type 1 sources. We speculate that this soft X-ray emission may arise in an extended region of ionized gas, perhaps linked with the polarized (scattered) light which is a feature of these sources. The spectral complexity revealed by XMM emphasizes the limitations of the low S/N Chandra data. Overall, the new XMM results strengthen our conclusions (Wilkes et al. 2002) that the observed X-ray continua of red AGN are unusually hard at energies greater than 2 keV. Whether due to substantial line-of-sight absorption or to an intrinsically hard or reflection-dominated spectrum, these 'red' AGN have an observed spectral form consistent with contributing significantly to the missing had absorbed population of the Cosmic X-ray Background (CXRB). When absorption and or reflection is taken into account, all these AGN have power law slopes typical of broad-line (Type 1) AGN (Gamma approximately 1.9). This appears to resolve the spectral paradox which for so long has existed between the CXRB and the AGN thought to be the dominant contributors. It also suggests two scenarios whereby Type 1 AGN/QSOs may be responsible for a significant fraction of the CXRB at energies above 2 keV: 1) X-ray absorbed AGN/QSOs with visible broad emission lines; 2) AGN/QSOs with complex spectra whose hardness greater than 2 keV is not

  3. A computationally optimized broadly reactive H5 hemagglutinin vaccine provides protection against homologous and heterologous H5N1 highly pathogenic avian influenza virus infection in chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Since its emergence in 1996 in China, H5N1 highly pathogenic avian influenza (HPAI) virus has continuously evolved into different genetic clades that have created challenges to maintaining antigenically relevant H5N1 vaccine seeds. Therefore, a universal (multi-hemagglutinin [HA] subtype) or more c...

  4. Brush-like polycarbonates containing dopamine, cations, and PEG providing a broad-spectrum, antibacterial, and antifouling surface via one-step coating.

    PubMed

    Yang, Chuan; Ding, Xin; Ono, Robert J; Lee, Haeshin; Hsu, Li Yang; Tong, Yen Wah; Hedrick, James; Yang, Yi Yan

    2014-11-19

    An antibacterial and antifouling surface is obtained by simple one-step immersion of a catheter surface with brush-like polycarbonates containing pendent adhesive dopamine, antifouling polyethylene glycol (PEG), and antibacterial cations. This coating demonstrates excellent antibacterial and antifouling activities against both Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria, proteins, and platelets, good stability under simulated blood-flow conditions, and no toxicity.

  5. Genome Sequence of the Versatile Fish Pathogen Edwardsiella tarda Provides Insights into its Adaptation to Broad Host Ranges and Intracellular Niches

    PubMed Central

    Xiao, Jingfan; Wu, Haizhen; Wang, Xin; Lv, Yuanzhi; Xu, Lili; Zheng, Huajun; Wang, Shengyue; Zhao, Guoping; Liu, Qin; Zhang, Yuanxing

    2009-01-01

    Background Edwardsiella tarda is the etiologic agent of edwardsiellosis, a devastating fish disease prevailing in worldwide aquaculture industries. Here we describe the complete genome of E. tarda, EIB202, a highly virulent and multi-drug resistant isolate in China. Methodology/Principal Findings E. tarda EIB202 possesses a single chromosome of 3,760,463 base pairs containing 3,486 predicted protein coding sequences, 8 ribosomal rRNA operons, and 95 tRNA genes, and a 43,703 bp conjugative plasmid harboring multi-drug resistant determinants and encoding type IV A secretion system components. We identified a full spectrum of genetic properties related to its genome plasticity such as repeated sequences, insertion sequences, phage-like proteins, integrases, recombinases and genomic islands. In addition, analysis also indicated that a substantial proportion of the E. tarda genome might be devoted to the growth and survival under diverse conditions including intracellular niches, with a large number of aerobic or anaerobic respiration-associated proteins, signal transduction proteins as well as proteins involved in various stress adaptations. A pool of genes for secretion systems, pili formation, nonfimbrial adhesions, invasions and hemagglutinins, chondroitinases, hemolysins, iron scavenging systems as well as the incomplete flagellar biogenesis might feature its surface structures and pathogenesis in a fish body. Conclusion/Significance Genomic analysis of the bacterium offered insights into the phylogeny, metabolism, drug-resistance, stress adaptation, and virulence characteristics of this versatile pathogen, which constitutes an important first step in understanding the pathogenesis of E. tarda to facilitate construction of a practical effective vaccine used for combating fish edwardsiellosis. PMID:19865481

  6. REVERBERATION AND PHOTOIONIZATION ESTIMATES OF THE BROAD-LINE REGION RADIUS IN LOW-z QUASARS

    SciTech Connect

    Negrete, C. Alenka; Dultzin, Deborah; Marziani, Paola; Sulentic, Jack W. E-mail: deborah@astro.unam.mx E-mail: sulentic@iaa.es

    2013-07-01

    Black hole mass estimation in quasars, especially at high redshift, involves the use of single-epoch spectra with signal-to-noise ratio and resolution that permit accurate measurement of the width of a broad line assumed to be a reliable virial estimator. Coupled with an estimate of the radius of the broad-line region (BLR) this yields the black hole mass M{sub BH}. The radius of the BLR may be inferred from an extrapolation of the correlation between source luminosity and reverberation-derived r{sub BLR} measures (the so-called Kaspi relation involving about 60 low-z sources). We are exploring a different method for estimating r{sub BLR} directly from inferred physical conditions in the BLR of each source. We report here on a comparison of r{sub BLR} estimates that come from our method and from reverberation mapping. Our ''photoionization'' method employs diagnostic line intensity ratios in the rest-frame range 1400-2000 A (Al III {lambda}1860/Si III] {lambda}1892, C IV {lambda}1549/Al III {lambda}1860) that enable derivation of the product of density and ionization parameter with the BLR distance derived from the definition of the ionization parameter. We find good agreement between our estimates of the density, ionization parameter, and r{sub BLR} and those from reverberation mapping. We suggest empirical corrections to improve the agreement between individual photoionization-derived r{sub BLR} values and those obtained from reverberation mapping. The results in this paper can be exploited to estimate M{sub BH} for large samples of high-z quasars using an appropriate virial broadening estimator. We show that the width of the UV intermediate emission lines are consistent with the width of H{beta}, thereby providing a reliable virial broadening estimator that can be measured in large samples of high-z quasars.

  7. Childhood Psychosocial Stressors and Adult Onset Arthritis: Broad Spectrum Risk Factors and Allostatic Load

    PubMed Central

    Von Korff, Michael; Alonso, Jordi; Ormel, Johan; Angermeyer, Matthais; Bruffaerts, Ronny; Fleiz, Clara; de Girolamo, Giovanni; Kessler, Ronald C.; Kovess-Masfety, Viviane; Posada-Villa, José; Scott, Kate M.; Uda, Hidenori

    2009-01-01

    Neural, endocrine and immune stress mediators are hypothesized to increase risks of diverse chronic diseases, including arthritis. Retrospective data from the World Mental Health Surveys (N=18,309) were employed to assess whether adult onset of arthritis was associated with childhood adversities and early onset psychological disorder. Cox proportional hazard models assessed the association of number of childhood adversities and the presence of early onset psychological disorder with arthritis age of onset. Controlling for age, sex and early onset mental disorder, relative to persons with no childhood adversities, persons with two adversities had increased risk of adult onset arthritis (Hazard ratio=1.27, 95% CI= 1.08, 1.50), while persons with three or more adversities had higher risk (HR=1.44, CI=1.24,1.67). Early onset depressive and/or anxiety disorder was associated with increased risk of adult-onset arthritis after controlling for childhood adversities (HR=1.43, CI=1.28, 1.61). Since psychosocial stressors may be broad spectrum risk factors that increase risks of diverse chronic conditions in later life (e.g., arthritis, heart disease, diabetes, asthma, chronic pain), prospective studies of childhood psychosocial stressors may be most productive if multiple disease outcomes are assessed in the same study. Results from this study provide methodological guidance for future prospective studies of the relationship between childhood psychosocial stressors and subsequent risk of adult onset arthritis. PERSPECTIVE Retrospective reports of early onset mood-anxiety disorder and multiple childhood adversities were independently associated with increased risk of adult onset arthritis. Carrying out prospective studies of these relationships entails significant challenges. Since childhood psychosocial stressors may be broad spectrum risk factors for diverse chronic conditions, multiple disease outcomes should be assessed in prospective studies assessing health consequences

  8. Reducing Insecticide Use in Broad-Acre Grains Production: An Australian Study

    PubMed Central

    Macfadyen, Sarina; Hardie, Darryl C.; Fagan, Laura; Stefanova, Katia; Perry, Kym D.; DeGraaf, Helen E.; Holloway, Joanne; Spafford, Helen; Umina, Paul A.

    2014-01-01

    Prophylactic use of broad-spectrum insecticides is a common feature of broad-acre grains production systems around the world. Efforts to reduce pesticide use in these systems have the potential to deliver environmental benefits to large areas of agricultural land. However, research and extension initiatives aimed at decoupling pest management decisions from the simple act of applying a cheap insecticide have languished. This places farmers in a vulnerable position of high reliance on a few products that may lose their efficacy due to pests developing resistance, or be lost from use due to regulatory changes. The first step towards developing Integrated Pest Management (IPM) strategies involves an increased efficiency of pesticide inputs. Especially challenging is an understanding of when and where an insecticide application can be withheld without risking yield loss. Here, we quantify the effect of different pest management strategies on the abundance of pest and beneficial arthropods, crop damage and yield, across five sites that span the diversity of contexts in which grains crops are grown in southern Australia. Our results show that while greater insecticide use did reduce the abundance of many pests, this was not coupled with higher yields. Feeding damage by arthropod pests was seen in plots with lower insecticide use but this did not translate into yield losses. For canola, we found that plots that used insecticide seed treatments were most likely to deliver a yield benefit; however other insecticides appear to be unnecessary and economically costly. When considering wheat, none of the insecticide inputs provided an economically justifiable yield gain. These results indicate that there are opportunities for Australian grain growers to reduce insecticide inputs without risking yield loss in some seasons. We see this as the critical first step towards developing IPM practices that will be widely adopted across intensive production systems. PMID:24586535

  9. X-Ray Absorbed, Broad-Lined, Red AGN and the Cosmic X-ray Background

    NASA Technical Reports Server (NTRS)

    Schmidt, Gary D.

    2005-01-01

    This award represents the second phase of an X-ray study of QSOs that are heavily obscured in the optical/near-IR. An earlier survey revealed that these active galactic nuclei (AGN) are also typically strongly absorbed at high photon energies, but the enhanced sensitivity of XMM-Newton provided for the first time the opportunity to measure the spectral indices of individual sources and to test the possibility that obscured AGN are responsible for a substantial portion of the cosmic X-ray background (CXRB). The new observations confirm and greatly extend the earlier results. Substantial intervening absorbing material is detected for 3 of the sources, and 2 additional targets show hard power-law continua. In addition, soft X-ray excesses are detected in 3 of sources, indicating the presence of extended regions of ionized gas. This component is-particularly well-defined in the Type 1 source 2MASS2344+1221, allowing analysis and modeling at a level of detail unusual for such distant sources. An important finding that parallels conclusions from optical polarimetry is the lack of dependence of absorption on optical spectral class (Type 1 or 2). The combination of strong polarization and X-ray absorption in sources that show strong, broad emission lines indicates either a very small (nuclear) absorber or a favored viewing angle which allows the X-ray source to be covered but the surrounding broad emission-line region to be largely exposed. The observed spectral also indicate that obscured AGN of both Type 1 and 2 contribute significantly to the CXRB at higher X-ray energies.

  10. Characterization of FGFR1 Locus in sqNSCLC Reveals a Broad and Heterogeneous Amplicon

    PubMed Central

    Rooney, Claire; Geh, Catherine; Williams, Victoria; Heuckmann, Johannes M.; Menon, Roopika; Schneider, Petra; Al-Kadhimi, Katherine; Dymond, Michael; Smith, Neil R.; Baker, Dawn; French, Tim; Smith, Paul D.; Harrington, Elizabeth A.; Barrett, J. Carl; Kilgour, Elaine

    2016-01-01

    FGFR1 amplification occurs in ~20% of sqNSCLC and trials with FGFR inhibitors have selected FGFR1 amplified patients by FISH. Lung cancer cell lines were profiled for sensitivity to AZD4547, a potent, selective inhibitor of FGFRs 1–3. Sensitivity to FGFR inhibition was associated with but not wholly predicted by increased FGFR1 gene copy number. Additional biomarker assays evaluating expression of FGFRs and correlation between amplification and expression in clinical tissues are therefore warranted. We validated nanoString for mRNA expression analysis of 194 genes, including FGFRs, from clinical tumour tissue. In a panel of sqNSCLC tumours 14.4% (13/90) were FGFR1 amplified by FISH. Although mean FGFR1 expression was significantly higher in amplified samples, there was significant overlap in the range of expression levels between the amplified and non-amplified cohorts with several non-amplified samples expressing FGFR1 to levels equivalent to amplified samples. Statistical analysis revealed increased expression of FGFR1 neighboring genes on the 8p12 amplicon (BAG4, LSM1 and WHSC1L1) in FGFR1 amplified tumours, suggesting a broad rather than focal amplicon and raises the potential for codependencies. High resolution aCGH analysis of pre-clinical and clinical samples supported the presence of a broad and heterogeneous amplicon around the FGFR1 locus. In conclusion, the range of FGFR1 expression levels in both FGFR1 amplified and non-amplified NSCLC tissues, together with the breadth and intra-patient heterogeneity of the 8p amplicon highlights the need for gene expression analysis of clinical samples to inform the understanding of determinants of response to FGFR inhibitors. In this respect the nanoString platform provides an attractive option for RNA analysis of FFPE clinical samples. PMID:26905262

  11. Characterization of FGFR1 Locus in sqNSCLC Reveals a Broad and Heterogeneous Amplicon.

    PubMed

    Rooney, Claire; Geh, Catherine; Williams, Victoria; Heuckmann, Johannes M; Menon, Roopika; Schneider, Petra; Al-Kadhimi, Katherine; Dymond, Michael; Smith, Neil R; Baker, Dawn; French, Tim; Smith, Paul D; Harrington, Elizabeth A; Barrett, J Carl; Kilgour, Elaine

    2016-01-01

    FGFR1 amplification occurs in ~20% of sqNSCLC and trials with FGFR inhibitors have selected FGFR1 amplified patients by FISH. Lung cancer cell lines were profiled for sensitivity to AZD4547, a potent, selective inhibitor of FGFRs 1-3. Sensitivity to FGFR inhibition was associated with but not wholly predicted by increased FGFR1 gene copy number. Additional biomarker assays evaluating expression of FGFRs and correlation between amplification and expression in clinical tissues are therefore warranted. We validated nanoString for mRNA expression analysis of 194 genes, including FGFRs, from clinical tumour tissue. In a panel of sqNSCLC tumours 14.4% (13/90) were FGFR1 amplified by FISH. Although mean FGFR1 expression was significantly higher in amplified samples, there was significant overlap in the range of expression levels between the amplified and non-amplified cohorts with several non-amplified samples expressing FGFR1 to levels equivalent to amplified samples. Statistical analysis revealed increased expression of FGFR1 neighboring genes on the 8p12 amplicon (BAG4, LSM1 and WHSC1L1) in FGFR1 amplified tumours, suggesting a broad rather than focal amplicon and raises the potential for codependencies. High resolution aCGH analysis of pre-clinical and clinical samples supported the presence of a broad and heterogeneous amplicon around the FGFR1 locus. In conclusion, the range of FGFR1 expression levels in both FGFR1 amplified and non-amplified NSCLC tissues, together with the breadth and intra-patient heterogeneity of the 8p amplicon highlights the need for gene expression analysis of clinical samples to inform the understanding of determinants of response to FGFR inhibitors. In this respect the nanoString platform provides an attractive option for RNA analysis of FFPE clinical samples. PMID:26905262

  12. Access and success with less: improving productivity in broad-access postsecondary institutions.

    PubMed

    Jenkins, Davis; Rodríguez, Olga

    2013-01-01

    Achieving national goals for increased college completion in a time of scarce resources will require the postsecondary institutions that enroll the majority of undergraduates--community colleges and less-selective public universities--to graduate more students at a lower cost. Davis Jenkins and Olga Rodriguez examine research on how these "broad-access" institutions can do so without sacrificing access or quality. Research indicates that the strategies broad-access institutions have relied on in the past to cut costs--using part-time instructors and increasing student-faculty ratios--may in fact reduce productivity and efficiency. The limited evidence available suggests that some of the most popular strategies for improving student success are not cost-effective. New strategies to cut costs and improve college success are therefore imperative. Some believe that redesigning courses to make use of instructional technologies will lead to better outcomes at lower cost, although the evidence is mixed. Recently, a growing number of institutions are going beyond redesigning courses and instead changing the way they organize programs and supports along the student's "pathway" through college. These efforts are promising, but their effects on cost per completion are not yet certain. Meager funding has so far hampered efforts by policy makers to fund colleges based on outcomes rather than how many students they enroll, but some states are beginning to increase the share of appropriations tied to outcomes. Jenkins and Rodriquez argue that as policy makers push colleges to lower the cost per graduate, they must avoid providing incentives to lower academic standards. They encourage policy makers to capitalize on recent research on the economic value of postsecondary education to measure quality, and urge colleges and universities to redouble efforts to define learning outcomes and measure student mastery. PMID:25522651

  13. Reducing insecticide use in broad-acre grains production: an Australian study.

    PubMed

    Macfadyen, Sarina; Hardie, Darryl C; Fagan, Laura; Stefanova, Katia; Perry, Kym D; DeGraaf, Helen E; Holloway, Joanne; Spafford, Helen; Umina, Paul A

    2014-01-01

    Prophylactic use of broad-spectrum insecticides is a common feature of broad-acre grains production systems around the world. Efforts to reduce pesticide use in these systems have the potential to deliver environmental benefits to large areas of agricultural land. However, research and extension initiatives aimed at decoupling pest management decisions from the simple act of applying a cheap insecticide have languished. This places farmers in a vulnerable position of high reliance on a few products that may lose their efficacy due to pests developing resistance, or be lost from use due to regulatory changes. The first step towards developing Integrated Pest Management (IPM) strategies involves an increased efficiency of pesticide inputs. Especially challenging is an understanding of when and where an insecticide application can be withheld without risking yield loss. Here, we quantify the effect of different pest management strategies on the abundance of pest and beneficial arthropods, crop damage and yield, across five sites that span the diversity of contexts in which grains crops are grown in southern Australia. Our results show that while greater insecticide use did reduce the abundance of many pests, this was not coupled with higher yields. Feeding damage by arthropod pests was seen in plots with lower insecticide use but this did not translate into yield losses. For canola, we found that plots that used insecticide seed treatments were most likely to deliver a yield benefit; however other insecticides appear to be unnecessary and economically costly. When considering wheat, none of the insecticide inputs provided an economically justifiable yield gain. These results indicate that there are opportunities for Australian grain growers to reduce insecticide inputs without risking yield loss in some seasons. We see this as the critical first step towards developing IPM practices that will be widely adopted across intensive production systems.

  14. LDRD final report on high power broadly tunable Mid-IR quantum cascade lasers for improved chemical species detection.

    SciTech Connect

    Wanke, Michael Clement; Hudgens, James J.; Fuller, Charles T.; Samora, Sally; Klem, John Frederick; Young, Erik W.

    2006-01-01

    The goal of our project was to examine a novel quantum cascade laser design that should inherently increase the output power of the laser while simultaneously providing a broad tuning range. Such a laser source enables multiple chemical species identification with a single laser and/or very broad frequency coverage with a small number of different lasers, thus reducing the size and cost of laser based chemical detection systems. In our design concept, the discrete states in quantum cascade lasers are replaced by minibands made of multiple closely spaced electron levels. To facilitate the arduous task of designing miniband-to-miniband quantum cascade lasers, we developed a program that works in conjunction with our existing modeling software to completely automate the design process. Laser designs were grown, characterized, and iterated. The details of the automated design program and the measurement results are summarized in this report.

  15. Providing global WLCG transfer monitoring

    NASA Astrophysics Data System (ADS)

    Andreeva, J.; Dieguez Arias, D.; Campana, S.; Flix, J.; Keeble, O.; Magini, N.; Molnar, Z.; Oleynik, D.; Petrosyan, A.; Ro, G.; Saiz, P.; Salichos, M.; Tuckett, D.; Uzhinsky, A.; Wildish, T.

    2012-12-01

    The WLCG[1] Transfers Dashboard is a monitoring system which aims to provide a global view of WLCG data transfers and to reduce redundancy in monitoring tasks performed by the LHC experiments. The system is designed to work transparently across LHC experiments and across the various technologies used for data transfer. Currently each LHC experiment monitors data transfers via experiment-specific systems but the overall cross-experiment picture is missing. Even for data transfers handled by FTS, which is used by 3 LHC experiments, monitoring tasks such as aggregation of FTS transfer statistics or estimation of transfer latencies are performed by every experiment separately. These tasks could be performed once, centrally, and then served to all experiments via a well-defined set of APIs. In the design and development of the new system, experience accumulated by the LHC experiments in the data management monitoring area is taken into account and a considerable part of the code of the ATLAS DDM Dashboard is being re-used. The paper describes the architecture of the Global Transfer monitoring system, the implementation of its components and the first prototype.

  16. Environmental standards provide competitive advantage

    SciTech Connect

    Chynoweth, E.; Kirshner, E.

    1993-04-28

    Quality organizations are breaking new ground with the development of international standards for environmental management. These promise to provide the platform for chemical companies wanting to establish their environmental credibility with a global audience. [open quotes]It will be similar to auditing our customers to ISO 9000[close quote], says the environmental manager for a European chemical firm. [open quote]We will only want to deal with people who have got their environmental act together. And we'll be in a better competitive positions[close quote]. The International Organization for Standardization (ISO;Geneva) has set up a taskforce to develop an environmental management standard, which is expected to be completed by the mid-1990s. Observers think the ISO standard will draw heavily on the British Standard Institute's (BSI;London) environmental management standard, BS7750, which will likely be the first system adopted in the world. Published last year, BS7750 has been extensively piloted in the UK (CW, Sept. 30, 1992, p. 62) and is now set to be revised before being offically adopted by BSI. The UK's Chemical Industries Association (CIA;London) is anxious to prevent a proliferation of standards, and its report on BS7750 pilot projects calls for an approach integrating quality, environment, and health and safety. But standard setters, including ISO, appear to be moving in the opposite direction. In the US, the American national Standards Institute (ANSI;Washington) has started work on an environmental management standard.

  17. Grounding meaning in experience: A broad perspective on embodied language.

    PubMed

    Buccino, Giovanni; Colagè, Ivan; Gobbi, Nicola; Bonaccorso, Giorgio

    2016-10-01

    This work reviews key behavioural, neurophysiological and neuroimaging data on the neural substrates for processing the meaning of linguistic material, and tries to articulate the picture emerging from those findings with the notion of meaning coming from specific approaches in philosophy of language (the "internalist" view) and linguistics (words point at experiential clusters). The reviewed findings provide evidence in favour of a causal role of brain neural structures responsible for sensory, motor and even emotional experiences in attributing meaning to words expressing those experiences and, consequently, lend substantial support to an embodied and "internalist" conception of linguistic meaning. Key evidence concern verbs, nouns and adjectives with a concrete content, but the challenge that abstract domains pose to the embodied approach to language is also discussed. This work finally suggests that the most fundamental role of embodiment might be that of establishing commonalities among individual experiences of different members of a linguistic community, and that those experiences ground shared linguistic meanings. PMID:27477443

  18. Grounding meaning in experience: A broad perspective on embodied language.

    PubMed

    Buccino, Giovanni; Colagè, Ivan; Gobbi, Nicola; Bonaccorso, Giorgio

    2016-10-01

    This work reviews key behavioural, neurophysiological and neuroimaging data on the neural substrates for processing the meaning of linguistic material, and tries to articulate the picture emerging from those findings with the notion of meaning coming from specific approaches in philosophy of language (the "internalist" view) and linguistics (words point at experiential clusters). The reviewed findings provide evidence in favour of a causal role of brain neural structures responsible for sensory, motor and even emotional experiences in attributing meaning to words expressing those experiences and, consequently, lend substantial support to an embodied and "internalist" conception of linguistic meaning. Key evidence concern verbs, nouns and adjectives with a concrete content, but the challenge that abstract domains pose to the embodied approach to language is also discussed. This work finally suggests that the most fundamental role of embodiment might be that of establishing commonalities among individual experiences of different members of a linguistic community, and that those experiences ground shared linguistic meanings.

  19. Medicinal plants, human health and biodiversity: a broad review.

    PubMed

    Sen, Tuhinadri; Samanta, Samir Kumar

    2015-01-01

    Biodiversity contributes significantly towards human livelihood and development and thus plays a predominant role in the well being of the global population. According to WHO reports, around 80 % of the global population still relies on botanical drugs; today several medicines owe their origin to medicinal plants. Natural substances have long served as sources of therapeutic drugs, where drugs including digitalis (from foxglove), ergotamine (from contaminated rye), quinine (from cinchona), and salicylates (willow bark) can be cited as some classical examples.Drug discovery from natural sources involve a multifaceted approach combining botanical, phytochemical, biological, and molecular techniques. Accordingly, medicinal-plant-based drug discovery still remains an important area, hitherto unexplored, where a systematic search may definitely provide important leads against various pharmacological targets.Ironically, the potential benefits of plant-based medicines have led to unscientific exploitation of the natural resources, a phenomenon that is being observed globally. This decline in biodiversity is largely the result of the rise in the global population, rapid and sometimes unplanned industrialization, indiscriminate deforestation, overexploitation of natural resources, pollution, and finally global climate change.Therefore, it is of utmost importance that plant biodiversity be preserved, to provide future structural diversity and lead compounds for the sustainable development of human civilization at large. This becomes even more important for developing nations, where well-planned bioprospecting coupled with nondestructive commercialization could help in the conservation of biodiversity, ultimately benefiting mankind in the long run.Based on these findings, the present review is an attempt to update our knowledge about the diverse therapeutic application of different plant products against various pharmacological targets including cancer, human brain

  20. Modelling broad-band poroelastic propagation using an asymptotic approach

    NASA Astrophysics Data System (ADS)

    Vasco, D. W.

    2009-10-01

    An asymptotic method, valid in the presence of smoothly varying heterogeneity, is used to derive a semi-analytic solution to the equations for fluid and solid displacements in a poroelastic medium. The solution is defined along trajectories through the porous medium model, in the manner of ray theory. The lowest order expression in the asymptotic expansion provides an eikonal equation for the phase. There are three modes of propagation, two modes of longitudinal displacement and a single mode of transverse displacement. The two longitudinal modes define the Biot fast and slow waves which have very different propagation characteristics. In the limit of low frequency, the Biot slow wave propagates as a diffusive disturbance, in essence a transient pressure pulse. Conversely, at low frequencies the Biot fast wave and the transverse mode are modified elastic waves. At intermediate frequencies the wave characteristics of the longitudinal modes are mixed. A comparison of the asymptotic solution with analytic and numerical solutions shows reasonably good agreement for both homogeneous and heterogeneous earth models.