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Sample records for flaviviruses correlating variance

  1. Flaviviruses.

    PubMed

    Best, Sonja M

    2016-12-19

    What do Zika, Dengue and West Nile viruses have in common? All are members of a family of viruses called the Flaviviruses. Here, Sonja Best lays out the essentials of this group of significant human pathogens. Published by Elsevier Ltd.

  2. Remotely sensed correlates of phylogeny: tick-borne flaviviruses.

    PubMed

    Randolph, Sarah E; Rogers, David J

    2002-01-01

    Vector-borne pathogen systems are limited by climate, principally through its impact on the distribution, abundance and population dynamics of the vectors and on the interaction of vectors with their hosts. This leads to the prediction that climate has been a significant factor in the evolution of these pathogens and, by implication, will be important in future events on both evolutionary and ecological time-scales. New phylogenetic trees of organisms, that describe their evolutionary history, are routinely available, but explanations for the driving force and constraints that have shaped the evolutionary origin of new pathogen strains are rare. Under the force of environmental pressures that change in space and time, which pathogens are likely to emerge in new places and where will this be? To answer such questions, data from molecular biology can be linked with data from satellites that allow us to characterize environmental conditions on a global scale. Broad-scale patterns in the satellite imagery are consistent with the pattern of new tick-borne flaviviruses having evolved sequentially in a cline across the world. So far, the distribution of three tick-borne flaviviruses from western Europe have been captured simultaneously by the same 10 satellite-derived seasonal climatic variables. Once this procedure is extended to the remaining viruses in this clade, we shall test for significant matches between their phylogenetic tree and an independent tree derived from quantitative descriptions of the viruses' 'eco-space'. This will indicate the extent of key ecological drivers for specific evolutionary events, whose biological basis can then be explored in detail.

  3. Correlative scanning-transmission electron microscopy reveals that a chimeric flavivirus is released as individual particles in secretory vesicles.

    PubMed

    Burlaud-Gaillard, Julien; Sellin, Caroline; Georgeault, Sonia; Uzbekov, Rustem; Lebos, Claude; Guillaume, Jean-Marc; Roingeard, Philippe

    2014-01-01

    The intracellular morphogenesis of flaviviruses has been well described, but flavivirus release from the host cell remains poorly documented. We took advantage of the optimized production of an attenuated chimeric yellow fever/dengue virus for vaccine purposes to study this phenomenon by microscopic approaches. Scanning electron microscopy (SEM) showed the release of numerous viral particles at the cell surface through a short-lived process. For transmission electron microscopy (TEM) studies of the intracellular ultrastructure of the small number of cells releasing viral particles at a given time, we developed a new correlative microscopy method: CSEMTEM (for correlative scanning electron microscopy - transmission electron microscopy). CSEMTEM analysis suggested that chimeric flavivirus particles were released as individual particles, in small exocytosis vesicles, via a regulated secretory pathway. Our morphological findings provide new insight into interactions between flaviviruses and cells and demonstrate that CSEMTEM is a useful new method, complementary to SEM observations of biological events by intracellular TEM investigations.

  4. Correlative Scanning-Transmission Electron Microscopy Reveals that a Chimeric Flavivirus Is Released as Individual Particles in Secretory Vesicles

    PubMed Central

    Burlaud-Gaillard, Julien; Sellin, Caroline; Georgeault, Sonia; Uzbekov, Rustem; Lebos, Claude; Guillaume, Jean-Marc; Roingeard, Philippe

    2014-01-01

    The intracellular morphogenesis of flaviviruses has been well described, but flavivirus release from the host cell remains poorly documented. We took advantage of the optimized production of an attenuated chimeric yellow fever/dengue virus for vaccine purposes to study this phenomenon by microscopic approaches. Scanning electron microscopy (SEM) showed the release of numerous viral particles at the cell surface through a short-lived process. For transmission electron microscopy (TEM) studies of the intracellular ultrastructure of the small number of cells releasing viral particles at a given time, we developed a new correlative microscopy method: CSEMTEM (for correlative scanning electron microscopy - transmission electron microscopy). CSEMTEM analysis suggested that chimeric flavivirus particles were released as individual particles, in small exocytosis vesicles, via a regulated secretory pathway. Our morphological findings provide new insight into interactions between flaviviruses and cells and demonstrate that CSEMTEM is a useful new method, complementary to SEM observations of biological events by intracellular TEM investigations. PMID:24681578

  5. Estimating the generalized concordance correlation coefficient through variance components.

    PubMed

    Carrasco, Josep L; Jover, Lluís

    2003-12-01

    The intraclass correlation coefficient (ICC) and the concordance correlation coefficient (CCC) are two of the most popular measures of agreement for variables measured on a continuous scale. Here, we demonstrate that ICC and CCC are the same measure of agreement estimated in two ways: by the variance components procedure and by the moment method. We propose estimating the CCC using variance components of a mixed effects model, instead of the common method of moments. With the variance components approach, the CCC can easily be extended to more than two observers, and adjusted using confounding covariates, by incorporating them in the mixed model. A simulation study is carried out to compare the variance components approach with the moment method. The importance of adjusting by confounding covariates is illustrated with a case example.

  6. The Variance of Intraclass Correlations in Three and Four Level

    ERIC Educational Resources Information Center

    Hedges, Larry V.; Hedberg, Eric C.; Kuyper, Arend M.

    2012-01-01

    Intraclass correlations are used to summarize the variance decomposition in popula- tions with multilevel hierarchical structure. There has recently been considerable interest in estimating intraclass correlations from surveys or designed experiments to provide design parameters for planning future large-scale randomized experiments. The large…

  7. The Variance of Intraclass Correlations in Three and Four Level

    ERIC Educational Resources Information Center

    Hedges, Larry V.; Hedberg, Eric C.; Kuyper, Arend M.

    2012-01-01

    Intraclass correlations are used to summarize the variance decomposition in popula- tions with multilevel hierarchical structure. There has recently been considerable interest in estimating intraclass correlations from surveys or designed experiments to provide design parameters for planning future large-scale randomized experiments. The large…

  8. Genetic Variance in the SES-IQ Correlation.

    ERIC Educational Resources Information Center

    Eckland, Bruce K.

    1979-01-01

    Discusses questions dealing with genetic aspects of the correlation between IQ and socioeconomic status (SES). Questions include: How does assortative mating affect the genetic variance of IQ? Is the relationship between an individual's IQ and adult SES a causal one? And how can IQ research improve schools and schooling? (Author/DB)

  9. Variance Formulae for Correlation Measures of Linkage Disequilibrium.

    PubMed

    Roop, Mary L; Cole, David E C; Hamilton, David C

    2016-01-01

    Linkage disequilibrium (LD) is the non-random association between alleles at different loci and remains important for disease mapping studies in humans. A common measure of LD is the sample correlation between indicator variables for alleles at the 2 loci. Knowledge of LD estimate precision may help inform biomedical decisions based on those estimates. Variance formulae are obtained for correlation measures of LD in 4 scenarios. These scenarios include data in the form of gametic and genotypic counts, with different assumptions used to simplify the analysis. The formulae are expressed as polynomials (or ratios of polynomials) in higher-order disequilibrium coefficients with constants which are functions of the allele frequencies and Hardy-Weinberg disequilibrium coefficients. With genotypic data, the variance is the same as with gametic data when the phase is known and there is random mating. When the phase is unknown, the correlation LD has variance which is twice as large. Symbolic computation proved to be effective in facilitating algebraic derivations which would otherwise have been intractable. © 2017 S. Karger AG, Basel.

  10. On computations of variance, covariance and correlation for interval data

    NASA Astrophysics Data System (ADS)

    Kishida, Masako

    2017-02-01

    In many practical situations, the data on which statistical analysis is to be performed is only known with interval uncertainty. Different combinations of values from the interval data usually lead to different values of variance, covariance, and correlation. Hence, it is desirable to compute the endpoints of possible values of these statistics. This problem is, however, NP-hard in general. This paper shows that the problem of computing the endpoints of possible values of these statistics can be rewritten as the problem of computing skewed structured singular values ν, for which there exist feasible (polynomial-time) algorithms that compute reasonably tight bounds in most practical cases. This allows one to find tight intervals of the aforementioned statistics for interval data.

  11. On the Mean and Variance of the Tetrachoric Correlation Coefficient

    ERIC Educational Resources Information Center

    Brown, Morton B.; Benedetti, Jacqueline K.

    1977-01-01

    Estimates of the mean and standard deviation of the tetrachoric correlation are compared with their expected values in several two by two tables. Significant bias in the mean is found when the minimum cell frequency is less than five. Three formulas for the standard deviation are discussed. (Author/JKS)

  12. Microscopy techniques in flavivirus research.

    PubMed

    Chong, Mun Keat; Chua, Anthony Jin Shun; Tan, Terence Tze Tong; Tan, Suat Hoon; Ng, Mah Lee

    2014-04-01

    The Flavivirus genus is composed of many medically important viruses that cause high morbidity and mortality, which include Dengue and West Nile viruses. Various molecular and biochemical techniques have been developed in the endeavour to study flaviviruses. However, microscopy techniques still have irreplaceable roles in the identification of novel virus pathogens and characterization of morphological changes in virus-infected cells. Fluorescence microscopy contributes greatly in understanding the fundamental viral protein localizations and virus-host protein interactions during infection. Electron microscopy remains the gold standard for visualizing ultra-structural features of virus particles and infected cells. New imaging techniques and combinatory applications are continuously being developed to push the limit of resolution and extract more quantitative data. Currently, correlative live cell imaging and high resolution three-dimensional imaging have already been achieved through the tandem use of optical and electron microscopy in analyzing biological specimens. Microscopy techniques are also used to measure protein binding affinities and determine the mobility pattern of proteins in cells. This chapter will consolidate on the applications of various well-established microscopy techniques in flavivirus research, and discuss how recently developed microscopy techniques can potentially help advance our understanding in these membrane viruses.

  13. The concordance correlation coefficient for repeated measures estimated by variance components.

    PubMed

    Carrasco, Josep L; King, Tonya S; Chinchilli, Vernon M

    2009-01-01

    The concordance correlation coefficient (CCC) is an index that is commonly used to assess the degree of agreement between observers on measuring a continuous characteristic. Here, a CCC for longitudinal repeated measurements is developed through the appropriate specification of the intraclass correlation coefficient from a variance components linear mixed model. A case example and the results of a simulation study are provided.

  14. The Variance of Intraclass Correlations in Three- and Four-Level Models

    ERIC Educational Resources Information Center

    Hedges, Larry V.; Hedberg, E. C.; Kuyper, Arend M.

    2012-01-01

    Intraclass correlations are used to summarize the variance decomposition in populations with multilevel hierarchical structure. There has recently been considerable interest in estimating intraclass correlations from surveys or designed experiments to provide design parameters for planning future large-scale randomized experiments. The large…

  15. The Variance of Intraclass Correlations in Three- and Four-Level Models

    ERIC Educational Resources Information Center

    Hedges, Larry V.; Hedberg, E. C.; Kuyper, Arend M.

    2012-01-01

    Intraclass correlations are used to summarize the variance decomposition in populations with multilevel hierarchical structure. There has recently been considerable interest in estimating intraclass correlations from surveys or designed experiments to provide design parameters for planning future large-scale randomized experiments. The large…

  16. Detection of rheumatoid arthritis by evaluation of normalized variances of fluorescence time correlation functions

    NASA Astrophysics Data System (ADS)

    Dziekan, Thomas; Weissbach, Carmen; Voigt, Jan; Ebert, Bernd; MacDonald, Rainer; Bahner, Malte L.; Mahler, Marianne; Schirner, Michael; Berliner, Michael; Berliner, Birgitt; Osel, Jens; Osel, Ilka

    2011-07-01

    Fluorescence imaging using the dye indocyanine green as a contrast agent was investigated in a prospective clinical study for the detection of rheumatoid arthritis. Normalized variances of correlated time series of fluorescence intensities describing the bolus kinetics of the contrast agent in certain regions of interest were analyzed to differentiate healthy from inflamed finger joints. These values are determined using a robust, parameter-free algorithm. We found that the normalized variance of correlation functions improves the differentiation between healthy joints of volunteers and joints with rheumatoid arthritis of patients by about 10% compared to, e.g., ratios of areas under the curves of raw data.

  17. A new interpretation and validation of variance based importance measures for models with correlated inputs

    NASA Astrophysics Data System (ADS)

    Hao, Wenrui; Lu, Zhenzhou; Li, Luyi

    2013-05-01

    In order to explore the contributions by correlated input variables to the variance of the output, a novel interpretation framework of importance measure indices is proposed for a model with correlated inputs, which includes the indices of the total correlated contribution and the total uncorrelated contribution. The proposed indices accurately describe the connotations of the contributions by the correlated input to the variance of output, and they can be viewed as the complement and correction of the interpretation about the contributions by the correlated inputs presented in "Estimation of global sensitivity indices for models with dependent variables, Computer Physics Communications, 183 (2012) 937-946". Both of them contain the independent contribution by an individual input. Taking the general form of quadratic polynomial as an illustration, the total correlated contribution and the independent contribution by an individual input are derived analytically, from which the components and their origins of both contributions of correlated input can be clarified without any ambiguity. In the special case that no square term is included in the quadratic polynomial model, the total correlated contribution by the input can be further decomposed into the variance contribution related to the correlation of the input with other inputs and the independent contribution by the input itself, and the total uncorrelated contribution can be further decomposed into the independent part by interaction between the input and others and the independent part by the input itself. Numerical examples are employed and their results demonstrate that the derived analytical expressions of the variance-based importance measure are correct, and the clarification of the correlated input contribution to model output by the analytical derivation is very important for expanding the theory and solutions of uncorrelated input to those of the correlated one.

  18. Estimation of the biserial correlation and its sampling variance for use in meta-analysis.

    PubMed

    Jacobs, Perke; Viechtbauer, Wolfgang

    2017-06-01

    Meta-analyses are often used to synthesize the findings of studies examining the correlational relationship between two continuous variables. When only dichotomous measurements are available for one of the two variables, the biserial correlation coefficient can be used to estimate the product-moment correlation between the two underlying continuous variables. Unlike the point-biserial correlation coefficient, biserial correlation coefficients can therefore be integrated with product-moment correlation coefficients in the same meta-analysis. The present article describes the estimation of the biserial correlation coefficient for meta-analytic purposes and reports simulation results comparing different methods for estimating the coefficient's sampling variance. The findings indicate that commonly employed methods yield inconsistent estimates of the sampling variance across a broad range of research situations. In contrast, consistent estimates can be obtained using two methods that appear to be unknown in the meta-analytic literature. A variance-stabilizing transformation for the biserial correlation coefficient is described that allows for the construction of confidence intervals for individual coefficients with close to nominal coverage probabilities in most of the examined conditions. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  19. Variance in population firing rate as a measure of slow time-scale correlation

    PubMed Central

    Snyder, Adam C.; Morais, Michael J.; Smith, Matthew A.

    2013-01-01

    Correlated variability in the spiking responses of pairs of neurons, also known as spike count correlation, is a key indicator of functional connectivity and a critical factor in population coding. Underscoring the importance of correlation as a measure for cognitive neuroscience research is the observation that spike count correlations are not fixed, but are rather modulated by perceptual and cognitive context. Yet while this context fluctuates from moment to moment, correlation must be calculated over multiple trials. This property undermines its utility as a dependent measure for investigations of cognitive processes which fluctuate on a trial-to-trial basis, such as selective attention. A measure of functional connectivity that can be assayed on a moment-to-moment basis is needed to investigate the single-trial dynamics of populations of spiking neurons. Here, we introduce the measure of population variance in normalized firing rate for this goal. We show using mathematical analysis, computer simulations and in vivo data how population variance in normalized firing rate is inversely related to the latent correlation in the population, and how this measure can be used to reliably classify trials from different typical correlation conditions, even when firing rate is held constant. We discuss the potential advantages for using population variance in normalized firing rate as a dependent measure for both basic and applied neuroscience research. PMID:24367326

  20. Estimating the Correlation in Bivariate Normal Data with Known Variances and Small Sample Sizes1

    PubMed Central

    Fosdick, Bailey K.; Raftery, Adrian E.

    2013-01-01

    We consider the problem of estimating the correlation in bivariate normal data when the means and variances are assumed known, with emphasis on the small sample case. We consider eight different estimators, several of them considered here for the first time in the literature. In a simulation study, we found that Bayesian estimators using the uniform and arc-sine priors outperformed several empirical and exact or approximate maximum likelihood estimators in small samples. The arc-sine prior did better for large values of the correlation. For testing whether the correlation is zero, we found that Bayesian hypothesis tests outperformed significance tests based on the empirical and exact or approximate maximum likelihood estimators considered in small samples, but that all tests performed similarly for sample size 50. These results lead us to suggest using the posterior mean with the arc-sine prior to estimate the correlation in small samples when the variances are assumed known. PMID:23378667

  1. Quantum variance: A measure of quantum coherence and quantum correlations for many-body systems

    NASA Astrophysics Data System (ADS)

    Frérot, Irénée; Roscilde, Tommaso

    2016-08-01

    Quantum coherence is a fundamental common trait of quantum phenomena, from the interference of matter waves to quantum degeneracy of identical particles. Despite its importance, estimating and measuring quantum coherence in generic, mixed many-body quantum states remains a formidable challenge, with fundamental implications in areas as broad as quantum condensed matter, quantum information, quantum metrology, and quantum biology. Here, we provide a quantitative definition of the variance of quantum coherent fluctuations (the quantum variance) of any observable on generic quantum states. The quantum variance generalizes the concept of thermal de Broglie wavelength (for the position of a free quantum particle) to the space of eigenvalues of any observable, quantifying the degree of coherent delocalization in that space. The quantum variance is generically measurable and computable as the difference between the static fluctuations and the static susceptibility of the observable; despite its simplicity, it is found to provide a tight lower bound to most widely accepted estimators of "quantumness" of observables (both as a feature as well as a resource), such as the Wigner-Yanase skew information and the quantum Fisher information. When considering bipartite fluctuations in an extended quantum system, the quantum variance expresses genuine quantum correlations among the two parts. In the case of many-body systems, it is found to obey an area law at finite temperature, extending therefore area laws of entanglement and quantum fluctuations of pure states to the mixed-state context. Hence the quantum variance paves the way to the measurement of macroscopic quantum coherence and quantum correlations in most complex quantum systems.

  2. Weighted least-squares phase unwrapping algorithm based on derivative variance correlation map

    NASA Astrophysics Data System (ADS)

    Lu, Yuangang; Wang, Xiangzhao; Zhang, Xuping

    2007-02-01

    Among different phase unwrapping approaches, the weighted least-squares minimization methods are gaining attention. In these algorithms, weighting coefficient is generated from a quality map. The intrinsic drawbacks of existing quality maps constrain the application of these algorithms. They often fail to handle wrapped phase data contains error sources, such as phase discontinuities, noise and undersampling. In order to deal with those intractable wrapped phase data, a new weighted least-squares phase unwrapping algorithm based on derivative variance correlation map is proposed. In the algorithm, derivative variance correlation map, a novel quality map, can truly reflect wrapped phase quality, ensuring a more reliable unwrapped result. The definition of the derivative variance correlation map and the principle of the proposed algorithm are present in detail. The performance of the new algorithm has been tested by use of a simulated spherical surface wrapped data and an experimental interferometric synthetic aperture radar (IFSAR) wrapped data. Computer simulation and experimental results have verified that the proposed algorithm can work effectively even when a wrapped phase map contains intractable error sources.

  3. Flavivirus RNA in phlebotomine sandflies.

    PubMed

    Moureau, Gregory; Ninove, Laetitia; Izri, Arezki; Cook, Shelley; De Lamballerie, Xavier; Charrel, Remi N

    2010-03-01

    Sandfly-transmitted phleboviruses, such as Toscana, sandfly fever Sicilian, and sandfly fever Naples, can cause human disease and circulate at high rates in Mediterranean countries. Previous studies have also established that viruses other than phleboviruses may be detected in and isolated from sand flies. The recent detection and isolation (in a large variety of mosquito species) of insect-only flaviviruses related to cell fusing agent virus has indicated that the latter is not an evolutionary remnant but the first discovered member of a group of viruses, larger than initially assumed, that has high genetic heterogeneity. Insect-only flaviviruses have been detected in and/or isolated from various species of mosquitoes, but nevertheless only from mosquitoes to date; other dipterans have not been screened for the presence of insect-only flaviviruses. The possible presence of flaviviruses, including insect-only flaviviruses, was investigated in sand flies collected around the Mediterranean during a trapping campaign already underway. Accordingly, a total of 1508 sand flies trapped in France and Algeria, between August 2006 and July 2007, were tested for the presence of flaviviruses using a PCR assay previously demonstrated experimentally to amplify all recognized members of the genus Flavivirus, including insect-only flaviviruses. Two of 67 pools consisting of male Phlebotomus perniciosus trapped in Algeria were positive. The two resulting sequences formed a monophyletic group and appeared more closely related to insect-only flaviviruses associated with Culex mosquitoes than with Aedes mosquitoes, and more closely related to insect-only flaviviruses than to arthropod-borne or to no-known-vector vertebrate flaviviruses. This is the first description of insect-only flaviviruses in dipterans distinct from those belonging to the family Culicidae (including Aedes, Culex, Mansonia, Culiseta, and Anopheles mosquito genera), namely sand flies within the family Psychodidae

  4. The large-scale correlations of multicell densities and profiles: implications for cosmic variance estimates

    NASA Astrophysics Data System (ADS)

    Codis, Sandrine; Bernardeau, Francis; Pichon, Christophe

    2016-08-01

    In order to quantify the error budget in the measured probability distribution functions of cell densities, the two-point statistics of cosmic densities in concentric spheres is investigated. Bias functions are introduced as the ratio of their two-point correlation function to the two-point correlation of the underlying dark matter distribution. They describe how cell densities are spatially correlated. They are computed here via the so-called large deviation principle in the quasi-linear regime. Their large-separation limit is presented and successfully compared to simulations for density and density slopes: this regime is shown to be rapidly reached allowing to get sub-percent precision for a wide range of densities and variances. The corresponding asymptotic limit provides an estimate of the cosmic variance of standard concentric cell statistics applied to finite surveys. More generally, no assumption on the separation is required for some specific moments of the two-point statistics, for instance when predicting the generating function of cumulants containing any powers of concentric densities in one location and one power of density at some arbitrary distance from the rest. This exact `one external leg' cumulant generating function is used in particular to probe the rate of convergence of the large-separation approximation.

  5. Concordance correlation coefficients estimated by generalized estimating equations and variance components for longitudinal repeated measurements.

    PubMed

    Tsai, Miao-Yu

    2017-04-15

    The concordance correlation coefficient (CCC) is a commonly accepted measure of agreement between two observers for continuous responses. This paper proposes a generalized estimating equations (GEE) approach allowing dependency between repeated measurements over time to assess intra-agreement for each observer and inter- and total agreement among multiple observers simultaneously. Furthermore, the indices of intra-, inter-, and total agreement through variance components (VC) from an extended three-way linear mixed model (LMM) are also developed with consideration of the correlation structure of longitudinal repeated measurements. Simulation studies are conducted to compare the performance of the GEE and VC approaches for repeated measurements from longitudinal data. An application of optometric conformity study is used for illustration. In conclusion, the GEE approach allowing flexibility in model assumptions and correlation structures of repeated measurements gives satisfactory results with small mean square errors and nominal 95% coverage rates for large data sets, and when the assumption of the relationship between variances and covariances for the extended three-way LMM holds, the VC approach performs outstandingly well for all sample sizes. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  6. Variance of speed of sound and correlation with acoustic impedance in canine corneas.

    PubMed

    Tang, Junhua; Liu, Jun

    2011-10-01

    The clinical standard for measuring corneal thickness is ultrasound pachymetry that assumes a constant speed of sound. The purpose of this study was to examine the variance of speed of sound and its relationship with acoustic impedance in healthy eyes of canines with a large age span. Corneal speed of sound and acoustic impedance were measured in 34 canine eyes at room temperature (21 ± 1°C). The mean speed of sound was 1577 ± 10 m/s ranging from 1553 to 1594 m/s. There was a strong correlation between speed of sound and acoustic impedance (R = 0.84, p < 0.001). Corneal speed of sound had a small variance in healthy canines over 1-year-old, but was significantly lower in younger canines suggesting an age effect. The strong correlation between corneal speed of sound and acoustic impedance may offer a potential means to noninvasively detect abnormal speed of sound for more accurate corneal thickness estimation. Copyright © 2011 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

  7. Minimum L0-Norm Two-Dimensional Phase Unwrapping Algorithm Based on the Derivative Variance Correlation Map

    NASA Astrophysics Data System (ADS)

    Lu, Y. G.; Zhang, X. P.

    2006-10-01

    A new minimum L0-norm two-dimensional phase unwrapping algorithm, based on the derivative variance correlation map, is proposed. In the algorithm, the novel derivative variance correlation map can truly reflect wrapped phase quality, ensuring a more reliable unwrapped result. After the definition of the derivative variance correlation map and the principle of the proposed algorithm are present, the performance of the new algorithm has been tested by use of wrapped phase data from an interferometric synthetic aperture radar experiment. Experimental result has verified that the proposed algorithm can cope well with the intractable noisy wrapped data.

  8. Disentangling Stability, Variability and Adaptability in Human Performance: Focus on the Interplay between Local Variance and Serial Correlation

    ERIC Educational Resources Information Center

    Torre, Kjerstin; Balasubramaniam, Ramesh

    2011-01-01

    We address the complex relationship between the stability, variability, and adaptability of psychological systems by decomposing the global variance of serial performance into two independent parts: the local variance (LV) and the serial correlation structure. For two time series with equal LV, the presence of persistent long-range correlations…

  9. Minimum variance imaging based on correlation analysis of Lamb wave signals.

    PubMed

    Hua, Jiadong; Lin, Jing; Zeng, Liang; Luo, Zhi

    2016-08-01

    In Lamb wave imaging, MVDR (minimum variance distortionless response) is a promising approach for the detection and monitoring of large areas with sparse transducer network. Previous studies in MVDR use signal amplitude as the input damage feature, and the imaging performance is closely related to the evaluation accuracy of the scattering characteristic. However, scattering characteristic is highly dependent on damage parameters (e.g. type, orientation and size), which are unknown beforehand. The evaluation error can degrade imaging performance severely. In this study, a more reliable damage feature, LSCC (local signal correlation coefficient), is established to replace signal amplitude. In comparison with signal amplitude, one attractive feature of LSCC is its independence of damage parameters. Therefore, LSCC model in the transducer network could be accurately evaluated, the imaging performance is improved subsequently. Both theoretical analysis and experimental investigation are given to validate the effectiveness of the LSCC-based MVDR algorithm in improving imaging performance.

  10. Variance components and correlations of female fertility traits in Chinese Holstein population.

    PubMed

    Liu, Aoxing; Lund, Mogens Sandø; Wang, Yachun; Guo, Gang; Dong, Ganghui; Madsen, Per; Su, Guosheng

    2017-01-01

    The objective of the present study was to estimate (co)variance components of female fertility traits in Chinese Holsteins, considering fertility traits in different parities as different traits. Data on 88,647 females with 215,632 records (parities) were collected during 2000 to 2014 from 32 herds in the Sanyuan Lvhe Dairy Cattle Center, Beijing, China. The analyzed female fertility traits included interval from calving to first insemination, interval from first to last insemination, days open, conception rate at first insemination, number of inseminations per conception and non-return rates within 56 days after first insemination. The descriptive statistics showed that the average fertility of heifers was superior to that of cows. Moreover, the genetic correlations between the performances of a trait in heifers and in cows were all moderate to high but far from one, which suggested that the performances of a trait in heifers and cows should be considered as different but genetically correlated traits in genetic evaluations. On the other hand, genetic correlations between performances of a trait in different parities of cows were greater than 0.87, with only a few exceptions, but variances were not homogeneous across parities for some traits. The estimated heritabilities of female fertility traits were low; all were below 0.049 (except for interval from calving to first insemination). Additionally, the heritabilities of the heifer interval traits were lower than those of the corresponding cow interval traits. Moreover, the heritabilities of the interval traits were higher than those of the threshold traits when measuring similar fertility functions. In general, estimated genetic correlations between traits were highly consistent with the biological categories of the female fertility traits. Interval from calving to first insemination, interval from first to last insemination and non-return rates within 56 days after first insemination are recommended to be

  11. Multilevel covariance regression with correlated random effects in the mean and variance structure.

    PubMed

    Quintero, Adrian; Lesaffre, Emmanuel

    2017-09-01

    Multivariate regression methods generally assume a constant covariance matrix for the observations. In case a heteroscedastic model is needed, the parametric and nonparametric covariance regression approaches can be restrictive in the literature. We propose a multilevel regression model for the mean and covariance structure, including random intercepts in both components and allowing for correlation between them. The implied conditional covariance function can be different across clusters as a result of the random effect in the variance structure. In addition, allowing for correlation between the random intercepts in the mean and covariance makes the model convenient for skewedly distributed responses. Furthermore, it permits us to analyse directly the relation between the mean response level and the variability in each cluster. Parameter estimation is carried out via Gibbs sampling. We compare the performance of our model to other covariance modelling approaches in a simulation study. Finally, the proposed model is applied to the RN4CAST dataset to identify the variables that impact burnout of nurses in Belgium. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Attention-Induced Variance and Noise Correlation Reduction in Macaque V1 Is Mediated by NMDA Receptors

    PubMed Central

    Herrero, Jose L.; Gieselmann, Marc A.; Sanayei, Mehdi; Thiele, Alexander

    2013-01-01

    Summary Attention improves perception by affecting different aspects of the neuronal code. It enhances firing rates, it reduces firing rate variability and noise correlations of neurons, and it alters the strength of oscillatory activity. Attention-induced rate enhancement in striate cortex requires cholinergic mechanisms. The neuropharmacological mechanisms responsible for attention-induced variance and noise correlation reduction or those supporting changes in oscillatory activity are unknown. We show that ionotropic glutamatergic receptor activation is required for attention-induced rate variance, noise correlation, and LFP gamma power reduction in macaque V1, but not for attention-induced rate modulations. NMDA receptors mediate attention-induced variance reduction and attention-induced noise correlation reduction. Our results demonstrate that attention improves sensory processing by a variety of mechanisms that are dissociable at the receptor level. PMID:23719166

  13. Estimation of breeding values for mean and dispersion, their variance and correlation using double hierarchical generalized linear models.

    PubMed

    Felleki, M; Lee, D; Lee, Y; Gilmour, A R; Rönnegård, L

    2012-12-01

    The possibility of breeding for uniform individuals by selecting animals expressing a small response to environment has been studied extensively in animal breeding. Bayesian methods for fitting models with genetic components in the residual variance have been developed for this purpose, but have limitations due to the computational demands. We use the hierarchical (h)-likelihood from the theory of double hierarchical generalized linear models (DHGLM) to derive an estimation algorithm that is computationally feasible for large datasets. Random effects for both the mean and residual variance parts of the model are estimated together with their variance/covariance components. An important feature of the algorithm is that it can fit a correlation between the random effects for mean and variance. An h-likelihood estimator is implemented in the R software and an iterative reweighted least square (IRWLS) approximation of the h-likelihood is implemented using ASReml. The difference in variance component estimates between the two implementations is investigated, as well as the potential bias of the methods, using simulations. IRWLS gives the same results as h-likelihood in simple cases with no severe indication of bias. For more complex cases, only IRWLS could be used, and bias did appear. The IRWLS is applied on the pig litter size data previously analysed by Sorensen & Waagepetersen (2003) using Bayesian methodology. The estimates we obtained by using IRWLS are similar to theirs, with the estimated correlation between the random genetic effects being -0·52 for IRWLS and -0·62 in Sorensen & Waagepetersen (2003).

  14. Fast patient-specific Monte Carlo brachytherapy dose calculations via the correlated sampling variance reduction technique

    PubMed Central

    Sampson, Andrew; Le, Yi; Williamson, Jeffrey F.

    2012-01-01

    Purpose: To demonstrate potential of correlated sampling Monte Carlo (CMC) simulation to improve the calculation efficiency for permanent seed brachytherapy (PSB) implants without loss of accuracy. Methods: CMC was implemented within an in-house MC code family (PTRAN) and used to compute 3D dose distributions for two patient cases: a clinical PSB postimplant prostate CT imaging study and a simulated post lumpectomy breast PSB implant planned on a screening dedicated breast cone-beam CT patient exam. CMC tallies the dose difference, ΔD, between highly correlated histories in homogeneous and heterogeneous geometries. The heterogeneous geometry histories were derived from photon collisions sampled in a geometrically identical but purely homogeneous medium geometry, by altering their particle weights to correct for bias. The prostate case consisted of 78 Model-6711 125I seeds. The breast case consisted of 87 Model-200 103Pd seeds embedded around a simulated lumpectomy cavity. Systematic and random errors in CMC were unfolded using low-uncertainty uncorrelated MC (UMC) as the benchmark. CMC efficiency gains, relative to UMC, were computed for all voxels, and the mean was classified in regions that received minimum doses greater than 20%, 50%, and 90% of D90, as well as for various anatomical regions. Results: Systematic errors in CMC relative to UMC were less than 0.6% for 99% of the voxels and 0.04% for 100% of the voxels for the prostate and breast cases, respectively. For a 1 × 1 × 1 mm3 dose grid, efficiency gains were realized in all structures with 38.1- and 59.8-fold average gains within the prostate and breast clinical target volumes (CTVs), respectively. Greater than 99% of the voxels within the prostate and breast CTVs experienced an efficiency gain. Additionally, it was shown that efficiency losses were confined to low dose regions while the largest gains were located where little difference exists between the homogeneous and heterogeneous doses

  15. Impact of apolipoprotein E genotype variation on means, variances, and correlations of plasma lipid, lipoprotein, and apolipoprotein traits in octogenarians

    SciTech Connect

    Haviland, M.B.; Sing, C.F.; Lussier-Cacan, S.; Davignon, J.

    1995-09-25

    The impact of apolipoprotein (apo) E genotype variation on means, variances and correlations between plasma lipid traits was studied in male and female octogenarians. Females had significantly higher mean levels of all 10 of the measured plasma lipid traits than males. The subset of concomitants (i.e., age, height, weight, body mass index, glucose and uric acid) that made a statistically significant contribution to interindividual variability was different in males and females for every trait considered. Gender-specific associations between variation in apo E genotype and variation in particular measures of lipid metabolism, adjusted for concomitant variation, were observed: in females there were no statistically significant associations while in males the means of the three common apo E genotypes were significantly different for adjusted measures of total cholesterol, low density lipoprotein cholesterol and low density lipoprotein-apo B. The common apo E genotypes were heterogeneous with respect to intragenotypic variance for adjusted log-transformed triglyceride levels in females only. Finally, the three common apo E genotypes were heterogeneous with respect to the correlation between traits, adjusted for concomitant variation, and gender influenced the manner in which the genotypes differed for specific correlations. This study documents that variation in the apo E gene has a significant impact on means, variances and correlations of plasma lipid traits in octogenarians, but the effects are context-, that is, gender- and age-, dependent. 65 refs., 4 figs., 3 tabs.

  16. Considerations of the Error Variances of Time-Averaged Estimators for Correlated Processes

    DTIC Science & Technology

    1992-12-01

    comments in the preparation of this report. Acces/on For NTIS CRA&I DTIC TAB El Unarnounced LI JustfiiCdIIOin By Dt,’jt’bution I " M TIN I.. AvAvijdbdlty...expressed in terms of these fundamental process characteristics is derived in this paper . Specifically, analytic expressions are developed for the variance...first term on the RHS of eq(3.2b), we have for positive and negative I I NT-I-1 NT-I-1T ,N 2 N I xi(n)xi(n-I)xi(p)xi(P-I) NT n=0 p=0 t In this paper

  17. NIAID Workshop on Flavivirus Immunity

    PubMed Central

    Cassetti, M. Cristina; Ennis, Francis A.; Harris, Eva; Hildebrand, William H.; Repik, Patricia M.

    2010-01-01

    Abstract On September 16, 2009, the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health, convened a workshop to discuss current knowledge of T- and B-cell immune epitopes for members of the Flavivirus genus (family Flaviviridae), and how this information could be used to increase our basic understanding of host-pathogen interactions and/or advance the development of new or improved vaccines and diagnostics for these pathogens. B-cell and T-cell responses to flaviviruses are critical components of protective immunity against these pathogens. However, they have also been linked to disease pathogenesis. A detailed understanding of the biological significance of immune epitope information may provide clues regarding the mechanisms governing the induction of protective versus pathogenic adaptive immune responses. PMID:20565288

  18. Flavivirus transmission focusing on Zika.

    PubMed

    Vasilakis, Nikos; Weaver, Scott C

    2017-02-01

    Flaviviruses are among the most diverse viruses with over 85 species recognized. Taxonomically, this genus is one of the 4 recognized genera within the family Flaviviridae. Most flaviviruses of human public health significance, for example, dengue, yellow fever and Zika viruses, are arthropod-borne (arboviruses) and have two evolutionarily and ecologically distinct transmission cycles: a sylvatic transmission cycle, where the virus circulates between zoonotic vertebrate reservoir and amplification hosts and arboreal mosquitoes; and an urban transmission cycle, where the virus circulates between humans and peridomestic Aedes spp. mosquitoes. Zika virus (ZIKV), a flavivirus closely related to West Nile, dengue, Spondweni, Japanese encephalitis and yellow fever viruses, remained in obscurity since its discovery in 1947, but has recently emerged to cause a series of epidemics in the South Pacific, and most recently reaching nearly pandemic levels with its introduction in the Americas. Available epidemiologic and experimental evidence points to Aedes aegypti as the principal urban vector, possibly supplemented by Aedes albopictus in some locations. Unfortunately, the former is one of the most difficult mosquitoes to control owing to its highly anthropophilic behavior.

  19. Commonality and the Common Man: Understanding Variance Contributions to Overall Canonical Correlation Effects.

    ERIC Educational Resources Information Center

    Capraro, Robert M.

    Canonical correlation analysis is the most general linear model subsuming all other univariate and multivariate cases (N. Kerlinger & E. Pedhazur, 1973; B. Thompson, 1985, 1991). Because "reality" is a complex place, a multivariate analysis such as canonical correlation analysis is demanded to match the research design. The purpose…

  20. Dengue and other flavivirus infections.

    PubMed

    Choumet, V; Desprès, Ph

    2015-08-01

    Flaviviruses are responsible for yellow fever, Zika fever and dengue, all of which are major human diseases found in tropical regions of the globe. They are zoonoses with a transmission cycle that involves primates as reservoirs and mosquitoes of the genus Aedes as vectors. The recent upsurge of urban epidemics of yellow fever, Zika fever and dengue has involved human-to-human transmission with mosquitoes as the vector. This paper is primarily concerned with dengue, which has become the pre-eminent arbovirosis in terms of public health.

  1. Sex-specific genetic variance and the evolution of sexual dimorphism: a systematic review of cross-sex genetic correlations.

    PubMed

    Poissant, Jocelyn; Wilson, Alastair J; Coltman, David W

    2010-01-01

    The independent evolution of the sexes may often be constrained if male and female homologous traits share a similar genetic architecture. Thus, cross-sex genetic covariance is assumed to play a key role in the evolution of sexual dimorphism (SD) with consequent impacts on sexual selection, population dynamics, and speciation processes. We compiled cross-sex genetic correlations (r(MF)) estimates from 114 sources to assess the extent to which the evolution of SD is typically constrained and test several specific hypotheses. First, we tested if r(MF) differed among trait types and especially between fitness components and other traits. We also tested the theoretical prediction of a negative relationship between r(MF) and SD based on the expectation that increases in SD should be facilitated by sex-specific genetic variance. We show that r(MF) is usually large and positive but that it is typically smaller for fitness components. This demonstrates that the evolution of SD is typically genetically constrained and that sex-specific selection coefficients may often be opposite in sign due to sub-optimal levels of SD. Most importantly, we confirm that sex-specific genetic variance is an important contributor to the evolution of SD by validating the prediction of a negative correlation between r(MF) and SD.

  2. Variance-based sensitivity indices for stochastic models with correlated inputs

    SciTech Connect

    Kala, Zdeněk

    2015-03-10

    The goal of this article is the formulation of the principles of one of the possible strategies in implementing correlation between input random variables so as to be usable for algorithm development and the evaluation of Sobol’s sensitivity analysis. With regard to the types of stochastic computational models, which are commonly found in structural mechanics, an algorithm was designed for effective use in conjunction with Monte Carlo methods. Sensitivity indices are evaluated for all possible permutations of the decorrelation procedures for input parameters. The evaluation of Sobol’s sensitivity coefficients is illustrated on an example in which a computational model was used for the analysis of the resistance of a steel bar in tension with statistically dependent input geometric characteristics.

  3. The Importance of Parameter Variances, Correlations Lengths, and Cross-Correlations in Reactive Transport Models: Key Considerations for Assessing the Need for Microscale Information (Invited)

    NASA Astrophysics Data System (ADS)

    Reimus, P. W.

    2010-12-01

    A process-oriented modeling approach is implemented to examine the importance of parameter variances, correlation lengths, and especially cross-correlations in contaminant transport predictions over large scales. It is shown that the most important consideration is the correlation between flow rates and retardation processes (e.g., sorption, matrix diffusion) in the system. If flow rates are negatively correlated with retardation factors in systems containing multiple flow pathways, then characterizing these negative correlation(s) may have more impact on reactive transport modeling than microscale information. Such negative correlations are expected in porous-media systems where permeability is negatively correlated with clay content and rock alteration (which are usually associated with increased sorption). Likewise, negative correlations are expected in fractured rocks where permeability is positively correlated with fracture apertures, which in turn are negatively correlated with sorption and matrix diffusion. Parameter variances and correlation lengths are also shown to have important effects on reactive transport predictions, but they are less important than parameter cross-correlations. Microscale information pertaining to contaminant transport has become more readily available as characterization methods and spectroscopic instrumentation have achieved lower detection limits, greater resolution, and better precision. Obtaining detailed mechanistic insights into contaminant-rock-water interactions is becoming a routine practice in characterizing reactive transport processes in groundwater systems (almost necessary for high-profile publications). Unfortunately, a quantitative link between microscale information and flow and transport parameter distributions or cross-correlations has not yet been established. One reason for this is that quantitative microscale information is difficult to obtain in complex, heterogeneous systems, so simple systems that lack the

  4. Structural and Functional Analyses of a Conserved Hydrophobic Pocket of Flavivirus Methyltransferase*

    PubMed Central

    Dong, Hongping; Liu, Lihui; Zou, Gang; Zhao, Yiwei; Li, Zhong; Lim, Siew Pheng; Shi, Pei-Yong; Li, Hongmin

    2010-01-01

    The flavivirus methyltransferase (MTase) sequentially methylates the N7 and 2′-O positions of the viral RNA cap (GpppA-RNA → m7GpppA-RNA → m7GpppAm-RNA), using S-adenosyl-l-methionine (AdoMet) as a methyl donor. We report here that sinefungin (SIN), an AdoMet analog, inhibits several flaviviruses through suppression of viral MTase. The crystal structure of West Nile virus MTase in complex with SIN inhibitor at 2.0-Å resolution revealed a flavivirus-conserved hydrophobic pocket located next to the AdoMet-binding site. The pocket is functionally critical in the viral replication and cap methylations. In addition, the N7 methylation efficiency was found to correlate with the viral replication ability. Thus, SIN analogs with modifications that interact with the hydrophobic pocket are potential specific inhibitors of flavivirus MTase. PMID:20685660

  5. Flaviviruses

    DTIC Science & Technology

    1990-01-01

    vein in the 4 hippocampus of a fatal human - case of St. Louis encephalitis. He- matoxylin and eosin. x 400. (Cour- tesy of M. G. Reyes.) surrounded by...West Nile cide resistance, but the efficacy of this approach is in encephalitis have been reported in horses (128); how- question. ever, low-level...after intra- cides have been used (136,240). cerebral or intranasal infection; cynomolgus monkeys develop fever without nervous system signs. The de

  6. Variances and correlations of milk production, fertility, longevity, and type traits over time in Australian Holstein cattle.

    PubMed

    Haile-Mariam, M; Pryce, J E

    2015-10-01

    When using historical data, it is often assumed that the genetic correlation of the same trait recorded at different time points is reasonably close to 1. However, selection and possible changes in trait definitions means that this may not necessarily be the case. Regularly monitoring genetic parameters over time is important, as changes could reduce the accuracy of genetic evaluations. About 20 yr (1993 to 2012) of data on milk yield as well as functional and type traits from Australian Holstein dairy cattle were analyzed to assess changes in genetic correlations within and among traits over time by considering 2 traits at a time using linear random regression (RR) and multitrait (MT) models. Both residual and genetic variances for milk yield traits and calving interval (CI) increased over time, with the highest increase observed for protein yield. For most type traits some fluctuations over time were noted in both the residual and additive genetic variances. Genetic correlations among survival (i.e., from first to second lactation), milk yield traits, CI, and some type traits varied over time. The genetic correlation of the same trait (e.g., protein yield, fat yield, and some type traits) measured in different years was also less than 1.0 (0.1-0.9), which is likely to be due to selection or changes in trait definitions. Estimates of parameters from the RR model were generally similar to those from MT models that considered the same trait recorded in different year groups as different traits. However, in the case of survival and CI (i.e., lowly heritable traits), the genetic correlations over time obtained from the MT model were lower (0.21 to 0.75) than those from the RR models (0.9-1.0). Genetic correlations of survival with milk, fat, and protein yields declined from ~0.4 to 0.5 at the beginning of the study period (1993/94) to zero or negative at the end (2009/10), whereas the correlation between CI and milk yield became more unfavorable and increased from 0

  7. Joint analysis of beef growth and carcass quality traits through calculation of co-variance components and correlations.

    PubMed

    Mirzaei, H R; Verbyla, A P; Pitchford, W S

    2011-03-15

    A joint growth-carcass model using random regression was used to estimate the (co)variance components of beef cattle body weights and carcass quality traits and correlations between them. During a four-year period (1994-1997) of the Australian "southern crossbreeding project", mature Hereford cows (N = 581) were mated to 97 sires of Jersey, Wagyu, Angus, Hereford, South Devon, Limousin, and Belgian Blue breeds, resulting in 1141 calves. Data included 13 (for steers) and 8 (for heifers) body weight measurements approximately every 50 days from birth until slaughter and four carcass quality traits: hot standard carcass weight, rump fat depth, rib eye muscle area, and intramuscular fat content. The mixed model included fixed effects of sex, sire breed, age (linear, quadratic and cubic), and their interactions between sex and sire breed with age. Random effects were sire, dam, management (birth location, year, post-weaning groups), and permanent environmental effects, and their interactions with linear, quadratic and cubic growth, when possible. Phenotypic, sire and dam correlations between body weights and hot standard carcass weight and rib eye muscle area were positive and moderate to high from birth to feedlot period. Management variation accounted for the largest proportion of total variation in both growth and carcass traits. Management correlations between carcass traits were high, except between rump fat depth and intramuscular fat (r = 0.26). Management correlations between body weight and carcass traits during the pre-weaning period were positive except for intramuscular fat. The correlations were low from birth to weaning, then increased dramatically and were high during the feedlot period.

  8. Complete genome sequence of Menghai flavivirus, a novel insect-specific flavivirus from China.

    PubMed

    Zhang, Xianglilan; Guo, Xiaofang; Fan, Hang; Zhao, Qiumin; Zuo, Shuqing; Sun, Qiang; Pei, Guangqian; Cheng, Shi; An, Xiaoping; Wang, Yunfei; Mi, Zhiqiang; Huang, Yong; Zhang, Zhiyi; Tong, Yigang; Zhou, Hongning; Zhang, Jiusong

    2017-05-01

    Menghai flavivirus (MFV) was isolated from Aedes albopictus in Menghai county of Yunnan Province, China, during an arboviruses screening program in August 2010. Whole genome sequencing of MFV was performed using an Ion PGM™ Sequencer. The complete genome of MFV was 10897 nucleotides in length and encoded a polyprotein and fairly interesting flavivirus orf (FIFO). The polyprotein contained three flavivirus structural proteins (C, prM/M and E) and seven nonstructural proteins. Nucleotide BLAST analysis revealed that the MFV genome showed highest similarity to Xishuangbanna Aedes flavivirus, a novel insect-specific flavivirus recently isolated from the same area. These species shared a query cover of 99%, but only 71% identity, while FIFO showed no similarity with any of the published sequences. Genomic and phylogenetic analyses suggested that MFV was a novel species of the genus Flavivirus. Our findings enrich our understanding of the genetics and prevalence of the family Flaviviridae.

  9. Flavivirus RNA Synthesis in vitro

    PubMed Central

    Padmanabhan, Radhakrishnan; Takhampunya, Ratree; Teramoto, Tadahisa; Choi, Kyung H.

    2015-01-01

    Summary Establishment of in vitro systems to study mechanisms of RNA synthesis for positive strand RNA viruses have been very useful in the past and have shed light on the composition of protein and RNA components, optimum conditions, the nature of the products formed, cis-acting RNA elements and trans-acting protein factors required for efficient synthesis. In this review, we summarize our current understanding regarding the requirements for flavivirus RNA synthesis in vitro. We describe details of reaction conditions, the specificity of template used by either the multi-component membrane-bound viral replicase complex or by purified, recombinant RNA-dependent RNA polymerase. We also discuss future perspectives to extend the boundaries of our knowledge. PMID:26272247

  10. Complete genome sequence of Xishuangbanna flavivirus, a novel mosquito-specific flavivirus from China.

    PubMed

    Fan, Hang; Zhao, Qiumin; Guo, Xiaofang; Sun, Qiang; Zuo, Shuqing; Wu, Chao; Zhou, Hongning; An, Xiaoping; Pei, Guangqian; Tong, Yigang; Zhang, Jiusong; Shi, Taoxing

    2016-06-01

    A new flavivirus, Xishuangbanna flavivirus (XFV), infecting Aedes albopictus mosquitoes in Yunnan Province, China, was isolated and sequenced. The single-stranded RNA genome of 10,884 nt contained two open reading frames (ORFs) encoding the polyprotein and FIFO. The genome had a maximum nucleotide sequence identity of 65 % to Parramatta River virus with coverage of only 27 %. Phylogenetic analysis suggested that this virus is most closely related to recognized classical insect-specific flaviviruses (cISF) and most likely has a similar host range. Sequence comparisons and phylogenetic analysis demonstrated that XFV is a new member of the genus Flavivirus.

  11. Variance components, heritability and correlation analysis of anther and ovary size during the floral development of bread wheat.

    PubMed

    Guo, Zifeng; Chen, Dijun; Schnurbusch, Thorsten

    2015-06-01

    Anther and ovary development play an important role in grain setting, a crucial factor determining wheat (Triticum aestivum L.) yield. One aim of this study was to determine the heritability of anther and ovary size at different positions within a spikelet at seven floral developmental stages and conduct a variance components analysis. Relationships between anther and ovary size and other traits were also assessed. The thirty central European winter wheat genotypes used in this study were based on reduced height (Rht) and photoperiod sensitivity (Ppd) genes with variable genetic backgrounds. Identical experimental designs were conducted in a greenhouse and field simultaneously. Heritability of anther and ovary size indicated strong genetic control. Variance components analysis revealed that anther and ovary sizes of floret 3 (i.e. F3, the third floret from the spikelet base) and floret 4 (F4) were more sensitive to the environment compared with those in floret 1 (F1). Good correlations were found between spike dry weight and anther and ovary size in both greenhouse and field, suggesting that anther and ovary size are good predictors of each other, as well as spike dry weight in both conditions. Relationships between spike dry weight and anther and ovary size at F3/4 positions were stronger than at F1, suggesting that F3/4 anther and ovary size are better predictors of spike dry weight. Generally, ovary size showed a closer relationship with spike dry weight than anther size, suggesting that ovary size is a more reliable predictor of spike dry weight.

  12. Regulation of Flavivirus RNA Synthesis and Capping

    PubMed Central

    Saeedi, Bejan J.; Geiss, Brian J.

    2013-01-01

    RNA viruses, such as flaviviruses, are able to efficiently replicate and cap their RNA genomes in vertebrate and invertebrate cells. Flaviviruses use several specialized proteins to first make an uncapped negative strand copy of the viral genome that is used as a template for the synthesis of large numbers of capped genomic RNAs. Despite using relatively simple mechanisms to replicate their RNA genomes, there are significant gaps in our understanding of how flaviviruses switch between negative and positive strand RNA synthesis and how RNA capping is regulated. Recent work has begun to provide a conceptual framework for flavivirus RNA replication and capping and shown some surprising roles for genomic RNA during replication and pathogenesis. PMID:23929625

  13. SHH Protein Variance in the Limb Bud Is Constrained by Feedback Regulation and Correlates with Altered Digit Patterning

    PubMed Central

    Zhang, Rui; Lee, Chanmi; Lawson, Lisa Y.; Svete, Lillian J.; McIntyre, Lauren M.; Harfe, Brian D.

    2017-01-01

    mRNA variance has been proposed to play key roles in normal development, population fitness, adaptability, and disease. While variance in gene expression levels may be beneficial for certain cellular processes, for example in a cell’s ability to respond to external stimuli, variance may be detrimental for the development of some organs. In the bilaterally symmetric vertebrate limb buds, the amount of Sonic Hedgehog (SHH) protein present at specific stages of development is essential to ensure proper patterning of this structure. To our surprise, we found that SHH protein variance is present during the first 10 hr of limb development. The variance is virtually eliminated after the first 10 hr of limb development. By examining mutant animals, we determined that the ability of the limb bud apical ectodermal ridge (AER) to respond to SHH protein was required for reducing SHH variance during limb formation. One consequence of the failure to eliminate variance in SHH protein was the presence of polydactyly and an increase in digit length. These data suggest a potential novel mechanism in which alterations in SHH variance during evolution may have driven changes in limb patterning and digit length. PMID:28131983

  14. Zika virus: An emerging flavivirus.

    PubMed

    Yun, Sang-Im; Lee, Young-Min

    2017-03-01

    Zika virus (ZIKV) is a previously little-known flavivirus closely related to Japanese encephalitis, West Nile, dengue, and yellow fever viruses, all of which are primarily transmitted by blood-sucking mosquitoes. Since its discovery in Uganda in 1947, ZIKV has continued to expand its geographic range, from equatorial Africa and Asia to the Pacific Islands, then further afield to South and Central America and the Caribbean. Currently, ZIKV is actively circulating not only in much of Latin America and its neighbors but also in parts of the Pacific Islands and Southeast Asia. Although ZIKV infection generally causes only mild symptoms in some infected individuals, it is associated with a range of neuroimmunological disorders, including Guillain-Barré syndrome, meningoencephalitis, and myelitis. Recently, maternal ZIKV infection during pregnancy has been linked to neonatal malformations, resulting in various degrees of congenital abnormalities, microcephaly, and even abortion. Despite its emergence as an important public health problem, however, little is known about ZIKV biology, and neither vaccine nor drug is available to control ZIKV infection. This article provides a brief introduction to ZIKV with a major emphasis on its molecular virology, in order to help facilitate the development of diagnostics, therapeutics, and vaccines.

  15. Live flavivirus vaccines: reasons for caution.

    PubMed

    Seligman, Stephen J; Gould, Ernest A

    2004-06-19

    Dengue, Japanese encephalitis, tick-borne encephalitis, yellow fever, and West Nile viruses cause substantial morbidity and mortality each year. Modern transportation and the relaxation of mosquito-control measures are largely responsible for the increase of disease caused by flaviviruses. Without effective antiviral drugs, vaccination offers the best chance of decreasing the incidence of these diseases, and live virus vaccines are the most promising and cost effective. However, flaviviruses can recombine, which raises the possibility of recombination between a vaccine strain and wild-type virus resulting in a new virus with potentially undesirable properties. Recently, Arunee Sabchareon and colleagues reported up to 90% seroconversion rates in a phase I trial of live-attenuated dengue-virus vaccines in children (Pediatr Infect Dis J 2004; 23: 99-109). Other live flavivirus vaccines have also been tested against dengue, Japanese encephalitis, and West Nile viruses. Thus far, efficacy seems promising. Safety issues with the live flavivirus vaccines need to be recognised and addressed. The theoretical possibility of untoward recombination events can never be entirely dismissed, but steps can be taken to minimise risk. The development of non-live flavivirus vaccines should be encouraged.

  16. Stratospheric Assimilation of Chemical Tracer Observations Using a Kalman Filter. Pt. 2; Chi-Square Validated Results and Analysis of Variance and Correlation Dynamics

    NASA Technical Reports Server (NTRS)

    Menard, Richard; Chang, Lang-Ping

    1998-01-01

    A Kalman filter system designed for the assimilation of limb-sounding observations of stratospheric chemical tracers, which has four tunable covariance parameters, was developed in Part I (Menard et al. 1998) The assimilation results of CH4 observations from the Cryogenic Limb Array Etalon Sounder instrument (CLAES) and the Halogen Observation Experiment instrument (HALOE) on board of the Upper Atmosphere Research Satellite are described in this paper. A robust (chi)(sup 2) criterion, which provides a statistical validation of the forecast and observational error covariances, was used to estimate the tunable variance parameters of the system. In particular, an estimate of the model error variance was obtained. The effect of model error on the forecast error variance became critical after only three days of assimilation of CLAES observations, although it took 14 days of forecast to double the initial error variance. We further found that the model error due to numerical discretization as arising in the standard Kalman filter algorithm, is comparable in size to the physical model error due to wind and transport modeling errors together. Separate assimilations of CLAES and HALOE observations were compared to validate the state estimate away from the observed locations. A wave-breaking event that took place several thousands of kilometers away from the HALOE observation locations was well captured by the Kalman filter due to highly anisotropic forecast error correlations. The forecast error correlation in the assimilation of the CLAES observations was found to have a structure similar to that in pure forecast mode except for smaller length scales. Finally, we have conducted an analysis of the variance and correlation dynamics to determine their relative importance in chemical tracer assimilation problems. Results show that the optimality of a tracer assimilation system depends, for the most part, on having flow-dependent error correlation rather than on evolving the

  17. The Complement System in Flavivirus Infections.

    PubMed

    Conde, Jonas N; Silva, Emiliana M; Barbosa, Angela S; Mohana-Borges, Ronaldo

    2017-01-01

    The incidence of flavivirus infections has increased dramatically in recent decades in tropical and sub-tropical climates worldwide, affecting hundreds of millions of people each year. The Flaviviridae family includes dengue, West Nile, Zika, Japanese encephalitis, and yellow fever viruses that are typically transmitted by mosquitoes or ticks, and cause a wide range of symptoms, such as fever, shock, meningitis, paralysis, birth defects, and death. The flavivirus genome is composed of a single positive-sense RNA molecule encoding a single viral polyprotein. This polyprotein is further processed by viral and host proteases into three structural proteins (C, prM/M, E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5) that are involved in viral replication and pathogenicity. The complement system has been described to play an important role in flavivirus infection either by protecting the host and/or by influencing disease pathogenesis. In this mini-review, we will explore the role of complement system inhibition and/or activation against infection by the Flavivirus genus, with an emphasis on dengue and West Nile viruses.

  18. The Complement System in Flavivirus Infections

    PubMed Central

    Conde, Jonas N.; Silva, Emiliana M.; Barbosa, Angela S.; Mohana-Borges, Ronaldo

    2017-01-01

    The incidence of flavivirus infections has increased dramatically in recent decades in tropical and sub-tropical climates worldwide, affecting hundreds of millions of people each year. The Flaviviridae family includes dengue, West Nile, Zika, Japanese encephalitis, and yellow fever viruses that are typically transmitted by mosquitoes or ticks, and cause a wide range of symptoms, such as fever, shock, meningitis, paralysis, birth defects, and death. The flavivirus genome is composed of a single positive-sense RNA molecule encoding a single viral polyprotein. This polyprotein is further processed by viral and host proteases into three structural proteins (C, prM/M, E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5) that are involved in viral replication and pathogenicity. The complement system has been described to play an important role in flavivirus infection either by protecting the host and/or by influencing disease pathogenesis. In this mini-review, we will explore the role of complement system inhibition and/or activation against infection by the Flavivirus genus, with an emphasis on dengue and West Nile viruses. PMID:28261172

  19. Nuclear entropy, angular second moment, variance and texture correlation of thymus cortical and medullar lymphocytes: grey level co-occurrence matrix analysis.

    PubMed

    Pantic, Igor; Pantic, Senka; Paunovic, Jovana; Perovic, Milan

    2013-09-01

    Grey level co-occurrence matrix analysis (GLCM) is a well-known mathematical method for quantification of cell and tissue textural properties, such as homogeneity, complexity and level of disorder. Recently, it was demonstrated that this method is capable of evaluating fine structural changes in nuclear structure that otherwise are undetectable during standard microscopy analysis. In this article, we present the results indicating that entropy, angular second moment, variance, and texture correlation of lymphocyte nuclear structure determined by GLCM method are different in thymus cortex when compared to medulla. A total of 300 thymus lymphocyte nuclei from 10 one-month-old mice were analyzed: 150 nuclei from cortex and 150 nuclei from medullar regions of thymus. Nuclear GLCM analysis was carried out using National Institutes of Health ImageJ software. For each nucleus, entropy, angular second moment, variance and texture correlation were determined. Cortical lymphocytes had significantly higher chromatin angular second moment (p < 0.001) and texture correlation (p < 0.05) compared to medullar lymphocytes. Nuclear GLCM entropy and variance of cortical lymphocytes were on the other hand significantly lower than in medullar lymphocytes (p < 0.001). These results suggest that GLCM as a method might have a certain potential in detecting discrete changes in nuclear structure associated with lymphocyte migration and maturation in thymus.

  20. Using exposure biomarkers in children to compare between-child and within-child variance and calculate correlations among siblings for multiple environmental chemicals.

    PubMed

    Sexton, Ken; Ryan, Andrew D

    2012-01-01

    Longitudinal measurements of biomarkers for metals, phthalates, environmental tobacco smoke, organochlorine and organophosphate pesticides, polychlorinated biphenyls, and volatile organic compounds were made in blood and/or urine from a stratified, random sample of more than 100 elementary school-aged children living in an inner-city section of Minneapolis. Repeated measures of 31 exposure biomarkers indicate that between-child variance (B-CV) was greater than within-child variance (W-CV) for 8 compounds, B-CV was a significant proportion of total variance for 9 compounds, and variances were homogeneous for 14 compounds. Among siblings living in the same household, positive correlations were observed for biomarker concentrations of polychlorinated biphenyls, organochlorine pesticides, metals, and volatile organic chemicals in blood, and total cotinine in urine. Biologic markers confirm that children from a low-income, ethnically diverse neighborhood experienced concurrent exposure to a variety of hazardous environmental chemicals during their everyday activities. Future monitoring studies should examine the nature and magnitude of children's cumulative exposure to both chemical and non-chemical stressors, especially in disadvantaged populations.

  1. Antibodies to flaviviruses in wild ducks captured in Hokkaido, Japan: risk assessment of invasive flaviviruses.

    PubMed

    Saito, Mika; Osa, Yuichi; Asakawa, Mitsuhiko

    2009-06-01

    Recently, the distribution of Japanese encephalitis virus (JEV) and West Nile virus (WNV) has expanded into new territories. The invasion of WNV into Japan is of great concern. The migration of birds is suggested to be involved in the expanded distribution of these flaviviruses. In this study, 92 wild ducks--20 Anas poecilorhyncha (migratory breeders), 50 Anas platyrhynchos (undetermined), 16 Anas acuta (winter visitors), and 6 Anas penelope (winter visitors)--were captured in autumn of 2005 and 2006, in the central part of Hokkaido, a low JEV activity area. A seroepidemiologic analysis of flavivirus infections was conducted with 90% and 50% focus reduction neutralization tests (FRNT(90) and FRNT(50)). Of the 92 serum samples, 1 (1.1%) and 5 (5.4%) tested positive for WNV-specific and JEV-specific antibodies, respectively, in the FRNT(90), and 61 (66.3%) and 79 (85.9%) tested positive for WNV and JEV, respectively, in the FRNT(50). These results indicate that wild ducks in this study had been exposed to flaviviruses. The results together with the recognized distribution of flaviviruses and migratory routes of individual duck species strongly suggested that the birds captured in this study had been exposed to flaviviruses, including WNV, on the flyway, not in Hokkaido.

  2. Coupling of Replication and Assembly in Flaviviruses

    PubMed Central

    Apte-Sengupta, Swapna; Sirohi, Devika; Kuhn, Richard J.

    2014-01-01

    Flaviviruses affect hundreds of millions of people each year causing tremendous morbidity and mortality worldwide. This genus includes significant human pathogens such as dengue, West Nile, yellow fever, tick-borne encephalitis and Japanese encephalitis virus among many others. The disease caused by these viruses can range from febrile illness to hemorrhagic fever and encephalitis. A deeper understanding of the virus life cycle is required to foster development of antivirals and vaccines, which are an urgent need for many flaviviruses, especially dengue. The focus of this review is to summarize our current knowledge of flaviviral replication and assembly, the proteins and lipids involved therein, and how these processes are coordinated for efficient virus production. PMID:25462445

  3. Risk assessment of flavivirus transmission in Namibia.

    PubMed

    Noden, Bruce H; Musuuo, Milka; Aku-Akai, Larai; van der Colf, Berta; Chipare, Israel; Wilkinson, Rob

    2014-09-01

    The role of arboviruses causing acute febrile illness in sub-Saharan Africa is receiving more attention. Reports of dengue in tourists were published nearly 10 years ago in Namibia, but the current epidemiology of arboviruses is unknown and surveys of mosquito vectors have not been carried out since the 1950s. To begin addressing this knowledge gap, a prospective cross-sectional study was conducted using samples from volunteer blood donors linked to questionnaire. Serum samples were tested using a Dengue IgG Indirect ELISA which measured exposure to dengue virus/flaviviruses. Entomological samples were collected from tires during the rainy season (February-March 2012) in six locations across Namibia's capital city, Windhoek. Among 312 blood donors tested, 25 (8.0%) were positive for dengue virus/flavivirus exposure. The only significant risk factor was age group with high exposure rates among those older than 50 (29%) compared with those below 40 years old (between 2.9% and 8.3%) (P<0.002). Larvae and pupae of Aedes aegypti and Culex pipiens complex accounted for 100% of the 2751 samples collected, of which only 12.2% (n=336) were Ae. aegypti. Each site demonstrated high variability of species composition between sampling times. While the significant dengue virus/flavivirus exposure rate among those above 50 years old is likely indicative of the West Nile epidemic in the 70s and 80s, the low exposure among those under 50 suggests that flaviviruses are still circulating in Namibia. While Ae. aegypti and C. pipiens sp. may play a role in future epidemics, the significance of presence may be reduced due to short rain periods, dry, arid, cold winters and policies and social understandings that limit non-structured storage and use of tires in low income areas. Future studies should further characterize the circulating arboviruses and investigate mosquito ecology nationally to map areas at higher risk for future arbovirus outbreaks.

  4. Evolution and dispersal of encephalitic flaviviruses.

    PubMed

    Gould, E A; Moss, S R; Turner, S L

    2004-01-01

    There are two major groups of encephalitic flaviviruses, those that infect and are transmitted by ticks, particularly Ixodes spp. and those that infect and are transmitted by mosquitoes, particularly Culex spp. The tick-borne encephalitic flaviviruses exhibit evolutionary characteristics that are largely determined by the protracted life cycle of the tick, its habitat and the prevailing climatic conditions. These viruses appear to have evolved gradually from non-encephalitic viruses that radiated eastwards and north eastwards out of Africa into Asia and the southern islands, then northwards to far east Asia and finally westwards across Eurasia to western Europe, during the past two to four thousand years. Only one of these recognized species has found its way to North America viz. Powassan virus. In contrast, the evolution of the recognized mosquito-borne encephalitic flaviviruses reflects the wide range of mosquito species that they infect. They emerged out of Africa relatively recently and at roughly the same time, i.e., probably during the past few centuries. Although many of these mosquito-borne viruses are geographically widely dispersed, with the exception of West Nile virus, they are found either in the Old World or the New World, never in both, and we are now beginning to understand the reasons. Phylogenetic trees will be used here to describe the evolution, epidemiology and dispersal characteristics of these viruses, taking into account the importance of virus persistence and recombination.

  5. Structure and Expression of Genes for Flavivirus Immunogens

    DTIC Science & Technology

    1988-02-01

    cDNAs. Keywords: Japanese encephalitis virus; Dengue virus; Flaviviruses; Subunit vaccines; Diagnosis; Mice; Gene mapping; Biotechnology; BW; CDNA; Cloning; Dengue fever ; DNA probes; Recombinant DNA.

  6. Impact of prior flavivirus immunity on Zika virus infection in rhesus macaques.

    PubMed

    McCracken, Michael K; Gromowski, Gregory D; Friberg, Heather L; Lin, Xiaoxu; Abbink, Peter; De La Barrera, Rafael; Eckles, Kenneth H; Garver, Lindsey S; Boyd, Michael; Jetton, David; Barouch, Dan H; Wise, Matthew C; Lewis, Bridget S; Currier, Jeffrey R; Modjarrad, Kayvon; Milazzo, Mark; Liu, Michelle; Mullins, Anna B; Putnak, J Robert; Michael, Nelson L; Jarman, Richard G; Thomas, Stephen J

    2017-08-01

    Studies have demonstrated cross-reactivity of anti-dengue virus (DENV) antibodies in human sera against Zika virus (ZIKV), promoting increased ZIKV infection in vitro. However, the correlation between in vitro and in vivo findings is not well characterized. Thus, we evaluated the impact of heterotypic flavivirus immunity on ZIKV titers in biofluids of rhesus macaques. Animals previously infected (≥420 days) with DENV2, DENV4, or yellow fever virus were compared to flavivirus-naïve animals following infection with a Brazilian ZIKV strain. Sera from DENV-immune macaques demonstrated cross-reactivity with ZIKV by antibody-binding and neutralization assays prior to ZIKV infection, and promoted increased ZIKV infection in cell culture assays. Despite these findings, no significant differences between flavivirus-naïve and immune animals were observed in viral titers, neutralizing antibody levels, or immune cell kinetics following ZIKV infection. These results indicate that prior infection with heterologous flaviviruses neither conferred protection nor increased observed ZIKV titers in this non-human primate ZIKV infection model.

  7. Zika Vaccine Development: Flavivirus Foils

    DTIC Science & Technology

    2016-09-01

    the response to the 2014 Ebola virus outbreak in West Africa. However, Zika virus is not Ebola virus. As of February 2016 there were only 296...contrast, work had been underway for decades on the development of an Ebola virus vaccine, laying the groundwork for a rapid response in 2014. The...seeking predictive correlates of protection 16,21-23. Just as Zika is not Ebola virus, with a plethora of vaccine options advanced in the pipeline

  8. Mechanism and Significance of Cell Type-Dependent Neutralization of Flaviviruses

    PubMed Central

    Mukherjee, Swati; Dowd, Kimberly A.; Manhart, Carolyn J.; Ledgerwood, Julie E.; Durbin, Anna P.; Whitehead, Stephen S.

    2014-01-01

    ABSTRACT The production of neutralizing antibodies (NAbs) is a correlate of protection for many human vaccines, including currently licensed vaccines against flaviviruses. NAbs are typically measured using a plaque reduction neutralization test (PRNT). Despite its extensive use, parameters that impact the performance of the PRNT have not been investigated from a mechanistic perspective. The results of a recent phase IIb clinical trial of a tetravalent dengue virus (DENV) vaccine suggest that NAbs, as measured using a PRNT performed with Vero cells, do not correlate with protection. This surprising finding highlights the importance of understanding how well the PRNT captures the complexity of the NAb response to DENV. In this study, we demonstrated that the structural heterogeneity of flaviviruses arising from inefficient virion maturation impacts the results of neutralization assays in a cell type-dependent manner. Neutralization titers of several monoclonal antibodies were significantly reduced when assayed on Vero cells compared to Raji cells expressing DC-SIGNR. This pattern can be explained by differences in the efficiency with which partially mature flaviviruses attach to each cell type, rather than a differential capacity of antibody to block infection. Vero cells are poorly permissive to the fraction of virions that are most sensitive to neutralization. Analysis of sera from recipients of live-attenuated monovalent DENV vaccine candidates revealed a strong correlation between the sensitivity of serum antibodies to the maturation state of DENV and cell type-dependent patterns of neutralization. Cross-reactive patterns of neutralization may be underrepresented by the “gold-standard” PRNT that employs Vero cells. IMPORTANCE Cell type-dependent patterns of neutralization describe a differential capacity of antibodies to inhibit virus infection when assayed on multiple cellular substrates. In this study, we established a link between antibodies that

  9. Mechanism and significance of cell type-dependent neutralization of flaviviruses.

    PubMed

    Mukherjee, Swati; Dowd, Kimberly A; Manhart, Carolyn J; Ledgerwood, Julie E; Durbin, Anna P; Whitehead, Stephen S; Pierson, Theodore C

    2014-07-01

    The production of neutralizing antibodies (NAbs) is a correlate of protection for many human vaccines, including currently licensed vaccines against flaviviruses. NAbs are typically measured using a plaque reduction neutralization test (PRNT). Despite its extensive use, parameters that impact the performance of the PRNT have not been investigated from a mechanistic perspective. The results of a recent phase IIb clinical trial of a tetravalent dengue virus (DENV) vaccine suggest that NAbs, as measured using a PRNT performed with Vero cells, do not correlate with protection. This surprising finding highlights the importance of understanding how well the PRNT captures the complexity of the NAb response to DENV. In this study, we demonstrated that the structural heterogeneity of flaviviruses arising from inefficient virion maturation impacts the results of neutralization assays in a cell type-dependent manner. Neutralization titers of several monoclonal antibodies were significantly reduced when assayed on Vero cells compared to Raji cells expressing DC-SIGNR. This pattern can be explained by differences in the efficiency with which partially mature flaviviruses attach to each cell type, rather than a differential capacity of antibody to block infection. Vero cells are poorly permissive to the fraction of virions that are most sensitive to neutralization. Analysis of sera from recipients of live-attenuated monovalent DENV vaccine candidates revealed a strong correlation between the sensitivity of serum antibodies to the maturation state of DENV and cell type-dependent patterns of neutralization. Cross-reactive patterns of neutralization may be underrepresented by the "gold-standard" PRNT that employs Vero cells. Cell type-dependent patterns of neutralization describe a differential capacity of antibodies to inhibit virus infection when assayed on multiple cellular substrates. In this study, we established a link between antibodies that neutralize infection in a cell

  10. Minimum variance geographic sampling

    NASA Technical Reports Server (NTRS)

    Terrell, G. R. (Principal Investigator)

    1980-01-01

    Resource inventories require samples with geographical scatter, sometimes not as widely spaced as would be hoped. A simple model of correlation over distances is used to create a minimum variance unbiased estimate population means. The fitting procedure is illustrated from data used to estimate Missouri corn acreage.

  11. A generalized concordance correlation coefficient based on the variance components generalized linear mixed models for overdispersed count data.

    PubMed

    Carrasco, Josep L

    2010-09-01

    The classical concordance correlation coefficient (CCC) to measure agreement among a set of observers assumes data to be distributed as normal and a linear relationship between the mean and the subject and observer effects. Here, the CCC is generalized to afford any distribution from the exponential family by means of the generalized linear mixed models (GLMMs) theory and applied to the case of overdispersed count data. An example of CD34+ cell count data is provided to show the applicability of the procedure. In the latter case, different CCCs are defined and applied to the data by changing the GLMM that fits the data. A simulation study is carried out to explore the behavior of the procedure with a small and moderate sample size. © 2009, The International Biometric Society.

  12. An update on modeling dose-response relationships: Accounting for correlated data structure and heterogeneous error variance in linear and nonlinear mixed models.

    PubMed

    Gonçalves, M A D; Bello, N M; Dritz, S S; Tokach, M D; DeRouchey, J M; Woodworth, J C; Goodband, R D

    2016-05-01

    Advanced methods for dose-response assessments are used to estimate the minimum concentrations of a nutrient that maximizes a given outcome of interest, thereby determining nutritional requirements for optimal performance. Contrary to standard modeling assumptions, experimental data often present a design structure that includes correlations between observations (i.e., blocking, nesting, etc.) as well as heterogeneity of error variances; either can mislead inference if disregarded. Our objective is to demonstrate practical implementation of linear and nonlinear mixed models for dose-response relationships accounting for correlated data structure and heterogeneous error variances. To illustrate, we modeled data from a randomized complete block design study to evaluate the standardized ileal digestible (SID) Trp:Lys ratio dose-response on G:F of nursery pigs. A base linear mixed model was fitted to explore the functional form of G:F relative to Trp:Lys ratios and assess model assumptions. Next, we fitted 3 competing dose-response mixed models to G:F, namely a quadratic polynomial (QP) model, a broken-line linear (BLL) ascending model, and a broken-line quadratic (BLQ) ascending model, all of which included heteroskedastic specifications, as dictated by the base model. The GLIMMIX procedure of SAS (version 9.4) was used to fit the base and QP models and the NLMIXED procedure was used to fit the BLL and BLQ models. We further illustrated the use of a grid search of initial parameter values to facilitate convergence and parameter estimation in nonlinear mixed models. Fit between competing dose-response models was compared using a maximum likelihood-based Bayesian information criterion (BIC). The QP, BLL, and BLQ models fitted on G:F of nursery pigs yielded BIC values of 353.7, 343.4, and 345.2, respectively, thus indicating a better fit of the BLL model. The BLL breakpoint estimate of the SID Trp:Lys ratio was 16.5% (95% confidence interval [16.1, 17.0]). Problems with

  13. Flavivirus RNAi suppression: decoding non-coding RNA.

    PubMed

    Pijlman, Gorben P

    2014-08-01

    Flaviviruses are important human pathogens that are transmitted by invertebrate vectors, mostly mosquitoes and ticks. During replication in their vector, flaviviruses are subject to a potent innate immune response known as antiviral RNA interference (RNAi). This defense mechanism is associated with the production of small interfering (si)RNA that lead to degradation of viral RNA. To what extent flaviviruses would benefit from counteracting antiviral RNAi is subject of debate. Here, the experimental evidence to suggest the existence of flavivirus RNAi suppressors is discussed. I will highlight the putative role of non-coding, subgenomic flavivirus RNA in suppression of RNAi in insect and mammalian cells. Novel insights from ongoing research will reveal how arthropod-borne viruses modulate innate immunity including antiviral RNAi. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. The IMPORTance of the Nucleus during Flavivirus Replication

    PubMed Central

    Lopez-Denman, Adam J.; Mackenzie, Jason M.

    2017-01-01

    Flaviviruses are a large group of arboviruses of significant medical concern worldwide. With outbreaks a common occurrence, the need for efficient viral control is required more than ever. It is well understood that flaviviruses modulate the composition and structure of membranes in the cytoplasm that are crucial for efficient replication and evading immune detection. As the flavivirus genome consists of positive sense RNA, replication can occur wholly within the cytoplasm. What is becoming more evident is that some viral proteins also have the ability to translocate to the nucleus, with potential roles in replication and immune system perturbation. In this review, we discuss the current understanding of flavivirus nuclear localisation, and the function it has during flavivirus infection. We also describe—while closely related—the functional differences between similar viral proteins in their nuclear translocation. PMID:28106839

  15. The IMPORTance of the Nucleus during Flavivirus Replication.

    PubMed

    Lopez-Denman, Adam J; Mackenzie, Jason M

    2017-01-19

    Flaviviruses are a large group of arboviruses of significant medical concern worldwide. With outbreaks a common occurrence, the need for efficient viral control is required more than ever. It is well understood that flaviviruses modulate the composition and structure of membranes in the cytoplasm that are crucial for efficient replication and evading immune detection. As the flavivirus genome consists of positive sense RNA, replication can occur wholly within the cytoplasm. What is becoming more evident is that some viral proteins also have the ability to translocate to the nucleus, with potential roles in replication and immune system perturbation. In this review, we discuss the current understanding of flavivirus nuclear localisation, and the function it has during flavivirus infection. We also describe-while closely related-the functional differences between similar viral proteins in their nuclear translocation.

  16. Cycluridine: A novel antiviral effective against flaviviruses.

    PubMed

    Galabov, Angel S; Mukova, Lucia; Abashev, Yuriy P; Wassilewa, Lilia; Tzvetkov, Petko; Minkov, Vassil; Barinskiy, Igor F; Rice, Charles M; Ouzounov, Sergey; Sidzhakova, Dorotea

    2017-08-01

    This review describes the contemporary state of research for antivirals effective against flaviviruses, especially focusing on inhibitors of the pestivirus causative agent of bovine viral diarrhoea virus. We highlight cycluridine, an originally synthesized Mannich's base [a tetrahydro-2(1H)-pyrimidinones derivative], as a highly effective antiviral possessing a strong inhibitory effect on bovine viral diarrhoea virus replication. Cycluridine was active against replication of a wide variety of bovine viral diarrhoea virus strains in cell cultures. The drug-sensitive period in the bovine viral diarrhoea virus replication cycle included the latent period and the exponential phase; a 90-min delay in the peak of viral RNA synthesis was observed. Cycluridine administered orally manifested a pronounced protective effect in calves with natural mucosal disease/viral diarrhoea and calves experimentally infected with bovine viral diarrhoea virus. Its magnitude of activity and selectivity places cycluridine in the lead among all known substances with anti- bovine viral diarrhoea virus activity. Additionally, cycluridine applied subcutaneously showed anti-tick-born encephalitis virus activity, manifesting a marked protective effect in mice infected with tick-born encephalitis virus. Cycluridine could be a prospective antiviral in veterinary and medical practice for the treatment of bovine viral diarrhoea virus and other flavivirus infections.

  17. Usutu Virus: An Emerging Flavivirus in Europe

    PubMed Central

    Ashraf, Usama; Ye, Jing; Ruan, Xindi; Wan, Shengfeng; Zhu, Bibo; Cao, Shengbo

    2015-01-01

    Usutu virus (USUV) is an African mosquito-borne flavivirus belonging to the Japanese encephalitis virus serocomplex. USUV is closely related to Murray Valley encephalitis virus, Japanese encephalitis virus, and West Nile virus. USUV was discovered in South Africa in 1959. In Europe, the first true demonstration of circulation of USUV was reported in Austria in 2001 with a significant die-off of Eurasian blackbirds. In the subsequent years, USUV expanded to neighboring countries, including Italy, Germany, Spain, Hungary, Switzerland, Poland, England, Czech Republic, Greece, and Belgium, where it caused unusual mortality in birds. In 2009, the first two human cases of USUV infection in Europe have been reported in Italy, causing meningoencephalitis in immunocompromised patients. This review describes USUV in terms of its life cycle, USUV surveillance from Africa to Europe, human cases, its cellular tropism and pathogenesis, its genetic relationship with other flaviviruses, genetic diversity among USUV strains, its diagnosis, and a discussion of the potential future threat to Asian countries. PMID:25606971

  18. Organization of the Flavivirus RNA replicase complex.

    PubMed

    Brand, Carolin; Bisaillon, Martin; Geiss, Brian J

    2017-08-16

    Flaviviruses, such as dengue, Japanese encephalitis, West Nile, yellow fever, and Zika viruses, are serious human pathogens that cause significant morbidity and mortality globally each year. Flaviviruses are single-stranded, positive-sense RNA viruses, and encode two multidomain proteins, NS3 and NS5, that possess all enzymatic activities required for genome replication and capping. NS3 and NS5 interact within virus-induced replication compartments to form the RNA genome replicase complex. Although the individual enzymatic activities of both proteins have been extensively studied and are well characterized, there are still gaps in our understanding of how they interact to efficiently coordinate their respective activities during positive-strand RNA synthesis and capping. Here, we discuss what is known about the structures and functions of the NS3 and NS5 proteins and propose a preliminary NS3:NS5:RNA interaction model based on a large body of literature about how the viral enzymes function, physical restraints between NS3 and NS5, as well as critical steps in the replication process. For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

  19. [When some Flaviviruses are throwing our certainties].

    PubMed

    Chastel, C

    2012-10-01

    During the past two decades, a number of mosquito-borne flaviviruses, mainly of African origin, have invaded new geographical areas where they have never been active. This was the case for the Japanese encephalitis virus which reached the northeastern part of Australia (1995) and, above all, for the West Nile virus which, since 1999, entirely colonized the American continent. Then, the Usutu virus invaded a large part of the Western Europe (2001) while the Zika virus caused a large epidemic in an island of Micronesia (2007). Finally, in 2010, the Tembusu virus devastated many duck farms in China while the Bagaza virus, after having provoked human encephalitis in India, reached the southern part of Spain. In the affected areas, new pathogenic outcomes were observed in humans and animals while new vertebrate hosts and mosquito species were infected. Moreover, unusual ways of contamination were described. The origins of this unprecedented evolution remain to be clarified.

  20. Conformational Changes of the Flavivirus E Glycoprotein

    PubMed Central

    Zhang, Ying; Zhang, Wei; Ogata, Steven; Clements, David; Strauss, James H.; Baker, Timothy S.; Kuhn, Richard J.; Rossmann, Michael G.

    2014-01-01

    Summary Dengue virus, a member of the Flaviviridae family, has a surface composed of 180 copies each of the envelope (E) glycoprotein and the membrane (M) protein. The crystal structure of an N-terminal fragment of E has been determined and compared with a previously described structure. The primary difference between these structures is a 10° rotation about a hinge relating the fusion domain DII to domains DI and DIII. These two rigid body components were used for independent fitting of E into the cryo-electron microscopy maps of both immature and mature dengue viruses. The fitted E structures in these two particles showed a difference of 27° between the two components. Comparison of the E structure in its postfusion state with that in the immature and mature virions shows a rotation approximately around the same hinge. Flexibility of E is apparently a functional requirement for assembly and infection of flaviviruses. PMID:15341726

  1. Flavivirus-induced antibody cross-reactivity

    PubMed Central

    Mansfield, Karen L.; Horton, Daniel L.; Johnson, Nicholas; Li, Li; Barrett, Alan D. T.; Smith, Derek J.; Galbraith, Sareen E.; Solomon, Tom

    2011-01-01

    Dengue viruses (DENV) cause countless human deaths each year, whilst West Nile virus (WNV) has re-emerged as an important human pathogen. There are currently no WNV or DENV vaccines licensed for human use, yet vaccines exist against other flaviviruses. To investigate flavivirus cross-reactivity, sera from a human cohort with a history of vaccination against tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV) and yellow fever virus (YFV) were tested for antibodies by plaque reduction neutralization test. Neutralization of louping ill virus (LIV) occurred, but no significant neutralization of Murray Valley encephalitis virus was observed. Sera from some individuals vaccinated against TBEV and JEV neutralized WNV, which was enhanced by YFV vaccination in some recipients. Similarly, some individuals neutralized DENV-2, but this was not significantly influenced by YFV vaccination. Antigenic cartography techniques were used to generate a geometric illustration of the neutralization titres of selected sera against WNV, TBEV, JEV, LIV, YFV and DENV-2. This demonstrated the individual variation in antibody responses. Most sera had detectable titres against LIV and some had titres against WNV and DENV-2. Generally, LIV titres were similar to titres against TBEV, confirming the close antigenic relationship between TBEV and LIV. JEV was also antigenically closer to TBEV than WNV, using these sera. The use of sera from individuals vaccinated against multiple pathogens is unique relative to previous applications of antigenic cartography techniques. It is evident from these data that notable differences exist between amino acid sequence identity and mapped antigenic relationships within the family Flaviviridae. PMID:21900425

  2. Mercadeo Virus: A Novel Mosquito-Specific Flavivirus from Panama

    PubMed Central

    Carrera, Jean-Paul; Guzman, Hilda; Beltrán, Davis; Díaz, Yamilka; López-Vergès, Sandra; Torres-Cosme, Rolando; Popov, Vsevolod; Widen, Steven G.; Wood, Thomas G.; Weaver, Scott C.; Cáceres-Carrera, Lorenzo; Vasilakis, Nikos; Tesh, Robert B.

    2015-01-01

    Viruses in the genus Flavivirus (family Flaviviridae) include many arthropod-borne viruses of public health and veterinary importance. However, during the past two decades an explosion of novel insect-specific flaviviruses (ISFs), some closely related to vertebrate pathogens, have been discovered. Although many flavivirus pathogens of vertebrates have been isolated from naturally infected mosquitoes in Panama, ISFs have not previously been reported from the country. This report describes the isolation and characterization of a novel ISF, tentatively named Mercadeo virus (MECDV), obtained from Culex spp. mosquitoes collected in Panama. Two MECDV isolates were sequenced and cluster phylogenetically with cell-fusing agent virus (CFAV) and Nakiwogo virus (NAKV) to form a distinct lineage within the insect-specific group of flaviviruses. PMID:26304915

  3. Mercadeo Virus: A Novel Mosquito-Specific Flavivirus from Panama.

    PubMed

    Carrera, Jean-Paul; Guzman, Hilda; Beltrán, Davis; Díaz, Yamilka; López-Vergès, Sandra; Torres-Cosme, Rolando; Popov, Vsevolod; Widen, Steven G; Wood, Thomas G; Weaver, Scott C; Cáceres-Carrera, Lorenzo; Vasilakis, Nikos; Tesh, Robert B

    2015-11-01

    Viruses in the genus Flavivirus (family Flaviviridae) include many arthropod-borne viruses of public health and veterinary importance. However, during the past two decades an explosion of novel insect-specific flaviviruses (ISFs), some closely related to vertebrate pathogens, have been discovered. Although many flavivirus pathogens of vertebrates have been isolated from naturally infected mosquitoes in Panama, ISFs have not previously been reported from the country. This report describes the isolation and characterization of a novel ISF, tentatively named Mercadeo virus (MECDV), obtained from Culex spp. mosquitoes collected in Panama. Two MECDV isolates were sequenced and cluster phylogenetically with cell-fusing agent virus (CFAV) and Nakiwogo virus (NAKV) to form a distinct lineage within the insect-specific group of flaviviruses. © The American Society of Tropical Medicine and Hygiene.

  4. Viral Interference and Persistence in Mosquito-Borne Flaviviruses

    PubMed Central

    Salas-Benito, Juan Santiago; De Nova-Ocampo, Mónica

    2015-01-01

    Mosquito-borne flaviviruses are important pathogens for humans, and the detection of two or more flaviviruses cocirculating in the same geographic area has often been reported. However, the epidemiological impact remains to be determined. Mosquito-borne flaviviruses are primarily transmitted through Aedes and Culex mosquitoes; these viruses establish a life-long or persistent infection without apparent pathological effects. This establishment requires a balance between virus replication and the antiviral host response. Viral interference is a phenomenon whereby one virus inhibits the replication of other viruses, and this condition is frequently associated with persistent infections. Viral interference and persistent infection are determined by several factors, such as defective interfering particles, competition for cellular factors required for translation/replication, and the host antiviral response. The interaction between two flaviviruses typically results in viral interference, indicating that these viruses share common features during the replicative cycle in the vector. The potential mechanisms involved in these processes are reviewed here. PMID:26583158

  5. Antibody-mediated neutralization of flaviviruses: A reductionist view

    PubMed Central

    Dowd, Kimberly A.; Pierson, Theodore C.

    2011-01-01

    Flaviviruses are a group of ~70 small RNA viruses responsible for significant morbidity and mortality across the globe. Efforts to develop effective vaccines for several clinically important flaviviruses are underway. Antibodies are a significant component of the host’s protective response against flavivirus infection with the potential to contribute to immunity via several distinct mechanisms, including an ability to directly neutralize virus infection. Conversely, virus-reactive antibodies have been implicated in the increased risk of severe clinical manifestations following secondary dengue virus infection. In this review, we will discuss recent progress toward understanding the molecular basis of antibody-mediated neutralization of flaviviruses. Neutralization requires engagement of the virion with a stoichiometry that exceeds a required threshold. From this perspective, we will discuss viral and host factors that impact the number of antibody molecules bound to the virus particle and significantly modulate the potency of neutralizing antibodies. PMID:21255816

  6. Thermodynamic mechanism for the evasion of antibody neutralization in flaviviruses.

    PubMed

    Maillard, Rodrigo A; Liu, Tong; Beasley, David W C; Barrett, Alan D T; Hilser, Vincent J; Lee, J Ching

    2014-07-23

    Mutations in the epitopes of antigenic proteins can confer viral resistance to antibody-mediated neutralization. However, the fundamental properties that characterize epitope residues and how mutations affect antibody binding to alter virus susceptibility to neutralization remain largely unknown. To address these questions, we used an ensemble-based algorithm to characterize the effects of mutations on the thermodynamics of protein conformational fluctuations. We applied this method to the envelope protein domain III (ED3) of two medically important flaviviruses: West Nile and dengue 2. We determined an intimate relationship between the susceptibility of a residue to thermodynamic perturbations and epitope location. This relationship allows the successful identification of the primary epitopes in each ED3, despite their high sequence and structural similarity. Mutations that allow the ED3 to evade detection by the antibody either increase or decrease conformational fluctuations of the epitopes through local effects or long-range interactions. Spatially distant interactions originate in the redistribution of conformations of the ED3 ensembles, not through a mechanically connected array of contiguous amino acids. These results reconcile previous observations of evasion of neutralization by mutations at a distance from the epitopes. Finally, we established a quantitative correlation between subtle changes in the conformational fluctuations of the epitope and large defects in antibody binding affinity. This correlation suggests that mutations that allow viral growth, while reducing neutralization, do not generate significant structural changes and underscores the importance of protein fluctuations and long-range interactions in the mechanism of antibody-mediated neutralization resistance.

  7. Flavivirus Infections of Bats: Potential Role in Zika Virus Ecology.

    PubMed

    Kading, Rebekah C; Schountz, Tony

    2016-11-02

    Understanding the vector and nonhuman vertebrate species contributing to Zika virus (ZIKAV) transmission is critical to understanding the ecology of this emerging arbovirus and its potential to establish in new geographic areas. This minireview summarizes what is known regarding the association of bats with flaviviruses (Flaviviridae: Flavivirus) with a particular emphasis on the potential role of bats in the sylvatic transmission of ZIKAV. Key research directions that remain to be addressed are also discussed.

  8. Analysis of variance, normal quantile-quantile correlation and effective expression support of pooled expression ratio of reference genes for defining expression stability.

    PubMed

    Priyadarshi, Himanshu; Das, Rekha; Kumar, Shivendra; Kishore, Pankaj; Kumar, Sujit

    2017-01-01

    Identification of a reference gene unaffected by the experimental conditions is obligatory for accurate measurement of gene expression through relative quantification. Most existing methods directly analyze variability in crossing point (Cp) values of reference genes and fail to account for template-independent factors that affect Cp values in their estimates. We describe the use of three simple statistical methods namely analysis of variance (ANOVA), normal quantile-quantile correlation (NQQC) and effective expression support (EES), on pooled expression ratios of reference genes in a panel to overcome this issue. The pooling of expression ratios across the genes in the panel nullify the sample specific effects uniformly affecting all genes that are falsely reflected as instability. Our methods also offer the flexibility to include sample specific PCR efficiencies in estimations, when available, for improved accuracy. Additionally, we describe a correction factor from the ANOVA method to correct the relative fold change of a target gene if no truly stable reference gene could be found in the analyzed panel. The analysis is described on a synthetic data set to simplify the explanation of the statistical treatment of data.

  9. Novel flaviviruses from mosquitoes: mosquito-specific evolutionary lineages within the phylogenetic group of mosquito-borne flaviviruses.

    PubMed

    Huhtamo, Eili; Cook, Shelley; Moureau, Gregory; Uzcátegui, Nathalie Y; Sironen, Tarja; Kuivanen, Suvi; Putkuri, Niina; Kurkela, Satu; Harbach, Ralph E; Firth, Andrew E; Vapalahti, Olli; Gould, Ernest A; de Lamballerie, Xavier

    2014-09-01

    Novel flaviviruses that are genetically related to pathogenic mosquito-borne flaviviruses (MBFV) have been isolated from mosquitoes in various geographical locations, including Finland. We isolated and characterized another novel virus of this group from Finnish mosquitoes collected in 2007, designated as Ilomantsi virus (ILOV). Unlike the MBFV that infect both vertebrates and mosquitoes, the MBFV-related viruses appear to be specific to mosquitoes similar to the insect-specific flaviviruses (ISFs). In this overview of MBFV-related viruses we conclude that they differ from the ISFs genetically and antigenically. Phylogenetic analyses separated the MBFV-related viruses isolated in Africa, the Middle East and South America from those isolated in Europe and Asia. Serological cross-reactions of MBFV-related viruses with other flaviviruses and their potential for vector-borne transmission require further characterization. The divergent MBFV-related viruses are probably significantly under sampled to date and provide new information on the variety, properties and evolution of vector-borne flaviviruses. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Novel flaviviruses from mosquitoes: Mosquito-specific evolutionary lineages within the phylogenetic group of mosquito-borne flaviviruses

    PubMed Central

    Huhtamo, Eili; Cook, Shelley; Moureau, Gregory; Uzcátegui, Nathalie Y.; Sironen, Tarja; Kuivanen, Suvi; Putkuri, Niina; Kurkela, Satu; Harbach, Ralph E.; Firth, Andrew E.; Vapalahti, Olli; Gould, Ernest A.; de Lamballerie, Xavier

    2014-01-01

    Novel flaviviruses that are genetically related to pathogenic mosquito-borne flaviviruses (MBFV) have been isolated from mosquitoes in various geographical locations, including Finland. We isolated and characterized another novel virus of this group from Finnish mosquitoes collected in 2007, designated as Ilomantsi virus (ILOV). Unlike the MBFV that infect both vertebrates and mosquitoes, the MBFV-related viruses appear to be specific to mosquitoes similar to the insect-specific flaviviruses (ISFs). In this overview of MBFV-related viruses we conclude that they differ from the ISFs genetically and antigenically. Phylogenetic analyses separated the MBFV-related viruses isolated in Africa, the Middle East and South America from those isolated in Europe and Asia. Serological cross-reactions of MBFV-related viruses with other flaviviruses and their potential for vector-borne transmission require further characterization. The divergent MBFV-related viruses are probably significantly under sampled to date and provide new information on the variety, properties and evolution of vector-borne flaviviruses. PMID:25108382

  11. Pathophysiological mechanisms of Flavivirus infection of the central nervous system.

    PubMed

    Pardigon, N

    2017-09-01

    Flaviviruses are important human pathogens. Transmitted by the bite of infected mosquitoes, Flaviviruses such as West Nile and Japanese encephalitis may reach the central nervous system where they can elicit severe diseases. Their ability to cross the blood-brain-barrier is still poorly understood. The newly emerging Zika Flavivirus on the other hand very rarely reaches the brain of adults, but can infect neural progenitors in the developing central nervous system of fetuses, eliciting devastating congenital malformations including microcephaly. This short review focuses on selected aspects of West Nile, Japanese encephalitis and Zika virus pathophysiological features such as neuroinvasion and neurovirulence, and highlights what we know about some possible mechanisms involved in Flaviviral neuropathogenesis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. Development of one-step quantitative reverse transcription PCR for the rapid detection of flaviviruses.

    PubMed

    Patel, Pranav; Landt, Olfert; Kaiser, Marco; Faye, Oumar; Koppe, Tanja; Lass, Ulrich; Sall, Amadou A; Niedrig, Matthias

    2013-02-14

    The genus Flavivirus includes several pathogenic agents that cause severe illness in humans. Re-emergence of West Nile virus in Europe and continuous spread of certain flaviviruses such as dengue, yellow fever and Japanese encephalitis viruses represent a global danger to public health. Therefore, a rapid and accurate molecular method is required for diagnostics and epidemiological surveillance of flaviviruses. A Pan-Flavi quantitative RT-PCR assay using a Locked-Nucleic Acid probe targeting the flavivirus NS5 gene was developed and optimized to detect a wide range of flaviviruses simultaneously. The specificity and sensitivity of the Pan-Flavi assay were tested using RNA of different flaviviruses and non-flaviviruses. Furthermore, the assay was compared directly to flavivirus species-specific assays for the ability to detect flaviviruses sensitively. Two degenerate primers and one Locked-Nucleic Acids probe were designed to amplify most of the flaviviruses. To increase the specificity and fluorescence signal of the Pan-Flavi assay for detection of yellow fever virus and dengue virus 4, additional primers and probes were included. Viral RNA of thirty different flaviviruses was detected, verifying the broad range specificity. The testing of this assay was successful, using standard plasmid and RNA dilutions of yellow fever virus vaccine strain, dengue virus 1 and tick-borne encephalitis virus, with a sensitivity limit of 10-100 genome copies/reaction. Also comparatively good results were achieved for detecting different flaviviruses by the Pan-Flavi assay when compared to the flavivirus species-specific assays. The assay is rapid, broad-range flavivirus-specific and highly sensitive making it a valuable tool for rapid detection of flaviviruses in livestock samples, epidemiological studies or as useful complement to single flavivirus-specific assays for clinical diagnosis.

  13. VARAN: A Linear Model Variance Analysis Program.

    ERIC Educational Resources Information Center

    Hall, Charles E.; And Others

    This memorandum is the manual for the VARAN (VARiance ANalysis) program, which is the latest addition to a series of computer programs for multivariate analysis of variance. As with earlier programs, analysis of variance, univariate and multivariate, is the main target of the program. Correlation analysis of all types is available with printout in…

  14. Flavivirus Infection Impairs Peroxisome Biogenesis and Early Antiviral Signaling.

    PubMed

    You, Jaehwan; Hou, Shangmei; Malik-Soni, Natasha; Xu, Zaikun; Kumar, Anil; Rachubinski, Richard A; Frappier, Lori; Hobman, Tom C

    2015-12-01

    Flaviviruses are significant human pathogens that have an enormous impact on the global health burden. Currently, there are very few vaccines against or therapeutic treatments for flaviviruses, and our understanding of how these viruses cause disease is limited. Evidence suggests that the capsid proteins of flaviviruses play critical nonstructural roles during infection, and therefore, elucidating how these viral proteins affect cellular signaling pathways could lead to novel targets for antiviral therapy. We used affinity purification to identify host cell proteins that interact with the capsid proteins of West Nile and dengue viruses. One of the cellular proteins that formed a stable complex with flavivirus capsid proteins is the peroxisome biogenesis factor Pex19. Intriguingly, flavivirus infection resulted in a significant loss of peroxisomes, an effect that may be due in part to capsid expression. We posited that capsid protein-mediated sequestration and/or degradation of Pex19 results in loss of peroxisomes, a situation that could result in reduced early antiviral signaling. In support of this hypothesis, we observed that induction of the lambda interferon mRNA in response to a viral RNA mimic was reduced by more than 80%. Together, our findings indicate that inhibition of peroxisome biogenesis may be a novel mechanism by which flaviviruses evade the innate immune system during early stages of infection. RNA viruses infect hundreds of millions of people each year, causing significant morbidity and mortality. Chief among these pathogens are the flaviviruses, which include dengue virus and West Nile virus. Despite their medical importance, there are very few prophylactic or therapeutic treatments for these viruses. Moreover, the manner in which they subvert the innate immune response in order to establish infection in mammalian cells is not well understood. Recently, peroxisomes were reported to function in early antiviral signaling, but very little is known

  15. Degrees of maturity: the complex structure and biology of flaviviruses.

    PubMed

    Pierson, Theodore C; Diamond, Michael S

    2012-04-01

    Flaviviruses are small enveloped virions that enter target cells in a pH-dependent fashion. Virus attachment, entry, and membrane fusion are orchestrated by the envelope (E) and pre-membrane (prM) proteins, the two structural proteins displayed on the surface of virions. Flaviviruses assemble as an immature non-infectious form onto which prM and E form trimeric spikes. During egress from infected cells, flaviviruses undergo dramatic structural changes characterized by the formation of a herringbone arrangement of E proteins that lie flat against the surface of the virion and cleavage of the prM protein by the cellular protease furin. The result is a relatively smooth, infectious mature virion. This dynamic process is now understood in structural detail at the atomic level. However, recent studies indicate that many of the virions released from cells share structural features of both immature and mature virus particles. These mosaic partially mature virions are infectious and interact uniquely with target cells and the host immune response. Here, we will discuss recent advances in our understanding of the biology and significance of partially mature flaviviruses.

  16. The role of viral persistence in flavivirus biology

    PubMed Central

    Mlera, Luwanika; Melik, Wessam; Bloom, Marshall E.

    2014-01-01

    In nature, vector-borne flaviviruses are persistently cycled between either the tick or mosquito vector and small mammals such as rodents, skunks, and swine. These viruses account for considerable human morbidity and mortality worldwide. Increasing and substantial evidence of viral persistence in humans, which includes the isolation of RNA by RT-PCR and infectious virus by culture, continues to be reported. Viral persistence can also be established in vitro in various human, animal, arachnid and insect cell lines in culture. Although some research has focused on the potential roles of defective virus particles, evasion of the immune response through the manipulation of autophagy and/or apoptosis, the precise mechanism of flavivirus persistence is still not well understood. We propose additional research for further understanding of how viral persistence is established in different systems. Avenues for additional studies include determining if the multifunctional flavivirus protein NS5 has a role in viral persistence, the development of relevant animal models of viral persistence as well as investigating the host responses that allow vector borne flavivirus replication without detrimental effects on infected cells. Such studies might shed more light on the viral-host relationships, and could be used to unravel the mechanisms for establishment of persistence. PMID:24737600

  17. Entomological surveillance for flaviviruses at migratory bird stopover sites in Hokkaido, Japan, and a new insect flavivirus detected in Aedes galloisi (Diptera: Culicidae).

    PubMed

    Hoshino, Keita; Takahashi-Nakaguchi, Azusa; Isawa, Haruhiko; Sasaki, Toshinori; Higa, Yukiko; Kasai, Shinji; Tsuda, Yoshio; Sawabe, Kyoko; Kobayashi, Mutsuo

    2012-01-01

    To investigate the possible spread of West Nile virus (WNV) into Japan, we carried out entomological surveillance for flaviviruses at migratory bird stopover sites in Hokkaido, Japan, during 2003-2006. A total of 3,826 mosquitoes, identified as 15 species in five genera, were collected and 2,465 of these were grouped into 123 pools that were assayed for cytopathic effects on mosquito and mammalian cell cultures and for flavivirus RNA by reverse transcription-polymerase chain reaction using flavivirus universal primer sets for fragments of the NS3 and NS5 genes. Neither WNV nor other mosquito-vertebrate transmitted flaviviruses were detected in mosquitoes collected at any of the sites in Hokkaido, but five Culex flaviviruses and one novel Aedes galloisi flavivirus were identified from Culex pipiens L. s. l. and Aedes galloisi Yamada, respectively. Genetic and phylogenetic analyses based on the partial NS5 nucleotide sequences classified Aedes galloisi flavivirus with the insect flavivirus, but distant from Cell fusing agent, Kamiti river virus, and Culex flaviviruses, showing <74% sequence identities. Polymerase chain reaction-based bloodmeal analysis of 79 females showed that all of the Aedes and Ochlerotatus mosquitoes fed on mammals (deer and humans), whereas, Cx. pipiens s. l. mosquitoes fed on both of avian (ducks and sparrows, 85.7%) and mammalian hosts (dog, 14.3%). We suggest that to date WNV has not become established in Japan.

  18. Characterization of a Novel Flavivirus from Mosquitoes in Northern Europe That Is Related to Mosquito-Borne Flaviviruses of the Tropics▿

    PubMed Central

    Huhtamo, Eili; Putkuri, Niina; Kurkela, Satu; Manni, Tytti; Vaheri, Antti; Vapalahti, Olli; Uzcátegui, Nathalie Y.

    2009-01-01

    A novel flavivirus was isolated from mosquitoes in Finland, representing the first mosquito-borne flavivirus from Northern Europe. The isolate, designated Lammi virus (LAMV), was antigenically cross-reactive with other flaviviruses and exhibited typical flavivirus morphology as determined by electron microscopy. The genomic sequence of LAMV was highly divergent from the recognized flaviviruses, and yet the polyprotein properties resembled those of mosquito-borne flaviviruses. Phylogenetic analysis of the complete coding sequence showed that LAMV represented a distinct lineage related to the Aedes sp.-transmitted human pathogenic flaviviruses, similarly to the newly described Nounané virus (NOUV), a flavivirus from Africa (S. Junglen et al., J. Virol. 83:4462-4468, 2009). Despite the low sequence homology, LAMV and NOUV were phylogenetically grouped closely, likely representing separate species of a novel group of flaviviruses. Despite the biological properties preferring replication in mosquito cells, the genetic relatedness of LAMV to viruses associated with vertebrate hosts warrants a search for disease associations. PMID:19570865

  19. [Detection of flavivirus in mosquitoes (Diptera: Culicidae) from Easter Island-Chile].

    PubMed

    Collao, Ximena; Prado, Lorena; González, Christian; Vásquez, Ana; Araki, Romina; Henríquez, Tuki; Peña, Cindy M

    2015-02-01

    Flaviviruses are arthropod-borne viruses, mainly by mosquitoes of the genera Aedes and Culex (Culicidae) that are detected in tropical and subtropical areas. Main flaviviruses of public health importance are: dengue, West Nile virus, yellow fever, among others. In continental Chile, flaviviruses has not been detected. However, there are indigenous cases of dengue detected in Easter Island since 2002, as the presence of its vector Aedes aegypti. The aim of this study was: To determine diversity of flavivirus mosquitoes present in Easter Island. Thirty pools of mosquitoes collected in Hanga Roa were analyzed; a RT-PCR nested flavivirus was performed. Thirteen positive samples were detected and the amplification products were sequenced, identifying two specific flavivirus Insect, the Cell fusing agent virus and other related viruses Kamiti River. This is the first study in Chile showed the presence of flavivirus in vectors in Easter Island.

  20. Ecuador Paraiso Escondido Virus, a New Flavivirus Isolated from New World Sand Flies in Ecuador, Is the First Representative of a Novel Clade in the Genus Flavivirus

    PubMed Central

    Zapata, Sonia; Bichaud, Laurence; Moureau, Grégory; Lemey, Philippe; Firth, Andrew E.; Gritsun, Tamara S.; Gould, Ernest A.; de Lamballerie, Xavier; Depaquit, Jérôme

    2015-01-01

    ABSTRACT A new flavivirus, Ecuador Paraiso Escondido virus (EPEV), named after the village where it was discovered, was isolated from sand flies (Psathyromyia abonnenci, formerly Lutzomyia abonnenci) that are unique to the New World. This represents the first sand fly-borne flavivirus identified in the New World. EPEV exhibited a typical flavivirus genome organization. Nevertheless, the maximum pairwise amino acid sequence identity with currently recognized flaviviruses was 52.8%. Phylogenetic analysis of the complete coding sequence showed that EPEV represents a distinct clade which diverged from a lineage that was ancestral to the nonvectored flaviviruses Entebbe bat virus, Yokose virus, and Sokoluk virus and also the Aedes-associated mosquito-borne flaviviruses, which include yellow fever virus, Sepik virus, Saboya virus, and others. EPEV replicated in C6/36 mosquito cells, yielding high infectious titers, but failed to reproduce either in vertebrate cell lines (Vero, BHK, SW13, and XTC cells) or in suckling mouse brains. This surprising result, which appears to eliminate an association with vertebrate hosts in the life cycle of EPEV, is discussed in the context of the evolutionary origins of EPEV in the New World. IMPORTANCE The flaviviruses are rarely (if ever) vectored by sand fly species, at least in the Old World. We have identified the first representative of a sand fly-associated flavivirus, Ecuador Paraiso Escondido virus (EPEV), in the New World. EPEV constitutes a novel clade according to current knowledge of the flaviviruses. Phylogenetic analysis of the virus genome showed that EPEV roots the Aedes-associated mosquito-borne flaviviruses, including yellow fever virus. In light of this new discovery, the New World origin of EPEV is discussed together with that of the other flaviviruses. PMID:26355096

  1. Ecuador Paraiso Escondido Virus, a New Flavivirus Isolated from New World Sand Flies in Ecuador, Is the First Representative of a Novel Clade in the Genus Flavivirus.

    PubMed

    Alkan, Cigdem; Zapata, Sonia; Bichaud, Laurence; Moureau, Grégory; Lemey, Philippe; Firth, Andrew E; Gritsun, Tamara S; Gould, Ernest A; de Lamballerie, Xavier; Depaquit, Jérôme; Charrel, Rémi N

    2015-12-01

    A new flavivirus, Ecuador Paraiso Escondido virus (EPEV), named after the village where it was discovered, was isolated from sand flies (Psathyromyia abonnenci, formerly Lutzomyia abonnenci) that are unique to the New World. This represents the first sand fly-borne flavivirus identified in the New World. EPEV exhibited a typical flavivirus genome organization. Nevertheless, the maximum pairwise amino acid sequence identity with currently recognized flaviviruses was 52.8%. Phylogenetic analysis of the complete coding sequence showed that EPEV represents a distinct clade which diverged from a lineage that was ancestral to the nonvectored flaviviruses Entebbe bat virus, Yokose virus, and Sokoluk virus and also the Aedes-associated mosquito-borne flaviviruses, which include yellow fever virus, Sepik virus, Saboya virus, and others. EPEV replicated in C6/36 mosquito cells, yielding high infectious titers, but failed to reproduce either in vertebrate cell lines (Vero, BHK, SW13, and XTC cells) or in suckling mouse brains. This surprising result, which appears to eliminate an association with vertebrate hosts in the life cycle of EPEV, is discussed in the context of the evolutionary origins of EPEV in the New World. The flaviviruses are rarely (if ever) vectored by sand fly species, at least in the Old World. We have identified the first representative of a sand fly-associated flavivirus, Ecuador Paraiso Escondido virus (EPEV), in the New World. EPEV constitutes a novel clade according to current knowledge of the flaviviruses. Phylogenetic analysis of the virus genome showed that EPEV roots the Aedes-associated mosquito-borne flaviviruses, including yellow fever virus. In light of this new discovery, the New World origin of EPEV is discussed together with that of the other flaviviruses. Copyright © 2015 Alkan et al.

  2. The variances of Sp1 and NF-κB elements correlate with the greater capacity of Chinese HIV-1 B′-LTR for driving gene expression

    PubMed Central

    Qu, Di; Li, Chuan; Sang, Feng; Li, Qiang; Jiang, Zhi-Qiang; Xu, Li-Ran; Guo, Hui-Jun; Zhang, Chiyu; Wang, Jian-Hua

    2016-01-01

    The 5′ end of HIV-1 long terminal repeat (LTR) serves as a promoter that plays an essential role in driving viral gene transcription. Manipulation of HIV-1 LTR provides a potential therapeutic strategy for suppressing viral gene expression or excising integrated provirus. Subtype-specific genetic diversity in the LTR region has been observed. The minor variance of LTR, particularly in the transcription factor binding sites, can have a profound impact on its activity. However, the LTR profiles from major endemic Chinese subtypes are not well characterized. Here, by characterizing the sequences and functions of LTRs from endemic Chinese HIV-1 subtypes, we showed that nucleotide variances of Sp1 core promoter and NF-κB element are associated with varied LTR capacity for driving viral gene transcription. The greater responsiveness of Chinese HIV-1 B′-LTR for driving viral gene transcription upon stimulation is associated with an increased level of viral reactivation. Moreover, we demonstrated that the introduction of CRISPR/dead Cas9 targeting Sp1 or NF-κB element suppressed viral gene expression. Taken together, our study characterized LTRs from endemic HIV-1 subtypes in China and suggests a potential target for the suppression of viral gene expression and a novel strategy that facilitates the accomplishment of a functional cure. PMID:27698388

  3. The variances of Sp1 and NF-κB elements correlate with the greater capacity of Chinese HIV-1 B'-LTR for driving gene expression.

    PubMed

    Qu, Di; Li, Chuan; Sang, Feng; Li, Qiang; Jiang, Zhi-Qiang; Xu, Li-Ran; Guo, Hui-Jun; Zhang, Chiyu; Wang, Jian-Hua

    2016-10-04

    The 5' end of HIV-1 long terminal repeat (LTR) serves as a promoter that plays an essential role in driving viral gene transcription. Manipulation of HIV-1 LTR provides a potential therapeutic strategy for suppressing viral gene expression or excising integrated provirus. Subtype-specific genetic diversity in the LTR region has been observed. The minor variance of LTR, particularly in the transcription factor binding sites, can have a profound impact on its activity. However, the LTR profiles from major endemic Chinese subtypes are not well characterized. Here, by characterizing the sequences and functions of LTRs from endemic Chinese HIV-1 subtypes, we showed that nucleotide variances of Sp1 core promoter and NF-κB element are associated with varied LTR capacity for driving viral gene transcription. The greater responsiveness of Chinese HIV-1 B'-LTR for driving viral gene transcription upon stimulation is associated with an increased level of viral reactivation. Moreover, we demonstrated that the introduction of CRISPR/dead Cas9 targeting Sp1 or NF-κB element suppressed viral gene expression. Taken together, our study characterized LTRs from endemic HIV-1 subtypes in China and suggests a potential target for the suppression of viral gene expression and a novel strategy that facilitates the accomplishment of a functional cure.

  4. Salicylates Inhibit Flavivirus Replication Independently of Blocking Nuclear Factor Kappa B Activation

    PubMed Central

    Liao, Ching-Len; Lin, Yi-Ling; Wu, Bi-Ching; Tsao, Chang-Huei; Wang, Mei-Chuan; Liu, Chiu-I; Huang, Yue-Ling; Chen, Jui-Hui; Wang, Jia-Pey; Chen, Li-Kuang

    2001-01-01

    Flaviviruses comprise a positive-sense RNA genome that replicates exclusively in the cytoplasm of infected cells. Whether flaviviruses require an activated nuclear factor(s) to complete their life cycle and trigger apoptosis in infected cells remains elusive. Flavivirus infections quickly activate nuclear factor kappa B (NF-κB), and salicylates have been shown to inhibit NF-κB activation. In this study, we investigated whether salicylates suppress flavivirus replication and virus-induced apoptosis in cultured cells. In a dose-dependent inhibition, we found salicylates within a range of 1 to 5 mM not only restricted flavivirus replication but also abrogated flavivirus-triggered apoptosis. However, flavivirus replication was not affected by a specific NF-κB peptide inhibitor, SN50, and a proteosome inhibitor, lactacystin. Flaviviruses also replicated and triggered apoptosis in cells stably expressing IκBα-ΔN, a dominant-negative mutant that antagonizes NF-κB activation, as readily as in wild-type BHK-21 cells, suggesting that NF-κB activation is not essential for either flavivirus replication or flavivirus-induced apoptosis. Salicylates still diminished flavivirus replication and blocked apoptosis in the same IκBα-ΔN cells. This inhibition of flaviviruses by salicylates could be partially reversed by a specific p38 mitogen-activated protein (MAP) kinase inhibitor, SB203580. Together, these results show that the mechanism by which salicylates suppress flavivirus infection may involve p38 MAP kinase activity but is independent of blocking the NF-κB pathway. PMID:11483726

  5. Visualization of a neurotropic flavivirus infection in mouse reveals unique viscerotropism controlled by host type I interferon signaling

    PubMed Central

    Li, Xiao-Feng; Li, Xiao-Dan; Deng, Cheng-Lin; Dong, Hao-Long; Zhang, Qiu-Yan; Ye, Qing; Ye, Han-Qing; Huang, Xing-Yao; Deng, Yong-Qiang; Zhang, Bo; Qin, Cheng-Feng

    2017-01-01

    Flavivirus includes a large group of human pathogens with medical importance. Especially, neurotropic flaviviruses capable of invading central and peripheral nervous system, e.g. Japanese encephalitis virus (JEV) and Zika virus (ZIKV), are highly pathogenic to human and constitute major global health problems. However, the dynamic dissemination and pathogenesis of neurotropic flavivirus infections remain largely unknown. Here, using JEV as a model, we rationally designed and constructed a recombinant reporter virus that stably expressed Renilla luciferase (Rluc). The resulting JEV reporter virus (named Rluc-JEV) and parental JEV exhibited similar replication and infection characteristics, and the magnitude of Rluc activity correlated well with progeny viral production in vitro and in vivo. By using in vivo bioluminescence imaging (BLI) technology, we dissected the replication and dissemination dynamics of JEV infection in mice upon different inoculation routes. Interestingly, besides replicating in mouse brain, Rluc-JEV predominantly invaded the abdominal organs in mice with typical viscerotropism. Further tests in mice deficient in type I interferon (IFN) receptors demonstrated robust and prolonged viral replication in the intestine, spleen, liver, kidney and other abdominal organs. Combined with histopathological and immunohistochemical results, the host type I IFN signaling was evidenced as the major barrier to the viscerotropism and pathogenicity of this neurotropic flavivirus. Additionally, the Rluc-JEV platform was readily adapted for efficacy assay of known antiviral compounds and a live JE vaccine. Collectively, our study revealed abdominal organs as important targets of JEV infection in mice and profiled the unique viscerotropism trait controlled by the host type I IFN signaling. This in vivo visualization technology described here provides a powerful tool for testing antiviral agents and vaccine candidates for flaviviral infection. PMID:28382163

  6. [Prospects for treating mosquito-borne flavivirus encephalitides].

    PubMed

    Platonov, A E; Karan', L S; Vengerov, Iu Ia; Galimzianov, Kh M

    2009-01-01

    The Japanese encephalitis virus and West Nile virus belong to the family Flaviviridae, genus Flavivirus; they have a similar transmission cycle, with birds serving as the natural vertebrate host and mosquitoes, primarily, Culex species, both serving as the enzootic vectors and infecting humans. These arboviruses have caused more human cases of severe neuroinvasive disease worldwide during the past decade than other mosquito-borne flaviviruses. The current data and concepts on the clinical manifestations, pathogenesis, diagnosis, and treatment of infections caused by West Nile virus and Japanese encephalitis virus, are considered. The need for developing innovative approaches to etiotropic therapy for West Nile fever and Japanese encephalitis is emphasized; these approaches should be based on the comprehensive insight and extensive studies of the pathogenesis of flaviviral infections.

  7. Focus on flaviviruses: current and future drug targets

    PubMed Central

    Geiss, Brian J; Stahla, Hillary; Hannah, Amanda M; Gari, Harmid H; Keenan, Susan M

    2009-01-01

    Background Infection by mosquito-borne flaviviruses (family Flaviviridae) is increasing in prevalence worldwide. The vast global, social and economic impact due to the morbidity and mortality associated with the diseases caused by these viruses necessitates therapeutic intervention. There is currently no effective clinical treatment for any flaviviral infection. Therefore, there is a great need for the identification of novel inhibitors to target the virus lifecycle. Discussion In this article, we discuss structural and nonstructural viral proteins that are the focus of current target validation and drug discovery efforts. Both inhibition of essential enzymatic activities and disruption of necessary protein–protein interactions are considered. In addition, we address promising new targets for future research. Conclusion As our molecular and biochemical understanding of the flavivirus life cycle increases, the number of targets for antiviral therapeutic discovery grows and the possibility for novel drug discovery continues to strengthen. PMID:20165556

  8. Cacipacore virus as an emergent mosquito-borne Flavivirus.

    PubMed

    Figueiredo, Mario Luis Garcia de; Amarilla, Alberto Anastacio; Figueiredo, Glauciane Garcia de; Alfonso, Helda Liz; Lippi, Veronica; Maia, Felipe Gonçalves Motta; Morais, Felipe Alves; Costa, Cristóvão Alves da; Henriques, Dyana Alves; Durigon, Edison Luis; Figueiredo, Luiz Tadeu Moraes; Aquino, Victor Hugo

    2017-01-01

    Cacipacore virus (CPCV), a possible bird-associated flavivirus, has yet to be detected in mosquitoes. Our purpose is examining CPCV in mosquitoes from the Amazon region of Brazil. Approximately 3,253 Culicidae (grouped into 264 pools) were collected from the Amazon region during 2002-2006 and analyzed using a Flavivirus genus-specific reverse transcription- polymerase chain reaction followed by nested polymerase chain reaction assay and by nucleotide sequencing of amplicons. Nucleotide sequences from five mosquito samples showed high similarity to the those of CPCV originally isolated in the Amazon region. This is the first report of CPCV-infected mosquitoes which has implications on the arbovirus maintenance in nature and transmission to man.

  9. Local image variance of 7 Tesla SWI is a new technique for preoperative characterization of diffusely infiltrating gliomas: correlation with tumour grade and IDH1 mutational status.

    PubMed

    Grabner, Günther; Kiesel, Barbara; Wöhrer, Adelheid; Millesi, Matthias; Wurzer, Aygül; Göd, Sabine; Mallouhi, Ammar; Knosp, Engelbert; Marosi, Christine; Trattnig, Siegfried; Wolfsberger, Stefan; Preusser, Matthias; Widhalm, Georg

    2017-04-01

    To investigate the value of local image variance (LIV) as a new technique for quantification of hypointense microvascular susceptibility-weighted imaging (SWI) structures at 7 Tesla for preoperative glioma characterization. Adult patients with neuroradiologically suspected diffusely infiltrating gliomas were prospectively recruited and 7 Tesla SWI was performed in addition to standard imaging. After tumour segmentation, quantification of intratumoural SWI hypointensities was conducted by the SWI-LIV technique. Following surgery, the histopathological tumour grade and isocitrate dehydrogenase 1 (IDH1)-R132H mutational status was determined and SWI-LIV values were compared between low-grade gliomas (LGG) and high-grade gliomas (HGG), IDH1-R132H negative and positive tumours, as well as gliomas with significant and non-significant contrast-enhancement (CE) on MRI. In 30 patients, 9 LGG and 21 HGG were diagnosed. The calculation of SWI-LIV values was feasible in all tumours. Significantly higher mean SWI-LIV values were found in HGG compared to LGG (92.7 versus 30.8; p < 0.0001), IDH1-R132H negative compared to IDH1-R132H positive gliomas (109.9 versus 38.3; p < 0.0001) and tumours with significant CE compared to non-significant CE (120.1 versus 39.0; p < 0.0001). Our data indicate that 7 Tesla SWI-LIV might improve preoperative characterization of diffusely infiltrating gliomas and thus optimize patient management by quantification of hypointense microvascular structures. • 7 Tesla local image variance helps to quantify hypointense susceptibility-weighted imaging structures. • SWI-LIV is significantly increased in high-grade and IDH1-R132H negative gliomas. • SWI-LIV is a promising technique for improved preoperative glioma characterization. • Preoperative management of diffusely infiltrating gliomas will be optimized.

  10. Structure and Function of Flavivirus NS5 Methyltransferase

    SciTech Connect

    Zhou,Y.; Ray, D.; Zhao, Y.; Dong, H.; Ren, S.; Li, Z.; Guo, Y.; Bernard, K.; Shi, P.; Li, H.

    2007-01-01

    The plus-strand RNA genome of flavivirus contains a 5' terminal cap 1 structure (m{sup 7}GpppAmG). The flaviviruses encode one methyltransferase, located at the N-terminal portion of the NS5 protein, to catalyze both guanine N-7 and ribose 2'-OH methylations during viral cap formation. Representative flavivirus methyltransferases from dengue, yellow fever, and West Nile virus (WNV) sequentially generate GpppA {yields} m{sup 7}GpppA {yields} m{sup 7}GpppAm. The 2'-O methylation can be uncoupled from the N-7 methylation, since m{sup 7}GpppA-RNA can be readily methylated to m{sup 7}GpppAm-RNA. Despite exhibiting two distinct methylation activities, the crystal structure of WNV methyltransferase at 2.8 {angstrom} resolution showed a single binding site for S-adenosyl-L-methionine (SAM), the methyl donor. Therefore, substrate GpppA-RNA should be repositioned to accept the N-7 and 2'-O methyl groups from SAM during the sequential reactions. Electrostatic analysis of the WNV methyltransferase structure showed that, adjacent to the SAM-binding pocket, is a highly positively charged surface that could serve as an RNA binding site during cap methylations. Biochemical and mutagenesis analyses show that the N-7 and 2'-O cap methylations require distinct buffer conditions and different side chains within the K{sub 61}-D{sub 146}-K{sub 182}-E{sub 218} motif, suggesting that the two reactions use different mechanisms. In the context of complete virus, defects in both methylations are lethal to WNV; however, viruses defective solely in 2'-O methylation are attenuated and can protect mice from later wild-type WNV challenge. The results demonstrate that the N-7 methylation activity is essential for the WNV life cycle and, thus, methyltransferase represents a novel target for flavivirus therapy.

  11. Structure and Expression of Genes for Flavivirus Immunogens.

    DTIC Science & Technology

    1983-09-01

    alternative approaches to the development of vaccines for JE and DHS-DSS. In deciding which dengue serotype to study, we initially considered the advantages of...progress in the development of a synthetic hepatitis B vaccine from genetically engineered yeast (see Newa and Views section - Nature 304, 395, 1983...noceasmy and Identify by block number) Flavivirus, Japanese encephalitis, Dengue , gene cloning, neutralizing antibody, monoclonal antibody, synthetic

  12. Flavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses

    PubMed Central

    Roth, Hanna; Magg, Vera; Uch, Fabian; Mutz, Pascal; Klein, Philipp; Haneke, Katharina; Lohmann, Volker; Bartenschlager, Ralf; Fackler, Oliver T.; Locker, Nicolas; Stoecklin, Georg

    2017-01-01

    ABSTRACT As obligate parasites, viruses strictly depend on host cell translation for the production of new progeny, yet infected cells also synthesize antiviral proteins to limit virus infection. Modulation of host cell translation therefore represents a frequent strategy by which viruses optimize their replication and spread. Here we sought to define how host cell translation is regulated during infection of human cells with dengue virus (DENV) and Zika virus (ZIKV), two positive-strand RNA flaviviruses. Polysome profiling and analysis of de novo protein synthesis revealed that flavivirus infection causes potent repression of host cell translation, while synthesis of viral proteins remains efficient. Selective repression of host cell translation was mediated by the DENV polyprotein at the level of translation initiation. In addition, DENV and ZIKV infection suppressed host cell stress responses such as the formation of stress granules and phosphorylation of the translation initiation factor eIF2α (α subunit of eukaryotic initiation factor 2). Mechanistic analyses revealed that translation repression was uncoupled from the disruption of stress granule formation and eIF2α signaling. Rather, DENV infection induced p38-Mnk1 signaling that resulted in the phosphorylation of the eukaryotic translation initiation factor eIF4E and was essential for the efficient production of virus particles. Together, these results identify the uncoupling of translation suppression from the cellular stress responses as a conserved strategy by which flaviviruses ensure efficient replication in human cells. PMID:28074025

  13. Flaviviruses Are Sensitive to Inhibition of Thymidine Synthesis Pathways

    PubMed Central

    Fischer, Matthew A.; Smith, Jessica L.; Shum, David; Stein, David A.; Parkins, Christopher; Bhinder, Bhavneet; Radu, Constantin; Hirsch, Alec J.; Djaballah, Hakim; Nelson, Jay A.

    2013-01-01

    Dengue virus has emerged as a global health threat to over one-third of humankind. As a positive-strand RNA virus, dengue virus relies on the host cell metabolism for its translation, replication, and egress. Therefore, a better understanding of the host cell metabolic pathways required for dengue virus infection offers the opportunity to develop new approaches for therapeutic intervention. In a recently described screen of known drugs and bioactive molecules, we observed that methotrexate and floxuridine inhibited dengue virus infections at low micromolar concentrations. Here, we demonstrate that all serotypes of dengue virus, as well as West Nile virus, are highly sensitive to both methotrexate and floxuridine, whereas other RNA viruses (Sindbis virus and vesicular stomatitis virus) are not. Interestingly, flavivirus replication was restored by folinic acid, a thymidine precursor, in the presence of methotrexate and by thymidine in the presence of floxuridine, suggesting an unexpected role for thymidine in flavivirus replication. Since thymidine is not incorporated into RNA genomes, it is likely that increased thymidine production is indirectly involved in flavivirus replication. A possible mechanism is suggested by the finding that p53 inhibition restored dengue virus replication in the presence of floxuridine, consistent with thymidine-less stress triggering p53-mediated antiflavivirus effects in infected cells. Our data reveal thymidine synthesis pathways as new and unexpected therapeutic targets for antiflaviviral drug development. PMID:23824813

  14. The flavivirus capsid protein: Structure, function and perspectives towards drug design.

    PubMed

    Oliveira, Edson R A; Mohana-Borges, Ronaldo; de Alencastro, Ricardo B; Horta, Bruno A C

    2017-01-02

    Flaviviruses, such as dengue and zika viruses, are etiologic agents transmitted to humans mainly by arthropods and are of great epidemiological interest. The flavivirus capsid protein is a structural element required for the viral nucleocapsid assembly that presents the classical function of sheltering the viral genome. After decades of research, many reports have shown its different functionalities and influence over cell normal functioning. The subcellular distribution of this protein, which involves accumulation around lipid droplets and nuclear localization, also corroborates with its multi-functional characteristic. As flavivirus diseases are still in need of global control and in view of the possible key functionalities that the capsid protein promotes over flavivirus biology, novel considerations arise towards anti-flavivirus drug research. This review covers the main aspects concerning structural and functional features of the flavivirus C protein, ultimately, highlighting prospects in drug discovery based on this viral target.

  15. Efficacy and Mode of Action of Immune Response Modifying Compounds against Alphaviruses and Flaviviruses

    DTIC Science & Technology

    1987-12-01

    UTJC RE F mnpv Lfl AD _ _ _ _ _ _ _ 0 N Efficacy and Node of A-tion of Imune Response Modifying Compounds Against Alphaviruses and Flaviviruses...Against Alphaviruses and Flaviviruses 12. PERSONAL AUTHOR(S) Page S. Morahan, Margo Brinton, Angelo J. Pinto 13a. TYPE OF REPORT 13b. TIME COVERED 14...prophylactic and/or therapeutic treatment with immunomodulators alone and in combination with antiviral drugs against alphavirus , flavivirus, bunyavirus and

  16. Inverse modeling for seawater intrusion in coastal aquifers: Insights about parameter sensitivities, variances, correlations and estimation procedures derived from the Henry problem

    USGS Publications Warehouse

    Sanz, E.; Voss, C.I.

    2006-01-01

    Inverse modeling studies employing data collected from the classic Henry seawater intrusion problem give insight into several important aspects of inverse modeling of seawater intrusion problems and effective measurement strategies for estimation of parameters for seawater intrusion. Despite the simplicity of the Henry problem, it embodies the behavior of a typical seawater intrusion situation in a single aquifer. Data collected from the numerical problem solution are employed without added noise in order to focus on the aspects of inverse modeling strategies dictated by the physics of variable-density flow and solute transport during seawater intrusion. Covariances of model parameters that can be estimated are strongly dependent on the physics. The insights gained from this type of analysis may be directly applied to field problems in the presence of data errors, using standard inverse modeling approaches to deal with uncertainty in data. Covariance analysis of the Henry problem indicates that in order to generally reduce variance of parameter estimates, the ideal places to measure pressure are as far away from the coast as possible, at any depth, and the ideal places to measure concentration are near the bottom of the aquifer between the center of the transition zone and its inland fringe. These observations are located in and near high-sensitivity regions of system parameters, which may be identified in a sensitivity analysis with respect to several parameters. However, both the form of error distribution in the observations and the observation weights impact the spatial sensitivity distributions, and different choices for error distributions or weights can result in significantly different regions of high sensitivity. Thus, in order to design effective sampling networks, the error form and weights must be carefully considered. For the Henry problem, permeability and freshwater inflow can be estimated with low estimation variance from only pressure or only

  17. Discovery of flavivirus-derived endogenous viral elements in Anopheles mosquito genomes supports the existence of Anopheles-associated insect-specific flaviviruses.

    PubMed

    Lequime, Sebastian; Lambrechts, Louis

    2017-01-01

    The Flavivirus genus encompasses several arboviruses of public health significance such as dengue, yellow fever, and Zika viruses. It also includes insect-specific flaviviruses (ISFs) that are only capable of infecting insect hosts. The vast majority of mosquito-infecting flaviviruses have been associated with mosquito species of the Aedes and Culex genera in the Culicinae subfamily, which also includes most arbovirus vectors. Mosquitoes of the Anophelinae subfamily are not considered significant arbovirus vectors; however, flaviviruses have occasionally been detected in field-caught Anopheles specimens. Whether such observations reflect occasional spillover or laboratory contamination or whether Anopheles mosquitoes are natural hosts of flaviviruses is unknown. Here, we provide in silico and in vivo evidence of transcriptionally active, flavivirus-derived endogenous viral elements (EVEs) in the genome of Anopheles minimus and Anopheles sinensis. Such non-retroviral endogenization of RNA viruses is consistent with a shared evolutionary history between flaviviruses and Anopheles mosquitoes. Phylogenetic analyses of the two newly described EVEs support the existence of a distinct clade of Anopheles-associated ISFs.

  18. Discovery of flavivirus-derived endogenous viral elements in Anopheles mosquito genomes supports the existence of Anopheles-associated insect-specific flaviviruses

    PubMed Central

    Lequime, Sebastian; Lambrechts, Louis

    2017-01-01

    The Flavivirus genus encompasses several arboviruses of public health significance such as dengue, yellow fever, and Zika viruses. It also includes insect-specific flaviviruses (ISFs) that are only capable of infecting insect hosts. The vast majority of mosquito-infecting flaviviruses have been associated with mosquito species of the Aedes and Culex genera in the Culicinae subfamily, which also includes most arbovirus vectors. Mosquitoes of the Anophelinae subfamily are not considered significant arbovirus vectors; however, flaviviruses have occasionally been detected in field-caught Anopheles specimens. Whether such observations reflect occasional spillover or laboratory contamination or whether Anopheles mosquitoes are natural hosts of flaviviruses is unknown. Here, we provide in silico and in vivo evidence of transcriptionally active, flavivirus-derived endogenous viral elements (EVEs) in the genome of Anopheles minimus and Anopheles sinensis. Such non-retroviral endogenization of RNA viruses is consistent with a shared evolutionary history between flaviviruses and Anopheles mosquitoes. Phylogenetic analyses of the two newly described EVEs support the existence of a distinct clade of Anopheles-associated ISFs. PMID:28078104

  19. A Cosmic Variance Cookbook

    NASA Astrophysics Data System (ADS)

    Moster, Benjamin P.; Somerville, Rachel S.; Newman, Jeffrey A.; Rix, Hans-Walter

    2011-04-01

    Deep pencil beam surveys (<1 deg2) are of fundamental importance for studying the high-redshift universe. However, inferences about galaxy population properties (e.g., the abundance of objects) are in practice limited by "cosmic variance." This is the uncertainty in observational estimates of the number density of galaxies arising from the underlying large-scale density fluctuations. This source of uncertainty can be significant, especially for surveys which cover only small areas and for massive high-redshift galaxies. Cosmic variance for a given galaxy population can be determined using predictions from cold dark matter theory and the galaxy bias. In this paper, we provide tools for experiment design and interpretation. For a given survey geometry, we present the cosmic variance of dark matter as a function of mean redshift \\bar{z} and redshift bin size Δz. Using a halo occupation model to predict galaxy clustering, we derive the galaxy bias as a function of mean redshift for galaxy samples of a given stellar mass range. In the linear regime, the cosmic variance of these galaxy samples is the product of the galaxy bias and the dark matter cosmic variance. We present a simple recipe using a fitting function to compute cosmic variance as a function of the angular dimensions of the field, \\bar{z}, Δz, and stellar mass m *. We also provide tabulated values and a software tool. The accuracy of the resulting cosmic variance estimates (δσ v /σ v ) is shown to be better than 20%. We find that for GOODS at \\bar{z}=2 and with Δz = 0.5, the relative cosmic variance of galaxies with m *>1011 M sun is ~38%, while it is ~27% for GEMS and ~12% for COSMOS. For galaxies of m * ~ 1010 M sun, the relative cosmic variance is ~19% for GOODS, ~13% for GEMS, and ~6% for COSMOS. This implies that cosmic variance is a significant source of uncertainty at \\bar{z}=2 for small fields and massive galaxies, while for larger fields and intermediate mass galaxies, cosmic variance is

  20. A COSMIC VARIANCE COOKBOOK

    SciTech Connect

    Moster, Benjamin P.; Rix, Hans-Walter; Somerville, Rachel S.; Newman, Jeffrey A. E-mail: rix@mpia.de E-mail: janewman@pitt.edu

    2011-04-20

    Deep pencil beam surveys (<1 deg{sup 2}) are of fundamental importance for studying the high-redshift universe. However, inferences about galaxy population properties (e.g., the abundance of objects) are in practice limited by 'cosmic variance'. This is the uncertainty in observational estimates of the number density of galaxies arising from the underlying large-scale density fluctuations. This source of uncertainty can be significant, especially for surveys which cover only small areas and for massive high-redshift galaxies. Cosmic variance for a given galaxy population can be determined using predictions from cold dark matter theory and the galaxy bias. In this paper, we provide tools for experiment design and interpretation. For a given survey geometry, we present the cosmic variance of dark matter as a function of mean redshift z-bar and redshift bin size {Delta}z. Using a halo occupation model to predict galaxy clustering, we derive the galaxy bias as a function of mean redshift for galaxy samples of a given stellar mass range. In the linear regime, the cosmic variance of these galaxy samples is the product of the galaxy bias and the dark matter cosmic variance. We present a simple recipe using a fitting function to compute cosmic variance as a function of the angular dimensions of the field, z-bar , {Delta}z, and stellar mass m{sub *}. We also provide tabulated values and a software tool. The accuracy of the resulting cosmic variance estimates ({delta}{sigma}{sub v}/{sigma}{sub v}) is shown to be better than 20%. We find that for GOODS at z-bar =2 and with {Delta}z = 0.5, the relative cosmic variance of galaxies with m{sub *}>10{sup 11} M{sub sun} is {approx}38%, while it is {approx}27% for GEMS and {approx}12% for COSMOS. For galaxies of m{sub *} {approx} 10{sup 10} M{sub sun}, the relative cosmic variance is {approx}19% for GOODS, {approx}13% for GEMS, and {approx}6% for COSMOS. This implies that cosmic variance is a significant source of uncertainty at z

  1. Orthomyxo-, paramyxo- and flavivirus infections in wild waterfowl in Finland

    PubMed Central

    Lindh, Erika; Huovilainen, Anita; Rätti, Osmo; Ek-Kommonen, Christine; Sironen, Tarja; Huhtamo, Eili; Pöysä, Hannu; Vaheri, Antti; Vapalahti, Olli

    2008-01-01

    Background Screening wild birds for viral pathogens has become increasingly important. We tested a screening approach based on blood and cloacal and tracheal swabs collected by hunters to study the prevalence of influenza A, paramyxo-, flavi-, and alphaviruses in Finnish wild waterfowl, which has been previously unknown. We studied 310 blood samples and 115 mixed tracheal and cloacal swabs collected from hunted waterfowl in 2006. Samples were screened by RT-PCR and serologically by hemagglutination inhibition (HI) test or enzyme-linked immunosorbent assay (ELISA) for influenza A (FLUAV), type 1 avian paramyxo-(APMV-1), Sindbis (SINV), West Nile (WNV) and tick-borne encephalitis (TBEV) virus infections. Results FLUAV RNA was found in 13 tracheal/cloacal swabs and seven strains were isolated. Five blood samples were antibody positive. Six APMV-1 RNA-positive samples were found from which four strains were isolated, while two blood samples were antibody positive. None of the birds were positive for flavivirus RNA but three birds had flavivirus antibodies by HI test. No antibodies to SINV were detected. Conclusion We conclude that circulation of both influenza A virus and avian paramyxovirus-1 in Finnish wild waterfowl was documented. The FLUAV and APMV-1 prevalences in wild waterfowl were 11.3% and 5.2% respectively, by this study. The subtype H3N8 was the only detected FLUAV subtype while APMV-1 strains clustered into two distinct lineages. Notably, antibodies to a likely mosquito-borne flavivirus were detected in three samples. The screening approach based on hunted waterfowl seemed reliable for monitoring FLUAV and APMV by RT-PCR from cloacal or tracheal samples, but antibody testing in this format seemed to be of low sensitivity. PMID:18307758

  2. Rapid Identification of Vector-Borne Flaviviruses by Mass Spectrometry

    DTIC Science & Technology

    2010-02-01

    from a known titer and tested in replicates of 10. All six mosquito-borne primer sets (VIR2215, VIR2217, VIR2211, VIR2216, VIR1026, VIR1028) had 100...Flavivirus RT-PCR primer pairs. From a known West Nile virus (WNV) titer, the RNA was serially diluted ten-fold. Ten replicates were performed to...219e228 225 Author’s personal copy alphaviruses (assuming that 30 genome equivalents is approxi- mately equal to 3 PFU) [10]. One benefit of the pan

  3. Rapid Identification of Vector-Borne Flaviviruses by Mass Spectrometry

    DTIC Science & Technology

    2010-01-01

    replicates of 10. All six mosquito-borne primer sets (VIR2215, VIR2217, VIR2211, VIR2216, VIR1026, VIR1028) had 100% sensitivity (10/10 reactions were...borne Flavivirus RT-PCR primer pairs. From a known West Nile virus (WNV) titer, the RNA was serially diluted ten-fold. Ten replicates were performed...mass spectrometry, Molecular and Cellular Probes (2010), doi:10.1016/j.mcp.2010.04.003 alphaviruses (assuming that 30 genome equivalents is approxi

  4. Evidence of mosquito-transmitted flavivirus circulation in Piedmont, north-western Italy.

    PubMed

    Cerutti, Francesco; Giacobini, Mario; Mosca, Andrea; Grasso, Ivan; Rambozzi, Luisa; Rossi, Luca; Bertolotti, Luigi

    2012-05-22

    Flavivirus is a highly heterogeneous viral genus that includes important human pathogens and several viral strains with unknown zoonotic potential. Mosquito-borne flaviviruses have been isolated and characterized in Northern Italy: West Nile virus and Usutu virus were detected in mosquitoes and in different host species and recent studies provided evidence about the circulation of "insect Flavivirus" strains. In order to clarify the diffusion and the distribution of the mosquito-transmitted flaviviruses in Italy, we analyzed Culex and Ochlerotatus mosquitoes collected in 2009 and 2010 in an area divided evenly between hills and plains and where the landscape is dominated by mixed agricultural patches, rice fields, deciduous tree forests, and urban environments. Each mosquito pool was tested for the presence of Flavivirus strains and we characterized positive samples by genetic sequencing. Positive mosquito pools revealed low infection prevalence, but suggested a continuous circulation of both Usutu virus and insect Flavivirus. Interestingly, phylogenetic analyses based on NS5 gene partial sequences showed a closer relationship among new Usutu virus strains from Piedmont and the reference sequences from the Eastern Europe, with respect to Italian samples characterized so far. Moreover, NS5 gene phylogeny suggested that mosquito flaviviruses found in Italy could belong to different lineages. Our results contribute to a wider point of view on the heterogeneity of viruses infecting mosquitoes suggesting a taxonomical revision of the Mosquito-borne Flavivirus group.

  5. Characterization of a novel insect-specific flavivirus from Brazil: Potential for inhibition of infection of arthropod cells with medically important flaviviruses.

    SciTech Connect

    Kenney, Joan L.; Solberg, Owen D.; Langevin, Stanley A.; Brault, Aaron C.

    2014-01-12

    In the past decade, there has been an upsurge in the number of newly described insect-specific flaviviruses isolated pan-globally. We recently described the isolation of a novel flavivirus (tentatively designated ‘Nhumirim virus’; NHUV) that represents an example of a unique subset of apparently insect-specific viruses that phylogenetically affiliate with dual-host mosquito-borne flaviviruses despite appearing to be limited to replication in mosquito cells. We characterized the in vitro growth potential and 3' untranslated region (UTR) sequence homology with alternative flaviviruses, and evaluated the virus’s capacity to suppress replication of representative Culex spp.-vectored pathogenic flaviviruses in mosquito cells. Only mosquito cell lines were found to support NHUV replication, further reinforcing the insect-specific phenotype of this virus. Analysis of the sequence and predicted RNA secondary structures of the 3' UTR indicated NHUV to be most similar to viruses within the yellow fever serogroup and Japanese encephalitis serogroup, and viruses in the tick-borne flavivirus clade. NHUV was found to share the fewest conserved sequence elements when compared with traditional insect-specific flaviviruses. This suggests that, despite apparently being insect specific, this virus probably diverged from an ancestral mosquito-borne flavivirus. Co-infection experiments indicated that prior or concurrent infection of mosquito cells with NHUV resulted in a significant reduction in virus production of West Nile virus (WNV), St Louis encephalitis virus (SLEV) and Japanese encephalitis virus. As a result, the inhibitory effect was most effective against WNV and SLEV with over a 106-fold and 104-fold reduction in peak titres, respectively.

  6. Characterization of a novel insect-specific flavivirus from Brazil: Potential for inhibition of infection of arthropod cells with medically important flaviviruses.

    DOE PAGES

    Kenney, Joan L.; Solberg, Owen D.; Langevin, Stanley A.; ...

    2014-01-12

    In the past decade, there has been an upsurge in the number of newly described insect-specific flaviviruses isolated pan-globally. We recently described the isolation of a novel flavivirus (tentatively designated ‘Nhumirim virus’; NHUV) that represents an example of a unique subset of apparently insect-specific viruses that phylogenetically affiliate with dual-host mosquito-borne flaviviruses despite appearing to be limited to replication in mosquito cells. We characterized the in vitro growth potential and 3' untranslated region (UTR) sequence homology with alternative flaviviruses, and evaluated the virus’s capacity to suppress replication of representative Culex spp.-vectored pathogenic flaviviruses in mosquito cells. Only mosquito cell linesmore » were found to support NHUV replication, further reinforcing the insect-specific phenotype of this virus. Analysis of the sequence and predicted RNA secondary structures of the 3' UTR indicated NHUV to be most similar to viruses within the yellow fever serogroup and Japanese encephalitis serogroup, and viruses in the tick-borne flavivirus clade. NHUV was found to share the fewest conserved sequence elements when compared with traditional insect-specific flaviviruses. This suggests that, despite apparently being insect specific, this virus probably diverged from an ancestral mosquito-borne flavivirus. Co-infection experiments indicated that prior or concurrent infection of mosquito cells with NHUV resulted in a significant reduction in virus production of West Nile virus (WNV), St Louis encephalitis virus (SLEV) and Japanese encephalitis virus. As a result, the inhibitory effect was most effective against WNV and SLEV with over a 106-fold and 104-fold reduction in peak titres, respectively.« less

  7. Characterization of a novel insect-specific flavivirus from Brazil: potential for inhibition of infection of arthropod cells with medically important flaviviruses

    PubMed Central

    Kenney, Joan L.; Solberg, Owen D.; Langevin, Stanley A.; Brault, Aaron C.

    2015-01-01

    In the past decade there has been an upsurge in the number of newly described insect-specific flaviviruses isolated pan-globally. We recently described the isolation of a novel flavivirus (tentatively designated “Nhumirim virus”; NHUV) (Pauvolid-Correa et al., in review) that represents an example of a unique subset of apparently insect-specific viruses that phylogenetically affiliate with dual-host mosquito-borne flaviviruses despite appearing to be limited to replication in mosquito cells. We characterized the in vitro growth potential, 3’ untranslated region (UTR) sequence homology with alternative flaviviruses, and evaluated the virus’s capacity to suppress replication of representative Culex spp. vectored pathogenic flaviviruses in mosquito cells. Only mosquito cell lines were found to support NHUV replication, further reinforcing the insect-specific phenotype of this virus. Analysis of the sequence and predicted RNA secondary structures of the 3’ UTR indicate NHUV to be most similar to viruses within the yellow fever serogroup, Japanese encephalitis serogroup, and viruses in the tick-borne flavivirus clade. NHUV was found to share the fewest conserved sequence elements when compared to traditional insect-specific flaviviruses. This suggests that, despite being apparently insect-specific, this virus likely diverged from an ancestral mosquito-borne flavivirus. Co-infection experiments indicated that prior or concurrent infection of mosquito cells with NHUV resulted in significant reduction in viral production of West Nile virus (WNV), St. Louis encephalitis virus (SLEV) and Japanese encephalitis virus. The inhibitory effect was most effective against WNV and SLEV with over a million-fold and 10,000-fold reduction in peak titers, respectively. PMID:25146007

  8. Serologic Evidence of Flavivirus Infections in Peridomestic Rodents in Merida, Mexico.

    PubMed

    Cigarroa-Toledo, Nohemi; Talavera-Aguilar, Lourdes G; Baak-Baak, Carlos M; García-Rejón, Julián E; Hernandez-Betancourt, Silvia; Blitvich, Bradley J; Machain-Williams, Carlos

    2016-01-01

    We conducted surveillance for flavivirus infection in peridomestic rodents in Merida, Mexico in 2011-12. We captured 161 rodents inside private residences, using Sherman traps, including 86 house mice (Mus musculus) and 75 black rats (Rattus rattus). Serum from each animal was assayed by plaque reduction neutralization test (PRNT) using two vertebrate-specific flaviviruses (Apoi and Modoc viruses) and five mosquito-borne flaviviruses (dengue 2, dengue 4, St. Louis encephalitis virus, West Nile, and yellow fever viruses). Sixty-one (37.9%) rodents had antibodies that neutralized at least one virus. Prevalences for flaviviruses were 64.0% and 15.1% for black rats and house mice, respectively. None of the PRNT90 titers exceeded 80, and often they were highest for Modoc virus. These data suggest that a subset of rodents had been infected with Modoc virus or a closely related flavivirus that was not included in the PRNT analysis.

  9. The quantum Allan variance

    NASA Astrophysics Data System (ADS)

    Chabuda, Krzysztof; Leroux, Ian D.; Demkowicz-Dobrzański, Rafał

    2016-08-01

    The instability of an atomic clock is characterized by the Allan variance, a measure widely used to describe the noise of frequency standards. We provide an explicit method to find the ultimate bound on the Allan variance of an atomic clock in the most general scenario where N atoms are prepared in an arbitrarily entangled state and arbitrary measurement and feedback are allowed, including those exploiting coherences between succeeding interrogation steps. While the method is rigorous and general, it becomes numerically challenging for large N and long averaging times.

  10. Conversations across Meaning Variance

    ERIC Educational Resources Information Center

    Cordero, Alberto

    2013-01-01

    Progressive interpretations of scientific theories have long been denounced as naive, because of the inescapability of meaning variance. The charge reportedly applies to recent realist moves that focus on theory-parts rather than whole theories. This paper considers the question of what "theory-parts" of epistemic significance (if any) relevantly…

  11. Conversations across Meaning Variance

    ERIC Educational Resources Information Center

    Cordero, Alberto

    2013-01-01

    Progressive interpretations of scientific theories have long been denounced as naive, because of the inescapability of meaning variance. The charge reportedly applies to recent realist moves that focus on theory-parts rather than whole theories. This paper considers the question of what "theory-parts" of epistemic significance (if any) relevantly…

  12. Naive Analysis of Variance

    ERIC Educational Resources Information Center

    Braun, W. John

    2012-01-01

    The Analysis of Variance is often taught in introductory statistics courses, but it is not clear that students really understand the method. This is because the derivation of the test statistic and p-value requires a relatively sophisticated mathematical background which may not be well-remembered or understood. Thus, the essential concept behind…

  13. Detection of Culex flavivirus and Aedes flavivirus nucleotide sequences in mosquitoes from parks in the city of São Paulo, Brazil.

    PubMed

    Fernandes, Licia Natal; de Paula, Marcia Bicudo; Araújo, Alessandra Bergamo; Gonçalves, Elisabeth Fernandes Bertoletti; Romano, Camila Malta; Natal, Delsio; Malafronte, Rosely dos Santos; Marrelli, Mauro Toledo; Levi, José Eduardo

    2016-05-01

    The dengue viruses are widespread in Brazil and are a major public health concern. Other flaviviruses also cause diseases in humans, although on a smaller scale. The city of São Paulo is in a highly urbanized area with few green spaces apart from its parks, which are used for recreation and where potential vertebrate hosts and mosquito vectors of pathogenic Flavivirus species can be found. Although this scenario can contribute to the transmission of Flavivirus to humans, little is known about the circulation of members of this genus in these areas. In light of this, the present study sought to identify Flavivirus infection in mosquitoes (Diptera: Culicidae) collected in parks in the city of São Paulo. Seven parks in different sectors of the city were selected. Monthly mosquito collections were carried out in each park from March 2011 to February 2012 using aspiration and traps (Shannon and CD C-CO2). Nucleic acids were extracted from the mosquitoes collected and used for reverse-transcriptase and real-time polymerase chain reactions with genus-specific primers targeting a 200-nucleotide region in the Flavivirus NS5 gene. Positive samples were sequenced, and phylogenetic analyses were performed. Culex and Aedes were the most frequent genera of Culicidae collected. Culex flavivirus (CxFV)-related and Aedes flavivirus (AEFV)- related nucleotide sequences were detected in 17 pools of Culex and two pools of Aedes mosquitoes, respectively, among the 818 pools of non-engorged females analyzed. To the best of our knowledge, this is the first report of CxFV and AEFV in the city of São Paulo and Latin America, respectively. Both viruses are insect- specific flaviviruses, a group known to replicate only in mosquito cells and induce a cytopathic effect in some situations. Hence, our data suggests that CxFV and AEFV are present in Culex and Aedes mosquitoes, respectively, in parks in the city of São Paulo. Even though Flavivirus species of medical importance were not

  14. A High-Performance Multiplex Immunoassay for Serodiagnosis of Flavivirus-Associated Neurological Diseases in Horses

    PubMed Central

    Beck, Cécile; Desprès, Philippe; Paulous, Sylvie; Vanhomwegen, Jessica; Lowenski, Steeve; Nowotny, Norbert; Durand, Benoit; Garnier, Annabelle; Blaise-Boisseau, Sandra; Guitton, Edouard; Yamanaka, Takashi; Zientara, Stéphan; Lecollinet, Sylvie

    2015-01-01

    West Nile virus (WNV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBEV) are flaviviruses responsible for severe neuroinvasive infections in humans and horses. The confirmation of flavivirus infections is mostly based on rapid serological tests such as enzyme-linked immunosorbent assays (ELISAs). These tests suffer from poor specificity, mainly due to antigenic cross-reactivity among flavivirus members. Robust diagnosis therefore needs to be validated through virus neutralisation tests (VNTs) which are time-consuming and require BSL3 facilities. The flavivirus envelope (E) glycoprotein ectodomain is composed of three domains (D) named DI, DII, and DIII, with EDIII containing virus-specific epitopes. In order to improve the serological differentiation of flavivirus infections, the recombinant soluble ectodomain of WNV E (WNV.sE) and EDIIIs (rEDIIIs) of WNV, JEV, and TBEV were synthesised using the Drosophila S2 expression system. Purified antigens were covalently bonded to fluorescent beads. The microspheres coupled to WNV.sE or rEDIIIs were assayed with about 300 equine immune sera from natural and experimental flavivirus infections and 172 nonimmune equine sera as negative controls. rEDIII-coupled microspheres captured specific antibodies against WNV, TBEV, or JEV in positive horse sera. This innovative multiplex immunoassay is a powerful alternative to ELISAs and VNTs for veterinary diagnosis of flavivirus-related diseases. PMID:26457301

  15. Characterization of a novel flavivirus isolated from Culex (Melanoconion) ocossa mosquitoes from Iquitos, Peru.

    PubMed

    Evangelista, Julio; Cruz, Cristhopher; Guevara, Carolina; Astete, Helvio; Carey, Cristiam; Kochel, Tadeusz J; Morrison, Amy C; Williams, Maya; Halsey, Eric S; Forshey, Brett M

    2013-06-01

    We describe the isolation and characterization of a novel flavivirus, isolated from a pool of Culex (Melanoconion) ocossa Dyar and Knab mosquitoes collected in 2009 in an urban area of the Amazon basin city of Iquitos, Peru. Flavivirus infection was detected by indirect immunofluorescent assay of inoculated C6/36 cells using polyclonal flavivirus antibodies (St. Louis encephalitis virus, yellow fever virus and dengue virus type 1) and confirmed by RT-PCR. Based on partial sequencing of the E and NS5 gene regions, the virus isolate was most closely related to the mosquito-borne flaviviruses but divergent from known species, with less than 45 and 71 % pairwise amino acid identity in the E and NS5 gene products, respectively. Phylogenetic analysis of E and NS5 amino acid sequences demonstrated that this flavivirus grouped with mosquito-borne flaviviruses, forming a clade with Nounané virus (NOUV). Like NOUV, no replication was detected in a variety of mammalian cells (Vero-76, Vero-E6, BHK, LLCMK, MDCK, A549 and RD) or in intracerebrally inoculated newborn mice. We tentatively designate this genetically distinct flavivirus as representing a novel species, Nanay virus, after the river near where it was first detected.

  16. New insights into flavivirus evolution, taxonomy and biogeographic history, extended by analysis of canonical and alternative coding sequences.

    PubMed

    Moureau, Gregory; Cook, Shelley; Lemey, Philippe; Nougairede, Antoine; Forrester, Naomi L; Khasnatinov, Maxim; Charrel, Remi N; Firth, Andrew E; Gould, Ernest A; de Lamballerie, Xavier

    2015-01-01

    To generate the most diverse phylogenetic dataset for the flaviviruses to date, we determined the genomic sequences and phylogenetic relationships of 14 flaviviruses, of which 10 are primarily associated with Culex spp. mosquitoes. We analyze these data, in conjunction with a comprehensive collection of flavivirus genomes, to characterize flavivirus evolutionary and biogeographic history in unprecedented detail and breadth. Based on the presumed introduction of yellow fever virus into the Americas via the transatlantic slave trade, we extrapolated a timescale for a relevant subset of flaviviruses whose evolutionary history, shows that different Culex-spp. associated flaviviruses have been introduced from the Old World to the New World on at least five separate occasions, with 2 different sets of factors likely to have contributed to the dispersal of the different viruses. We also discuss the significance of programmed ribosomal frameshifting in a central region of the polyprotein open reading frame in some mosquito-associated flaviviruses.

  17. New Insights into Flavivirus Evolution, Taxonomy and Biogeographic History, Extended by Analysis of Canonical and Alternative Coding Sequences

    PubMed Central

    Moureau, Gregory; Cook, Shelley; Lemey, Philippe; Nougairede, Antoine; Forrester, Naomi L.; Khasnatinov, Maxim; Charrel, Remi N.; Firth, Andrew E.; Gould, Ernest A.; de Lamballerie, Xavier

    2015-01-01

    To generate the most diverse phylogenetic dataset for the flaviviruses to date, we determined the genomic sequences and phylogenetic relationships of 14 flaviviruses, of which 10 are primarily associated with Culex spp. mosquitoes. We analyze these data, in conjunction with a comprehensive collection of flavivirus genomes, to characterize flavivirus evolutionary and biogeographic history in unprecedented detail and breadth. Based on the presumed introduction of yellow fever virus into the Americas via the transatlantic slave trade, we extrapolated a timescale for a relevant subset of flaviviruses whose evolutionary history, shows that different Culex-spp. associated flaviviruses have been introduced from the Old World to the New World on at least five separate occasions, with 2 different sets of factors likely to have contributed to the dispersal of the different viruses. We also discuss the significance of programmed ribosomal frameshifting in a central region of the polyprotein open reading frame in some mosquito-associated flaviviruses. PMID:25719412

  18. A survey of flaviviruses in birds in green areas of São Paulo, Brazil.

    PubMed

    Orico, Lilian Dias; Fernandes, Licia Natal; Melo, Marcos Antônio; Zwarg, Ticiana; Levi, José Eduardo; Marrelli, Mauro Toledo

    2016-01-01

    This study aimed to investigate Flavivirus infection in birds captured in green areas of São Paulo. Oropharyngeal swabs, cloacal swabs, and blood samples from 170 birds captured in two green areas in São Paulo, Brazil were subjected to real time-polymerase chain reaction (RT-qPCR) analysis of Flavivirus specific NS5 gene fragment. All samples were negative for the presence of viral ribonucleic acid (RNA). Despite the negative results, Flavivirus surveillance must be performed regularly due to favorable ecological conditions for virus circulation and transmission among birds in these areas and their close proximity to humans.

  19. Co-circulation of West Nile virus and distinct insect-specific flaviviruses in Turkey.

    PubMed

    Ergünay, Koray; Litzba, Nadine; Brinkmann, Annika; Günay, Filiz; Sarıkaya, Yasemen; Kar, Sırrı; Örsten, Serra; Öter, Kerem; Domingo, Cristina; Erisoz Kasap, Özge; Özkul, Aykut; Mitchell, Luke; Nitsche, Andreas; Alten, Bülent; Linton, Yvonne-Marie

    2017-03-20

    Active vector surveillance provides an efficient tool for monitoring the presence or spread of emerging or re-emerging vector-borne viruses. This study was undertaken to investigate the circulation of flaviviruses. Mosquitoes were collected from 58 locations in 10 provinces across the Aegean, Thrace and Mediterranean Anatolian regions of Turkey in 2014 and 2015. Following morphological identification, mosquitoes were pooled and screened by nested and real-time PCR assays. Detected viruses were further characterised by sequencing. Positive pools were inoculated onto cell lines for virus isolation. Next generation sequencing was employed for genomic characterisation of the isolates. A total of 12,711 mosquito specimens representing 15 species were screened in 594 pools. Eleven pools (2%) were reactive in the virus screening assays. Sequencing revealed West Nile virus (WNV) in one Culex pipiens (s.l.) pool from Thrace. WNV sequence corresponded to lineage one clade 1a but clustered distinctly from the Turkish prototype isolate. In 10 pools, insect-specific flaviviruses were characterised as Culex theileri flavivirus in 5 pools of Culex theileri and one pool of Cx. pipiens (s.l.), Ochlerotatus caspius flavivirus in two pools of Aedes (Ochlerotatus) caspius, Flavivirus AV-2011 in one pool of Culiseta annulata, and an undetermined flavivirus in one pool of Uranotaenia unguiculata from the Aegean and Thrace regions. DNA forms or integration of the detected insect-specific flaviviruses were not observed. A virus strain, tentatively named as "Ochlerotatus caspius flavivirus Turkey", was isolated from an Ae. caspius pool in C6/36 cells. The viral genome comprised 10,370 nucleotides with a putative polyprotein of 3,385 amino acids that follows the canonical flavivirus polyprotein organisation. Sequence comparisons and phylogenetic analyses revealed the close relationship of this strain with Ochlerotatus caspius flavivirus from Portugal and Hanko virus from Finland. Several

  20. Spectral Ambiguity of Allan Variance

    NASA Technical Reports Server (NTRS)

    Greenhall, C. A.

    1996-01-01

    We study the extent to which knowledge of Allan variance and other finite-difference variances determines the spectrum of a random process. The variance of first differences is known to determine the spectrum. We show that, in general, the Allan variance does not. A complete description of the ambiguity is given.

  1. Identification and Characterization of Novel Broad-Spectrum Inhibitors of the Flavivirus Methyltransferase

    PubMed Central

    Brecher, Matthew; Chen, Hui; Li, Zhong; Banavali, Nilesh K.; Jones, Susan A.; Zhang, Jing; Kramer, Laura D.; Li, Hongmin

    2015-01-01

    Flavivirus methyltransferase (MTase) is essential for viral replication. Here we report the identification of small molecules through virtual screening that putatively bind to the SAM-binding site of flavivirus MTase and inhibit its function. Six of these computationally predicted binders were identified to show significant MTase inhibition with low micromolar inhibitory activity. The most active compounds showed broad-spectrum activity against the MTase proteins of other flaviviruses. Two of these compounds also showed low cytotoxicity and high antiviral efficacy in cell-based assays. Competitive binding analyses indicated that the inhibitors performed their inhibitory function through competitive binding to the SAM cofactor binding site of the MTase. The crystal structure of the MTase–inhibitor complex further supports the mode of action and provides routes for their further optimization as flavivirus MTase inhibitors. PMID:26726314

  2. Flaviviruses in Europe: Complex Circulation Patterns and Their Consequences for the Diagnosis and Control of West Nile Disease

    PubMed Central

    Beck, Cécile; Jimenez-Clavero, Miguel Angel; Leblond, Agnès; Durand, Benoît; Nowotny, Norbert; Leparc-Goffart, Isabelle; Zientara, Stéphan; Jourdain, Elsa; Lecollinet, Sylvie

    2013-01-01

    In Europe, many flaviviruses are endemic (West Nile, Usutu, tick-borne encephalitis viruses) or occasionally imported (dengue, yellow fever viruses). Due to the temporal and geographical co-circulation of flaviviruses in Europe, flavivirus differentiation by diagnostic tests is crucial in the adaptation of surveillance and control efforts. Serological diagnosis of flavivirus infections is complicated by the antigenic similarities among the Flavivirus genus. Indeed, most flavivirus antibodies are directed against the highly immunogenic envelope protein, which contains both flavivirus cross-reactive and virus-specific epitopes. Serological assay results should thus be interpreted with care and confirmed by comparative neutralization tests using a panel of viruses known to circulate in Europe. However, antibody cross-reactivity could be advantageous in efforts to control emerging flaviviruses because it ensures partial cross-protection. In contrast, it might also facilitate subsequent diseases, through a phenomenon called antibody-dependent enhancement mainly described for dengue virus infections. Here, we review the serological methods commonly used in WNV diagnosis and surveillance in Europe. By examining past and current epidemiological situations in different European countries, we present the challenges involved in interpreting flavivirus serological tests and setting up appropriate surveillance programs; we also address the consequences of flavivirus circulation and vaccination for host immunity. PMID:24225644

  3. Nominal analysis of "variance".

    PubMed

    Weiss, David J

    2009-08-01

    Nominal responses are the natural way for people to report actions or opinions. Because nominal responses do not generate numerical data, they have been underutilized in behavioral research. On those occasions in which nominal responses are elicited, the responses are customarily aggregated over people or trials so that large-sample statistics can be employed. A new analysis is proposed that directly associates differences among responses with particular sources in factorial designs. A pair of nominal responses either matches or does not; when responses do not match, they vary. That analogue to variance is incorporated in the nominal analysis of "variance" (NANOVA) procedure, wherein the proportions of matches associated with sources play the same role as do sums of squares in an ANOVA. The NANOVA table is structured like an ANOVA table. The significance levels of the N ratios formed by comparing proportions are determined by resampling. Fictitious behavioral examples featuring independent groups and repeated measures designs are presented. A Windows program for the analysis is available.

  4. Deployable Pan-Flavivirus and Pan-alphavirus Assays for Screening Pools of Medically Relevant Arthropod

    DTIC Science & Technology

    2011-09-01

    Venezuelan equine encephalitis virus (TC-83 strain). The flaviviruses included West Nile Virus and Dengue 3 virus. We chose these organisms because these...and Venezuelan Equine Encephalitis (VEE, TC-83 strain). Flaviviruses: Dengue 3 and West Nile Virus (WNV). We purified these lysates using the...call “by- eye ” which tells us that only the VEE (tc-83) virus is present. Refinements to our pathogen calling algorithm, although minor, will be

  5. Isolation of a novel species of flavivirus and a new strain of Culex flavivirus (Flaviviridae) from a natural mosquito population in Uganda.

    PubMed

    Cook, Shelley; Moureau, Gregory; Harbach, Ralph E; Mukwaya, Louis; Goodger, Kim; Ssenfuka, Fred; Gould, Ernest; Holmes, Edward C; de Lamballerie, Xavier

    2009-11-01

    The genus Flavivirus, which contains approximately 70 single-stranded, positive-sense RNA viruses, represents a unique model for studying the evolution of vector-borne disease, as it includes viruses that are mosquito-borne, tick-borne or have no known vector. Both theoretical work and field studies suggest the existence of a large number of undiscovered flaviviruses. Recently, the first isolation of cell fusing agent virus (CFAV) was reported from a natural mosquito population in Puerto Rico, and sequences related to CFAV have been discovered in mosquitoes from Thailand. CFAV had previously been isolated from a mosquito cell line in 1975 and represented the only known 'insect-only' flavivirus, appearing to replicate in insect cells alone. A second member of the 'insect-only' group, Kamiti River virus (KRV), was isolated from Kenyan mosquitoes in 2003. A third tentative member of the 'insect-only' group, Culex flavivirus (CxFV), was first isolated in 2007 from Japan and further strains have subsequently been reported from the Americas. We report the discovery, isolation and characterization of two novel 'insect-only' flaviviruses from Entebbe, Uganda: a novel lineage tentatively designated Nakiwogo virus (NAKV) and a new strain of CxFV. The individual mosquitoes from which these strains were isolated, identified retrospectively by using a reference molecular phylogeny generated using voucher specimens from the region, were Mansonia africana nigerrima and Culex quinquefasciatus, respectively. This represents the first isolation, to our knowledge, of a novel insect-only flavivirus from a Mansonia species and the first isolation of a strain of CxFV from Africa.

  6. Cosmic Strings and Cosmic Variance

    NASA Astrophysics Data System (ADS)

    Gangui, Alejandro; Perivolaropoulos, Leandros

    1995-07-01

    By using a simple analytical model based on counting random multiple impulses inflicted on photons by a network of cosmic strings we show how to construct the general q-point temperature correlation function of the cosmic microwave background radiation. Our analysis is especially sensible for large angular scales where the Kaiser-Stebbins effect is dominant. Then we concentrate on the four-point function and, in particular, on its zero-lag limit, namely, the excess kurtosis parameter, for which we obtain a predicted value of ˜10-2. In addition, we estimate the cosmic variance for the kurtosis due to a Gaussian fluctuation field, showing its dependence on the primordial spectral index of density fluctuations n and finding agreement with previous published results for the particular case of a flat Harrison-Zel'dovich spectrum. Our value for the kurtosis compares well with previous analyses but falls below the threshold imposed by the cosmic variance when commonly accepted parameters from string simulations are considered. In particular the non-Gaussian signal is found to be inversely proportional to the scaling number of defects, as could be expected by the central limit theorem.

  7. Insect-Specific Flaviviruses from Culex Mosquitoes in Colorado, with Evidence of Vertical Transmission

    PubMed Central

    Bolling, Bethany G.; Eisen, Lars; Moore, Chester G.; Blair, Carol D.

    2011-01-01

    Mosquitoes were collected in Colorado during 2006 and 2007 to examine spatial and seasonal patterns of risk for exposure to Culex vectors and West Nile virus. We used universal flavivirus primers to test pools of Culex mosquitoes for viral RNA. This led to the detection and subsequent isolation of two insect-specific flaviviruses: Culex flavivirus (CxFV), which was first described from Japan, and a novel insect flavivirus, designated Calbertado virus (CLBOV), which has also been detected in California and Canada. We recorded both viruses in Cx. tarsalis and Cx. pipiens from Colorado. Furthermore, quantitative reverse transcription polymerase chain reaction (RT-PCR) revealed the presence of CxFV RNA in Cx. pipiens eggs and larvae from a laboratory colony established in 2005 and naturally infected with CxFV, suggesting vertical transmission as a means of viral maintenance in natural Culex populations. Finally, we present phylogenetic analyses of the relationships between insect-specific flaviviruses and other selected flaviviruses. PMID:21734144

  8. Serologic Evidence of Flavivirus Infection in Bats in the Yucatan Peninsula of Mexico

    PubMed Central

    Machain-Williams, Carlos; López-Uribe, Mildred; Talavera-Aguilar, Lourdes; Carrillo-Navarrete, Jaquelin; Vera-Escalante, Luis; Puerto-Manzano, Fernando; Ulloa, Armando; Farfán-Ale, José Arturo; Garcia-Rejon, Julián; Blitvich, Bradley J.; Loroño-Pino, María Alba

    2013-01-01

    We captured 140 bats of seven species in Merida City in the Yucatan Peninsula of Mexico in 2010. Serum was collected from each bat and assayed by plaque reduction neutralization test (PRNT) using six flaviviruses: West Nile virus, St. Louis encephalitis virus, and dengue viruses 1–4. Flavivirus-specific antibodies were detected in 26 bats (19%). The antibody-positive bats belonged to three species: the Pallas's long-tongued bat (Glossophaga soricina), Jamaican fruit bat (Artibeus jamaicensis), and great fruit-eating bat (Artibeus lituratus), and their flavivirus antibody prevalences were 33%, 24%, and 9%, respectively. The PRNT titers were usually highest for dengue virus 2 or dengue virus 4, but none of the titers exceeded 80. These data could indicate that most of the antibody-positive bats had been infected with dengue virus. However, because all titers were low, it is possible that the bats had been infected with another (perhaps unrecognized) flavivirus not included in the PRNT analysis, possibly a virus more closely related to dengue virus than to other flaviviruses. Each serum sample was assayed for flavivirus RNA by reverse transcription PCR, but all were negative. PMID:23778622

  9. Serological evidence for the circulation of flaviviruses in seabird populations of the western Indian Ocean.

    PubMed

    Jaeger, A; Lecollinet, S; Beck, C; Bastien, M; Le Corre, M; Dellagi, K; Pascalis, H; Boulinier, T; Lebarbenchon, C

    2016-02-01

    Birds play a central role in the epidemiology of several flaviviruses of concern for public and veterinary health. Seabirds represent the most abundant and widespread avifauna in the western Indian Ocean and may play an important role as host reservoirs and spreaders of arthropod-borne pathogens such as flaviviruses. We report the results of a serological investigation based on blood samples collected from nine seabird species from seven islands in the Indian Ocean. Using a commercial competitive enzyme-linked immunosorbent assay directed against the prototypic West Nile flavivirus, antibodies against flaviviruses were detected in the serum of 47 of the 855 seabirds tested. They were detected in bird samples from three islands and from four bird species. Seroneutralization tests on adults and chicks suggested that great frigatebirds (Fregata minor) from Europa were infected by West Nile virus during their non-breeding period, and that Usutu virus probably circulated within bird colonies on Tromelin and on Juan de Nova. Real-time polymerase chain reactions performed on bird blood samples did not yield positive results precluding the genetic characterization of flavivirus using RNA sequencing. Our findings stress the need to further investigate flavivirus infections in arthropod vectors present in seabird colonies.

  10. Antibody Responses to Zika Virus Infections in Environments of Flavivirus Endemicity.

    PubMed

    Keasey, Sarah L; Pugh, Christine L; Jensen, Stig M R; Smith, Jessica L; Hontz, Robert D; Durbin, Anna P; Dudley, Dawn M; O'Connor, David H; Ulrich, Robert G

    2017-04-01

    Zika virus (ZIKV) infections occur in areas where dengue virus (DENV), West Nile virus (WNV), yellow fever virus (YFV), and other viruses of the genus Flavivirus cocirculate. The envelope (E) proteins of these closely related flaviviruses induce specific long-term immunity, yet subsequent infections are associated with cross-reactive antibody responses that may enhance disease susceptibility and severity. To gain a better understanding of ZIKV infections against a background of similar viral diseases, we examined serological immune responses to ZIKV, WNV, DENV, and YFV infections of humans and nonhuman primates (NHPs). Using printed microarrays, we detected very specific antibody responses to primary infections with probes of recombinant E proteins from 15 species and lineages of flaviviruses pathogenic to humans, while high cross-reactivity between ZIKV and DENV was observed with 11 printed native viruses. Notably, antibodies from human primary ZIKV or secondary DENV infections that occurred in areas where flavivirus is endemic broadly recognized E proteins from many flaviviruses, especially DENV, indicating a strong influence of infection history on immune responses. A predictive algorithm was used to tentatively identify previous encounters with specific flaviviruses based on serum antibody interactions with the multispecies panel of E proteins. These results illustrate the potential impact of exposure to related viruses on the outcome of ZIKV infection and offer considerations for development of vaccines and diagnostics.

  11. Detection of Flaviviruses and Orthobunyaviruses in Mosquitoes in the Yucatan Peninsula of Mexico in 2008

    PubMed Central

    Farfan-Ale, Jose A.; Loroño-Pino, Maria A.; Garcia-Rejon, Julian E.; Soto, Victor; Lin, Ming; Staley, Molly; Dorman, Karin S.; Bartholomay, Lyric C.; Hovav, Einat

    2010-01-01

    Abstract A total of 191,244 mosquitoes from 24 species were collected in the Yucatan Peninsula of Mexico from January to December 2008, and tested for the presence of cytopathic virus by virus isolation in Vero cells. Eighteen virus isolates were obtained, all of which were orthobunyaviruses. These were identified by reverse transcription-polymerase chain reaction (RT-PCR) and nucleotide sequencing as Cache Valley virus (n = 17) and South River virus (n = 1). A subset (n = 20,124) of Culex quinquefasciatus collected throughout the year was further tested by RT-PCR using flavivirus-specific primers. Flavivirus RNA was present in this mosquito species year-round. The overall flavivirus minimal infection rate, expressed as the number of positive mosquito pools per 1000 mosquitoes tested, was 7.7 and the monthly flavivirus minimal infection rates ranged from 4.3 to 16.6. Approximately one-third of the RT-PCR products were sequenced and all corresponded to Culex flavivirus, a recently discovered insect-specific flavivirus. PMID:20370430

  12. Serologic evidence of flavivirus infection in bats in the Yucatan Peninsula of Mexico.

    PubMed

    Machain-Williams, Carlos; López-Uribe, Mildred; Talavera-Aguilar, Lourdes; Carrillo-Navarrete, Jaquelin; Vera-Escalante, Luis; Puerto-Manzano, Fernando; Ulloa, Armando; Farfán-Ale, José Arturo; Garcia-Rejon, Julián; Blitvich, Bradley J; Loroño-Pino, María Alba

    2013-07-01

    We captured 140 bats of seven species in Merida City in the Yucatan Peninsula of Mexico in 2010. Serum was collected from each bat and assayed by plaque reduction neutralization test (PRNT) using six flaviviruses: West Nile virus, St. Louis encephalitis virus, and dengue viruses 1-4. Flavivirus-specific antibodies were detected in 26 bats (19%). The antibody-positive bats belonged to three species: the Pallas's long-tongued bat (Glossophaga soricina), Jamaican fruit bat (Artibeus jamaicensis), and great fruit-eating bat (Artibeus lituratus), and their flavivirus antibody prevalences were 33%, 24%, and 9%, respectively. The PRNT titers were usually highest for dengue virus 2 or dengue virus 4, but none of the titers exceeded 80. These data could indicate that most of the antibody-positive bats had been infected with dengue virus. However, because all titers were low, it is possible that the bats had been infected with another (perhaps unrecognized) flavivirus not included in the PRNT analysis, possibly a virus more closely related to dengue virus than to other flaviviruses. Each serum sample was assayed for flavivirus RNA by reverse transcription PCR, but all were negative.

  13. Assessing ubiquitination of viral proteins: Lessons from flavivirus NS5.

    PubMed

    Taylor, R Travis; Best, Sonja M

    2011-10-01

    Ubiquitin (Ub) conjugation to a substrate protein is a widely used cellular mechanism for control of protein stability and function, modulation of signal transduction pathways and antiviral responses. Identification and characterization of ubiquitinated viral proteins is an important step in understanding novel mechanisms of viral protein regulation as well as elucidating cellular antiviral strategies. Here we describe a protocol to easily detect and characterize the ubiquitination status of a viral substrate protein expressed either during infection or ectopically expressed as a fusion with a biotinylatable epitope tag. This tag provides advantages over current immunoprecipitation techniques by making use of the extremely tight biotin-streptavidin interaction. We provide an example of this protocol using the nonstructural protein 5 (NS5) from Langat virus (LGTV), a member of the tick-borne encephalitis virus (TBEV) serocomplex within the Flavivirus genus. Using the protocols outlined here, we describe some of the pitfalls inherent in determination of Ub linkage and demonstrate that NS5 is modified by at least two distinct ubiquitination types, multiubiquitination and K48-linked polyubiquitin chains.

  14. The Golgi associated ERI3 is a Flavivirus host factor

    PubMed Central

    Ward, Alex Michael; Calvert, Meredith E. K.; Read, Leah R.; Kang, Seokyoung; Levitt, Brandt E.; Dimopoulos, George; Bradrick, Shelton S.; Gunaratne, Jayantha; Garcia-Blanco, Mariano A.

    2016-01-01

    Dengue virus (DENV) is a mosquito-borne Flavivirus classified into four serotypes (DENV-1-4) that causes Dengue fever (DF), Dengue hemorrhagic Fever (DHF) or Dengue shock syndrome (DSS). An estimated 390 million people are at risk for infection with DENV and there are no effective vaccines or therapeutics. We utilized RNA chromatography coupled with quantitative mass spectrometry (qMS) to identify host RNA binding proteins (RBPs) that interact with DENV-2 RNA. We identified ERI3 (also PRNPIP and PINT1), a putative 3′–5′ RNA exonuclease, which preferentially associates with DENV-2 genomic RNA via interactions with dumbbell structures in the 3′ UTR. ERI3 is required for accumulation of DENV-2 genomic RNA and production of infectious particles. Furthermore, the mosquito homologue of ERI3 is required for DENV-2 replication in adult Aedes aegypti mosquitos implying that the requirement for ERI3 is conserved in both DENV hosts. In human cells ERI3 localizes to the Golgi in uninfected cells, but relocalizes near sites of DENV-2 replication in infected cells. ERI3 is not required for maintaining DENV-2 RNA stability or translation of the viral polyprotein, but is required for viral RNA synthesis. Our results define a specific role for ERI3 and highlight the importance of Golgi proteins in DENV-2 replication. PMID:27682269

  15. Stability of a Tick-Borne Flavivirus in Milk.

    PubMed

    Offerdahl, Danielle K; Clancy, Niall G; Bloom, Marshall E

    2016-01-01

    The tick-borne flaviviruses (TBFV) occur worldwide and the tick-borne encephalitis virus (TBEV) members of the group often cause severe, debilitating neurological disease in humans. Although the primary route of infection is through the bite of an infected tick, alimentary infection through the consumption of TBEV-contaminated dairy products is also well-documented and is responsible for some disease in endemic areas. Experimental infection of goats, cattle, and sheep with TBEV shows that the virus can be excreted in the milk of infected animals. Additionally, the virus remains infectious after exposure to low pH levels, similar to those found in the stomach. To evaluate the survival of virus in milk, we studied the stability of the BSL-2 TBFV, Langat virus, in unpasteurized goat milk over time and after different thermal treatments. Virus was stable in milk maintained under refrigeration conditions; however, there was a marked reduction in virus titer after incubation at room temperature. High temperature, short time pasteurization protocols completely inactivated the virus. Interestingly, simulation of a typical thermal regime utilized for cheese did not completely inactivate the virus in milk. These findings stress the importance of proper milk handling and pasteurization processes in areas endemic for TBEV.

  16. Assessing ubiquitination of viral proteins: lessons from flavivirus NS5

    PubMed Central

    Taylor, R. Travis; Best, Sonja M.

    2011-01-01

    Ubiquitin (Ub) conjugation to a substrate protein is a widely used cellular mechanism for control of protein stability and function, modulation of signal transduction pathways and antiviral responses. Identification and characterization of ubiquitinated viral proteins is an important step in understanding novel mechanisms of viral protein regulation as well as elucidating cellular antiviral strategies. Here we describe a protocol to easily detect and characterize the ubiquitination status of a viral substrate protein expressed either during infection or ectopically expressed as a fusion with a biotinylatable epitope tag. This tag provides advantages over current immunoprecipitation techniques by making use of the extremely tight biotin-streptavidin interaction. We provide an example of this protocol using the nonstructural protein 5 (NS5) from Langat virus (LGTV), a member of the tick-borne encephalitis virus (TBEV) serocomplex within the Flavivirus genus. Using the protocols outlined here, we describe some of the pitfalls inherent in determination of Ub linkage and demonstrate that NS5 is modified by at least two distinct ubiquitination types, multiubiquitination and K48-linked polyubiquitin chains. PMID:21855635

  17. The mysterious Zika virus: Adding to the tropical flavivirus mayhem.

    PubMed

    Mishra, B; Behera, B

    2016-01-01

    Until now, known as the demure cousin of dengue virus (DENV) inhabiting Africa, Zika virus (ZIKV) has reinvented itself to cause explosive epidemics captivating the Western hemisphere. The outbreak causing potential for ZIKV was realized when it made its way from Africa to Yap Island Micronesia in 2007, and in French Polynesia in 2013. From there, it moved on to Brazil in 2015. Now ZIKV has infected people in more than 33 countries in Central and South America and the Caribbean. Moreover the epidemiological and subsequent virological association with microcephaly cases in Brazil has prompted the World Health Organization to declare a public health emergency of International Concern. ZIKV shares not only its vector Aedes aegypti with dengue and chikungunya but also the geographic distribution and clinical features, which makes the laboratory confirmation mandatory for definitive diagnosis. The serological cross-reactivity with other Flavivirus, particularly with DENV makes laboratory confirmation challenging and will place additional burden on health systems to establish molecular diagnostic facilities. The evidence of additional nonvector modes of transmission, such as perinatal, sexual as well as transfusion has made preventative strategies more difficult. As ZIKV disease continues to mystify us with several unanswered questions, it calls for coordinated effort of global scientific community to address the ever growing arboviral threat to mankind.

  18. The mysterious Zika virus: Adding to the tropical flavivirus mayhem.

    PubMed

    Mishra, B; Behera, B

    2016-09-21

    Until now, known as the demure cousin of dengue virus (DENV) inhabiting Africa, Zika virus (ZIKV) has reinvented itself to cause explosive epidemics captivating the Western hemisphere. The outbreak causing potential for ZIKV was realized when it made its way from Africa to Yap Island Micronesia in 2007, and in French Polynesia in 2013. From there, it moved on to Brazil in 2015. Now ZIKV has infected people in more than 33 countries in Central and South America and the Caribbean. Moreover the epidemiological and subsequent virological association with microcephaly cases in Brazil has prompted the World Health Organization to declare a public health emergency of International Concern. ZIKV shares not only its vector Aedes aegypti with dengue and chikungunya but also the geographic distribution and clinical features, which makes the laboratory confirmation mandatory for definitive diagnosis. The serological cross-reactivity with other Flavivirus, particularly with DENV makes laboratory confirmation challenging and will place additional burden on health systems to establish molecular diagnostic facilities. The evidence of additional nonvector modes of transmission, such as perinatal, sexual as well as transfusion has made preventative strategies more difficult. As ZIKV disease continues to mystify us with several unanswered questions, it calls for coordinated effort of global scientific community to address the ever growing arboviral threat to mankind.

  19. The mysterious Zika virus: Adding to the tropical flavivirus mayhem

    PubMed Central

    Mishra, B; Behera, B

    2016-01-01

    Until now, known as the demure cousin of dengue virus (DENV) inhabiting Africa, Zika virus (ZIKV) has reinvented itself to cause explosive epidemics captivating the Western hemisphere. The outbreak causing potential for ZIKV was realized when it made its way from Africa to Yap Island Micronesia in 2007, and in French Polynesia in 2013. From there, it moved on to Brazil in 2015. Now ZIKV has infected people in more than 33 countries in Central and South America and the Caribbean. Moreover the epidemiological and subsequent virological association with microcephaly cases in Brazil has prompted the World Health Organization to declare a public health emergency of International Concern. ZIKV shares not only its vector Aedes aegypti with dengue and chikungunya but also the geographic distribution and clinical features, which makes the laboratory confirmation mandatory for definitive diagnosis. The serological cross-reactivity with other Flavivirus, particularly with DENV makes laboratory confirmation challenging and will place additional burden on health systems to establish molecular diagnostic facilities. The evidence of additional nonvector modes of transmission, such as perinatal, sexual as well as transfusion has made preventative strategies more difficult. As ZIKV disease continues to mystify us with several unanswered questions, it calls for coordinated effort of global scientific community to address the ever growing arboviral threat to mankind. PMID:27763483

  20. Development of a novel protocol for generating flavivirus reporter particles.

    PubMed

    Fernández, Igor Velado; Okamoto, Natsumi; Ito, Aki; Fukuda, Miki; Someya, Azusa; Nishino, Yosii; Sasaki, Nobuya; Maeda, Akihiko

    2014-11-01

    Infection with West Nile virus (WNV), a mosquito-borne flavivirus, is a growing public and animal health concern worldwide. Prevention, diagnosis and treatment strategies for the infection are urgently required. Recently, viral reverse genetic systems have been developed and applied to clinical WNV virology. We developed a protocol for generating reporter virus particles (RVPs) of WNV with the aim of overcoming two major problems associated with conventional protocols, the difficulty in generating RVPs due to the specific skills required for handling RNAs, and the potential for environmental contamination by antibiotic-resistant genes encoded within the genome RNA of the RVPs. By using the proposed protocol, cells were established in which the RVP genome RNA is replicated constitutively and does not encode any antibiotic-resistant genes, and used as the cell supply for RVP genome RNA. Generation of the WNV RVPs requires only the simple transfection of the expression vectors for the viral structural proteins into the cells. Therefore, no RNA handling is required in this protocol. The WNV RVP yield obtained using this protocol was similar that obtained using the conventional protocol. According to these results, the newly developed protocol appears to be a good alternative for the generation of WNV RVPs, particularly for clinical applications. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Extrinsic MAVS signaling is critical for Treg maintenance of Foxp3 expression following acute flavivirus infection.

    PubMed

    Da Costa, Andreia; Garza, Esteban; Graham, Jessica B; Swarts, Jessica L; Soerens, Andrew G; Gale, Michael; Lund, Jennifer M

    2017-01-17

    Given the rapid spread of flaviviruses such as West Nile virus (WNV) and Zika virus, it is critical that we develop a complete understanding of the key mediators of an effective anti-viral response. We previously demonstrated that WNV infection of mice deficient in mitochondrial antiviral-signaling protein (MAVS), the signaling adaptor for RNA helicases such as RIG-I, resulted in increased death and dysregulated immunity, which correlated with a failure of Treg expansion following infection. Thus, we sought to determine if intrinsic MAVS signaling is required for participation of Tregs in anti-WNV immunity. Despite evidence of increased Treg cell division, Foxp3 expression was not stably maintained after WNV infection in MAVS-deficient mice. However, intrinsic MAVS signaling was dispensable for Treg proliferation and suppressive capacity. Further, we observed generation of an effective anti-WNV immune response when Tregs lacked MAVS, thereby demonstrating that Treg detection of the presence of WNV through the MAVS signaling pathway is not required for generation of effective immunity. Together, these data suggest that while MAVS signaling has a considerable impact on Treg identity, this effect is not mediated by intrinsic MAVS signaling but rather is likely an effect of the overproduction of pro-inflammatory cytokines generated in MAVS-deficient mice after WNV infection.

  2. Extrinsic MAVS signaling is critical for Treg maintenance of Foxp3 expression following acute flavivirus infection

    PubMed Central

    Da Costa, Andreia; Garza, Esteban; Graham, Jessica B.; Swarts, Jessica L.; Soerens, Andrew G.; Gale, Michael; Lund, Jennifer M.

    2017-01-01

    Given the rapid spread of flaviviruses such as West Nile virus (WNV) and Zika virus, it is critical that we develop a complete understanding of the key mediators of an effective anti-viral response. We previously demonstrated that WNV infection of mice deficient in mitochondrial antiviral-signaling protein (MAVS), the signaling adaptor for RNA helicases such as RIG-I, resulted in increased death and dysregulated immunity, which correlated with a failure of Treg expansion following infection. Thus, we sought to determine if intrinsic MAVS signaling is required for participation of Tregs in anti-WNV immunity. Despite evidence of increased Treg cell division, Foxp3 expression was not stably maintained after WNV infection in MAVS-deficient mice. However, intrinsic MAVS signaling was dispensable for Treg proliferation and suppressive capacity. Further, we observed generation of an effective anti-WNV immune response when Tregs lacked MAVS, thereby demonstrating that Treg detection of the presence of WNV through the MAVS signaling pathway is not required for generation of effective immunity. Together, these data suggest that while MAVS signaling has a considerable impact on Treg identity, this effect is not mediated by intrinsic MAVS signaling but rather is likely an effect of the overproduction of pro-inflammatory cytokines generated in MAVS-deficient mice after WNV infection. PMID:28094802

  3. Cosmology without cosmic variance

    SciTech Connect

    Bernstein, Gary M.; Cai, Yan -Chuan

    2011-10-01

    The growth of structures in the Universe is described by a function G that is predicted by the combination of the expansion history of the Universe and the laws of gravity within it. We examine the improvements in constraints on G that are available from the combination of a large-scale galaxy redshift survey with a weak gravitational lensing survey of background sources. We describe a new combination of such observations that in principle this yields a measure of the growth rate that is free of sample variance, i.e. the uncertainty in G can be reduced without bound by increasing the number of redshifts obtained within a finite survey volume. The addition of background weak lensing data to a redshift survey increases information on G by an amount equivalent to a 10-fold increase in the volume of a standard redshift-space distortion measurement - if the lensing signal can be measured to sub-per cent accuracy. This argues that a combined lensing and redshift survey over a common low-redshift volume of the Universe is a more powerful test of general relativity than an isolated redshift survey over larger volume at high redshift, especially as surveys begin to cover most of the available sky.

  4. Cosmology without cosmic variance

    DOE PAGES

    Bernstein, Gary M.; Cai, Yan -Chuan

    2011-10-01

    The growth of structures in the Universe is described by a function G that is predicted by the combination of the expansion history of the Universe and the laws of gravity within it. We examine the improvements in constraints on G that are available from the combination of a large-scale galaxy redshift survey with a weak gravitational lensing survey of background sources. We describe a new combination of such observations that in principle this yields a measure of the growth rate that is free of sample variance, i.e. the uncertainty in G can be reduced without bound by increasing themore » number of redshifts obtained within a finite survey volume. The addition of background weak lensing data to a redshift survey increases information on G by an amount equivalent to a 10-fold increase in the volume of a standard redshift-space distortion measurement - if the lensing signal can be measured to sub-per cent accuracy. This argues that a combined lensing and redshift survey over a common low-redshift volume of the Universe is a more powerful test of general relativity than an isolated redshift survey over larger volume at high redshift, especially as surveys begin to cover most of the available sky.« less

  5. Identifying Attenuating Mutations: Tools for a New Vaccine Design against Flaviviruses.

    PubMed

    Khou, Cécile; Pardigon, Nathalie

    2017-09-05

    Emerging Flaviviruses pose an increasing threat to global human health. To date, human vaccines against yellow fever virus (YFV), Japanese encephalitis virus (JEV), dengue virus (DV), and tick-borne encephalitis virus (TBEV) exist. However, there is no human vaccine against other Flaviviruses such as Zika virus (ZIKV) and West Nile virus (WNV). In order to restrict their spread and to protect populations against the diseases they induce, vaccines against these emerging viruses must be designed. Obtaining new live attenuated Flavivirus vaccines using molecular biology methods is now possible. Molecular infectious clones of the parental viruses are relatively easy to generate. Key mutations present in live attenuated vaccines or mutations known to have a key role in the Flavivirus life cycle and/or interactions with their hosts can be identified by sequencing, and are then inserted in infectious clones by site-directed mutagenesis. More recently, the use of chimeric viruses and large-scale reencoding and introduction of microRNA target sequences have also been tested. Indeed, a combination of these methods will help in designing new generations of vaccines against emerging and reemerging Flaviviruses. © 2017 S. Karger AG, Basel.

  6. A CRISPR screen defines a signal peptide processing pathway required by flaviviruses.

    PubMed

    Zhang, Rong; Miner, Jonathan J; Gorman, Matthew J; Rausch, Keiko; Ramage, Holly; White, James P; Zuiani, Adam; Zhang, Ping; Fernandez, Estefania; Zhang, Qiang; Dowd, Kimberly A; Pierson, Theodore C; Cherry, Sara; Diamond, Michael S

    2016-07-07

    Flaviviruses infect hundreds of millions of people annually, and no antiviral therapy is available. We performed a genome-wide CRISPR/Cas9-based screen to identify host genes that, when edited, resulted in reduced flavivirus infection. Here, we validated nine human genes required for flavivirus infectivity, and these were associated with endoplasmic reticulum functions including translocation, protein degradation, and N-linked glycosylation. In particular, a subset of endoplasmic reticulum-associated signal peptidase complex (SPCS) proteins was necessary for proper cleavage of the flavivirus structural proteins (prM and E) and secretion of viral particles. Loss of SPCS1 expression resulted in markedly reduced yield of all Flaviviridae family members tested (West Nile, Dengue, Zika, yellow fever, Japanese encephalitis, and hepatitis C viruses), but had little impact on alphavirus, bunyavirus, or rhabdovirus infection or the surface expression or secretion of diverse host proteins. We found that SPCS1 dependence could be bypassed by replacing the native prM protein leader sequences with a class I major histocompatibility complex (MHC) antigen leader sequence. Thus, SPCS1, either directly or indirectly via its interactions with unknown host proteins, preferentially promotes the processing of specific protein cargo, and Flaviviridae have a unique dependence on this signal peptide processing pathway. SPCS1 and other signal processing pathway members could represent pharmacological targets for inhibiting infection by the expanding number of flaviviruses of medical concern.

  7. Host influence in the genomic composition of flaviviruses: A multivariate approach.

    PubMed

    Simón, Diego; Fajardo, Alvaro; Sóñora, Martín; Delfraro, Adriana; Musto, Héctor

    2017-10-28

    Flaviviruses present substantial differences in their host range and transmissibility. We studied the evolution of base composition, dinucleotide biases, codon usage and amino acid frequencies in the genus Flavivirus within a phylogenetic framework by principal components analysis. There is a mutual interplay between the evolutionary history of flaviviruses and their respective vectors and/or hosts. Hosts associated to distinct phylogenetic groups may be driving flaviviruses at different pace and through various sequence landscapes, as can be seen for viruses associated with Aedes or Culex spp., although phylogenetic inertia cannot be ruled out. In some cases, viruses face even opposite forces. For instance, in tick-borne flaviviruses, while vertebrate hosts exert pressure to deplete their CpG, tick vectors drive them to exhibit GC-rich codons. Within a vertebrate environment, natural selection appears to be acting on the viral genome to overcome the immune system. On the other side, within an arthropod environment, mutational biases seem to be the dominant forces. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Duck egg-drop syndrome caused by BYD virus, a new Tembusu-related flavivirus.

    PubMed

    Su, Jingliang; Li, Shuang; Hu, Xudong; Yu, Xiuling; Wang, Yongyue; Liu, Peipei; Lu, Xishan; Zhang, Guozhong; Hu, Xueying; Liu, Di; Li, Xiaoxia; Su, Wenliang; Lu, Hao; Mok, Ngai Shing; Wang, Peiyi; Wang, Ming; Tian, Kegong; Gao, George F

    2011-03-24

    Since April 2010, a severe outbreak of duck viral infection, with egg drop, feed uptake decline and ovary-oviduct disease, has spread around the major duck-producing regions in China. A new virus, named BYD virus, was isolated in different areas, and a similar disease was reproduced in healthy egg-producing ducks, infecting with the isolated virus. The virus was re-isolated from the affected ducks and replicated well in primary duck embryo fibroblasts and Vero cells, causing the cytopathic effect. The virus was identified as an enveloped positive-stranded RNA virus with a size of approximately 55 nm in diameter. Genomic sequencing of the isolated virus revealed that it is closely related to Tembusu virus (a mosquito-borne Ntaya group flavivirus), with 87-91% nucleotide identity of the partial E (envelope) proteins to that of Tembusu virus and 72% of the entire genome coding sequence with Bagaza virus, the most closely related flavivirus with an entirely sequenced genome. Collectively our systematic studies fulfill Koch's postulates, and therefore, the causative agent of the duck egg drop syndrome occurring in China is a new flavivirus. Flavivirus is an emerging and re-emerging zoonotic pathogen and BYD virus that causes severe egg-drop, could be disastrous for the duck industry. More importantly its public health concerns should also be evaluated, and its epidemiology should be closely watched due to the zoonotic nature of flaviviruses.

  9. A CRISPR screen defines a signal peptide processing pathway required by flaviviruses

    PubMed Central

    Zhang, Rong; Miner, Jonathan J.; Gorman, Matthew J.; Rausch, Keiko; Ramage, Holly; White, James P.; Zuiani, Adam; Zhang, Ping; Fernandez, Estefania; Zhang, Qiang; Dowd, Kimberly A.; Pierson, Theodore C.; Cherry, Sara; Diamond, Michael S.

    2016-01-01

    Flaviviruses infect hundreds of millions of people annually, with no antiviral therapy available1,2. We performed a genome-wide CRISPR/Cas9-based screen to identify host genes that when edited resulted in reduced flavivirus infection. We validated nine human genes required for flavivirus infectivity, and these were associated with endoplasmic reticulum (ER) functions including translocation, protein degradation, and N-linked glycosylation. In particular, a subset of ER-associated signal peptidase complex (SPCS) proteins was necessary for the proper cleavage of the flavivirus structural proteins (prM and E) and secretion of viral particles. Loss of SPCS1 expression resulted in markedly reduced yield of all Flaviviridae family members tested (West Nile, Dengue, Zika, yellow fever, Japanese encephalitis, and hepatitis C viruses), yet had little impact on alphavirus, bunyavirus, or rhabdovirus infection or the surface expression or secretion of diverse host proteins. We found that SPCS1 dependence could be bypassed by replacing the native prM protein leader sequences with a class I MHC antigen leader sequence. Thus, SPCS1, either directly or indirectly via its interactions with unknown host proteins, preferentially promotes the processing of specific protein cargo, and Flaviviridae have a unique dependence on this signal peptide processing pathway. SPCS1 and other signal processing pathway members could represent pharmacological targets for inhibiting infection of the expanding number of flaviviruses of medical concern. PMID:27383988

  10. Structures of the Zika Virus Envelope Protein and Its Complex with a Flavivirus Broadly Protective Antibody.

    PubMed

    Dai, Lianpan; Song, Jian; Lu, Xishan; Deng, Yong-Qiang; Musyoki, Abednego Moki; Cheng, Huijun; Zhang, Yanfang; Yuan, Yuan; Song, Hao; Haywood, Joel; Xiao, Haixia; Yan, Jinghua; Shi, Yi; Qin, Cheng-Feng; Qi, Jianxun; Gao, George F

    2016-05-11

    Zika virus (ZIKV), a mosquito-borne flavivirus, is a current global public health concern. The flavivirus envelope (E) glycoprotein is responsible for virus entry and represents a major target of neutralizing antibodies for other flaviviruses. Here, we report the structures of ZIKV E protein at 2.0 Å and in complex with a flavivirus broadly neutralizing murine antibody 2A10G6 at 3.0 Å. ZIKV-E resembles all the known flavivirus E structures but contains a unique, positively charged patch adjacent to the fusion loop region of the juxtaposed monomer, which may influence host attachment. The ZIKV-E-2A10G6 complex structure reveals antibody recognition of a highly conserved fusion loop. 2A10G6 binds to ZIKV-E with high affinity in vitro and neutralizes currently circulating ZIKV strains in vitro and in mice. The E protein fusion loop epitope represents a potential candidate for therapeutic antibodies against ZIKV.

  11. Tick-borne flaviviruses: dissecting host immune responses and virus countermeasures.

    PubMed

    Robertson, Shelly J; Mitzel, Dana N; Taylor, R Travis; Best, Sonja M; Bloom, Marshall E

    2009-01-01

    The tick-borne encephalitis (TBE) serocomplex of viruses, genus Flavivirus, includes a number of important human pathogens that cause serious neurological illnesses and hemorrhagic fevers. These viruses pose a significant public health problem due to high rates of morbidity and mortality, their emergence to new geographic areas, and the recent rise in the incidence of human infections. The most notable member of the TBE serocomplex is tick-borne encephalitis virus (TBEV), a neurotropic flavivirus that causes debilitating and sometimes fatal encephalitis. Although effective prophylactic anti-TBEV vaccines have been developed, there is currently no specific treatment for infection. To identify new targets for therapeutical intervention, it is imperative to understand interactions between TBEV and the host immune response to infection. Interferon (IFN) has a critical role in controlling flavivirus replication. Dendritic cells (DCs) represent an early target of TBEV infection and are major producers of IFN. Thus, interactions between DCs, IFN responses, and the virus are likely to substantially influence the outcome of infection. Early IFN and DC responses are modulated not only by the virus, but also by the tick vector and immunomodulatory compounds of tick saliva inoculated with virus into the skin. Our laboratory is examining interactions between the triad of virus, tick vector, and mammalian host that contribute to the pathogenesis of tick-borne flaviviruses. This work will provide a more detailed understanding of early events in virus infection and their impact on flavivirus pathogenesis.

  12. Tick-borne flaviviruses: dissecting host immune responses and virus countermeasures

    PubMed Central

    Robertson, Shelly J.; Mitzel, Dana N.; Taylor, R. Travis; Best, Sonja M.

    2009-01-01

    The tick-borne encephalitis (TBE) serocomplex of viruses, genus Flavivirus, includes a number of important human pathogens that cause serious neurological illnesses and hemorrhagic fevers. These viruses pose a significant public health problem due to high rates of morbidity and mortality, their emergence to new geographic areas, and the recent rise in the incidence of human infections. The most notable member of the TBE serocomplex is tick-borne encephalitis virus (TBEV), a neurotropic flavivirus that causes debilitating and sometimes fatal encephalitis. Although effective prophylactic anti-TBEV vaccines have been developed, there is currently no specific treatment for infection. To identify new targets for therapeutical intervention, it is imperative to understand interactions between TBEV and the host immune response to infection. Interferon (IFN) has a critical role in controlling flavivirus replication. Dendritic cells (DCs) represent an early target of TBEV infection and are major producers of IFN. Thus, interactions between DCs, IFN responses, and the virus are likely to substantially influence the outcome of infection. Early IFN and DC responses are modulated not only by the virus, but also by the tick vector and immunomodulatory compounds of tick saliva inoculated with virus into the skin. Our laboratory is examining interactions between the triad of virus, tick vector, and mammalian host that contribute to the pathogenesis of tick-borne flaviviruses. This work will provide a more detailed understanding of early events in virus infection and their impact on flavivirus pathogenesis. PMID:18841330

  13. Variance Decomposition Using an IRT Measurement Model

    PubMed Central

    Glas, Cees A. W.; Boomsma, Dorret I.

    2007-01-01

    Large scale research projects in behaviour genetics and genetic epidemiology are often based on questionnaire or interview data. Typically, a number of items is presented to a number of subjects, the subjects’ sum scores on the items are computed, and the variance of sum scores is decomposed into a number of variance components. This paper discusses several disadvantages of the approach of analysing sum scores, such as the attenuation of correlations amongst sum scores due to their unreliability. It is shown that the framework of Item Response Theory (IRT) offers a solution to most of these problems. We argue that an IRT approach in combination with Markov chain Monte Carlo (MCMC) estimation provides a flexible and efficient framework for modelling behavioural phenotypes. Next, we use data simulation to illustrate the potentially huge bias in estimating variance components on the basis of sum scores. We then apply the IRT approach with an analysis of attention problems in young adult twins where the variance decomposition model is extended with an IRT measurement model. We show that when estimating an IRT measurement model and a variance decomposition model simultaneously, the estimate for the heritability of attention problems increases from 40% (based on sum scores) to 73%. PMID:17534709

  14. Production and characterization of vaccines based on flaviviruses defective in replication

    SciTech Connect

    Mason, Peter W.; Shustov, Alexandr V.; Frolov, Ilya . E-mail: ivfrolov@utmb.edu

    2006-08-01

    To develop new vaccine candidates for flavivirus infections, we have engineered two flaviviruses, yellow fever virus (YFV) and West Nile virus (WNV), that are deficient in replication. These defective pseudoinfectious viruses (PIVs) lack a functional copy of the capsid (C) gene in their genomes and are incapable of causing spreading infection upon infection of cells both in vivo and in vitro. However, they produce extracellular E protein in form of secreted subviral particles (SVPs) that are known to be an effective immunogen. PIVs can be efficiently propagated in trans-complementing cell lines making high levels of C or all three viral structural proteins. PIVs derived from YFV and WNV, demonstrated very high safety and immunization produced high levels of neutralizing antibodies and protective immune response. Such defective flaviviruses can be produced in large scale under low biocontainment conditions and should be useful for diagnostic or vaccine applications.

  15. Genetic characterization of tick-borne flaviviruses: new insights into evolution, pathogenetic determinants and taxonomy.

    PubMed

    Grard, Gilda; Moureau, Grégory; Charrel, Rémi N; Lemasson, Jean-Jacques; Gonzalez, Jean-Paul; Gallian, Pierre; Gritsun, Tamara S; Holmes, Edward C; Gould, Ernest A; de Lamballerie, Xavier

    2007-04-25

    Here, we analyze the complete coding sequences of all recognized tick-borne flavivirus species, including Gadgets Gully, Royal Farm and Karshi virus, seabird-associated flaviviruses, Kadam virus and previously uncharacterized isolates of Kyasanur Forest disease virus and Omsk hemorrhagic fever virus. Significant taxonomic improvements are proposed, e.g. the identification of three major groups (mammalian, seabird and Kadam tick-borne flavivirus groups), the creation of a new species (Karshi virus) and the assignment of Tick-borne encephalitis and Louping ill viruses to a unique species (Tick-borne encephalitis virus) including four viral types (i.e. Western Tick-borne encephalitis virus, Eastern Tick-borne encephalitis virus, Turkish sheep Tick-borne encephalitis virus and Louping ill Tick-borne encephalitis virus). The analyses also suggest a complex relationship between viruses infecting birds and those infecting mammals. Ticks that feed on both categories of vertebrates may constitute the evolutionary bridge between the three distinct identified lineages.

  16. Flaviviruses, an expanding threat in public health: focus on Dengue, West Nile, and Japanese encephalitis virus

    PubMed Central

    Daep, Carlo Amorin; Muñoz-Jordán, Jorge L.; Eugenin, Eliseo Alberto

    2014-01-01

    The flaviviruses Dengue, West Nile, and Japanese encephalitis represent three major mosquito-borne viruses worldwide. These pathogens impact the lives of millions of individuals and potentially could affect non-endemic areas already colonized by mosquito vectors. Unintentional transport of infected vectors (Aedes and Culex sp), traveling within endemic areas, rapid adaptation of the insects into new geographic locations, climate change, and lack of medical surveillance have greatly contributed to the increase in flaviviral infections worldwide. The mechanisms by which flaviviruses alter the immune and the central nervous system have only recently been examined despite the alarming number of infections, related deaths, and increasing global distribution. In this review, we will discuss the expansion of the geographic areas affected by flaviviruses, the potential threats to previously unaffected countries, the mechanisms of pathogenesis, and the potential therapeutic interventions to limit the devastating consequences of these viruses. PMID:25287260

  17. Flaviviruses, an expanding threat in public health: focus on dengue, West Nile, and Japanese encephalitis virus.

    PubMed

    Daep, Carlo Amorin; Muñoz-Jordán, Jorge L; Eugenin, Eliseo Alberto

    2014-12-01

    The flaviviruses dengue, West Nile, and Japanese encephalitis represent three major mosquito-borne viruses worldwide. These pathogens impact the lives of millions of individuals and potentially could affect non-endemic areas already colonized by mosquito vectors. Unintentional transport of infected vectors (Aedes and Culex spp.), traveling within endemic areas, rapid adaptation of the insects into new geographic locations, climate change, and lack of medical surveillance have greatly contributed to the increase in flaviviral infections worldwide. The mechanisms by which flaviviruses alter the immune and the central nervous system have only recently been examined despite the alarming number of infections, related deaths, and increasing global distribution. In this review, we will discuss the expansion of the geographic areas affected by flaviviruses, the potential threats to previously unaffected countries, the mechanisms of pathogenesis, and the potential therapeutic interventions to limit the devastating consequences of these viruses.

  18. Detection of flaviviruses by reverse transcriptase-polymerase chain reaction with the universal primer set.

    PubMed

    Meiyu, F; Huosheng, C; Cuihua, C; Xiaodong, T; Lianhua, J; Yifei, P; Weijun, C; Huiyu, G

    1997-01-01

    Using a universal primer set designed to match the sequence of the NS1 gene of flaviviruses, the virus RNA of dengue (DEN), Japanese encephalitis (JEV), powassan and langat of Flaviviridae were successfully amplified by polymerase chain reaction (PCR) via cDNA; and with different internal primers, the serotypes of the dengue viruses were identified. Of the 78 clinically diagnosed dengue fever patients, 18 patients were positive for DEN 1, 48 patients for DEN 2 and 8 patients concurrently infected with DEN 4. Of the 52 patients admitted with Japanese encephalitis (JE), 45 were determined to be JEV infections. By nested PCR, we completed the identification of flaviviruses within 2 days. The results show that seven primers have a potential value for rapid clinical diagnosis of flavivirus infections.

  19. Lipids and flaviviruses, present and future perspectives for the control of dengue, Zika, and West Nile viruses.

    PubMed

    Martín-Acebes, Miguel A; Vázquez-Calvo, Ángela; Saiz, Juan-Carlos

    2016-10-01

    Flaviviruses are emerging arthropod-borne pathogens that cause life-threatening diseases such as yellow fever, dengue, West Nile encephalitis, tick-borne encephalitis, Kyasanur Forest disease, tick-borne encephalitis, or Zika disease. This viral genus groups >50 viral species of small enveloped plus strand RNA virus that are phylogenetically closely related to hepatitis C virus. Importantly, the flavivirus life cycle is intimately associated to host cell lipids. Along this line, flaviviruses rearrange intracellular membranes from the endoplasmic-reticulum of the infected cells to develop adequate platforms for viral replication and particle biogenesis. Moreover, flaviviruses dramatically orchestrate a profound reorganization of the host cell lipid metabolism to create a favorable environment for viral multiplication. Consistently, recent work has shown the importance of specific lipid classes in flavivirus infections. For instances, fatty acid synthesis is linked to viral replication, phosphatidylserine and phosphatidylethanolamine are involved on the entry of flaviviruses, sphingolipids (ceramide and sphingomyelin) play a key role on virus assembly and pathogenesis, and cholesterol is essential for innate immunity evasion in flavivirus-infected cells. Here, we revise the current knowledge on the interactions of the flaviviruses with the cellular lipid metabolism to identify potential targets for future antiviral development aimed to combat these relevant health-threatening pathogens. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Cyclosporine Inhibits Flavivirus Replication through Blocking the Interaction between Host Cyclophilins and Viral NS5 Protein▿

    PubMed Central

    Qing, Min; Yang, Feng; Zhang, Bo; Zou, Gang; Robida, John M.; Yuan, Zhiming; Tang, Hengli; Shi, Pei-Yong

    2009-01-01

    Although flaviviruses cause significant human diseases, no effective therapy is currently available. Host factors essential for viral replication are potential targets for antiviral development. Here we report that cyclophilins (CyPs), a family of cellular peptidyl-prolyl isomerases (PPIases), play a role in flavivirus replication. Huh-7.5 cells with knockdown of different isoforms of CyP were less efficient than parental cells in supporting flavivirus replication, including West Nile virus (WNV), dengue virus, and yellow fever virus. The low viral replication in CyP A (CyPA) knockdown cells could be rescued by trans supplying of a wild-type CyPA but not by trans supplying of a mutant CyPA (defective in the PPIase activity), indicating that the isomerase activity of CyPA is critical for viral replication. Immunoprecipitation and biochemical pulldown analyses showed that CyPA interacts with WNV genomic RNA and viral NS5 protein in the replication complex. Furthermore, antiviral experiments demonstrated that cyclosporine (Cs; an 11-amino-acid cyclic peptide known to block the PPIase activity of CyPA) inhibits flavivirus replication in cell culture at nontoxic concentrations. Time-of-addition and transient replicon results indicated that Cs inhibits flavivirus at the step of viral RNA synthesis. Biochemical analysis showed that Cs directly blocks the interaction between CyPA and WNV NS5 protein. Our results suggest that host CyPA is a component of flavivirus replication complex and could be targeted for potential antiviral development. PMID:19451286

  1. Cyclosporine inhibits flavivirus replication through blocking the interaction between host cyclophilins and viral NS5 protein.

    PubMed

    Qing, Min; Yang, Feng; Zhang, Bo; Zou, Gang; Robida, John M; Yuan, Zhiming; Tang, Hengli; Shi, Pei-Yong

    2009-08-01

    Although flaviviruses cause significant human diseases, no effective therapy is currently available. Host factors essential for viral replication are potential targets for antiviral development. Here we report that cyclophilins (CyPs), a family of cellular peptidyl-prolyl isomerases (PPIases), play a role in flavivirus replication. Huh-7.5 cells with knockdown of different isoforms of CyP were less efficient than parental cells in supporting flavivirus replication, including West Nile virus (WNV), dengue virus, and yellow fever virus. The low viral replication in CyP A (CyPA) knockdown cells could be rescued by trans supplying of a wild-type CyPA but not by trans supplying of a mutant CyPA (defective in the PPIase activity), indicating that the isomerase activity of CyPA is critical for viral replication. Immunoprecipitation and biochemical pulldown analyses showed that CyPA interacts with WNV genomic RNA and viral NS5 protein in the replication complex. Furthermore, antiviral experiments demonstrated that cyclosporine (Cs; an 11-amino-acid cyclic peptide known to block the PPIase activity of CyPA) inhibits flavivirus replication in cell culture at nontoxic concentrations. Time-of-addition and transient replicon results indicated that Cs inhibits flavivirus at the step of viral RNA synthesis. Biochemical analysis showed that Cs directly blocks the interaction between CyPA and WNV NS5 protein. Our results suggest that host CyPA is a component of flavivirus replication complex and could be targeted for potential antiviral development.

  2. Sampling Errors of Variance Components.

    ERIC Educational Resources Information Center

    Sanders, Piet F.

    A study on sampling errors of variance components was conducted within the framework of generalizability theory by P. L. Smith (1978). The study used an intuitive approach for solving the problem of how to allocate the number of conditions to different facets in order to produce the most stable estimate of the universe score variance. Optimization…

  3. Variance and covariance of accumulated displacement estimates.

    PubMed

    Bayer, Matthew; Hall, Timothy J

    2013-04-01

    Tracking large deformations in tissue using ultrasound can enable the reconstruction of nonlinear elastic parameters, but poses a challenge to displacement estimation algorithms. Such large deformations have to be broken up into steps, each of which contributes an estimation error to the final accumulated displacement map. The work reported here measured the error variance for single-step and accumulated displacement estimates using one-dimensional numerical simulations of ultrasound echo signals, subjected to tissue strain and electronic noise. The covariance between accumulation steps was also computed. These simulations show that errors due to electronic noise are negatively correlated between steps, and therefore accumulate slowly, whereas errors due to tissue deformation are positively correlated and accumulate quickly. For reasonably low electronic noise levels, the error variance in the accumulated displacement estimates is remarkably constant as a function of step size, but increases with the length of the tracking kernel.

  4. Variance and Covariance of Accumulated Displacement Estimates

    PubMed Central

    Bayer, Matthew; Hall, Timothy J.

    2013-01-01

    Tracking large deformations in tissue using ultrasound can enable the reconstruction of nonlinear elastic parameters, but poses a challenge to displacement estimation algorithms. Such large deformations have to be broken up into steps, each of which contributes an estimation error to the final accumulated displacement map. The work reported here measured the error variance for single-step and accumulated displacement estimates using one-dimensional numerical simulations of ultrasound echo signals, subjected to tissue strain and electronic noise. The covariance between accumulation steps was also computed. These simulations show that errors due to electronic noise are negatively correlated between steps, and therefore accumulate slowly, while errors due to tissue deformation are positively correlated and accumulate quickly. For reasonably low electronic noise levels, the error variance in the accumulated displacement estimates is remarkably constant as a function of step size, but increases with the length of the tracking kernel. PMID:23493610

  5. Variances and Covariances of Kendall's Tau and Their Estimation.

    ERIC Educational Resources Information Center

    Cliff, Norman; Charlin, Ventura

    1991-01-01

    Variance formulas of H. E. Daniels and M. G. Kendall (1947) are generalized to allow for the presence of ties and variance of the sample tau correlation. Applications of these generalized formulas are discussed and illustrated using data from a 1965 study of contraceptive use in 15 developing countries. (SLD)

  6. Genetic recombination of tick-borne flaviviruses among wild-type strains.

    PubMed

    Norberg, Peter; Roth, Anette; Bergström, Tomas

    2013-06-05

    Genetic recombination has been suggested to occur in mosquito-borne flaviviruses. In contrast, tick-borne flaviviruses have been thought to evolve in a clonal manner, although recent studies suggest that recombination occurs also for these viruses. We re-analyzed the data and found that previous conclusions on wild type recombination were probably falsely drawn due to misalignments of nucleotide sequences, ambiguities in GenBank sequences, or different laboratory culture histories suggestive of recombination events in laboratory. To evaluate if reliable predictions of wild type recombination of tick-borne flaviviruses can be made, we analyzed viral strains sequenced exclusively for this study, and other flavivirus sequences retrieved from GenBank. We detected genetic signals supporting recombination between viruses within the three clades of TBEV-Eu, TBEV-Sib and TBEV-Fe, respectively. Our results suggest that the tick-borne encephalitis viruses may undergo recombination under natural conditions, but that geographic barriers restrict most recombination events to involve only closely genetically related viruses. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Structure and functionality in flavivirus NS-proteins: perspectives for drug design.

    PubMed

    Bollati, Michela; Alvarez, Karin; Assenberg, René; Baronti, Cécile; Canard, Bruno; Cook, Shelley; Coutard, Bruno; Decroly, Etienne; de Lamballerie, Xavier; Gould, Ernest A; Grard, Gilda; Grimes, Jonathan M; Hilgenfeld, Rolf; Jansson, Anna M; Malet, Hélène; Mancini, Erika J; Mastrangelo, Eloise; Mattevi, Andrea; Milani, Mario; Moureau, Grégory; Neyts, Johan; Owens, Raymond J; Ren, Jingshan; Selisko, Barbara; Speroni, Silvia; Steuber, Holger; Stuart, David I; Unge, Torsten; Bolognesi, Martino

    2010-08-01

    Flaviviridae are small enveloped viruses hosting a positive-sense single-stranded RNA genome. Besides yellow fever virus, a landmark case in the history of virology, members of the Flavivirus genus, such as West Nile virus and dengue virus, are increasingly gaining attention due to their re-emergence and incidence in different areas of the world. Additional environmental and demographic considerations suggest that novel or known flaviviruses will continue to emerge in the future. Nevertheless, up to few years ago flaviviruses were considered low interest candidates for drug design. At the start of the European Union VIZIER Project, in 2004, just two crystal structures of protein domains from the flaviviral replication machinery were known. Such pioneering studies, however, indicated the flaviviral replication complex as a promising target for the development of antiviral compounds. Here we review structural and functional aspects emerging from the characterization of two main components (NS3 and NS5 proteins) of the flavivirus replication complex. Most of the reviewed results were achieved within the European Union VIZIER Project, and cover topics that span from viral genomics to structural biology and inhibition mechanisms. The ultimate aim of the reported approaches is to shed light on the design and development of antiviral drug leads. Copyright 2009 Elsevier B.V. All rights reserved.

  8. The Many Faces of the Flavivirus NS5 Protein in Antagonism of Type I Interferon Signaling.

    PubMed

    Best, Sonja M

    2017-02-01

    The vector-borne flaviviruses cause severe disease in humans on every inhabited continent on earth. Their transmission by arthropods, particularly mosquitoes, facilitates large emergence events such as witnessed with Zika virus (ZIKV) or West Nile virus in the Americas. Every vector-borne flavivirus examined thus far that causes disease in humans, from dengue virus to ZIKV, antagonizes the host type I interferon (IFN-I) response by preventing JAK-STAT signaling, suggesting that suppression of this pathway is an important determinant of infection. The most direct and potent viral inhibitor of this pathway is the nonstructural protein NS5. However, the mechanisms utilized by NS5 from different flaviviruses are often quite different, sometimes despite close evolutionary relationships between viruses. The varied mechanisms of NS5 as an IFN-I antagonist are also surprising given that the evolution of NS5 is restrained by the requirement to maintain function of two enzymatic activities critical for virus replication, the methyltransferase and RNA-dependent RNA polymerase. This review discusses the different strategies used by flavivirus NS5 to evade the antiviral effects of IFN-I and how this information can be used to better model disease and develop antiviral countermeasures. Copyright © 2017 American Society for Microbiology.

  9. Viral RNA switch mediates the dynamic control of flavivirus replicase recruitment by genome cyclization

    PubMed Central

    Liu, Zhong-Yu; Li, Xiao-Feng; Jiang, Tao; Deng, Yong-Qiang; Ye, Qing; Zhao, Hui; Yu, Jiu-Yang; Qin, Cheng-Feng

    2016-01-01

    Viral replicase recruitment and long-range RNA interactions are essential for RNA virus replication, yet the mechanism of their interplay remains elusive. Flaviviruses include numerous important human pathogens, e.g., dengue virus (DENV) and Zika virus (ZIKV). Here, we revealed a highly conserved, conformation-tunable cis-acting element named 5′-UAR-flanking stem (UFS) in the flavivirus genomic 5′ terminus. We demonstrated that the UFS was critical for efficient NS5 recruitment and viral RNA synthesis in different flaviviruses. Interestingly, stabilization of the DENV UFS impaired both genome cyclization and vRNA replication. Moreover, the UFS unwound in response to genome cyclization, leading to the decreased affinity of NS5 for the viral 5′ end. Thus, we propose that the UFS is switched by genome cyclization to regulate dynamic RdRp binding for vRNA replication. This study demonstrates that the UFS enables communication between flavivirus genome cyclization and RdRp recruitment, highlighting the presence of switch-like mechanisms among RNA viruses. DOI: http://dx.doi.org/10.7554/eLife.17636.001 PMID:27692070

  10. Structure and functionality in flavivirus NS-proteins: Perspectives for drug design

    PubMed Central

    Bollati, Michela; Alvarez, Karin; Assenberg, René; Baronti, Cécile; Canard, Bruno; Cook, Shelley; Coutard, Bruno; Decroly, Etienne; de Lamballerie, Xavier; Gould, Ernest A.; Grard, Gilda; Grimes, Jonathan M.; Hilgenfeld, Rolf; Jansson, Anna M.; Malet, Hélène; Mancini, Erika J.; Mastrangelo, Eloise; Mattevi, Andrea; Milani, Mario; Moureau, Grégory; Neyts, Johan; Owens, Raymond J.; Ren, Jingshan; Selisko, Barbara; Speroni, Silvia; Steuber, Holger; Stuart, David I.; Unge, Torsten; Bolognesi, Martino

    2010-01-01

    Flaviviridae are small enveloped viruses hosting a positive-sense single-stranded RNA genome. Besides yellow fever virus, a landmark case in the history of virology, members of the Flavivirus genus, such as West Nile virus and dengue virus, are increasingly gaining attention due to their re-emergence and incidence in different areas of the world. Additional environmental and demographic considerations suggest that novel or known flaviviruses will continue to emerge in the future. Nevertheless, up to few years ago flaviviruses were considered low interest candidates for drug design. At the start of the European Union VIZIER Project, in 2004, just two crystal structures of protein domains from the flaviviral replication machinery were known. Such pioneering studies, however, indicated the flaviviral replication complex as a promising target for the development of antiviral compounds. Here we review structural and functional aspects emerging from the characterization of two main components (NS3 and NS5 proteins) of the flavivirus replication complex. Most of the reviewed results were achieved within the European Union VIZIER Project, and cover topics that span from viral genomics to structural biology and inhibition mechanisms. The ultimate aim of the reported approaches is to shed light on the design and development of antiviral drug leads. PMID:19945487

  11. Flavivirus NS1 protein in infected host sera enhances viral acquisition by mosquitoes

    PubMed Central

    Liu, Jianying; Liu, Yang; Nie, Kaixiao; Du, Senyan; Qiu, Jingjun; Pang, Xiaojing; Wang, Penghua; Cheng, Gong

    2016-01-01

    Summary The arbovirus life cycle involves viral transfer between a vertebrate host and an arthropod vector, and acquisition of virus from an infected mammalian host by a vector is an essential step in this process. Here, we report that flavivirus nonstructural protein-1 (NS1), which is abundantly secreted into the serum of an infected host, plays a critical role in flavivirus acquisition by mosquitoes. The presence of dengue virus (DENV) and Japanese encephalitis virus (JEV) NS1s in the blood of infected interferon alpha and gamma receptor-deficient mice (AG6) facilitated virus acquisition by their native mosquito vectors because the protein enabled the virus to overcome the immune barrier of the mosquito midgut. Active immunization of AG6 mice with a modified DENV NS1 reduced DENV acquisition by mosquitoes and protected mice against a lethal DENV challenge, suggesting that immunization with NS1 could reduce the number of virus-carrying mosquitoes as well as the incidence of flaviviral diseases. Our study demonstrates that flaviviruses utilize NS1 proteins produced during their vertebrate phases to enhance their acquisition by vectors, which might be a result of flavivirus evolution to adapt to multiple host environments. PMID:27562253

  12. Small Drinking Water System Variances

    EPA Pesticide Factsheets

    Small system variances allow a small system to install and maintain technology that can remove a contaminant to the maximum extent that is affordable and protective of public health in lieu of technology that can achieve compliance with the regulation.

  13. A Novel Pan-Flavivirus Detection and Identification Assay Based on RT-qPCR and Microarray

    PubMed Central

    Sachse, Konrad; Ziegler, Ute; Keller, Markus

    2017-01-01

    The genus Flavivirus includes arthropod-borne viruses responsible for a large number of infections in humans and economically important animals. While RT-PCR protocols for specific detection of most Flavivirus species are available, there has been also a demand for a broad-range Flavivirus assay covering all members of the genus. It is particularly challenging to balance specificity at genus level with equal sensitivity towards each target species. In the present study, a novel assay combining a SYBR Green-based RT-qPCR with a low-density DNA microarray has been developed. Validation experiments confirmed that the RT-qPCR exhibited roughly equal sensitivity of detection and quantification for all flaviviruses tested. These PCR products are subjected to hybridization on a microarray carrying 84 different oligonucleotide probes that represent all known Flavivirus species. This assay has been used as a screening and confirmation tool for Flavivirus presence in laboratory and field samples, and it performed successfully in international External Quality Assessment of NAT studies. Twenty-six Flavivirus strains were tested with the assay, showing equivalent or superior characteristics compared with the original or even with species-specific RT-PCRs. As an example, test results on West Nile virus detection in a panel of 340 mosquito pool samples from Greece are presented. PMID:28626758

  14. The Influence of Urbanization Modes on the Spatial Circulation of Flaviviruses within Ouagadougou (Burkina Faso)

    PubMed Central

    Fournet, Florence; Rican, Stéphane; Vaillant, Zoé; Roudot, Anna; Meunier-Nikiema, Aude; Kassié, Daouda; Dabiré, Roch K.; Salem, Gérard

    2016-01-01

    Dengue is an emerging infectious disease of global significance. Although this virus has been reported for a long time, its significance within the burden of diseases in West Africa is not obvious, especially in Burkina Faso. Our objective was to evaluate flavivirus presence in Ouagadougou (Burkina Faso) and the link between anti-flavivirus antibody seroprevalence and urbanization modes. A population-based cross-sectional survey was conducted and 3015 children were enrolled from Ouagadougou districts with different types and degrees of urbanization (with/without equipment and high/low building density). Flavivirus (FLAV) IgM MAC-ELISA and FLAV indirect IgG ELISA were performed. Associations between FLAV IgG presence (sign of past infection) and various independent variables were assessed using the chi-square test and a multivariate logistic regression analysis. The apparent prevalence of past flavivirus infections among the enrolled children was 22.7% (95% CI: 22.4–26.7) (n = 685). Eleven children (0.4%; 95% CI: 0.61–2.14) were positive for FLAV IgM, indicating active transmission. Factors associated with flavivirus infection were identified among the enrolled children (age, sex), householders (educational level, asset index) and in the environment (building density, water access, waste management and house appearance); however, they showed great variability according to the city districts. The water access modality did not significantly influence FLAV IgG positivity. Conversely, apparently good practices of waste management had unexpected consequences (increased risk related to municipal dumpsters). Given the scale of ongoing urbanization and the spread of arboviral diseases, close collaboration between health and city stakeholders is needed. PMID:27973402

  15. Interferon signaling in Peromyscus leucopus confers a potent and specific restriction to vector-borne flaviviruses.

    PubMed

    Izuogu, Adaeze O; McNally, Kristin L; Harris, Stephen E; Youseff, Brian H; Presloid, John B; Burlak, Christopher; Munshi-South, Jason; Best, Sonja M; Taylor, R Travis

    2017-01-01

    Tick-borne flaviviruses (TBFVs), including Powassan virus and tick-borne encephalitis virus cause encephalitis or hemorrhagic fevers in humans with case-fatality rates ranging from 1-30%. Despite severe disease in humans, TBFV infection of natural rodent hosts has little noticeable effect. Currently, the basis for resistance to disease is not known. We hypothesize that the coevolution of flaviviruses with their respective hosts has shaped the evolution of potent antiviral factors that suppress virus replication and protect the host from lethal infection. In the current study, we compared virus infection between reservoir host cells and related susceptible species. Infection of primary fibroblasts from the white-footed mouse (Peromyscus leucopus, a representative host) with a panel of vector-borne flaviviruses showed up to a 10,000-fold reduction in virus titer compared to control Mus musculus cells. Replication of vesicular stomatitis virus was equivalent in P. leucopus and M. musculus cells suggesting that restriction was flavivirus-specific. Step-wise comparison of the virus infection cycle revealed a significant block to viral RNA replication, but not virus entry, in P. leucopus cells. To understand the role of the type I interferon (IFN) response in virus restriction, we knocked down signal transducer and activator of transcription 1 (STAT1) or the type I IFN receptor (IFNAR1) by RNA interference. Loss of IFNAR1 or STAT1 significantly relieved the block in virus replication in P. leucopus cells. The major IFN antagonist encoded by TBFV, nonstructural protein 5, was functional in P. leucopus cells, thus ruling out ineffective viral antagonism of the host IFN response. Collectively, this work demonstrates that the IFN response of P. leucopus imparts a strong and virus-specific barrier to flavivirus replication. Future identification of the IFN-stimulated genes responsible for virus restriction specifically in P. leucopus will yield mechanistic insight into

  16. Interferon signaling in Peromyscus leucopus confers a potent and specific restriction to vector-borne flaviviruses

    PubMed Central

    Izuogu, Adaeze O.; McNally, Kristin L.; Harris, Stephen E.; Youseff, Brian H.; Burlak, Christopher; Best, Sonja M.

    2017-01-01

    Tick-borne flaviviruses (TBFVs), including Powassan virus and tick-borne encephalitis virus cause encephalitis or hemorrhagic fevers in humans with case-fatality rates ranging from 1–30%. Despite severe disease in humans, TBFV infection of natural rodent hosts has little noticeable effect. Currently, the basis for resistance to disease is not known. We hypothesize that the coevolution of flaviviruses with their respective hosts has shaped the evolution of potent antiviral factors that suppress virus replication and protect the host from lethal infection. In the current study, we compared virus infection between reservoir host cells and related susceptible species. Infection of primary fibroblasts from the white-footed mouse (Peromyscus leucopus, a representative host) with a panel of vector-borne flaviviruses showed up to a 10,000-fold reduction in virus titer compared to control Mus musculus cells. Replication of vesicular stomatitis virus was equivalent in P. leucopus and M. musculus cells suggesting that restriction was flavivirus-specific. Step-wise comparison of the virus infection cycle revealed a significant block to viral RNA replication, but not virus entry, in P. leucopus cells. To understand the role of the type I interferon (IFN) response in virus restriction, we knocked down signal transducer and activator of transcription 1 (STAT1) or the type I IFN receptor (IFNAR1) by RNA interference. Loss of IFNAR1 or STAT1 significantly relieved the block in virus replication in P. leucopus cells. The major IFN antagonist encoded by TBFV, nonstructural protein 5, was functional in P. leucopus cells, thus ruling out ineffective viral antagonism of the host IFN response. Collectively, this work demonstrates that the IFN response of P. leucopus imparts a strong and virus-specific barrier to flavivirus replication. Future identification of the IFN-stimulated genes responsible for virus restriction specifically in P. leucopus will yield mechanistic insight into

  17. Noncoding flavivirus RNA displays RNA interference suppressor activity in insect and Mammalian cells.

    PubMed

    Schnettler, Esther; Sterken, Mark G; Leung, Jason Y; Metz, Stefan W; Geertsema, Corinne; Goldbach, Rob W; Vlak, Just M; Kohl, Alain; Khromykh, Alexander A; Pijlman, Gorben P

    2012-12-01

    West Nile virus (WNV) and dengue virus (DENV) are highly pathogenic, mosquito-borne flaviviruses (family Flaviviridae) that cause severe disease and death in humans. WNV and DENV actively replicate in mosquitoes and human hosts and thus encounter different host immune responses. RNA interference (RNAi) is the predominant antiviral response against invading RNA viruses in insects and plants. As a countermeasure, plant and insect RNA viruses encode RNA silencing suppressor (RSS) proteins to block the generation/activity of small interfering RNA (siRNA). Enhanced flavivirus replication in mosquitoes depleted for RNAi factors suggests an important biological role for RNAi in restricting virus replication, but it has remained unclear whether or not flaviviruses counteract RNAi via expression of an RSS. First, we established that flaviviral RNA replication suppressed siRNA-induced gene silencing in WNV and DENV replicon-expressing cells. Next, we showed that none of the WNV encoded proteins displayed RSS activity in mammalian and insect cells and in plants by using robust RNAi suppressor assays. In contrast, we found that the 3'-untranslated region-derived RNA molecule known as subgenomic flavivirus RNA (sfRNA) efficiently suppressed siRNA- and miRNA-induced RNAi pathways in both mammalian and insect cells. We also showed that WNV sfRNA inhibits in vitro cleavage of double-stranded RNA by Dicer. The results of the present study suggest a novel role for sfRNA, i.e., as a nucleic acid-based regulator of RNAi pathways, a strategy that may be conserved among flaviviruses.

  18. Identification of diagnostic peptide regions that distinguish Zika virus from related mosquito-borne Flaviviruses.

    PubMed

    Lee, Alexandra J; Bhattacharya, Roshni; Scheuermann, Richard H; Pickett, Brett E

    2017-01-01

    Zika virus (ZIKV) is a member of the Flavivirus genus of positive-sense single-stranded RNA viruses, which includes Dengue, West Nile, Yellow Fever, and other mosquito-borne arboviruses. Infection by ZIKV can be difficult to distinguish from infection by other mosquito-borne Flaviviruses due to high sequence similarity, serum antibody cross-reactivity, and virus co-circulation in endemic areas. Indeed, existing serological methods are not able to consistently differentiate ZIKV from other Flaviviruses, which makes it extremely difficult to accurately calculate the incidence rate of Zika-associated Guillain-Barre in adults, microcephaly in newborns, or asymptomatic infections within a geographical area. In order to identify Zika-specific peptide regions that could be used as serology reagents, we have applied comparative genomics and protein structure analyses to identify amino acid residues that distinguish each of 10 Flavivirus species and subtypes from each other by calculating the specificity, sensitivity, and surface exposure of each residue in relevant target proteins. For ZIKV we identified 104 and 116 15-mer peptides in the E glycoprotein and NS1 non-structural protein, respectively, that contain multiple diagnostic sites and are located in surface-exposed regions in the tertiary protein structure. These sensitive, specific, and surface-exposed peptide regions should serve as useful reagents for seroprevalence studies to better distinguish between prior infections with any of these mosquito-borne Flaviviruses. The development of better detection methods and diagnostic tools will enable clinicians and public health workers to more accurately estimate the true incidence rate of asymptomatic infections, neurological syndromes, and birth defects associated with ZIKV infection.

  19. The Influence of Urbanization Modes on the Spatial Circulation of Flaviviruses within Ouagadougou (Burkina Faso).

    PubMed

    Fournet, Florence; Rican, Stéphane; Vaillant, Zoé; Roudot, Anna; Meunier-Nikiema, Aude; Kassié, Daouda; Dabiré, Roch K; Salem, Gérard

    2016-12-10

    Dengue is an emerging infectious disease of global significance. Although this virus has been reported for a long time, its significance within the burden of diseases in West Africa is not obvious, especially in Burkina Faso. Our objective was to evaluate flavivirus presence in Ouagadougou (Burkina Faso) and the link between anti-flavivirus antibody seroprevalence and urbanization modes. A population-based cross-sectional survey was conducted and 3015 children were enrolled from Ouagadougou districts with different types and degrees of urbanization (with/without equipment and high/low building density). Flavivirus (FLAV) IgM MAC-ELISA and FLAV indirect IgG ELISA were performed. Associations between FLAV IgG presence (sign of past infection) and various independent variables were assessed using the chi-square test and a multivariate logistic regression analysis. The apparent prevalence of past flavivirus infections among the enrolled children was 22.7% (95% CI: 22.4-26.7) (n = 685). Eleven children (0.4%; 95% CI: 0.61-2.14) were positive for FLAV IgM, indicating active transmission. Factors associated with flavivirus infection were identified among the enrolled children (age, sex), householders (educational level, asset index) and in the environment (building density, water access, waste management and house appearance); however, they showed great variability according to the city districts. The water access modality did not significantly influence FLAV IgG positivity. Conversely, apparently good practices of waste management had unexpected consequences (increased risk related to municipal dumpsters). Given the scale of ongoing urbanization and the spread of arboviral diseases, close collaboration between health and city stakeholders is needed.

  20. Variance and skewness in the FIRST survey

    NASA Astrophysics Data System (ADS)

    Magliocchetti, M.; Maddox, S. J.; Lahav, O.; Wall, J. V.

    1998-10-01

    We investigate the large-scale clustering of radio sources in the FIRST 1.4-GHz survey by analysing the distribution function (counts in cells). We select a reliable sample from the the FIRST catalogue, paying particular attention to the problem of how to define single radio sources from the multiple components listed. We also consider the incompleteness of the catalogue. We estimate the angular two-point correlation function w(theta), the variance Psi_2 and skewness Psi_3 of the distribution for the various subsamples chosen on different criteria. Both w(theta) and Psi_2 show power-law behaviour with an amplitude corresponding to a spatial correlation length of r_0~10h^-1Mpc. We detect significant skewness in the distribution, the first such detection in radio surveys. This skewness is found to be related to the variance through Psi_3=S_3(Psi_2)^alpha, with alpha=1.9+/-0.1, consistent with the non-linear gravitational growth of perturbations from primordial Gaussian initial conditions. We show that the amplitude of variance and the skewness are consistent with realistic models of galaxy clustering.

  1. Structural Insights into the Mechanisms of Antibody-Mediated Neutralization of Flavivirus Infection: Implications for Vaccine Development

    PubMed Central

    Pierson, Theodore C.; Fremont, Daved H.; Kuhn, Richard J.; Diamond, Michael S.

    2009-01-01

    Flaviviruses are a group of small RNA viruses that cause severe disease in humans worldwide and are the target of several vaccine development programs. A primary goal of these efforts is to elicit a protective humoral response directed against the envelope proteins arrayed on the surface of the flavivirus virion. Advances in the structural biology of these viruses has catalyzed rapid progress toward understanding the complexity of the flavivirus immunogen and the molecular basis of antibody-mediated neutralization. These insights have identified factors that govern the potency of neutralizing antibodies and will inform the design and evaluation of novel vaccines. PMID:18779049

  2. Saturation of number variance in embedded random-matrix ensembles.

    PubMed

    Prakash, Ravi; Pandey, Akhilesh

    2016-05-01

    We study fluctuation properties of embedded random matrix ensembles of noninteracting particles. For ensemble of two noninteracting particle systems, we find that unlike the spectra of classical random matrices, correlation functions are nonstationary. In the locally stationary region of spectra, we study the number variance and the spacing distributions. The spacing distributions follow the Poisson statistics, which is a key behavior of uncorrelated spectra. The number variance varies linearly as in the Poisson case for short correlation lengths but a kind of regularization occurs for large correlation lengths, and the number variance approaches saturation values. These results are known in the study of integrable systems but are being demonstrated for the first time in random matrix theory. We conjecture that the interacting particle cases, which exhibit the characteristics of classical random matrices for short correlation lengths, will also show saturation effects for large correlation lengths.

  3. Blood meal analysis, flavivirus screening, and influence of meteorological variables on the dynamics of potential mosquito vectors of West Nile virus in northern Italy.

    PubMed

    Roiz, David; Vazquez, Ana; Rosà, Roberto; Muñoz, Joaquin; Arnoldi, Daniele; Rosso, Fausta; Figuerola, Jordi; Tenorio, Antonio; Rizzoli, Annapaola

    2012-06-01

    An extended area of northern Italy has experienced several West Nile virus (WNV) outbreaks and the emergence of Usutu virus (USUV) during previous years. Our aim was to study some of the factors that could explain disease patterns in the Trentino region, where circulation was detected in human sera and sentinel chickens, but no human or equine cases were reported. We collected Culex species (Diptera: Culicidae) in peridomestic environments. The collected specimens were analyzed for feeding behavior, the influence of temperature and rainfall on the abundance of mosquitoes, and the occurrence of flaviviruses. Analysis of blood meals showed that Culex pipiens fed mainly on blackbirds (Turdus merula) and house sparrows (Passer domesticus), while Culex hortensis fed strictly on lizards. The abundance of Cx. pipiens females correlated positively with mean temperature and negatively with rainfall (one to four weeks before capture). This negative relationship could be due to the direct effect of the flushing of habitats together with an indirect effect of oviposition repellency. The mean weekly temperature influenced the abundance of Cx. hortensis. No flaviviruses were detected in the analyzed Culex mosquitoes. These data suggest a silent cycle at low enzootic transmission levels in the area. Furthermore, we present the first contribution to understanding the transmission role of Cx. pipiens mosquitoes in Italy by identifying vertebrate hosts to species level.

  4. Analysis of Variance: Variably Complex

    ERIC Educational Resources Information Center

    Drummond, Gordon B.; Vowler, Sarah L.

    2012-01-01

    These authors have previously described how to use the "t" test to compare two groups. In this article, they describe the use of a different test, analysis of variance (ANOVA) to compare more than two groups. ANOVA is a test of group differences: do at least two of the means differ from each other? ANOVA assumes (1) normal distribution…

  5. VPSim: Variance propagation by simulation

    SciTech Connect

    Burr, T.; Coulter, C.A.; Prommel, J.

    1997-12-01

    One of the fundamental concepts in a materials control and accountability system for nuclear safeguards is the materials balance (MB). All transfers into and out of a material balance area are measured, as are the beginning and ending inventories. The resulting MB measures the material loss, MB = T{sub in} + I{sub B} {minus} T{sub out} {minus} I{sub E}. To interpret the MB, the authors must estimate its measurement error standard deviation, {sigma}{sub MB}. When feasible, they use a method usually known as propagation of variance (POV) to estimate {sigma}{sub MB}. The application of POV for estimating the measurement error variance of an MB is straightforward but tedious. By applying POV to individual measurement error standard deviations they can estimate {sigma}{sub MB} (or more generally, they can estimate the variance-covariance matrix, {Sigma}, of a sequence of MBs). This report describes a new computer program (VPSim) that uses simulation to estimate the {Sigma} matrix of a sequence of MBs. Given the proper input data, VPSim calculates the MB and {sigma}{sub MB}, or calculates a sequence of n MBs and the associated n-by-n covariance matrix, {Sigma}. The covariance matrix, {Sigma}, contains the variance of each MB in the diagonal entries and the covariance between pairs of MBs in the off-diagonal entries.

  6. Dominance genetic variance for traits under directional selection in Drosophila serrata.

    PubMed

    Sztepanacz, Jacqueline L; Blows, Mark W

    2015-05-01

    In contrast to our growing understanding of patterns of additive genetic variance in single- and multi-trait combinations, the relative contribution of nonadditive genetic variance, particularly dominance variance, to multivariate phenotypes is largely unknown. While mechanisms for the evolution of dominance genetic variance have been, and to some degree remain, subject to debate, the pervasiveness of dominance is widely recognized and may play a key role in several evolutionary processes. Theoretical and empirical evidence suggests that the contribution of dominance variance to phenotypic variance may increase with the correlation between a trait and fitness; however, direct tests of this hypothesis are few. Using a multigenerational breeding design in an unmanipulated population of Drosophila serrata, we estimated additive and dominance genetic covariance matrices for multivariate wing-shape phenotypes, together with a comprehensive measure of fitness, to determine whether there is an association between directional selection and dominance variance. Fitness, a trait unequivocally under directional selection, had no detectable additive genetic variance, but significant dominance genetic variance contributing 32% of the phenotypic variance. For single and multivariate morphological traits, however, no relationship was observed between trait-fitness correlations and dominance variance. A similar proportion of additive and dominance variance was found to contribute to phenotypic variance for single traits, and double the amount of additive compared to dominance variance was found for the multivariate trait combination under directional selection. These data suggest that for many fitness components a positive association between directional selection and dominance genetic variance may not be expected.

  7. Dominance Genetic Variance for Traits Under Directional Selection in Drosophila serrata

    PubMed Central

    Sztepanacz, Jacqueline L.; Blows, Mark W.

    2015-01-01

    In contrast to our growing understanding of patterns of additive genetic variance in single- and multi-trait combinations, the relative contribution of nonadditive genetic variance, particularly dominance variance, to multivariate phenotypes is largely unknown. While mechanisms for the evolution of dominance genetic variance have been, and to some degree remain, subject to debate, the pervasiveness of dominance is widely recognized and may play a key role in several evolutionary processes. Theoretical and empirical evidence suggests that the contribution of dominance variance to phenotypic variance may increase with the correlation between a trait and fitness; however, direct tests of this hypothesis are few. Using a multigenerational breeding design in an unmanipulated population of Drosophila serrata, we estimated additive and dominance genetic covariance matrices for multivariate wing-shape phenotypes, together with a comprehensive measure of fitness, to determine whether there is an association between directional selection and dominance variance. Fitness, a trait unequivocally under directional selection, had no detectable additive genetic variance, but significant dominance genetic variance contributing 32% of the phenotypic variance. For single and multivariate morphological traits, however, no relationship was observed between trait–fitness correlations and dominance variance. A similar proportion of additive and dominance variance was found to contribute to phenotypic variance for single traits, and double the amount of additive compared to dominance variance was found for the multivariate trait combination under directional selection. These data suggest that for many fitness components a positive association between directional selection and dominance genetic variance may not be expected. PMID:25783700

  8. Evidence for ribosomal frameshifting and a novel overlapping gene in the genomes of insect-specific flaviviruses

    SciTech Connect

    Firth, Andrew E.; Blitvich, Bradley J.; Wills, Norma M.; Miller, Cathy L.; Atkins, John F.

    2010-03-30

    Flaviviruses have a positive-sense, single-stranded RNA genome of approx11 kb, encoding a large polyprotein that is cleaved to produce approx10 mature proteins. Cell fusing agent virus, Kamiti River virus, Culex flavivirus and several recently discovered flaviviruses have no known vertebrate host and apparently infect only insects. We present compelling bioinformatic evidence for a 253-295 codon overlapping gene (designated fifo) conserved throughout these insect-specific flaviviruses and immunofluorescent detection of its product. Fifo overlaps the NS2A/NS2B coding sequence in the - 1/+ 2 reading frame and is most likely expressed as a trans-frame fusion protein via ribosomal frameshifting at a conserved GGAUUUY slippery heptanucleotide with 3'-adjacent RNA secondary structure (which stimulates efficient frameshifting in vitro). The discovery bears striking parallels to the recently discovered ribosomal frameshifting site in the NS2A coding sequence of the Japanese encephalitis serogroup of flaviviruses and suggests that programmed ribosomal frameshifting may be more widespread in flaviviruses than currently realized.

  9. Evidence for ribosomal frameshifting and a novel overlapping gene in the genomes of insect-specific flaviviruses

    PubMed Central

    Firth, Andrew E; Blitvich, Bradley J; Wills, Norma M; Miller, Cathy L; Atkins, John F

    2010-01-01

    Flaviviruses have a positive-sense, single-stranded RNA genome of ∼11 kb, encoding a large polyprotein that is cleaved to produce ∼10 mature proteins. Cell fusing agent virus, Kamiti River virus, Culex flavivirus and several recently discovered flaviviruses have no known vertebrate host and apparently infect only insects. We present compelling bioinformatic evidence for a 253-295 codon overlapping gene (designated fifo) conserved throughout these insect-specific flaviviruses, and immunofluorescent detection of its product. Fifo overlaps the NS2A/NS2B coding sequence in the -1/+2 reading frame and is most likely expressed as a trans-frame fusion protein via ribosomal frameshifting at a conserved GGAUUUY slippery heptanucleotide with 3′-adjacent RNA secondary structure (which stimulates efficient frameshifting in vitro). The discovery bears striking parallels to the recently discovered ribosomal frameshifting site in the NS2A coding sequence of the Japanese encephalitis serogroup of flaviviruses, and suggests that programmed ribosomal frameshifting may be more widespread in flaviviruses than currently realized. PMID:20097399

  10. Evidence for ribosomal frameshifting and a novel overlapping gene in the genomes of insect-specific flaviviruses.

    PubMed

    Firth, Andrew E; Blitvich, Bradley J; Wills, Norma M; Miller, Cathy L; Atkins, John F

    2010-03-30

    Flaviviruses have a positive-sense, single-stranded RNA genome of approximately 11 kb, encoding a large polyprotein that is cleaved to produce approximately 10 mature proteins. Cell fusing agent virus, Kamiti River virus, Culex flavivirus and several recently discovered flaviviruses have no known vertebrate host and apparently infect only insects. We present compelling bioinformatic evidence for a 253-295 codon overlapping gene (designated fifo) conserved throughout these insect-specific flaviviruses and immunofluorescent detection of its product. Fifo overlaps the NS2A/NS2B coding sequence in the -1/+2 reading frame and is most likely expressed as a trans-frame fusion protein via ribosomal frameshifting at a conserved GGAUUUY slippery heptanucleotide with 3'-adjacent RNA secondary structure (which stimulates efficient frameshifting in vitro). The discovery bears striking parallels to the recently discovered ribosomal frameshifting site in the NS2A coding sequence of the Japanese encephalitis serogroup of flaviviruses and suggests that programmed ribosomal frameshifting may be more widespread in flaviviruses than currently realized.

  11. Flavivirus infection from mosquitoes in vitro reveals cell entry at the plasma membrane.

    PubMed

    Vancini, Ricardo; Kramer, Laura D; Ribeiro, Mariana; Hernandez, Raquel; Brown, Dennis

    2013-01-20

    Dengue and West Nile viruses are enveloped RNA viruses that belong to genus Flavivirus (family Flaviviridae) and are considered important mosquito-borne viral pathogenic agents worldwide. A potential target for intervention strategies is the virus cell entry mechanism. Previous studies of flavivirus entry have focused on the effects of biochemical and molecular inhibitors on viral entry leading to controversial conclusions suggesting that the process is dependent upon endocytosis and low pH mediated membrane fusion. In this study we analyzed the early events in the infection process by means of electron microscopy and immuno-gold labeling of viral particles during cell entry, and used as a new approach for infecting cells with viruses obtained directly from mosquitoes. The results show that Dengue and West Nile viruses may infect cells by a mechanism that involves direct penetration of the host cell plasma membrane as proposed for alphaviruses. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Adaptor protein complexes-1 and 3 are involved at distinct stages of flavivirus life-cycle.

    PubMed

    Agrawal, Tanvi; Schu, Peter; Medigeshi, Guruprasad R

    2013-01-01

    Intracellular protein trafficking pathways are hijacked by viruses at various stages of viral life-cycle. Heterotetrameric adaptor protein complexes (APs) mediate vesicular trafficking at distinct intracellular sites and are essential for maintaining the organellar homeostasis. In the present study, we studied the effect of AP-1 and AP-3 deficiency on flavivirus infection in cells functionally lacking these proteins. We show that AP-1 and AP-3 participate in flavivirus life-cycle at distinct stages. AP-3-deficient cells showed delay in initiation of Japanese encephalitis virus and dengue virus RNA replication, which resulted in reduction of infectious virus production. AP-3 was found to colocalize with RNA replication compartments in infected wild-type cells. AP-1 deficiency affected later stages of dengue virus infection where increased intracellular accumulation of infectious virus was observed. Therefore, our results propose a novel role for AP-1 and AP-3 at distinct stages of infection of some of the RNA viruses.

  13. Adaptor protein complexes-1 and 3 are involved at distinct stages of flavivirus life-cycle

    PubMed Central

    Agrawal, Tanvi; Schu, Peter; Medigeshi, Guruprasad R.

    2013-01-01

    Intracellular protein trafficking pathways are hijacked by viruses at various stages of viral life-cycle. Heterotetrameric adaptor protein complexes (APs) mediate vesicular trafficking at distinct intracellular sites and are essential for maintaining the organellar homeostasis. In the present study, we studied the effect of AP-1 and AP-3 deficiency on flavivirus infection in cells functionally lacking these proteins. We show that AP-1 and AP-3 participate in flavivirus life-cycle at distinct stages. AP-3-deficient cells showed delay in initiation of Japanese encephalitis virus and dengue virus RNA replication, which resulted in reduction of infectious virus production. AP-3 was found to colocalize with RNA replication compartments in infected wild-type cells. AP-1 deficiency affected later stages of dengue virus infection where increased intracellular accumulation of infectious virus was observed. Therefore, our results propose a novel role for AP-1 and AP-3 at distinct stages of infection of some of the RNA viruses. PMID:23657274

  14. Decreased Flight Activity in Culex pipiens (Diptera: Culicidae) Naturally Infected With Culex flavivirus.

    PubMed

    Newman, Christina M; Anderson, Tavis K; Goldberg, Tony L

    2016-01-01

    Insect-specific flaviviruses (ISFVs) commonly infect vectors of mosquito-borne arboviruses. To investigate whether infection with an ISFV might affect mosquito flight behavior, we quantified flight behavior in Culex pipiens L. naturally infected with Culex flavivirus (CxFV). We observed a significant reduction in the scotophase (dark hours) flight activity of CxFV-positive mosquitoes relative to CxFV-negative mosquitoes, but only a marginal reduction in photophase (light hours) flight activity, and no change in the circadian pattern of flight activity. These results suggest that CxFV infection alters the flight activity of naturally infected Cx. pipiens most dramatically when these vectors are likely to be host seeking and may therefore affect the transmission of medically important arboviruses. © The Authors 2015. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Culex Flavivirus During West Nile Virus Epidemic and Interepidemic Years in Chicago, United States.

    PubMed

    Newman, Christina M; Krebs, Bethany L; Anderson, Tavis K; Hamer, Gabriel L; Ruiz, Marilyn O; Brawn, Jeffrey D; Brown, William M; Kitron, Uriel D; Goldberg, Tony L

    2017-08-01

    Culex flavivirus (CxFV) is an insect-specific flavivirus infecting Culex mosquitoes, which are important vectors of West Nile virus (WNV). CxFV and WNV cocirculate in nature and coinfect Culex mosquitoes, including in a WNV "hotspot" in suburban Chicago. We previously identified a positive association between CxFV and WNV in mosquito pools collected from suburban Chicago in 2006. To further investigate this phenomenon, we compared the spatial and temporal distribution of CxFV during an interepidemic year (2011) and an epidemic year (2012) for WNV. Both viruses were more prevalent in mosquito pools in 2012 compared to 2011. During both years, the CxFV infection status of mosquito pools was associated with environmental factors such as habitat type and precipitation frequency rather than coinfection with WNV. These results support the idea that WNV and CxFV are ecologically associated, perhaps because both viruses respond to similar environmental drivers of mosquito populations.

  16. [Prevalence of Flavivirus antibodies in Alouatta caraya primate autochthonous of Argentina].

    PubMed

    Contigiani, M S; Fernández, C; Spinsanti, L I; Díaz, G E

    2000-01-01

    Flavivirus constitute a human health problem in our country. Primates are known to participate in the maintenance of Dengue and Yellow Fever viruses. However, these animals play a role which still remains to be determined in the maintenance of other viruses with potential pathogenicity for human beings and/or animals. Detección of antibodies was performed for different flavivirus in 105 sera samples of Alouatta caraya primates by the hemagglutination inhibition (HI) test. The neutralization (NT) test confirmed only infections caused by St. Louis Encephalitis (SLE) virus with a high prevalence in HI (35.23%) and NT (32.38%) antibodies. No antibody titres indicative of infections by Yellow Fever, Dengue and Bussuquara viruses were registered. Infection by the liheus virus could not be confirmed in these primates. There is a need for studies to detect new or reemergent viral infections in Argentina and the role that these primates could play in the maintenance of such infections.

  17. A game of numbers: the stoichiometry of antibody-mediated neutralization of flavivirus infection

    PubMed Central

    Pierson, Theodore C.; Diamond, Michael S.

    2016-01-01

    The humoral response contributes to the protection against viral pathogens. Although antibodies have the potential to inhibit viral infections via several mechanisms, an ability to neutralize viruses directly may be particularly important. Neutralizing antibody titers are commonly used as predictors of protection from infection, especially in the context of vaccine responses and immunity. Despite the simplicity of the concept, how antibody binding results in virus inactivation is incompletely understood despite decades of research. Flaviviruses have been an attractive system in which to seek a structural and quantitative understanding of how antibody interactions with virions modulate infection because of the contribution of antibodies to both protection and pathogenesis. This review will present a stoichiometric model of antibody-mediated neutralization of flaviviruses and discuss how these concepts can inform the development of vaccines and antibody-based therapeutics. PMID:25595803

  18. Zoonotic encephalitides caused by arboviruses: transmission and epidemiology of alphaviruses and flaviviruses

    PubMed Central

    Balasuriya, Udeni B. R.; Lee, Chong-kyo

    2014-01-01

    In this review, we mainly focus on zoonotic encephalitides caused by arthropod-borne viruses (arboviruses) of the families Flaviviridae (genus Flavivirus) and Togaviridae (genus Alphavirus) that are important in both humans and domestic animals. Specifically, we will focus on alphaviruses (Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus) and flaviviruses (Japanese encephalitis virus and West Nile virus). Most of these viruses were originally found in tropical regions such as Africa and South America or in some regions in Asia. However, they have dispersed widely and currently cause diseases around the world. Global warming, increasing urbanization and population size in tropical regions, faster transportation and rapid spread of arthropod vectors contribute in continuous spreading of arboviruses into new geographic areas causing reemerging or resurging diseases. Most of the reemerging arboviruses also have emerged as zoonotic disease agents and created major public health issues and disease epidemics. PMID:24427764

  19. Flavivirus infection from mosquitoes in vitro reveals cell entry at the plasma membrane

    SciTech Connect

    Vancini, Ricardo; Kramer, Laura D.; Ribeiro, Mariana; Hernandez, Raquel; Brown, Dennis

    2013-01-20

    Dengue and West Nile viruses are enveloped RNA viruses that belong to genus Flavivirus (family Flaviviridae) and are considered important mosquito-borne viral pathogenic agents worldwide. A potential target for intervention strategies is the virus cell entry mechanism. Previous studies of flavivirus entry have focused on the effects of biochemical and molecular inhibitors on viral entry leading to controversial conclusions suggesting that the process is dependent upon endocytosis and low pH mediated membrane fusion. In this study we analyzed the early events in the infection process by means of electron microscopy and immuno-gold labeling of viral particles during cell entry, and used as a new approach for infecting cells with viruses obtained directly from mosquitoes. The results show that Dengue and West Nile viruses may infect cells by a mechanism that involves direct penetration of the host cell plasma membrane as proposed for alphaviruses.

  20. Culex flavivirus and West Nile virus mosquito coinfection and positive ecological association in Chicago, United States.

    PubMed

    Newman, Christina M; Cerutti, Francesco; Anderson, Tavis K; Hamer, Gabriel L; Walker, Edward D; Kitron, Uriel D; Ruiz, Marilyn O; Brawn, Jeffery D; Goldberg, Tony L

    2011-08-01

    Culex flavivirus (CxFV) is an insect-specific flavivirus globally distributed in mosquitoes of the genus Culex. CxFV was positively associated with West Nile virus (WNV) infection in a case-control study of 268 mosquito pools from an endemic focus of WNV transmission in Chicago, United States. Specifically, WNV-positive Culex mosquito pools were four times more likely also to be infected with CxFV than were spatiotemporally matched WNV-negative pools. In addition, mosquito pools from residential sites characterized by dense housing and impermeable surfaces were more likely to be infected with CxFV than were pools from nearby urban green spaces. Further, 6/15 (40%) WNV-positive individual mosquitoes were also CxFV positive, demonstrating that both viruses can coinfect mosquitoes in nature. Phylogenetic analysis of CxFV from Chicago demonstrated a pattern similar to WNV, consisting of low global viral diversity and lack of geographic clustering. These results illustrate a positive ecological association between CxFV and WNV, and that coinfection of individual mosquitoes can occur naturally in areas of high flaviviral transmission. These conclusions represent a challenge to the hypothesis of super-infection exclusion in the CxFV/WNV system, whereby an established infection with one virus may interfere with secondary viral infection with a similar virus. This study suggests that infection with insect-specific flaviviruses such as CxFV may not exclude secondary infection with genetically distinct flaviviruses such as WNV, and that both viruses can naturally coinfect mosquitoes that are epidemic bridge vectors of WNV to humans.

  1. Culex Flavivirus and West Nile Virus Mosquito Coinfection and Positive Ecological Association in Chicago, United States

    PubMed Central

    Newman, Christina M.; Cerutti, Francesco; Anderson, Tavis K.; Hamer, Gabriel L.; Walker, Edward D.; Kitron, Uriel D.; Ruiz, Marilyn O.; Brawn, Jeffery D.

    2011-01-01

    Abstract Culex flavivirus (CxFV) is an insect-specific flavivirus globally distributed in mosquitoes of the genus Culex. CxFV was positively associated with West Nile virus (WNV) infection in a case–control study of 268 mosquito pools from an endemic focus of WNV transmission in Chicago, United States. Specifically, WNV-positive Culex mosquito pools were four times more likely also to be infected with CxFV than were spatiotemporally matched WNV-negative pools. In addition, mosquito pools from residential sites characterized by dense housing and impermeable surfaces were more likely to be infected with CxFV than were pools from nearby urban green spaces. Further, 6/15 (40%) WNV-positive individual mosquitoes were also CxFV positive, demonstrating that both viruses can coinfect mosquitoes in nature. Phylogenetic analysis of CxFV from Chicago demonstrated a pattern similar to WNV, consisting of low global viral diversity and lack of geographic clustering. These results illustrate a positive ecological association between CxFV and WNV, and that coinfection of individual mosquitoes can occur naturally in areas of high flaviviral transmission. These conclusions represent a challenge to the hypothesis of super-infection exclusion in the CxFV/WNV system, whereby an established infection with one virus may interfere with secondary viral infection with a similar virus. This study suggests that infection with insect-specific flaviviruses such as CxFV may not exclude secondary infection with genetically distinct flaviviruses such as WNV, and that both viruses can naturally coinfect mosquitoes that are epidemic bridge vectors of WNV to humans. PMID:21254845

  2. Recent circulation of West Nile virus and potentially other closely related flaviviruses in Southern France.

    PubMed

    Vittecoq, Marion; Lecollinet, Sylvie; Jourdain, Elsa; Thomas, Frédéric; Blanchon, Thomas; Arnal, Audrey; Lowenski, Steeve; Gauthier-Clerc, Michel

    2013-08-01

    In recent years, the number of West Nile virus (WNV) cases reported in horses and humans has increased dramatically throughout the Mediterranean basin. Furthermore, the emergence of Usutu virus (USUV) in Austria in 2001, and its subsequent expansion to Hungary, Spain, Italy, Switzerland, the United Kingdom, and Germany, has given added cause for concern regarding the impact of the spread of flaviviruses on human and animal health in western Europe. Despite frequent detection of WNV and USUV cases in neighboring countries, no case of WNV has been detected in France since 2006 and USUV has never been reported. However, recent investigations focused on detecting the circulation of flaviviruses in France are lacking. We investigated the circulation of WNV and USUV viruses in wild birds in southern France on the basis of a serological survey conducted on a sentinel species, the magpie (Pica pica), in the Camargue area from November, 2009, to December, 2010. We detected WNV-neutralizing antibodies at a high titer (160) in a second-year bird showing recent exposure to WNV, although no WNV case has been detected in humans or in horses since 2004 in the Camargue. In addition, we observed low titers (10 or 20) of USUV-specific antibodies in six magpies, two of which were also seropositive for WNV. Such low titers do not give grounds for concluding that these birds had been exposed to USUV; cross-reactions at low titers may occur between antigenically closely related flaviviruses. But these results urge for further investigations into the circulation of flaviviruses in southern France. They also emphasize the necessity of undertaking epidemiological studies on a long-term basis, rather than over short periods following public health crises, to gain insight into viral dynamics within natural reservoirs.

  3. Isolation of a Novel Insect-Specific Flavivirus from Culiseta melanura in the Northeastern United States

    PubMed Central

    Misencik, Michael J.; Grubaugh, Nathan D.; Andreadis, Theodore G.; Ebel, Gregory D.

    2016-01-01

    Abstract The genus Flavivirus includes a number of newly recognized viruses that infect and replicate only within mosquitoes. To determine whether insect-specific flaviviruses (ISFs) may infect Culiseta (Cs.) melanura mosquitoes, we screened pools of field-collected mosquitoes for virus infection by RT-PCR targeting conserved regions of the NS5 gene. NS5 nucleotide sequences amplified from Cs. melanura pools were genetically similar to other ISFs and most closely matched Calbertado virus from Culex tarsalis, sharing 68.7% nucleotide and 76.1% amino acid sequence identity. The complete genome of one virus isolate was sequenced to reveal a primary open reading frame (ORF) encoding a viral polyprotein characteristic of the genus Flavivirus. Phylogenetic analysis showed that this virus represents a distinct evolutionary lineage that belongs to the classical ISF group. The virus was detected solely in Cs. melanura pools, occurred in sampled populations from Connecticut, New York, New Hampshire, and Maine, and infected both adult and larval stages of the mosquito. Maximum likelihood estimate infection rates (MLE-IR) were relatively stable in overwintering Cs. melanura larvae collected monthly from November of 2012 through May of 2013 (MLE-IR = 0.7–2.1/100 mosquitoes) and in host-seeking females collected weekly from June through October of 2013 (MLE-IR = 3.8–11.5/100 mosquitoes). Phylogenetic analysis of viral sequences revealed limited genetic variation that lacked obvious geographic structure among strains in the northeastern United States. This new virus is provisionally named Culiseta flavivirus on the basis of its host association with Cs. melanura. PMID:26807512

  4. Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses.

    PubMed

    Sironi, Manuela; Forni, Diego; Clerici, Mario; Cagliani, Rachele

    2016-09-01

    The Flavivirus genus comprises several human pathogens such as dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV). Although ZIKV usually causes mild symptoms, growing evidence is linking it to congenital birth defects and to increased risk of Guillain-Barré syndrome. ZIKV encodes a polyprotein that is processed to produce three structural and seven nonstructural (NS) proteins. We investigated the evolution of the viral polyprotein in ZIKV and in related flaviviruses (DENV, Spondweni virus, and Kedougou virus). After accounting for saturation issues, alignment uncertainties, and recombination, we found evidence of episodic positive selection on the branch that separates DENV from the other flaviviruses. NS1 emerged as the major selection target, and selected sites were located in immune epitopes or in functionally important protein regions. Three of these sites are located in an NS1 region that interacts with structural proteins and is essential for virion biogenesis. Analysis of the more recent evolutionary history of ZIKV lineages indicated that positive selection acted on NS5 and NS4B, this latter representing the preferential target. All selected sites were located in the N-terminal portion of NS4B, which inhibits interferon response. One of the positively selected sites (26M/I/T/V) in ZIKV also represents a selection target in sylvatic DENV2 isolates, and a nearby residue evolves adaptively in JEV. Two additional positively selected sites are within a protein region that interacts with host (e.g. STING) and viral (i.e. NS1, NS4A) proteins. Notably, mutations in the NS4B region of other flaviviruses modulate neurovirulence and/or neuroinvasiveness. These results suggest that the positively selected sites we identified modulate viral replication and contribute to immune evasion. These sites should be prioritized in future experimental studies. However, analyses herein detected no selective events associated to the spread of the Asian

  5. Antibody-based assay discriminates Zika virus infection from other flaviviruses.

    PubMed

    Balmaseda, Angel; Stettler, Karin; Medialdea-Carrera, Raquel; Collado, Damaris; Jin, Xia; Zambrana, José Victor; Jaconi, Stefano; Cameroni, Elisabetta; Saborio, Saira; Rovida, Francesca; Percivalle, Elena; Ijaz, Samreen; Dicks, Steve; Ushiro-Lumb, Ines; Barzon, Luisa; Siqueira, Patricia; Brown, David W G; Baldanti, Fausto; Tedder, Richard; Zambon, Maria; de Filippis, A M Bispo; Harris, Eva; Corti, Davide

    2017-08-01

    Zika virus (ZIKV) is a mosquito-borne flavivirus that emerged recently as a global health threat, causing a pandemic in the Americas. ZIKV infection mostly causes mild disease, but is linked to devastating congenital birth defects and Guillain-Barré syndrome in adults. The high level of cross-reactivity among flaviviruses and their cocirculation has complicated serological approaches to differentially detect ZIKV and dengue virus (DENV) infections, accentuating the urgent need for a specific and sensitive serological test. We previously generated a ZIKV nonstructural protein 1 (NS1)-specific human monoclonal antibody, which we used to develop an NS1-based competition ELISA. Well-characterized samples from RT-PCR-confirmed patients with Zika and individuals exposed to other flavivirus infections or vaccination were used in a comprehensive analysis to determine the sensitivity and specificity of the NS1 blockade-of-binding (BOB) assay, which was established in laboratories in five countries (Nicaragua, Brazil, Italy, United Kingdom, and Switzerland). Of 158 sera/plasma from RT-PCR-confirmed ZIKV infections, 145 (91.8%) yielded greater than 50% inhibition. Of 171 patients with primary or secondary DENV infections, 152 (88.9%) scored negative. When the control group was extended to patients infected by other flaviviruses, other viruses, or healthy donors (n = 540), the specificity was 95.9%. We also analyzed longitudinal samples from DENV-immune and DENV-naive ZIKV infections and found inhibition was achieved within 10 d postonset of illness and maintained over time. Thus, the Zika NS1 BOB assay is sensitive, specific, robust, simple, low-cost, and accessible, and can detect recent and past ZIKV infections for surveillance, seroprevalence studies, and intervention trials.

  6. Zika virus NS1 structure reveals diversity of electrostatic surfaces among flaviviruses.

    PubMed

    Song, Hao; Qi, Jianxun; Haywood, Joel; Shi, Yi; Gao, George F

    2016-05-01

    The association of Zika virus (ZIKV) infections with microcephaly has resulted in an ongoing public-health emergency. Here we report the crystal structure of a C-terminal fragment of ZIKV nonstructural protein 1 (NS1), a major host-interaction molecule that functions in flaviviral replication, pathogenesis and immune evasion. Comparison with West Nile and dengue virus NS1 structures reveals conserved features but diverse electrostatic characteristics at host-interaction interfaces, thus possibly implying different modes of flavivirus pathogenesis.

  7. Detection of Flavivirus Antibodies in Human Serum by Epitope-Blocking Immunoassay

    DTIC Science & Technology

    1987-01-01

    Molecular Biology, Walter Reed Army Institute of Research, Washington, DC (M.K. G.) _ Human flavivirus group-reactive, dengue complex-reactive, and... dengue , to Japanese encephalitis, or both viruses. Key words. dengue virus, Japanese encephalitis virs, sermn antihodles, rapid viral dgsis...neutralization tests. One such complex is comprised of the four serotypes of dengue viruses: dengue -I, dengue -2, Accepted for publication February 17

  8. Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses

    PubMed Central

    Sironi, Manuela; Forni, Diego; Clerici, Mario; Cagliani, Rachele

    2016-01-01

    The Flavivirus genus comprises several human pathogens such as dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV). Although ZIKV usually causes mild symptoms, growing evidence is linking it to congenital birth defects and to increased risk of Guillain-Barré syndrome. ZIKV encodes a polyprotein that is processed to produce three structural and seven nonstructural (NS) proteins. We investigated the evolution of the viral polyprotein in ZIKV and in related flaviviruses (DENV, Spondweni virus, and Kedougou virus). After accounting for saturation issues, alignment uncertainties, and recombination, we found evidence of episodic positive selection on the branch that separates DENV from the other flaviviruses. NS1 emerged as the major selection target, and selected sites were located in immune epitopes or in functionally important protein regions. Three of these sites are located in an NS1 region that interacts with structural proteins and is essential for virion biogenesis. Analysis of the more recent evolutionary history of ZIKV lineages indicated that positive selection acted on NS5 and NS4B, this latter representing the preferential target. All selected sites were located in the N-terminal portion of NS4B, which inhibits interferon response. One of the positively selected sites (26M/I/T/V) in ZIKV also represents a selection target in sylvatic DENV2 isolates, and a nearby residue evolves adaptively in JEV. Two additional positively selected sites are within a protein region that interacts with host (e.g. STING) and viral (i.e. NS1, NS4A) proteins. Notably, mutations in the NS4B region of other flaviviruses modulate neurovirulence and/or neuroinvasiveness. These results suggest that the positively selected sites we identified modulate viral replication and contribute to immune evasion. These sites should be prioritized in future experimental studies. However, analyses herein detected no selective events associated to the spread of the Asian

  9. Genotypic-specific variance in Caenorhabditis elegans lifetime fecundity

    PubMed Central

    Diaz, S Anaid; Viney, Mark

    2014-01-01

    Organisms live in heterogeneous environments, so strategies that maximze fitness in such environments will evolve. Variation in traits is important because it is the raw material on which natural selection acts during evolution. Phenotypic variation is usually thought to be due to genetic variation and/or environmentally induced effects. Therefore, genetically identical individuals in a constant environment should have invariant traits. Clearly, genetically identical individuals do differ phenotypically, usually thought to be due to stochastic processes. It is now becoming clear, especially from studies of unicellular species, that phenotypic variance among genetically identical individuals in a constant environment can be genetically controlled and that therefore, in principle, this can be subject to selection. However, there has been little investigation of these phenomena in multicellular species. Here, we have studied the mean lifetime fecundity (thus a trait likely to be relevant to reproductive success), and variance in lifetime fecundity, in recently-wild isolates of the model nematode Caenorhabditis elegans. We found that these genotypes differed in their variance in lifetime fecundity: some had high variance in fecundity, others very low variance. We find that this variance in lifetime fecundity was negatively related to the mean lifetime fecundity of the lines, and that the variance of the lines was positively correlated between environments. We suggest that the variance in lifetime fecundity may be a bet-hedging strategy used by this species. PMID:25360248

  10. A single mutation in the envelope protein modulates flavivirus antigenicity, stability, and pathogenesis

    PubMed Central

    Goo, Leslie; VanBlargan, Laura A.; Dowd, Kimberly A.; Diamond, Michael S.

    2017-01-01

    The structural flexibility or ‘breathing’ of the envelope (E) protein of flaviviruses allows virions to sample an ensemble of conformations at equilibrium. The molecular basis and functional consequences of virus conformational dynamics are poorly understood. Here, we identified a single mutation at residue 198 (T198F) of the West Nile virus (WNV) E protein domain I-II hinge that regulates virus breathing. The T198F mutation resulted in a ~70-fold increase in sensitivity to neutralization by a monoclonal antibody targeting a cryptic epitope in the fusion loop. Increased exposure of this otherwise poorly accessible fusion loop epitope was accompanied by reduced virus stability in solution at physiological temperatures. Introduction of a mutation at the analogous residue of dengue virus (DENV), but not Zika virus (ZIKV), E protein also increased accessibility of the cryptic fusion loop epitope and decreased virus stability in solution, suggesting that this residue modulates the structural ensembles sampled by distinct flaviviruses at equilibrium in a context dependent manner. Although the T198F mutation did not substantially impair WNV growth kinetics in vitro, studies in mice revealed attenuation of WNV T198F infection. Overall, our study provides insight into the molecular basis and the in vitro and in vivo consequences of flavivirus breathing. PMID:28207910

  11. Modeling the Role of Epitope Arrangement on Antibody Binding Stoichiometry in Flaviviruses.

    PubMed

    Ripoll, Daniel R; Khavrutskii, Ilja; Wallqvist, Anders; Chaudhury, Sidhartha

    2016-10-18

    Cryo-electron-microscopy (cryo-EM) structures of flaviviruses reveal significant variation in epitope occupancy across different monoclonal antibodies that have largely been attributed to epitope-level differences in conformation or accessibility that affect antibody binding. The consequences of these variations for macroscopic properties such as antibody binding and neutralization are the results of the law of mass action-a stochastic process of innumerable binding and unbinding events between antibodies and the multiple binding sites on the flavivirus in equilibrium-that cannot be directly imputed from structure alone. We carried out coarse-grained spatial stochastic binding simulations for nine flavivirus antibodies with epitopes defined by cryo-EM or x-ray crystallography to assess the role of epitope spatial arrangement on antibody-binding stoichiometry, occupancy, and neutralization. In our simulations, all epitopes were equally competent for binding, representing the upper limit of binding stoichiometry that results from epitope spatial arrangement alone. Surprisingly, our simulations closely reproduced the relative occupancy and binding stoichiometry observed in cryo-EM, without having to account for differences in epitope accessibility or conformation, suggesting that epitope spatial arrangement alone may be sufficient to explain differences in binding occupancy and stoichiometry between antibodies. Furthermore, we found that there was significant heterogeneity in binding configurations even at saturating antibody concentrations, and that bivalent antibody binding may be more common than previously thought. Finally, we propose a structure-based explanation for the stoichiometric threshold model of neutralization.

  12. A single mutation in the envelope protein modulates flavivirus antigenicity, stability, and pathogenesis.

    PubMed

    Goo, Leslie; VanBlargan, Laura A; Dowd, Kimberly A; Diamond, Michael S; Pierson, Theodore C

    2017-02-01

    The structural flexibility or 'breathing' of the envelope (E) protein of flaviviruses allows virions to sample an ensemble of conformations at equilibrium. The molecular basis and functional consequences of virus conformational dynamics are poorly understood. Here, we identified a single mutation at residue 198 (T198F) of the West Nile virus (WNV) E protein domain I-II hinge that regulates virus breathing. The T198F mutation resulted in a ~70-fold increase in sensitivity to neutralization by a monoclonal antibody targeting a cryptic epitope in the fusion loop. Increased exposure of this otherwise poorly accessible fusion loop epitope was accompanied by reduced virus stability in solution at physiological temperatures. Introduction of a mutation at the analogous residue of dengue virus (DENV), but not Zika virus (ZIKV), E protein also increased accessibility of the cryptic fusion loop epitope and decreased virus stability in solution, suggesting that this residue modulates the structural ensembles sampled by distinct flaviviruses at equilibrium in a context dependent manner. Although the T198F mutation did not substantially impair WNV growth kinetics in vitro, studies in mice revealed attenuation of WNV T198F infection. Overall, our study provides insight into the molecular basis and the in vitro and in vivo consequences of flavivirus breathing.

  13. Viral Membrane Fusion and Nucleocapsid Delivery into the Cytoplasm are Distinct Events in Some Flaviviruses

    PubMed Central

    Nour, Adel M.; Li, Yue; Wolenski, Joseph; Modis, Yorgo

    2013-01-01

    Flaviviruses deliver their genome into the cell by fusing the viral lipid membrane to an endosomal membrane. The sequence and kinetics of the steps required for nucleocapsid delivery into the cytoplasm remain unclear. Here we dissect the cell entry pathway of virions and virus-like particles from two flaviviruses using single-particle tracking in live cells, a biochemical membrane fusion assay and virus infectivity assays. We show that the virus particles fuse with a small endosomal compartment in which the nucleocapsid remains trapped for several minutes. Endosomal maturation inhibitors inhibit infectivity but not membrane fusion. We propose a flavivirus cell entry mechanism in which the virus particles fuse preferentially with small endosomal carrier vesicles and depend on back-fusion of the vesicles with the late endosomal membrane to deliver the nucleocapsid into the cytoplasm. Virus entry modulates intracellular calcium release and phosphatidylinositol-3-phosphate kinase signaling. Moreover, the broadly cross-reactive therapeutic antibody scFv11 binds to virus-like particles and inhibits fusion. PMID:24039574

  14. Unique Requirement for ESCRT Factors in Flavivirus Particle Formation on the Endoplasmic Reticulum.

    PubMed

    Tabata, Keisuke; Arimoto, Masaru; Arakawa, Masashi; Nara, Atsuki; Saito, Kazunobu; Omori, Hiroko; Arai, Arisa; Ishikawa, Tomohiro; Konishi, Eiji; Suzuki, Ryosuke; Matsuura, Yoshiharu; Morita, Eiji

    2016-08-30

    Flavivirus infection induces endoplasmic reticulum (ER) membrane rearrangements to generate a compartment for replication of the viral genome and assembly of viral particles. Using quantitative mass spectrometry, we identified several ESCRT (endosomal sorting complex required for transport) proteins that are recruited to sites of virus replication on the ER. Systematic small interfering RNA (siRNA) screening revealed that release of both dengue virus and Japanese encephalitis virus was dramatically decreased by single depletion of TSG101 or co-depletion of specific combinations of ESCRT-III proteins, resulting in ≥1,000-fold titer reductions. By contrast, release was unaffected by depletion of some core ESCRTs, including VPS4. Reintroduction of ESCRT proteins to siRNA-depleted cells revealed interactions among ESCRT proteins that are crucial for flavivirus budding. Electron-microscopy studies revealed that the CHMP2 and CHMP4 proteins function directly in membrane deformation at the ER. Thus, a unique and specific subset of ESCRT contributes to ER membrane biogenesis during flavivirus infection.

  15. Identification and molecular characterization of a novel flavivirus isolated from geese in China.

    PubMed

    Huang, Xinmei; Han, Kaikai; Zhao, Dongmin; Liu, Yuzhuo; Zhang, Jingfeng; Niu, Huimin; Zhang, Kangning; Zhu, Jiangning; Wu, Dongming; Gao, Lei; Li, Yin

    2013-06-01

    Since April 2010, a novel contagious disease in ducks and geese, with egg drop, feed uptake decline and neurological signs, caused by a newly emerged virus has spread around Eastern China. Dissection conducted on the dead geese demonstrated hemorrhage in brain, lung, liver, heart, ovary, and enlarged and necrotic spleen. A new virus, named Goose/Jiangsu/804/2010 (JS804) virus, was isolated in Jiangsu area from geese. Then the virus was re-isolated from the affected geese and replicated well in duck embryo fibroblasts and Vero cells, causing the cytopathic effect. The virus was identified as an enveloped positive stranded RNA virus with a size of approximately 40-60 nm in diameter. The full-length genome of this isolated virus was determined, showing that it is closely related to Tembusu virus (a mosquito-borne Ntaya group flavivirus) than other members of the Flaviviridae based on the data of phylogenetic analyses. Our systematic studies fulfill Koch's postulates precisely, and therefore, the causative agent of geese occurring in Eastern China is a new flavivirus. This is the first report that flavivirus infects not only egg-laying and breeder ducks but also geese. The findings extend our understanding of how the virus spreads and causes disease.

  16. Viral membrane fusion and nucleocapsid delivery into the cytoplasm are distinct events in some flaviviruses.

    PubMed

    Nour, Adel M; Li, Yue; Wolenski, Joseph; Modis, Yorgo

    2013-01-01

    Flaviviruses deliver their genome into the cell by fusing the viral lipid membrane to an endosomal membrane. The sequence and kinetics of the steps required for nucleocapsid delivery into the cytoplasm remain unclear. Here we dissect the cell entry pathway of virions and virus-like particles from two flaviviruses using single-particle tracking in live cells, a biochemical membrane fusion assay and virus infectivity assays. We show that the virus particles fuse with a small endosomal compartment in which the nucleocapsid remains trapped for several minutes. Endosomal maturation inhibitors inhibit infectivity but not membrane fusion. We propose a flavivirus cell entry mechanism in which the virus particles fuse preferentially with small endosomal carrier vesicles and depend on back-fusion of the vesicles with the late endosomal membrane to deliver the nucleocapsid into the cytoplasm. Virus entry modulates intracellular calcium release and phosphatidylinositol-3-phosphate kinase signaling. Moreover, the broadly cross-reactive therapeutic antibody scFv11 binds to virus-like particles and inhibits fusion.

  17. Induction and suppression of tick cell antiviral RNAi responses by tick-borne flaviviruses.

    PubMed

    Schnettler, Esther; Tykalová, Hana; Watson, Mick; Sharma, Mayuri; Sterken, Mark G; Obbard, Darren J; Lewis, Samuel H; McFarlane, Melanie; Bell-Sakyi, Lesley; Barry, Gerald; Weisheit, Sabine; Best, Sonja M; Kuhn, Richard J; Pijlman, Gorben P; Chase-Topping, Margo E; Gould, Ernest A; Grubhoffer, Libor; Fazakerley, John K; Kohl, Alain

    2014-08-01

    Arboviruses are transmitted by distantly related arthropod vectors such as mosquitoes (class Insecta) and ticks (class Arachnida). RNA interference (RNAi) is the major antiviral mechanism in arthropods against arboviruses. Unlike in mosquitoes, tick antiviral RNAi is not understood, although this information is important to compare arbovirus/host interactions in different classes of arbovirus vectos. Using an Ixodes scapularis-derived cell line, key Argonaute proteins involved in RNAi and the response against tick-borne Langat virus (Flaviviridae) replication were identified and phylogenetic relationships characterized. Analysis of small RNAs in infected cells showed the production of virus-derived small interfering RNAs (viRNAs), which are key molecules of the antiviral RNAi response. Importantly, viRNAs were longer (22 nucleotides) than those from other arbovirus vectors and mapped at highest frequency to the termini of the viral genome, as opposed to mosquito-borne flaviviruses. Moreover, tick-borne flaviviruses expressed subgenomic flavivirus RNAs that interfere with tick RNAi. Our results characterize the antiviral RNAi response in tick cells including phylogenetic analysis of genes encoding antiviral proteins, and viral interference with this pathway. This shows important differences in antiviral RNAi between the two major classes of arbovirus vectors, and our data broadens our understanding of arthropod antiviral RNAi. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  18. Functional Information Stored in the Conserved Structural RNA Domains of Flavivirus Genomes

    PubMed Central

    Fernández-Sanlés, Alba; Ríos-Marco, Pablo; Romero-López, Cristina; Berzal-Herranz, Alfredo

    2017-01-01

    The genus Flavivirus comprises a large number of small, positive-sense single-stranded, RNA viruses able to replicate in the cytoplasm of certain arthropod and/or vertebrate host cells. The genus, which has some 70 member species, includes a number of emerging and re-emerging pathogens responsible for outbreaks of human disease around the world, such as the West Nile, dengue, Zika, yellow fever, Japanese encephalitis, St. Louis encephalitis, and tick-borne encephalitis viruses. Like other RNA viruses, flaviviruses have a compact RNA genome that efficiently stores all the information required for the completion of the infectious cycle. The efficiency of this storage system is attributable to supracoding elements, i.e., discrete, structural units with essential functions. This information storage system overlaps and complements the protein coding sequence and is highly conserved across the genus. It therefore offers interesting potential targets for novel therapeutic strategies. This review summarizes our knowledge of the features of flavivirus genome functional RNA domains. It also provides a brief overview of the main achievements reported in the design of antiviral nucleic acid-based drugs targeting functional genomic RNA elements. PMID:28421048

  19. Identification of a Novel Antiviral Inhibitor of the Flavivirus Guanylyltransferase Enzyme

    PubMed Central

    Stahla-Beek, Hillary J.; April, Daniel G.; Saeedi, Bejan J.; Hannah, Amanda M.

    2012-01-01

    Arthropod-borne flavivirus infection causes serious morbidity and mortality worldwide, but there are currently no effective antiflaviviral chemotherapeutics available for human use. Therefore, it is critical that new therapeutics against virus-specific targets be developed. To identify new compounds that may be used as broadly active flavivirus therapeutics, we have performed a high-throughput screening of 235,456 commercially available compounds for small-molecule inhibitors of the dengue virus NS5 RNA capping enzyme. We identified a family of compounds, the 2-thioxothiazolidin-4-ones, that show potent biochemical inhibition of capping enzyme GTP binding and guanylyltransferase function. During the course of structure-activity relationship analysis, a molecule within this family, (E)-{3-[5-(4-tert-butylbenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]propanoic acid} (BG-323), was found to possess significant antiviral activity in a dengue virus subgenomic replicon assay. Further testing of BG-323 demonstrated that this molecule is able to reduce the replication of infectious West Nile virus and yellow fever virus in cell culture with low toxicity. The results of this study describe the first inhibitor that targets the GTP-binding/guanylyltransferase activity of the flavivirus RNA capping enzyme. PMID:22674988

  20. Variance decomposition in stochastic simulators

    SciTech Connect

    Le Maître, O. P.; Knio, O. M.; Moraes, A.

    2015-06-28

    This work aims at the development of a mathematical and computational approach that enables quantification of the inherent sources of stochasticity and of the corresponding sensitivities in stochastic simulations of chemical reaction networks. The approach is based on reformulating the system dynamics as being generated by independent standardized Poisson processes. This reformulation affords a straightforward identification of individual realizations for the stochastic dynamics of each reaction channel, and consequently a quantitative characterization of the inherent sources of stochasticity in the system. By relying on the Sobol-Hoeffding decomposition, the reformulation enables us to perform an orthogonal decomposition of the solution variance. Thus, by judiciously exploiting the inherent stochasticity of the system, one is able to quantify the variance-based sensitivities associated with individual reaction channels, as well as the importance of channel interactions. Implementation of the algorithms is illustrated in light of simulations of simplified systems, including the birth-death, Schlögl, and Michaelis-Menten models.

  1. Estimating the Modified Allan Variance

    NASA Technical Reports Server (NTRS)

    Greenhall, Charles

    1995-01-01

    The third-difference approach to modified Allan variance (MVAR) leads to a tractable formula for a measure of MVAR estimator confidence, the equivalent degrees of freedom (edf), in the presence of power-law phase noise. The effect of estimation stride on edf is tabulated. A simple approximation for edf is given, and its errors are tabulated. A theorem allowing conservative estimates of edf in the presence of compound noise processes is given.

  2. A New Clade of Insect-Specific Flaviviruses from Australian Anopheles Mosquitoes Displays Species-Specific Host Restriction.

    PubMed

    Colmant, Agathe M G; Hobson-Peters, Jody; Bielefeldt-Ohmann, Helle; van den Hurk, Andrew F; Hall-Mendelin, Sonja; Chow, Weng Kong; Johansen, Cheryl A; Fros, Jelke; Simmonds, Peter; Watterson, Daniel; Cazier, Chris; Etebari, Kayvan; Asgari, Sassan; Schulz, Benjamin L; Beebe, Nigel; Vet, Laura J; Piyasena, Thisun B H; Nguyen, Hong-Duyen; Barnard, Ross T; Hall, Roy A

    2017-01-01

    Flaviviruses are arthropod-borne viruses found worldwide and are responsible for significant human and veterinary diseases, including dengue, Zika, and West Nile fever. Some flaviviruses are insect specific and replicate only in mosquitoes. We report a genetically divergent group of insect-specific flaviviruses from Anopheles mosquitoes that do not replicate in arthropod cell lines or heterologous Anopheles species, exhibiting unprecedented specialization for their host species. Determination of the complete sequences of the RNA genomes of three of these viruses, Karumba virus (KRBV), Haslams Creek virus, and Mac Peak virus (McPV), that are found in high prevalence in some Anopheles mosquito populations and detection of virus-specific proteins, replicative double-stranded RNA, and small interfering RNA responses in the host mosquito species provided strong evidence of a functional replicating virus in the mosquito midgut. Analysis of nucleotide composition in the KRBV and McPV sequences also revealed a pattern consistent with the virus evolving to replicate only in insects. These findings represent a significant advance in our knowledge of mosquito-borne flavivirus ecology, host restriction, and evolution. IMPORTANCE Flaviviruses like dengue, Zika, or West Nile virus infect millions of people each year and are transmitted to humans via infected-mosquito bites. A subset of flaviviruses can only replicate in the mosquito host, and recent studies have shown that some can interfere with pathogenic flaviviruses in mosquitoes and limit the replication and transmission of the latter. The insect-specific flaviviruses (ISFs) reported here form a new Anopheles mosquito-associated clade separate from the Aedes- and Culex-associated ISF clades. The identification of distinct clades for each mosquito genus provides new insights into the evolution and ecology of flaviviruses. One of these viruses was shown to replicate in the midgut of the mosquito host and exhibit the most

  3. A New Clade of Insect-Specific Flaviviruses from Australian Anopheles Mosquitoes Displays Species-Specific Host Restriction

    PubMed Central

    Colmant, Agathe M. G.; Hobson-Peters, Jody; Bielefeldt-Ohmann, Helle; van den Hurk, Andrew F.; Hall-Mendelin, Sonja; Chow, Weng Kong; Johansen, Cheryl A.; Fros, Jelke; Simmonds, Peter; Watterson, Daniel; Cazier, Chris; Etebari, Kayvan; Asgari, Sassan; Schulz, Benjamin L.; Beebe, Nigel; Vet, Laura J.; Nguyen, Hong-Duyen; Barnard, Ross T.

    2017-01-01

    ABSTRACT Flaviviruses are arthropod-borne viruses found worldwide and are responsible for significant human and veterinary diseases, including dengue, Zika, and West Nile fever. Some flaviviruses are insect specific and replicate only in mosquitoes. We report a genetically divergent group of insect-specific flaviviruses from Anopheles mosquitoes that do not replicate in arthropod cell lines or heterologous Anopheles species, exhibiting unprecedented specialization for their host species. Determination of the complete sequences of the RNA genomes of three of these viruses, Karumba virus (KRBV), Haslams Creek virus, and Mac Peak virus (McPV), that are found in high prevalence in some Anopheles mosquito populations and detection of virus-specific proteins, replicative double-stranded RNA, and small interfering RNA responses in the host mosquito species provided strong evidence of a functional replicating virus in the mosquito midgut. Analysis of nucleotide composition in the KRBV and McPV sequences also revealed a pattern consistent with the virus evolving to replicate only in insects. These findings represent a significant advance in our knowledge of mosquito-borne flavivirus ecology, host restriction, and evolution. IMPORTANCE Flaviviruses like dengue, Zika, or West Nile virus infect millions of people each year and are transmitted to humans via infected-mosquito bites. A subset of flaviviruses can only replicate in the mosquito host, and recent studies have shown that some can interfere with pathogenic flaviviruses in mosquitoes and limit the replication and transmission of the latter. The insect-specific flaviviruses (ISFs) reported here form a new Anopheles mosquito-associated clade separate from the Aedes- and Culex-associated ISF clades. The identification of distinct clades for each mosquito genus provides new insights into the evolution and ecology of flaviviruses. One of these viruses was shown to replicate in the midgut of the mosquito host and exhibit the

  4. The Emerging Duck Flavivirus Is Not Pathogenic for Primates and Is Highly Sensitive to Mammalian Interferon Antiviral Signaling

    PubMed Central

    Wang, Hong-Jiang; Li, Xiao-Feng; Liu, Long; Xu, Yan-Peng; Ye, Qing; Deng, Yong-Qiang; Huang, Xing-Yao; Zhao, Hui; Qin, E-De; Shi, Pei-Yong; Gao, George F.

    2016-01-01

    ABSTRACT Flaviviruses pose a significant threat to both animals and humans. Recently, a novel flavivirus, duck Tembusu virus (DTMUV), was identified to be the causative agent of a serious duck viral disease in Asia. Its rapid spread, expanding host range, and uncertain transmission routes have raised substantial concerns regarding its potential threats to nonavian hosts, including humans. Here, we demonstrate that DTMUV is not pathogenic for nonhuman primates and is highly sensitive to mammal type I interferon (IFN) signaling. In vitro assays demonstrated that DTMUV infected and replicated efficiently in various mammalian cell lines. Further tests in mice demonstrated high neurovirulence and the age-dependent neuroinvasiveness of the virus. In particular, the inoculation of DTMUV into rhesus monkeys did not result in either viremia or apparent clinical symptoms, although DTMUV-specific humoral immune responses were detected. Furthermore, we revealed that although avian IFN failed to inhibit DTMUV in avian cells, DTMUV was more sensitive to the antiviral effects of type I interferon than other known human-pathogenic flaviviruses. Knockout of the type I IFN receptor in mice caused apparent viremia, viscerotropic disease, and mortality, indicating a vital role of IFN signaling in protection against DTMUV infection. Collectively, we provide direct experimental evidence that this novel avian-origin DTMUV possesses a limited capability to establish infection in immunocompetent primates due to its decreased antagonistic activity in the mammal IFN system. Furthermore, our findings highlight the potential risk of DTMUV infection in immunocompromised individuals and warrant studies on the cross-species transmission and pathogenesis of this novel flavivirus. IMPORTANCE Mosquito-borne flaviviruses comprise a large group of pathogenic and nonpathogenic members. The pathogenic flaviviruses include dengue, West Nile, and Japanese encephalitis viruses, and the nonpathogenic

  5. Comparison of imputation variance estimators.

    PubMed

    Hughes, R A; Sterne, Jac; Tilling, K

    2016-12-01

    Appropriate imputation inference requires both an unbiased imputation estimator and an unbiased variance estimator. The commonly used variance estimator, proposed by Rubin, can be biased when the imputation and analysis models are misspecified and/or incompatible. Robins and Wang proposed an alternative approach, which allows for such misspecification and incompatibility, but it is considerably more complex. It is unknown whether in practice Robins and Wang's multiple imputation procedure is an improvement over Rubin's multiple imputation. We conducted a critical review of these two multiple imputation approaches, a re-sampling method called full mechanism bootstrapping and our modified Rubin's multiple imputation procedure via simulations and an application to data. We explored four common scenarios of misspecification and incompatibility. In general, for a moderate sample size (n = 1000), Robins and Wang's multiple imputation produced the narrowest confidence intervals, with acceptable coverage. For a small sample size (n = 100) Rubin's multiple imputation, overall, outperformed the other methods. Full mechanism bootstrapping was inefficient relative to the other methods and required modelling of the missing data mechanism under the missing at random assumption. Our proposed modification showed an improvement over Rubin's multiple imputation in the presence of misspecification. Overall, Rubin's multiple imputation variance estimator can fail in the presence of incompatibility and/or misspecification. For unavoidable incompatibility and/or misspecification, Robins and Wang's multiple imputation could provide more robust inferences. © The Author(s) 2014.

  6. Variance and Skewness in the FIRST Survey

    NASA Astrophysics Data System (ADS)

    Magliocchetti, M.; Maddox, S. J.; Lahav, O.; Wall, J. V.

    We investigate the large-scale clustering of radio sources by analysing the distribution function of the FIRST 1.4 GHz survey. We select a reliable galaxy sample from the FIRST catalogue, paying particular attention to the definition of single radio sources from the multiple components listed in the FIRST catalogue. We estimate the variance, Ψ2, and skewness, Ψ3, of the distribution function for the best galaxy subsample. Ψ2 shows power-law behaviour as a function of cell size, with an amplitude corresponding a spatial correlation length of r0 ~10 h-1 Mpc. We detect significant skewness in the distribution, and find that it is related to the variance through the relation Ψ3 = S3 (Ψ2)α with α = 1.9 +/- 0.1 consistent with the non-linear growth of perturbations from primordial Gaussian initial conditions. We show that the amplitude of clustering (corresponding to a spatial correlation length of r0 ~10 h-1 Mpc) and skewness are consistent with realistic models of galaxy clustering.

  7. Spot the Difference—Development of a Syndrome Based Protein Microarray for Specific Serological Detection of Multiple Flavivirus Infections in Travelers

    PubMed Central

    Cleton, Natalie B.; Godeke, Gert-Jan; Reimerink, Johan; Beersma, Mathias F.; van Doorn, H. Rogier; Franco, Leticia; Goeijenbier, Marco; Jimenez-Clavero, Miguel A.; Johnson, Barbara W.; Niedrig, Matthias; Papa, Anna; Sambri, Vittorio; Tami, Adriana; Velasco-Salas, Zoraida I.; Koopmans, Marion P. G.; Reusken, Chantal B. E. M.

    2015-01-01

    Background The family Flaviviridae, genus Flavivirus, holds many of the world’s most prevalent arboviral diseases that are also considered the most important travel related arboviral infections. In most cases, flavivirus diagnosis in travelers is primarily based on serology as viremia is often low and typically has already been reduced to undetectable levels when symptoms set in and patients seek medical attention. Serological differentiation between flaviviruses and the false-positive results caused by vaccination and cross-reactivity among the different species, are problematic for surveillance and diagnostics of flaviviruses. Their partially overlapping geographic distribution and symptoms, combined with increase in travel, and preexisting antibodies due to flavivirus vaccinations, expand the need for rapid and reliable multiplex diagnostic tests to supplement currently used methods. Goal We describe the development of a multiplex serological protein microarray using recombinant NS1 proteins for detection of medically important viruses within the genus Flavivirus. Sera from clinical flavivirus patients were used for primary development of the protein microarray. Results Results show a high IgG and IgM sensitivity and specificity for individual NS1 antigens, and limited cross reactivity, even within serocomplexes. In addition, the serology based on this array allows for discrimination between infection and vaccination response for JEV vaccine, and no cross-reactivity with TBEV and YFV vaccine induced antibodies when testing for antibodies to other flaviviruses. Conclusion Based on these data, multiplex NS1-based protein microarray is a promising tool for surveillance and diagnosis of flaviviruses. PMID:25767876

  8. Flavivirus NS3 and NS5 proteins interaction network: a high-throughput yeast two-hybrid screen

    PubMed Central

    2011-01-01

    Background The genus Flavivirus encompasses more than 50 distinct species of arthropod-borne viruses, including several major human pathogens, such as West Nile virus, yellow fever virus, Japanese encephalitis virus and the four serotypes of dengue viruses (DENV type 1-4). Each year, flaviviruses cause more than 100 million infections worldwide, some of which lead to life-threatening conditions such as encephalitis or haemorrhagic fever. Among the viral proteins, NS3 and NS5 proteins constitute the major enzymatic components of the viral replication complex and are essential to the flavivirus life cycle. Results We report here the results of a high-throughput yeast two-hybrid screen to identify the interactions between human host proteins and the flavivirus NS3 and NS5 proteins. Using our screen results and literature curation, we performed a global analysis of the NS3 and NS5 cellular targets based on functional annotation with the Gene Ontology features. We finally created the first flavivirus NS3 and NS5 proteins interaction network and analysed the topological features of this network. Our proteome mapping screen identified 108 human proteins interacting with NS3 or NS5 proteins or both. The global analysis of the cellular targets revealed the enrichment of host proteins involved in RNA binding, transcription regulation, vesicular transport or innate immune response regulation. Conclusions We proposed that the selective disruption of these newly identified host/virus interactions could represent a novel and attractive therapeutic strategy in treating flavivirus infections. Our virus-host interaction map provides a basis to unravel fundamental processes about flavivirus subversion of the host replication machinery and/or immune defence strategy. PMID:22014111

  9. Spatio-temporal trends and risk factors affecting West Nile virus and related flavivirus exposure in Spanish wild ruminants.

    PubMed

    García-Bocanegra, Ignacio; Paniagua, Jorge; Gutiérrez-Guzmán, Ana V; Lecollinet, Sylvie; Boadella, Mariana; Arenas-Montes, Antonio; Cano-Terriza, David; Lowenski, Steeve; Gortázar, Christian; Höfle, Ursula

    2016-11-09

    During the last decade, the spread of many flaviviruses (Genus Flavivirus) has been reported, representing an emerging threat for both animal and human health. To further study utility of wild ruminant samples in West Nile virus (WNV) surveillance, we assessed spatio-temporal trends and factors associated with WNV and cross-reacting flaviviruses exposure, particularly Usutu virus (USUV) and Meaban virus (MBV), in wild ruminants in Spain. Serum samples from 4693 wild ruminants, including 3073 free-living red deer (Cervus elaphus), 201 fallow deer (Dama dama), 125 mouflon (Ovis aries musimon), 32 roe deer (Capreolus capreolus) and 1262 farmed red deer collected in 2003-2014, were screened for WNV and antigenically-related flavivirus antibodies using a blocking ELISA (bELISA). Positive samples were tested for neutralizing antibodies against WNV, USUV and MBV by virus micro-neutralization tests. Mean flavivirus seroprevalence according to bELISA was 3.4 ± 0.5 % in red deer, 1.0 ± 1.4 % in fallow deer, 2.4 ± 2.7 % in mouflon and 0 % in roe deer. A multivariate logistic regression model revealed as main risk factors for seropositivity in red deer; year (2011), the specific south-coastal bioregion (bioregion 5) and presence of wetlands. Red deer had neutralizing antibodies against WNV, USUV and MBV. The results indicate endemic circulation of WNV, USUV and MBV in Spanish red deer, even in areas without known flavivirus outbreaks. WNV antibodies detected in a free-living red deer yearling sampled in 2010, confirmed circulation this year. Co-circulation of WNV and USUV was detected in bioregions 3 and 5, and of WNV and MBV in bioregion 3. Sampling of hunted and farmed wild ruminants, specifically of red deer yearlings, could be a complementary way to national surveillance programs to monitor the activity of emerging flaviviruses.

  10. Flavivirus NS3 and NS5 proteins interaction network: a high-throughput yeast two-hybrid screen.

    PubMed

    Le Breton, Marc; Meyniel-Schicklin, Laurène; Deloire, Alexandre; Coutard, Bruno; Canard, Bruno; de Lamballerie, Xavier; Andre, Patrice; Rabourdin-Combe, Chantal; Lotteau, Vincent; Davoust, Nathalie

    2011-10-20

    The genus Flavivirus encompasses more than 50 distinct species of arthropod-borne viruses, including several major human pathogens, such as West Nile virus, yellow fever virus, Japanese encephalitis virus and the four serotypes of dengue viruses (DENV type 1-4). Each year, flaviviruses cause more than 100 million infections worldwide, some of which lead to life-threatening conditions such as encephalitis or haemorrhagic fever. Among the viral proteins, NS3 and NS5 proteins constitute the major enzymatic components of the viral replication complex and are essential to the flavivirus life cycle. We report here the results of a high-throughput yeast two-hybrid screen to identify the interactions between human host proteins and the flavivirus NS3 and NS5 proteins. Using our screen results and literature curation, we performed a global analysis of the NS3 and NS5 cellular targets based on functional annotation with the Gene Ontology features. We finally created the first flavivirus NS3 and NS5 proteins interaction network and analysed the topological features of this network. Our proteome mapping screen identified 108 human proteins interacting with NS3 or NS5 proteins or both. The global analysis of the cellular targets revealed the enrichment of host proteins involved in RNA binding, transcription regulation, vesicular transport or innate immune response regulation. We proposed that the selective disruption of these newly identified host/virus interactions could represent a novel and attractive therapeutic strategy in treating flavivirus infections. Our virus-host interaction map provides a basis to unravel fundamental processes about flavivirus subversion of the host replication machinery and/or immune defence strategy.

  11. The Influence of Therapist Variance on the Dependability of Therapists' Alliance Scores: A Brief Comment on "The Dependability of Alliance Assessments: The Alliance-Outcome Correlation Is Larger than You Think" (Crits-Christoph et al., 2011)

    ERIC Educational Resources Information Center

    Baldwin, Scott A.; Imel, Zac E.; Atkins, David C.

    2012-01-01

    Objective: Crits-Christoph, Connolly Gibbons, Hamilton, Ring-Kurtz, and Gallop (2011) used generalizability theory to critique the measurement of the therapeutic alliance in psychotherapy research, showing that the dependability of alliance scores may be quite low, which in turn can lead to attenuated alliance-outcome correlation estimates. Method…

  12. The Influence of Therapist Variance on the Dependability of Therapists' Alliance Scores: A Brief Comment on "The Dependability of Alliance Assessments: The Alliance-Outcome Correlation Is Larger than You Think" (Crits-Christoph et al., 2011)

    ERIC Educational Resources Information Center

    Baldwin, Scott A.; Imel, Zac E.; Atkins, David C.

    2012-01-01

    Objective: Crits-Christoph, Connolly Gibbons, Hamilton, Ring-Kurtz, and Gallop (2011) used generalizability theory to critique the measurement of the therapeutic alliance in psychotherapy research, showing that the dependability of alliance scores may be quite low, which in turn can lead to attenuated alliance-outcome correlation estimates. Method…

  13. Variance propagation by simulation (VPSim)

    SciTech Connect

    Burr, T.L.; Coulter, C.A.; Prommel, J.M.

    1997-07-01

    The application of propagation of variance (POV) for estimating the variance of a material balance is straightforward but tedious. Several computer codes exist today to help perform POV. Examples include MAWST (`materials accounting with sequential testing,` used by some Department of Energy sites) and VP (`variance propagation,` used for training). Also, some sites have such simple error models that custom `spreadsheet like` calculations are adequate. Any software to perform POV will have its strengths and weaknesses. A main disadvantage of MAWST is probably its limited form of error models. This limited form forces the user to use cryptic pseudo measurements to effectively extend the allowed error models. A common example is to include sampling error in the total random error by dividing the actual measurement into two pseudo measurements. Because POV can be tedious and input files can be presented in multiple ways to MAWST, it is valuable to have an alternative method to compare results. This paper describes a new code, VPSim, that uses Monte Carlo simulation to do POV. VPSim does not need to rely on pseudo measurements. It is written in C++, runs under Windows NT, and has a user friendly interface. VPSim has been tested on several example problems, and in this paper we compare its results to results from MAWST. We also describe its error models and indicate the structure of its input files. A main disadvantage of VPSim is its long run times. If many simulations are required (20,000 or more, repeated two or more times) and if each balance period has many (10,000 or more) measurements, then run times can be one-half hour or more. For small and modest sized problems, run times are a few minutes. The main advantage of VPSim is that its input files are simple to construct, and therefore also are relatively easy to inspect.

  14. Estimating the Modified Allan Variance

    NASA Technical Reports Server (NTRS)

    Greenhall, Charles

    1995-01-01

    A paper at the 1992 FCS showed how to express the modified Allan variance (mvar) in terms of the third difference of the cumulative sum of time residuals. Although this reformulated definition was presented merely as a computational trick for simplifying the calculation of mvar estimates, it has since turned out to be a powerful theoretical tool for deriving the statistical quality of those estimates in terms of their equivalent degrees of freedom (edf), defined for an estimator V by edf V = 2(EV)2/(var V). Confidence intervals for mvar can then be constructed from levels of the appropriate 2 distribution.

  15. Mitral disc-valve variance

    PubMed Central

    Berroya, Renato B.; Escano, Fernando B.

    1972-01-01

    This report deals with a rare complication of disc-valve prosthesis in the mitral area. A significant disc poppet and struts destruction of mitral Beall valve prostheses occurred 20 and 17 months after implantation. The resulting valve incompetence in the first case contributed to the death of the patient. The durability of Teflon prosthetic valves appears to be in question and this type of valve probably will be unacceptable if there is an increasing number of disc-valve variance in the future. Images PMID:5017573

  16. Improving variance estimation in Monte Carlo eigenvalue simulations

    DOE PAGES

    Jin, Lei; Banerjee, Kaushik; Hamilton, Steven P.; ...

    2017-07-27

    Monte Carlo (MC) methods have been widely used to solve eigenvalue problems in complex nuclear systems. Once a stationary fission source is obtained in MC simulations, the sample mean of many stationary cycles is calculated. Variance or standard deviation of the sample mean is needed to indicate the level of statistical uncertainty of the simulation and to understand the convergence of the sample mean. Current MC codes typically use sample variance to estimate the statistical uncertainty of the simulation and assume that the MC stationary cycles are independent. But, there is a correlation between these cycles, and estimators of themore » variance that ignore these correlations will systematically underestimate the variance. Our paper discusses some statistical properties of the sample mean and the asymptotic variance and introduces two novel estimators based on (a) covariance-adjusted methods and (b) bootstrap methods to reduce the variance underestimation. For three test problems, it has been observed that both new methods can improve the estimation of the standard deviation of the sample mean by more than an order of magnitude. Additionally, there are some interesting patterns revealed for these estimates over the spatial regions, providing additional insights into MC simulations for nuclear systems. These new methodologies are based on post-processing the tally results and are therefore easy to implement and code agnostic.« less

  17. Wide detection of Aedes flavivirus in north-eastern Italy--a European hotspot of emerging mosquito-borne diseases.

    PubMed

    Grisenti, Michela; Vázquez, Ana; Herrero, Laura; Cuevas, Laureano; Perez-Pastrana, Esperanza; Arnoldi, Daniele; Rosà, Roberto; Capelli, Gioia; Tenorio, Antonio; Sánchez-Seco, Maria Paz; Rizzoli, Annapaola

    2015-02-01

    The pattern of flavivirus infection in mosquitoes belonging to the genera Aedes and Culex collected in two regions of north-eastern Italy (Trentino and Veneto) was assessed. Mosquitoes were collected during 2012 and screened for flaviviruses using a generic reverse transcription-nested-PCR targeted on a region of the non-structural NS5 gene. The phylogenetic analysis was performed on a fragment of ~1000 bp. Virus isolation was attempted in C6/36 insect cell lines and the infected cell cultures were studied by electron microscopy. We detected a wide distribution of Aedes flavivirus (AeFV) in Aedes albopictus, with higher infection prevalence in Trentino than in Veneto. In Culex pipiens collected in Veneto, we detected a new sequence of an insect-specific flavivirus and one of Usutu virus. Interestingly, we detected AeFV in C. pipiens, for the first time to our knowledge, in both regions. Viral isolation in cell culture was successful for AeFV. AeFV sequences found in Veneto showed a high percentage of similarity to those detected in Trentino and to those previously reported in other areas of northern Italy. Co-infections with different flaviviruses were not detected.

  18. A Wavelet Perspective on the Allan Variance.

    PubMed

    Percival, Donald B

    2016-04-01

    The origins of the Allan variance trace back 50 years ago to two seminal papers, one by Allan (1966) and the other by Barnes (1966). Since then, the Allan variance has played a leading role in the characterization of high-performance time and frequency standards. Wavelets first arose in the early 1980s in the geophysical literature, and the discrete wavelet transform (DWT) became prominent in the late 1980s in the signal processing literature. Flandrin (1992) briefly documented a connection between the Allan variance and a wavelet transform based upon the Haar wavelet. Percival and Guttorp (1994) noted that one popular estimator of the Allan variance-the maximal overlap estimator-can be interpreted in terms of a version of the DWT now widely referred to as the maximal overlap DWT (MODWT). In particular, when the MODWT is based on the Haar wavelet, the variance of the resulting wavelet coefficients-the wavelet variance-is identical to the Allan variance when the latter is multiplied by one-half. The theory behind the wavelet variance can thus deepen our understanding of the Allan variance. In this paper, we review basic wavelet variance theory with an emphasis on the Haar-based wavelet variance and its connection to the Allan variance. We then note that estimation theory for the wavelet variance offers a means of constructing asymptotically correct confidence intervals (CIs) for the Allan variance without reverting to the common practice of specifying a power-law noise type a priori. We also review recent work on specialized estimators of the wavelet variance that are of interest when some observations are missing (gappy data) or in the presence of contamination (rogue observations or outliers). It is a simple matter to adapt these estimators to become estimators of the Allan variance. Finally we note that wavelet variances based upon wavelets other than the Haar offer interesting generalizations of the Allan variance.

  19. Hybrid biasing approaches for global variance reduction.

    PubMed

    Wu, Zeyun; Abdel-Khalik, Hany S

    2013-02-01

    A new variant of Monte Carlo-deterministic (DT) hybrid variance reduction approach based on Gaussian process theory is presented for accelerating convergence of Monte Carlo simulation and compared with Forward-Weighted Consistent Adjoint Driven Importance Sampling (FW-CADIS) approach implemented in the SCALE package from Oak Ridge National Laboratory. The new approach, denoted the Gaussian process approach, treats the responses of interest as normally distributed random processes. The Gaussian process approach improves the selection of the weight windows of simulated particles by identifying a subspace that captures the dominant sources of statistical response variations. Like the FW-CADIS approach, the Gaussian process approach utilizes particle importance maps obtained from deterministic adjoint models to derive weight window biasing. In contrast to the FW-CADIS approach, the Gaussian process approach identifies the response correlations (via a covariance matrix) and employs them to reduce the computational overhead required for global variance reduction (GVR) purpose. The effective rank of the covariance matrix identifies the minimum number of uncorrelated pseudo responses, which are employed to bias simulated particles. Numerical experiments, serving as a proof of principle, are presented to compare the Gaussian process and FW-CADIS approaches in terms of the global reduction in standard deviation of the estimated responses.

  20. Zika Virus Is Not Uniquely Stable at Physiological Temperatures Compared to Other Flaviviruses.

    PubMed

    Goo, Leslie; Dowd, Kimberly A; Smith, Alexander R Y; Pelc, Rebecca S; DeMaso, Christina R; Pierson, Theodore C

    2016-09-06

    Zika virus (ZIKV) is a flavivirus that has emerged as a global health threat due in part to its association with congenital abnormalities. Other globally relevant flaviviruses include dengue virus (DENV) and West Nile virus (WNV). High-resolution structures of ZIKV reveal many similarities to DENV and suggest some differences, including an extended glycan loop (D. Sirohi, Z. Chen, L. Sun, T. Klose, T. C. Pierson, et al., 352:467-470, 2016, http://dx.doi.org/10.1126/science.aaf5316) and unique interactions among envelope (E) protein residues that were proposed to confer increased virion stability and contribute mechanistically to the distinctive pathobiology of ZIKV (V. A. Kostyuchenko, E. X. Lim, S. Zhang, G. Fibriansah, T. S. Ng, et al., Nature 533:425-428, 2016, http://dx.doi.org/10.1038/nature17994). However, in the latter study, virus stability was inferred by measuring the loss of infectivity following a short incubation period. Here, we rigorously assessed the relative stability of ZIKV, DENV, and WNV by measuring changes in infectivity following prolonged incubation at physiological temperatures. At 37°C, the half-life of ZIKV was approximately twice as long as the half-life of DENV (11.8 and 5.2 h, respectively) but shorter than that of WNV (17.7 h). Incubation at 40°C accelerated the loss of ZIKV infectivity. Increasing virion maturation efficiency modestly increased ZIKV stability, as observed previously with WNV and DENV. Finally, mutations at E residues predicted to confer increased stability to ZIKV did not affect virion half-life. Our results demonstrate that ZIKV is not uniquely stable relative to other flaviviruses, suggesting that its unique pathobiology is explained by an alternative mechanism. Zika virus (ZIKV) belongs to the Flavivirus genus, which includes other clinically relevant mosquito-borne pathogens such as dengue virus (DENV) and West Nile virus (WNV). Historically, ZIKV infection was characterized by a self-limiting, mild disease

  1. The Unique Transmembrane Hairpin of Flavivirus Fusion Protein E Is Essential for Membrane Fusion▿

    PubMed Central

    Fritz, Richard; Blazevic, Janja; Taucher, Christian; Pangerl, Karen; Heinz, Franz X.; Stiasny, Karin

    2011-01-01

    The fusion of enveloped viruses with cellular membranes is mediated by proteins that are anchored in the lipid bilayer of the virus and capable of triggered conformational changes necessary for driving fusion. The flavivirus envelope protein E is the only known viral fusion protein with a double membrane anchor, consisting of two antiparallel transmembrane helices (TM1 and TM2). TM1 functions as a stop-transfer sequence and TM2 as an internal signal sequence for the first nonstructural protein during polyprotein processing. The possible role of this peculiar C-terminal helical hairpin in membrane fusion has not been investigated so far. We addressed this question by studying TM mutants of tick-borne encephalitis virus (TBEV) recombinant subviral particles (RSPs), an established model system for flavivirus membrane fusion. The engineered mutations included the deletion of TM2, the replacement of both TM domains (TMDs) by those of the related Japanese encephalitis virus (JEV), and the use of chimeric TBEV-JEV membrane anchors. Using these mutant RSPs, we provide evidence that TM2 is not just a remnant of polyprotein processing but, together with TM1, plays an active role in fusion. None of the TM mutations, including the deletion of TM2, affected early steps of the fusion process, but TM interactions apparently contribute to the stability of the postfusion E trimer and the completion of the merger of the membranes. Our data provide evidence for both intratrimer and intertrimer interactions mediated by the TMDs of E and thus extend the existing models of flavivirus membrane fusion. PMID:21325407

  2. Warped functional analysis of variance.

    PubMed

    Gervini, Daniel; Carter, Patrick A

    2014-09-01

    This article presents an Analysis of Variance model for functional data that explicitly incorporates phase variability through a time-warping component, allowing for a unified approach to estimation and inference in presence of amplitude and time variability. The focus is on single-random-factor models but the approach can be easily generalized to more complex ANOVA models. The behavior of the estimators is studied by simulation, and an application to the analysis of growth curves of flour beetles is presented. Although the model assumes a smooth latent process behind the observed trajectories, smootheness of the observed data is not required; the method can be applied to irregular time grids, which are common in longitudinal studies.

  3. Flavivirus and Filovirus EvoPrinters: New alignment tools for the comparative analysis of viral evolution

    PubMed Central

    Brody, Thomas; Yavatkar, Amarendra S.; Park, Dong Sun; Kuzin, Alexander; Ross, Jermaine

    2017-01-01

    Background Flavivirus and Filovirus infections are serious epidemic threats to human populations. Multi-genome comparative analysis of these evolving pathogens affords a view of their essential, conserved sequence elements as well as progressive evolutionary changes. While phylogenetic analysis has yielded important insights, the growing number of available genomic sequences makes comparisons between hundreds of viral strains challenging. We report here a new approach for the comparative analysis of these hemorrhagic fever viruses that can superimpose an unlimited number of one-on-one alignments to identify important features within genomes of interest. Methodology/Principal finding We have adapted EvoPrinter alignment algorithms for the rapid comparative analysis of Flavivirus or Filovirus sequences including Zika and Ebola strains. The user can input a full genome or partial viral sequence and then view either individual comparisons or generate color-coded readouts that superimpose hundreds of one-on-one alignments to identify unique or shared identity SNPs that reveal ancestral relationships between strains. The user can also opt to select a database genome in order to access a library of pre-aligned genomes of either 1,094 Flaviviruses or 460 Filoviruses for rapid comparative analysis with all database entries or a select subset. Using EvoPrinter search and alignment programs, we show the following: 1) superimposing alignment data from many related strains identifies lineage identity SNPs, which enable the assessment of sublineage complexity within viral outbreaks; 2) whole-genome SNP profile screens uncover novel Dengue2 and Zika recombinant strains and their parental lineages; 3) differential SNP profiling identifies host cell A-to-I hyper-editing within Ebola and Marburg viruses, and 4) hundreds of superimposed one-on-one Ebola genome alignments highlight ultra-conserved regulatory sequences, invariant amino acid codons and evolutionarily variable protein

  4. Preparation of pure, high titer, pseudoinfectious Flavivirus particles by hollow fiber tangential flow filtration and anion exchange chromatography.

    PubMed

    Mundle, Sophia T; Giel-Moloney, Maryann; Kleanthous, Harry; Pugachev, Konstantin V; Anderson, Stephen F

    2015-08-20

    Purification of enveloped viruses such as live flavivirus vaccine candidates poses a challenge as one must retain viral infectivity to preserve immunogenicity. Here we describe a laboratory-scale purification procedure for two replication defective (single-cycle) flavivirus variants for use in a pre-clinical setting. The two step purification scheme based on hollow fiber tangential flow filtration (TFF) followed by anion exchange chromatography using convective interaction media (CIM(®)) monoliths results in a ∼60% recovery of infectious virus titer and can be used to prepare nearly homogenous, highly purified vaccine viruses with titers as high as 1×10(9) focus forming units per mL. Flavivirus virions prepared by this method are 2 and 3 orders of magnitude more pure with respect to dsDNA and BHK host cell proteins, respectively, as compared to the raw feed stream.

  5. Identification and characterization of a novel tick-borne flavivirus subtype in goats (Capra hircus) in Spain.

    PubMed

    Mansfield, Karen L; Morales, Ana Balseiro; Johnson, Nicholas; Ayllón, Nieves; Höfle, Ursula; Alberdi, Pilar; Fernández de Mera, Isabel G; Marín, Juan Francisco García; Gortázar, Christian; de la Fuente, José; Fooks, Anthony R

    2015-07-01

    In 2011, a neurological disease was reported in a herd of goats (Capra hircus) in Asturias, Spain. Initial sequencing identified the causative agent as louping ill virus (LIV). Subsequently, with the application of whole genome sequencing and phylogenetic analysis, empirical data demonstrates that the LIV-like virus detected is significantly divergent from LIV and Spanish sheep encephalitis virus (SSEV). This virus encoded an amino acid sequence motif at the site of a previously identified marker for differentiating tick-borne flaviviruses that was shared with a virus previously isolated in Ireland in 1968. The significance of these observations reflects the diversity of tick-borne flaviviruses in Europe. These data also contribute to our knowledge of the evolution of tick-borne flaviviruses and could reflect the movement of viruses throughout Europe. Based on these observations, the proposed name for this virus is Spanish goat encephalitis virus (SGEV), to distinguish it from SSEV.

  6. 40 CFR 52.2183 - Variance provision.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS (CONTINUED) South Dakota § 52.2183 Variance provision. The revisions to the variance provisions in Chapter 74:26:01:31.01 of the South Dakota Air Pollution...

  7. 40 CFR 52.2183 - Variance provision.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS (CONTINUED) South Dakota § 52.2183 Variance provision. The revisions to the variance provisions in Chapter 74:26:01:31.01 of the South Dakota Air Pollution...

  8. 40 CFR 52.2183 - Variance provision.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS (CONTINUED) South Dakota § 52.2183 Variance provision. The revisions to the variance provisions in Chapter 74:26:01:31.01 of the South Dakota Air Pollution...

  9. 40 CFR 52.2183 - Variance provision.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS (CONTINUED) South Dakota § 52.2183 Variance provision. The revisions to the variance provisions in Chapter 74:26:01:31.01 of the South Dakota Air Pollution...

  10. 40 CFR 52.2183 - Variance provision.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS (CONTINUED) South Dakota § 52.2183 Variance provision. The revisions to the variance provisions in Chapter 74:26:01:31.01 of the South Dakota Air Pollution...

  11. Mother and adolescent reports of associations between child behavior problems and mother-child relationship qualities: separating shared variance from individual variance.

    PubMed

    Burk, William J; Laursen, Brett

    2010-07-01

    This study contrasts results from different correlational methods for examining links between mother and child (N = 72 dyads) reports of early adolescent (M = 11.5 years) behavior problems and relationship negativity and support. Simple (Pearson) correlations revealed a consistent pattern of statistically significant associations, regardless of whether scores came from the same reporter or from different reporters. When correlations between behavior problems and relationship quality differed, within-reporter correlations were always greater in magnitude than between-reporter correlations. Dyadic (common fate) analyses designed for interdependent data decomposed within-reporter correlations into variance shared across reporters (dyadic correlations) and variance unique to specific reporters (individual correlations). Dyadic correlations were responsible for most associations between adolescent behavior problems and relationship negativity; after partitioning variance shared across reporters, no individual correlations emerged as statistically significant. In contrast, adolescent behavior problems were linked to relationship support via both shared variance and variance unique to maternal perceptions. Dyadic analyses provide a parsimonious alternative to multiple contrasts in instances when identical measures have been collected from multiple reporters. Findings from these analyses indicate that same-reporter variance bias should not be assumed in the absence of dyadic statistical analyses.

  12. Correcting an analysis of variance for clustering.

    PubMed

    Hedges, Larry V; Rhoads, Christopher H

    2011-02-01

    A great deal of educational and social data arises from cluster sampling designs where clusters involve schools, classrooms, or communities. A mistake that is sometimes encountered in the analysis of such data is to ignore the effect of clustering and analyse the data as if it were based on a simple random sample. This typically leads to an overstatement of the precision of results and too liberal conclusions about precision and statistical significance of mean differences. This paper gives simple corrections to the test statistics that would be computed in an analysis of variance if clustering were (incorrectly) ignored. The corrections are multiplicative factors depending on the total sample size, the cluster size, and the intraclass correlation structure. For example, the corrected F statistic has Fisher's F distribution with reduced degrees of freedom. The corrected statistic reduces to the F statistic computed by ignoring clustering when the intraclass correlations are zero. It reduces to the F statistic computed using cluster means when the intraclass correlations are unity, and it is in between otherwise. A similar adjustment to the usual statistic for testing a linear contrast among group means is described.

  13. Cyclostationary analysis with logarithmic variance stabilisation

    NASA Astrophysics Data System (ADS)

    Borghesani, Pietro; Shahriar, Md Rifat

    2016-03-01

    Second order cyclostationary (CS2) components in vibration or acoustic emission signals are typical symptoms of a wide variety of faults in rotating and alternating mechanical systems. The square envelope spectrum (SES), obtained via Hilbert transform of the original signal, is at the basis of the most common indicators used for detection of CS2 components. It has been shown that the SES is equivalent to an autocorrelation of the signal's discrete Fourier transform, and that CS2 components are a cause of high correlations in the frequency domain of the signal, thus resulting in peaks in the SES. Statistical tests have been proposed to determine if peaks in the SES are likely to belong to a normal variability in the signal or if they are proper symptoms of CS2 components. Despite the need for automated fault recognition and the theoretical soundness of these tests, this approach to machine diagnostics has been mostly neglected in industrial applications. In fact, in a series of experimental applications, even with proper pre-whitening steps, it has been found that healthy machines might produce high spectral correlations and therefore result in a highly biased SES distribution which might cause a series of false positives. In this paper a new envelope spectrum is defined, with the theoretical intent of rendering the hypothesis test variance-free. This newly proposed indicator will prove unbiased in case of multiple CS2 sources of spectral correlation, thus reducing the risk of false alarms.

  14. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug

    PubMed Central

    Mastrangelo, Eloise; Pezzullo, Margherita; De Burghgraeve, Tine; Kaptein, Suzanne; Pastorino, Boris; Dallmeier, Kai; de Lamballerie, Xavier; Neyts, Johan; Hanson, Alicia M.; Frick, David N.; Bolognesi, Martino; Milani, Mario

    2012-01-01

    Objectives Infection with yellow fever virus (YFV), the prototypic mosquito-borne flavivirus, causes severe febrile disease with haemorrhage, multi-organ failure and a high mortality. Moreover, in recent years the Flavivirus genus has gained further attention due to re-emergence and increasing incidence of West Nile, dengue and Japanese encephalitis viruses. Potent and safe antivirals are urgently needed. Methods Starting from the crystal structure of the NS3 helicase from Kunjin virus (an Australian variant of West Nile virus), we identified a novel, unexploited protein site that might be involved in the helicase catalytic cycle and could thus in principle be targeted for enzyme inhibition. In silico docking of a library of small molecules allowed us to identify a few selected compounds with high predicted affinity for the new site. Their activity against helicases from several flaviviruses was confirmed in in vitro helicase/enzymatic assays. The effect on the in vitro replication of flaviviruses was then evaluated. Results Ivermectin, a broadly used anti-helminthic drug, proved to be a highly potent inhibitor of YFV replication (EC50 values in the sub-nanomolar range). Moreover, ivermectin inhibited, although less efficiently, the replication of several other flaviviruses, i.e. dengue fever, Japanese encephalitis and tick-borne encephalitis viruses. Ivermectin exerts its effect at a timepoint that coincides with the onset of intracellular viral RNA synthesis, as expected for a molecule that specifically targets the viral helicase. Conclusions The well-tolerated drug ivermectin may hold great potential for treatment of YFV infections. Furthermore, structure-based optimization may result in analogues exerting potent activity against flaviviruses other than YFV. PMID:22535622

  15. Speed Variance and Its Influence on Accidents.

    ERIC Educational Resources Information Center

    Garber, Nicholas J.; Gadirau, Ravi

    A study was conducted to investigate the traffic engineering factors that influence speed variance and to determine to what extent speed variance affects accident rates. Detailed analyses were carried out to relate speed variance with posted speed limit, design speeds, and other traffic variables. The major factor identified was the difference…

  16. Molecular detection of flaviviruses and alphaviruses in mosquitoes (Diptera: Culicidae) from coastal ecosystems in the Colombian Caribbean.

    PubMed

    Hoyos-López, Richard; Suaza-Vasco, Juan; Rúa-Uribe, Guillermo; Uribe, Sandra; Gallego-Gómez, Juan Carlos

    2016-10-01

    Arboviruses belonging to the genera Flavivirus and Alphavirus were detected in mosquitoes in a rural area of San Bernardo del Viento (Córdoba, Colombia). A total of 22,180 mosquitoes were collected, sorted into 2,102 pools, and tested by generic/nested reverse transcription-polymerase chain reaction. Venezuelan equine encephalitis virus, dengue virus, West Nile virus, St. Louis encephalitis virus, yellow fever virus, and Culex flavivirus were detected and identified by sequencing. The detection of arboviral pathogens in this zone represents possible circulation and indicates a human health risk, demonstrating the importance of virological surveillance activities.

  17. Molecular detection of flaviviruses and alphaviruses in mosquitoes (Diptera: Culicidae) from coastal ecosystems in the Colombian Caribbean

    PubMed Central

    Hoyos-López, Richard; Suaza-Vasco, Juan; Rúa-Uribe, Guillermo; Uribe, Sandra; Gallego-Gómez, Juan Carlos

    2016-01-01

    Arboviruses belonging to the genera Flavivirus and Alphavirus were detected in mosquitoes in a rural area of San Bernardo del Viento (Córdoba, Colombia). A total of 22,180 mosquitoes were collected, sorted into 2,102 pools, and tested by generic/nested reverse transcription-polymerase chain reaction. Venezuelan equine encephalitis virus, dengue virus, West Nile virus, St. Louis encephalitis virus, yellow fever virus, and Culex flavivirus were detected and identified by sequencing. The detection of arboviral pathogens in this zone represents possible circulation and indicates a human health risk, demonstrating the importance of virological surveillance activities. PMID:27706377

  18. Variance in Math Achievement Attributable to Visual Cognitive Constructs

    ERIC Educational Resources Information Center

    Oehlert, Jeremy J.

    2012-01-01

    Previous research has reported positive correlations between math achievement and the cognitive constructs of spatial visualization, working memory, and general intelligence; however, no single study has assessed variance in math achievement attributable to all three constructs, examined in combination. The current study fills this gap in the…

  19. Variance in Math Achievement Attributable to Visual Cognitive Constructs

    ERIC Educational Resources Information Center

    Oehlert, Jeremy J.

    2012-01-01

    Previous research has reported positive correlations between math achievement and the cognitive constructs of spatial visualization, working memory, and general intelligence; however, no single study has assessed variance in math achievement attributable to all three constructs, examined in combination. The current study fills this gap in the…

  20. Explaining Common Variance Shared by Early Numeracy and Literacy

    ERIC Educational Resources Information Center

    Davidse, N. J.; De Jong, M. T.; Bus, A. G.

    2014-01-01

    How can it be explained that early literacy and numeracy share variance? We specifically tested whether the correlation between four early literacy skills (rhyming, letter knowledge, emergent writing, and orthographic knowledge) and simple sums (non-symbolic and story condition) reduced after taking into account preschool attention control,…

  1. Explaining Common Variance Shared by Early Numeracy and Literacy

    ERIC Educational Resources Information Center

    Davidse, N. J.; De Jong, M. T.; Bus, A. G.

    2014-01-01

    How can it be explained that early literacy and numeracy share variance? We specifically tested whether the correlation between four early literacy skills (rhyming, letter knowledge, emergent writing, and orthographic knowledge) and simple sums (non-symbolic and story condition) reduced after taking into account preschool attention control,…

  2. Bicluster pattern of codon context usages between flavivirus and vector mosquito Aedes aegypti: relevance to infection and transcriptional response of mosquito genes.

    PubMed

    Behura, Susanta K; Severson, David W

    2014-10-01

    The mosquito Aedes aegypti is the primary vector of dengue virus (DENV) infection in most of the subtropical and tropical countries. Besides DENV, yellow fever virus (YFV) is also transmitted by A. aegypti. Susceptibility of A. aegypti to West Nile virus (WNV) has also been confirmed. Although studies have indicated correlation of codon bias between flaviviridae and their animal/insect hosts, it is not clear if codon sequences have any relation to susceptibility of A. aegypti to DENV, YFV and WNV. In the current study, usages of codon context sequences (codon pairs for neighboring amino acids) of the vector (A. aegypti) genome as well as the flaviviral genomes are investigated. We used bioinformatics methods to quantify codon context bias in a genome-wide manner of A. aegypti as well as DENV, WNV and YFV sequences. Mutual information statistics was applied to perform bicluster analysis of codon context bias between vector and flaviviral sequences. Functional relevance of the bicluster pattern was inferred from published microarray data. Our study shows that codon context bias of DENV, WNV and YFV sequences varies in a bicluster manner with that of specific sets of genes of A. aegypti. Many of these mosquito genes are known to be differentially expressed in response to flaviviral infection suggesting that codon context sequences of A. aegypti and the flaviviruses may play a role in the susceptible interaction between flaviviruses and this mosquito. The bias in usages of codon context sequences likely has a functional association with susceptibility of A. aegypti to flaviviral infection. The results from this study will allow us to conduct hypothesis-driven tests to examine the role of codon context bias in evolution of vector-virus interactions at the molecular level.

  3. Characterizing the Conformational Landscape of Flavivirus Fusion Peptides via Simulation and Experiment.

    PubMed

    Marzinek, Jan K; Lakshminarayanan, Rajamani; Goh, Eunice; Huber, Roland G; Panzade, Sadhana; Verma, Chandra; Bond, Peter J

    2016-01-20

    Conformational changes in the envelope proteins of flaviviruses help to expose the highly conserved fusion peptide (FP), a region which is critical to membrane fusion and host cell infection, and which represents a significant target for antiviral drugs and antibodies. In principle, extended timescale atomic-resolution simulations may be used to characterize the dynamics of such peptides. However, the resultant accuracy is critically dependent upon both the underlying force field and sufficient conformational sampling. In the present study, we report a comprehensive comparison of three simulation methods and four force fields comprising a total of more than 40 μs of sampling. Additionally, we describe the conformational landscape of the FP fold across all flavivirus family members. All investigated methods sampled conformations close to available X-ray structures, but exhibited differently populated ensembles. The best force field / sampling combination was sufficiently accurate to predict that the solvated peptide fold is less ordered than in the crystallographic state, which was subsequently confirmed via circular dichroism and spectrofluorometric measurements. Finally, the conformational landscape of a mutant incapable of membrane fusion was significantly shallower than wild-type variants, suggesting that dynamics should be considered when therapeutically targeting FP epitopes.

  4. Polymerases of hepatitis C viruses and flaviviruses: structural and mechanistic insights and drug development.

    PubMed

    Caillet-Saguy, Célia; Lim, Siew Pheng; Shi, Pei-Yong; Lescar, Julien; Bressanelli, Stéphane

    2014-05-01

    The family Flaviviridae comprises several major human pathogens including hepatitis C virus (genus hepacivirus), yellow fever virus, West Nile virus and dengue virus (genus flavivirus). Flaviviridae genomes comprise a single-stranded RNA segment encoding a single polyprotein that is subsequently processed into 10 mature viral proteins. The nonstructural proteins are released from the C-terminus of the polyprotein and contribute to the infectious cycle by forming membrane-bound, multi-protein compartments within host cells, named the replication complexes, where synthesis of new viral genomes takes place. Two nonstructural proteins are endowed with multiple enzymatic activities and represent important targets against which specific antiviral inhibitors have been developed. X-ray crystal structures of these viral enzymes as well as in-depth understanding of the molecular basis of their activities have contributed tremendously to the development of antiviral compounds, currently approved or in advanced clinical trials for hepatitis C treatment. One of the prime targets is the RNA-dependent RNA polymerase (RdRp, NS5B for hepatitis C virus, NS5 for flaviviruses). Here we review current knowledge of the structural basis for viral RNA synthesis by NS5B and NS5. These data offer perspectives for further drug design and constitute major advances in our basic understanding of viral RdRp. They thus point to future research directions in the field. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Dendritic transport of tick-borne flavivirus RNA by neuronal granules affects development of neurological disease.

    PubMed

    Hirano, Minato; Muto, Memi; Sakai, Mizuki; Kondo, Hirofumi; Kobayashi, Shintaro; Kariwa, Hiroaki; Yoshii, Kentaro

    2017-09-12

    Neurological diseases caused by encephalitic flaviviruses are severe and associated with high levels of mortality. However, little is known about the detailed mechanisms of viral replication and pathogenicity in the brain. Previously, we reported that the genomic RNA of tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus, is transported and replicated in the dendrites of neurons. In the present study, we analyzed the transport mechanism of the viral genome to dendrites. We identified specific sequences of the 5' untranslated region of TBEV genomic RNA that act as a cis-acting element for RNA transport. Mutated TBEV with impaired RNA transport in dendrites caused a reduction in neurological symptoms in infected mice. We show that neuronal granules, which regulate the transport and local translation of dendritic mRNAs, are involved in TBEV genomic RNA transport. TBEV genomic RNA bound an RNA-binding protein of neuronal granules and disturbed the transport of dendritic mRNAs. These results demonstrated a neuropathogenic virus hijacking the neuronal granule system for the transport of viral genomic RNA in dendrites, resulting in severe neurological disease.

  6. PCA criterion for SVM (MLP) classifier for flavivirus biomarker from salivary SERS spectra at febrile stage.

    PubMed

    Radzol, A R M; Lee, Khuan Y; Mansor, W; Omar, I S

    2016-08-01

    Non-structural protein (NS1) has been conceded as one of the biomarkers for flavivirus that causes diseases with life threatening consequences. NS1 is an antigen that allows detection of the illness at febrile stage, mostly from blood samples currently. Our work here intends to define an optimum model for PCA-SVM with MLP kernel for classification of flavivirus biomarker, NS1 molecule, from SERS spectra of saliva, which to the best of our knowledge has never been explored. Since performance of the model depends on the PCA criterion and MLP parameters, both are examined in tandem. Input vector to classifier determined by each PCA criterion is subjected to brute force tuning of MLP parameters for entirety. Its performance is also compared to our previous works where a Linear and RBF kernel are used. It is found that the best PCA-SVM (MLP) model can be defined by 5 PCs from Cattel's Scree test for PCA, together with P1 and P2 values of 0.1 and -0.2 respectively, with a classification performance of [96.9%, 93.8%, 100.0%].

  7. AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses

    PubMed Central

    Richard, Audrey Stéphanie; Shim, Byoung-Shik; Kwon, Young-Chan; Zhang, Rong; Otsuka, Yuka; Schmitt, Kimberly; Berri, Fatma; Diamond, Michael S.; Choe, Hyeryun

    2017-01-01

    Although a causal relationship between Zika virus (ZIKV) and microcephaly has been established, it remains unclear why ZIKV, but not other pathogenic flaviviruses, causes congenital defects. Here we show that when viruses are produced in mammalian cells, ZIKV, but not the closely related dengue virus (DENV) or West Nile virus (WNV), can efficiently infect key placental barrier cells that directly contact the fetal bloodstream. We show that AXL, a receptor tyrosine kinase, is the primary ZIKV entry cofactor on human umbilical vein endothelial cells (HUVECs), and that ZIKV uses AXL with much greater efficiency than does DENV or WNV. Consistent with this observation, only ZIKV, but not WNV or DENV, bound the AXL ligand Gas6. In comparison, when DENV and WNV were produced in insect cells, they also infected HUVECs in an AXL-dependent manner. Our data suggest that ZIKV, when produced from mammalian cells, infects fetal endothelial cells much more efficiently than other pathogenic flaviviruses because it binds Gas6 more avidly, which in turn facilitates its interaction with AXL. PMID:28167751

  8. AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses.

    PubMed

    Richard, Audrey Stéphanie; Shim, Byoung-Shik; Kwon, Young-Chan; Zhang, Rong; Otsuka, Yuka; Schmitt, Kimberly; Berri, Fatma; Diamond, Michael S; Choe, Hyeryun

    2017-02-21

    Although a causal relationship between Zika virus (ZIKV) and microcephaly has been established, it remains unclear why ZIKV, but not other pathogenic flaviviruses, causes congenital defects. Here we show that when viruses are produced in mammalian cells, ZIKV, but not the closely related dengue virus (DENV) or West Nile virus (WNV), can efficiently infect key placental barrier cells that directly contact the fetal bloodstream. We show that AXL, a receptor tyrosine kinase, is the primary ZIKV entry cofactor on human umbilical vein endothelial cells (HUVECs), and that ZIKV uses AXL with much greater efficiency than does DENV or WNV. Consistent with this observation, only ZIKV, but not WNV or DENV, bound the AXL ligand Gas6. In comparison, when DENV and WNV were produced in insect cells, they also infected HUVECs in an AXL-dependent manner. Our data suggest that ZIKV, when produced from mammalian cells, infects fetal endothelial cells much more efficiently than other pathogenic flaviviruses because it binds Gas6 more avidly, which in turn facilitates its interaction with AXL.

  9. Duck egg drop syndrome virus: an emerging Tembusu-related flavivirus in China.

    PubMed

    Liu, PeiPei; Lu, Hao; Li, Shuang; Wu, Ying; Gao, George Fu; Su, JingLiang

    2013-08-01

    Duck egg drop syndrome virus (DEDSV) is a newly emerging pathogenic flavivirus isolated from ducks in China. DEDSV infection mainly results in severe egg drop syndrome in domestic poultry, which leads to huge economic losses. Thus, the discovery of ways and means to combat DEDSV is urgent. Since 2010, a remarkable amount of progress concerning DEDSV research has been achieved. Here, we review current knowledge on the epidemiology, symptomatology, and pathology of DEDSV. A detailed dissection of the viral genome and polyprotein sequences, comparative analysis of viral antigenicity and the corresponding potential immunity against the virus are also summarized. Current findings indicate that DEDSV should be a distinct species from Tembusu virus. Moreover, the adaption of DEDSV in wildlife and its high homology to pathogenic flaviviruses (e.g., West Nile virus, Japanese encephalitis virus, and dengue virus), illustrate its reemergence and potential to become a zoonotic pathogen that should not be overlooked. Detailed insight into the antigenicity and corresponding immunity against the virus is of clear significance for the development of vaccines and antiviral drugs specific for DEDSV.

  10. Direct Complement Restriction of Flavivirus Infection Requires Glycan Recognition by Mannose Binding Lectin

    PubMed Central

    Fuchs, Anja; Lin, Tsai-Yu; Beasley, David W.; Stover, Cordula M.; Schwaeble, Wilhelm J.; Pierson, Theodore C.; Diamond, Michael S.

    2010-01-01

    SUMMARY An intact complement system is crucial for limiting West Nile virus (WNV) dissemination. Herein, we define how complement directly restricts flavivirus infection in an antibody-independent fashion. Mannose binding lectin (MBL) recognized N-linked glycans on the structural proteins of WNV and Dengue virus (DENV), resulting in neutralization through a C3 and C4-dependent mechanism that utilized both the canonical and bypass lectin activation pathways. For WNV, neutralization occurred with virus produced in insect cells, whereas for DENV, neutralization of insect and mammalian cell-derived virus was observed. Mechanism of action studies suggested that the MBL-dependent neutralization occurred in part, by blocking viral fusion. Experiments in mice showed an MBL-dependent accelerated intravascular clearance of DENV or a WNV mutant with two N-linked glycans on its E protein, but not with wild type WNV. Our studies show that MBL recognizes terminal mannose containing carbohydrates on flaviviruses, resulting in neutralization and efficient clearance in vivo. PMID:20709295

  11. Noncoding subgenomic flavivirus RNA: multiple functions in West Nile virus pathogenesis and modulation of host responses.

    PubMed

    Roby, Justin A; Pijlman, Gorben P; Wilusz, Jeffrey; Khromykh, Alexander A

    2014-01-27

    Flaviviruses are a large group of positive strand RNA viruses transmitted by arthropods that include many human pathogens such as West Nile virus (WNV), Japanese encephalitis virus (JEV), yellow fever virus, dengue virus, and tick-borne encephalitis virus. All members in this genus tested so far are shown to produce a unique subgenomic flavivirus RNA (sfRNA) derived from the 3' untranslated region (UTR). sfRNA is a product of incomplete degradation of genomic RNA by the cell 5'-3' exoribonuclease XRN1 which stalls at highly ordered secondary RNA structures at the beginning of the 3'UTR. Generation of sfRNA results in inhibition of XRN1 activity leading to an increase in stability of many cellular mRNAs. Mutant WNV deficient in sfRNA generation was highly attenuated displaying a marked decrease in cytopathicity in cells and pathogenicity in mice. sfRNA has also been shown to inhibit the antiviral activity of IFN-α/β by yet unknown mechanism and of the RNAi pathway by likely serving as a decoy substrate for Dicer. Thus, sfRNA is involved in modulating multiple cellular pathways to facilitate viral pathogenicity; however the overlying mechanism linking all these multiple functions of sfRNA remains to be elucidated.

  12. Standing your Ground to Exoribonucleases: Function of Flavivirus Long Non-coding RNAs

    PubMed Central

    Charley, Phillida A.; Wilusz, Jeffrey

    2015-01-01

    Members of the Flaviviridae (e.g. Dengue virus, West Nile virus, and Hepatitis C virus) contain a positive-sense RNA genome that encodes a large polyprotein. It is now also clear most if not all of these viruses also produce an abundant subgenomic long non-coding RNA. These non-coding RNAs, which are called subgenomicflavivirus RNAs (sfRNAs) or Xrn1-resistant RNAs (xrRNAs), are stable decay intermediates generated from the viral genomic RNA through the stalling of the cellular exoribonuclease Xrn1 at highly structured regions. Several functions of these flavivirus long non-coding RNAs have been revealed in recent years. The generation of these sfRNAs/xrRNAs from viral transcripts results in the repression of Xrn1 and the dysregulation of cellular mRNA stability. The abundant sfRNAs also serve directly as a decoy for important cellular protein regulators of the interferon and RNA interference antiviral pathways. Thus the generation of long non-coding RNAs from flaviviruses, hepaciviruses and pestiviruses likely disrupts aspects of innate immunity and may directly contribute to viral replication, cytopathology and pathogenesis. PMID:26368052

  13. Preliminary characterization of (nucleoside-2′-O-)-methyltransferase crystals from Meaban and Yokose flaviviruses

    SciTech Connect

    Mastrangelo, Eloise; Bollati, Michela; Milani, Mario; Lamballeire, Xavier de; Brisbare, Nadege; Dalle, Karen; Lantez, Violaine; Egloff, Marie-Pierre; Coutard, Bruno; Canard, Bruno; Gould, Ernest; Forrester, Naomi; Bolognesi, Martino

    2006-08-01

    Two methyltransferases from flaviviruses (Meaban and Yokose viruses) have been overexpressed and crystallized. Diffraction data and characterization of the two crystal forms are presented, together with a preliminary molecular-replacement solution for both enzymes. Viral methyltranferases (MTase) are involved in the third step of the mRNA-capping process, transferring a methyl group from S-adenosyl-l-methionine (SAM) to the capped mRNA. MTases are classified into two groups: (guanine-N7)-methyltransferases (N7MTases), which add a methyl group onto the N7 atom of guanine, and (nucleoside-2′-O-)-methyltransferases (2′OMTases), which add a methyl group to a ribose hydroxyl. The MTases of two flaviviruses, Meaban and Yokose viruses, have been overexpressed, purified and crystallized in complex with SAM. Characterization of the crystals together with details of preliminary X-ray diffraction data collection (at 2.8 and 2.7 Å resolution, respectively) are reported here. The sequence homology relative to Dengue virus 2′OMTase and the structural conservation of specific residues in the putative active sites suggest that both enzymes belong to the 2′OMTase subgroup.

  14. Characterizing the Conformational Landscape of Flavivirus Fusion Peptides via Simulation and Experiment

    PubMed Central

    Marzinek, Jan K.; Lakshminarayanan, Rajamani; Goh, Eunice; Huber, Roland G.; Panzade, Sadhana; Verma, Chandra; Bond, Peter J.

    2016-01-01

    Conformational changes in the envelope proteins of flaviviruses help to expose the highly conserved fusion peptide (FP), a region which is critical to membrane fusion and host cell infection, and which represents a significant target for antiviral drugs and antibodies. In principle, extended timescale atomic-resolution simulations may be used to characterize the dynamics of such peptides. However, the resultant accuracy is critically dependent upon both the underlying force field and sufficient conformational sampling. In the present study, we report a comprehensive comparison of three simulation methods and four force fields comprising a total of more than 40 μs of sampling. Additionally, we describe the conformational landscape of the FP fold across all flavivirus family members. All investigated methods sampled conformations close to available X-ray structures, but exhibited differently populated ensembles. The best force field / sampling combination was sufficiently accurate to predict that the solvated peptide fold is less ordered than in the crystallographic state, which was subsequently confirmed via circular dichroism and spectrofluorometric measurements. Finally, the conformational landscape of a mutant incapable of membrane fusion was significantly shallower than wild-type variants, suggesting that dynamics should be considered when therapeutically targeting FP epitopes. PMID:26785994

  15. Characterizing the Conformational Landscape of Flavivirus Fusion Peptides via Simulation and Experiment

    NASA Astrophysics Data System (ADS)

    Marzinek, Jan K.; Lakshminarayanan, Rajamani; Goh, Eunice; Huber, Roland G.; Panzade, Sadhana; Verma, Chandra; Bond, Peter J.

    2016-01-01

    Conformational changes in the envelope proteins of flaviviruses help to expose the highly conserved fusion peptide (FP), a region which is critical to membrane fusion and host cell infection, and which represents a significant target for antiviral drugs and antibodies. In principle, extended timescale atomic-resolution simulations may be used to characterize the dynamics of such peptides. However, the resultant accuracy is critically dependent upon both the underlying force field and sufficient conformational sampling. In the present study, we report a comprehensive comparison of three simulation methods and four force fields comprising a total of more than 40 μs of sampling. Additionally, we describe the conformational landscape of the FP fold across all flavivirus family members. All investigated methods sampled conformations close to available X-ray structures, but exhibited differently populated ensembles. The best force field / sampling combination was sufficiently accurate to predict that the solvated peptide fold is less ordered than in the crystallographic state, which was subsequently confirmed via circular dichroism and spectrofluorometric measurements. Finally, the conformational landscape of a mutant incapable of membrane fusion was significantly shallower than wild-type variants, suggesting that dynamics should be considered when therapeutically targeting FP epitopes.

  16. Restricted sample variance reduces generalizability.

    PubMed

    Lakes, Kimberley D

    2013-06-01

    One factor that affects the reliability of observed scores is restriction of range on the construct measured for a particular group of study participants. This study illustrates how researchers can use generalizability theory to evaluate the impact of restriction of range in particular sample characteristics on the generalizability of test scores and to estimate how changes in measurement design could improve the generalizability of the test scores. An observer-rated measure of child self-regulation (Response to Challenge Scale; Lakes, 2011) is used to examine scores for 198 children (Grades K through 5) within the generalizability theory (GT) framework. The generalizability of ratings within relatively developmentally homogeneous samples is examined and illustrates the effect of reduced variance among ratees on generalizability. Forecasts for g coefficients of various D study designs demonstrate how higher generalizability could be achieved by increasing the number of raters or items. In summary, the research presented illustrates the importance of and procedures for evaluating the generalizability of a set of scores in a particular research context.

  17. VARIANCE OF MICROSOMAL PROTEIN AND ...

    EPA Pesticide Factsheets

    Differences in the pharmacokinetics of xenobiotics among humans makes them differentially susceptible to risk. Differences in enzyme content can mediate pharmacokinetic differences. Microsomal protein is often isolated fromliver to characterize enzyme content and activity, but no measures exist to extrapolate these data to the intact liver. Measures were developed from up to 60 samples of adult human liver to characterize the content of microsomal protein and cytochrome P450 (CYP) enzymes. Statistical evaluations are necessary to estimate values far from the mean value. Adult human liver contains 52.9 - 1.476 mg microsomal protein per g; 2587 - 1.84 pmoles CYP2E1 per g; and 5237 - 2.214 pmols CYP3A per g (geometric mean - geometric standard deviation). These values are useful for identifying and testing susceptibility as a function of enzyme content when used to extrapolate in vitro rates of chemical metabolism for input to physiologically based pharmacokinetic models which can then be exercised to quantify the effect of variance in enzyme expression on risk-relevant pharmacokinetic outcomes.

  18. Gene set analysis using variance component tests.

    PubMed

    Huang, Yen-Tsung; Lin, Xihong

    2013-06-28

    Gene set analyses have become increasingly important in genomic research, as many complex diseases are contributed jointly by alterations of numerous genes. Genes often coordinate together as a functional repertoire, e.g., a biological pathway/network and are highly correlated. However, most of the existing gene set analysis methods do not fully account for the correlation among the genes. Here we propose to tackle this important feature of a gene set to improve statistical power in gene set analyses. We propose to model the effects of an independent variable, e.g., exposure/biological status (yes/no), on multiple gene expression values in a gene set using a multivariate linear regression model, where the correlation among the genes is explicitly modeled using a working covariance matrix. We develop TEGS (Test for the Effect of a Gene Set), a variance component test for the gene set effects by assuming a common distribution for regression coefficients in multivariate linear regression models, and calculate the p-values using permutation and a scaled chi-square approximation. We show using simulations that type I error is protected under different choices of working covariance matrices and power is improved as the working covariance approaches the true covariance. The global test is a special case of TEGS when correlation among genes in a gene set is ignored. Using both simulation data and a published diabetes dataset, we show that our test outperforms the commonly used approaches, the global test and gene set enrichment analysis (GSEA). We develop a gene set analyses method (TEGS) under the multivariate regression framework, which directly models the interdependence of the expression values in a gene set using a working covariance. TEGS outperforms two widely used methods, GSEA and global test in both simulation and a diabetes microarray data.

  19. Gene set analysis using variance component tests

    PubMed Central

    2013-01-01

    Background Gene set analyses have become increasingly important in genomic research, as many complex diseases are contributed jointly by alterations of numerous genes. Genes often coordinate together as a functional repertoire, e.g., a biological pathway/network and are highly correlated. However, most of the existing gene set analysis methods do not fully account for the correlation among the genes. Here we propose to tackle this important feature of a gene set to improve statistical power in gene set analyses. Results We propose to model the effects of an independent variable, e.g., exposure/biological status (yes/no), on multiple gene expression values in a gene set using a multivariate linear regression model, where the correlation among the genes is explicitly modeled using a working covariance matrix. We develop TEGS (Test for the Effect of a Gene Set), a variance component test for the gene set effects by assuming a common distribution for regression coefficients in multivariate linear regression models, and calculate the p-values using permutation and a scaled chi-square approximation. We show using simulations that type I error is protected under different choices of working covariance matrices and power is improved as the working covariance approaches the true covariance. The global test is a special case of TEGS when correlation among genes in a gene set is ignored. Using both simulation data and a published diabetes dataset, we show that our test outperforms the commonly used approaches, the global test and gene set enrichment analysis (GSEA). Conclusion We develop a gene set analyses method (TEGS) under the multivariate regression framework, which directly models the interdependence of the expression values in a gene set using a working covariance. TEGS outperforms two widely used methods, GSEA and global test in both simulation and a diabetes microarray data. PMID:23806107

  20. Increasing selection response by Bayesian modeling of heterogeneous environmental variances

    USDA-ARS?s Scientific Manuscript database

    Heterogeneity of environmental variance among genotypes reduces selection response because genotypes with higher variance are more likely to be selected than low-variance genotypes. Modeling heterogeneous variances to obtain weighted means corrected for heterogeneous variances is difficult in likel...

  1. Generalized Analysis of Molecular Variance

    PubMed Central

    Nievergelt, Caroline M; Libiger, Ondrej; Schork, Nicholas J

    2007-01-01

    Many studies in the fields of genetic epidemiology and applied population genetics are predicated on, or require, an assessment of the genetic background diversity of the individuals chosen for study. A number of strategies have been developed for assessing genetic background diversity. These strategies typically focus on genotype data collected on the individuals in the study, based on a panel of DNA markers. However, many of these strategies are either rooted in cluster analysis techniques, and hence suffer from problems inherent to the assignment of the biological and statistical meaning to resulting clusters, or have formulations that do not permit easy and intuitive extensions. We describe a very general approach to the problem of assessing genetic background diversity that extends the analysis of molecular variance (AMOVA) strategy introduced by Excoffier and colleagues some time ago. As in the original AMOVA strategy, the proposed approach, termed generalized AMOVA (GAMOVA), requires a genetic similarity matrix constructed from the allelic profiles of individuals under study and/or allele frequency summaries of the populations from which the individuals have been sampled. The proposed strategy can be used to either estimate the fraction of genetic variation explained by grouping factors such as country of origin, race, or ethnicity, or to quantify the strength of the relationship of the observed genetic background variation to quantitative measures collected on the subjects, such as blood pressure levels or anthropometric measures. Since the formulation of our test statistic is rooted in multivariate linear models, sets of variables can be related to genetic background in multiple regression-like contexts. GAMOVA can also be used to complement graphical representations of genetic diversity such as tree diagrams (dendrograms) or heatmaps. We examine features, advantages, and power of the proposed procedure and showcase its flexibility by using it to analyze a

  2. Generalized analysis of molecular variance.

    PubMed

    Nievergelt, Caroline M; Libiger, Ondrej; Schork, Nicholas J

    2007-04-06

    Many studies in the fields of genetic epidemiology and applied population genetics are predicated on, or require, an assessment of the genetic background diversity of the individuals chosen for study. A number of strategies have been developed for assessing genetic background diversity. These strategies typically focus on genotype data collected on the individuals in the study, based on a panel of DNA markers. However, many of these strategies are either rooted in cluster analysis techniques, and hence suffer from problems inherent to the assignment of the biological and statistical meaning to resulting clusters, or have formulations that do not permit easy and intuitive extensions. We describe a very general approach to the problem of assessing genetic background diversity that extends the analysis of molecular variance (AMOVA) strategy introduced by Excoffier and colleagues some time ago. As in the original AMOVA strategy, the proposed approach, termed generalized AMOVA (GAMOVA), requires a genetic similarity matrix constructed from the allelic profiles of individuals under study and/or allele frequency summaries of the populations from which the individuals have been sampled. The proposed strategy can be used to either estimate the fraction of genetic variation explained by grouping factors such as country of origin, race, or ethnicity, or to quantify the strength of the relationship of the observed genetic background variation to quantitative measures collected on the subjects, such as blood pressure levels or anthropometric measures. Since the formulation of our test statistic is rooted in multivariate linear models, sets of variables can be related to genetic background in multiple regression-like contexts. GAMOVA can also be used to complement graphical representations of genetic diversity such as tree diagrams (dendrograms) or heatmaps. We examine features, advantages, and power of the proposed procedure and showcase its flexibility by using it to analyze a

  3. Serological Evidence of Widespread Circulation of West Nile Virus and Other Flaviviruses in Equines of the Pantanal, Brazil

    PubMed Central

    Pauvolid-Corrêa, Alex; Campos, Zilca; Juliano, Raquel; Velez, Jason; Nogueira, Rita Maria Ribeiro; Komar, Nicholas

    2014-01-01

    A recent study reported neutralizing antibodies to West Nile virus (WNV) in horses from four ranches of southern Pantanal. To extend that study, a serosurvey for WNV and 11 Brazilian flaviviruses was conducted with 760 equines, 238 sheep and 61 caimans from 17 local cattle ranches. Among the tested equines, 32 were collected from a ranch where a neurologic disorder outbreak had been recently reported. The sera were initially screened by using a blocking ELISA and then titrated by 90% plaque-reduction neutralization test (PRNT90) for 12 flaviviruses. Employing the criterion of 4-fold greater titer, 78 (10.3%) equines were seropositive for Ilheus virus, 59 (7.8%) for Saint Louis encephalitis virus, 24 (3.2%) for WNV, two (0.3%) for Cacipacore virus and one (0.1%) for Rocio virus. No serological evidence was found linking the neurological disease that affected local equines to WNV. All caimans and sheep were negative by blocking ELISA for flaviviruses. There were no seropositive equines for Bussuquara, Iguape, Yellow fever and all four Dengue virus serotypes. The detection of WNV-seropositive equines in ten ranches and ILHV and SLEV-seropositive equines in fourteen ranches of two different sub-regions of Pantanal is strong evidence of widespread circulation of these flaviviruses in the region. PMID:24551266

  4. Variance in the reproductive success of dominant male mountain gorillas.

    PubMed

    Robbins, Andrew M; Gray, Maryke; Uwingeli, Prosper; Mburanumwe, Innocent; Kagoda, Edwin; Robbins, Martha M

    2014-10-01

    Using 30 years of demographic data from 15 groups, this study estimates how harem size, female fertility, and offspring survival may contribute to variance in the siring rates of dominant male mountain gorillas throughout the Virunga Volcano Region. As predicted for polygynous species, differences in harem size were the greatest source of variance in the siring rate, whereas differences in female fertility and offspring survival were relatively minor. Harem size was positively correlated with offspring survival, even after removing all known and suspected cases of infanticide, so the correlation does not seem to reflect differences in the ability of males to protect their offspring. Harem size was not significantly correlated with female fertility, which is consistent with the hypothesis that mountain gorillas have minimal feeding competition. Harem size, offspring survival, and siring rates were not significantly correlated with the proportion of dominant tenures that occurred in multimale groups versus one-male groups; even though infanticide is less likely when those tenures end in multimale groups than one-male groups. In contrast with the relatively small contribution of offspring survival to variance in the siring rates of this study, offspring survival is a major source of variance in the male reproductive success of western gorillas, which have greater predation risks and significantly higher rates of infanticide. If differences in offspring protection are less important among male mountain gorillas than western gorillas, then the relative importance of other factors may be greater for mountain gorillas. Thus, our study illustrates how variance in male reproductive success and its components can differ between closely related species.

  5. Detection of RNA from a Novel West Nile-like Virus and High Prevalence of an Insect-specific Flavivirus in Mosquitoes in the Yucatan Peninsula of Mexico

    PubMed Central

    Farfan-Ale, Jose A.; Loroño-Pino, Maria A.; Garcia-Rejon, Julian E.; Hovav, Einat; Powers, Ann M.; Lin, Ming; Dorman, Karin S.; Platt, Kenneth B.; Bartholomay, Lyric C.; Soto, Victor; Beaty, Barry J.; Lanciotti, Robert S.; Blitvich, Bradley J.

    2009-01-01

    As part of our ongoing surveillance efforts for West Nile virus (WNV) in the Yucatan Peninsula of Mexico, 96,687 mosquitoes collected from January through December 2007 were assayed by virus isolation in mammalian cells. Three mosquito pools caused cytopathic effect. Two isolates were orthobunyaviruses (Cache Valley virus and Kairi virus) and the identity of the third infectious agent was not determined. A subset of mosquitoes was also tested by reverse transcription–polymerase chain reaction (RT-PCR) using WNV-, flavivirus-, alphavirus-, and orthobunyavirus-specific primers. A total of 7,009 Culex quinquefasciatus in 210 pools were analyzed. Flavivirus RNA was detected in 146 (70%) pools, and all PCR products were sequenced. The nucleotide sequence of one PCR product was most closely related (71–73% identity) with homologous regions of several other flaviviruses, including WNV, St. Louis encephalitis virus, and Ilheus virus. These data suggest that a novel flavivirus (tentatively named T’Ho virus) is present in Mexico. The other 145 PCR products correspond to Culex flavivirus, an insect-specific flavivirus first isolated in Japan in 2003. Culex flavivirus was isolated in mosquito cells from approximately one in four homogenates tested. The genomic sequence of one isolate was determined. Surprisingly, heterogeneous sequences were identified at the distal end of the 5′ untranslated region. PMID:19141845

  6. Envelope-modified tetravalent dengue virus-like particle vaccine: implication for flavivirus vaccine design.

    PubMed

    Urakami, Akane; Ngwe Tun, Mya Myat; Moi, Meng Ling; Sakurai, Atsuko; Ishikawa, Momoko; Kuno, Sachiko; Ueno, Ryuji; Morita, Kouichi; Akahata, Wataru

    2017-09-27

    Dengue viruses (DENV) infect 50-100 million people each year. The spread of DENV-associated infections is one of the most serious public health problems worldwide, as there is no widely available vaccine or specific therapeutic for DENV infections. To address this, we developed a novel tetravalent dengue vaccine utilizing virus-like particle (VLP) technology. We created recombinant DENV1-4 VLPs by co-expressing precursor membrane (prM) and envelope (E) proteins, with a F108A mutation in the fusion loop structure of E to increase the production of VLPs in mammalian cells. Immunization with DENV1-4 VLPs as individual, monovalent vaccines elicited strong neutralization activity against each DENV serotype in mice. When immunized as a tetravalent vaccine, DENV1-4 VLPs elicited high levels of neutralization activity against all four serotypes simultaneously. The neutralization antibody response induced by the VLPs was significantly higher than DNA or recombinant E proteins immunization. Moreover, antibody-dependent enhancement (ADE) was not observed against any serotype at 1:10 serum dilution. We also demonstrated that Zika virus (ZIKV) VLP production level was enhanced by introducing the same F108A mutation in ZIKV envelope protein. Taken together, these results suggest that our strategy for DENV VLP production is applicable to other flavivirus VLP vaccine development, due to the similarity in their viral structures and describes the promising development of an effective tetravalent vaccine against the prevalent flavivirus.Importance: The dengue virus poses one of the most serious public health problems worldwide, and the incidence of diseases caused by the virus has increased dramatically. Despite decades of effort, there is no effective treatment against dengue. A safe and potent vaccine against dengue is still needed. We have developed a novel tetravalent dengue vaccine using virus-like particle (VLP) technology, which is non-infectious as it lacks viral genome

  7. Membrane Anchors of the Structural Flavivirus Proteins and Their Role in Virus Assembly

    PubMed Central

    Blazevic, Janja; Rouha, Harald; Bradt, Victoria; Heinz, Franz X.

    2016-01-01

    ABSTRACT The structural proteins of flaviviruses carry a unique set of transmembrane domains (TMDs) at their C termini that are derived from the mode of viral polyprotein processing. They function as internal signal and stop-transfer sequences during protein translation, but possible additional roles in protein interactions required during assembly and maturation of viral particles are ill defined. To shed light on the role of TMDs in these processes, we engineered a set of tick-borne encephalitis virus mutants in which these structural elements were replaced in different combinations by the homologous sequences of a distantly related flavivirus (Japanese encephalitis virus). The effects of these modifications were analyzed with respect to protein synthesis, viral particle secretion, specific infectivity, and acidic-pH-induced maturation processes. We provide evidence that interactions involving the double-membrane anchor of the envelope protein E (a unique feature compared to other viral fusion proteins) contribute substantially to particle assembly, stability, and maturation. Disturbances of the inter- and intra-TMD interactions of E resulted in the secretion of a larger proportion of capsidless subviral particles at the expense of whole virions, suggesting a possible role in the still incompletely understood mechanism of capsid integration during virus budding. In contrast, the TMD initially anchoring the C protein to the endoplasmic reticulum membrane does not appear to take part in envelope protein interactions. We also show that E TMDs are involved in the envelope protein rearrangements that are triggered by acidic pH in the trans-Golgi network and represent a hallmark of virus maturation. IMPORTANCE The assembly of flaviviruses occurs in the endoplasmic reticulum and leads to the formation of immature, noninfectious particles composed of an RNA-containing capsid surrounded by a lipid membrane, with the two integrated envelope proteins, prM and E, arranged in

  8. Formation of the flavivirus envelope: role of the viral NS2B-NS3 protease.

    PubMed Central

    Yamshchikov, V F; Compans, R W

    1995-01-01

    One of the late processing events in the flavivirus replication cycle involves cleavage of the intracellular form of the flavivirus capsid protein (Cint) to the mature virion form (Cvir) lacking the carboxy-terminal stretch of hydrophobic amino acids which serves as a signal peptide for the downstream prM protein. This cleavage event was hypothesized to be effected by a viral protease and to be associated with virion formation. We have proposed a model of flavivirus virion formation in which processing of the C-prM precursor at the upstream signalase site is upregulated by interaction of the NS2B part of the protease with the prM signal peptide or with an adjacent carboxy-terminal region of the capsid protein in the precursor, and processing of Cint by the NS2B-NS3 protease follows the signalase cleavage. Recently, an alternative hypothesis was proposed which suggests a reverse order of these two cleavage events, namely, that cleavage of the C-prM precursor by the NS2B-NS3 protease at the Cint-->Cvir dibasic cleavage site is a prerequisite for the subsequent signalase cleavage of the prM signal peptide. To distinguish between these alternative models, we prepared a series of expression cassettes carrying mutations at the Cint-->Cvir dibasic cleavage site and investigated the effects of these mutations on signalase processing of C-prM and on formation and secretion of prM-E heterodimers. For certain mutated C-prM precursors, namely, for those with Lys-->Gly disruption of the dibasic site, efficient formation of prM was observed upon expression from larger cassettes encoding the viral protease, despite the absence of processing at the Cint-->Cvir cleavage site. Surprisingly, formation and secretion of prM-E heterodimers accompanied by late cleavage of prM was also observed for these cassettes, with an efficiency comparable to that of the wild-type expression cassette. These observations contradict the model in which cleavage of the C-prM precursor at the Cint

  9. The Impact of Prior Flavivirus Infections on the Development of Type 2 Diabetes Among the Indigenous Australians.

    PubMed

    Sorenson, Alanna; Owens, Leigh; Caltabiano, Marie; Cadet-James, Yvonne; Hall, Roy; Govan, Brenda; Clancy, Paula

    2016-08-03

    It is estimated that 5% of Australians over the age of 18 have diabetes, with the number of new cases increasing every year. Type 2 diabetes (T2D) also represents a significant disease burden in the Australian indigenous population, where prevalence is three times greater than that of non-indigenous Australians. Prevalence of T2D has been found to be higher in rural and remote indigenous Australian populations compared with urban indigenous Australian populations. Several studies have also found that body mass index and waist circumference are not appropriate for the prediction of T2D risk in indigenous Australians. Regional and remote areas of Australia are endemic for a variety of mosquito-borne flaviviruses. Studies that have investigated seroprevalence of flaviviruses in remote aboriginal communities have found high proportions of seroconversion. The family Flaviviridae comprises several genera of viruses with non-segmented single-stranded positive sense RNA genomes, and includes the flaviviruses and hepaciviruses. Hepatitis C virus (HCV) has been shown to be associated with insulin resistance and subsequent development of T2D. Flaviviruses and HCV possess conserved proteins and subgenomic RNA structures that may play similar roles in the development of insulin resistance. Although dietary and lifestyle factors are associated with increased risk of developing T2D, the impact of infectious diseases such as arboviruses has not been assessed. Flaviviruses circulating in indigenous Australian communities may play a significant role in inducing glucose intolerance and exacerbating T2D. © The American Society of Tropical Medicine and Hygiene.

  10. Understanding the role of microRNAs in the interaction of Aedes aegypti mosquitoes with an insect-specific flavivirus.

    PubMed

    Lee, Morris; Etebari, Kayvan; Hall-Mendelin, Sonja; van den Hurk, Andrew F; Hobson-Peters, Jody; Vatipally, Sreenu; Schnettler, Esther; Hall, Roy; Asgari, Sassan

    2017-07-01

    The Flavivirus genus contains some of the most prevalent vector-borne viruses, such as the dengue, Zika and yellow fever viruses that cause devastating diseases in humans. However, the insect-specific clade of flaviviruses is restricted to mosquito hosts, albeit they have retained the general features of the genus, such as genome structure and replication. The interactions between insect-specific flaviviruses (ISFs) and their mosquito hosts are largely unknown. Pathogenic flaviviruses are known to modulate host-derived microRNAs (miRNAs), a class of non-coding RNAs that are important in controlling gene expression. Alterations in miRNAs may represent changes in host gene expression and promote understanding of virus-host interactions. The role of miRNAs in ISF-mosquito interactions is largely unknown. A recently discovered Australian ISF, Palm Creek virus (PCV), has the ability to suppress medically relevant flaviviruses. Here, we investigated the potential involvement of miRNAs in PCV infection using the model mosquito Aedes aegypti. By combining small-RNA sequencing and bioinformatics analysis, differentially expressed miRNAs were determined. Our results indicated that PCV infection hardly affects host miRNAs. Out of 101 reported miRNAs of Ae. aegypti, only aae-miR-2940-5p had a significantly altered expression over the course of infection. However, further analysis of aae-miR-2940-5p revealed that this miRNA does not have any direct impact on PCV replication in vitro. Thus, overall the results suggest that PCV infection has a limited effect on the mosquito miRNA profile and therefore miRNAs may not play a significant role in the PCV-Ae. aegypti interaction.

  11. Increased spatial variance accompanies reorganization of two continental shelf ecosystems.

    PubMed

    Litzow, Michael A; Urban, J Daniel; Laurel, Benjamin J

    2008-09-01

    Phase transitions between alternate stable states in marine ecosystems lead to disruptive changes in ecosystem services, especially fisheries productivity. We used trawl survey data spanning phase transitions in the North Pacific (Gulf of Alaska) and the North Atlantic (Scotian Shelf) to test for increases in ecosystem variability that might provide early warning of such transitions. In both time series, elevated spatial variability in a measure of community composition (ratio of cod [Gadus sp.] abundance to prey abundance) accompanied transitions between ecosystem states, and variability was negatively correlated with distance from the ecosystem transition point. In the Gulf of Alaska, where the phase transition was apparently the result of a sudden perturbation (climate regime shift), variance increased one year before the transition in mean state occurred. On the Scotian Shelf, where ecosystem reorganization was the result of persistent overfishing, a significant increase in variance occurred three years before the transition in mean state was detected. However, we could not reject the alternate explanation that increased variance may also have simply been inherent to the final stable state in that ecosystem. Increased variance has been previously observed around transition points in models, but rarely in real ecosystems, and our results demonstrate the possible management value in tracking the variance of key parameters in exploited ecosystems.

  12. Right versus left symmetry of ulnar variance. A radiographic assessment.

    PubMed

    Freedman, D M; Edwards, G S; Willems, M J; Meals, R A

    1998-09-01

    One hundred skeletally mature healthy volunteers underwent standardized bilateral posteroanterior radiographs in unloaded (static) and loaded (dynamic) conditions to determine the symmetry of ulnar variance. The mean age was 32 +/- 9 years (range, 19-61 years), with 58 women and 42 men. Ulnar variance was measured to the closest 0.5 mm using the method of perpendiculars. Three separate measurements were made of each radiograph in a blinded fashion by the same investigator. An intraobserver standard deviation of 0.21 was used to calculate a 95% tolerance interval of 0.7 mm (rounded up to 1 mm) as a measure of significance. The average static ulnar variance was -0.13 +/- 1.5 mm on the left and -0.29 +/- 1.6 mm on the right. The average dynamic ulnar variance was 0.93 +/- 1.5 mm on the left and 0.82 +/- 1.5 mm on the right. When compared individually, there was a greater than or equal to 1 mm side to side difference in 37% of volunteers under static and 38% under dynamic conditions. There were no significant correlations between ulnar variance measurements and patient age, gender, race, or handedness. Use of the normal wrist radiograph as a baseline for static radial length measurements is valid in only 63% of cases.

  13. Practice reduces task relevant variance modulation and forms nominal trajectory

    NASA Astrophysics Data System (ADS)

    Osu, Rieko; Morishige, Ken-Ichi; Nakanishi, Jun; Miyamoto, Hiroyuki; Kawato, Mitsuo

    2015-12-01

    Humans are capable of achieving complex tasks with redundant degrees of freedom. Much attention has been paid to task relevant variance modulation as an indication of online feedback control strategies to cope with motor variability. Meanwhile, it has been discussed that the brain learns internal models of environments to realize feedforward control with nominal trajectories. Here we examined trajectory variance in both spatial and temporal domains to elucidate the relative contribution of these control schemas. We asked subjects to learn reaching movements with multiple via-points, and found that hand trajectories converged to stereotyped trajectories with the reduction of task relevant variance modulation as learning proceeded. Furthermore, variance reduction was not always associated with task constraints but was highly correlated with the velocity profile. A model assuming noise both on the nominal trajectory and motor command was able to reproduce the observed variance modulation, supporting an expression of nominal trajectories in the brain. The learning-related decrease in task-relevant modulation revealed a reduction in the influence of optimal feedback around the task constraints. After practice, the major part of computation seems to be taken over by the feedforward controller around the nominal trajectory with feedback added only when it becomes necessary.

  14. Practice reduces task relevant variance modulation and forms nominal trajectory.

    PubMed

    Osu, Rieko; Morishige, Ken-ichi; Nakanishi, Jun; Miyamoto, Hiroyuki; Kawato, Mitsuo

    2015-12-07

    Humans are capable of achieving complex tasks with redundant degrees of freedom. Much attention has been paid to task relevant variance modulation as an indication of online feedback control strategies to cope with motor variability. Meanwhile, it has been discussed that the brain learns internal models of environments to realize feedforward control with nominal trajectories. Here we examined trajectory variance in both spatial and temporal domains to elucidate the relative contribution of these control schemas. We asked subjects to learn reaching movements with multiple via-points, and found that hand trajectories converged to stereotyped trajectories with the reduction of task relevant variance modulation as learning proceeded. Furthermore, variance reduction was not always associated with task constraints but was highly correlated with the velocity profile. A model assuming noise both on the nominal trajectory and motor command was able to reproduce the observed variance modulation, supporting an expression of nominal trajectories in the brain. The learning-related decrease in task-relevant modulation revealed a reduction in the influence of optimal feedback around the task constraints. After practice, the major part of computation seems to be taken over by the feedforward controller around the nominal trajectory with feedback added only when it becomes necessary.

  15. 40 CFR 59.106 - Variance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... VOLATILE ORGANIC COMPOUND EMISSION STANDARDS FOR CONSUMER AND COMMERCIAL PRODUCTS National Volatile Organic Compound Emission Standards for Automobile Refinish Coatings § 59.106 Variance. (a) Any regulated...

  16. 40 CFR 59.106 - Variance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... VOLATILE ORGANIC COMPOUND EMISSION STANDARDS FOR CONSUMER AND COMMERCIAL PRODUCTS National Volatile Organic Compound Emission Standards for Automobile Refinish Coatings § 59.106 Variance. (a) Any regulated...

  17. 40 CFR 59.106 - Variance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... VOLATILE ORGANIC COMPOUND EMISSION STANDARDS FOR CONSUMER AND COMMERCIAL PRODUCTS National Volatile Organic Compound Emission Standards for Automobile Refinish Coatings § 59.106 Variance. (a) Any regulated...

  18. 40 CFR 59.106 - Variance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... VOLATILE ORGANIC COMPOUND EMISSION STANDARDS FOR CONSUMER AND COMMERCIAL PRODUCTS National Volatile Organic Compound Emission Standards for Automobile Refinish Coatings § 59.106 Variance. (a) Any regulated...

  19. 40 CFR 59.106 - Variance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... VOLATILE ORGANIC COMPOUND EMISSION STANDARDS FOR CONSUMER AND COMMERCIAL PRODUCTS National Volatile Organic Compound Emission Standards for Automobile Refinish Coatings § 59.106 Variance. (a) Any regulated...

  20. The phenotypic variance gradient - a novel concept.

    PubMed

    Pertoldi, Cino; Bundgaard, Jørgen; Loeschcke, Volker; Barker, James Stuart Flinton

    2014-11-01

    Evolutionary ecologists commonly use reaction norms, which show the range of phenotypes produced by a set of genotypes exposed to different environments, to quantify the degree of phenotypic variance and the magnitude of plasticity of morphometric and life-history traits. Significant differences among the values of the slopes of the reaction norms are interpreted as significant differences in phenotypic plasticity, whereas significant differences among phenotypic variances (variance or coefficient of variation) are interpreted as differences in the degree of developmental instability or canalization. We highlight some potential problems with this approach to quantifying phenotypic variance and suggest a novel and more informative way to plot reaction norms: namely "a plot of log (variance) on the y-axis versus log (mean) on the x-axis, with a reference line added". This approach gives an immediate impression of how the degree of phenotypic variance varies across an environmental gradient, taking into account the consequences of the scaling effect of the variance with the mean. The evolutionary implications of the variation in the degree of phenotypic variance, which we call a "phenotypic variance gradient", are discussed together with its potential interactions with variation in the degree of phenotypic plasticity and canalization.

  1. An updated review of avian-origin Tembusu virus: a newly emerging avian Flavivirus.

    PubMed

    Zhang, Wei; Chen, Shun; Mahalingam, Suresh; Wang, Mingshu; Cheng, Anchun

    2017-09-06

    Tembusu virus (TMUV, genus Flavivirus, family Flaviviridae) was first isolated in 1955 from Culex tritaeniorhynchus mosquitoes in Kuala Lumpur, Malaysia. In April 2010, duck TMUV was first identified as the causative agent of egg-drop syndrome, characterized by a substantial decrease in egg laying and depression, growth retardation and neurological signs or death in infected egg-laying and breeder ducks, in the People's Republic of China. Since 2010, duck TMUV has spread to most of the duck-producing regions in China, including many of the coastal provinces, neighbouring regions and certain Southeast Asia areas (i.e. Thailand and Malaysia). This review describes the current understanding of the genome characteristics, host range, transmission, epidemiology, phylogenetic and immune evasion of avian-origin TMUV and the innate immune response of the host.

  2. Seroprevalence of St. Louis Encephalitis Virus and West Nile Virus (Flavivirus, Flaviviridae) in Horses, Uruguay

    PubMed Central

    Burgueño, Analía; Spinsanti, Lorena; Díaz, Luis Adrián; Rivarola, María Elisa; Arbiza, Juan; Contigiani, Marta

    2013-01-01

    St. Louis encephalitis virus (SLEV) and West Nile virus (WNV) belong to the Japanese encephalitis antigenic complex (Flavivirus genus, Flaviviridae family). They show antigenic close relationships and share many similarities in their ecology. Both are responsible for serious human diseases. The aim of this study was to investigate the presence of neutralizing antibodies to these viruses in horses from Uruguay. To do this, 425 horse sera were collected in 2007 and analyzed by plaque reduction neutralization tests. As a result, 205 sera (48.2%) were found positive for SLEV, with titers ranging between 10 and 80. Two sera remained inconclusive, since they showed low titers to WNV and SLEV (10 and 20), not allowing us to demonstrate activity of WNV in our territory. This is the first report of circulation of SLEV in horses in Uruguay. PMID:24490165

  3. The Flavivirus Precursor Membrane-Envelope Protein Complex: Structure and Maturation

    SciTech Connect

    Li, Long; Lok, Shee-Mei; Yu, I-Mei; Zhang, Ying; Kuhn, Richard J.; Chen, Jue; Rossmann, Michael G.

    2008-09-17

    Many viruses go through a maturation step in the final stages of assembly before being transmitted to another host. The maturation process of flaviviruses is directed by the proteolytic cleavage of the precursor membrane protein (prM), turning inert virus into infectious particles. We have determined the 2.2 angstrom resolution crystal structure of a recombinant protein in which the dengue virus prM is linked to the envelope glycoprotein E. The structure represents the prM-E heterodimer and fits well into the cryo-electron microscopy density of immature virus at neutral pH. The pr peptide {beta}-barrel structure covers the fusion loop in E, preventing fusion with host cell membranes. The structure provides a basis for identifying the stages of its pH-directed conformational metamorphosis during maturation, ending with release of pr when budding from the host.

  4. Peptide Inhibitors of Flavivirus Entry Derived from the E Protein Stem▿ †

    PubMed Central

    Schmidt, Aaron G.; Yang, Priscilla L.; Harrison, Stephen C.

    2010-01-01

    Peptides derived from the “stem” of dengue virus (DV) type 2 (DV2) envelope (E) protein inhibit DV2 infectivity, targeting a late-stage fusion intermediate. We show here that stem peptides from all DV serotypes cross-inhibit DV1 to DV4 but that corresponding peptides derived from related flaviviruses do not. This failure to inhibit infection is not due to poor interaction with the E protein but rather to loss of association with the virion membrane. Residues 442 to 444 of the stem are determinants of inhibition; increasing hydrophobicity in this region increases inhibitory strength. These results support a two-step model of how stem-derived peptides inhibit viral entry. PMID:20881042

  5. Molecular characterization of three Zika flaviviruses obtained from sylvatic mosquitoes in the Central African Republic.

    PubMed

    Berthet, Nicolas; Nakouné, Emmanuel; Kamgang, Basile; Selekon, Benjamin; Descorps-Declère, Stéphane; Gessain, Antoine; Manuguerra, Jean-Claude; Kazanji, Mirdad

    2014-12-01

    Zika virus (ZIKV) is an emerging pathogen belonging to the Spondweni serocomplex within the genus Flavivirus. It has been isolated from several mosquito species. Two lineages of ZIKV have been defined by polyprotein homology. Using high-throughput sequencing, we obtained and characterized three complete genomes of ZIKV isolated between 1976 and 1980 in the Central African Republic. The three viruses were isolated from two species of mosquito, Aedes africanus and Ae. opok. Two sequences from Ae. africanus had 99.9% nucleotide sequence identity and 100% amino acid identity, whereas the complete genome obtained from Ae. opok had 98.3% nucleotide identity and 99.4% amino acid identity with the other two genomes. Phylogenetic analysis based on the amino acid sequence of the polyprotein showed that the three ZIKV strains clustered together but diverged from all other ZIKV strains. Our molecular data suggest that a different subtype of West African ZIKV strains circulated in Aedes species in Central Africa.

  6. flowVS: channel-specific variance stabilization in flow cytometry

    DOE PAGES

    Azad, Ariful; Rajwa, Bartek; Pothen, Alex

    2016-07-28

    Comparing phenotypes of heterogeneous cell populations from multiple biological conditions is at the heart of scientific discovery based on flow cytometry (FC). When the biological signal is measured by the average expression of a biomarker, standard statistical methods require that variance be approximately stabilized in populations to be compared. Since the mean and variance of a cell population are often correlated in fluorescence-based FC measurements, a preprocessing step is needed to stabilize the within-population variances.

  7. Rational design of a flavivirus vaccine by abolishing viral RNA 2'-O methylation.

    PubMed

    Li, Shi-Hua; Dong, Hongping; Li, Xiao-Feng; Xie, Xuping; Zhao, Hui; Deng, Yong-Qiang; Wang, Xiao-Yu; Ye, Qing; Zhu, Shun-Ya; Wang, Hong-Jiang; Zhang, Bo; Leng, Qi-Bin; Zuest, Roland; Qin, E-De; Qin, Cheng-Feng; Shi, Pei-Yong

    2013-05-01

    Viruses that replicate in the cytoplasm cannot access the host nuclear capping machinery. These viruses have evolved viral methyltransferase(s) to methylate N-7 and 2'-O cap of their RNA; alternatively, they "snatch" host mRNA cap to form the 5' end of viral RNA. The function of 2'-O methylation of viral RNA cap is to mimic cellular mRNA and to evade host innate immune restriction. A cytoplasmic virus defective in 2'-O methylation is replicative, but its viral RNA lacks 2'-O methylation and is recognized and eliminated by the host immune response. Such a mutant virus could be rationally designed as a live attenuated vaccine. Here, we use Japanese encephalitis virus (JEV), an important mosquito-borne flavivirus, to prove this novel vaccine concept. We show that JEV methyltransferase is responsible for both N-7 and 2'-O cap methylations as well as evasion of host innate immune response. Recombinant virus completely defective in 2'-O methylation was stable in cell culture after being passaged for >30 days. The mutant virus was attenuated in mice, elicited robust humoral and cellular immune responses, and retained the engineered mutation in vivo. A single dose of immunization induced full protection against lethal challenge with JEV strains in mice. Mechanistically, the attenuation phenotype was attributed to the enhanced sensitivity of the mutant virus to the antiviral effects of interferon and IFIT proteins. Collectively, the results demonstrate the feasibility of using 2'-O methylation-defective virus as a vaccine approach; this vaccine approach should be applicable to other flaviviruses and nonflaviviruses that encode their own viral 2'-O methyltransferases.

  8. Identification and analysis of truncated and elongated species of the flavivirus NS1 protein.

    PubMed

    Blitvich, B J; Scanlon, D; Shiell, B J; Mackenzie, J S; Hall, R A

    1999-03-01

    The flavivirus non-structural glycoprotein NS1 is often detected in Western blots as a heterogeneous cluster of bands due to glycosylation variations, precursor-product relationships and/or alternative cleavage sites in the viral polyprotein. In this study, we determined the basis of structural heterogeneity of the NS1 protein of Murray Valley encephalitis virus (MVE) by glycosylation analysis, pulse-chase experiments and terminal amino acid sequencing. Inhibition of N-linked glycosylation by tunicamycin revealed that NS1 synthesised in MVE-infected C6/36 cells was derived from two polypeptide backbones of 39 kDa (NS1(o)) and 47 kDa (NS1'). Pulse-chase experiments established that no precursor-product relationship existed between NS1(o) and NS1' and that both were stable end products. Terminal sequencing revealed that the N- and C-termini of NS1(o) were located at amino acid positions 714 and 1145 in the polyprotein respectively, consistent with the predicted sites based upon sequence homology with other flaviviruses. Expression of the NS1 gene alone or in conjunction with NS2A by recombinant baculoviruses demonstrated that the production of NS1' was dependent on the presence of NS2A, indicating that the C-terminus of the larger protein was generated within NS2A. A smaller form (31 kDa) of NS1 (deltaNS1) was also identified in MVE-infected Vero cultures, and amino acid sequencing revealed a 120-residue truncation at the N-terminus of this protein. This corresponds closely with the in-frame 121-codon deletion at the 5' end of the NS1 gene of defective MVE viral RNA (described by Lancaster et al. in 1998), suggesting that deltaNS1 may be a translation product of defective viral RNA.

  9. Transmission of West Nile Virus by Culex quinquefasciatus Say Infected with Culex Flavivirus Izabal

    PubMed Central

    Kent, Rebekah J.; Crabtree, Mary B.; Miller, Barry R.

    2010-01-01

    Background The natural history and potential impact of mosquito-specific flaviviruses on the transmission efficiency of West Nile virus (WNV) is unknown. The objective of this study was to determine whether or not prior infection with Culex flavivirus (CxFV) Izabal altered the vector competence of Cx. quinquefasciatus Say for transmission of a co-circulating strain of West Nile virus (WNV) from Guatemala. Methods and Findings CxFV-negative Culex quinquefasciatus and those infected with CxFV Izabal by intrathoracic inoculation were administered WNV-infectious blood meals. Infection, dissemination, and transmission of WNV were measured by plaque titration on Vero cells of individual mosquito bodies, legs, or saliva, respectively, two weeks following WNV exposure. Additional groups of Cx. quinquefasciatus were intrathoracically inoculated with WNV alone or WNV+CxFV Izabal simultaneously, and saliva collected nine days post inoculation. Growth of WNV in Aedes albopictus C6/36 cells or Cx. quinquefasciatus was not inhibited by prior infection with CxFV Izabal. There was no significant difference in the vector competence of Cx. quinquefasciatus for WNV between mosquitoes uninfected or infected with CxFV Izabal across multiple WNV blood meal titers and two colonies of Cx. quinquefasciatus (p>0.05). However, significantly more Cx. quinquefasciatus from Honduras that were co-inoculated simultaneously with both viruses transmitted WNV than those inoculated with WNV alone (p = 0.0014). Co-inoculated mosquitoes that transmitted WNV also contained CxFV in their saliva, whereas mosquitoes inoculated with CxFV alone did not contain virus in their saliva. Conclusions In the sequential infection experiments, prior infection with CxFV Izabal had no significant impact on WNV replication, infection, dissemination, or transmission by Cx. quinquefasciatus, however WNV transmission was enhanced in the Honduras colony when mosquitoes were inoculated simultaneously with both viruses

  10. Rational Design of a Flavivirus Vaccine by Abolishing Viral RNA 2′-O Methylation

    PubMed Central

    Li, Shi-Hua; Dong, Hongping; Li, Xiao-Feng; Xie, Xuping; Zhao, Hui; Deng, Yong-Qiang; Wang, Xiao-Yu; Ye, Qing; Zhu, Shun-Ya; Wang, Hong-Jiang; Zhang, Bo; Leng, Qi-Bin; Zuest, Roland; Qin, E-De

    2013-01-01

    Viruses that replicate in the cytoplasm cannot access the host nuclear capping machinery. These viruses have evolved viral methyltransferase(s) to methylate N-7 and 2′-O cap of their RNA; alternatively, they “snatch” host mRNA cap to form the 5′ end of viral RNA. The function of 2′-O methylation of viral RNA cap is to mimic cellular mRNA and to evade host innate immune restriction. A cytoplasmic virus defective in 2′-O methylation is replicative, but its viral RNA lacks 2′-O methylation and is recognized and eliminated by the host immune response. Such a mutant virus could be rationally designed as a live attenuated vaccine. Here, we use Japanese encephalitis virus (JEV), an important mosquito-borne flavivirus, to prove this novel vaccine concept. We show that JEV methyltransferase is responsible for both N-7 and 2′-O cap methylations as well as evasion of host innate immune response. Recombinant virus completely defective in 2′-O methylation was stable in cell culture after being passaged for >30 days. The mutant virus was attenuated in mice, elicited robust humoral and cellular immune responses, and retained the engineered mutation in vivo. A single dose of immunization induced full protection against lethal challenge with JEV strains in mice. Mechanistically, the attenuation phenotype was attributed to the enhanced sensitivity of the mutant virus to the antiviral effects of interferon and IFIT proteins. Collectively, the results demonstrate the feasibility of using 2′-O methylation-defective virus as a vaccine approach; this vaccine approach should be applicable to other flaviviruses and nonflaviviruses that encode their own viral 2′-O methyltransferases. PMID:23487465

  11. Flaviviruses as a Cause of Undifferentiated Fever in Sindh Province, Pakistan: A Preliminary Report

    PubMed Central

    Khan, Erum; Farooqi, Joveria Q.; Barr, Kelli L.; Prakoso, Dhani; Nasir, Amna; Kanji, Akbar; Shakoor, Sadia; Malik, Faisal Riaz; Hasan, Rumina; Lednicky, John A.; Long, Maureen T.

    2016-01-01

    Arboviral diseases are expanding worldwide, yet global surveillance is often limited due to diplomatic and cultural barriers between nations. With human encroachment into new habitats, mosquito-borne viruses are also invading new areas. The actual prevalence of expanding arboviruses is unknown in Pakistan due to inappropriate diagnosis and poor testing for arboviral diseases. The primary objective of this study was to document evidence of flavivirus infections as the cause of undifferentiated fever in Pakistan. Through a cooperative effort between the USA and Pakistan, patient exposure to dengue virus (DENV), West Nile virus (WNV), and Japanese encephalitis virus (JEV) was examined in Sindh Province for the first time in decades. Initial results from the 2015 arbovirus season consisting of a cross-sectional study of 467 patients in 5 sites, DENV NS1 antigen was identified in 63 of the screened subjects, WNV IgM antibodies in 16 patients, and JEV IgM antibodies in 32 patients. In addition, a number of practical findings were made including (1) in silico optimization of RT-PCR primers for flavivirus strains circulating in the Middle East, (2) shipping and storage of RT-PCR master mix and other reagents at ambient temperature, (3) Smart phone applications for the collection of data in areas with limited infrastructure, and (4) fast and reliable shipping for transport of reagents and specimens to and from the Middle East. Furthermore, this work is producing a group of highly trained local scientists and medical professionals disseminating modern scientific methods and more accurate diagnostic procedures to the community. PMID:26909342

  12. Nonlinear Epigenetic Variance: Review and Simulations

    ERIC Educational Resources Information Center

    Kan, Kees-Jan; Ploeger, Annemie; Raijmakers, Maartje E. J.; Dolan, Conor V.; van Der Maas, Han L. J.

    2010-01-01

    We present a review of empirical evidence that suggests that a substantial portion of phenotypic variance is due to nonlinear (epigenetic) processes during ontogenesis. The role of such processes as a source of phenotypic variance in human behaviour genetic studies is not fully appreciated. In addition to our review, we present simulation studies…

  13. 40 CFR 142.41 - Variance request.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ....41 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) NATIONAL PRIMARY DRINKING WATER REGULATIONS IMPLEMENTATION Variances Issued by the Administrator Under Section 1415(a) of the Act § 142.41 Variance request. A supplier of water may request the granting of...

  14. 40 CFR 142.41 - Variance request.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ....41 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) NATIONAL PRIMARY DRINKING WATER REGULATIONS IMPLEMENTATION Variances Issued by the Administrator Under Section 1415(a) of the Act § 142.41 Variance request. A supplier of water may request the granting of...

  15. Variance Design and Air Pollution Control

    ERIC Educational Resources Information Center

    Ferrar, Terry A.; Brownstein, Alan B.

    1975-01-01

    Air pollution control authorities were forced to relax air quality standards during the winter of 1972 by granting variances. This paper examines the institutional characteristics of these variance policies from an economic incentive standpoint, sets up desirable structural criteria for institutional design and arrives at policy guidelines for…

  16. 20 CFR 654.402 - Variances.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... EMPLOYMENT SERVICE SYSTEM Housing for Agricultural Workers Purpose and Applicability § 654.402 Variances. (a... which the employer has taken to protect the health and safety of workers and adequately show that such... the health and safety of the workers. The RA shall send the approved variance to the employer and...

  17. 20 CFR 654.402 - Variances.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... EMPLOYMENT SERVICE SYSTEM Housing for Agricultural Workers Purpose and Applicability § 654.402 Variances. (a... which the employer has taken to protect the health and safety of workers and adequately show that such... the health and safety of the workers. The RA shall send the approved variance to the employer and...

  18. 20 CFR 654.402 - Variances.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... EMPLOYMENT SERVICE SYSTEM Housing for Agricultural Workers Purpose and Applicability § 654.402 Variances. (a... which the employer has taken to protect the health and safety of workers and adequately show that such... the health and safety of the workers. The RA shall send the approved variance to the employer and...

  19. 20 CFR 654.402 - Variances.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... EMPLOYMENT SERVICE SYSTEM Housing for Agricultural Workers Purpose and Applicability § 654.402 Variances. (a... which the employer has taken to protect the health and safety of workers and adequately show that such... the health and safety of the workers. The RA shall send the approved variance to the employer and...

  20. 20 CFR 654.402 - Variances.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... EMPLOYMENT SERVICE SYSTEM Housing for Agricultural Workers Purpose and Applicability § 654.402 Variances. (a... which the employer has taken to protect the health and safety of workers and adequately show that such... the health and safety of the workers. The RA shall send the approved variance to the employer and...

  1. 10 CFR 851.31 - Variance process.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... and health standard and, in addition to the content required by paragraph (c) of this section, must.... Contractors desiring a variance from a safety and health standard, or portion thereof, may submit a written... standard, or portion thereof, from which the contractor seeks a variance; (4) A description of the steps...

  2. 10 CFR 851.31 - Variance process.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... and health standard and, in addition to the content required by paragraph (c) of this section, must.... Contractors desiring a variance from a safety and health standard, or portion thereof, may submit a written... standard, or portion thereof, from which the contractor seeks a variance; (4) A description of the steps...

  3. 10 CFR 851.31 - Variance process.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... and health standard and, in addition to the content required by paragraph (c) of this section, must.... Contractors desiring a variance from a safety and health standard, or portion thereof, may submit a written... standard, or portion thereof, from which the contractor seeks a variance; (4) A description of the steps...

  4. 10 CFR 1022.16 - Variances.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 4 2012-01-01 2012-01-01 false Variances. 1022.16 Section 1022.16 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) COMPLIANCE WITH FLOODPLAIN AND WETLAND ENVIRONMENTAL REVIEW REQUIREMENTS Procedures for Floodplain and Wetland Reviews § 1022.16 Variances. (a) Emergency actions. DOE may...

  5. 10 CFR 1022.16 - Variances.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 4 2014-01-01 2014-01-01 false Variances. 1022.16 Section 1022.16 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) COMPLIANCE WITH FLOODPLAIN AND WETLAND ENVIRONMENTAL REVIEW REQUIREMENTS Procedures for Floodplain and Wetland Reviews § 1022.16 Variances. (a) Emergency actions. DOE may...

  6. 10 CFR 1022.16 - Variances.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Variances. 1022.16 Section 1022.16 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) COMPLIANCE WITH FLOODPLAIN AND WETLAND ENVIRONMENTAL REVIEW REQUIREMENTS Procedures for Floodplain and Wetland Reviews § 1022.16 Variances. (a) Emergency actions. DOE may...

  7. 10 CFR 1022.16 - Variances.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 4 2011-01-01 2011-01-01 false Variances. 1022.16 Section 1022.16 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) COMPLIANCE WITH FLOODPLAIN AND WETLAND ENVIRONMENTAL REVIEW REQUIREMENTS Procedures for Floodplain and Wetland Reviews § 1022.16 Variances. (a) Emergency actions. DOE may...

  8. 10 CFR 1022.16 - Variances.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 4 2013-01-01 2013-01-01 false Variances. 1022.16 Section 1022.16 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) COMPLIANCE WITH FLOODPLAIN AND WETLAND ENVIRONMENTAL REVIEW REQUIREMENTS Procedures for Floodplain and Wetland Reviews § 1022.16 Variances. (a) Emergency actions. DOE may...

  9. Variance Design and Air Pollution Control

    ERIC Educational Resources Information Center

    Ferrar, Terry A.; Brownstein, Alan B.

    1975-01-01

    Air pollution control authorities were forced to relax air quality standards during the winter of 1972 by granting variances. This paper examines the institutional characteristics of these variance policies from an economic incentive standpoint, sets up desirable structural criteria for institutional design and arrives at policy guidelines for…

  10. Nonlinear Epigenetic Variance: Review and Simulations

    ERIC Educational Resources Information Center

    Kan, Kees-Jan; Ploeger, Annemie; Raijmakers, Maartje E. J.; Dolan, Conor V.; van Der Maas, Han L. J.

    2010-01-01

    We present a review of empirical evidence that suggests that a substantial portion of phenotypic variance is due to nonlinear (epigenetic) processes during ontogenesis. The role of such processes as a source of phenotypic variance in human behaviour genetic studies is not fully appreciated. In addition to our review, we present simulation studies…

  11. Portfolio optimization with mean-variance model

    NASA Astrophysics Data System (ADS)

    Hoe, Lam Weng; Siew, Lam Weng

    2016-06-01

    Investors wish to achieve the target rate of return at the minimum level of risk in their investment. Portfolio optimization is an investment strategy that can be used to minimize the portfolio risk and can achieve the target rate of return. The mean-variance model has been proposed in portfolio optimization. The mean-variance model is an optimization model that aims to minimize the portfolio risk which is the portfolio variance. The objective of this study is to construct the optimal portfolio using the mean-variance model. The data of this study consists of weekly returns of 20 component stocks of FTSE Bursa Malaysia Kuala Lumpur Composite Index (FBMKLCI). The results of this study show that the portfolio composition of the stocks is different. Moreover, investors can get the return at minimum level of risk with the constructed optimal mean-variance portfolio.

  12. Variance Assistance Document: Land Disposal Restrictions Treatability Variances and Determinations of Equivalent Treatment

    EPA Pesticide Factsheets

    This document provides assistance to those seeking to submit a variance request for LDR treatability variances and determinations of equivalent treatment regarding the hazardous waste land disposal restrictions program.

  13. Small Variance in Growth Rate in Annual Plants has Large Effects on Genetic Drift

    USDA-ARS?s Scientific Manuscript database

    When plant size is strongly correlated with plant reproduction, variance in growth rates results in a lognormal distribution of seed production within a population. Fecundity variance affects effective population size (Ne), which reflects the ability of a population to maintain beneficial mutations ...

  14. Consistent Small-Sample Variances for Six Gamma-Family Measures of Ordinal Association

    ERIC Educational Resources Information Center

    Woods, Carol M.

    2009-01-01

    Gamma-family measures are bivariate ordinal correlation measures that form a family because they all reduce to Goodman and Kruskal's gamma in the absence of ties (1954). For several gamma-family indices, more than one variance estimator has been introduced. In previous research, the "consistent" variance estimator described by Cliff and…

  15. Consistent Small-Sample Variances for Six Gamma-Family Measures of Ordinal Association

    ERIC Educational Resources Information Center

    Woods, Carol M.

    2009-01-01

    Gamma-family measures are bivariate ordinal correlation measures that form a family because they all reduce to Goodman and Kruskal's gamma in the absence of ties (1954). For several gamma-family indices, more than one variance estimator has been introduced. In previous research, the "consistent" variance estimator described by Cliff and…

  16. Host Range Restriction of Insect-Specific Flaviviruses Occurs at Several Levels of the Viral Life Cycle.

    PubMed

    Junglen, Sandra; Korries, Marvin; Grasse, Wolfgang; Wieseler, Janett; Kopp, Anne; Hermanns, Kyra; León-Juárez, Moises; Drosten, Christian; Kümmerer, Beate Mareike

    2017-01-01

    The genus Flavivirus contains emerging arthropod-borne viruses (arboviruses) infecting vertebrates, as well as insect-specific viruses (ISVs) (i.e., viruses whose host range is restricted to insects). ISVs are evolutionary precursors to arboviruses. Knowledge of the nature of the ISV infection block in vertebrates could identify functions necessary for the expansion of the host range toward vertebrates. Mapping of host restrictions by complementation of ISV and arbovirus genome functions could generate knowledge critical to predicting arbovirus emergence. Here we isolated a novel flavivirus, termed Niénokoué virus (NIEV), from mosquitoes sampled in Côte d'Ivoire. NIEV groups with insect-specific flaviviruses (ISFs) in phylogeny and grows in insect cells but not in vertebrate cells. We generated an infectious NIEV cDNA clone and a NIEV reporter replicon to study growth restrictions of NIEV in comparison to yellow fever virus (YFV), for which the same tools are available. Efficient RNA replication of the NIEV reporter replicon was observed in insect cells but not in vertebrate cells. Initial translation of the input replicon RNA in vertebrate cells was functional, but RNA replication did not occur. Chimeric YFV carrying the envelope proteins of NIEV was recovered via electroporation in C6/36 insect cells but did not infect vertebrate cells, indicating a block at the level of entry. Since the YF/NIEV chimera readily produced infectious particles in insect cells but not in vertebrate cells despite efficient RNA replication, restriction is also determined at the level of assembly/release. Taking the results together, the ability of ISF to infect vertebrates is blocked at several levels, including attachment/entry and RNA replication as well as assembly/release. IMPORTANCE Most viruses of the genus Flavivirus, e.g., YFV and dengue virus, are mosquito borne and transmitted to vertebrates during blood feeding of mosquitoes. Within the last decade, an increasing number

  17. Host Range Restriction of Insect-Specific Flaviviruses Occurs at Several Levels of the Viral Life Cycle

    PubMed Central

    Junglen, Sandra; Korries, Marvin; Grasse, Wolfgang; Wieseler, Janett; Kopp, Anne; Hermanns, Kyra; León-Juárez, Moises; Drosten, Christian

    2017-01-01

    ABSTRACT The genus Flavivirus contains emerging arthropod-borne viruses (arboviruses) infecting vertebrates, as well as insect-specific viruses (ISVs) (i.e., viruses whose host range is restricted to insects). ISVs are evolutionary precursors to arboviruses. Knowledge of the nature of the ISV infection block in vertebrates could identify functions necessary for the expansion of the host range toward vertebrates. Mapping of host restrictions by complementation of ISV and arbovirus genome functions could generate knowledge critical to predicting arbovirus emergence. Here we isolated a novel flavivirus, termed Niénokoué virus (NIEV), from mosquitoes sampled in Côte d’Ivoire. NIEV groups with insect-specific flaviviruses (ISFs) in phylogeny and grows in insect cells but not in vertebrate cells. We generated an infectious NIEV cDNA clone and a NIEV reporter replicon to study growth restrictions of NIEV in comparison to yellow fever virus (YFV), for which the same tools are available. Efficient RNA replication of the NIEV reporter replicon was observed in insect cells but not in vertebrate cells. Initial translation of the input replicon RNA in vertebrate cells was functional, but RNA replication did not occur. Chimeric YFV carrying the envelope proteins of NIEV was recovered via electroporation in C6/36 insect cells but did not infect vertebrate cells, indicating a block at the level of entry. Since the YF/NIEV chimera readily produced infectious particles in insect cells but not in vertebrate cells despite efficient RNA replication, restriction is also determined at the level of assembly/release. Taking the results together, the ability of ISF to infect vertebrates is blocked at several levels, including attachment/entry and RNA replication as well as assembly/release. IMPORTANCE Most viruses of the genus Flavivirus, e.g., YFV and dengue virus, are mosquito borne and transmitted to vertebrates during blood feeding of mosquitoes. Within the last decade, an

  18. The mean and variance of phylogenetic diversity under rarefaction.

    PubMed

    Nipperess, David A; Matsen, Frederick A

    2013-06-01

    Phylogenetic diversity (PD) depends on sampling depth, which complicates the comparison of PD between samples of different depth. One approach to dealing with differing sample depth for a given diversity statistic is to rarefy, which means to take a random subset of a given size of the original sample. Exact analytical formulae for the mean and variance of species richness under rarefaction have existed for some time but no such solution exists for PD.We have derived exact formulae for the mean and variance of PD under rarefaction. We confirm that these formulae are correct by comparing exact solution mean and variance to that calculated by repeated random (Monte Carlo) subsampling of a dataset of stem counts of woody shrubs of Toohey Forest, Queensland, Australia. We also demonstrate the application of the method using two examples: identifying hotspots of mammalian diversity in Australasian ecoregions, and characterising the human vaginal microbiome.There is a very high degree of correspondence between the analytical and random subsampling methods for calculating mean and variance of PD under rarefaction, although the Monte Carlo method requires a large number of random draws to converge on the exact solution for the variance.Rarefaction of mammalian PD of ecoregions in Australasia to a common standard of 25 species reveals very different rank orderings of ecoregions, indicating quite different hotspots of diversity than those obtained for unrarefied PD. The application of these methods to the vaginal microbiome shows that a classical score used to quantify bacterial vaginosis is correlated with the shape of the rarefaction curve.The analytical formulae for the mean and variance of PD under rarefaction are both exact and more efficient than repeated subsampling. Rarefaction of PD allows for many applications where comparisons of samples of different depth is required.

  19. Distribution and Phylogenetic Comparisons of a Novel Mosquito Flavivirus Sequence Present in Culex tarsalis Mosquitoes from Western Canada with Viruses Isolated in California and Colorado

    PubMed Central

    Tyler, Shaun; Bolling, Bethany G.; Blair, Carol D.; Brault, Aaron C.; Pabbaraju, Kanti; Armijos, M. Veronica; Clark, David C.; Calisher, Charles H.; Drebot, Michael A.

    2011-01-01

    In a previous study, a new flavivirus genome sequence was identified in Culex tarsalis mosquitoes obtained in Alberta, Canada and was shown to be genetically related to but distinct from members of the insect-specific flaviviruses. Nonstructural protein 5–encoding sequences amplified from Cx. tarsalis pools from western Canada have shown a high similarity to genome sequences of novel flaviviruses isolated from mosquitoes in California and Colorado. Despite wide distribution of this virus, designated Calbertado virus, strains demonstrate a high degree of nonstructural protein 5 nucleotide (> 90%) and amino acid (> 97%) identity. The ecology and geographic range of Calbertado virus warrants further study because it may potentially influence transmission of mosquito-borne flaviviruses, including important human pathogens such as West Nile and Saint Louis encephalitis viruses. PMID:21734143

  20. Portfolio optimization using median-variance approach

    NASA Astrophysics Data System (ADS)

    Wan Mohd, Wan Rosanisah; Mohamad, Daud; Mohamed, Zulkifli

    2013-04-01

    Optimization models have been applied in many decision-making problems particularly in portfolio selection. Since the introduction of Markowitz's theory of portfolio selection, various approaches based on mathematical programming have been introduced such as mean-variance, mean-absolute deviation, mean-variance-skewness and conditional value-at-risk (CVaR) mainly to maximize return and minimize risk. However most of the approaches assume that the distribution of data is normal and this is not generally true. As an alternative, in this paper, we employ the median-variance approach to improve the portfolio optimization. This approach has successfully catered both types of normal and non-normal distribution of data. With this actual representation, we analyze and compare the rate of return and risk between the mean-variance and the median-variance based portfolio which consist of 30 stocks from Bursa Malaysia. The results in this study show that the median-variance approach is capable to produce a lower risk for each return earning as compared to the mean-variance approach.

  1. Variance estimation for stratified propensity score estimators.

    PubMed

    Williamson, E J; Morley, R; Lucas, A; Carpenter, J R

    2012-07-10

    Propensity score methods are increasingly used to estimate the effect of a treatment or exposure on an outcome in non-randomised studies. We focus on one such method, stratification on the propensity score, comparing it with the method of inverse-probability weighting by the propensity score. The propensity score--the conditional probability of receiving the treatment given observed covariates--is usually an unknown probability estimated from the data. Estimators for the variance of treatment effect estimates typically used in practice, however, do not take into account that the propensity score itself has been estimated from the data. By deriving the asymptotic marginal variance of the stratified estimate of treatment effect, correctly taking into account the estimation of the propensity score, we show that routinely used variance estimators are likely to produce confidence intervals that are too conservative when the propensity score model includes variables that predict (cause) the outcome, but only weakly predict the treatment. In contrast, a comparison with the analogous marginal variance for the inverse probability weighted (IPW) estimator shows that routinely used variance estimators for the IPW estimator are likely to produce confidence intervals that are almost always too conservative. Because exact calculation of the asymptotic marginal variance is likely to be complex, particularly for the stratified estimator, we suggest that bootstrap estimates of variance should be used in practice.

  2. Neural field theory with variance dynamics.

    PubMed

    Robinson, P A

    2013-06-01

    Previous neural field models have mostly been concerned with prediction of mean neural activity and with second order quantities such as its variance, but without feedback of second order quantities on the dynamics. Here the effects of feedback of the variance on the steady states and adiabatic dynamics of neural systems are calculated using linear neural field theory to estimate the neural voltage variance, then including this quantity in the total variance parameter of the nonlinear firing rate-voltage response function, and thus into determination of the fixed points and the variance itself. The general results further clarify the limits of validity of approaches with and without inclusion of variance dynamics. Specific applications show that stability against a saddle-node bifurcation is reduced in a purely cortical system, but can be either increased or decreased in the corticothalamic case, depending on the initial state. Estimates of critical variance scalings near saddle-node bifurcation are also found, including physiologically based normalizations and new scalings for mean firing rate and the position of the bifurcation.

  3. Selection and genetic (co)variance in bighorn sheep.

    PubMed

    Coltman, David W; O'Donoghue, Paul; Hogg, John T; Festa-Bianchet, Marco

    2005-06-01

    Genetic theory predicts that directional selection should deplete additive genetic variance for traits closely related to fitness, and may favor the maintenance of alleles with antagonistically pleiotropic effects on fitness-related traits. Trait heritability is therefore expected to decline with the degree of association with fitness, and some genetic correlations between selected traits are expected to be negative. Here we demonstrate a negative relationship between trait heritability and association with lifetime reproductive success in a wild population of bighorn sheep (Ovis canadensis) at Ram Mountain, Alberta, Canada. Lower heritability for fitness-related traits, however, was not wholly a consequence of declining genetic variance, because those traits showed high levels of residual variance. Genetic correlations estimated between pairs of traits with significant heritability were positive. Principal component analyses suggest that positive relationships between morphometric traits constitute the main axis of genetic variation. Trade-offs in the form of negative genetic or phenotypic correlations among the traits we have measured do not appear to constrain the potential for evolution in this population.

  4. Negative ulnar variance is not a risk factor for Kienböck's disease.

    PubMed

    D'Hoore, K; De Smet, L; Verellen, K; Vral, J; Fabry, G

    1994-03-01

    Ulnar variance was measured in standardized conditions in 125 normal wrists and in 52 patients with Kienböck's disease. No significant difference in ulnar variance between a sex/age-matched control group and a group of patients affected with Kienböck's disease was found. A positive correlation was found between age and ulnar variance. No significant difference was found between men and women. Based on these results, negative ulnar variance does not seem to be an important factor in the etiology of Kienböck's disease.

  5. Experimental Transmission of Karshi (Mammalian Tick-Borne Flavivirus Group) Virus by Ornithodoros Ticks >2,900 Days after Initial Virus Exposure Supports the Role of Soft Ticks as a Long-Term Maintenance Mechanism for Certain Flaviviruses

    PubMed Central

    Turell, Michael J.

    2015-01-01

    Background Members of the mammalian tick-borne flavivirus group, including tick-borne encephalitis virus, are responsible for at least 10,000 clinical cases of tick-borne encephalitis each year. To attempt to explain the long-term maintenance of members of this group, we followed Ornithodoros parkeri, O. sonrai, and O. tartakovskyi for >2,900 days after they had been exposed to Karshi virus, a member of the mammalian tick-borne flavivirus group. Methodology/Principal Findings Ticks were exposed to Karshi virus either by allowing them to feed on viremic suckling mice or by intracoelomic inoculation. The ticks were then allowed to feed individually on suckling mice after various periods of extrinsic incubation to determine their ability to transmit virus by bite and to determine how long the ticks would remain infectious. The ticks remained efficient vectors of Karshi virus, even when tested >2,900 d after their initial exposure to virus, including those ticks exposed to Karshi virus either orally or by inoculation. Conclusions/Significance Ornithodoros spp. ticks were able to transmit Karshi virus for >2,900 days (nearly 8 years) after a single exposure to a viremic mouse. Therefore, these ticks may serve as a long-term maintenance mechanism for Karshi virus and potentially other members of the mammalian tick-borne flavivirus group. PMID:26285211

  6. Encoding of natural sounds by variance of the cortical local field potential

    PubMed Central

    Simon, Jonathan Z.; Shamma, Shihab A.; David, Stephen V.

    2016-01-01

    Neural encoding of sensory stimuli is typically studied by averaging neural signals across repetitions of the same stimulus. However, recent work has suggested that the variance of neural activity across repeated trials can also depend on sensory inputs. Here we characterize how intertrial variance of the local field potential (LFP) in primary auditory cortex of awake ferrets is affected by continuous natural sound stimuli. We find that natural sounds often suppress the intertrial variance of low-frequency LFP (<16 Hz). However, the amount of the variance reduction is not significantly correlated with the amplitude of the mean response at the same recording site. Moreover, the variance changes occur with longer latency than the mean response. Although the dynamics of the mean response and intertrial variance differ, spectro-temporal receptive field analysis reveals that changes in LFP variance have frequency tuning similar to multiunit activity at the same recording site, suggesting a local origin for changes in LFP variance. In summary, the spectral tuning of LFP intertrial variance and the absence of a correlation with the amplitude of the mean evoked LFP suggest substantial heterogeneity in the interaction between spontaneous and stimulus-driven activity across local neural populations in auditory cortex. PMID:26912594

  7. Single-cell tracking of flavivirus RNA uncovers species-specific interactions with the immune system dictating disease outcome.

    PubMed

    Douam, Florian; Hrebikova, Gabriela; Albrecht, Yentli E Soto; Sellau, Julie; Sharon, Yael; Ding, Qiang; Ploss, Alexander

    2017-03-14

    Positive-sense RNA viruses pose increasing health and economic concerns worldwide. Our limited understanding of how these viruses interact with their host and how these processes lead to virulence and disease seriously hampers the development of anti-viral strategies. Here, we demonstrate the tracking of (+) and (-) sense viral RNA at single-cell resolution within complex subsets of the human and murine immune system in different mouse models. Our results provide insights into how a prototypic flavivirus, yellow fever virus (YFV-17D), differentially interacts with murine and human hematopoietic cells in these mouse models and how these dynamics influence distinct outcomes of infection. We detect (-) YFV-17D RNA in specific secondary lymphoid compartments and cell subsets not previously recognized as permissive for YFV replication, and we highlight potential virus-host interaction events that could be pivotal in regulating flavivirus virulence and attenuation.

  8. Environmental stress, inbreeding, and the nature of phenotypic and genetic variance in Drosophila melanogaster.

    PubMed Central

    Fowler, Kevin; Whitlock, Michael C

    2002-01-01

    Fifty-two lines of Drosophila melanogaster founded by single-pair population bottlenecks were used to study the effects of inbreeding and environmental stress on phenotypic variance, genetic variance and survivorship. Cold temperature and high density cause reduced survivorship, but these stresses do not cause repeatable changes in the phenotypic variance of most wing morphological traits. Wing area, however, does show increased phenotypic variance under both types of environmental stress. This increase is no greater in inbred than in outbred lines, showing that inbreeding does not increase the developmental effects of stress. Conversely, environmental stress does not increase the extent of inbreeding depression. Genetic variance is not correlated with environmental stress, although the amount of genetic variation varies significantly among environments and lines vary significantly in their response to environmental change. Drastic changes in the environment can cause changes in phenotypic and genetic variance, but not in a way reliably predicted by the notion of 'stress'. PMID:11934358

  9. Module organization and variance in protein-protein interaction networks

    NASA Astrophysics Data System (ADS)

    Lin, Chun-Yu; Lee, Tsai-Ling; Chiu, Yi-Yuan; Lin, Yi-Wei; Lo, Yu-Shu; Lin, Chih-Ta; Yang, Jinn-Moon

    2015-03-01

    A module is a group of closely related proteins that act in concert to perform specific biological functions through protein-protein interactions (PPIs) that occur in time and space. However, the underlying module organization and variance remain unclear. In this study, we collected module templates to infer respective module families, including 58,041 homologous modules in 1,678 species, and PPI families using searches of complete genomic database. We then derived PPI evolution scores and interface evolution scores to describe the module elements, including core and ring components. Functions of core components were highly correlated with those of essential genes. In comparison with ring components, core proteins/PPIs were conserved across multiple species. Subsequently, protein/module variance of PPI networks confirmed that core components form dynamic network hubs and play key roles in various biological functions. Based on the analyses of gene essentiality, module variance, and gene co-expression, we summarize the observations of module organization and variance as follows: 1) a module consists of core and ring components; 2) core components perform major biological functions and collaborate with ring components to execute certain functions in some cases; 3) core components are more conserved and essential during organizational changes in different biological states or conditions.

  10. Heritable Micro-environmental Variance Covaries with Fitness in an Outbred Population of Drosophila serrata.

    PubMed

    Sztepanacz, Jacqueline L; McGuigan, Katrina; Blows, Mark W

    2017-08-01

    The genetic basis of stochastic variation within a defined environment, and the consequences of such micro-environmental variance for fitness are poorly understood . Using a multigenerational breeding design in Drosophila serrata, we demonstrated that the micro-environmental variance in a set of morphological wing traits in a randomly mating population had significant additive genetic variance in most single wing traits. Although heritability was generally low (<1%), coefficients of additive genetic variance were of a magnitude typical of other morphological traits, indicating that the micro-environmental variance is an evolvable trait. Multivariate analyses demonstrated that the micro-environmental variance in wings was genetically correlated among single traits, indicating that common mechanisms of environmental buffering exist for this functionally related set of traits. In addition, through the dominance genetic covariance between the major axes of micro-environmental variance and fitness, we demonstrated that micro-environmental variance shares a genetic basis with fitness, and that the pattern of selection is suggestive of variance-reducing selection acting on micro-environmental variance. Copyright © 2017 by the Genetics Society of America.

  11. 40 CFR 59.206 - Variances.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... VOLATILE ORGANIC COMPOUND EMISSION STANDARDS FOR CONSUMER AND COMMERCIAL PRODUCTS National Volatile Organic Compound Emission Standards for Consumer Products § 59.206 Variances. (a) Any regulated entity who...

  12. 40 CFR 59.206 - Variances.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... VOLATILE ORGANIC COMPOUND EMISSION STANDARDS FOR CONSUMER AND COMMERCIAL PRODUCTS National Volatile Organic Compound Emission Standards for Consumer Products § 59.206 Variances. (a) Any regulated entity who...

  13. 40 CFR 59.206 - Variances.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... VOLATILE ORGANIC COMPOUND EMISSION STANDARDS FOR CONSUMER AND COMMERCIAL PRODUCTS National Volatile Organic Compound Emission Standards for Consumer Products § 59.206 Variances. (a) Any regulated entity who...

  14. 40 CFR 59.206 - Variances.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... VOLATILE ORGANIC COMPOUND EMISSION STANDARDS FOR CONSUMER AND COMMERCIAL PRODUCTS National Volatile Organic Compound Emission Standards for Consumer Products § 59.206 Variances. (a) Any regulated entity who...

  15. 40 CFR 59.206 - Variances.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... VOLATILE ORGANIC COMPOUND EMISSION STANDARDS FOR CONSUMER AND COMMERCIAL PRODUCTS National Volatile Organic Compound Emission Standards for Consumer Products § 59.206 Variances. (a) Any regulated entity who...

  16. 13 CFR 307.22 - Variances.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false Variances. 307.22 Section 307.22 Business Credit and Assistance ECONOMIC DEVELOPMENT ADMINISTRATION, DEPARTMENT OF COMMERCE ECONOMIC... Federal, State and local law. ...

  17. Reducing variance in batch partitioning measurements

    SciTech Connect

    Mariner, Paul E.

    2010-08-11

    The partitioning experiment is commonly performed with little or no attention to reducing measurement variance. Batch test procedures such as those used to measure K{sub d} values (e.g., ASTM D 4646 and EPA402 -R-99-004A) do not explain how to evaluate measurement uncertainty nor how to minimize measurement variance. In fact, ASTM D 4646 prescribes a sorbent:water ratio that prevents variance minimization. Consequently, the variance of a set of partitioning measurements can be extreme and even absurd. Such data sets, which are commonplace, hamper probabilistic modeling efforts. An error-savvy design requires adjustment of the solution:sorbent ratio so that approximately half of the sorbate partitions to the sorbent. Results of Monte Carlo simulations indicate that this simple step can markedly improve the precision and statistical characterization of partitioning uncertainty.

  18. Serosurvey of West Nile virus and other flaviviruses of the Japanese encephalitis antigenic complex in birds from Andalusia, southern Spain.

    PubMed

    García-Bocanegra, Ignacio; Busquets, Núria; Napp, Sebastián; Alba, Ana; Zorrilla, Irene; Villalba, Rubén; Arenas, Antonio

    2011-08-01

    Flaviviruses of the Japanese encephalitis virus (JEV) antigenic complex, including West Nile virus (WNV), are recognized as emerging and reemerging pathogens. Circulation of flaviviruses has been recently detected in different mosquito and vertebrate species in several European countries. A serosurvey study was carried out to evaluate the circulation of WNV and other flaviviruses of the JEV antigenic complex in different wild bird species in Spain between 2006 and 2009. Seropositiviy against JEV using a competitive enzyme-linked immunosorbent assay was found in common coot, Montagu's Harrier, black kite, black vulture, Bonelli's eagle, Spanish imperial eagle, Egyptian vulture, and Eurasian spoonbill. Seropositivity to JEV antigenic complex viruses was significantly higher in samples collected during autumn compared with animals sampled during summer. Significantly higher seroprevalence was also observed in 2007 compared with 2009, whereas there were no significant differences in seropositivity among taxonomic levels, migratory versus resident behavior, body size (large vs. medium), or habitats (free-ranging vs. captivity). Neutralizing antibodies against WNV were detected in common coot and Spanish imperial eagle using a virus-neutralization test. Oral shedding of WNV was not detected in any of the Spanish imperial eagles, Egyptian vultures, Eurasian Spoonbills, Lammergeiers, and the Black vultures analyzed by means of real-time reverse transcription-polymerase chain reaction. The results indicate that WNV and others flaviviruses of the JEV antigenic group circulated in migratory and resident wild bird species in Spain between 2007 and 2008. Further studies are necessary to determine the precise role that each of these wild bird species, some of them cataloged as "near threatened," "vulnerable," or "endangered," play in the epidemiology of those viruses.

  19. FLAVIdB: A data mining system for knowledge discovery in flaviviruses with direct applications in immunology and vaccinology.

    PubMed

    Olsen, Lars Rønn; Zhang, Guang Lan; Reinherz, Ellis L; Brusic, Vladimir

    2011-01-01

    The flavivirus genus is unusually large, comprising more than 70 species, of which more than half are known human pathogens. It includes a set of clinically relevant infectious agents such as dengue, West Nile, yellow fever, and Japanese encephalitis viruses. Although these pathogens have been studied extensively, safe and efficient vaccines lack for the majority of the flaviviruses. We have assembled a database that combines antigenic data of flaviviruses, specialized analysis tools, and workflows for automated complex analyses focusing on applications in immunology and vaccinology. FLAVIdB contains 12,858 entries of flavivirus antigen sequences, 184 verified T-cell epitopes, 201 verified B-cell epitopes, and 4 representative molecular structures of the dengue virus envelope protein. FLAVIdB was assembled by collection, annotation, and integration of data from GenBank, GenPept, UniProt, IEDB, and PDB. The data were subject to extensive quality control (redundancy elimination, error detection, and vocabulary consolidation). Further annotation of selected functionally relevant features was performed by organizing information extracted from the literature. The database was incorporated into a web-accessible data mining system, combining specialized data analysis tools for integrated analysis of relevant data categories (protein sequences, macromolecular structures, and immune epitopes). The data mining system includes tools for variability and conservation analysis, T-cell epitope prediction, and characterization of neutralizing components of B-cell epitopes. FLAVIdB is accessible at cvc.dfci.harvard.edu/flavi/ FLAVIdB represents a new generation of databases in which data and tools are integrated into a data mining infrastructures specifically designed to aid rational vaccine design by discovery of vaccine targets.

  20. FLAVIdB: A data mining system for knowledge discovery in flaviviruses with direct applications in immunology and vaccinology

    PubMed Central

    Olsen, Lars Rønn; Zhang, Guang Lan; Reinherz, Ellis L.; Brusic, Vladimir

    2013-01-01

    Background The flavivirus genus is unusually large, comprising more than 70 species, of which more than half are known human pathogens. It includes a set of clinically relevant infectious agents such as dengue, West Nile, yellow fever, and Japanese encephalitis viruses. Although these pathogens have been studied extensively, safe and efficient vaccines lack for the majority of the flaviviruses. Results We have assembled a database that combines antigenic data of flaviviruses, specialized analysis tools, and workflows for automated complex analyses focusing on applications in immunology and vaccinology. FLAVIdB contains 12,858 entries of flavivirus antigen sequences, 184 verified T-cell epitopes, 201 verified B-cell epitopes, and 4 representative molecular structures of the dengue virus envelope protein. FLAVIdB was assembled by collection, annotation, and integration of data from GenBank, GenPept, UniProt, IEDB, and PDB. The data were subject to extensive quality control (redundancy elimination, error detection, and vocabulary consolidation). Further annotation of selected functionally relevant features was performed by organizing information extracted from the literature. The database was incorporated into a web-accessible data mining system, combining specialized data analysis tools for integrated analysis of relevant data categories (protein sequences, macromolecular structures, and immune epitopes). The data mining system includes tools for variability and conservation analysis, T-cell epitope prediction, and characterization of neutralizing components of B-cell epitopes. FLAVIdB is accessible at cvc.dfci.harvard.edu/flavi/ Conclusion FLAVIdB represents a new generation of databases in which data and tools are integrated into a data mining infrastructures specifically designed to aid rational vaccine design by discovery of vaccine targets. PMID:25544857

  1. Variance components in discrete force production tasks.

    PubMed

    Varadhan, S K M; Zatsiorsky, Vladimir M; Latash, Mark L

    2010-09-01

    The study addresses the relationships between task parameters and two components of variance, "good" and "bad", during multi-finger accurate force production. The variance components are defined in the space of commands to the fingers (finger modes) and refer to variance that does ("bad") and does not ("good") affect total force. Based on an earlier study of cyclic force production, we hypothesized that speeding-up an accurate force production task would be accompanied by a drop in the regression coefficient linking the "bad" variance and force rate such that variance of the total force remains largely unaffected. We also explored changes in parameters of anticipatory synergy adjustments with speeding-up the task. The subjects produced accurate ramps of total force over different times and in different directions (force-up and force-down) while pressing with the four fingers of the right hand on individual force sensors. The two variance components were quantified, and their normalized difference was used as an index of a total force stabilizing synergy. "Good" variance scaled linearly with force magnitude and did not depend on force rate. "Bad" variance scaled linearly with force rate within each task, and the scaling coefficient did not change across tasks with different ramp times. As a result, a drop in force ramp time was associated with an increase in total force variance, unlike the results of the study of cyclic tasks. The synergy index dropped 100-200 ms prior to the first visible signs of force change. The timing and magnitude of these anticipatory synergy adjustments did not depend on the ramp time. Analysis of the data within an earlier model has shown adjustments in the variance of a timing parameter, although these adjustments were not as pronounced as in the earlier study of cyclic force production. Overall, we observed qualitative differences between the discrete and cyclic force production tasks: Speeding-up the cyclic tasks was associated with

  2. Variance Components in Discrete Force Production Tasks

    PubMed Central

    SKM, Varadhan; Zatsiorsky, Vladimir M.; Latash, Mark L.

    2010-01-01

    The study addresses the relationships between task parameters and two components of variance, “good” and “bad”, during multi-finger accurate force production. The variance components are defined in the space of commands to the fingers (finger modes) and refer to variance that does (“bad”) and does not (“good”) affect total force. Based on an earlier study of cyclic force production, we hypothesized that speeding-up an accurate force production task would be accompanied by a drop in the regression coefficient linking the “bad” variance and force rate such that variance of the total force remains largely unaffected. We also explored changes in parameters of anticipatory synergy adjustments with speeding-up the task. The subjects produced accurate ramps of total force over different times and in different directions (force-up and force-down) while pressing with the four fingers of the right hand on individual force sensors. The two variance components were quantified, and their normalized difference was used as an index of a total force stabilizing synergy. “Good” variance scaled linearly with force magnitude and did not depend on force rate. “Bad” variance scaled linearly with force rate within each task, and the scaling coefficient did not change across tasks with different ramp times. As a result, a drop in force ramp time was associated with an increase in total force variance, unlike the results of the study of cyclic tasks. The synergy index dropped 100-200 ms prior to the first visible signs of force change. The timing and magnitude of these anticipatory synergy adjustments did not depend on the ramp time. Analysis of the data within an earlier model has shown adjustments in the variance of a timing parameter, although these adjustments were not as pronounced as in the earlier study of cyclic force production. Overall, we observed qualitative differences between the discrete and cyclic force production tasks: Speeding-up the cyclic

  3. Phonocardiographic diagnosis of aortic ball variance.

    PubMed

    Hylen, J C; Kloster, F E; Herr, R H; Hull, P Q; Ames, A W; Starr, A; Griswold, H E

    1968-07-01

    Fatty infiltration causing changes in the silastic poppet of the Model 1000 series Starr-Edwards aortic valve prostheses (ball variance) has been detected with increasing frequency and can result in sudden death. Phonocardiograms were recorded on 12 patients with ball variance confirmed by operation and of 31 controls. Ten of the 12 patients with ball variance were distinguished from the controls by an aortic opening sound (AO) less than half as intense as the aortic closure sound (AC) at the second right intercostal space (AO/AC ratio less than 0.5). Both AO and AC were decreased in two patients with ball variance, with the loss of the characteristic high frequency and amplitude of these sounds. The only patient having a diminished AO/AC ratio (0.42) without ball variance at reoperation had a clot extending over the aortic valve struts. The phonocardiographic findings have been the most reliable objective evidence of ball variance in patients with Starr-Edwards aortic prosthesis of the Model 1000 series.

  4. Variational bayesian method of estimating variance components.

    PubMed

    Arakawa, Aisaku; Taniguchi, Masaaki; Hayashi, Takeshi; Mikawa, Satoshi

    2016-07-01

    We developed a Bayesian analysis approach by using a variational inference method, a so-called variational Bayesian method, to determine the posterior distributions of variance components. This variational Bayesian method and an alternative Bayesian method using Gibbs sampling were compared in estimating genetic and residual variance components from both simulated data and publically available real pig data. In the simulated data set, we observed strong bias toward overestimation of genetic variance for the variational Bayesian method in the case of low heritability and low population size, and less bias was detected with larger population sizes in both methods examined. The differences in the estimates of variance components between the variational Bayesian and the Gibbs sampling were not found in the real pig data. However, the posterior distributions of the variance components obtained with the variational Bayesian method had shorter tails than those obtained with the Gibbs sampling. Consequently, the posterior standard deviations of the genetic and residual variances of the variational Bayesian method were lower than those of the method using Gibbs sampling. The computing time required was much shorter with the variational Bayesian method than with the method using Gibbs sampling. © 2016 Japanese Society of Animal Science.

  5. Effect of initial variance of microstructures on grain growth under mean curvature

    NASA Astrophysics Data System (ADS)

    Baskaran, Arun; Crist, David; Lewis, Daniel

    2017-09-01

    Surface Evolver was used to simulate grain growth under motion by mean curvature starting with non-uniform microstructures. The study was conducted for different microstructures that begin evolving with an identical mean grain area and a differing value of statistical variance of the grain areas. Correlation between a microstructure’s initial variance, a geometric property of the polycrystalline network, and its growth rate in the normal regime was studied. It was observed that the microstructures evolved at different growth rates. The microstructures with the largest and smallest variances evolved with highest and lowest growth rates. The analysis was performed in the normal grain growth regime. It is observed that a direct correlation can be made between the initial variance of the microstructure and its growth rate in the normal regime. These results highlight the importance of including the grain size variance when controlling microstructure using non-uniform thermal fields.

  6. Identifying Candidate Targets of Immune Responses in Zika Virus Based on Homology to Epitopes in Other Flavivirus Species.

    PubMed

    Xu, Xiaojun; Vaughan, Kerrie; Weiskopf, Daniela; Grifoni, Alba; Diamond, Michael S; Sette, Alessandro; Peters, Bjoern

    2016-11-15

    The current outbreak of Zika virus has resulted in a massive effort to accelerate the development of ZIKV-specific diagnostics and vaccines. These efforts would benefit greatly from the definition of the specific epitope targets of immune responses in ZIKV, but given the relatively recent emergence of ZIKV as a pandemic threat, few such data are available. We used a large body of epitope data for other Flaviviruses that was available from the IEDB for a comparative analysis against the ZIKV proteome in order to project targets of immune responses in ZIKV. We found a significant level of overlap between known antigenic sites from other Flavivirus proteins with residues on the ZIKV polyprotein. The E and NS1 proteins shared functional antibody epitope sites, whereas regions of T cell reactivity were conserved within NS3 and NS5 for ZIKV.  Discussion: Our epitope based analysis provides guidance for which regions of the ZIKV polyprotein are most likely unique targets of ZIKV-specific antibodies, and which targets in ZIKV are most likely to be cross-reactive with other Flavivirus species. These data may therefore provide insights for the development of antibody- and T cell-based ZIKV-specific diagnostics, therapeutics and prophylaxis.

  7. A conserved region in the prM protein is a critical determinant in the assembly of flavivirus particles.

    PubMed

    Yoshii, Kentaro; Igarashi, Manabu; Ichii, Osamu; Yokozawa, Kana; Ito, Kimihito; Kariwa, Hiroaki; Takashima, Ikuo

    2012-01-01

    Flaviviruses are assembled to bud into the lumen of the endoplasmic reticulum (ER) and are secreted through the vesicle transport pathway, but the details of the molecular mechanism of virion assembly remain largely unknown. In this study, a highly conserved region in the prM protein was identified among flaviviruses. In the subviral particle (SP) system of tick-borne encephalitis virus (TBEV) and Japanese encephalitis virus, secretion of SPs was impaired by a mutation in the conserved region in the prM protein. Viral proteins were sparse in the Golgi complex and accumulated in the ER. Ultrastructural analysis revealed that long filamentous structures, rather than spherical SPs, were observed in the lumen of the ER as a result of the mutation. The production of infectious virions derived from infectious cDNA of TBEV was also reduced by mutations in the conserved region. Molecular modelling analysis suggested that the conserved region is important for the association of prM-envelope protein heterodimers in the formation of a spike of immature virion. These results are the first demonstration that the conserved region in the prM protein is a molecular determinant for the flavivirus assembly process.

  8. Sequence, structure and function relationships in flaviviruses as assessed by evolutive aspects of its conserved non-structural protein domains.

    PubMed

    da Fonseca, Néli José; Lima Afonso, Marcelo Querino; Pedersolli, Natan Gonçalves; de Oliveira, Lucas Carrijo; Andrade, Dhiego Souto; Bleicher, Lucas

    2017-01-11

    Flaviviruses are responsible for serious diseases such as dengue, yellow fever, and zika fever. Their genomes encode a polyprotein which, after cleavage, results in three structural and seven non-structural proteins. Homologous proteins can be studied by conservation and coevolution analysis as detected in multiple sequence alignments, usually reporting positions which are strictly necessary for the structure and/or function of all members in a protein family or which are involved in a specific sub-class feature requiring the coevolution of residue sets. This study provides a complete conservation and coevolution analysis on all flaviviruses non-structural proteins, with results mapped on all well-annotated available sequences. A literature review on the residues found in the analysis enabled us to compile available information on their roles and distribution among different flaviviruses. Also, we provide the mapping of conserved and coevolved residues for all sequences currently in SwissProt as a supplementary material, so that particularities in different viruses can be easily analyzed. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Identifying Candidate Targets of Immune Responses in Zika Virus Based on Homology to Epitopes in Other Flavivirus Species

    PubMed Central

    Xu, Xiaojun; Vaughan, Kerrie; Weiskopf, Daniela; Grifoni, Alba; Diamond, Michael S.; Sette, Alessandro; Peters, Bjoern

    2016-01-01

    Introduction: The current outbreak of Zika virus has resulted in a massive effort to accelerate the development of ZIKV-specific diagnostics and vaccines. These efforts would benefit greatly from the definition of the specific epitope targets of immune responses in ZIKV, but given the relatively recent emergence of ZIKV as a pandemic threat, few such data are available. Methods: We used a large body of epitope data for other Flaviviruses that was available from the IEDB for a comparative analysis against the ZIKV proteome in order to project targets of immune responses in ZIKV. Results: We found a significant level of overlap between known antigenic sites from other Flavivirus proteins with residues on the ZIKV polyprotein. The E and NS1 proteins shared functional antibody epitope sites, whereas regions of T cell reactivity were conserved within NS3 and NS5 for ZIKV.  Discussion: Our epitope based analysis provides guidance for which regions of the ZIKV polyprotein are most likely unique targets of ZIKV-specific antibodies, and which targets in ZIKV are most likely to be cross-reactive with other Flavivirus species. These data may therefore provide insights for the development of antibody- and T cell-based ZIKV-specific diagnostics, therapeutics and prophylaxis. PMID:28018746

  10. Variance of wind estimates using spaced antenna techniques with the MU radar

    NASA Astrophysics Data System (ADS)

    Hassenpflug, G.; Yamamoto, M.; Fukao, S.

    2004-11-01

    Variance of horizontal wind estimates in conditions of anisotropic scattering are obtained for the Spaced Antenna (SA) Full Correlation Analysis (FCA) method of Holloway et al. (1997b) and Doviak et al. (1996), but are equally applicable to the Briggs method of FCA. Variance and covariance of cross-correlation magnitudes are theoretically estimated, and the standard theory of error propagation is used to estimate the variance of the wind components for the infinite SNR case. The effect of baseline orientation is investigated, and experimental data from the MU radar in Japan is presented.

  11. Antagonism of the complement component C4 by flavivirus nonstructural protein NS1

    PubMed Central

    Avirutnan, Panisadee; Fuchs, Anja; Hauhart, Richard E.; Somnuke, Pawit; Youn, Soonjeon

    2010-01-01

    The complement system plays an essential protective role in the initial defense against many microorganisms. Flavivirus NS1 is a secreted nonstructural glycoprotein that accumulates in blood, is displayed on the surface of infected cells, and has been hypothesized to have immune evasion functions. Herein, we demonstrate that dengue virus (DENV), West Nile virus (WNV), and yellow fever virus (YFV) NS1 attenuate classical and lectin pathway activation by directly interacting with C4. Binding of NS1 to C4 reduced C4b deposition and C3 convertase (C4b2a) activity. Although NS1 bound C4b, it lacked intrinsic cofactor activity to degrade C4b, and did not block C3 convertase formation or accelerate decay of the C3 and C5 convertases. Instead, NS1 enhanced C4 cleavage by recruiting and activating the complement-specific protease C1s. By binding C1s and C4 in a complex, NS1 promotes efficient degradation of C4 to C4b. Through this mechanism, NS1 protects DENV from complement-dependent neutralization in solution. These studies define a novel immune evasion mechanism for restricting complement control of microbial infection. PMID:20308361

  12. Generation of long flavivirus expression cassettes by in vivo recombination and transient dominant selection.

    PubMed

    Yamshchikov, V F; Compans, R W

    1994-11-18

    Assembly of expression cassettes coding for large segments of viral polyproteins is often complicated or impossible due to the instability of the resulting recombinant (re-) plasmids during propagation in Escherichia coli. Using the transient dominant selection approach described for the construction of vaccinia virus recombinants (re-VV), we have constructed several intermediate vectors and developed a procedure which enables direct assembly of long expression cassettes in the VV genome by in vivo recombination and does not require preliminary assembly of long cassettes in intermediate plasmids, thus eliminating the instability problems. The procedure was used to construct re-VV carrying fragments of the West Nile (WN), Murray Valley encephalitis (MVE), tick-borne encephalitis (TBE) and dengue type-2 (DEN2) viral genomes. Using this procedure, we have assembled a WN expression cassette which represents 86% of the WN genome and codes for 91% of its polyprotein and constitutes the longest flavivirus (FV) expression cassette inserted so far into the VV genome. Analysis of FV protein expression from the obtained recombinants indicates that recombination occurs with a high degree of specificity and the ORF remains intact. The procedure described offers a possible approach for the assembly of infectious cDNA clones.

  13. Structural Differences Observed in Arboviruses of the Alphavirus and Flavivirus Genera

    PubMed Central

    Hernandez, Raquel; Brown, Dennis T.; Paredes, Angel

    2014-01-01

    Arthropod borne viruses have developed a complex life cycle adapted to alternate between insect and vertebrate hosts. These arthropod-borne viruses belong mainly to the families Togaviridae, Flaviviridae, and Bunyaviridae. This group of viruses contains many pathogens that cause febrile, hemorrhagic, and encephalitic disease or arthritic symptoms which can be persistent. It has been appreciated for many years that these viruses were evolutionarily adapted to function in the highly divergent cellular environments of both insect and mammalian phyla. These viruses are hybrid in nature, containing viral-encoded RNA and proteins which are glycosylated by the host and encapsulate viral nucleocapsids in the context of a host-derived membrane. From a structural perspective, these virus particles are macromolecular machines adapted in design to assemble into a packaging and delivery system for the virus genome and, only when associated with the conditions appropriate for a productive infection, to disassemble and deliver the RNA cargo. It was initially assumed that the structures of the virus from both hosts were equivalent. New evidence that alphaviruses and flaviviruses can exist in more than one conformation postenvelopment will be discussed in this review. The data are limited but should refocus the field of structural biology on the metastable nature of these viruses. PMID:25309597

  14. Transmission bottlenecks and RNAi collectively influence tick-borne flavivirus evolution

    PubMed Central

    Grubaugh, Nathan D.; Rückert, Claudia; Armstrong, Philip M.; Bransfield, Angela; Anderson, John F.; Ebel, Gregory D.; Brackney, Doug E.

    2016-01-01

    Arthropod-borne RNA viruses exist within hosts as heterogeneous populations of viral variants and, as a result, possess great genetic plasticity. Understanding the micro-evolutionary forces shaping these viruses can provide insights into how they emerge, adapt, and persist in new and changing ecological niches. While considerable attention has been directed toward studying the population dynamics of mosquito-borne viruses, little is known about tick-borne virus populations. Therefore, using a mouse and Ixodes scapularis tick transmission model, we examined Powassan virus (POWV; Flaviviridae, Flavivirus) populations in and between both the vertebrate host and arthropod vector. We found that genetic bottlenecks, RNAi-mediated diversification, and selective constraints collectively influence POWV evolution. Together, our data provide a mechanistic explanation for the slow, long-term evolutionary trends of POWV, and suggest that all arthropod-borne viruses encounter similar selective pressures at the molecular level (i.e. RNAi), yet evolve much differently due to their unique rates and modes of transmission. PMID:28058113

  15. Eared dove (Zenaida auriculata, Columbidae) as host for St. Louis encephalitis virus (Flaviviridae, Flavivirus).

    PubMed

    Diaz, Luis A; Occelli, Maricel; Almeida, Francisco Ludueña; Almirón, Walter R; Contigiani, Marta S

    2008-04-01

    St. Louis encephalitis virus (SLEV) is an emerging Flavivirus in South American countries. Its ecology and biological transmission cycles are scarcely known. Eared doves (Zenaida auriculata) have frequently been found infected by SLEV, and therefore, could be suspected as SLEV hosts. Thirty post-hatch-year eared doves were subcutaneously inoculated with the genotype V SLEV 78V-6507 viral strain and subsequently bled. No deaths or clinical signs of illness were observed in the inoculated doves. The viremia titers ranged from 2 to 5.5 log(10) plaque-forming units (PFU)/mL during 1-7 days postinoculation (dpi), the highest being observed on the 4th dpi. Mosquitoes were collected using can traps baited with chicken and eared doves for comparison. A total of 2792 mosquitoes belonging to 5 species were collected. Ninety percent of the mosquitoes collected in eared dove-baited can traps were Culex quinquefasciatus. Statistical differences were not observed in either Cx. quinquefasciatus (Chi(2) = 0.86; df = 1; p = 0.354) or in Cx. interfor (Chi(2) = 0.63; df = 1; p = 0.426) mosquitoes collected in both chicken- and eared dove-baited can traps. Considering that eared doves were frequently found naturally infected by SLEV, that they developed viremia titers higher than the minimum infection threshold needed to infect Cx. quinquefasciatus, and that these mosquitoes also fed on eared doves, they could be considered competent hosts for SLEV.

  16. Patterns of Flavivirus Seroprevalence in the Human Population of Northern Laos

    PubMed Central

    Conlan, James V.; Vongxay, Khamphouth; Khamlome, Boualam; Jarman, Richard G.; Gibbons, Robert V.; Fenwick, Stanley G.; Thompson, R. C. A.; Blacksell, Stuart D.

    2015-01-01

    A total of 1,136 samples from 289 households in four provinces in northern Laos were subjected to Japanese encephalitis virus (JEV) and dengue virus hemagglutination inhibition (DENV HI). Overall, antibodies to JEV were detected by HI in 620 (54.6%) of 1,136 people; of which 217 (19.1%) had HI activity against JEV only. Antibodies to DENV4 were detected by HI in 526 (46.3%) of 1,136 people; of which 124 (10.9%) had HI activity against DENV4 only. Antibodies to DENV1–3 were detected by HI in 296 (26.1%), 274 (24.1%), and 283 (24.9) of 1,136 people, respectively; of which 7, 1, and 0, respectively, had HI activity against DENV1–3 only. JEV was the most prevalent Flavivirus in Oudomxay, Luangprabang, and Huaphan provinces and DENV4 was the most prevalent in Xiengkhouang province. Seroprevalence for JEV increased with increasing age and wealth and was higher in villages where rice was cultivated in paddy fields and highest for people of Lao-Tai ethnicity. PMID:26304925

  17. Wolbachia restricts insect-specific flavivirus infection in Aedes aegypti cells

    PubMed Central

    Sreenu, Vatipally B.; Mottram, Timothy; McFarlane, Melanie

    2016-01-01

    Mosquito-borne viruses are known to cause disease in humans and livestock and are often difficult to control due to the lack of specific antivirals and vaccines. The Wolbachia endosymbiont has been widely studied for its ability to restrict positive-strand RNA virus infection in mosquitoes, although little is known about the precise antiviral mechanism. In recent years, a variety of insect-specific viruses have been discovered in mosquitoes and an interaction with mosquito-borne viruses has been reported for some of them; however, nothing is known about the effect of Wolbachia on insect-specific virus infection in mosquitoes. Here, we show that transinfection of the Drosophila-derived wMelPop Wolbachia strain into Aedes aegypti-derived cells resulted in inhibition and even clearance of the persistent cell-fusing agent flavivirus infection in these cells. This broadens the antiviral activity of Wolbachia from acute infections to persistent infections and from arboviruses to mosquito-specific viruses. In contrast, no effect on the Phasi Charoen-like bunyavirus persistent infection in these cells was observed, suggesting a difference in Wolbachia inhibition between positive- and negative-strand RNA viruses. PMID:27692043

  18. Wolbachia restricts insect-specific flavivirus infection in Aedes aegypti cells.

    PubMed

    Schnettler, Esther; Sreenu, Vatipally B; Mottram, Timothy; McFarlane, Melanie

    2016-11-01

    Mosquito-borne viruses are known to cause disease in humans and livestock and are often difficult to control due to the lack of specific antivirals and vaccines. The Wolbachia endosymbiont has been widely studied for its ability to restrict positive-strand RNA virus infection in mosquitoes, although little is known about the precise antiviral mechanism. In recent years, a variety of insect-specific viruses have been discovered in mosquitoes and an interaction with mosquito-borne viruses has been reported for some of them; however, nothing is known about the effect of Wolbachia on insect-specific virus infection in mosquitoes. Here, we show that transinfection of the Drosophila-derived wMelPop Wolbachia strain into Aedes aegypti-derived cells resulted in inhibition and even clearance of the persistent cell-fusing agent flavivirus infection in these cells. This broadens the antiviral activity of Wolbachia from acute infections to persistent infections and from arboviruses to mosquito-specific viruses. In contrast, no effect on the Phasi Charoen-like bunyavirus persistent infection in these cells was observed, suggesting a difference in Wolbachia inhibition between positive- and negative-strand RNA viruses.

  19. Functions of the 3' and 5' genome RNA regions of members of the genus Flavivirus.

    PubMed

    Brinton, Margo A; Basu, Mausumi

    2015-08-03

    The positive sense genomes of members of the genus Flavivirus in the family Flaviviridae are ∼ 11 kb in length and have a 5' type I cap but no 3' poly-A. The 3' and 5' terminal regions contain short conserved sequences that are proposed to be repeated remnants of an ancient sequence. However, the functions of most of these conserved sequences have not yet been determined. The terminal regions of the genome also contain multiple conserved RNA structures. Functional data for many of these structures have been obtained. Three sets of complementary 3' and 5' terminal region sequences, some of which are located in conserved RNA structures, interact to form a panhandle structure that is required for initiation of minus strand RNA synthesis with the 5' terminal structure functioning as the promoter. How the switch from the terminal RNA structure base pairing to the long distance RNA-RNA interaction is triggered and regulated is not well understood but evidence suggests involvement of a cell protein binding to three sites on the 3' terminal RNA structures and a cis-acting metastable 3' RNA element in the 3' terminal RNA structure. Cell proteins may also be involved in facilitating exponential replication of nascent genomic RNA within replication vesicles at later times of the infection cycle. Other conserved RNA structures and/or sequences in the 3' and 5' terminal regions have been proposed to regulate genome translation. Additional functions of the 3' and 5' terminal sequences have also been reported.

  20. Defining Hsp70 Subnetworks in Dengue Virus Replication Reveals Key Vulnerability in Flavivirus Infection

    PubMed Central

    Taguwa, Shuhei; Maringer, Kevin; Li, Xiaokai; Bernal-Rubio, Dabeiba; Rauch, Jennifer N.; Gestwicki, Jason E.; Andino, Raul; Fernandez-Sesma, Ana; Frydman, Judith

    2015-01-01

    Summary Viral protein homeostasis depends entirely on the machinery of the infected cell. Accordingly, viruses can illuminate the interplay between cellular proteostasis components and their distinct substrates. Here we define how the Hsp70 chaperone network mediates the dengue virus life cycle. Cytosolic Hsp70 isoforms are required at distinct steps of the viral cycle, including entry, RNA replication and virion biogenesis. Hsp70 function at each step is specified by nine distinct DNAJ cofactors. Of these, DnaJB11 relocalizes to virus-induced replication complexes to promote RNA synthesis, while DnaJB6 associates with capsid protein and facilitates virion biogenesis. Importantly, an allosteric Hsp70 inhibitor, JG40, potently blocks infection of different dengue serotypes in human primary blood cells without eliciting viral resistance or exerting toxicity to the host cells. JG40 also blocks replication of other medically-important flaviviruses including yellow fever, West Nile and Japanese encephalitis viruses. Thus, targeting host Hsp70 subnetworks provides a path for broad-spectrum antivirals. PMID:26582131

  1. Response variance in functional maps: neural darwinism revisited.

    PubMed

    Takahashi, Hirokazu; Yokota, Ryo; Kanzaki, Ryohei

    2013-01-01

    The mechanisms by which functional maps and map plasticity contribute to cortical computation remain controversial. Recent studies have revisited the theory of neural Darwinism to interpret the learning-induced map plasticity and neuronal heterogeneity observed in the cortex. Here, we hypothesize that the Darwinian principle provides a substrate to explain the relationship between neuron heterogeneity and cortical functional maps. We demonstrate in the rat auditory cortex that the degree of response variance is closely correlated with the size of its representational area. Further, we show that the response variance within a given population is altered through training. These results suggest that larger representational areas may help to accommodate heterogeneous populations of neurons. Thus, functional maps and map plasticity are likely to play essential roles in Darwinian computation, serving as effective, but not absolutely necessary, structures to generate diverse response properties within a neural population.

  2. Response Variance in Functional Maps: Neural Darwinism Revisited

    PubMed Central

    Takahashi, Hirokazu; Yokota, Ryo; Kanzaki, Ryohei

    2013-01-01

    The mechanisms by which functional maps and map plasticity contribute to cortical computation remain controversial. Recent studies have revisited the theory of neural Darwinism to interpret the learning-induced map plasticity and neuronal heterogeneity observed in the cortex. Here, we hypothesize that the Darwinian principle provides a substrate to explain the relationship between neuron heterogeneity and cortical functional maps. We demonstrate in the rat auditory cortex that the degree of response variance is closely correlated with the size of its representational area. Further, we show that the response variance within a given population is altered through training. These results suggest that larger representational areas may help to accommodate heterogeneous populations of neurons. Thus, functional maps and map plasticity are likely to play essential roles in Darwinian computation, serving as effective, but not absolutely necessary, structures to generate diverse response properties within a neural population. PMID:23874733

  3. flowVS: channel-specific variance stabilization in flow cytometry.

    PubMed

    Azad, Ariful; Rajwa, Bartek; Pothen, Alex

    2016-07-28

    Comparing phenotypes of heterogeneous cell populations from multiple biological conditions is at the heart of scientific discovery based on flow cytometry (FC). When the biological signal is measured by the average expression of a biomarker, standard statistical methods require that variance be approximately stabilized in populations to be compared. Since the mean and variance of a cell population are often correlated in fluorescence-based FC measurements, a preprocessing step is needed to stabilize the within-population variances. We present a variance-stabilization algorithm, called flowVS, that removes the mean-variance correlations from cell populations identified in each fluorescence channel. flowVS transforms each channel from all samples of a data set by the inverse hyperbolic sine (asinh) transformation. For each channel, the parameters of the transformation are optimally selected by Bartlett's likelihood-ratio test so that the populations attain homogeneous variances. The optimum parameters are then used to transform the corresponding channels in every sample. flowVS is therefore an explicit variance-stabilization method that stabilizes within-population variances in each channel by evaluating the homoskedasticity of clusters with a likelihood-ratio test. With two publicly available datasets, we show that flowVS removes the mean-variance dependence from raw FC data and makes the within-population variance relatively homogeneous. We demonstrate that alternative transformation techniques such as flowTrans, flowScape, logicle, and FCSTrans might not stabilize variance. Besides flow cytometry, flowVS can also be applied to stabilize variance in microarray data. With a publicly available data set we demonstrate that flowVS performs as well as the VSN software, a state-of-the-art approach developed for microarrays. The homogeneity of variance in cell populations across FC samples is desirable when extracting features uniformly and comparing cell populations with

  4. Discrimination of frequency variance for tonal sequences.

    PubMed

    Byrne, Andrew J; Viemeister, Neal F; Stellmack, Mark A

    2014-12-01

    Real-world auditory stimuli are highly variable across occurrences and sources. The present study examined the sensitivity of human listeners to differences in global stimulus variability. In a two-interval, forced-choice task, variance discrimination was measured using sequences of five 100-ms tone pulses. The frequency of each pulse was sampled randomly from a distribution that was Gaussian in logarithmic frequency. In the non-signal interval, the sampled distribution had a variance of σSTAN (2), while in the signal interval, the variance of the sequence was σSIG (2) (with σSIG (2) >  σSTAN (2)). The listener's task was to choose the interval with the larger variance. To constrain possible decision strategies, the mean frequency of the sampling distribution of each interval was randomly chosen for each presentation. Psychometric functions were measured for various values of σSTAN (2). Although the performance was remarkably similar across listeners, overall performance was poorer than that of an ideal observer (IO) which perfectly compares interval variances. However, like the IO, Weber's Law behavior was observed, with a constant ratio of ( σSIG (2)- σSTAN (2)) to σSTAN (2) yielding similar performance. A model which degraded the IO with a frequency-resolution noise and a computational noise provided a reasonable fit to the real data.

  5. Variance estimation for nucleotide substitution models.

    PubMed

    Chen, Weishan; Wang, Hsiuying

    2015-09-01

    The current variance estimators for most evolutionary models were derived when a nucleotide substitution number estimator was approximated with a simple first order Taylor expansion. In this study, we derive three variance estimators for the F81, F84, HKY85 and TN93 nucleotide substitution models, respectively. They are obtained using the second order Taylor expansion of the substitution number estimator, the first order Taylor expansion of a squared deviation and the second order Taylor expansion of a squared deviation, respectively. These variance estimators are compared with the existing variance estimator in terms of a simulation study. It shows that the variance estimator, which is derived using the second order Taylor expansion of a squared deviation, is more accurate than the other three estimators. In addition, we also compare these estimators with an estimator derived by the bootstrap method. The simulation shows that the performance of this bootstrap estimator is similar to the estimator derived by the second order Taylor expansion of a squared deviation. Since the latter one has an explicit form, it is more efficient than the bootstrap estimator.

  6. Insect-Specific Flaviviruses: A Systematic Review of Their Discovery, Host Range, Mode of Transmission, Superinfection Exclusion Potential and Genomic Organization

    PubMed Central

    Blitvich, Bradley J.; Firth, Andrew E.

    2015-01-01

    There has been a dramatic increase in the number of insect-specific flaviviruses (ISFs) discovered in the last decade. Historically, these viruses have generated limited interest due to their inability to infect vertebrate cells. This viewpoint has changed in recent years because some ISFs have been shown to enhance or suppress the replication of medically important flaviviruses in co-infected mosquito cells. Additionally, comparative studies between ISFs and medically important flaviviruses can provide a unique perspective as to why some flaviviruses possess the ability to infect and cause devastating disease in humans while others do not. ISFs have been isolated exclusively from mosquitoes in nature but the detection of ISF-like sequences in sandflies and chironomids indicates that they may also infect other dipterans. ISFs can be divided into two distinct phylogenetic groups. The first group currently consists of approximately 12 viruses and includes cell fusing agent virus, Kamiti River virus and Culex flavivirus. These viruses are phylogenetically distinct from all other known flaviviruses. The second group, which is apparently not monophyletic, currently consists of nine viruses and includes Chaoyang virus, Nounané virus and Lammi virus. These viruses phylogenetically affiliate with mosquito/vertebrate flaviviruses despite their apparent insect-restricted phenotype. This article provides a review of the discovery, host range, mode of transmission, superinfection exclusion ability and genomic organization of ISFs. This article also attempts to clarify the ISF nomenclature because some of these viruses have been assigned more than one name due to their simultaneous discoveries by independent research groups. PMID:25866904

  7. Cross-bispectrum computation and variance estimation

    NASA Technical Reports Server (NTRS)

    Lii, K. S.; Helland, K. N.

    1981-01-01

    A method for the estimation of cross-bispectra of discrete real time series is developed. The asymptotic variance properties of the bispectrum are reviewed, and a method for the direct estimation of bispectral variance is given. The symmetry properties are described which minimize the computations necessary to obtain a complete estimate of the cross-bispectrum in the right-half-plane. A procedure is given for computing the cross-bispectrum by subdividing the domain into rectangular averaging regions which help reduce the variance of the estimates and allow easy application of the symmetry relationships to minimize the computational effort. As an example of the procedure, the cross-bispectrum of a numerically generated, exponentially distributed time series is computed and compared with theory.

  8. Integrating Variances into an Analytical Database

    NASA Technical Reports Server (NTRS)

    Sanchez, Carlos

    2010-01-01

    For this project, I enrolled in numerous SATERN courses that taught the basics of database programming. These include: Basic Access 2007 Forms, Introduction to Database Systems, Overview of Database Design, and others. My main job was to create an analytical database that can handle many stored forms and make it easy to interpret and organize. Additionally, I helped improve an existing database and populate it with information. These databases were designed to be used with data from Safety Variances and DCR forms. The research consisted of analyzing the database and comparing the data to find out which entries were repeated the most. If an entry happened to be repeated several times in the database, that would mean that the rule or requirement targeted by that variance has been bypassed many times already and so the requirement may not really be needed, but rather should be changed to allow the variance's conditions permanently. This project did not only restrict itself to the design and development of the database system, but also worked on exporting the data from the database to a different format (e.g. Excel or Word) so it could be analyzed in a simpler fashion. Thanks to the change in format, the data was organized in a spreadsheet that made it possible to sort the data by categories or types and helped speed up searches. Once my work with the database was done, the records of variances could be arranged so that they were displayed in numerical order, or one could search for a specific document targeted by the variances and restrict the search to only include variances that modified a specific requirement. A great part that contributed to my learning was SATERN, NASA's resource for education. Thanks to the SATERN online courses I took over the summer, I was able to learn many new things about computers and databases and also go more in depth into topics I already knew about.

  9. A variance-decomposition approach to investigating multiscale habitat associations

    USGS Publications Warehouse

    Lawler, J.J.; Edwards, T.C.

    2006-01-01

    The recognition of the importance of spatial scale in ecology has led many researchers to take multiscale approaches to studying habitat associations. However, few of the studies that investigate habitat associations at multiple spatial scales have considered the potential effects of cross-scale correlations in measured habitat variables. When cross-scale correlations in such studies are strong, conclusions drawn about the relative strength of habitat associations at different spatial scales may be inaccurate. Here we adapt and demonstrate an analytical technique based on variance decomposition for quantifying the influence of cross-scale correlations on multiscale habitat associations. We used the technique to quantify the variation in nest-site locations of Red-naped Sapsuckers (Sphyrapicus nuchalis) and Northern Flickers (Colaptes auratus) associated with habitat descriptors at three spatial scales. We demonstrate how the method can be used to identify components of variation that are associated only with factors at a single spatial scale as well as shared components of variation that represent cross-scale correlations. Despite the fact that no explanatory variables in our models were highly correlated (r < 0.60), we found that shared components of variation reflecting cross-scale correlations accounted for roughly half of the deviance explained by the models. These results highlight the importance of both conducting habitat analyses at multiple spatial scales and of quantifying the effects of cross-scale correlations in such analyses. Given the limits of conventional analytical techniques, we recommend alternative methods, such as the variance-decomposition technique demonstrated here, for analyzing habitat associations at multiple spatial scales. ?? The Cooper Ornithological Society 2006.

  10. Variance in binary stellar population synthesis

    NASA Astrophysics Data System (ADS)

    Breivik, Katelyn; Larson, Shane L.

    2016-03-01

    In the years preceding LISA, Milky Way compact binary population simulations can be used to inform the science capabilities of the mission. Galactic population simulation efforts generally focus on high fidelity models that require extensive computational power to produce a single simulated population for each model. Each simulated population represents an incomplete sample of the functions governing compact binary evolution, thus introducing variance from one simulation to another. We present a rapid Monte Carlo population simulation technique that can simulate thousands of populations in less than a week, thus allowing a full exploration of the variance associated with a binary stellar evolution model.

  11. Variance Reduction Using Nonreversible Langevin Samplers.

    PubMed

    Duncan, A B; Lelièvre, T; Pavliotis, G A

    A standard approach to computing expectations with respect to a given target measure is to introduce an overdamped Langevin equation which is reversible with respect to the target distribution, and to approximate the expectation by a time-averaging estimator. As has been noted in recent papers [30, 37, 61, 72], introducing an appropriately chosen nonreversible component to the dynamics is beneficial, both in terms of reducing the asymptotic variance and of speeding up convergence to the target distribution. In this paper we present a detailed study of the dependence of the asymptotic variance on the deviation from reversibility. Our theoretical findings are supported by numerical simulations.

  12. A Simple Algorithm for Approximating Confidence on the Modified Allan Variance and the Time Variance

    NASA Technical Reports Server (NTRS)

    Weiss, Marc A.; Greenhall, Charles A.

    1996-01-01

    An approximating algorithm for computing equvalent degrees of freedom of the Modified Allan Variance and its square root, the Modified Allan Deviation (MVAR and MDEV), and the Time Variance and Time Deviation (TVAR and TDEV) is presented, along with an algorithm for approximating the inverse chi-square distribution.

  13. A Simple Algorithm for Approximating Confidence on the Modified Allan Variance and the Time Variance

    NASA Technical Reports Server (NTRS)

    Weiss, Marc A.; Greenhall, Charles A.

    1996-01-01

    An approximating algorithm for computing equvalent degrees of freedom of the Modified Allan Variance and its square root, the Modified Allan Deviation (MVAR and MDEV), and the Time Variance and Time Deviation (TVAR and TDEV) is presented, along with an algorithm for approximating the inverse chi-square distribution.

  14. Molecular archaeology of Flaviviridae untranslated regions: duplicated RNA structures in the replication enhancer of flaviviruses and pestiviruses emerged via convergent evolution.

    PubMed

    Gritsun, Dmitri J; Jones, Ian M; Gould, Ernest A; Gritsun, Tamara S

    2014-01-01

    RNA secondary structures in the 3'untranslated regions (3'UTR) of the viruses of the family Flaviviridae, previously identified as essential (promoters) or beneficial (enhancers) for replication, have been analysed. Duplicated enhancer elements are revealed as a global feature in the evolution of the 3'UTR of distantly related viruses within the genera Flavivirus and Pestivirus. For the flaviviruses, duplicated structures occur in the 3'UTR of all four distantly related ecological virus subgroups (tick-borne, mosquito-borne, no known vector and insect-specific flaviviruses (ISFV). RNA structural differences distinguish tick-borne flaviviruses with discrete pathogenetic characteristics. For Aedes- and Culex-associated ISFV, secondary RNA structures with different conformations display numerous short ssRNA direct repeats, exposed as loops and bulges. Long quadruplicate regions comprise almost the entire 3'UTR of Culex-associated ISFV. Extended duplicated sequence and associated RNA structures were also discovered in the 3'UTR of pestiviruses. In both the Flavivirus and Pestivirus genera, duplicated RNA structures were localized to the enhancer regions of the 3'UTR suggesting an adaptive role predominantly in wild-type viruses. We propose sequence reiteration might act as a scaffold for dimerization of proteins involved in assembly of viral replicase complexes. Numerous nucleotide repeats exposed as loops/bulges might also interfere with host immune responses acting as a molecular sponge to sequester key host proteins or microRNAs.

  15. 10 CFR 1021.343 - Variances.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Variances. 1021.343 Section 1021.343 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) NATIONAL ENVIRONMENTAL POLICY ACT IMPLEMENTING PROCEDURES Implementing... arrangements for emergency actions having significant environmental impacts. DOE shall document,...

  16. Regression calibration with heteroscedastic error variance.

    PubMed

    Spiegelman, Donna; Logan, Roger; Grove, Douglas

    2011-01-01

    The problem of covariate measurement error with heteroscedastic measurement error variance is considered. Standard regression calibration assumes that the measurement error has a homoscedastic measurement error variance. An estimator is proposed to correct regression coefficients for covariate measurement error with heteroscedastic variance. Point and interval estimates are derived. Validation data containing the gold standard must be available. This estimator is a closed-form correction of the uncorrected primary regression coefficients, which may be of logistic or Cox proportional hazards model form, and is closely related to the version of regression calibration developed by Rosner et al. (1990). The primary regression model can include multiple covariates measured without error. The use of these estimators is illustrated in two data sets, one taken from occupational epidemiology (the ACE study) and one taken from nutritional epidemiology (the Nurses' Health Study). In both cases, although there was evidence of moderate heteroscedasticity, there was little difference in estimation or inference using this new procedure compared to standard regression calibration. It is shown theoretically that unless the relative risk is large or measurement error severe, standard regression calibration approximations will typically be adequate, even with moderate heteroscedasticity in the measurement error model variance. In a detailed simulation study, standard regression calibration performed either as well as or better than the new estimator. When the disease is rare and the errors normally distributed, or when measurement error is moderate, standard regression calibration remains the method of choice.

  17. 21 CFR 1010.4 - Variances.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... the study was conducted in compliance with the good laboratory practice regulations set forth in part... application for variance shall include the following information: (i) A description of the product and its... equipment, the proposed location of each unit. (viii) Such other information required by regulation or...

  18. 40 CFR 142.41 - Variance request.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) NATIONAL PRIMARY DRINKING WATER REGULATIONS IMPLEMENTATION Variances Issued by the Administrator Under... primary drinking water regulations. (c) For any request made under § 142.40(a): (1) Explanation in full... alternative raw water source or improvement of existing raw water source will be completed. (ii) Date of...

  19. Formative Use of Intuitive Analysis of Variance

    ERIC Educational Resources Information Center

    Trumpower, David L.

    2013-01-01

    Students' informal inferential reasoning (IIR) is often inconsistent with the normative logic underlying formal statistical methods such as Analysis of Variance (ANOVA), even after instruction. In two experiments reported here, student's IIR was assessed using an intuitive ANOVA task at the beginning and end of a statistics course. In both…

  20. Generalized Variance Function Applications in Forestry

    Treesearch

    James Alegria; Charles T. Scott; Charles T. Scott

    1991-01-01

    Adequately predicting the sampling errors of tabular data can reduce printing costs by eliminating the need to publish separate sampling error tables. Two generalized variance functions (GVFs) found in the literature and three GVFs derived for this study were evaluated for their ability to predict the sampling error of tabular forestry estimates. The recommended GVFs...

  1. 10 CFR 1021.343 - Variances.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 4 2013-01-01 2013-01-01 false Variances. 1021.343 Section 1021.343 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) NATIONAL ENVIRONMENTAL POLICY ACT IMPLEMENTING PROCEDURES Implementing... arrangements for emergency actions having significant environmental impacts. DOE shall document, including...

  2. 10 CFR 1021.343 - Variances.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 4 2011-01-01 2011-01-01 false Variances. 1021.343 Section 1021.343 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) NATIONAL ENVIRONMENTAL POLICY ACT IMPLEMENTING PROCEDURES Implementing... arrangements for emergency actions having significant environmental impacts. DOE shall document, including...

  3. 10 CFR 1021.343 - Variances.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 4 2012-01-01 2012-01-01 false Variances. 1021.343 Section 1021.343 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) NATIONAL ENVIRONMENTAL POLICY ACT IMPLEMENTING PROCEDURES Implementing... arrangements for emergency actions having significant environmental impacts. DOE shall document, including...

  4. 10 CFR 1021.343 - Variances.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 4 2014-01-01 2014-01-01 false Variances. 1021.343 Section 1021.343 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) NATIONAL ENVIRONMENTAL POLICY ACT IMPLEMENTING PROCEDURES Implementing... arrangements for emergency actions having significant environmental impacts. DOE shall document, including...

  5. 29 CFR 1920.2 - Variances.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 7 2011-07-01 2011-07-01 false Variances. 1920.2 Section 1920.2 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) PROCEDURE FOR VARIATIONS FROM SAFETY AND HEALTH REGULATIONS UNDER THE LONGSHOREMEN'S AND HARBOR WORKERS...

  6. 29 CFR 1920.2 - Variances.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 7 2010-07-01 2010-07-01 false Variances. 1920.2 Section 1920.2 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) PROCEDURE FOR VARIATIONS FROM SAFETY AND HEALTH REGULATIONS UNDER THE LONGSHOREMEN'S AND HARBOR...

  7. Multiple Comparison Procedures when Population Variances Differ.

    ERIC Educational Resources Information Center

    Olejnik, Stephen; Lee, JaeShin

    A review of the literature on multiple comparison procedures suggests several alternative approaches for comparing means when population variances differ. These include: (1) the approach of P. A. Games and J. F. Howell (1976); (2) C. W. Dunnett's C confidence interval (1980); and (3) Dunnett's T3 solution (1980). These procedures control the…

  8. 21 CFR 1010.4 - Variances.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... Dockets Management, except for information regarded as confidential under section 537(e) of the act. (d... Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. (1) The application for variance shall include the following information: (i) A description of the product and...

  9. Understanding gender variance in children and adolescents.

    PubMed

    Simons, Lisa K; Leibowitz, Scott F; Hidalgo, Marco A

    2014-06-01

    Gender variance is an umbrella term used to describe gender identity, expression, or behavior that falls outside of culturally defined norms associated with a specific gender. In recent years, growing media coverage has heightened public awareness about gender variance in childhood and adolescence, and an increasing number of referrals to clinics specializing in care for gender-variant youth have been reported in the United States. Gender-variant expression, behavior, and identity may present in childhood and adolescence in a number of ways, and youth with gender variance have unique health needs. For those experiencing gender dysphoria, or distress encountered by the discordance between biological sex and gender identity, puberty is often an exceptionally challenging time. Pediatric primary care providers may be families' first resource for education and support, and they play a critical role in supporting the health of youth with gender variance by screening for psychosocial problems and health risks, referring for gender-specific mental health and medical care, and providing ongoing advocacy and support. Copyright 2014, SLACK Incorporated.

  10. Variance approximations for assessments of classification accuracy

    Treesearch

    R. L. Czaplewski

    1994-01-01

    Variance approximations are derived for the weighted and unweighted kappa statistics, the conditional kappa statistic, and conditional probabilities. These statistics are useful to assess classification accuracy, such as accuracy of remotely sensed classifications in thematic maps when compared to a sample of reference classifications made in the field. Published...

  11. Bias and variance of planning level estimates of pollutant loads

    NASA Astrophysics Data System (ADS)

    Schwartz, Stuart S.; Naiman, Daniel Q.

    1999-11-01

    Planning level techniques typically use the product of runoff volume and a characteristic concentration to estimate mean annual contaminant loads when monitoring data are inadequate or unavailable. In contrast to the extensive literature on sampling properties, bias, and precision of loads estimated from monitoring data, the unconstrained and often inconsistent alternatives for choosing "representative" runoff volumes and concentrations for use in planning level estimates limit the opportunities of generalizing analytical results on the properties of these estimators. The ease with which these simple load estimates can be calculated belies their inherent uncertainty, motivating this examination of their bias and variability. The mean and variance of planning level load estimators are derived both under mild parametric assumptions and using a distribution free approximation. Common use of the mean, median, or geometric mean of event concentrations is shown to result, in general, in biased estimates of the mean annual load. Sensitivity analysis of the mean and variance demonstrates the need to incorporate the relative variance as well as the correlation of cumulative discharge and characteristic concentration in planning level load estimates. While analogous to load estimation from monitoring data, the results presented here are distinct and unrelated to retransformation or sampling biases that have been well documented in the river load literature. Substantive implications for regional assessments, planning, and watershed management are illustrated with a simple example drawn from Chesapeake Bay.

  12. Cosmic variance of the galaxy cluster weak lensing signal

    DOE PAGES

    Gruen, D.; Seitz, S.; Becker, M. R.; ...

    2015-04-13

    Intrinsic variations of the projected density profiles of clusters of galaxies at fixed mass are a source of uncertainty for cluster weak lensing. We present a semi-analytical model to account for this effect, based on a combination of variations in halo concentration, ellipticity and orientation, and the presence of correlated haloes. We calibrate the parameters of our model at the 10 per cent level to match the empirical cosmic variance of cluster profiles at M200m ≈ 1014…1015h–1M⊙, z = 0.25…0.5 in a cosmological simulation. We show that weak lensing measurements of clusters significantly underestimate mass uncertainties if intrinsic profile variationsmore » are ignored, and that our model can be used to provide correct mass likelihoods. Effects on the achievable accuracy of weak lensing cluster mass measurements are particularly strong for the most massive clusters and deep observations (with ≈20 per cent uncertainty from cosmic variance alone at M200m ≈ 1015h–1M⊙ and z = 0.25), but significant also under typical ground-based conditions. We show that neglecting intrinsic profile variations leads to biases in the mass-observable relation constrained with weak lensing, both for intrinsic scatter and overall scale (the latter at the 15 per cent level). Furthermore, these biases are in excess of the statistical errors of upcoming surveys and can be avoided if the cosmic variance of cluster profiles is accounted for.« less

  13. Parameterization of Incident and Infragravity Swash Variance

    NASA Astrophysics Data System (ADS)

    Stockdon, H. F.; Holman, R. A.; Sallenger, A. H.

    2002-12-01

    By clearly defining the forcing and morphologic controls of swash variance in both the incident and infragravity frequency bands, we are able to derive a more complete parameterization for extreme runup that may be applicable to a wide range of beach and wave conditions. It is expected that the dynamics of the incident and infragravity bands will have different dependencies on offshore wave conditions and local beach slopes. For example, previous studies have shown that swash variance in the incident band depends on foreshore beach slope while the infragravity variance depends more on a weighted mean slope across the surf zone. Because the physics of each band is parameterized differently, the amount that each frequency band contributes to the total swash variance will vary from site to site and, often, at a single site as the profile configuration changes over time. Using water level time series (measured at the shoreline) collected during nine dynamically different field experiments, we test the expected behavior of both incident and infragravity swash and the contribution each makes to total variance. At the dissipative sites (Iribarren number, \\xi0, <0.3) located in Oregon and the Netherlands, the incident band swash is saturated with respect to offshore wave height. Conversely, on the intermediate and reflective beaches, the amplitudes of both incident and infragravity swash variance grow with increasing offshore wave height. While infragravity band swash at all sites appears to increase linearly with offshore wave height, the magnitudes of the response are somewhat greater on reflective beaches than on dissipative beaches. This means that for the same offshore wave conditions the swash on a steeper foreshore will be larger than that on a more gently sloping foreshore. The potential control of the surf zone slope on infragravity band swash is examined at Duck, North Carolina, (0.3 < \\xi0 < 4.0), where significant differences in the relationship between swash

  14. Limonoids from Melia azedarach Fruits as Inhibitors of Flaviviruses and Mycobacterium tubercolosis

    PubMed Central

    Sanna, Giuseppina; Madeddu, Silvia; Giliberti, Gabriele; Ntalli, Nikoletta G.; Cottiglia, Filippo; De Logu, Alessandro; Agus, Emanuela; Caboni, Pierluigi

    2015-01-01

    The biological diversity of nature is the source of a wide range of bioactive molecules. The natural products, either as pure compounds or as standardized plant extracts, have been a successful source of inspiration for the development of new drugs. The present work was carried out to investigate the cytotoxicity, antiviral and antimycobacterial activity of the methanol extract and of four identified limonoids from the fruits of Melia azedarach (Meliaceae). The extract and purified limonoids were tested in cell-based assays for antiviral activity against representatives of ssRNA, dsRNA and dsDNA viruses and against Mycobacterium tuberculosis. Very interestingly, 3-α-tigloyl-melianol and melianone showed a potent antiviral activity (EC50 in the range of 3–11μM) against three important human pathogens, belonging to Flaviviridae family, West Nile virus, Dengue virus and Yellow Fever virus. Mode of action studies demonstrated that title compounds were inhibitors of West Nile virus only when added during the infection, acting as inhibitors of the entry or of a very early event of life cycle. Furthermore, 3-α-tigloyl-melianol and methyl kulonate showed interesting antimycobacterial activity (with MIC values of 29 and 70 μM respectively). The limonoids are typically lipophilic compounds present in the fruits of Melia azeradach. They are known as cytotoxic compounds against different cancer cell lines, while their potential as antiviral and antibacterial was poorly investigated. Our studies show that they may serve as a good starting point for the development of novel drugs for the treatment of infections by Flaviviruses and Mycobacterium tuberculosis, for which there is a continued need. PMID:26485025

  15. Limonoids from Melia azedarach Fruits as Inhibitors of Flaviviruses and Mycobacterium tubercolosis.

    PubMed

    Sanna, Giuseppina; Madeddu, Silvia; Giliberti, Gabriele; Ntalli, Nikoletta G; Cottiglia, Filippo; De Logu, Alessandro; Agus, Emanuela; Caboni, Pierluigi

    2015-01-01

    The biological diversity of nature is the source of a wide range of bioactive molecules. The natural products, either as pure compounds or as standardized plant extracts, have been a successful source of inspiration for the development of new drugs. The present work was carried out to investigate the cytotoxicity, antiviral and antimycobacterial activity of the methanol extract and of four identified limonoids from the fruits of Melia azedarach (Meliaceae). The extract and purified limonoids were tested in cell-based assays for antiviral activity against representatives of ssRNA, dsRNA and dsDNA viruses and against Mycobacterium tuberculosis. Very interestingly, 3-α-tigloyl-melianol and melianone showed a potent antiviral activity (EC50 in the range of 3-11μM) against three important human pathogens, belonging to Flaviviridae family, West Nile virus, Dengue virus and Yellow Fever virus. Mode of action studies demonstrated that title compounds were inhibitors of West Nile virus only when added during the infection, acting as inhibitors of the entry or of a very early event of life cycle. Furthermore, 3-α-tigloyl-melianol and methyl kulonate showed interesting antimycobacterial activity (with MIC values of 29 and 70 μM respectively). The limonoids are typically lipophilic compounds present in the fruits of Melia azeradach. They are known as cytotoxic compounds against different cancer cell lines, while their potential as antiviral and antibacterial was poorly investigated. Our studies show that they may serve as a good starting point for the development of novel drugs for the treatment of infections by Flaviviruses and Mycobacterium tuberculosis, for which there is a continued need.

  16. 42 CFR 456.525 - Request for renewal of variance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS UTILIZATION CONTROL Utilization Review Plans: FFP, Waivers, and Variances for Hospitals and Mental Hospitals Ur Plan: Remote Facility Variances from...

  17. 42 CFR 456.521 - Conditions for granting variance requests.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS UTILIZATION CONTROL Utilization Review Plans: FFP, Waivers, and Variances for Hospitals and Mental Hospitals Ur Plan: Remote Facility Variances from...

  18. Cell-mediated immunity induced by chimeric tetravalent dengue vaccine in naive or flavivirus-primed subjects.

    PubMed

    Guy, Bruno; Nougarede, Nolwenn; Begue, Sarah; Sanchez, Violette; Souag, Nadia; Carre, Murielle; Chambonneau, Laurent; Morrisson, Dennis N; Shaw, David; Qiao, Ming; Dumas, Rafaele; Lang, Jean; Forrat, Remi

    2008-10-23

    Three independent, phase 1 clinical trials were conducted in Australia and in USA to assess the safety and immunogenicity of sanofi pasteur dengue vaccine candidates. In this context, Dengue 1-4 and Yellow Fever 17D-204 (YF 17D)-specific CD4 and CD8 cellular responses induced by tetravalent chimeric dengue vaccines (CYD) were analyzed in flavivirus-naive or flavivirus-immune patients. Tetravalent CYD vaccine did not trigger detectable changes in serum pro-inflammatory cytokines, whatever the vaccinees immune status, while inducing significant YF 17D NS3-specific CD8 responses and dengue serotype-specific T helper responses. These responses were dominated by serotype 4 in naive individuals, but a booster vaccination (dose #2) performed 4 months following dose #1 broadened serotype-specific responses. A similar, broader response was seen after primary tetravalent immunization in subjects with pre-existing dengue 1 or 2 immunity caused by prior monovalent live-attenuated dengue vaccination. In all three trials, the profile of induced response was similar, whatever the subjects' immune status, i.e. an absence of Th2 response, and an IFN-gamma/TNF-alpha ratio dominated by IFN-gamma, for both CD4 and CD8 responses. Our results also showed an absence of cross-reactivity between YF 17D or Dengue NS3-specific CD8 responses, and allowed the identification of 3 new CD8 epitopes in the YF 17D NS3 antigen. These data are consistent with the previously demonstrated excellent safety of these dengue vaccines in flavivirus-naive and primed individuals.

  19. Exploring of Primate Models of Tick-Borne Flaviviruses Infection for Evaluation of Vaccines and Drugs Efficacy

    PubMed Central

    Pripuzova, Natalia S.; Gmyl, Larissa V.; Romanova, Lidiya Iu.; Tereshkina, Natalia V.; Rogova, Yulia V.; Terekhina, Liubov L.; Kozlovskaya, Liubov I.; Vorovitch, Mikhail F.; Grishina, Karina G.; Timofeev, Andrey V.; Karganova, Galina G.

    2013-01-01

    Tick-borne encephalitis virus (TBEV) is one of the most prevalent and medically important tick-borne arboviruses in Eurasia. There are overlapping foci of two flaviviruses: TBEV and Omsk hemorrhagic fever virus (OHFV) in Russia. Inactivated vaccines exist only against TBE. There are no antiviral drugs for treatment of both diseases. Optimal animal models are necessary to study efficacy of novel vaccines and treatment preparations against TBE and relative flaviviruses. The models for TBE and OHF using subcutaneous inoculation were tested in Cercopithecus aethiops and Macaca fascicularis monkeys with or without prior immunization with inactivated TBE vaccine. No visible clinical signs or severe pathomorphological lesions were observed in any monkey infected with TBEV or OHFV. C. aethiops challenged with OHFV showed massive hemolytic syndrome and thrombocytopenia. Infectious virus or viral RNA was revealed in visceral organs and CNS of C. aethiops infected with both viruses; however, viremia was low. Inactivated TBE vaccines induced high antibody titers against both viruses and expressed booster after challenge. The protective efficacy against TBE was shown by the absence of virus in spleen, lymph nodes and CNS of immunized animals after challenge. Despite the absence of expressed hemolytic syndrome in immunized C. aethiops TBE vaccine did not prevent the reproduction of OHFV in CNS and visceral organs. Subcutaneous inoculation of M. fascicularis with two TBEV strains led to a febrile disease with well expressed viremia, fever, and virus reproduction in spleen, lymph nodes and CNS. The optimal terms for estimation of the viral titers in CNS were defined as 8–16 days post infection. We characterized two animal models similar to humans in their susceptibility to tick-borne flaviviruses and found the most optimal scheme for evaluation of efficacy of preventive and therapeutic preparations. We also identified M. fascicularis to be more susceptible to TBEV than C

  20. Exploring of primate models of tick-borne flaviviruses infection for evaluation of vaccines and drugs efficacy.

    PubMed

    Pripuzova, Natalia S; Gmyl, Larissa V; Romanova, Lidiya Iu; Tereshkina, Natalia V; Rogova, Yulia V; Terekhina, Liubov L; Kozlovskaya, Liubov I; Vorovitch, Mikhail F; Grishina, Karina G; Timofeev, Andrey V; Karganova, Galina G

    2013-01-01

    Tick-borne encephalitis virus (TBEV) is one of the most prevalent and medically important tick-borne arboviruses in Eurasia. There are overlapping foci of two flaviviruses: TBEV and Omsk hemorrhagic fever virus (OHFV) in Russia. Inactivated vaccines exist only against TBE. There are no antiviral drugs for treatment of both diseases. Optimal animal models are necessary to study efficacy of novel vaccines and treatment preparations against TBE and relative flaviviruses. The models for TBE and OHF using subcutaneous inoculation were tested in Cercopithecus aethiops and Macaca fascicularis monkeys with or without prior immunization with inactivated TBE vaccine. No visible clinical signs or severe pathomorphological lesions were observed in any monkey infected with TBEV or OHFV. C. aethiops challenged with OHFV showed massive hemolytic syndrome and thrombocytopenia. Infectious virus or viral RNA was revealed in visceral organs and CNS of C. aethiops infected with both viruses; however, viremia was low. Inactivated TBE vaccines induced high antibody titers against both viruses and expressed booster after challenge. The protective efficacy against TBE was shown by the absence of virus in spleen, lymph nodes and CNS of immunized animals after challenge. Despite the absence of expressed hemolytic syndrome in immunized C. aethiops TBE vaccine did not prevent the reproduction of OHFV in CNS and visceral organs. Subcutaneous inoculation of M. fascicularis with two TBEV strains led to a febrile disease with well expressed viremia, fever, and virus reproduction in spleen, lymph nodes and CNS. The optimal terms for estimation of the viral titers in CNS were defined as 8-16 days post infection. We characterized two animal models similar to humans in their susceptibility to tick-borne flaviviruses and found the most optimal scheme for evaluation of efficacy of preventive and therapeutic preparations. We also identified M. fascicularis to be more susceptible to TBEV than C. aethiops.

  1. Ulnar variance and Kienböck's disease. An investigation in Taiwan.

    PubMed

    Chen, W S; Shih, C H

    1990-06-01

    The correlation between negative ulnar variance and the occurrence of Kienböck's disease was evaluated in Taiwan. Two groups of subjects were studied. The first group consisted of 1000 normal subjects and the second of 18 patients with Kienböck's disease. Student's t-test was used to evaluate the significance of the difference between this and other published series. The mean was 0.313 mm in Group 1 and -1.222 mm in Group 2. The percentage with significant negative ulnar variance (the distal ulnar was at least 2 mm shorter than the radius) was 6.0% in Group 1 and 55.6% in Group 2. The difference between the two groups was significant. The mean ulnar variance of normal subjects in Taiwan differed significantly from the variance in Swedes and American blacks but not American whites. In Chinese patients with Kienböck's disease, the ulnar variance was predominantly negative, and the distribution of ulnar variance was similar to that of Swedish or American white patients. This study confirmed the association between negative ulnar variance and the occurrence of Kienböck's disease. This supports Hultén's hypothesis that negative ulnar variance may predispose certain individuals to the occurrence of Kienböck's disease.

  2. Analysis of variance of microarray data.

    PubMed

    Ayroles, Julien F; Gibson, Greg

    2006-01-01

    Analysis of variance (ANOVA) is an approach used to identify differentially expressed genes in complex experimental designs. It is based on testing for the significance of the magnitude of effect of two or more treatments taking into account the variance within and between treatment classes. ANOVA is a highly flexible analytical approach that allows investigators to simultaneously assess the contributions of multiple factors to gene expression variation, including technical (dye, batch) effects and biological (sex, genotype, drug, time) ones, as well as interactions between factors. This chapter provides an overview of the theory of linear mixture modeling and the sequence of steps involved in fitting gene-specific models and discusses essential features of experimental design. Commercial and open-source software for performing ANOVA is widely available.

  3. Analysis of Variance of Multiply Imputed Data.

    PubMed

    van Ginkel, Joost R; Kroonenberg, Pieter M

    2014-01-01

    As a procedure for handling missing data, Multiple imputation consists of estimating the missing data multiple times to create several complete versions of an incomplete data set. All these data sets are analyzed by the same statistical procedure, and the results are pooled for interpretation. So far, no explicit rules for pooling F-tests of (repeated-measures) analysis of variance have been defined. In this paper we outline the appropriate procedure for the results of analysis of variance for multiply imputed data sets. It involves both reformulation of the ANOVA model as a regression model using effect coding of the predictors and applying already existing combination rules for regression models. The proposed procedure is illustrated using three example data sets. The pooled results of these three examples provide plausible F- and p-values.

  4. Stress Variances Among Informal Hospice Caregivers

    PubMed Central

    Wittenberg-Lyles, Elaine; Demiris, George; Oliver, Debra Parker; Washington, Karla; Burt, Stephanie; Shaunfield, Sara

    2013-01-01

    Care interventions are not routinely provided for hospice caregivers, despite widespread documentation of the burden and toll of the caregiving experience. Assessing caregivers for team interventions (ACT) proposes that holistic patient and family care includes ongoing caregiver needs assessment of primary, secondary, and intrapsychic stressors. In this study, our goal was to describe the variance in stressors for caregivers to establish evidence for the ACT theoretical framework. We used secondary interview data from a randomized controlled trial to analyze hospice caregiver discussions about concerns. We found variances in stress types, suggesting that caregiver interventions should range from knowledge and skill building to cognitive-behavioral interventions that aid in coping. Family members who assume the role of primary caregiver for a dying loved one need to be routinely assessed by hospice providers for customized interventions. PMID:22673093

  5. Analysis of Variance of Multiply Imputed Data

    PubMed Central

    van Ginkel, Joost R.; Kroonenberg, Pieter M.

    2014-01-01

    As a procedure for handling missing data, Multiple imputation consists of estimating the missing data multiple times to create several complete versions of an incomplete data set. All these data sets are analyzed by the same statistical procedure, and the results are pooled for interpretation. So far, no explicit rules for pooling F-tests of (repeated-measures) analysis of variance have been defined. In this paper we outline the appropriate procedure for the results of analysis of variance for multiply imputed data sets. It involves both reformulation of the ANOVA model as a regression model using effect coding of the predictors and applying already existing combination rules for regression models. The proposed procedure is illustrated using three example data sets. The pooled results of these three examples provide plausible F- and p-values. PMID:24860197

  6. Linear transformations of variance/covariance matrices.

    PubMed

    Parois, Pascal; Lutz, Martin

    2011-07-01

    Many applications in crystallography require the use of linear transformations on parameters and their standard uncertainties. While the transformation of the parameters is textbook knowledge, the transformation of the standard uncertainties is more complicated and needs the full variance/covariance matrix. For the transformation of second-rank tensors it is suggested that the 3 × 3 matrix is re-written into a 9 × 1 vector. The transformation of the corresponding variance/covariance matrix is then straightforward and easily implemented into computer software. This method is applied in the transformation of anisotropic displacement parameters, the calculation of equivalent isotropic displacement parameters, the comparison of refinements in different space-group settings and the calculation of standard uncertainties of eigenvalues.

  7. Systems Engineering Programmatic Estimation Using Technology Variance

    NASA Technical Reports Server (NTRS)

    Mog, Robert A.

    2000-01-01

    Unique and innovative system programmatic estimation is conducted using the variance of the packaged technologies. Covariance analysis is performed on the subsystems and components comprising the system of interest. Technological "return" and "variation" parameters are estimated. These parameters are combined with the model error to arrive at a measure of system development stability. The resulting estimates provide valuable information concerning the potential cost growth of the system under development.

  8. Systems Engineering Programmatic Estimation Using Technology Variance

    NASA Technical Reports Server (NTRS)

    Mog, Robert A.

    2000-01-01

    Unique and innovative system programmatic estimation is conducted using the variance of the packaged technologies. Covariance analysis is performed oil the subsystems and components comprising the system of interest. Technological "returns" and "variation" parameters, are estimated. These parameters are combined with the model error to arrive at a measure of system development stability. The resulting estimates provide valuable information concerning the potential cost growth of the system under development.

  9. The Theory of Variances in Equilibrium Reconstruction

    SciTech Connect

    Zakharov, Leonid E.; Lewandowski, Jerome; Foley, Elizabeth L.; Levinton, Fred M.; Yuh, Howard Y.; Drozdov, Vladimir; McDonald, Darren

    2008-01-14

    The theory of variances of equilibrium reconstruction is presented. It complements existing practices with information regarding what kind of plasma profiles can be reconstructed, how accurately, and what remains beyond the abilities of diagnostic systems. The σ-curves, introduced by the present theory, give a quantitative assessment of quality of effectiveness of diagnostic systems in constraining equilibrium reconstructions. The theory also suggests a method for aligning the accuracy of measurements of different physical nature.

  10. Gravity Wave Variance in LIMS Temperatures. Part II: Comparison with the Zonal-Mean Momentum Balance.

    NASA Astrophysics Data System (ADS)

    Fetzer, Eric J.; Gille, John C.

    1996-02-01

    Zonal-mean gravity wave variance in the Limb Infrared Monitor of the Stratosphere (LIMS) temperature data is seen to correlate strongly with the residual term in the LIMS zonal-mean momentum budget throughout much of the observed mesosphere. This momentum residual is attributed to gravity wave momentum transport at scales that cannot be directly sampled by the LIMS instrument Correlation is highest in the vicinity of the fall and winter mesospheric jets, where both gravity wave variance and momentum residual reach their largest values. Correlation is also high in the Southern Hemisphere subtropical mesophere, where gravity wave variance and the momentum residual have broad temporal maxima during the easterly acceleration of the stratopause semi-annual oscillation (SAO). This subtropical correlation has important implications for the SAO eastward acceleration, which several studies suggest is forced by gravity wave momentum flux divergence. Correlation between gravity wave variance and inferred gravity wave momentum flux divergence is unexpected because variance is dominated by large scales and long periods (inertio-gravity waves), while both theoretical arguments and ground-based observations indicate that momentum transport is dominated by periods under 1 h. The results of this study suggest a broadband gravity wave field experiencing forcing and loss processes, which are largely independent of frequency.

  11. Directional variance analysis of annual rings

    NASA Astrophysics Data System (ADS)

    Kumpulainen, P.; Marjanen, K.

    2010-07-01

    The wood quality measurement methods are of increasing importance in the wood industry. The goal is to produce more high quality products with higher marketing value than is produced today. One of the key factors for increasing the market value is to provide better measurements for increased information to support the decisions made later in the product chain. Strength and stiffness are important properties of the wood. They are related to mean annual ring width and its deviation. These indicators can be estimated from images taken from the log ends by two-dimensional power spectrum analysis. The spectrum analysis has been used successfully for images of pine. However, the annual rings in birch, for example are less distinguishable and the basic spectrum analysis method does not give reliable results. A novel method for local log end variance analysis based on Radon-transform is proposed. The directions and the positions of the annual rings can be estimated from local minimum and maximum variance estimates. Applying the spectrum analysis on the maximum local variance estimate instead of the original image produces more reliable estimate of the annual ring width. The proposed method is not limited to log end analysis only. It is usable in other two-dimensional random signal and texture analysis tasks.

  12. Hypothesis exploration with visualization of variance

    PubMed Central

    2014-01-01

    Background The Consortium for Neuropsychiatric Phenomics (CNP) at UCLA was an investigation into the biological bases of traits such as memory and response inhibition phenotypes—to explore whether they are linked to syndromes including ADHD, Bipolar disorder, and Schizophrenia. An aim of the consortium was in moving from traditional categorical approaches for psychiatric syndromes towards more quantitative approaches based on large-scale analysis of the space of human variation. It represented an application of phenomics—wide-scale, systematic study of phenotypes—to neuropsychiatry research. Results This paper reports on a system for exploration of hypotheses in data obtained from the LA2K, LA3C, and LA5C studies in CNP. ViVA is a system for exploratory data analysis using novel mathematical models and methods for visualization of variance. An example of these methods is called VISOVA, a combination of visualization and analysis of variance, with the flavor of exploration associated with ANOVA in biomedical hypothesis generation. It permits visual identification of phenotype profiles—patterns of values across phenotypes—that characterize groups. Visualization enables screening and refinement of hypotheses about variance structure of sets of phenotypes. Conclusions The ViVA system was designed for exploration of neuropsychiatric hypotheses by interdisciplinary teams. Automated visualization in ViVA supports ‘natural selection’ on a pool of hypotheses, and permits deeper understanding of the statistical architecture of the data. Large-scale perspective of this kind could lead to better neuropsychiatric diagnostics. PMID:25097666

  13. On Stabilizing the Variance of Dynamic Functional Brain Connectivity Time Series.

    PubMed

    Thompson, William Hedley; Fransson, Peter

    2016-12-01

    Assessment of dynamic functional brain connectivity based on functional magnetic resonance imaging (fMRI) data is an increasingly popular strategy to investigate temporal dynamics of the brain's large-scale network architecture. Current practice when deriving connectivity estimates over time is to use the Fisher transformation, which aims to stabilize the variance of correlation values that fluctuate around varying true correlation values. It is, however, unclear how well the stabilization of signal variance performed by the Fisher transformation works for each connectivity time series, when the true correlation is assumed to be fluctuating. This is of importance because many subsequent analyses either assume or perform better when the time series have stable variance or adheres to an approximate Gaussian distribution. In this article, using simulations and analysis of resting-state fMRI data, we analyze the effect of applying different variance stabilization strategies on connectivity time series. We focus our investigation on the Fisher transformation, the Box-Cox (BC) transformation and an approach that combines both transformations. Our results show that, if the intention of stabilizing the variance is to use metrics on the time series, where stable variance or a Gaussian distribution is desired (e.g., clustering), the Fisher transformation is not optimal and may even skew connectivity time series away from being Gaussian. Furthermore, we show that the suboptimal performance of the Fisher transformation can be substantially improved by including an additional BC transformation after the dynamic functional connectivity time series has been Fisher transformed.

  14. On Stabilizing the Variance of Dynamic Functional Brain Connectivity Time Series

    PubMed Central

    Fransson, Peter

    2016-01-01

    Abstract Assessment of dynamic functional brain connectivity based on functional magnetic resonance imaging (fMRI) data is an increasingly popular strategy to investigate temporal dynamics of the brain's large-scale network architecture. Current practice when deriving connectivity estimates over time is to use the Fisher transformation, which aims to stabilize the variance of correlation values that fluctuate around varying true correlation values. It is, however, unclear how well the stabilization of signal variance performed by the Fisher transformation works for each connectivity time series, when the true correlation is assumed to be fluctuating. This is of importance because many subsequent analyses either assume or perform better when the time series have stable variance or adheres to an approximate Gaussian distribution. In this article, using simulations and analysis of resting-state fMRI data, we analyze the effect of applying different variance stabilization strategies on connectivity time series. We focus our investigation on the Fisher transformation, the Box–Cox (BC) transformation and an approach that combines both transformations. Our results show that, if the intention of stabilizing the variance is to use metrics on the time series, where stable variance or a Gaussian distribution is desired (e.g., clustering), the Fisher transformation is not optimal and may even skew connectivity time series away from being Gaussian. Furthermore, we show that the suboptimal performance of the Fisher transformation can be substantially improved by including an additional BC transformation after the dynamic functional connectivity time series has been Fisher transformed. PMID:27784176

  15. Inheritance of dermatoglyphic traits in twins: univariate and bivariate variance decomposition analysis.

    PubMed

    Karmakar, Bibha; Malkin, Ida; Kobyliansky, Eugene

    2012-01-01

    Dermatoglyphic traits in a sample of twins were analyzed to estimate the resemblance between MZ and DZ twins and to evaluate the mode of inheritance by using the maximum likelihood-based Variance decomposition analysis. The additive genetic variance component was significant in both sexes for four traits--PII, AB_RC, RC_HB, and ATD_L. AB RC and RC_HB had significant sex differences in means, whereas PII and ATD_L did not. The results of the Bivariate Variance decomposition analysis revealed that PII and RC_HB have a significant correlation in both genetic and residual components. Significant correlation in the additive genetic variance between AB_RC and ATD_L was observed. The same analysis only for the females sub-sample in the three traits RBL, RBR and AB_DIS shows that the additive genetic RBR component was significant and the AB_DIS sibling component was not significant while others cannot be constrained to zero. The additive variance for AB DIS sibling component was not significant. The three components additive, sibling and residual were significantly correlated between each pair of traits revealed by the Bivariate Variance decomposition analysis.

  16. [Taxonomy of the Sokuluk virus (SOKV) (Flaviviridae, Flavivirus, Entebbe bat virus group) isolated from bats (Vespertilio pipistrellus Schreber, 1774), ticks (Argasidae Koch, 1844), and birds in Kyrgyzstan].

    PubMed

    L'vov, D K; Al'khovskiĭ, S V; Shchelkanov, M Iu; Shchetinin, A M; Deriabin, P G; Gitel'man, A K; Samokhvalov, E I; Botikov, A G

    2014-01-01

    Complete genome sequencing of the Sokuluk virus (SOKV) isolated in Kyrgyzstan from bats Vespertilio pipistrellus and their obligatory parasites--Argasidae Koch, 1844, ticks was carried out. SOKV was classified as attributed to the Flaviviridae family, Flavivirus genus. The maximum homology (71% for nucleotide and 79% for amino acid sequences) was detected with respect to the Entebbe bat virus (ENTV). ENTV and SOKV form a group joining to the yellow fever virus (YFV) within the limits of the mosquito flavivirus branch. Close relation of SOKV with bat covers and human housings permits to assume SOKV potentially patogenic to human health.

  17. Variance of the Quantum Dwell Time for a Nonrelativistic Particle

    NASA Technical Reports Server (NTRS)

    Hahne, Gerhard

    2012-01-01

    Munoz, Seidel, and Muga [Phys. Rev. A 79, 012108 (2009)], following an earlier proposal by Pollak and Miller [Phys. Rev. Lett. 53, 115 (1984)] in the context of a theory of a collinear chemical reaction, showed that suitable moments of a two-flux correlation function could be manipulated to yield expressions for the mean quantum dwell time and mean square quantum dwell time for a structureless particle scattering from a time-independent potential energy field between two parallel lines in a two-dimensional spacetime. The present work proposes a generalization to a charged, nonrelativistic particle scattering from a transient, spatially confined electromagnetic vector potential in four-dimensional spacetime. The geometry of the spacetime domain is that of the slab between a pair of parallel planes, in particular those defined by constant values of the third (z) spatial coordinate. The mean Nth power, N = 1, 2, 3, . . ., of the quantum dwell time in the slab is given by an expression involving an N-flux-correlation function. All these means are shown to be nonnegative. The N = 1 formula reduces to an S-matrix result published previously [G. E. Hahne, J. Phys. A 36, 7149 (2003)]; an explicit formula for N = 2, and of the variance of the dwell time in terms of the S-matrix, is worked out. A formula representing an incommensurability principle between variances of the output-minus-input flux of a pair of dynamical variables (such as the particle s time flux and others) is derived.

  18. Applications of non-parametric statistics and analysis of variance on sample variances

    NASA Technical Reports Server (NTRS)

    Myers, R. H.

    1981-01-01

    Nonparametric methods that are available for NASA-type applications are discussed. An attempt will be made here to survey what can be used, to attempt recommendations as to when each would be applicable, and to compare the methods, when possible, with the usual normal-theory procedures that are avavilable for the Gaussion analog. It is important here to point out the hypotheses that are being tested, the assumptions that are being made, and limitations of the nonparametric procedures. The appropriateness of doing analysis of variance on sample variances are also discussed and studied. This procedure is followed in several NASA simulation projects. On the surface this would appear to be reasonably sound procedure. However, difficulties involved center around the normality problem and the basic homogeneous variance assumption that is mase in usual analysis of variance problems. These difficulties discussed and guidelines given for using the methods.

  19. Minimum variance and variance of outgoing quality limit MDS-1(c1, c2) plans

    NASA Astrophysics Data System (ADS)

    Raju, C.; Vidya, R.

    2016-06-01

    In this article, the outgoing quality (OQ) and total inspection (TI) of multiple deferred state sampling plans MDS-1(c1,c2) are studied. It is assumed that the inspection is rejection rectification. Procedures for designing MDS-1(c1,c2) sampling plans with minimum variance of OQ and TI are developed. A procedure for obtaining a plan for a designated upper limit for the variance of the OQ (VOQL) is outlined.

  20. Variance Reduction Factor of Nuclear Data for Integral Neutronics Parameters

    SciTech Connect

    Chiba, G. Tsuji, M.; Narabayashi, T.

    2015-01-15

    We propose a new quantity, a variance reduction factor, to identify nuclear data for which further improvements are required to reduce uncertainties of target integral neutronics parameters. Important energy ranges can be also identified with this variance reduction factor. Variance reduction factors are calculated for several integral neutronics parameters. The usefulness of the variance reduction factors is demonstrated.

  1. An Experimental Model of Meningoencephalomyelitis by Rocio Flavivirus in Balb/C Mice: Inflammatory Response, Cytokine Production, and Histopathology

    PubMed Central

    de Barros, Veridiana Ester Dias; Saggioro, Fabiano P.; Neder, Luciano; de Oliveira França, Rafael Freitas; Mariguela, Viviane; Chávez, Juliana Helena; Penharvel, Sandra; Forjaz, Jorge; da Fonseca, Benedito Antônio Lopes; Figueiredo, Luiz Tadeu Moraes

    2011-01-01

    Rocio virus (ROCV) is a flavivirus, probably transmitted by Culex mosquitoes and maintained in nature as a zoonosis of wild birds. Rocio virus caused a human epidemic of severe encephalitis that lasted from 1973 to 1980 in the Ribeira valley, in the southeastern coast of Brazil. After this outbreak, serologic evidence of ROCV circulation has been reported and public health authorities are concerned about a return of ROCV outbreaks in Brazil. We show here a study on the pathogenesis and the physiopathology of ROCV disease in the central nervous system of a Balb/C young adult mice experimental model. The animals were intraperitoneally infected by ROCV and followed from 0 to 9 days after infection, when all of them died. Nervous tissue samples were collected from infected animals for immunohistochemistry and molecular biology analysis. We observed the virus in the central nervous system, the inflammatory changes induced by Th1 and Th2 cytokines, and the final irreversible damage of nervous tissues by neuronal degeneration and apoptosis. These findings can help to better understand the pathogenesis and physiopathology of the human meningoencephalomyelitis by ROCV and other flaviviruses. PMID:21813860

  2. Comparative Analysis Between Flaviviruses Reveals Specific Neural Stem Cell Tropism for Zika Virus in the Mouse Developing Neocortex.

    PubMed

    Brault, Jean-Baptiste; Khou, Cécile; Basset, Justine; Coquand, Laure; Fraisier, Vincent; Frenkiel, Marie-Pascale; Goud, Bruno; Manuguerra, Jean-Claude; Pardigon, Nathalie; Baffet, Alexandre D

    2016-08-01

    The recent Zika outbreak in South America and French Polynesia was associated with an epidemic of microcephaly, a disease characterized by a reduced size of the cerebral cortex. Other members of the Flavivirus genus, including West Nile virus (WNV), can cause encephalitis but were not demonstrated to cause microcephaly. It remains unclear whether Zika virus (ZIKV) and other flaviviruses may infect different cell populations in the developing neocortex and lead to distinct developmental defects. Here, we describe an assay to infect mouse E15 embryonic brain slices with ZIKV, WNV and dengue virus serotype 4 (DENV-4). We show that this tissue is able to support viral replication of ZIKV and WNV, but not DENV-4. Cell fate analysis reveals a remarkable tropism of ZIKV infection for neural stem cells. Closely related WNV displays a very different tropism of infection, with a bias towards neurons. We further show that ZIKV infection, but not WNV infection, impairs cell cycle progression of neural stem cells. Both viruses inhibited apoptosis at early stages of infection. This work establishes a powerful comparative approach to identify ZIKV-specific alterations in the developing neocortex and reveals specific preferential infection of neural stem cells by ZIKV.

  3. [Secondary serologic responses to dengue epidemic in 1998 in Salta, Argentina, where other flavivirus co-circulate].

    PubMed

    Aviles, G; Rangeon, G; Paz, M V; Baroni, P; Sabattini, M S; Enría, D

    2001-01-01

    In 1998, a dengue outbreak (serotype 2) occurred in Salta province in Northern Argentina, following the first detection of dengue in the same area in 1997. We classified the serologic response of cases from 1998 as primary or secondary, since the risk of severe disease is greater for secondary cases. We studied 154 cases by plaque reduction neutralization and hemagglutination inhibition tests. Thirty-eight cases (25%) were classified as primary serologic responses and 84 cases (54%) as secondary responses. Thirty-two cases (21%) with borderline IgG titers could not be classified. Previous exposure to potentially cross-reacting flaviviruses (Saint Louis Encephalitis [SLE] and Yellow Fever [YF] viruses) was analyzed, as a possible cause of the secondary response pattern. Our results indicated that among cases classified as dengue secondary response, 83% could be attributed to previous SLE or YF exposure or serologic cross-reactivity. Vaccination against YF virus was at most a minor contributor to the secondary response pattern. The finding of a positive YF serologic result among persons not vaccinated may indicate silent circulation of YF in a region that can support both urban and jungle cycles. Other cases showing dengue secondary responses remained unexplained, suggesting the unrecognized occurrence of a previous infection with other dengue serotypes or of flaviviruses other than SLE or YF.

  4. Flavivirus Antagonism of Type I Interferon Signaling Reveals Prolidase as a Regulator of IFNAR1 Surface Expression.

    PubMed

    Lubick, Kirk J; Robertson, Shelly J; McNally, Kristin L; Freedman, Brett A; Rasmussen, Angela L; Taylor, R Travis; Walts, Avram D; Tsuruda, Seitaro; Sakai, Mizuki; Ishizuka, Mariko; Boer, Elena F; Foster, Erin C; Chiramel, Abhilash I; Addison, Conrad B; Green, Richard; Kastner, Daniel L; Katze, Michael G; Holland, Steven M; Forlino, Antonella; Freeman, Alexandra F; Boehm, Manfred; Yoshii, Kentaro; Best, Sonja M

    2015-07-08

    Type I interferon (IFN-α/β or IFN-I) signals through two receptor subunits, IFNAR1 and IFNAR2, to orchestrate sterile and infectious immunity. Cellular pathways that regulate IFNAR1 are often targeted by viruses to suppress the antiviral effects of IFN-I. Here we report that encephalitic flaviviruses, including tick-borne encephalitis virus and West Nile virus, antagonize IFN-I signaling by inhibiting IFNAR1 surface expression. Loss of IFNAR1 was associated with binding of the viral IFN-I antagonist, NS5, to prolidase (PEPD), a cellular dipeptidase implicated in primary immune deficiencies in humans. Prolidase was required for IFNAR1 maturation and accumulation, activation of IFNβ-stimulated gene induction, and IFN-I-dependent viral control. Human fibroblasts derived from patients with genetic prolidase deficiency exhibited decreased IFNAR1 surface expression and reduced IFNβ-stimulated signaling. Thus, by understanding flavivirus IFN-I antagonism, prolidase is revealed as a central regulator of IFN-I responses.

  5. Identification of genetic determinants of a tick-borne flavivirus associated with host-specific adaptation and pathogenicity

    PubMed Central

    Mitzel, Dana N.; Best, Sonja M.; Masnick, Max F.; Porcella, Stephen F.; Wolfinbarger, James B.; Bloom, Marshall E.

    2008-01-01

    Tick-borne flaviviruses are maintained in nature in an enzootic cycle involving a tick vector and a vertebrate host. Thus, the virus replicates in two disparate hosts, each providing selective pressures that can influence virus replication and pathogenicity. To identify viral determinants associated with replication in the individual hosts, plaque purified Langat virus (TP21pp) was adapted to growth in mouse or tick cell lines to generate two virus variants, MNBp20 and ISEp20, respectively. Virus adaptation to mouse cells resulted in four amino acid changes in MNBp20 relative to TP21pp, occurring in E, NS4A and NS4B. A comparison between TP21pp and ISEp20 revealed three amino acid modifications in M, NS3 and NS4A of ISEp20. ISEp20, but not MNBp20, was attenuated following intraperitoneal inoculation of mice. Following isolation from mice brains, additional mutations reproducibly emerged in E and NS3 of ISEp20 that were possibly compensatory for the initial adaptation to tick cells. Thus, our data implicate a role for E, M, NS3, NS4A and NS4B in host adaptation and pathogenicity of tick-borne flaviviruses. PMID:18823640

  6. An RNA cap (nucleoside-2'-O-)-methyltransferase in the flavivirus RNA polymerase NS5: crystal structure and functional characterization.

    PubMed

    Egloff, Marie-Pierre; Benarroch, Delphine; Selisko, Barbara; Romette, Jean-Louis; Canard, Bruno

    2002-06-03

    Viruses represent an attractive system with which to study the molecular basis of mRNA capping and its relation to the RNA transcription machinery. The RNA-dependent RNA polymerase NS5 of flaviviruses presents a characteristic motif of S-adenosyl-L-methionine-dependent methyltransferases at its N-terminus, and polymerase motifs at its C-terminus. The crystal structure of an N-terminal fragment of Dengue virus type 2 NS5 is reported at 2.4 A resolution. We show that this NS5 domain includes a typical methyltransferase core and exhibits a (nucleoside-2'-O-)-methyltransferase activity on capped RNA. The structure of a ternary complex comprising S-adenosyl-L-homocysteine and a guanosine triphosphate (GTP) analogue shows that 54 amino acids N-terminal to the core provide a novel GTP-binding site that selects guanine using a previously unreported mechanism. Binding studies using GTP- and RNA cap-analogues, as well as the spatial arrangement of the methyltransferase active site relative to the GTP-binding site, suggest that the latter is a specific cap-binding site. As RNA capping is an essential viral function, these results provide a structural basis for the rational design of drugs against the emerging flaviviruses.

  7. Review: A neglected Flavivirus: an update on Zika virus in 2016 and the future direction of research.

    PubMed

    Bharucha, Tehmina; Breuer, Judith

    2016-06-01

    The 2015-16 global emergence of Zika virus infection (ZIKV) and its link with Guillain-Barré Syndrome and microcephaly, at the tail-end of the Ebola epidemic, has provoked unease throughout the international community. The World Health Organisation declared ZIKV a public health emergency on 1st February 2016, but until the 31st March 2016 maintained that there was insufficient evidence that ZIKV was independently responsible for any serious complications. Our current understanding of this arthropod-borne flavivirus is still at an early stage. The first reported human infections were 60 years ago, and until the first outbreak in Micronesia in 2007, there were only 14 documented cases. Nonetheless, there are parallels that we can draw from our understanding of other related arbo-flaviviruses, such as dengue, Japanese encephalitis and West Nile viruses. This article provides a focussed review of the literature on ZIKV to date, with perspectives on the direction of future research. © 2016 British Neuropathological Society.

  8. Serological Prevalence Against Japanese Encephalitis Virus-Serocomplex Flaviviruses in Commensal and Field Rodents in South China.

    PubMed

    Chen, Shao-Wei; Jiang, Li-Na; Zhong, Xue-Shan; Zheng, Xue-Yan; Ma, Shu-Juan; Xiong, Yi-Quan; Zhou, Jun-Hua; Li, Xing; Ke, Xue-Mei; Zhou, Wen; Chen, Qing

    2016-12-01

    Japanese encephalitis caused by Japanese encephalitis virus (JEV) is an endemic zoonotic disease of high public health importance in the Asian Pacific region. The aim of this study was to investigate the presence of JEV infection in commensal and field rodents in South China. RNA copies of JEV were detected in brain samples of rodents using real-time RT-PCR. Detection of serum against JEV-reactive antibodies was performed using indirect enzyme-linked immunosorbent assay and microneutralization test. In total, 198 rodents were collected from Guangzhou City and Xiamen City between November 2013 and May 2014. JEV RNA was not detected in 188 brain samples. Forty-four in 96 serum samples (45.8%) were positive for JEV-reactive IgG antibodies. The prevalence of neutralizing antibodies to against JEV-reactive in these serum samples was 61.5% (24/39), with titers ranging from 1:10 to 1:56. Rodents are not known to play a role in transmission of JEV in Asia, nor is there an evidence to support a role for rodents in transmission of other related flaviviruses in China. However, in the current study, we detected evidence of JEV-reactive antibodies in large numbers of Rattus norvegicus and Rattus losea Swinhoe. Further studies of rodents as potential hosts of JEV or other related flaviviruses are warranted.

  9. The Antigenic Structure of Zika Virus and Its Relation to Other Flaviviruses: Implications for Infection and Immunoprophylaxis.

    PubMed

    Heinz, Franz X; Stiasny, Karin

    2017-03-01

    Zika virus was discovered ∼70 years ago in Uganda and maintained a low profile as a human disease agent in Africa and Asia. Only recently has it caused explosive outbreaks in previously unaffected regions, first in Oceania and then in the Americas since 2015. Of special concern is the newly identified link between congenital malformations (especially microcephaly) and Zika virus infections during pregnancy. At present, it is unclear whether Zika virus changed its pathogenicity or whether the huge number of infections allowed the recognition of a previously cryptic pathogenic property. The purpose of this review is to discuss recent data on the molecular antigenic structure of Zika virus in the context of antibody-mediated neutralization and antibody-dependent enhancement (ADE) of infection, a phenomenon that has been implicated in the development of severe disease caused by the related dengue viruses. Emphasis is given to epitopes of antibodies that potently neutralize Zika virus and also to epitopes that provide antigenic links to other important human-pathogenic flaviviruses such as dengue, yellow fever, West Nile, Japanese encephalitis, and tick-borne encephalitis viruses. The antigenic cross talk between Zika and dengue viruses appears to be of special importance, since they cocirculate in many regions of endemicity and sequential infections are likely to occur frequently. New insights into the molecular antigenic structure of Zika virus and flaviviruses in general have provided the foundation for great progress made in developing Zika virus vaccines and antibodies for passive immunization.

  10. Noncoding Subgenomic Flavivirus RNA Is Processed by the Mosquito RNA Interference Machinery and Determines West Nile Virus Transmission by Culex pipiens Mosquitoes.

    PubMed

    Göertz, G P; Fros, J J; Miesen, P; Vogels, C B F; van der Bent, M L; Geertsema, C; Koenraadt, C J M; van Rij, R P; van Oers, M M; Pijlman, G P

    2016-11-15

    Flaviviruses, such as Zika virus, yellow fever virus, dengue virus, and West Nile virus (WNV), are a serious concern for human health. Flaviviruses produce an abundant noncoding subgenomic flavivirus RNA (sfRNA) in infected cells. sfRNA results from stalling of the host 5'-3' exoribonuclease XRN1/Pacman on conserved RNA structures in the 3' untranslated region (UTR) of the viral genomic RNA. sfRNA production is conserved in insect-specific, mosquito-borne, and tick-borne flaviviruses and flaviviruses with no known vector, suggesting a pivotal role for sfRNA in the flavivirus life cycle. Here, we investigated the function of sfRNA during WNV infection of Culex pipiens mosquitoes and evaluated its role in determining vector competence. An sfRNA1-deficient WNV was generated that displayed growth kinetics similar to those of wild-type WNV in both RNA interference (RNAi)-competent and -compromised mosquito cell lines. Small-RNA deep sequencing of WNV-infected mosquitoes indicated an active small interfering RNA (siRNA)-based antiviral response for both the wild-type and sfRNA1-deficient viruses. Additionally, we provide the first evidence that sfRNA is an RNAi substrate in vivo Two reproducible small-RNA hot spots within the 3' UTR/sfRNA of the wild-type virus mapped to RNA stem-loops SL-III and 3' SL, which stick out of the three-dimensional (3D) sfRNA structure model. Importantly, we demonstrate that sfRNA-deficient WNV displays significantly decreased infection and transmission rates in vivo when administered via the blood meal. Finally, we show that transmission and infection rates are not affected by sfRNA after intrathoracic injection, thereby identifying sfRNA as a key driver to overcome the mosquito midgut infection barrier. This is the first report to describe a key biological function of sfRNA for flavivirus infection of the arthropod vector, providing an explanation for the strict conservation of sfRNA production. Understanding the flavivirus transmission

  11. Visual SLAM Using Variance Grid Maps

    NASA Technical Reports Server (NTRS)

    Howard, Andrew B.; Marks, Tim K.

    2011-01-01

    An algorithm denoted Gamma-SLAM performs further processing, in real time, of preprocessed digitized images acquired by a stereoscopic pair of electronic cameras aboard an off-road robotic ground vehicle to build accurate maps of the terrain and determine the location of the vehicle with respect to the maps. Part of the name of the algorithm reflects the fact that the process of building the maps and determining the location with respect to them is denoted simultaneous localization and mapping (SLAM). Most prior real-time SLAM algorithms have been limited in applicability to (1) systems equipped with scanning laser range finders as the primary sensors in (2) indoor environments (or relatively simply structured outdoor environments). The few prior vision-based SLAM algorithms have been feature-based and not suitable for real-time applications and, hence, not suitable for autonomous navigation on irregularly structured terrain. The Gamma-SLAM algorithm incorporates two key innovations: Visual odometry (in contradistinction to wheel odometry) is used to estimate the motion of the vehicle. An elevation variance map (in contradistinction to an occupancy or an elevation map) is used to represent the terrain. The Gamma-SLAM algorithm makes use of a Rao-Blackwellized particle filter (RBPF) from Bayesian estimation theory for maintaining a distribution over poses and maps. The core idea of the RBPF approach is that the SLAM problem can be factored into two parts: (1) finding the distribution over robot trajectories, and (2) finding the map conditioned on any given trajectory. The factorization involves the use of a particle filter in which each particle encodes both a possible trajectory and a map conditioned on that trajectory. The base estimate of the trajectory is derived from visual odometry, and the map conditioned on that trajectory is a Cartesian grid of elevation variances. In comparison with traditional occupancy or elevation grid maps, the grid elevation variance

  12. The defect variance of random spherical harmonics

    NASA Astrophysics Data System (ADS)

    Marinucci, Domenico; Wigman, Igor

    2011-09-01

    The defect of a function f:M\\rightarrow {R} is defined as the difference between the measure of the positive and negative regions. In this paper, we begin the analysis of the distribution of defect of random Gaussian spherical harmonics. By an easy argument, the defect is non-trivial only for even degree and the expected value always vanishes. Our principal result is evaluating the defect variance, asymptotically in the high-frequency limit. As other geometric functionals of random eigenfunctions, the defect may be used as a tool to probe the statistical properties of spherical random fields, a topic of great interest for modern cosmological data analysis.

  13. The theory of variances in equilibrium reconstruction

    SciTech Connect

    Zakharov, Leonid E.; Lewandowski, Jerome; Foley, Elizabeth L.; Levinton, Fred M.; Yuh, Howard Y.; Drozdov, Vladimir; McDonald, D. C.

    2008-09-15

    The theory of variances of equilibrium reconstruction is presented. It complements existing practices with information regarding what kind of plasma characteristics can be reconstructed, how accurately, and what remains beyond the abilities of diagnostic systems. The {sigma}-curves, introduced by the present theory, give a quantitative assessment of quality of effectiveness of diagnostic systems in constraining equilibrium reconstructions. The theory also suggests a method for aligning the accuracy of measurements of different physical nature and for improvements of numerical algorithms used in reconstruction.

  14. Variance component estimates for alternative litter size traits in swine.

    PubMed

    Putz, A M; Tiezzi, F; Maltecca, C; Gray, K A; Knauer, M T

    2015-11-01

    Litter size at d 5 (LS5) has been shown to be an effective trait to increase total number born (TNB) while simultaneously decreasing preweaning mortality. The objective of this study was to determine the optimal litter size day for selection (i.e., other than d 5). Traits included TNB, number born alive (NBA), litter size at d 2, 5, 10, 30 (LS2, LS5, LS10, LS30, respectively), litter size at weaning (LSW), number weaned (NW), piglet mortality at d 30 (MortD30), and average piglet birth weight (BirthWt). Litter size traits were assigned to biological litters and treated as a trait of the sow. In contrast, NW was the number of piglets weaned by the nurse dam. Bivariate animal models included farm, year-season, and parity as fixed effects. Number born alive was fit as a covariate for BirthWt. Random effects included additive genetics and the permanent environment of the sow. Variance components were plotted for TNB, NBA, and LS2 to LS30 using univariate animal models to determine how variances changed over time. Additive genetic variance was minimized at d 7 in Large White and at d 14 in Landrace pigs. Total phenotypic variance for litter size traits decreased over the first 10 d and then stabilized. Heritability estimates increased between TNB and LS30. Genetic correlations between TNB, NBA, and LS2 to LS29 with LS30 plateaued within the first 10 d. A genetic correlation with LS30 of 0.95 was reached at d 4 for Large White and at d 8 for Landrace pigs. Heritability estimates ranged from 0.07 to 0.13 for litter size traits and MortD30. Birth weight had an h of 0.24 and 0.26 for Large White and Landrace pigs, respectively. Genetic correlations among LS30, LSW, and NW ranged from 0.97 to 1.00. In the Large White breed, genetic correlations between MortD30 with TNB and LS30 were 0.23 and -0.64, respectively. These correlations were 0.10 and -0.61 in the Landrace breed. A high genetic correlation of 0.98 and 0.97 was observed between LS10 and NW for Large White and

  15. Cosmic variance of the galaxy cluster weak lensing signal

    SciTech Connect

    Gruen, D.; Seitz, S.; Becker, M. R.; Friedrich, O.; Mana, A.

    2015-04-13

    Intrinsic variations of the projected density profiles of clusters of galaxies at fixed mass are a source of uncertainty for cluster weak lensing. We present a semi-analytical model to account for this effect, based on a combination of variations in halo concentration, ellipticity and orientation, and the presence of correlated haloes. We calibrate the parameters of our model at the 10 per cent level to match the empirical cosmic variance of cluster profiles at M200m ≈ 1014…1015h–1M, z = 0.25…0.5 in a cosmological simulation. We show that weak lensing measurements of clusters significantly underestimate mass uncertainties if intrinsic profile variations are ignored, and that our model can be used to provide correct mass likelihoods. Effects on the achievable accuracy of weak lensing cluster mass measurements are particularly strong for the most massive clusters and deep observations (with ≈20 per cent uncertainty from cosmic variance alone at M200m ≈ 1015h–1M and z = 0.25), but significant also under typical ground-based conditions. We show that neglecting intrinsic profile variations leads to biases in the mass-observable relation constrained with weak lensing, both for intrinsic scatter and overall scale (the latter at the 15 per cent level). Furthermore, these biases are in excess of the statistical errors of upcoming surveys and can be avoided if the cosmic variance of cluster profiles is accounted for.

  16. Heritable Environmental Variance Causes Nonlinear Relationships Between Traits: Application to Birth Weight and Stillbirth of Pigs

    PubMed Central

    Mulder, Herman A.; Hill, William G.; Knol, Egbert F.

    2015-01-01

    There is recent evidence from laboratory experiments and analysis of livestock populations that not only the phenotype itself, but also its environmental variance, is under genetic control. Little is known about the relationships between the environmental variance of one trait and mean levels of other traits, however. A genetic covariance between these is expected to lead to nonlinearity between them, for example between birth weight and survival of piglets, where animals of extreme weights have lower survival. The objectives were to derive this nonlinear relationship analytically using multiple regression and apply it to data on piglet birth weight and survival. This study provides a framework to study such nonlinear relationships caused by genetic covariance of environmental variance of one trait and the mean of the other. It is shown that positions of phenotypic and genetic optima may differ and that genetic relationships are likely to be more curvilinear than phenotypic relationships, dependent mainly on the environmental correlation between these traits. Genetic correlations may change if the population means change relative to the optimal phenotypes. Data of piglet birth weight and survival show that the presence of nonlinearity can be partly explained by the genetic covariance between environmental variance of birth weight and survival. The framework developed can be used to assess effects of artificial and natural selection on means and variances of traits and the statistical method presented can be used to estimate trade-offs between environmental variance of one trait and mean levels of others. PMID:25631318

  17. Heritable environmental variance causes nonlinear relationships between traits: application to birth weight and stillbirth of pigs.

    PubMed

    Mulder, Herman A; Hill, William G; Knol, Egbert F

    2015-04-01

    There is recent evidence from laboratory experiments and analysis of livestock populations that not only the phenotype itself, but also its environmental variance, is under genetic control. Little is known about the relationships between the environmental variance of one trait and mean levels of other traits, however. A genetic covariance between these is expected to lead to nonlinearity between them, for example between birth weight and survival of piglets, where animals of extreme weights have lower survival. The objectives were to derive this nonlinear relationship analytically using multiple regression and apply it to data on piglet birth weight and survival. This study provides a framework to study such nonlinear relationships caused by genetic covariance of environmental variance of one trait and the mean of the other. It is shown that positions of phenotypic and genetic optima may differ and that genetic relationships are likely to be more curvilinear than phenotypic relationships, dependent mainly on the environmental correlation between these traits. Genetic correlations may change if the population means change relative to the optimal phenotypes. Data of piglet birth weight and survival show that the presence of nonlinearity can be partly explained by the genetic covariance between environmental variance of birth weight and survival. The framework developed can be used to assess effects of artificial and natural selection on means and variances of traits and the statistical method presented can be used to estimate trade-offs between environmental variance of one trait and mean levels of others. Copyright © 2015 by the Genetics Society of America.

  18. Multivariate Granger causality and generalized variance.

    PubMed

    Barrett, Adam B; Barnett, Lionel; Seth, Anil K

    2010-04-01

    Granger causality analysis is a popular method for inference on directed interactions in complex systems of many variables. A shortcoming of the standard framework for Granger causality is that it only allows for examination of interactions between single (univariate) variables within a system, perhaps conditioned on other variables. However, interactions do not necessarily take place between single variables but may occur among groups or "ensembles" of variables. In this study we establish a principled framework for Granger causality in the context of causal interactions among two or more multivariate sets of variables. Building on Geweke's seminal 1982 work, we offer additional justifications for one particular form of multivariate Granger causality based on the generalized variances of residual errors. Taken together, our results support a comprehensive and theoretically consistent extension of Granger causality to the multivariate case. Treated individually, they highlight several specific advantages of the generalized variance measure, which we illustrate using applications in neuroscience as an example. We further show how the measure can be used to define "partial" Granger causality in the multivariate context and we also motivate reformulations of "causal density" and "Granger autonomy." Our results are directly applicable to experimental data and promise to reveal new types of functional relations in complex systems, neural and otherwise.

  19. Multivariate Granger causality and generalized variance

    NASA Astrophysics Data System (ADS)

    Barrett, Adam B.; Barnett, Lionel; Seth, Anil K.

    2010-04-01

    Granger causality analysis is a popular method for inference on directed interactions in complex systems of many variables. A shortcoming of the standard framework for Granger causality is that it only allows for examination of interactions between single (univariate) variables within a system, perhaps conditioned on other variables. However, interactions do not necessarily take place between single variables but may occur among groups or “ensembles” of variables. In this study we establish a principled framework for Granger causality in the context of causal interactions among two or more multivariate sets of variables. Building on Geweke’s seminal 1982 work, we offer additional justifications for one particular form of multivariate Granger causality based on the generalized variances of residual errors. Taken together, our results support a comprehensive and theoretically consistent extension of Granger causality to the multivariate case. Treated individually, they highlight several specific advantages of the generalized variance measure, which we illustrate using applications in neuroscience as an example. We further show how the measure can be used to define “partial” Granger causality in the multivariate context and we also motivate reformulations of “causal density” and “Granger autonomy.” Our results are directly applicable to experimental data and promise to reveal new types of functional relations in complex systems, neural and otherwise.

  20. River meanders - Theory of minimum variance

    USGS Publications Warehouse

    Langbein, Walter Basil; Leopold, Luna Bergere

    1966-01-01

    Meanders are the result of erosion-deposition processes tending toward the most stable form in which the variability of certain essential properties is minimized. This minimization involves the adjustment of the planimetric geometry and the hydraulic factors of depth, velocity, and local slope.The planimetric geometry of a meander is that of a random walk whose most frequent form minimizes the sum of the squares of the changes in direction in each successive unit length. The direction angles are then sine functions of channel distance. This yields a meander shape typically present in meandering rivers and has the characteristic that the ratio of meander length to average radius of curvature in the bend is 4.7.Depth, velocity, and slope are shown by field observations to be adjusted so as to decrease the variance of shear and the friction factor in a meander curve over that in an otherwise comparable straight reach of the same riverSince theory and observation indicate meanders achieve the minimum variance postulated, it follows that for channels in which alternating pools and riffles occur, meandering is the most probable form of channel geometry and thus is more stable geometry than a straight or nonmeandering alinement.

  1. Characterization of an insect-specific flavivirus (OCFVPT) co-isolated from Ochlerotatus caspius collected in southern Portugal along with a putative new Negev-like virus.

    PubMed

    Ferreira, Daniela Duque; Cook, Shelley; Lopes, Ângela; de Matos, António Pedro; Esteves, Aida; Abecasis, Ana; de Almeida, António Paulo Gouveia; Piedade, João; Parreira, Ricardo

    2013-12-01

    We describe the isolation and characterization of an insect-specific flavivirus (ISF) from Ochlerotatus caspius (Pallas, 1771) mosquitoes collected in southern Portugal. The RNA genome of this virus, tentatively designated OCFVPT, for O. caspius flavivirus from Portugal, encodes a polyprotein showing all the features expected for a flavivirus. As frequently observed for ISF, the viral genomes seems to encode a putative Fairly Interesting Flavivirus ORF (FIFO)-like product, the synthesis of which would occur as a result of a -1 translation frameshift event. OCFVPT was isolated in the C6/36 Stegomyia albopicta (= Aedes albopictus) cell line where it replicates rapidly, but failed to replicate in Vero cells in common with other ISFs. Unlike some of the latter, however, the OCFVPT genome does not seem to be integrated in the mosquito cells we tested. Phylogenetic analyses based on partial ISF NS5 nucleotide sequences placed OCFVPT among recently published viral strains documented from mosquitoes collected in the Iberian Peninsula, while analyses of ORF/E/NS3/or NS5 amino acid sequences cluster OCFVPT with HANKV (Hanko virus), an ISF recently isolated from O. caspius mosquitoes collected in Finland. Taking into account the genetic relatedness with this virus, OCFVPT is not expected to be overtly cytopathic to C6/36 cells. The cytopathic effects associated with its presence in culture supernatants are postulated to be the result of the replication of a co-isolated putative new Negev-like virus.

  2. Flavivirus cross-reactivity in serological tests and Guillain-Barré syndrome in a hematopoietic stem cell transplant patient: A case report.

    PubMed

    Raboni, Sonia M; Bonfim, Carmem; Almeida, Bernardo M; Zanluca, Camila; Koishi, Andrea C; Rodrigues, Paula R V P; Kay, Claudia K; Ribeiro, Lisandro L; Scola, Rosana H; Duarte Dos Santos, Claudia N

    2017-03-17

    Serological diagnosis of flavivirus infection is a challenge, particularly in the context of a disease associated with immune response enhancement in a transplant patient, where aspects such as previous flavivirus infections may be involved with the outcome. We report a case of a pediatric patient who developed Guillain-Barré syndrome (GBS) after matched-unrelated hematopoietic stem cell transplantation (HSCT). The patient lives in a Brazilian region that is experiencing an epidemic of Zika virus (ZIKV) and dengue virus (DENV). Because an increasing number of cases of GBS, likely triggered by ZIKV infection, are being reported in Brazil, samples from the patient were tested for both ZIKV and DENV infection. Serological assays strongly suggested a recent ZIKV infection, although infection by DENV or co-infection with both viruses cannot be ruled out. The presence of anti-DENV immunoglobulin-G in donor serum led to the hypothesis that antibodies from the donor could have enhanced the severity of the ZIKV infection. This hypothesis is in agreement with the recent findings that DENV sero-cross-reactivity drives antibody-dependent enhancement of ZIKV infection. These findings highlight the need for discussion of the indication to perform previous flavivirus tests in HSCT donors, especially in areas where ZIKV and other flaviviruses co-circulate. This article is protected by copyright. All rights reserved.

  3. A novel insect-specific flavivirus replicates only in Aedes-derived cells and persists at high prevalence in wild Aedes vigilax populations in Sydney, Australia.

    PubMed

    McLean, Breeanna J; Hobson-Peters, Jody; Webb, Cameron E; Watterson, Daniel; Prow, Natalie A; Nguyen, Hong Duyen; Hall-Mendelin, Sonja; Warrilow, David; Johansen, Cheryl A; Jansen, Cassie C; van den Hurk, Andrew F; Beebe, Nigel W; Schnettler, Esther; Barnard, Ross T; Hall, Roy A

    2015-12-01

    To date, insect-specific flaviviruses (ISFs) have only been isolated from mosquitoes and increasing evidence suggests that ISFs may affect the transmission of pathogenic flaviviruses. To investigate the diversity and prevalence of ISFs in Australian mosquitoes, samples from various regions were screened for flaviviruses by ELISA and RT-PCR. Thirty-eight pools of Aedes vigilax from Sydney in 2007 yielded isolates of a novel flavivirus, named Parramatta River virus (PaRV). Sequencing of the viral RNA genome revealed it was closely related to Hanko virus with 62.3% nucleotide identity over the open reading frame. PaRV failed to grow in vertebrate cells, with only Aedes-derived mosquito cell lines permissive to replication, suggesting a narrow host range. 2014 collections revealed that PaRV had persisted in A. vigilax populations in Sydney, with 88% of pools positive. Further investigations into its mode of transmission and potential to influence vector competence of A. vigilax for pathogenic viruses are warranted. Copyright © 2015. Published by Elsevier Inc.

  4. Flavivirus-cross-reactive, HLA-DR15-restricted epitope on NS3 recognized by human CD4+ CD8- cytotoxic T lymphocyte clones.

    PubMed

    Kurane, I; Okamoto, Y; Dai, L C; Zeng, L L; Brinton, M A; Ennis, F A

    1995-09-01

    The role of flavivirus-cross-reactive T lymphocytes in recovery from and pathogenesis of flavivirus infections is not known. In the present paper, we have defined a flavivirus-cross-reactive epitope recognized by two CD4+ CD8- cytotoxic T lymphocyte (CTL) clones, JK4 and JK43. The T cell clones were established from the peripheral blood T lymphocytes of a dengue-4-immune donor, using a limiting-dilution method with dengue-4 antigen. These two T cell clones were cross-reactive for dengue virus types 1, 2, 3 and 4, yellow fever virus and West Nile virus, and recognized NS3 protein. The smallest synthetic peptide recognized by these T cell clones was an identical 9 amino acid peptide which contains amino acids 146 to 154 (VIGLYGNGV) of dengue-4 NS3. HLA-DR15 was the restriction allele for recognition of this epitope by JK4 and JK43. JK4 and JK43 both used T cell receptor V alpha 8, but JK4 used V beta 8 and JK43 used V beta 2. This result indicates that this epitope is recognized by two flavivirus-cross-reactive CD4+ T cell clones which originated from different T cells in vivo.

  5. Approaches for the Development of Rapid Serological Assays for Surveillance and Diagnosis of Infections Caused by Zoonotic Flaviviruses of the Japanese Encephalitis Virus Serocomplex

    PubMed Central

    Hobson-Peters, Jody

    2012-01-01

    Flaviviruses are responsible for a number of important mosquito-borne diseases of man and animals globally. The short vireamic period in infected hosts means that serological assays are often the diagnostic method of choice. This paper will focus on the traditional methods to diagnose flaviviral infections as well as describing the modern rapid platforms and approaches for diagnostic antigen preparation. PMID:22570528

  6. The latitude dependence of the variance of zonally averaged quantities. [in polar meteorology with attention to geometrical effects of earth

    NASA Technical Reports Server (NTRS)

    North, G. R.; Bell, T. L.; Cahalan, R. F.; Moeng, F. J.

    1982-01-01

    Geometric characteristics of the spherical earth are shown to be responsible for the increase of variance with latitude of zonally averaged meteorological statistics. An analytic model is constructed to display the effect of a spherical geometry on zonal averages, employing a sphere labeled with radial unit vectors in a real, stochastic field expanded in complex spherical harmonics. The variance of a zonally averaged field is found to be expressible in terms of the spectrum of the vector field of the spherical harmonics. A maximum variance is then located at the poles, and the ratio of the variance to the zonally averaged grid-point variance, weighted by the cosine of the latitude, yields the zonal correlation typical of the latitude. An example is provided for the 500 mb level in the Northern Hemisphere compared to 15 years of data. Variance is determined to increase north of 60 deg latitude.

  7. The latitude dependence of the variance of zonally averaged quantities. [in polar meteorology with attention to geometrical effects of earth

    NASA Technical Reports Server (NTRS)

    North, G. R.; Bell, T. L.; Cahalan, R. F.; Moeng, F. J.

    1982-01-01

    Geometric characteristics of the spherical earth are shown to be responsible for the increase of variance with latitude of zonally averaged meteorological statistics. An analytic model is constructed to display the effect of a spherical geometry on zonal averages, employing a sphere labeled with radial unit vectors in a real, stochastic field expanded in complex spherical harmonics. The variance of a zonally averaged field is found to be expressible in terms of the spectrum of the vector field of the spherical harmonics. A maximum variance is then located at the poles, and the ratio of the variance to the zonally averaged grid-point variance, weighted by the cosine of the latitude, yields the zonal correlation typical of the latitude. An example is provided for the 500 mb level in the Northern Hemisphere compared to 15 years of data. Variance is determined to increase north of 60 deg latitude.

  8. Hidden temporal order unveiled in stock market volatility variance

    NASA Astrophysics Data System (ADS)

    Shapira, Y.; Kenett, D. Y.; Raviv, Ohad; Ben-Jacob, E.

    2011-06-01

    When analyzed by standard statistical methods, the time series of the daily return of financial indices appear to behave as Markov random series with no apparent temporal order or memory. This empirical result seems to be counter intuitive since investor are influenced by both short and long term past market behaviors. Consequently much effort has been devoted to unveil hidden temporal order in the market dynamics. Here we show that temporal order is hidden in the series of the variance of the stocks volatility. First we show that the correlation between the variances of the daily returns and means of segments of these time series is very large and thus cannot be the output of random series, unless it has some temporal order in it. Next we show that while the temporal order does not show in the series of the daily return, rather in the variation of the corresponding volatility series. More specifically, we found that the behavior of the shuffled time series is equivalent to that of a random time series, while that of the original time series have large deviations from the expected random behavior, which is the result of temporal structure. We found the same generic behavior in 10 different stock markets from 7 different countries. We also present analysis of specially constructed sequences in order to better understand the origin of the observed temporal order in the market sequences. Each sequence was constructed from segments with equal number of elements taken from algebraic distributions of three different slopes.

  9. Genomic and antigenic characterization of the newly emerging Chinese duck egg-drop syndrome flavivirus: genomic comparison with Tembusu and Sitiawan viruses.

    PubMed

    Liu, Peipei; Lu, Hao; Li, Shuang; Moureau, Gregory; Deng, Yong-Qiang; Wang, Yongyue; Zhang, Lijiao; Jiang, Tao; de Lamballerie, Xavier; Qin, Cheng-Feng; Gould, Ernest A; Su, Jingliang; Gao, George F

    2012-10-01

    Duck egg-drop syndrome virus (DEDSV) is a newly emerging pathogenic flavivirus causing avian diseases in China. The infection occurs in laying ducks characterized by a severe drop in egg production with a fatality rate of 5-15 %. The virus was found to be most closely related to Tembusu virus (TMUV), an isolate from mosquitoes in South-east Asia. Here, we have sequenced and characterized the full-length genomes of seven DEDSV strains, including the 5'- and 3'-non-coding regions (NCRs). We also report for the first time the ORF sequences of TMUV and Sitiawan virus (STWV), another closely related flavivirus isolated from diseased chickens. We analysed the phylogenetic and antigenic relationships of DEDSV in relation to the Asian viruses TMUV and STWV, and other representative flaviviruses. Our results confirm the close relationship between DEDSV and TMUV/STWV and we discuss their probable evolutionary origins. We have also characterized the cleavage sites, potential glycosylation sites and unique motifs/modules of these viruses. Additionally, conserved sequences in both 5'- and 3'-NCRs were identified and the predicted secondary structures of the terminal sequences were studied. Antigenic cross-reactivity comparisons of DEDSV with related pathogenic flaviviruses identified a surprisingly close relationship with dengue virus (DENV) and raised the question of whether or not DEDSV may have a potential infectious threat to man. Importantly, DEDSV can be efficiently recognized by a broadly cross-reactive flavivirus mAb, 2A10G6, derived against DENV. The significance of these studies is discussed in the context of the emergence, evolution, epidemiology, antigenicity and pathogenicity of the newly emergent DEDSV.

  10. A new insect-specific flavivirus from northern Australia suppresses replication of West Nile virus and Murray Valley encephalitis virus in co-infected mosquito cells.

    PubMed

    Hobson-Peters, Jody; Yam, Alice Wei Yee; Lu, Jennifer Wei Fei; Setoh, Yin Xiang; May, Fiona J; Kurucz, Nina; Walsh, Susan; Prow, Natalie A; Davis, Steven S; Weir, Richard; Melville, Lorna; Hunt, Neville; Webb, Richard I; Blitvich, Bradley J; Whelan, Peter; Hall, Roy A

    2013-01-01

    Recent reports of a novel group of flaviviruses that replicate only in mosquitoes and appear to spread through insect populations via vertical transmission have emerged from around the globe. To date, there is no information on the presence or prevalence of these insect-specific flaviviruses (ISFs) in Australian mosquito species. To assess whether such viruses occur locally, we used reverse transcription-polymerase chain reaction (RT-PCR) and flavivirus universal primers that are specific to the NS5 gene to detect these viruses in mosquito pools collected from the Northern Territory. Of 94 pools of mosquitoes, 13 were RT-PCR positive, and of these, 6 flavivirus isolates were obtained by inoculation of mosquito cell culture. Sequence analysis of the NS5 gene revealed that these isolates are genetically and phylogenetically similar to ISFs reported from other parts of the world. The entire coding region of one isolate (designated 56) was sequenced and shown to have approximately 63.7% nucleotide identity and 66.6% amino acid identity with its closest known relative (Nakiwogo virus) indicating that the prototype Australian ISF represents a new species. All isolates were obtained from Coquillettidia xanthogaster mosquitoes. The new virus is tentatively named Palm Creek virus (PCV) after its place of isolation. We also demonstrated that prior infection of cultured mosquito cells with PCV suppressed subsequent replication of the medically significant West Nile and Murray Valley encephalitis viruses by 10-43 fold (1 to 1.63 log) at 48 hr post-infection, suggesting that superinfection exclusion can occur between ISFs and vertebrate-infecting flaviviruses despite their high level of genetic diversity. We also generated several monoclonal antibodies (mAbs) that are specific to the NS1 protein of PCV, and these represent the first ISF-specific mAbs reported to date.

  11. A New Insect-Specific Flavivirus from Northern Australia Suppresses Replication of West Nile Virus and Murray Valley Encephalitis Virus in Co-infected Mosquito Cells

    PubMed Central

    Hobson-Peters, Jody; Yam, Alice Wei Yee; Lu, Jennifer Wei Fei; Setoh, Yin Xiang; May, Fiona J.; Kurucz, Nina; Walsh, Susan; Prow, Natalie A.; Davis, Steven S.; Weir, Richard; Melville, Lorna; Hunt, Neville; Webb, Richard I.; Blitvich, Bradley J.; Whelan, Peter; Hall, Roy A.

    2013-01-01

    Recent reports of a novel group of flaviviruses that replicate only in mosquitoes and appear to spread through insect populations via vertical transmission have emerged from around the globe. To date, there is no information on the presence or prevalence of these insect-specific flaviviruses (ISFs) in Australian mosquito species. To assess whether such viruses occur locally, we used reverse transcription-polymerase chain reaction (RT-PCR) and flavivirus universal primers that are specific to the NS5 gene to detect these viruses in mosquito pools collected from the Northern Territory. Of 94 pools of mosquitoes, 13 were RT-PCR positive, and of these, 6 flavivirus isolates were obtained by inoculation of mosquito cell culture. Sequence analysis of the NS5 gene revealed that these isolates are genetically and phylogenetically similar to ISFs reported from other parts of the world. The entire coding region of one isolate (designated 56) was sequenced and shown to have approximately 63.7% nucleotide identity and 66.6% amino acid identity with its closest known relative (Nakiwogo virus) indicating that the prototype Australian ISF represents a new species. All isolates were obtained from Coquillettidia xanthogaster mosquitoes. The new virus is tentatively named Palm Creek virus (PCV) after its place of isolation. We also demonstrated that prior infection of cultured mosquito cells with PCV suppressed subsequent replication of the medically significant West Nile and Murray Valley encephalitis viruses by 10–43 fold (1 to 1.63 log) at 48 hr post-infection, suggesting that superinfection exclusion can occur between ISFs and vertebrate-infecting flaviviruses despite their high level of genetic diversity. We also generated several monoclonal antibodies (mAbs) that are specific to the NS1 protein of PCV, and these represent the first ISF-specific mAbs reported to date. PMID:23460804

  12. The variance of the adjusted Rand index.

    PubMed

    Steinley, Douglas; Brusco, Michael J; Hubert, Lawrence

    2016-06-01

    For 30 years, the adjusted Rand index has been the preferred method for comparing 2 partitions (e.g., clusterings) of a set of observations. Although the index is widely used, little is known about its variability. Herein, the variance of the adjusted Rand index (Hubert & Arabie, 1985) is provided and its properties are explored. It is shown that a normal approximation is appropriate across a wide range of sample sizes and varying numbers of clusters. Further, it is shown that confidence intervals based on the normal distribution have desirable levels of coverage and accuracy. Finally, the first power analysis evaluating the ability to detect differences between 2, different adjusted Rand indices is provided. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  13. Applications of Variance Fractal Dimension: a Survey

    NASA Astrophysics Data System (ADS)

    Phinyomark, Angkoon; Phukpattaranont, Pornchai; Limsakul, Chusak

    2012-04-01

    Chaotic dynamical systems are pervasive in nature and can be shown to be deterministic through fractal analysis. There are numerous methods that can be used to estimate the fractal dimension. Among the usual fractal estimation methods, variance fractal dimension (VFD) is one of the most significant fractal analysis methods that can be implemented for real-time systems. The basic concept and theory of VFD are presented. Recent research and the development of several applications based on VFD are reviewed and explained in detail, such as biomedical signal processing and pattern recognition, speech communication, geophysical signal analysis, power systems and communication systems. The important parameters that need to be considered in computing the VFD are discussed, including the window size and the window increment of the feature, and the step size of the VFD. Directions for future research of VFD are also briefly outlined.

  14. Variance estimation for the Federal Waterfowl Harvest Surveys

    USGS Publications Warehouse

    Geissler, P.H.

    1988-01-01

    The Federal Waterfowl Harvest Surveys provide estimates of waterfowl harvest by species for flyways and states, harvests of most other migratory game bird species (by waterfowl hunters), crippling losses for ducks, geese, and coots, days hunted, and bag per hunter. The Waterfowl Hunter Questionnaire Survey separately estimates the harvest of ducks and geese using cluster samples of hunters who buy duck stamps at sample post offices. The Waterfowl Parts Collection estimates species, age, and sex ratios from parts solicited from successful hunters who responded to the Waterfowl Hunter Questionnaire Survey in previous years. These ratios are used to partition the duck and goose harvest into species, age, and sex specific harvest estimates. Annual estimates are correlated because successful hunters who respond to the Questionnaire Survey in one year may be asked to contribute to the Parts Collection for the next three years. Bootstrap variance estimates are used because covariances among years are difficult to estimate.

  15. Variance of vestibular-evoked myogenic potentials.

    PubMed

    Ochi, K; Ohashi, T; Nishino, H

    2001-03-01

    Vestibular-evoked myogenic potential (VEMP) has been thought to originate from sacculus. The variance of this potential and the effectiveness of the adjustments of pInII amplitudes using average muscle tonus of ipsilateral sternocleidomastoid muscle were evaluated. In addition, clinical application of VEMP was examined in patients with acoustic tumors (ATs) and vestibular neurolabyrinthitis (VNL). Prospective evaluation of the VEMP in 18 normal volunteers and 6 patients. Variance and left-right difference of each parameter, including pI latency, nII latency, pInII amplitude, and threshold, was analyzed. Input-output function of pInII amplitude was evaluated. Average muscle tonus was calculated in 20 ears and applied for adjustment of pInII amplitude. Sensitivity of each parameter of VEMP was examined in 3 patients with ATs and 3 patients with VNL. VEMP was present in all 36 ears of 18 control subjects. Thresholds of VEMP for normal subjects were 80 to 95 dB normal hearing level (nHL). The muscle tonus affected pInII amplitude significantly; however, no statistically significant improvement was observed in test-retest investigation after adjustment using muscle tonus. The threshold of the affected side was elevated compared with the non-affected side in all patients with ATs, whereas 2 of 3 patients showed normal pInII-ratio. One patient with VNL presented normal VEMP, whereas 2 patients presented no VEMP to the highest stimulus intensity. Interaural difference of thresholds might be the most useful parameters. Adjustment using average muscle tonus is not necessary when the subject is able to get sufficient muscle tonus.

  16. Isolation and sequence analysis of Culex flavivirus from Culex interrogator and Culex quinquefasciatus in the Yucatan Peninsula of Mexico

    PubMed Central

    Saiyasombat, Rungrat; Dorman, Karin S.; Garcia-Rejon, Julian E.; Loroño-Pino, Maria A.; Farfan-Ale, Jose A.

    2010-01-01

    Previously, we reported a high prevalence of Culex flavivirus (CxFV) in Culex quinquefasciatus (Say) in the Yucatan Peninsula of Mexico. To determine whether other Culex spp. mosquitoes in this region are susceptible to natural CxFV infection, Cx. bahamensis (Dyar and Knab), Cx. coronator (Dyar and Knab), Cx. interrogator (Dyar and Knab), Cx. nigripalpus (Theobald) and Cx. opisthopus (Komp) in the Yucatan Peninsula of Mexico were tested for CxFV. Two pools of Cx. interrogator were positive. The envelope protein genes of these isolates and 16 isolates from Cx. quinquefasciatus were sequenced and shown to have ≥99.2% nucleotide identity. These data suggest that there is limited genetic diversity among CxFV isolates in the Yucatan Peninsula of Mexico. PMID:20379749

  17. Tick-borne flavivirus infection in Ixodes scapularis larvae: development of a novel method for synchronous viral infection of ticks

    PubMed Central

    Mitzel, Dana N.; Wolfinbarger, James B.; Daniel Long, R.; Masnick, Max; Best, Sonja M.; Bloom, Marshall E.

    2007-01-01

    Following a bite from an infected tick, tick-borne flaviviruses cause encephalitis, meningitis and hemorrhagic fever in humans. Although these viruses spend most of their time in the tick, little is known regarding the virus-vector interactions. We developed a simple method for synchronously infecting Ixodes scapularis larvae with Langat virus (LGTV) by immersion in media containing the virus. This technique resulted in approximately 96% of ticks becoming infected. LGTV infection and replication were demonstrated by both viral antigen expression and the accumulation of viral RNA. Furthermore, ticks transmitted LGTV to 100% of the mice and maintained the virus through molting into the next life stage. This technique circumvents limitations present in the current methods by mimicking the natural route of infection and by using attenuated virus strains to infect ticks; thereby, making this technique a powerful tool to study both virus and tick determinants of replication, pathogenesis and transmission. PMID:17490700

  18. Emergence of Usutu virus, an African mosquito-borne flavivirus of the Japanese encephalitis virus group, central Europe.

    PubMed

    Weissenböck, Herbert; Kolodziejek, Jolanta; Url, Angelika; Lussy, Helga; Rebel-Bauder, Barbara; Nowotny, Norbert

    2002-07-01

    During late summer 2001 in Austria, a series of deaths in several species of birds occurred, similar to the beginning of the West Nile virus (WNV) epidemic in the United States. We necropsied the dead birds and examined them by various methods; pathologic and immunohistologic investigations suggested a WNV infection. Subsequently, the virus was isolated, identified, partially sequenced, and subjected to phylogenetic analysis. The isolates exhibited 97% identity to Usutu virus (USUV), a mosquito-borne Flavivirus of the Japanese encephalitis virus group; USUV has never previously been observed outside Africa nor associated with fatal disease in animals or humans. If established in central Europe, this virus may have considerable effects on avian populations; whether USUV has the potential to cause severe human disease is unknown.

  19. Tick-borne flavivirus infection in Ixodes scapularis larvae: development of a novel method for synchronous viral infection of ticks.

    PubMed

    Mitzel, Dana N; Wolfinbarger, James B; Long, R Daniel; Masnick, Max; Best, Sonja M; Bloom, Marshall E

    2007-09-01

    Following a bite from an infected tick, tick-borne flaviviruses cause encephalitis, meningitis and hemorrhagic fever in humans. Although these viruses spend most of their time in the tick, little is known regarding the virus-vector interactions. We developed a simple method for synchronously infecting Ixodes scapularis larvae with Langat virus (LGTV) by immersion in media containing the virus. This technique resulted in approximately 96% of ticks becoming infected. LGTV infection and replication were demonstrated by both viral antigen expression and the accumulation of viral RNA. Furthermore, ticks transmitted LGTV to 100% of the mice and maintained the virus through molting into the next life stage. This technique circumvents limitations present in the current methods by mimicking the natural route of infection and by using attenuated virus strains to infect ticks, thereby making this technique a powerful tool to study both virus and tick determinants of replication, pathogenesis and transmission.

  20. Variance of the quantum dwell time for a nonrelativistic particle

    NASA Astrophysics Data System (ADS)

    Hahne, G. E.

    2013-01-01

    Muñoz, Seidel, and Muga [Phys. Rev. A 79, 012108 (2009), 10.1103/PhysRevA.79.012108], following an earlier proposal by Pollak and Miller [Phys. Rev. Lett. 53, 115 (1984), 10.1103/PhysRevLett.53.115] in the context of a theory of a collinear chemical reaction, showed that suitable moments of a two-flux correlation function could be manipulated to yield expressions for the mean quantum dwell time and mean square quantum dwell time for a structureless particle scattering from a time-independent potential energy field between two parallel lines in a two-dimensional spacetime. The present work proposes a generalization to a charged, nonrelativistic particle scattering from a transient, spatially confined electromagnetic vector potential in four-dimensional spacetime. The geometry of the spacetime domain is that of the slab between a pair of parallel planes, in particular, those defined by constant values of the third (z) spatial coordinate. The mean Nth power, N = 1, 2, 3, …, of the quantum dwell time in the slab is given by an expression involving an N-flux-correlation function. All these means are shown to be nonnegative. The N = 1 formula reduces to an S-matrix result published previously [G. E. Hahne, J. Phys. A 36, 7149 (2003), 10.1088/0305-4470/36/25/316]; an explicit formula for N = 2, and of the variance of the dwell time in terms of the S-matrix, is worked out. A formula representing an incommensurability principle between variances of the output-minus-input flux of a pair of dynamical variables (such as the particle's time flux and others) is derived.