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Sample records for model linking viral

  1. Molecular modeling and conformational analysis of native and refolded viral genome-linked protein of cardamom mosaic virus.

    PubMed

    Jebasingh, T; Jose, M; Yadunandam, A Kasin; Backiyarani, S; Srividhya, K V; Krishnaswamy, S; Usha, R

    2011-10-01

    The viral genome-linked protein (VPg) of Potyviruses is covalently attached to the 5' end of the genomic RNA. Towards biophysical characterization, the VPg coding region of Cardamom mosaic virus (CdMV) was amplified from the cDNA and expressed in E. coli. Most of the expressed VPg aggregated as inclusion bodies that were solubilized with urea and refolded with L-arginine hydrochloride. The various forms of CdMV VPg (native, denatured and refolded) were purified and the conformational variations between these forms were observed with fluorescence spectroscopy. Native and refolded CdMV VPg showed unordered secondary structure in the circular dichroism (CD) spectrum. The model of CdMV VPg was built based on the crystal structure of phosphotriesterase (from Pseudomonas diminuta), which had the maximum sequence homology with VPg to identify the arrangement of conserved amino acids in the protein to study the functional diversity of VPg. This is the first report on the VPg of CdMV, which is classified as a new member of the Macluravirus genus of the Potyviridae family. PMID:22165292

  2. Modeling Viral Capsid Assembly

    PubMed Central

    2014-01-01

    I present a review of the theoretical and computational methodologies that have been used to model the assembly of viral capsids. I discuss the capabilities and limitations of approaches ranging from equilibrium continuum theories to molecular dynamics simulations, and I give an overview of some of the important conclusions about virus assembly that have resulted from these modeling efforts. Topics include the assembly of empty viral shells, assembly around single-stranded nucleic acids to form viral particles, and assembly around synthetic polymers or charged nanoparticles for nanotechnology or biomedical applications. I present some examples in which modeling efforts have promoted experimental breakthroughs, as well as directions in which the connection between modeling and experiment can be strengthened. PMID:25663722

  3. Stochastic models of viral infection

    NASA Astrophysics Data System (ADS)

    Chou, Tom

    2009-03-01

    We develop biophysical models of viral infections from a stochastic process perspective. The entry of enveloped viruses is treated as a stochastic multiple receptor and coreceptor engagement process that can lead to membrane fusion or endocytosis. The probabilities of entry via fusion and endocytosis are computed as functions of the receptor/coreceptor engagement rates. Since membrane fusion and endocytosis entry pathways can lead to very different infection outcomes, we delineate the parameter regimes conducive to each entry pathway. After entry, viral material is biochemically processed and degraded as it is transported towards the nucleus. Productive infections occur only when the material reaches the nucleus in the proper biochemical state. Thus, entry into the nucleus in an infectious state requires the proper timing of the cytoplasmic transport process. We compute the productive infection probability and show its nonmonotonic dependence on both transport speeds and biochemical transformation rates. Our results carry subtle consequences on the dosage and efficacy of antivirals such as reverse transcription inhibitors.

  4. Viral kinetic modeling: state of the art

    SciTech Connect

    Canini, Laetitia; Perelson, Alan S.

    2014-06-25

    Viral kinetic modeling has led to increased understanding of the within host dynamics of viral infections and the effects of therapy. Here we review recent developments in the modeling of viral infection kinetics with emphasis on two infectious diseases: hepatitis C and influenza. We review how viral kinetic modeling has evolved from simple models of viral infections treated with a drug or drug cocktail with an assumed constant effectiveness to models that incorporate drug pharmacokinetics and pharmacodynamics, as well as phenomenological models that simply assume drugs have time varying-effectiveness. We also discuss multiscale models that include intracellular events in viral replication, models of drug-resistance, models that include innate and adaptive immune responses and models that incorporate cell-to-cell spread of infection. Overall, viral kinetic modeling has provided new insights into the understanding of the disease progression and the modes of action of several drugs. In conclusion, we expect that viral kinetic modeling will be increasingly used in the coming years to optimize drug regimens in order to improve therapeutic outcomes and treatment tolerability for infectious diseases.

  5. Viral kinetic modeling: state of the art

    DOE PAGESBeta

    Canini, Laetitia; Perelson, Alan S.

    2014-06-25

    Viral kinetic modeling has led to increased understanding of the within host dynamics of viral infections and the effects of therapy. Here we review recent developments in the modeling of viral infection kinetics with emphasis on two infectious diseases: hepatitis C and influenza. We review how viral kinetic modeling has evolved from simple models of viral infections treated with a drug or drug cocktail with an assumed constant effectiveness to models that incorporate drug pharmacokinetics and pharmacodynamics, as well as phenomenological models that simply assume drugs have time varying-effectiveness. We also discuss multiscale models that include intracellular events in viralmore » replication, models of drug-resistance, models that include innate and adaptive immune responses and models that incorporate cell-to-cell spread of infection. Overall, viral kinetic modeling has provided new insights into the understanding of the disease progression and the modes of action of several drugs. In conclusion, we expect that viral kinetic modeling will be increasingly used in the coming years to optimize drug regimens in order to improve therapeutic outcomes and treatment tolerability for infectious diseases.« less

  6. Mathematical Modeling of Viral Zoonoses in Wildlife

    PubMed Central

    Allen, L. J. S.; Brown, V. L.; Jonsson, C. B.; Klein, S. L.; Laverty, S. M.; Magwedere, K.; Owen, J. C.; van den Driessche, P.

    2011-01-01

    Zoonoses are a worldwide public health concern, accounting for approximately 75% of human infectious diseases. In addition, zoonoses adversely affect agricultural production and wildlife. We review some mathematical models developed for the study of viral zoonoses in wildlife and identify areas where further modeling efforts are needed. PMID:22639490

  7. Gene Expression Profiles Link Respiratory Viral Infection, Platelet Response to Aspirin, and Acute Myocardial Infarction

    PubMed Central

    Cyr, Derek D.; Lucas, Joseph E.; Zaas, Aimee K.; Woods, Christopher W.; Newby, L. Kristin; Kraus, William E.; Ginsburg, Geoffrey S.

    2015-01-01

    Background Influenza infection is associated with myocardial infarction (MI), suggesting that respiratory viral infection may induce biologic pathways that contribute to MI. We tested the hypotheses that 1) a validated blood gene expression signature of respiratory viral infection (viral GES) was associated with MI and 2) respiratory viral exposure changes levels of a validated platelet gene expression signature (platelet GES) of platelet function in response to aspirin that is associated with MI. Methods A previously defined viral GES was projected into blood RNA data from 594 patients undergoing elective cardiac catheterization and used to classify patients as having evidence of viral infection or not and tested for association with acute MI using logistic regression. A previously defined platelet GES was projected into blood RNA data from 81 healthy subjects before and after exposure to four respiratory viruses: Respiratory Syncytial Virus (RSV) (n=20), Human Rhinovirus (HRV) (n=20), Influenza A virus subtype H1N1 (H1N1) (n=24), Influenza A Virus subtype H3N2 (H3N2) (n=17). We tested for the change in platelet GES with viral exposure using linear mixed-effects regression and by symptom status. Results In the catheterization cohort, 32 patients had evidence of viral infection based upon the viral GES, of which 25% (8/32) had MI versus 12.2% (69/567) among those without evidence of viral infection (OR 2.3; CI [1.03-5.5], p=0.04). In the infection cohorts, only H1N1 exposure increased platelet GES over time (time course p-value = 1e-04). Conclusions A viral GES of non-specific, respiratory viral infection was associated with acute MI; 18% of the top 49 genes in the viral GES are involved with hemostasis and/or platelet aggregation. Separately, H1N1 exposure, but not exposure to other respiratory viruses, increased a platelet GES previously shown to be associated with MI. Together, these results highlight specific genes and pathways that link viral infection

  8. Dynamic Models for Templated Viral Capsid Assembly

    NASA Astrophysics Data System (ADS)

    Hagan, Michael

    2008-03-01

    The replication of many viruses with single-stranded genomes requires the simultaneous assembly of an ordered protein shell, or capsid, and encapsidation of the genome. In this talk, I will present coarse-grained computational and theoretical models that describe the assembly of viral capsid proteins around interior cores, such as polymers and rigid spheres. These models are motivated by two recently developed experimental model systems in which viral proteins dynamically encapsidate inorganic nanoparticles and polyelectrolytes. Model predictions suggest that some forms of cooperative interactions between subunits and cores can dramatically enhance rates and robustness of assembly, as compared to the spontaneous assembly of subunits into empty capsids. For large core-subunit interactions, subunits adsorb onto a core en masse in a disordered manner, and then undergo a cooperative rearrangement into an ordered capsid structure. These assembly pathways are unlike any seen for empty capsids formation. While model predictions suggest that cooperative interactions between disparate assembling components can overcome some limitations of spontaneous assembly, the complexity of multicomponent assembly introduces new forms of kinetic traps that can frustrate assembly, and hence introduces new limitations. These findings have implications for a mechanism in which viruses use interactions between proteins and genomic molecules to promote and control assembly, and thereby control the replication process.

  9. Herpesvirus-dependent amplification and inversion of cell-associated viral thymidine kinase gene flanked by viral a sequences and linked to an origin of viral DNA replication.

    PubMed Central

    Mocarski, E S; Roizman, B

    1982-01-01

    The genome of herpes simplex virus 1 or 2 consists of two components, L and S, which invert relative to each other during infection. As a result, viral DNA consists of four equimolar populations of molecules differing solely in the relative orientations of the L and S components. Previous studies have shown that the a sequences, located in the same orientation at the genomic termini and in inverted orientation at the L-S junction, play a key role in the inversion of L and S components. In this report we describe a virus-dependent system designed to allow identification of the viral genes capable of acting in trans to invert DNA flanked by inverted copies of a sequences. In this system, cells are converted to the thymidine kinase-positive phenotype with a chimeric plasmid carrying the thymidine kinase gene flanked by inverted copies of the a sequence and linked to an origin of viral DNA replication derived from the S component. The DNA introduced into the cells is retained and propagated in its original sequence arrangement as head-to-tail concatemers. Infection of these cells with herpes simplex virus 1 or 2 results in as much as 100-fold amplification of the plasmid sequences and inversion of the DNA flanked by copies of the a sequence. In infected cells, the amplified resident DNA accumulates in head-to-tail concatemers and no rearrangement other than the inversions could be detected. These results suggest that the a sequence-dependent inversions required trans-acting viral gene products. Images PMID:6291055

  10. Spatiotemporal modelling of viral infection dynamics

    NASA Astrophysics Data System (ADS)

    Beauchemin, Catherine

    Viral kinetics have been studied extensively in the past through the use of ordinary differential equations describing the time evolution of the diseased state in a spatially well-mixed medium. However, emerging spatial structures such as localized populations of dead cells might affect the spread of infection, similar to the manner in which a counter-fire can stop a forest fire from spreading. In the first phase of the project, a simple two-dimensional cellular automaton model of viral infections was developed. It was validated against clinical immunological data for uncomplicated influenza A infections and shown to be accurate enough to adequately model them. In the second phase of the project, the simple two-dimensional cellular automaton model was used to investigate the effects of relaxing the well-mixed assumption on viral infection dynamics. It was shown that grouping the initially infected cells into patches rather than distributing them uniformly on the grid reduced the infection rate as only cells on the perimeter of the patch have healthy neighbours to infect. Use of a local epithelial cell regeneration rule where dead cells are replaced by healthy cells when an immediate neighbour divides was found to result in more extensive damage of the epithelium and yielded a better fit to experimental influenza A infection data than a global regeneration rule based on division rate of healthy cell. Finally, the addition of immune cell at the site of infection was found to be a better strategy at low infection levels, while addition at random locations on the grid was the better strategy at high infection level. In the last project, the movement of T cells within lymph nodes in the absence of antigen, was investigated. Based on individual T cell track data captured by two-photon microscopy experiments in vivo, a simple model was proposed for the motion of T cells. This is the first step towards the implementation of a more realistic spatiotemporal model of HIV than

  11. Linking Item Response Model Parameters.

    PubMed

    van der Linden, Wim J; Barrett, Michelle D

    2016-09-01

    With a few exceptions, the problem of linking item response model parameters from different item calibrations has been conceptualized as an instance of the problem of test equating scores on different test forms. This paper argues, however, that the use of item response models does not require any test score equating. Instead, it involves the necessity of parameter linking due to a fundamental problem inherent in the formal nature of these models-their general lack of identifiability. More specifically, item response model parameters need to be linked to adjust for the different effects of the identifiability restrictions used in separate item calibrations. Our main theorems characterize the formal nature of these linking functions for monotone, continuous response models, derive their specific shapes for different parameterizations of the 3PL model, and show how to identify them from the parameter values of the common items or persons in different linking designs. PMID:26155754

  12. Animal Models of CNS Viral Disease: Examples from Borna Disease Virus Models

    PubMed Central

    Solbrig, Marylou V.

    2010-01-01

    Borna disease (BD), caused by the neurotropic RNA virus, Borna Disease virus, is an affliction ranging from asymptomatic to fatal meningoencephalitis across naturally and experimentally infected warmblooded (mammalian and bird) species. More than 100 years after the first clinical descriptions of Borna disease in horses and studies beginning in the 1980's linking Borna disease virus to human neuropsychiatric diseases, experimentally infected rodents have been used as models for examining behavioral, neuropharmacological, and neurochemical responses to viral challenge at different stages of life. These studies have contributed to understanding the role of CNS viral injury in vulnerability to behavioral, developmental, epileptic, and neurodegenerative diseases and aided evaluation of the proposed and still controversial links to human disease. PMID:20204069

  13. Modeling HIV-1 viral capsid nucleation by dynamical systems.

    PubMed

    Sadre-Marandi, Farrah; Liu, Yuewu; Liu, Jiangguo; Tavener, Simon; Zou, Xiufen

    2015-12-01

    There are two stages generally recognized in the viral capsid assembly: nucleation and elongation. This paper focuses on the nucleation stage and develops mathematical models for HIV-1 viral capsid nucleation based on six-species dynamical systems. The Particle Swarm Optimization (PSO) algorithm is used for parameter fitting to estimate the association and dissociation rates from biological experiment data. Numerical simulations of capsid protein (CA) multimer concentrations demonstrate a good agreement with experimental data. Sensitivity and elasticity analysis of CA multimer concentrations with respect to the association and dissociation rates further reveals the importance of CA trimer-of- dimers in the nucleation stage of viral capsid self- assembly. PMID:26596714

  14. Construction of a mutagenesis cartridge for poliovirus genome-linked viral protein: isolation and characterization of viable and nonviable mutants

    SciTech Connect

    Kuhn, R.J.; Tada, H.; Ypma-Wong, M.F.; Dunn, J.J.; Semler, B.L.; Wimmer, E.

    1988-01-01

    By following a strategy of genetic analysis of poliovirus, the authors have constructed a synthetic mutagenesis cartridge spanning the genome-linked viral protein coding region and flanking cleavage sites in an infectious cDNA clone of the type I (Mahoney) genome. The insertion of new restriction sites within the infectious clone has allowed them to replace the wild-type sequences with short complementary pairs of synthetic oligonucleotides containing various mutations. A set of mutations have been made that create methionine codons within the genome-linked viral protein region. The resulting viruses have growth characteristics similar to wild type. Experiments that led to an alteration of the tyrosine residue responsible for the linkage to RNA have resulted in nonviable virus. In one mutant, proteolytic processing assayed in vitro appeared unimpaired by the mutation. They suggest that the position of the tyrosine residue is important for genome-linked viral protein function(s).

  15. Contribution of N-linked glycans on HSV-2 gB to cell–cell fusion and viral entry

    SciTech Connect

    Luo, Sukun; Hu, Kai; He, Siyi; Wang, Ping; Zhang, Mudan; Huang, Xin; Du, Tao; Zheng, Chunfu; Liu, Yalan; Hu, Qinxue

    2015-09-15

    HSV-2 is the major cause of genital herpes and its infection increases the risk of HIV-1 acquisition and transmission. HSV-2 glycoprotein B together with glycoproteins D, H and L are indispensable for viral entry, of which gB, as a class III fusogen, plays an essential role. HSV-2 gB has seven potential N-linked glycosylation (N-CHO) sites, but their significance has yet to be determined. For the first time, we systematically analyzed the contributions of N-linked glycans on gB to cell–cell fusion and viral entry. Our results demonstrated that, of the seven potential N-CHO sites on gB, mutation at N390, N483 or N668 decreased cell–cell fusion and viral entry, while mutation at N133 mainly affected protein expression and the production of infectious virus particles by blocking the transport of gB from the endoplasmic reticulum to Golgi. Our findings highlight the significance of N-linked glycans on HSV-2 gB expression and function. - Highlights: • N-linked glycan at N133 is important for gB intracellular trafficking and maturation. • N-linked glycans at N390, N483 and N668 on gB are necessary for optimal cell–cell fusion. • N-linked glycans at N390, N483 and N668 on gB are necessary for optimal viral entry.

  16. Modeling HIV persistence, the latent reservoir, and viral blips

    PubMed Central

    Rong, Libin; Perelson, Alan S.

    2009-01-01

    HIV-1 eradication from infected individuals has not been achieved with the use of highly active antiretroviral therapy (HAART) for a prolonged period of time. The cellular reservoir for HIV-1 in resting memory CD4+ T cells remains a major obstacle to viral elimination. The reservoir does not decay significantly over long periods of time but is able to release replication-competent HIV-1 upon cell activation. Residual ongoing viral replication may likely occur in many patients because low levels of virus can be detected in plasma by sensitive assays and transient episodes of viremia, or HIV-1 blips, are often observed in patients even with successful viral suppression for many years. Here we review our current knowledge of the factors contributing to viral persistence, the latent reservoir, and blips, and mathematical models developed to explore them and their relationships. We show how mathematical modeling can help improve our understanding of HIV-1 dynamics in patients on HAART and of the quantitative events underlying HIV-1 latency, reservoir stability, low-level viremic persistence, and emergence of intermittent viral blips. We also discuss treatment implications related to these studies. PMID:19539630

  17. Viral Spread to Enteric Neurons Links Genital HSV-1 Infection to Toxic Megacolon and Lethality.

    PubMed

    Khoury-Hanold, William; Yordy, Brian; Kong, Philip; Kong, Yong; Ge, William; Szigeti-Buck, Klara; Ralevski, Alexandra; Horvath, Tamas L; Iwasaki, Akiko

    2016-06-01

    Herpes simplex virus 1 (HSV-1), a leading cause of genital herpes, infects oral or genital mucosal epithelial cells before infecting the peripheral sensory nervous system. The spread of HSV-1 beyond the sensory nervous system and the resulting broader spectrum of disease are not well understood. Using a mouse model of genital herpes, we found that HSV-1-infection-associated lethality correlated with severe fecal and urinary retention. No inflammation or infection of the brain was evident. Instead, HSV-1 spread via the dorsal root ganglia to the autonomic ganglia of the enteric nervous system (ENS) in the colon. ENS infection led to robust viral gene transcription, pathological inflammatory responses, and neutrophil-mediated destruction of enteric neurons, ultimately resulting in permanent loss of peristalsis and the development of toxic megacolon. Laxative treatment rescued mice from lethality following genital HSV-1 infection. These results reveal an unexpected pathogenesis of HSV associated with ENS infection. PMID:27281569

  18. Uncertainty quantification in modeling HIV viral mechanics.

    PubMed

    Banks, H T; Baraldi, Robert; Cross, Karissa; Flores, Kevin; McChesney, Christina; Poag, Laura; Thorpe, Emma

    2015-10-01

    We consider an in-host model for HIV-1 infection dynamics developed and validated with patient data in earlier work [7]. We revisit the earlier model in light of progress over the last several years in understanding HIV-1 progression in humans. We then consider statistical models to describe the data and use these with residual plots in generalized least squares problems to develop accurate descriptions of the proper weights for the data. We use recent parameter subset selection techniques [5,6] to investigate the impact of estimated parameters on the corresponding selection scores. Bootstrapping and asymptotic theory are compared in the context of confidence intervals for the resulting parameter estimates. PMID:26280189

  19. Viral vector-based models of Parkinson's disease.

    PubMed

    Van der Perren, Anke; Van den Haute, Chris; Baekelandt, Veerle

    2015-01-01

    In order to study the molecular pathways of Parkinson's disease (PD) and to develop novel therapeutic strategies, scientific investigators rely on animal models. The identification of PD-associated genes has led to the development of genetic PD models as an alternative to toxin-based models. Viral vector-mediated loco-regional gene delivery provides an attractive way to express transgenes in the central nervous system. Several vector systems based on various viruses have been developed. In this chapter, we give an overview of the different viral vector systems used for targeting the CNS. Further, we describe the different viral vector-based PD models currently available based on overexpression strategies for autosomal dominant genes such as α-synuclein and LRRK2, and knockout or knockdown strategies for autosomal recessive genes, such as parkin, DJ-1, and PINK1. Models based on overexpression of α-synuclein are the most prevalent and extensively studied, and therefore the main focus of this chapter. Many efforts have been made to increase the expression levels of α-synuclein in the dopaminergic neurons. The best α-synuclein models currently available have been developed from a combined approach using newer AAV serotypes and optimized vector constructs, production, and purification methods. These third-generation α-synuclein models show improved face and predictive validity, and therefore offer the possibility to reliably test novel therapeutics. PMID:24839101

  20. Viral Vector-Based Modeling of Neurodegenerative Disorders: Parkinson's Disease.

    PubMed

    Fischer, D Luke; Gombash, Sara E; Kemp, Christopher J; Manfredsson, Fredric P; Polinski, Nicole K; Duffy, Megan F; Sortwell, Caryl E

    2016-01-01

    Gene therapy methods are increasingly used to model Parkinson's disease (PD) in animals in an effort to test experimental therapeutics within a more relevant context to disease pathophysiology and neuropathology. We have detailed several criteria that are critical or advantageous to accurately modeling PD in a murine model or in a nonhuman primate. Using these criteria, we then evaluate approaches made to model PD using viral vectors to date, including both adeno-associated viruses and lentiviruses. Lastly, we comment on the consideration of aging as a critical factor for modeling PD. PMID:26611600

  1. Open loop model for WDM links

    NASA Astrophysics Data System (ADS)

    D, Meena; Francis, Fredy; T, Sarath K.; E, Dipin; Srinivas, T.; K, Jayasree V.

    2014-10-01

    Wavelength Division Multiplexing (WDM) techniques overfibrelinks helps to exploit the high bandwidth capacity of single mode fibres. A typical WDM link consisting of laser source, multiplexer/demultiplexer, amplifier and detectoris considered for obtaining the open loop gain model of the link. The methodology used here is to obtain individual component models using mathematical and different curve fitting techniques. These individual models are then combined to obtain the WDM link model. The objective is to deduce a single variable model for the WDM link in terms of input current to system. Thus it provides a black box solution for a link. The Root Mean Square Error (RMSE) associated with each of the approximated models is given for comparison. This will help the designer to select the suitable WDM link model during a complex link design.

  2. Viral Genome-Linked Protein (VPg) Is Essential for Translation Initiation of Rabbit Hemorrhagic Disease Virus (RHDV)

    PubMed Central

    Zhu, Jie; Wang, Binbin; Miao, Qiuhong; Tan, Yonggui; Li, Chuanfeng; Chen, Zongyan; Guo, Huimin; Liu, Guangqing

    2015-01-01

    Rabbit hemorrhagic disease virus (RHDV), the causative agent of rabbit hemorrhagic disease, is an important member of the caliciviridae family. Currently, no suitable tissue culture system is available for proliferating RHDV, limiting the study of the pathogenesis of RHDV. In addition, the mechanisms underlying RHDV translation and replication are largely unknown compared with other caliciviridae viruses. The RHDV replicon recently constructed in our laboratory provides an appropriate model to study the pathogenesis of RHDV without in vitro RHDV propagation and culture. Using this RHDV replicon, we demonstrated that the viral genome-linked protein (VPg) is essential for RHDV translation in RK-13 cells for the first time. In addition, we showed that VPg interacts with eukaryotic initiation factor 4E (eIF4E) in vivo and in vitro and that eIF4E silencing inhibits RHDV translation, suggesting the interaction between VPg and eIF4E is involved in RHDV translation. Our results support the hypothesis that VPg serves as a novel cap substitute during the initiation of RHDV translation. PMID:26599265

  3. Viral Genome-Linked Protein (VPg) Is Essential for Translation Initiation of Rabbit Hemorrhagic Disease Virus (RHDV).

    PubMed

    Zhu, Jie; Wang, Binbin; Miao, Qiuhong; Tan, Yonggui; Li, Chuanfeng; Chen, Zongyan; Guo, Huimin; Liu, Guangqing

    2015-01-01

    Rabbit hemorrhagic disease virus (RHDV), the causative agent of rabbit hemorrhagic disease, is an important member of the caliciviridae family. Currently, no suitable tissue culture system is available for proliferating RHDV, limiting the study of the pathogenesis of RHDV. In addition, the mechanisms underlying RHDV translation and replication are largely unknown compared with other caliciviridae viruses. The RHDV replicon recently constructed in our laboratory provides an appropriate model to study the pathogenesis of RHDV without in vitro RHDV propagation and culture. Using this RHDV replicon, we demonstrated that the viral genome-linked protein (VPg) is essential for RHDV translation in RK-13 cells for the first time. In addition, we showed that VPg interacts with eukaryotic initiation factor 4E (eIF4E) in vivo and in vitro and that eIF4E silencing inhibits RHDV translation, suggesting the interaction between VPg and eIF4E is involved in RHDV translation. Our results support the hypothesis that VPg serves as a novel cap substitute during the initiation of RHDV translation. PMID:26599265

  4. Reconceptualizing the Linked Courses Model

    ERIC Educational Resources Information Center

    Baxter, Mary

    2008-01-01

    To help students meet the demands of society, the University of Houston is using the framework of learning communities and constructivism to create a cross-disciplinary approach to teaching to provide media-rich thematically linked courses to engage a diverse student population. A case study investigated three semesters of thematically linked…

  5. Animal models for viral infection and cell exhaustion

    PubMed Central

    McGary, Colleen S.; Silvestri, Guido; Paiardini, Mirko

    2014-01-01

    Purpose of review Despite eliciting an early antiviral T cell response, HIV-specific T cells are unable to prevent disease progression, partly due to their loss of effector functions, known as T cell exhaustion. Restoring this T cell functionality represents a critical step for regaining immunological control of HIV-1 replication, and may be fundamental for the development of a functional cure for HIV. In this context, the use of animal models is invaluable for evaluating the efficacy and mechanisms of novel therapeutics aimed at reinvigorating T cell functions. Recent findings While non-human primates continue to be a mainstay for studying HIV pathogenesis and therapies, recent advances in humanized mouse models have improved their ability to recapitulate the features of cell exhaustion during HIV infection. Targeting coinhibitory receptors in HIV- and SIV-infected animals has resulted in viral load reductions, presumably by reinvigorating the effector functions of T cells. Additionally, studies combining PD-1 blockade with suppressive ART provide further support of the use of coinhibitory receptor blockades in restoring T cell function by delaying viral load rebound upon ART interruption. Future in vivo studies should build on recent in vitro data supporting the simultaneous targeting of multiple regulators of cell exhaustion. Summary In this review, we describe the most recent advances in the use of animal models for the study of cell exhaustion following HIV/SIV infection. These findings suggest that the use of animal models is increasingly critical in translating immunotherapeutics into clinical practice. PMID:25023622

  6. Stochastical modeling for Viral Disease: Statistical Mechanics and Network Theory

    NASA Astrophysics Data System (ADS)

    Zhou, Hao; Deem, Michael

    2007-04-01

    Theoretical methods of statistical mechanics are developed and applied to study the immunological response against viral disease, such as dengue. We use this theory to show how the immune response to four different dengue serotypes may be sculpted. It is the ability of avian influenza, to change and to mix, that has given rise to the fear of a new human flu pandemic. Here we propose to utilize a scale free network based stochastic model to investigate the mitigation strategies and analyze the risk.

  7. Comorbidity and high viral load linked to clinical presentation of respiratory human bocavirus infection.

    PubMed

    Ghietto, Lucía María; Majul, Diego; Ferreyra Soaje, Patricia; Baumeister, Elsa; Avaro, Martín; Insfrán, Constanza; Mosca, Liliana; Cámara, Alicia; Moreno, Laura Beatriz; Adamo, Maria Pilar

    2015-01-01

    Human bocavirus (HBoV) is a new parvovirus associated with acute respiratory tract infection (ARTI). In order to evaluate HBoV significance as an agent of acute respiratory disease, we screened 1,135 respiratory samples from children and adults with and without symptoms during two complete calendar years. HBoV1 prevalence in patients with ARTI was 6.33 % in 2011 and 11.64 % in 2012, including neonatal and adult patients. HBoV1 was also detected in 3.77 % of asymptomatic individuals. The co-detection rate was 78.1 %. Among children, 87 % were clinically diagnosed with lower respiratory infection (no significant differences between patients with and without coinfection), and 31 % exhibited comorbidities. Pediatric patients with comorbidities were significantly older than patients without comorbidities. Patients with ARTI had either high or low viral load, while controls had only low viral load, but there were no clinical differences between patients with high or low viral load. In conclusion, we present evidence of the pathogenic potential of HBoV1 in young children with ARTI. Since patients with HBoV1-single infection are not significantly different from those with coinfection with respect to clinical features, the virus can be as pathogenic by itself as other respiratory agents are. Furthermore, an association between high HBoV1 load and disease could not be demonstrated in this study, but all asymptomatic individuals had low viral loads. Also, children with comorbidities are susceptible to HBoV1 infection at older ages than previously healthy children. Thus, the clinical presentation of infection may occur depending on both viral load and the particular interaction between the HBoV1 and the host. PMID:25269520

  8. Bovine viral diarrhea virus antigen detection across whole cattle hides using two antigen-capture enzyme-linked immunosorbent assays.

    PubMed

    Vander Ley, Brian L; Ridpath, Julia F; Sweiger, Shaun H

    2012-05-01

    Bovine viral diarrhea virus is a costly disease of cattle that can be controlled by vaccination, biosecurity, and removal of persistently infected cattle. Development and proficiency testing of assays to identify persistently infected cattle requires substantial quantities of known positive- and negative-sample material. The objective of this study was to determine what sections of bovine skin contained Bovine viral diarrhea virus antigen. Two commercially available antigen-capture enzyme-linked immunoassays were used to test subsamples representing the entire skin of 3 persistently infected calves. Both assays detected Bovine viral diarrhea virus antigen in the samples indicated for use by assay protocol. However, one assay identified all subsamples as positive, while the second assay identified 64.4% of subsamples as positive. These results show that use of samples other than those specified by the assay protocol must be validated for each individual assay. In this study, alternative sample sites and use of the entire hide for proficiency testing would be acceptable for only one of the assays tested. PMID:22529122

  9. Interval Between Infections and Viral Hierarchy Are Determinants of Viral Interference Following Influenza Virus Infection in a Ferret Model

    PubMed Central

    Laurie, Karen L.; Guarnaccia, Teagan A.; Carolan, Louise A.; Yan, Ada W. C.; Aban, Malet; Petrie, Stephen; Cao, Pengxing; Heffernan, Jane M.; McVernon, Jodie; Mosse, Jennifer; Kelso, Anne; McCaw, James M.; Barr, Ian G.

    2015-01-01

    Background. Epidemiological studies suggest that, following infection with influenza virus, there is a short period during which a host experiences a lower susceptibility to infection with other influenza viruses. This viral interference appears to be independent of any antigenic similarities between the viruses. We used the ferret model of human influenza to systematically investigate viral interference. Methods. Ferrets were first infected then challenged 1–14 days later with pairs of influenza A(H1N1)pdm09, influenza A(H3N2), and influenza B viruses circulating in 2009 and 2010. Results. Viral interference was observed when the interval between initiation of primary infection and subsequent challenge was <1 week. This effect was virus specific and occurred between antigenically related and unrelated viruses. Coinfections occurred when 1 or 3 days separated infections. Ongoing shedding from the primary virus infection was associated with viral interference after the secondary challenge. Conclusions. The interval between infections and the sequential combination of viruses were important determinants of viral interference. The influenza viruses in this study appear to have an ordered hierarchy according to their ability to block or delay infection, which may contribute to the dominance of different viruses often seen in an influenza season. PMID:25943206

  10. On Modeling Viral Diffusion in Heterogeneous Wireless Networks

    NASA Astrophysics Data System (ADS)

    Nguyen, Hoai-Nam; Shinoda, Yoichi

    Smart phones and computers now are able to co-work in a wireless environment where malware can propagate. Although many investigations have modeled the spread of malware, little has been done to take into account different characteristics of items to see how they affect disease diffusion in an ad hoc network. We have therefore developed a novel framework, consisting of two models, which consider diversity of objects as well as interactions between their different classes. Our framework is able to produce a huge result space thus makes it appropriate to describe many viral proliferating scenarios. Additionally, we have developed a formula to calculate the possible average number of newly infected devices in the considered system. An important contribution of our work is the comprehension of item diversity, which states that a mixture of device types causes a bigger malware spread as the number of device types in the network increases.

  11. Linking host prokaryotic physiology to viral lifestyle dynamics in a temperate freshwater lake (Lake Pavin, France).

    PubMed

    Palesse, S; Colombet, J; Pradeep Ram, A S; Sime-Ngando, T

    2014-11-01

    In aquatic ecosystems, fluctuations in environmental conditions and prokaryotic host physiological states can strongly affect the dynamics of viral life strategies. The influence of prokaryote physiology and environmental factors on viral replication cycles (lytic and lysogeny) was investigated from April to September 2011 at three different strata (epi, meta, and hypolimnion) in the mixolimnion of deep volcanic temperate freshwater Lake Pavin (France). Overall, the euphotic region (epi and metalimnion) was more dynamic and showed significant variation in microbial standing stocks, prokaryotic physiological state, and viral life strategies compared to the aphotic hypolimnion which was stable within sampled months. The prokaryotic host physiology as inferred from the nucleic acid content of prokaryotic cells (high or low nucleic acid) was strongly regulated by the chlorophyll concentration. The predominance of the high nucleic acid (HNA) prokaryotes (cells) over low nucleic acid (LNA) prokaryotes (cells) in the spring (HNA/LNA = 1.2) and vice versa in the summer period (HNA/LNA = 0.4) suggest that the natural prokaryotic communities underwent major shifts in their physiological states during investigated time period. The increase in the percentage of inducible lysogenic prokaryotes in the summer period was associated with the switch in the dominance of LNA over HNA cells, which coincided with the periods of strong resource (nutrient) limitation. This supports the idea that lysogeny represents a maintenance strategy for viruses in unproductive or harsh nutrient/host conditions. A negative correlation of percentage of lysogenic prokaryotes with HNA cell abundance and chlorophyll suggest that lysogenic cycle is closely related to prokaryotic cells which are stressed or starved due to unavailability of resources for its growth and activity. Our results provide support to previous findings that changes in prokaryote physiology are critical for the promotion and

  12. Semantically Linking In Silico Cancer Models

    PubMed Central

    Johnson, David; Connor, Anthony J; McKeever, Steve; Wang, Zhihui; Deisboeck, Thomas S; Quaiser, Tom; Shochat, Eliezer

    2014-01-01

    Multiscale models are commonplace in cancer modeling, where individual models acting on different biological scales are combined within a single, cohesive modeling framework. However, model composition gives rise to challenges in understanding interfaces and interactions between them. Based on specific domain expertise, typically these computational models are developed by separate research groups using different methodologies, programming languages, and parameters. This paper introduces a graph-based model for semantically linking computational cancer models via domain graphs that can help us better understand and explore combinations of models spanning multiple biological scales. We take the data model encoded by TumorML, an XML-based markup language for storing cancer models in online repositories, and transpose its model description elements into a graph-based representation. By taking such an approach, we can link domain models, such as controlled vocabularies, taxonomic schemes, and ontologies, with cancer model descriptions to better understand and explore relationships between models. The union of these graphs creates a connected property graph that links cancer models by categorizations, by computational compatibility, and by semantic interoperability, yielding a framework in which opportunities for exploration and discovery of combinations of models become possible. PMID:25520553

  13. Semantically linking in silico cancer models.

    PubMed

    Johnson, David; Connor, Anthony J; McKeever, Steve; Wang, Zhihui; Deisboeck, Thomas S; Quaiser, Tom; Shochat, Eliezer

    2014-01-01

    Multiscale models are commonplace in cancer modeling, where individual models acting on different biological scales are combined within a single, cohesive modeling framework. However, model composition gives rise to challenges in understanding interfaces and interactions between them. Based on specific domain expertise, typically these computational models are developed by separate research groups using different methodologies, programming languages, and parameters. This paper introduces a graph-based model for semantically linking computational cancer models via domain graphs that can help us better understand and explore combinations of models spanning multiple biological scales. We take the data model encoded by TumorML, an XML-based markup language for storing cancer models in online repositories, and transpose its model description elements into a graph-based representation. By taking such an approach, we can link domain models, such as controlled vocabularies, taxonomic schemes, and ontologies, with cancer model descriptions to better understand and explore relationships between models. The union of these graphs creates a connected property graph that links cancer models by categorizations, by computational compatibility, and by semantic interoperability, yielding a framework in which opportunities for exploration and discovery of combinations of models become possible. PMID:25520553

  14. Comparison of Five Bacteriophages as Models for Viral Aerosol Studies

    PubMed Central

    Turgeon, Nathalie; Toulouse, Marie-Josée; Martel, Bruno; Moineau, Sylvain

    2014-01-01

    Bacteriophages are perceived to be good models for the study of airborne viruses because they are safe to use, some of them display structural features similar to those of human and animal viruses, and they are relatively easy to produce in large quantities. Yet, only a few studies have investigated them as models. It has previously been demonstrated that aerosolization, environmental conditions, and sampling conditions affect viral infectivity, but viral infectivity is virus dependent. Thus, several virus models are likely needed to study their general behavior in aerosols. The aim of this study was to compare the effects of aerosolization and sampling on the infectivity of five tail-less bacteriophages and two pathogenic viruses: MS2 (a single-stranded RNA [ssRNA] phage of the Leviviridae family), Φ6 (a segmented double-stranded RNA [dsRNA] phage of the Cystoviridae family), ΦX174 (a single-stranded DNA [ssDNA] phage of the Microviridae family), PM2 (a double-stranded DNA [dsDNA] phage of the Corticoviridae family), PR772 (a dsDNA phage of the Tectiviridae family), human influenza A virus H1N1 (an ssRNA virus of the Orthomyxoviridae family), and the poultry virus Newcastle disease virus (NDV; an ssRNA virus of the Paramyxoviridae family). Three nebulizers and two nebulization salt buffers (with or without organic fluid) were tested, as were two aerosol sampling devices, a liquid cyclone (SKC BioSampler) and a dry cyclone (National Institute for Occupational Safety and Health two-stage cyclone bioaerosol sampler). The presence of viruses in collected air samples was detected by culture and quantitative PCR (qPCR). Our results showed that these selected five phages behave differently when aerosolized and sampled. RNA phage MS2 and ssDNA phage ΦX174 were the most resistant to aerosolization and sampling. The presence of organic fluid in the nebulization buffer protected phages PR772 and Φ6 throughout the aerosolization and sampling with dry cyclones. In this

  15. Multi-level slip-link modeling

    NASA Astrophysics Data System (ADS)

    Schieber, Jay

    2014-03-01

    That the dynamics of concentrated, high-molecular-weight polymers are largely governed by entanglements is now widely accepted, and typically understood by the tube model. Although the original idea for slip-links was proposed at the same time as tubes, only recently have detailed, quantitative mathematical models arisen based on this picture. We argue here for the use of a slip-link model that has strong connections to atomistic, multichain levels of description, agrees with non-equilibrium thermodynamics, applies to any chain architecture and can be used in linear or non-linear rheology. We present a hierarchy of slip-link models that are connected to each other through successive coarse graining. One might choose a particular member of the hierarchy depending on the problem at hand, in order to minimize computational effort. In particular, the most detailed level of description has four parameters, three of which can be determined directly from atomistic simulations. The least-detailed member is suitable for predicting non-linear, non-uniform flow fields. We will show how using this hierarchy of slip-link models we can make predictions about the nonlinear rheology of monodisperse homopolymer melts, polydisperse melts, or blends of different architectures.

  16. Loci on Bos taurus chromosome 2 and Bos taurus chromosome 26 are linked with bovine respiratory disease and associated with persistent infection of bovine viral diarrhea virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective of this study was to identify loci linked with bovine respiratory disease (BRD) and subsequently to determine if these same loci were associated with bovine viral diarrhea virus persistent infection (BVD-PI) in BVD-PI calves or their dams. A genome-wide linkage study using 312 microsa...

  17. A Mathematical Model of T1D Acceleration and Delay by Viral Infection.

    PubMed

    Moore, James R; Adler, Fred

    2016-03-01

    Type 1 diabetes (T1D) is often triggered by a viral infection, but the T1D prevalence is rising among populations that have a lower exposure to viral infection. In an animal model of T1D, the NOD mouse, viral infection at different ages may either accelerate or delay disease depending on the age of infection and the type of virus. Viral infection may affect the progression of T1D via multiple mechanisms: triggering inflammation, bystander activation of self-reactive T-cells, inducing a competitive immune response, or inducing a regulatory immune response. In this paper, we create mathematical models of the interaction of viral infection with T1D progression, incorporating each of these four mechanisms. Our goal is to understand how each viral mechanism interacts with the age of infection. The model predicts that each viral mechanism has a unique pattern of interaction with disease progression. Viral inflammation always accelerates disease, but the effect decreases with age of infection. Bystander activation has little effect at younger ages and actually decreases incidence at later ages while accelerating disease in mice that do get the disease. A competitive immune response to infection can decrease incidence at young ages and increase it at older ages, with the effect decreasing over time. Finally, an induced Treg response decreases incidence at any age of infection, but the effect decreases with age. Some of these patterns resemble those seen experimentally. PMID:27030351

  18. Modeling the Intracellular Dynamics of Influenza Virus Replication To Understand the Control of Viral RNA Synthesis

    PubMed Central

    Frensing, Timo; Reichl, Udo

    2012-01-01

    Influenza viruses transcribe and replicate their negative-sense RNA genome inside the nucleus of host cells via three viral RNA species. In the course of an infection, these RNAs show distinct dynamics, suggesting that differential regulation takes place. To investigate this regulation in a systematic way, we developed a mathematical model of influenza virus infection at the level of a single mammalian cell. It accounts for key steps of the viral life cycle, from virus entry to progeny virion release, while focusing in particular on the molecular mechanisms that control viral transcription and replication. We therefore explicitly consider the nuclear export of viral genome copies (vRNPs) and a recent hypothesis proposing that replicative intermediates (cRNA) are stabilized by the viral polymerase complex and the nucleoprotein (NP). Together, both mechanisms allow the model to capture a variety of published data sets at an unprecedented level of detail. Our findings provide theoretical support for an early regulation of replication by cRNA stabilization. However, they also suggest that the matrix protein 1 (M1) controls viral RNA levels in the late phase of infection as part of its role during the nuclear export of viral genome copies. Moreover, simulations show an accumulation of viral proteins and RNA toward the end of infection, indicating that transport processes or budding limits virion release. Thus, our mathematical model provides an ideal platform for a systematic and quantitative evaluation of influenza virus replication and its complex regulation. PMID:22593159

  19. Mathematical models of immune effector responses to viral infections: Virus control versus the development of pathology

    NASA Astrophysics Data System (ADS)

    Wodarz, Dominik

    2005-12-01

    This article reviews mathematical models which have investigated the importance of lytic and non-lytic immune responses for the control of viral infections. Lytic immune responses fight the virus by killing infected cells, while non-lytic immune responses fight the virus by inhibiting viral replication while leaving the infected cell alive. The models suggest which types or combinations of immune responses are required to resolve infections which vary in their characteristics, such as the rate of viral replication and the rate of virus-induced target cell death. This framework is then applied to persistent infections and viral evolution. It is investigated how viral evolution and antigenic escape can influence the relative balance of lytic and non-lytic responses over time, and how this might correlate with the transition from an asymptomatic infection to pathology. This is discussed in the specific context of hepatitis C virus infection.

  20. O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis.

    PubMed

    Zeng, Qinghua; Zhao, Rui-Xun; Chen, Jianfeng; Li, Yining; Li, Xiang-Dong; Liu, Xiao-Long; Zhang, Wei-Ming; Quan, Cheng-Shi; Wang, Yi-Shu; Zhai, Ying-Xian; Wang, Jian-Wei; Youssef, Mariam; Cui, Rutao; Liang, Jiyong; Genovese, Nicholas; Chow, Louise T; Li, Yu-Lin; Xu, Zhi-Xiang

    2016-08-16

    High-risk human papillomaviruses (HPVs) are causative agents of anogenital cancers and a fraction of head and neck cancers. The mechanisms involved in the progression of HPV neoplasias to cancers remain largely unknown. Here, we report that O-linked GlcNAcylation (O-GlcNAc) and O-GlcNAc transferase (OGT) were markedly increased in HPV-caused cervical neoplasms relative to normal cervix, whereas O-GlcNAcase (OGA) levels were not altered. Transduction of HPV16 oncogene E6 or E6/E7 into mouse embryonic fibroblasts (MEFs) up-regulated OGT mRNA and protein, elevated the level of O-GlcNAc, and promoted cell proliferation while reducing cellular senescence. Conversely, in HPV-18-transformed HeLa cervical carcinoma cells, inhibition of O-GlcNAc with a low concentration of a chemical inhibitor impaired the transformed phenotypes in vitro. We showed that E6 elevated c-MYC via increased protein stability attributable to O-GlcNAcylation on Thr58. Reduction of HPV-mediated cell viability by a high concentration of O-GlcNAc inhibitor was partially rescued by elevated c-MYC. Finally, knockdown of OGT or O-GlcNAc inhibition in HeLa cells or in TC-1 cells, a mouse cell line transformed by HPV16 E6/E7 and activated K-RAS, reduced c-MYC and suppressed tumorigenesis and metastasis. Thus, we have uncovered a mechanism for HPV oncoprotein-mediated transformation. These findings may eventually aid in the development of effective therapeutics for HPV-associated malignancies by targeting aberrant O-GlcNAc. PMID:27482104

  1. Structural and metabolic studies of O-linked fucose-containing proteins of normal and virally-transformed rat fibroblasts

    SciTech Connect

    Morton, P.A.

    1985-01-01

    Previous studies in this laboratory have demonstrated that cultured human and rodent cells contain a series of low molecular weight glycosylated amino acids of unusual structure, designated amino acid fucosides. The incorporation of radiolabelled-fucose into one of these components, designated FL4a (glucosylfucosylthreonine), is markedly-reduced in transformed epithelial and fibroblastic cells. The authors have examined fucose-labelled normal and virally-transformed rat fibroblast cell lines for glycoproteins which might be precursors to amino acid fucosides. Using milk alkaline/borohydride treatment (the beta-elimination reaction) to release O-linked oligosaccharides from proteins, they have isolated and partially characterized two low M/sub r/ reaction products (designated DS-ol and TS-ol) released from macromolecular cell material. The identity of one of these components (DS-ol, glucosylfucitol) suggested the existence in these cells of a direct protein precursor to FL4a. They examined fucose-labelled macromolecular cell material for proteins which release DS-ol (DS-proteins.). Using gel filtration chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) with subsequent autoradiography, they have observed DS-proteins which appear to exhibit a broad molecular weight size range, and are also present in culture medium from normal and transformed cells. The findings suggest that mammalian cells contain DS-proteins and TS-proteins with a novel carbohydrate-peptide linkage wherein L-fucose is O-linked to a polypeptide backbone. Metabolic studies were undertaken to examine both the relationship between DS-protein and FL4a and the biochemical basis for the decreased level of FL4a and the biochemical basis for the decreased level of FL4a observed in transformed cells.

  2. Use of hydrophilic extra-viral domain of canine distemper virus H protein for enzyme-linked immunosorbent assay development

    PubMed Central

    Cho, Ki-hyun; Kim, Jeongmi; Yoo, Hyun-ah; Kim, Dae-hee; Park, Seung-yong; Song, Chang-seon; Choi, In-soo

    2014-01-01

    Simple methods for measuring the levels of serum antibody against canine distemper virus (CDV) would assist in the effective vaccination of dogs. To develop an enzyme-linked immunosorbent assay (ELISA) specific for CDV, we expressed hydrophilic extra-viral domain (HEVD) protein of the A75/17-CDV H gene in a pET 28a plasmid-based Escherichia (E.) coli vector system. Expression was confirmed by dot and Western blotting. We proposed that detection of E. coli-expressed H protein might be conformation-dependent because intensities of the reactions observed with these two methods varied. The H gene HEVD protein was further purified and used as an antigen for an ELISA. Samples from dogs with undetectable to high anti-CDV antibody titers were analyzed using this HEVD-specific ELISA and a commercial CDV antibody detection kit (ImmunoComb). Levels of HEVD antigenicity measured with the assays and immunochromatography correlated. These data indicated that the HEDV protein may be used as antigen to develop techniques for detecting antibodies against CDV. PMID:25234325

  3. Use of hydrophilic extra-viral domain of canine distemper virus H protein for enzyme-linked immunosorbent assay development.

    PubMed

    Cho, Ki-hyun; Kim, Jeongmi; Yoo, Hyun-ah; Kim, Dae-hee; Park, Seung-yong; Song, Chang-seon; Choi, In-soo; Lee, Joong-bok

    2014-12-01

    Simple methods for measuring the levels of serum antibody against canine distemper virus (CDV) would assist in the effective vaccination of dogs. To develop an enzyme-linked immunosorbent assay (ELISA) specific for CDV, we expressed hydrophilic extra-viral domain (HEVD) protein of the A75/17-CDV H gene in a pET 28a plasmid-based Escherichia (E.) coli vector system. Expression was confirmed by dot and Western blotting. We proposed that detection of E. coli-expressed H protein might be conformation- dependent because intensities of the reactions observed with these two methods varied. The H gene HEVD protein was further purified and used as an antigen for an ELISA. Samples from dogs with undetectable to high anti-CDV antibody titers were analyzed using this HEVD-specific ELISA and a commercial CDV antibody detection kit (ImmunoComb). Levels of HEVD antigenicity measured with the assays and immunochromatography correlated. These data indicated that the HEDV protein may be used as antigen to develop techniques for detecting antibodies against CDV. PMID:25234325

  4. Multi-scale model for hepatitis C viral load kinetics under treatment with direct acting antivirals.

    PubMed

    Clausznitzer, Diana; Harnisch, Julia; Kaderali, Lars

    2016-06-15

    Hepatitis C virus (HCV) infections are a global health problem, and extensive research over the last decades has been targeted at understanding its molecular biology and developing effective antiviral treatments. Recently, a number of potent direct acting antiviral drugs have been developed targeting specific processes in the viral life cycle. Here, we developed a mathematical multi-scale model of the within-host dynamics of HCV infection by integrating a standard model for viral infection with a detailed model of the viral replication cycle inside infected cells. We use this model to study patient time courses of viral load under treatment with daclatasvir, an inhibitor of the viral non-structural protein NS5A. Model analysis predicts that treatment efficacy can be increased by combining daclatasvir with dedicated viral polymerase inhibitors, corresponding to promising current strategies in drug development. Hence, our model presents a predictive tool for in silico simulations, which can be used to study and optimize direct acting antiviral drug treatment. PMID:26409026

  5. Modeling viral and drug kinetics: hepatitis C virus treatment with pegylated interferon alfa-2b.

    PubMed

    Powers, Kimberly A; Dixit, Narendra M; Ribeiro, Ruy M; Golia, Preeti; Talal, Andrew H; Perelson, Alan S

    2003-01-01

    Administration of peginterferon alfa-2b plus ribavirin results in an early hepatitis C virus (HCV) RNA decay followed by an increase as the drug concentration declines between doses. Upon administration of the next dose 1 week later, the same pattern is observed. We have incorporated pharmacokinetic/pharmacodynamic analysis into a model of viral dynamics to describe the effect that changes in drug concentration and effectiveness can have on viral levels. To illustrate the relationship between pharmacokinetics and viral dynamics, we fit the model to data from four HCV/human immunodeficiency virus co-infected patients, and obtained good agreement with the measured serum HCV RNA levels. We were able to account for the observed increases in HCV RNA, and estimate virion and drug half-lives that are in agreement with previous reports. Models incorporating pharmacokinetics are needed to correctly interpret viral load changes and estimate drug effectiveness in treatment protocols using peginterferon alfa-2b. PMID:12934163

  6. An accurate two-phase approximate solution to the acute viral infection model

    SciTech Connect

    Perelson, Alan S

    2009-01-01

    During an acute viral infection, virus levels rise, reach a peak and then decline. Data and numerical solutions suggest the growth and decay phases are linear on a log scale. While viral dynamic models are typically nonlinear with analytical solutions difficult to obtain, the exponential nature of the solutions suggests approximations can be found. We derive a two-phase approximate solution to the target cell limited influenza model and illustrate the accuracy using data and previously established parameter values of six patients infected with influenza A. For one patient, the subsequent fall in virus concentration was not consistent with our predictions during the decay phase and an alternate approximation is derived. We find expressions for the rate and length of initial viral growth in terms of the parameters, the extent each parameter is involved in viral peaks, and the single parameter responsible for virus decay. We discuss applications of this analysis in antiviral treatments and investigating host and virus heterogeneities.

  7. Spin models inferred from patient-derived viral sequence data faithfully describe HIV fitness landscapes

    NASA Astrophysics Data System (ADS)

    Shekhar, Karthik; Ruberman, Claire F.; Ferguson, Andrew L.; Barton, John P.; Kardar, Mehran; Chakraborty, Arup K.

    2013-12-01

    Mutational escape from vaccine-induced immune responses has thwarted the development of a successful vaccine against AIDS, whose causative agent is HIV, a highly mutable virus. Knowing the virus' fitness as a function of its proteomic sequence can enable rational design of potent vaccines, as this information can focus vaccine-induced immune responses to target mutational vulnerabilities of the virus. Spin models have been proposed as a means to infer intrinsic fitness landscapes of HIV proteins from patient-derived viral protein sequences. These sequences are the product of nonequilibrium viral evolution driven by patient-specific immune responses and are subject to phylogenetic constraints. How can such sequence data allow inference of intrinsic fitness landscapes? We combined computer simulations and variational theory á la Feynman to show that, in most circumstances, spin models inferred from patient-derived viral sequences reflect the correct rank order of the fitness of mutant viral strains. Our findings are relevant for diverse viruses.

  8. Feature-Linking Model for Image Enhancement.

    PubMed

    Zhan, Kun; Teng, Jicai; Shi, Jinhui; Li, Qiaoqiao; Wang, Mingying

    2016-06-01

    Inspired by gamma-band oscillations and other neurobiological discoveries, neural networks research shifts the emphasis toward temporal coding, which uses explicit times at which spikes occur as an essential dimension in neural representations. We present a feature-linking model (FLM) that uses the timing of spikes to encode information. The first spiking time of FLM is applied to image enhancement, and the processing mechanisms are consistent with the human visual system. The enhancement algorithm achieves boosting the details while preserving the information of the input image. Experiments are conducted to demonstrate the effectiveness of the proposed method. Results show that the proposed method is effective. PMID:26942747

  9. Determining Host Metabolic Limitations on Viral Replication via Integrated Modeling and Experimental Perturbation

    PubMed Central

    Birch, Elsa W.; Ruggero, Nicholas A.; Covert, Markus W.

    2012-01-01

    Viral replication relies on host metabolic machinery and precursors to produce large numbers of progeny - often very rapidly. A fundamental example is the infection of Escherichia coli by bacteriophage T7. The resource draw imposed by viral replication represents a significant and complex perturbation to the extensive and interconnected network of host metabolic pathways. To better understand this system, we have integrated a set of structured ordinary differential equations quantifying T7 replication and an E. coli flux balance analysis metabolic model. Further, we present here an integrated simulation algorithm enforcing mutual constraint by the models across the entire duration of phage replication. This method enables quantitative dynamic prediction of virion production given only specification of host nutritional environment, and predictions compare favorably to experimental measurements of phage replication in multiple environments. The level of detail of our computational predictions facilitates exploration of the dynamic changes in host metabolic fluxes that result from viral resource consumption, as well as analysis of the limiting processes dictating maximum viral progeny production. For example, although it is commonly assumed that viral infection dynamics are predominantly limited by the amount of protein synthesis machinery in the host, our results suggest that in many cases metabolic limitation is at least as strict. Taken together, these results emphasize the importance of considering viral infections in the context of host metabolism. PMID:23093930

  10. A study of the spreading scheme for viral marketing based on a complex network model

    NASA Astrophysics Data System (ADS)

    Yang, Jianmei; Yao, Canzhong; Ma, Weicheng; Chen, Guanrong

    2010-02-01

    Buzzword-based viral marketing, known also as digital word-of-mouth marketing, is a marketing mode attached to some carriers on the Internet, which can rapidly copy marketing information at a low cost. Viral marketing actually uses a pre-existing social network where, however, the scale of the pre-existing network is believed to be so large and so random, so that its theoretical analysis is intractable and unmanageable. There are very few reports in the literature on how to design a spreading scheme for viral marketing on real social networks according to the traditional marketing theory or the relatively new network marketing theory. Complex network theory provides a new model for the study of large-scale complex systems, using the latest developments of graph theory and computing techniques. From this perspective, the present paper extends the complex network theory and modeling into the research of general viral marketing and develops a specific spreading scheme for viral marking and an approach to design the scheme based on a real complex network on the QQ instant messaging system. This approach is shown to be rather universal and can be further extended to the design of various spreading schemes for viral marketing based on different instant messaging systems.

  11. GROUNDWATER MODELING LINKS (SUBSURFACE PROTECTION AND REMEDIATION DIVISION, NRMRL)

    EPA Science Inventory

    From this site, the viewer will be able to access Groundwater Modeling Software Links as well as Groundwater Professionals Links. For the viewer's benefit, the site includes both USEPA and non-EPA links.To view and link to these sites, visit the website at http://www.epa.gov/ad...

  12. Evolutionary dynamics of viral escape under antibodies stress: A biophysical model.

    PubMed

    Chéron, Nicolas; Serohijos, Adrian W R; Choi, Jeong-Mo; Shakhnovich, Eugene I

    2016-07-01

    Viruses constantly face the selection pressure of antibodies, either from innate immune response of the host or from administered antibodies for treatment. We explore the interplay between the biophysical properties of viral proteins and the population and demographic variables in the viral escape. The demographic and population genetics aspect of the viral escape have been explored before; however one important assumption was the a priori distribution of fitness effects (DFE). Here, we relax this assumption by instead considering a realistic biophysics-based genotype-phenotype relationship for RNA viruses escaping antibodies stress. In this model the DFE is itself an evolvable property that depends on the genetic background (epistasis) and the distribution of biophysical effects of mutations, which is informed by biochemical experiments and theoretical calculations in protein engineering. We quantitatively explore in silico the viability of viral populations under antibodies pressure and derive the phase diagram that defines the fate of the virus population (extinction or escape from stress) in a range of viral mutation rates and antibodies concentrations. We find that viruses are most resistant to stress at an optimal mutation rate (OMR) determined by the competition between supply of beneficial mutation to facilitate escape from stressors and lethal mutagenesis caused by excess of destabilizing mutations. We then show the quantitative dependence of the OMR on genome length and viral burst size. We also recapitulate the experimental observation that viruses with longer genomes have smaller mutation rate per nucleotide. PMID:26939576

  13. Common data link (CDL) interference model

    NASA Astrophysics Data System (ADS)

    Cerasoli, Caramen; Zhao, Wiley; Santapietro, John J.; McAlinden, R. E.; Smith, B. F.; Jacyk, P. A.

    2002-07-01

    The increasing use of airwaves for military communication and surveillance and commercial applications places burdens on spectrum use. This crowding of the spectrum presents two broad problem categories. The first is "co-site interference" where numerous transmitters and receivers are physically located in a small area and share a given portion of the spectrum. Under these conditions, a receiver can be "victim" to a co-located transmitter. The second category involves numerous transmitters (typically airborne) well separated from each other but communicating to receivers placed in a relatively small area. The Common Data Link (CDL) refers to a standard protocol for military data delivery and communication. Surveillance platforms such as Tactical Unmanned Aerial Vehicles (TUAV), JSTARS, U2's, Global Hawks will stream high rate surveillance data (radar, visual and/or infrared imagery, etc.) down to ground terminals. As such, bandwidths are wide (100's MHz) and the potential exists for ground receivers to be victim to signals from airborne transmitters other than its desired source. MITRE has developed a CDL Interference Model to assess potential problems in realistic tactical surveillance scenarios. This paper documents the physical basis of the CDL Interference Model as well as the visualization software architecture that integrates the model with ModSAF/OneSAF.

  14. How Can Viral Dynamics Models Inform Endpoint Measures in Clinical Trials of Therapies for Acute Viral Infections?

    PubMed Central

    Cori, Anne; de Wolf, Frank; Anderson, Roy M.

    2016-01-01

    Acute viral infections pose many practical challenges for the accurate assessment of the impact of novel therapies on viral growth and decay. Using the example of influenza A, we illustrate how the measurement of infection-related quantities that determine the dynamics of viral load within the human host, can inform investigators on the course and severity of infection and the efficacy of a novel treatment. We estimated the values of key infection-related quantities that determine the course of natural infection from viral load data, using Markov Chain Monte Carlo methods. The data were placebo group viral load measurements collected during volunteer challenge studies, conducted by Roche, as part of the oseltamivir trials. We calculated the values of the quantities for each patient and the correlations between the quantities, symptom severity and body temperature. The greatest variation among individuals occurred in the viral load peak and area under the viral load curve. Total symptom severity correlated positively with the basic reproductive number. The most sensitive endpoint for therapeutic trials with the goal to cure patients is the duration of infection. We suggest laboratory experiments to obtain more precise estimates of virological quantities that can supplement clinical endpoint measurements. PMID:27367230

  15. ModeLang: A New Approach for Experts-Friendly Viral Infections Modeling

    PubMed Central

    Blazewicz, Jacek

    2013-01-01

    Computational modeling is an important element of systems biology. One of its important applications is modeling complex, dynamical, and biological systems, including viral infections. This type of modeling usually requires close cooperation between biologists and mathematicians. However, such cooperation often faces communication problems because biologists do not have sufficient knowledge to understand mathematical description of the models, and mathematicians do not have sufficient knowledge to define and verify these models. In many areas of systems biology, this problem has already been solved; however, in some of these areas there are still certain problematic aspects. The goal of the presented research was to facilitate this cooperation by designing seminatural formal language for describing viral infection models that will be easy to understand for biologists and easy to use by mathematicians and computer scientists. The ModeLang language was designed in cooperation with biologists and its computer implementation was prepared. Tests proved that it can be successfully used to describe commonly used viral infection models and then to simulate and verify them. As a result, it can make cooperation between biologists and mathematicians modeling viral infections much easier, speeding up computational verification of formulated hypotheses. PMID:24454531

  16. Dysplastic Hepatocytes Develop Nuclear Inclusions in a Mouse Model of Viral Hepatitis

    PubMed Central

    Thakur, Priyanka; Lamoke, Folami; Chaffin, Joanna M.; Bartoli, Manuela; Lee, Jeffrey R.; Duncan, Michael B.

    2014-01-01

    Viral hepatitis resulting in chronic liver disease is an important clinical challenge and insight into the cellular processes that drive pathogenesis will be critical in order to develop new diagnostic and therapeutic options. Nuclear inclusions in viral and non-viral hepatitis are well documented and have diagnostic significance in some disease contexts. However, the origins and functional consequences of these nuclear inclusions remain elusive. To date the clinical observation of nuclear inclusions in viral and non-viral hepatitis has not been explored at depth in murine models of liver disease. Herein, we report that in a transgenic model of hepatitis B surface antigen mediated hepatitis, murine hepatocytes exhibit nuclear inclusions. Cells bearing nuclear inclusions were more likely to express markers of cell proliferation. We also established a correlation between these inclusions and oxidative stress. N-acetyl cysteine treatment effectively reduced oxidative stress levels, relieved endoplasmic reticulum (ER) stress, and the number of nuclear inclusions we observed in the transgenic mice. Our results suggest that the presence of nuclear inclusions in hepatocytes correlates with oxidative stress and cellular proliferation in a model of antigen mediated hepatitis. PMID:24932583

  17. Rodent models of HAND and drug abuse: exogenous administration of viral protein(s) and cocaine.

    PubMed

    Yao, Honghong; Buch, Shilpa

    2012-06-01

    Humans and chimpanzees are the natural hosts for HIV. Non-human primate models of SIV/SHIV infection in rhesus, cynomologus and pigtail macaques have been used extensively as excellent model systems for pathogenesis and vaccine studies. However, owing to the variability of disease progression in infected macaques, a phenomenon identical to humans, coupled with their prohibitive costs, there exists a critical need for the development of small-animal models in which to study the untoward effects of HIV-1 infection. Owing to the fact that rodents are not the natural permissive hosts for lentiviral infection, development of small animal models for studying virus infection has used strategies that circumvent the steps of viral entry and infection. Such strategies involve overexpression of toxic viral proteins, SCID mice engrafted with the human PBLs or macrophages, and EcoHIV chimeric virus wherein the gp120 of HIV-1 was replaced with the gp80 of the ecotropic murine leukemia virus. Additional strategy that is often used by investigators to study the toxic effect of viral proteins involves direct stereotactic injection of the viral protein(s) into specific brain regions. The present report is a compilation of the applications of direct administration of Tat into the striatum to mimic the effects of the viral neurotoxin in the CNS. Added advantage of this model is that it is also amenable to repeated intraperitoneal cocaine injections, thereby allowing the study of the additive/synergistic effects of both the viral protein and cocaine. Such a model system recapitulates aspects of HAND in the context of drug abuse. PMID:22447295

  18. Rainfall-runoff model for prediction of waterborne viral contamination in a small river catchment

    NASA Astrophysics Data System (ADS)

    Gelati, E.; Dommar, C.; Lowe, R.; Polcher, J.; Rodó, X.

    2013-12-01

    We present a lumped rainfall-runoff model aimed at providing useful information for the prediction of waterborne viral contamination in small rivers. Viral contamination of water bodies may occur because of the discharge of sewage effluents and of surface runoff over areas affected by animal waste loads. Surface runoff is caused by precipitation that cannot infiltrate due to its intensity and to antecedent soil water content. It may transport animal feces to adjacent water bodies and cause viral contamination. We model streamflow by separating it into two components: subsurface flow, which is produced by infiltrated precipitation; and surface runoff. The model estimates infiltrated and non-infiltrated precipitation and uses impulse-response functions to compute the corresponding fractions of streamflow. The developed methodologies are applied to the Glafkos river, whose catchment extends for 102 km2 and includes the city of Patra. Streamflow and precipitation observations are available at a daily time resolution. Waterborne virus concentration measurements were performed approximately every second week from the beginning of 2011 to mid 2012. Samples were taken at several locations: in river water upstream of Patras and in the urban area; in sea water at the river outlet and approximately 2 km south-west of Patras; in sewage effluents before and after treatment. The rainfall-runoff model was calibrated and validated using observed streamflow and precipitation data. The model contribution to waterborne viral contamination prediction was benchmarked by analyzing the virus concentration measurements together with the estimated surface runoff values. The presented methodology may be a first step towards the development of waterborne viral contamination alert systems. Predicting viral contamination of water bodies would benefit sectors such as water supply and tourism.

  19. Getting to Know Viral Evolutionary Strategies: Towards the Next Generation of Quasispecies Models.

    PubMed

    Manrubia, Susanna; Lázaro, Ester

    2016-01-01

    Viral populations are formed by complex ensembles of genomes with broad phenotypic diversity. The adaptive strategies deployed by these ensembles are multiple and often cannot be predicted a priori. Our understanding of viral dynamics is mostly based on two kinds of empirical approaches: one directed towards characterizing molecular changes underlying fitness changes and another focused on population-level responses. Simultaneously, theoretical efforts are directed towards developing a formal picture of viral evolution by means of more realistic fitness landscapes and reliable population dynamics models. New technologies, chiefly the use of next-generation sequencing and related tools, are opening avenues connecting the molecular and the population levels. In the near future, we hope to be witnesses of an integration of these still decoupled approaches, leading into more accurate and realistic quasispecies models able to capture robust generalities and endowed with a satisfactory predictive power. PMID:26271604

  20. Modeling evolution and persistence of neurological viral diseases in wild populations.

    PubMed

    Dimitrov, Dobromir T; King, Aaron A

    2008-10-01

    Viral infections are one of the leading source of mortality worldwide. The great majority of them circulate and persist in wild reservoirs and periodically spill over into humans or domestic animals. In the wild reservoirs, the progression of disease is frequently quite different from that in spillover hosts. We propose a mathematical treatment of the dynamics of viral infections in wild mammals using models with alternative outcomes. We develop and analyze compartmental epizootic models assuming permanent or temporary immunity of the individuals surviving infections and apply them to rabies in bats. We identify parameter relations that support the existing patterns in the viral ecology and estimate those parameters that are unattainable through direct measurement. We also investigate how the duration of the acquired immunity affects the disease and population dynamics. PMID:19278278

  1. Bovine viral diarrhea virus antigen detection across whole cattle hides using two antigen-capture enzyme-linked immunosorbent assays

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine viral diarrhea virus is a costly disease of cattle that can be controlled by vaccination, biosecurity, and removal of persistently infected cattle. Development and proficiency testing of assays to identify persistently infected cattle substantial quantities of known positive and negative samp...

  2. Viral perturbations of host networks reflect disease etiology.

    PubMed

    Gulbahce, Natali; Yan, Han; Dricot, Amélie; Padi, Megha; Byrdsong, Danielle; Franchi, Rachel; Lee, Deok-Sun; Rozenblatt-Rosen, Orit; Mar, Jessica C; Calderwood, Michael A; Baldwin, Amy; Zhao, Bo; Santhanam, Balaji; Braun, Pascal; Simonis, Nicolas; Huh, Kyung-Won; Hellner, Karin; Grace, Miranda; Chen, Alyce; Rubio, Renee; Marto, Jarrod A; Christakis, Nicholas A; Kieff, Elliott; Roth, Frederick P; Roecklein-Canfield, Jennifer; Decaprio, James A; Cusick, Michael E; Quackenbush, John; Hill, David E; Münger, Karl; Vidal, Marc; Barabási, Albert-László

    2012-01-01

    Many human diseases, arising from mutations of disease susceptibility genes (genetic diseases), are also associated with viral infections (virally implicated diseases), either in a directly causal manner or by indirect associations. Here we examine whether viral perturbations of host interactome may underlie such virally implicated disease relationships. Using as models two different human viruses, Epstein-Barr virus (EBV) and human papillomavirus (HPV), we find that host targets of viral proteins reside in network proximity to products of disease susceptibility genes. Expression changes in virally implicated disease tissues and comorbidity patterns cluster significantly in the network vicinity of viral targets. The topological proximity found between cellular targets of viral proteins and disease genes was exploited to uncover a novel pathway linking HPV to Fanconi anemia. PMID:22761553

  3. Viral Perturbations of Host Networks Reflect Disease Etiology

    PubMed Central

    Dricot, Amélie; Padi, Megha; Byrdsong, Danielle; Franchi, Rachel; Lee, Deok-Sun; Rozenblatt-Rosen, Orit; Mar, Jessica C.; Calderwood, Michael A.; Baldwin, Amy; Zhao, Bo; Santhanam, Balaji; Braun, Pascal; Simonis, Nicolas; Huh, Kyung-Won; Hellner, Karin; Grace, Miranda; Chen, Alyce; Rubio, Renee; Marto, Jarrod A.; Christakis, Nicholas A.; Kieff, Elliott; Roth, Frederick P.; Roecklein-Canfield, Jennifer; DeCaprio, James A.; Cusick, Michael E.; Quackenbush, John; Hill, David E.; Münger, Karl; Vidal, Marc; Barabási, Albert-László

    2012-01-01

    Many human diseases, arising from mutations of disease susceptibility genes (genetic diseases), are also associated with viral infections (virally implicated diseases), either in a directly causal manner or by indirect associations. Here we examine whether viral perturbations of host interactome may underlie such virally implicated disease relationships. Using as models two different human viruses, Epstein-Barr virus (EBV) and human papillomavirus (HPV), we find that host targets of viral proteins reside in network proximity to products of disease susceptibility genes. Expression changes in virally implicated disease tissues and comorbidity patterns cluster significantly in the network vicinity of viral targets. The topological proximity found between cellular targets of viral proteins and disease genes was exploited to uncover a novel pathway linking HPV to Fanconi anemia. PMID:22761553

  4. A Highly Intensified ART Regimen Induces Long-Term Viral Suppression and Restriction of the Viral Reservoir in a Simian AIDS Model

    PubMed Central

    Della Corte, Alessandro; Collins, Matt; Yalley-Ogunro, Jake; Greenhouse, Jack; Iraci, Nunzio; Acosta, Edward P.; Barreca, Maria Letizia; Lewis, Mark G.; Savarino, Andrea

    2012-01-01

    Stably suppressed viremia during ART is essential for establishing reliable simian models for HIV/AIDS. We tested the efficacy of a multidrug ART (highly intensified ART) in a wide range of viremic conditions (103–107 viral RNA copies/mL) in SIVmac251-infected rhesus macaques, and its impact on the viral reservoir. Eleven macaques in the pre-AIDS stage of the disease were treated with a multidrug combination (highly intensified ART) consisting of two nucleosidic/nucleotidic reverse transcriptase inhibitors (emtricitabine and tenofovir), an integrase inhibitor (raltegravir), a protease inhibitor (ritonavir-boosted darunavir) and the CCR5 blocker maraviroc. All animals stably displayed viral loads below the limit of detection of the assay (i.e. <40 RNA copies/mL) after starting highly intensified ART. By increasing the sensitivity of the assay to 3 RNA copies/mL, viral load was still below the limit of detection in all subjects tested. Importantly, viral DNA resulted below the assay detection limit (<2 copies of DNA/5*105 cells) in PBMCs and rectal biopsies of all animals at the end of the follow-up, and in lymph node biopsies from the majority of the study subjects. Moreover, highly intensified ART decreased central/transitional memory, effector memory and activated (HLA-DR+) effector memory CD4+ T-cells in vivo, in line with the role of these subsets as the main cell subpopulations harbouring the virus. Finally, treatment with highly intensified ART at viral load rebound following suspension of a previous anti-reservoir therapy eventually improved the spontaneous containment of viral load following suspension of the second therapeutic cycle, thus leading to a persistent suppression of viremia in the absence of ART. In conclusion, we show, for the first time, complete suppression of viral load by highly intensified ART and a likely associated restriction of the viral reservoir in the macaque AIDS model, making it a useful platform for testing potential cures for

  5. An Investigation of Linking Methods under the Graded Response Model.

    ERIC Educational Resources Information Center

    Cohen, Allan S.; Kim, Seock-Ho

    1998-01-01

    Studied results from five linking methods under the graded-response model using simulated data. Results show that differences in the linking coefficients are small. The five methods yielded similar results for longer common-item links with large sample sizes and when the distribution of item-location parameters matched the underlying trait…

  6. A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV

    DOE PAGESBeta

    Canini, Laetitia; Chatterjee, Anushree; Guedj, Jeremie; Lemenuel-Diot, Annabelle; Brennan, Barbara; Smith, Patrick F.; Perelson, Alan S.

    2014-10-16

    Background—Viral kinetic models have proven useful to characterize treatment effectiveness during HCV therapy with interferon (IFN) or with direct acting antivirals (DAAs). Methods—We use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with danoprevir, a protease inhibitor. In a phase 1 study, danoprevir monotherapy was administered for 14 days in ascending doses ranging from 200 to 600 mg per day to 40 patients of whom 32 were treatment-naïve and 8 were non-responders to prior PEG-IFN-α/ribavirin treatment. Results—In most patients, a biphasic decline of HCV RNA during therapy was observed. A two-compartment PK model and a VKmore » model that considered treatment effectiveness to vary with the predicted danoprevir concentration inside the second compartment provided a good fit to the viral load data. A time-varying effectiveness model was also used to fit the viral load data. We found the antiviral effectiveness increased in a dose-dependent manner, with a 14-day time-averaged effectiveness of 0.95 at the lowest dose (100 mg bid) and 0.99 at the highest dose (200 mg tid). Prior IFN non-responders exhibited a 14-day time-averaged effectiveness of 0.98 (300 mg bid). Finally, the second phase decline showed two different behaviors, with 30% of patients exhibiting a rapid decline of HCV RNA, comparable to that seen with other protease inhibitors (>0.3 d-1), whereas the viral decline was slower in the other patients. Conclusions—Our results are consistent with the modest SVR rates from the INFORM-SVR study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir.« less

  7. A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV

    SciTech Connect

    Canini, Laetitia; Chatterjee, Anushree; Guedj, Jeremie; Lemenuel-Diot, Annabelle; Brennan, Barbara; Smith, Patrick F.; Perelson, Alan S.

    2014-10-16

    Background—Viral kinetic models have proven useful to characterize treatment effectiveness during HCV therapy with interferon (IFN) or with direct acting antivirals (DAAs). Methods—We use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with danoprevir, a protease inhibitor. In a phase 1 study, danoprevir monotherapy was administered for 14 days in ascending doses ranging from 200 to 600 mg per day to 40 patients of whom 32 were treatment-naïve and 8 were non-responders to prior PEG-IFN-α/ribavirin treatment. Results—In most patients, a biphasic decline of HCV RNA during therapy was observed. A two-compartment PK model and a VK model that considered treatment effectiveness to vary with the predicted danoprevir concentration inside the second compartment provided a good fit to the viral load data. A time-varying effectiveness model was also used to fit the viral load data. We found the antiviral effectiveness increased in a dose-dependent manner, with a 14-day time-averaged effectiveness of 0.95 at the lowest dose (100 mg bid) and 0.99 at the highest dose (200 mg tid). Prior IFN non-responders exhibited a 14-day time-averaged effectiveness of 0.98 (300 mg bid). Finally, the second phase decline showed two different behaviors, with 30% of patients exhibiting a rapid decline of HCV RNA, comparable to that seen with other protease inhibitors (>0.3 d-1), whereas the viral decline was slower in the other patients. Conclusions—Our results are consistent with the modest SVR rates from the INFORM-SVR study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir.

  8. Viral dynamics model with CTL immune response incorporating antiretroviral therapy.

    PubMed

    Wang, Yan; Zhou, Yicang; Brauer, Fred; Heffernan, Jane M

    2013-10-01

    We present two HIV models that include the CTL immune response, antiretroviral therapy and a full logistic growth term for uninfected CD4+ T-cells. The difference between the two models lies in the inclusion or omission of a loss term in the free virus equation. We obtain critical conditions for the existence of one, two or three steady states, and analyze the stability of these steady states. Through numerical simulation we find substantial differences in the reproduction numbers and the behaviour at the infected steady state between the two models, for certain parameter sets. We explore the effect of varying the combination drug efficacy on model behaviour, and the possibility of reconstituting the CTL immune response through antiretroviral therapy. Furthermore, we employ Latin hypercube sampling to investigate the existence of multiple infected equilibria. PMID:22930342

  9. Transgenic models of Alzheimer's disease: better utilization of existing models through viral transgenesis.

    PubMed

    Platt, Thomas L; Reeves, Valerie L; Murphy, M Paul

    2013-09-01

    Animal models have been used for decades in the Alzheimer's disease (AD) research field and have been crucial for the advancement of our understanding of the disease. Most models are based on familial AD mutations of genes involved in the amyloidogenic process, such as the amyloid precursor protein (APP) and presenilin 1 (PS1). Some models also incorporate mutations in tau (MAPT) known to cause frontotemporal dementia, a neurodegenerative disease that shares some elements of neuropathology with AD. While these models are complex, they fail to display pathology that perfectly recapitulates that of the human disease. Unfortunately, this level of pre-existing complexity creates a barrier to the further modification and improvement of these models. However, as the efficacy and safety of viral vectors improves, their use as an alternative to germline genetic modification is becoming a widely used research tool. In this review we discuss how this approach can be used to better utilize common mouse models in AD research. This article is part of a Special Issue entitled: Animal Models of Disease. PMID:23619198

  10. Modeling and simulation of the mechanical response from nanoindentation test of DNA-filled viral capsids.

    PubMed

    Ahadi, Aylin; Johansson, Dan; Evilevitch, Alex

    2013-03-01

    Viruses can be described as biological objects composed mainly of two parts: a stiff protein shell called a capsid, and a core inside the capsid containing the nucleic acid and liquid. In many double-stranded DNA bacterial viruses (aka phage), the volume ratio between the liquid and the encapsidated DNA is approximately 1:1. Due to the dominant DNA hydration force, water strongly mediates the interaction between the packaged DNA strands. Therefore, water that hydrates the DNA plays an important role in nanoindentation experiments of DNA-filled viral capsids. Nanoindentation measurements allow us to gain further insight into the nature of the hydration and electrostatic interactions between the DNA strands. With this motivation, a continuum-based numerical model for simulating the nanoindentation response of DNA-filled viral capsids is proposed here. The viral capsid is modeled as large- strain isotropic hyper-elastic material, whereas porous elasticity is adopted to capture the mechanical response of the filled viral capsid. The voids inside the viral capsid are assumed to be filled with liquid, which is modeled as a homogenous incompressible fluid. The motion of a fluid flowing through the porous medium upon capsid indentation is modeled using Darcy's law, describing the flow of fluid through a porous medium. The nanoindentation response is simulated using three-dimensional finite element analysis and the simulations are performed using the finite element code Abaqus. Force-indentation curves for empty, partially and completely DNA-filled capsids are directly compared to the experimental data for bacteriophage λ. Material parameters such as Young's modulus, shear modulus, and bulk modulus are determined by comparing computed force-indentation curves to the data from the atomic force microscopy (AFM) experiments. Predictions are made for pressure distribution inside the capsid, as well as the fluid volume ratio variation during the indentation test. PMID:23860868

  11. Modeling ecological drivers in marine viral communities using comparative metagenomics and network analyses

    PubMed Central

    Hurwitz, Bonnie L.; Westveld, Anton H.; Brum, Jennifer R.; Sullivan, Matthew B.

    2014-01-01

    Long-standing questions in marine viral ecology are centered on understanding how viral assemblages change along gradients in space and time. However, investigating these fundamental ecological questions has been challenging due to incomplete representation of naturally occurring viral diversity in single gene- or morphology-based studies and an inability to identify up to 90% of reads in viral metagenomes (viromes). Although protein clustering techniques provide a significant advance by helping organize this unknown metagenomic sequence space, they typically use only ∼75% of the data and rely on assembly methods not yet tuned for naturally occurring sequence variation. Here, we introduce an annotation- and assembly-free strategy for comparative metagenomics that combines shared k-mer and social network analyses (regression modeling). This robust statistical framework enables visualization of complex sample networks and determination of ecological factors driving community structure. Application to 32 viromes from the Pacific Ocean Virome dataset identified clusters of samples broadly delineated by photic zone and revealed that geographic region, depth, and proximity to shore were significant predictors of community structure. Within subsets of this dataset, depth, season, and oxygen concentration were significant drivers of viral community structure at a single open ocean station, whereas variability along onshore–offshore transects was driven by oxygen concentration in an area with an oxygen minimum zone and not depth or proximity to shore, as might be expected. Together these results demonstrate that this highly scalable approach using complete metagenomic network-based comparisons can both test and generate hypotheses for ecological investigation of viral and microbial communities in nature. PMID:25002514

  12. Modeling ecological drivers in marine viral communities using comparative metagenomics and network analyses.

    PubMed

    Hurwitz, Bonnie L; Westveld, Anton H; Brum, Jennifer R; Sullivan, Matthew B

    2014-07-22

    Long-standing questions in marine viral ecology are centered on understanding how viral assemblages change along gradients in space and time. However, investigating these fundamental ecological questions has been challenging due to incomplete representation of naturally occurring viral diversity in single gene- or morphology-based studies and an inability to identify up to 90% of reads in viral metagenomes (viromes). Although protein clustering techniques provide a significant advance by helping organize this unknown metagenomic sequence space, they typically use only ∼75% of the data and rely on assembly methods not yet tuned for naturally occurring sequence variation. Here, we introduce an annotation- and assembly-free strategy for comparative metagenomics that combines shared k-mer and social network analyses (regression modeling). This robust statistical framework enables visualization of complex sample networks and determination of ecological factors driving community structure. Application to 32 viromes from the Pacific Ocean Virome dataset identified clusters of samples broadly delineated by photic zone and revealed that geographic region, depth, and proximity to shore were significant predictors of community structure. Within subsets of this dataset, depth, season, and oxygen concentration were significant drivers of viral community structure at a single open ocean station, whereas variability along onshore-offshore transects was driven by oxygen concentration in an area with an oxygen minimum zone and not depth or proximity to shore, as might be expected. Together these results demonstrate that this highly scalable approach using complete metagenomic network-based comparisons can both test and generate hypotheses for ecological investigation of viral and microbial communities in nature. PMID:25002514

  13. Development of anti-viral agents using molecular modeling and virtual screening techniques.

    PubMed

    Kirchmair, Johannes; Distinto, Simona; Liedl, Klaus Roman; Markt, Patrick; Rollinger, Judith Maria; Schuster, Daniela; Spitzer, Gudrun Maria; Wolber, Gerhard

    2011-02-01

    Computational chemistry has always played a key role in anti-viral drug development. The challenges and the quickly rising public interest when a virus is becoming a threat has significantly influenced computational drug discovery. The most obvious example is anti-AIDS research, where HIV protease and reverse transcriptase have triggered enormous efforts in developing and improving computational methods. Methods applied to anti-viral research include (i) ligand-based approaches that rely on known active compounds to extrapolate biological activity, such as machine learning techniques or classical QSAR, (ii) structure-based methods that rely on an experimentally determined 3D structure of the targets, such as molecular docking or molecular dynamics, and (iii) universal approaches that can be applied in a structure- or ligand-based way, such as 3D QSAR or 3D pharmacophore elucidation. In this review we summarize these molecular modeling approaches as they were applied to fight anti-viral diseases and highlight their importance for anti-viral research. We discuss the role of computational chemistry in the development of small molecules as agents against HIV integrase, HIV-1 protease, HIV-1 reverse transcriptase, the influenza virus M2 channel protein, influenza virus neuraminidase, the SARS coronavirus main proteinase and spike protein, thymidine kinases of herpes viruses, hepatitis c virus proteins and other flaviviruses as well as human rhinovirus coat protein and proteases, and other picornaviridae. We highlight how computational approaches have helped in discovering anti-viral activities of natural products and give an overview on polypharmacology approaches that help to optimize drugs against several viruses or help to optimize the metabolic profile of and anti-viral drug. PMID:21303343

  14. VIRAL TRANSPORT AND FATE MODELS FOR GROUND WATER VULNERABILITY

    EPA Science Inventory

    The purpose of this project is to develop a model to assess the vulnerability of public water systems to pathogens. It is focused on the sources, fate and transport of viruses in aquifer systems in specific hydrologic settings. It's intended to be used by resource managers or r...

  15. [Families and psychiatry: models and evolving links].

    PubMed

    Frankhauser, Adeline

    2016-01-01

    The role of the families of persons with severe psychiatric disorders (schizophrenia in particular) in the care of their relatives has recently evolved: once seen as pathogenic to be kept at a distance, the family is now recognised by professionals as a partner in the care process. The links between families and psychiatric institutions remain complex and marked by ambivalence and paradoxes. PMID:27157191

  16. Tupaia belangeri as an experimental animal model for viral infection.

    PubMed

    Tsukiyama-Kohara, Kyoko; Kohara, Michinori

    2014-01-01

    Tupaias, or tree shrews, are small mammals that are similar in appearance to squirrels. The morphological and behavioral characteristics of the group have been extensively characterized, and despite previously being classified as primates, recent studies have placed the group in its own family, the Tupaiidae. Genomic analysis has revealed that the genus Tupaia is closer to humans than it is to rodents. In addition, tupaias are susceptible to hepatitis B virus and hepatitis C virus. The only other experimental animal that has been demonstrated to be sensitive to both of these viruses is the chimpanzee, but restrictions on animal testing have meant that experiments using chimpanzees have become almost impossible. Consequently, the development of the tupaia for use as an animal infection model could become a powerful tool for hepatitis virus research and in preclinical studies on drug development. PMID:25048261

  17. Use of a three-dimensional humanized liver model for the study of viral gene vectors.

    PubMed

    Wagner, Anke; Röhrs, Viola; Materne, Eva-Maria; Hiller, Thomas; Kedzierski, Radoslaw; Fechner, Henry; Lauster, Roland; Kurreck, Jens

    2015-10-20

    Reconstituted three-dimensional (3D) liver models obtained by engrafting hepatic cells into an extracellular matrix (ECM) are valuable tools to study tissue regeneration, drug action and toxicology ex vivo. The aim of the present study was to establish a system for the functional investigation of a viral vector in a 3D liver model composed of human HepG2 cells on a rat ECM. An adeno-associated viral (AAV) vector expressing the Emerald green fluorescent protein (EmGFP) and a short hairpin RNA (shRNA) directed against human cyclophilin b (hCycB) was injected into the portal vein of 3D liver models. Application of the vector did not exert toxic effects, as shown by analysis of metabolic parameters. Six days after transduction, fluorescence microscopy analysis of EmGFP production revealed widespread distribution of the AAV vectors. After optimization of the recellularization and transduction conditions, averages of 55 and 90 internalized vector genomes per cell in two replicates of the liver model were achieved, as determined by quantitative PCR analysis. Functionality of the AAV vector was confirmed by efficient shRNA-mediated knockdown of hCycB by 70-90%. Our study provides a proof-of-concept that a recellularized biological ECM provides a valuable model to study viral vectors ex vivo. PMID:26356676

  18. Model of influenza A virus infection: dynamics of viral antagonism and innate immune response

    PubMed Central

    Fribourg, M.; Hartmann, B.; Schmolke, M.; Marjanovic, N.; Albrecht, R.A.; García-Sastre, A.; Sealfon, S. C.; Jayaprakash, C.; Hayot, F.

    2014-01-01

    Viral antagonism of host responses is an essential component of virus pathogenicity. The study of the interplay between immune response and viral antagonism is challenging due to the involvement of many processes acting at multiple time scales. Here we develop an ordinary differential equation model to investigate the early, experimentally-measured, responses of human monocyte-derived dendritic cells to infection by two H1N1 influenza A viruses of different clinical outcome: pandemic A/California/4/2009 and seasonal A/New Caledonia/20/1999. Our results reveal how the strength of virus antagonism, and the time scale over which it acts to thwart the innate immune response, differ significantly between the two viruses, as is made clear by their impact on the temporal behavior of a number of measured genes. The model thus sheds light on the mechanisms that underlie the variability of innate immune responses to different H1N1 viruses. PMID:24594370

  19. Emergence of viral diseases: mathematical modeling as a tool for infection control, policy and decision making.

    PubMed

    Louz, Derrick; Bergmans, Hans E; Loos, Birgit P; Hoeben, Rob C

    2010-08-01

    Mathematical modeling can be used for the development and implementation of infection control policy to combat outbreaks and epidemics of communicable viral diseases. Here an outline is provided of basic concepts and approaches used in mathematical modeling and parameterization of disease transmission. The use of mathematical models is illustrated, using the 2001 UK foot-and-mouth disease (FMD) epidemic, the 2003 global severe acute respiratory syndrome (SARS) epidemic, and human influenza pandemics, as examples. This provides insights in the strengths, limitations, and weaknesses of the various models, and demonstrates their potential for supporting policy and decision making. PMID:20218764

  20. Viral quasispecies

    PubMed Central

    Andino, Raul; Domingo, Esteban

    2016-01-01

    New generation sequencing is greatly expanding the capacity to examine the composition of mutant spectra of viral quasispecies in infected cells and host organisms. Here we review recent progress in the understanding of quasispecies dynamics, notably the occurrence of intra-mutant spectrum interactions, and implications of fitness landscapes for virus adaptation and de-adaptation. Complementation or interference can be established among components of the same mutant spectrum, dependent on the mutational status of the ensemble. Replicative fitness relates to an optimal mutant spectrum that provides the molecular basis for phenotypic flexibility, with implications for antiviral therapy. The biological impact of viral fitness renders particularly relevant the capacity of new generation sequencing to establish viral fitness landscapes. Progress with experimental model systems is becoming an important asset to understand virus behavior in the more complex environments faced during natural infections. PMID:25824477

  1. The stability analysis of a general viral infection model with distributed delays and multi-staged infected progression

    NASA Astrophysics Data System (ADS)

    Wang, Jinliang; Liu, Shengqiang

    2015-01-01

    We investigate an in-host model with general incidence and removal rate, as well as distributed delays in virus infections and in productions. By employing Lyapunov functionals and LaSalle's invariance principle, we define and prove the basic reproductive number R0 as a threshold quantity for stability of equilibria. It is shown that if R0 > 1 , then the infected equilibrium is globally asymptotically stable, while if R0 ⩽ 1 , then the infection free equilibrium is globally asymptotically stable under some reasonable assumptions. Moreover, n + 1 distributed delays describe (i) the time between viral entry and the transcription of viral RNA, (ii) the n - 1 -stage time needed for activated infected cells between viral RNA transcription and viral release, and (iii) the time necessary for the newly produced viruses to be infectious (maturation), respectively. The model can describe the viral infection dynamics of many viruses such as HIV-1, HCV and HBV.

  2. Modeling viral coevolution: HIV multi-clonal persistence and competition dynamics

    NASA Astrophysics Data System (ADS)

    Bagnoli, F.; Liò, P.; Sguanci, L.

    2006-07-01

    The coexistence of different viral strains (quasispecies) within the same host are nowadays observed for a growing number of viruses, most notably HIV, Marburg and Ebola, but the conditions for the formation and survival of new strains have not yet been understood. We present a model of HIV quasispecies competition, which describes the conditions of viral quasispecies coexistence under different immune system conditions. Our model incorporates both T and B cells responses, and we show that the role of B cells is important and additive to that of T cells. Simulations of coinfection (simultaneous infection) and superinfection (delayed secondary infection) scenarios in the early stages (days) and in the late stages of the infection (years) are in agreement with emerging molecular biology findings. The immune response induces a competition among similar phenotypes, leading to differentiation (quasispeciation), escape dynamics and complex oscillations of viral strain abundance. We found that the quasispecies dynamics after superinfection or coinfection has time scales of several months and becomes even slower when the immune system response is weak. Our model represents a general framework to study the speed and distribution of HIV quasispecies during disease progression, vaccination and therapy.

  3. Simple Indirect Enzyme-Linked Immunosorbent Assay to Detect Antibodies Against Bovine Viral Diarrhea Virus, Based on Prokaryotically Expressed Recombinant MBP-NS3 Protein

    PubMed Central

    Mahmoodi, Pezhman; Seyfi Abad Shapouri, Masoud Reza; Ghorbanpour, Masoud; Haji Hajikolaei, Mohammad Rahim; Lotfi, Mohsen; Pourmahdi Boroujeni, Mahdi; Daghari, Maryam

    2015-01-01

    Background: Bovine viral diarrhea (BVD) is an economically important disease of cattle distributed worldwide. Diagnosis of BVD relies on laboratory-based detection of its viral causing agent or virus specific antibodies and the most common laboratory method for this purpose is Enzyme-Linked Immunosorbent Assay (ELISA). Objectives: The current study was aimed to develop a simple indirect ELISA to detect antibodies against Bovine Viral Diarrhea Virus (BVDV) in the sera of infected cattle. Materials and Methods: A new simple indirect ELISA method was developed to detect BVDV infection by prokaryotically (Escherichia coli, BL21 strain) expressed recombinant whole nonstructural protein 3 (NS3) of BVDV (NADL strain). Four hundred bovine serum samples were evaluated by the newly developed NS3-ELISA and virus neutralization test (VNT) as the gold standard method to diagnose BVD. Among these samples, 289 sera had been previously tested by a commercial ELISA kit. Results: Statistical analyses showed a very high correlation between the results of the developed NS3-ELISA and VNT (kappa coefficient = 0.935, P < 0.001), with the relative sensitivity and specificity of 94% and 98.8%, respectively. There was also a high correlation between the results of NS3-ELISA and the commercial ELISA kit (kappa coefficient = 0.802, P < 0.001) with the relative sensitivity and specificity of 90.72% and 91.15%, respectively. Conclusions: The newly developed simple indirect ELISA showed high sensitivity and specificity with respect to VNT. Developing such a simple, sensitive, and specific ELISA which is much less expensive than the available commercial ELISA kits can improve the detection of BVDV infections, help to eliminate the disease from herds, and decrease economic losses caused by this disease. PMID:25964844

  4. A nationwide database linking information on the hosts with sequence data of their virus strains: A useful tool for the eradication of bovine viral diarrhea (BVD) in Switzerland.

    PubMed

    Stalder, Hanspeter; Hug, Corinne; Zanoni, Reto; Vogt, Hans-Rudolf; Peterhans, Ernst; Schweizer, Matthias; Bachofen, Claudia

    2016-06-15

    Pestiviruses infect a wide variety of animals of the order Artiodactyla, with bovine viral diarrhea virus (BVDV) being an economically important pathogen of livestock globally. BVDV is maintained in the cattle population by infecting fetuses early in gestation and, thus, by generating persistently infected (PI) animals that efficiently transmit the virus throughout their lifetime. In 2008, Switzerland started a national control campaign with the aim to eradicate BVDV from all bovines in the country by searching for and eliminating every PI cattle. Different from previous eradication programs, all animals of the entire population were tested for virus within one year, followed by testing each newborn calf in the subsequent four years. Overall, 3,855,814 animals were tested from 2008 through 2011, 20,553 of which returned an initial BVDV-positive result. We were able to obtain samples from at least 36% of all initially positive tested animals. We sequenced the 5' untranslated region (UTR) of more than 7400 pestiviral strains and compiled the sequence data in a database together with an array of information on the PI animals, among others, the location of the farm in which they were born, their dams, and the locations where the animals had lived. To our knowledge, this is the largest database combining viral sequences with animal data of an endemic viral disease. Using unique identification tags, the different datasets within the database were connected to run diverse molecular epidemiological analyses. The large sets of animal and sequence data made it possible to run analyses in both directions, i.e., starting from a likely epidemiological link, or starting from related sequences. We present the results of three epidemiological investigations in detail and a compilation of 122 individual investigations that show the usefulness of such a database in a country-wide BVD eradication program. PMID:26403669

  5. Evolution of 2009 H1N1 influenza viruses during the pandemic correlates with increased viral pathogenicity and transmissibility in the ferret model.

    PubMed

    Otte, Anna; Marriott, Anthony C; Dreier, Carola; Dove, Brian; Mooren, Kyra; Klingen, Thorsten R; Sauter, Martina; Thompson, Katy-Anne; Bennett, Allan; Klingel, Karin; van Riel, Debby; McHardy, Alice C; Carroll, Miles W; Gabriel, Gülsah

    2016-01-01

    There is increasing evidence that 2009 pandemic H1N1 influenza viruses have evolved after pandemic onset giving rise to severe epidemics in subsequent waves. However, it still remains unclear which viral determinants might have contributed to disease severity after pandemic initiation. Here, we show that distinct mutations in the 2009 pandemic H1N1 virus genome have occurred with increased frequency after pandemic declaration. Among those, a mutation in the viral hemagglutinin was identified that increases 2009 pandemic H1N1 virus binding to human-like α2,6-linked sialic acids. Moreover, these mutations conferred increased viral replication in the respiratory tract and elevated respiratory droplet transmission between ferrets. Thus, our data show that 2009 H1N1 influenza viruses have evolved after pandemic onset giving rise to novel virus variants that enhance viral replicative fitness and respiratory droplet transmission in a mammalian animal model. These findings might help to improve surveillance efforts to assess the pandemic risk by emerging influenza viruses. PMID:27339001

  6. Evolution of 2009 H1N1 influenza viruses during the pandemic correlates with increased viral pathogenicity and transmissibility in the ferret model

    PubMed Central

    Otte, Anna; Marriott, Anthony C.; Dreier, Carola; Dove, Brian; Mooren, Kyra; Klingen, Thorsten R.; Sauter, Martina; Thompson, Katy-Anne; Bennett, Allan; Klingel, Karin; van Riel, Debby; McHardy, Alice C.; Carroll, Miles W.; Gabriel, Gülsah

    2016-01-01

    There is increasing evidence that 2009 pandemic H1N1 influenza viruses have evolved after pandemic onset giving rise to severe epidemics in subsequent waves. However, it still remains unclear which viral determinants might have contributed to disease severity after pandemic initiation. Here, we show that distinct mutations in the 2009 pandemic H1N1 virus genome have occurred with increased frequency after pandemic declaration. Among those, a mutation in the viral hemagglutinin was identified that increases 2009 pandemic H1N1 virus binding to human-like α2,6-linked sialic acids. Moreover, these mutations conferred increased viral replication in the respiratory tract and elevated respiratory droplet transmission between ferrets. Thus, our data show that 2009 H1N1 influenza viruses have evolved after pandemic onset giving rise to novel virus variants that enhance viral replicative fitness and respiratory droplet transmission in a mammalian animal model. These findings might help to improve surveillance efforts to assess the pandemic risk by emerging influenza viruses. PMID:27339001

  7. Linking models and data on vegetation structure

    NASA Astrophysics Data System (ADS)

    Hurtt, G. C.; Fisk, J.; Thomas, R. Q.; Dubayah, R.; Moorcroft, P. R.; Shugart, H. H.

    2010-06-01

    For more than a century, scientists have recognized the importance of vegetation structure in understanding forest dynamics. Now future satellite missions such as Deformation, Ecosystem Structure, and Dynamics of Ice (DESDynI) hold the potential to provide unprecedented global data on vegetation structure needed to reduce uncertainties in terrestrial carbon dynamics. Here, we briefly review the uses of data on vegetation structure in ecosystem models, develop and analyze theoretical models to quantify model-data requirements, and describe recent progress using a mechanistic modeling approach utilizing a formal scaling method and data on vegetation structure to improve model predictions. Generally, both limited sampling and coarse resolution averaging lead to model initialization error, which in turn is propagated in subsequent model prediction uncertainty and error. In cases with representative sampling, sufficient resolution, and linear dynamics, errors in initialization tend to compensate at larger spatial scales. However, with inadequate sampling, overly coarse resolution data or models, and nonlinear dynamics, errors in initialization lead to prediction error. A robust model-data framework will require both models and data on vegetation structure sufficient to resolve important environmental gradients and tree-level heterogeneity in forest structure globally.

  8. Viral obesity: fact or fiction?

    PubMed

    Mitra, A K; Clarke, K

    2010-04-01

    The aetiology of obesity is multifactorial. An understanding of the contributions of various causal factors is essential for the proper management of obesity. Although it is primarily thought of as a condition brought on by lifestyle choices, recent evidence shows there is a link between obesity and viral infections. Numerous animal models have documented an increased body weight and a number of physiologic changes, including increased insulin sensitivity, increased glucose uptake and decreased leptin secretion that contribute to an increase in body fat in adenovirus-36 infection. Other viral agents associated with increasing obesity in animals included canine distemper virus, rous-associated virus 7, scrapie, Borna disease virus, SMAM-1 and other adenoviruses. This review attempted to determine if viral infection is a possible cause of obesity. Also, this paper discussed mechanisms by which viruses might produce obesity. Based on the evidence presented in this paper, it can be concluded that a link between obesity and viral infections cannot be ruled out. Further epidemiologic studies are needed to establish a causal link between the two, and determine if these results can be used in future management and prevention of obesity. PMID:19874530

  9. Links between soil modelling and proximal sensing

    NASA Astrophysics Data System (ADS)

    Aitkenhead, Matt; McBratney, Alex; Minasny, Budiman

    2015-04-01

    Proximal sensing of soils can provide valuable information for soil modelling, by providing baseline data and validating model predictions through direct observation of soil characteristics. A wide range of soil parameters can be estimated using proximal sensing of soils (PSS), often simultaneously using single hand-held systems, of which there are many types. The benefits for soil modelling include direct observation of modelled parameters, rapid assessment in field conditions and digital data acquisition, making the transfer of information to soil models relatively straightforward. This is an active area of development, with research into improved methods of field-based capture of soil parameters directly relevant for soil modelling. A number of challenges exist, including the removal of or accounting for the effects of field conditions (e.g. soil moisture and structure), and the development of libraries of data that will allow calibration models to be produced. We present an overview of PSS as it relates to soil modelling, including equipment types, calibration approaches, cloud-based processing, soil parameters and processes estimated using PSS, and opportunities and challenges for the future. We also identify and discuss the possibilities for integration of modelling and proximal sensing within precision agriculture/precision land management.

  10. Development and evaluation of a blocking enzyme-linked immunosorbent assay and virus neutralization assay to detect antibodies to viral hemorrhagic septicemia virus

    USGS Publications Warehouse

    Wilson, Anna; Goldberg, Tony; Marcquenski, Susan; Olson, Wendy; Goetz, Frederick; Hershberger, Paul; Hart, Lucas M.; Toohey-Kurth, Kathy

    2014-01-01

    Viral hemorrhagic septicemia virus (VHSV) is a target of surveillance by many state and federal agencies in the United States. Currently, the detection of VHSV relies on virus isolation, which is lethal to fish and indicates only the current infection status. A serological method is required to ascertain prior exposure. Here, we report two serologic tests for VHSV that are nonlethal, rapid, and species independent, a virus neutralization (VN) assay and a blocking enzyme-linked immunosorbent assay (ELISA). The results show that the VN assay had a specificity of 100% and sensitivity of 42.9%; the anti-nucleocapsid-blocking ELISA detected nonneutralizing VHSV antibodies at a specificity of 88.2% and a sensitivity of 96.4%. The VN assay and ELISA are valuable tools for assessing exposure to VHSV.

  11. Development and Evaluation of a Blocking Enzyme-Linked Immunosorbent Assay and Virus Neutralization Assay To Detect Antibodies to Viral Hemorrhagic Septicemia Virus

    PubMed Central

    Wilson, Anna; Goldberg, Tony; Marcquenski, Susan; Olson, Wendy; Goetz, Frederick; Hershberger, Paul; Hart, Lucas

    2014-01-01

    Viral hemorrhagic septicemia virus (VHSV) is a target of surveillance by many state and federal agencies in the United States. Currently, the detection of VHSV relies on virus isolation, which is lethal to fish and indicates only the current infection status. A serological method is required to ascertain prior exposure. Here, we report two serologic tests for VHSV that are nonlethal, rapid, and species independent, a virus neutralization (VN) assay and a blocking enzyme-linked immunosorbent assay (ELISA). The results show that the VN assay had a specificity of 100% and sensitivity of 42.9%; the anti-nucleocapsid-blocking ELISA detected nonneutralizing VHSV antibodies at a specificity of 88.2% and a sensitivity of 96.4%. The VN assay and ELISA are valuable tools for assessing exposure to VHSV. PMID:24429071

  12. Multiscale model for the effects of adaptive immunity suppression on the viral therapy of cancer

    NASA Astrophysics Data System (ADS)

    Paiva, Leticia R.; Silva, Hallan S.; Ferreira, Silvio C.; Martins, Marcelo L.

    2013-04-01

    Oncolytic virotherapy—the use of viruses that specifically kill tumor cells—is an innovative and highly promising route for treating cancer. However, its therapeutic outcomes are mainly impaired by the host immune response to the viral infection. In this paper, we propose a multiscale mathematical model to study how the immune response interferes with the viral oncolytic activity. The model assumes that cytotoxic T cells can induce apoptosis in infected cancer cells and that free viruses can be inactivated by neutralizing antibodies or cleared at a constant rate by the innate immune response. Our simulations suggest that reprogramming the immune microenvironment in tumors could substantially enhance the oncolytic virotherapy in immune-competent hosts. Viable routes to such reprogramming are either in situ virus-mediated impairing of CD8+ T cells motility or blockade of B and T lymphocytes recruitment. Our theoretical results can shed light on the design of viral vectors or new protocols with neat potential impacts on the clinical practice.

  13. A VGI data integration framework based on linked data model

    NASA Astrophysics Data System (ADS)

    Wan, Lin; Ren, Rongrong

    2015-12-01

    This paper aims at the geographic data integration and sharing method for multiple online VGI data sets. We propose a semantic-enabled framework for online VGI sources cooperative application environment to solve a target class of geospatial problems. Based on linked data technologies - which is one of core components of semantic web, we can construct the relationship link among geographic features distributed in diverse VGI platform by using linked data modeling methods, then deploy these semantic-enabled entities on the web, and eventually form an interconnected geographic data network to support geospatial information cooperative application across multiple VGI data sources. The mapping and transformation from VGI sources to RDF linked data model is presented to guarantee the unique data represent model among different online social geographic data sources. We propose a mixed strategy which combined spatial distance similarity and feature name attribute similarity as the measure standard to compare and match different geographic features in various VGI data sets. And our work focuses on how to apply Markov logic networks to achieve interlinks of the same linked data in different VGI-based linked data sets. In our method, the automatic generating method of co-reference object identification model according to geographic linked data is discussed in more detail. It finally built a huge geographic linked data network across loosely-coupled VGI web sites. The results of the experiment built on our framework and the evaluation of our method shows the framework is reasonable and practicable.

  14. COMPARING AND LINKING PLUMES ACROSS MODELING APPROACHES

    EPA Science Inventory

    River plumes carry many pollutants, including microorganisms, into lakes and the coastal ocean. The physical scales of many stream and river plumes often lie between the scales for mixing zone plume models, such as the EPA Visual Plumes model, and larger-sized grid scales for re...

  15. Viral Hemorrhagic Fevers

    MedlinePlus

    ... Related Links About VSPB (Viral Special Pathogens Branch) File Formats Help: How do I view different file formats (PDF, DOC, PPT, MPEG) on this site? Adobe PDF file Microsoft PowerPoint file Microsoft Word file Microsoft Excel ...

  16. Multi-Scale Modeling of Cross-Linked Nanotube Materials

    NASA Technical Reports Server (NTRS)

    Frankland, S. J. V.; Odegard, G. M.; Herzog, M. N.; Gates, T. S.; Fay, C. C.

    2005-01-01

    The effect of cross-linking single-walled carbon nanotubes on the Young's modulus of a nanotube-reinforced composite is modeled with a multi-scale method. The Young's modulus is predicted as a function of nanotube volume fraction and cross-link density. In this method, the constitutive properties of molecular representative volume elements are determined using molecular dynamics simulation and equivalent-continuum modeling. The Young's modulus is subsequently calculated for cross-linked nanotubes in a matrix which consists of the unreacted cross-linking agent. Two different cross-linking agents are used in this study, one that is short and rigid (Molecule A), and one that is long and flexible (Molecule B). Direct comparisons between the predicted elastic constants are made for the models in which the nanotubes are either covalently bonded or not chemically bonded to the cross-linking agent. At a nanotube volume fraction of 10%, the Young's modulus of Material A is not affected by nanotube crosslinking, while the Young's modulus of Material B is reduced by 64% when the nanotubes are cross-linked relative to the non-cross-linked material with the same matrix.

  17. ON IDENTIFIABILITY OF NONLINEAR ODE MODELS AND APPLICATIONS IN VIRAL DYNAMICS

    PubMed Central

    MIAO, HONGYU; XIA, XIAOHUA; PERELSON, ALAN S.; WU, HULIN

    2011-01-01

    Ordinary differential equations (ODE) are a powerful tool for modeling dynamic processes with wide applications in a variety of scientific fields. Over the last 2 decades, ODEs have also emerged as a prevailing tool in various biomedical research fields, especially in infectious disease modeling. In practice, it is important and necessary to determine unknown parameters in ODE models based on experimental data. Identifiability analysis is the first step in determing unknown parameters in ODE models and such analysis techniques for nonlinear ODE models are still under development. In this article, we review identifiability analysis methodologies for nonlinear ODE models developed in the past one to two decades, including structural identifiability analysis, practical identifiability analysis and sensitivity-based identifiability analysis. Some advanced topics and ongoing research are also briefly reviewed. Finally, some examples from modeling viral dynamics of HIV, influenza and hepatitis viruses are given to illustrate how to apply these identifiability analysis methods in practice. PMID:21785515

  18. Linking Models and Data on Vegetation Structure

    NASA Astrophysics Data System (ADS)

    Hurtt, G. C.; Fisk, J.; Thomas, R.; Dubayah, R.; Moorcroft, P.; Shugart, H.

    2008-12-01

    Forested ecosystems consist of a dynamic mosaic of patches on the landscape at different stages of recovery from disturbances. Recent studies have addressed this heterogeneity by combining remotely sensed measurements of vegetation structure, and advanced ecological models that track the dynamics of vegetation structure, to produce accurate estimates of both carbon stocks and fluxes at a set of important study sites. Now future satellite missions such as DESDYNI hold the potential to provide key data on vegetation structure needed to reduce uncertainties in terrestrial carbon dynamics globally. Here, we developed and analyzed a set of models to quantify the effects of limited sampling and/or coarse resolution averaging of structure measurements on model predictions. Generally, both limited sampling and coarse resolution averaging caused model initialization error, and led to subsequent prediction uncertainty and error. In cases with representative sampling, sufficient resolution, and linear dynamics, errors in initialization tended to compensate at larger scales. However, with inadequate sampling, overly coarse resolution data, and non-linear dynamics, errors in initialization led to bias. This study provides a generalized framework for assessing the tradeoffs between the quantity and quality of data on vegetation structure, and the science from models which depend on it.

  19. Methamphetamine mediates immune dysregulation in a murine model of chronic viral infection

    PubMed Central

    Sriram, Uma; Haldar, Bijayesh; Cenna, Jonathan M.; Gofman, Larisa; Potula, Raghava

    2015-01-01

    Methamphetamine (METH) is a highly addictive psychostimulant that not only affects the brain and cognitive functions but also greatly impacts the host immune system, rendering the body susceptible to infections and exacerbating the severity of disease. Although there is gathering evidence about METH abuse and increased incidence of HIV and other viral infections, not much is known about the effects on the immune system in a chronic viral infection setting. We have used the lymphocytic choriomeningitis virus (LCMV) chronic mouse model of viral infection in a chronic METH environment and demonstrate that METH significantly increases CD3 marker on splenocytes and programmed death-1 (PD-1) expression on T cells, a cell surface signaling molecule known to inhibit T cell function and cause exhaustion in a lymphoid organ. Many of these METH effects were more pronounced during early stage of infection, which are gradually attenuated during later stages of infection. An essential cytokine for T-lymphocyte homeostasis, Interleukin-2 (IL-2) in serum was prominently reduced in METH-exposed infected mice. In addition, the serum pro-inflammatory (TNF, IL12 p70, IL1β, IL-6, and KC-GRO) and Th2 (IL-2, IL-10, and IL-4) cytokine profiles were also altered in the presence of METH. Interestingly CXCR3, an inflammatory chemokine receptor, showed significant increase in the METH treated LCMV infected mice. Similarly, compared to only infected mice, epidermal growth factor receptor (EGFR) in METH exposed LCMV infected mice were up regulated. Collectively, our data suggest that METH alters systemic, peripheral immune responses and modulates key markers on T cells involved in pathogenesis of chronic viral infection. PMID:26322025

  20. Extended model of restricted beam for FSO links

    NASA Astrophysics Data System (ADS)

    Poliak, Juraj; Wilfert, Otakar

    2012-10-01

    Modern wireless optical communication systems in many aspects overcome wire or radio communications. Their advantages are license-free operation and broad bandwidth that they offer. The medium in free-space optical (FSO) links is the atmosphere. Operation of outdoor FSO links struggles with many atmospheric phenomena that deteriorate phase and amplitude of the transmitted optical beam. This beam originates in the transmitter and is affected by its individual parts, especially by the lens socket and the transmitter aperture, where attenuation and diffraction effects take place. Both of these phenomena unfavourable influence the beam and cause degradation of link availability, or its total malfunction. Therefore, both of these phenomena should be modelled and simulated, so that one can judge the link function prior to the realization of the system. Not only the link availability and reliability are concerned, but also economic aspects. In addition, the transmitted beam is not, generally speaking, circularly symmetrical, what makes the link simulation more difficult. In a comprehensive model, it is necessary to take into account the ellipticity of the beam that is restricted by circularly symmetrical aperture where then the attenuation and diffraction occur. General model is too computationally extensive; therefore simplification of the calculations by means of analytical and numerical approaches will be discussed. Presented model is not only simulated using computer, but also experimentally proven. One can then deduce the ability of the model to describe the reality and to estimate how far can one go with approximations, i.e. limitations of the model are discussed.

  1. Skew-normal/independent linear mixed models for censored responses with applications to HIV viral loads

    PubMed Central

    Bandyopadhyay, Dipankar; Lachos, Victor H.; Castro, Luis M.; Dey, Dipak K.

    2012-01-01

    Often in biomedical studies, the routine use of linear mixed-effects models (based on Gaussian assumptions) can be questionable when the longitudinal responses are skewed in nature. Skew-normal/elliptical models are widely used in those situations. Often, those skewed responses might also be subjected to some upper and lower quantification limits (viz. longitudinal viral load measures in HIV studies), beyond which they are not measurable. In this paper, we develop a Bayesian analysis of censored linear mixed models replacing the Gaussian assumptions with skew-normal/independent (SNI) distributions. The SNI is an attractive class of asymmetric heavy-tailed distributions that includes the skew-normal, the skew-t, skew-slash and the skew-contaminated normal distributions as special cases. The proposed model provides flexibility in capturing the effects of skewness and heavy tail for responses which are either left- or right-censored. For our analysis, we adopt a Bayesian framework and develop a MCMC algorithm to carry out the posterior analyses. The marginal likelihood is tractable, and utilized to compute not only some Bayesian model selection measures but also case-deletion influence diagnostics based on the Kullback-Leibler divergence. The newly developed procedures are illustrated with a simulation study as well as a HIV case study involving analysis of longitudinal viral loads. PMID:22685005

  2. Transposon mouse models to elucidate the genetic mechanisms of hepatitis B viral induced hepatocellular carcinoma.

    PubMed

    Chiu, Amy P; Tschida, Barbara R; Lo, Lilian H; Moriarity, Branden S; Rowlands, Dewi K; Largaespada, David A; Keng, Vincent W

    2015-11-14

    The major type of human liver cancer is hepatocellular carcinoma (HCC), and there are currently many risk factors that contribute to this deadly disease. The majority of HCC occurrences are associated with chronic hepatitis viral infection, and hepatitis B viral (HBV) infection is currently a major health problem in Eastern Asia. Elucidating the genetic mechanisms associated with HBV-induced HCC has been difficult due to the heterogeneity and genetic complexity associated with this disease. A repertoire of animal models has been broadly used to study the pathophysiology and to develop potential treatment regimens for HBV-associated HCC. The use of these animal models has provided valuable genetic information and has been an important contributor to uncovering the factors involved in liver malignant transformation, invasion and metastasis. Recently, transposon-based mouse models are becoming more widely used in liver cancer research to interrogate the genome by forward genetics and also used to validate genes rapidly in a reverse genetic manner. Importantly, these transposon-based rapid reverse genetic mouse models could become crucial in testing potential therapeutic agents before proceeding to clinical trials in human. Therefore, this review will cover the use of transposon-based mouse models to address the problems of liver cancer, especially HBV-associated HCC occurrences in Asia. PMID:26576100

  3. Transposon mouse models to elucidate the genetic mechanisms of hepatitis B viral induced hepatocellular carcinoma

    PubMed Central

    Chiu, Amy P; Tschida, Barbara R; Lo, Lilian H; Moriarity, Branden S; Rowlands, Dewi K; Largaespada, David A; Keng, Vincent W

    2015-01-01

    The major type of human liver cancer is hepatocellular carcinoma (HCC), and there are currently many risk factors that contribute to this deadly disease. The majority of HCC occurrences are associated with chronic hepatitis viral infection, and hepatitis B viral (HBV) infection is currently a major health problem in Eastern Asia. Elucidating the genetic mechanisms associated with HBV-induced HCC has been difficult due to the heterogeneity and genetic complexity associated with this disease. A repertoire of animal models has been broadly used to study the pathophysiology and to develop potential treatment regimens for HBV-associated HCC. The use of these animal models has provided valuable genetic information and has been an important contributor to uncovering the factors involved in liver malignant transformation, invasion and metastasis. Recently, transposon-based mouse models are becoming more widely used in liver cancer research to interrogate the genome by forward genetics and also used to validate genes rapidly in a reverse genetic manner. Importantly, these transposon-based rapid reverse genetic mouse models could become crucial in testing potential therapeutic agents before proceeding to clinical trials in human. Therefore, this review will cover the use of transposon-based mouse models to address the problems of liver cancer, especially HBV-associated HCC occurrences in Asia. PMID:26576100

  4. Modelling and analysis of dynamics of viral infection of cells and of interferon resistance

    NASA Astrophysics Data System (ADS)

    Getto, Ph.; Kimmel, M.; Marciniak-Czochra, A.

    2008-08-01

    Interferons are active biomolecules, which help fight viral infections by spreading from infected to uninfected cells and activate effector molecules, which confer resistance from the virus on cells. We propose a new model of dynamics of viral infection, including endocytosis, cell death, production of interferon and development of resistance. The novel element is a specific biologically justified mechanism of interferon action, which results in dynamics different from other infection models. The model reflects conditions prevailing in liquid cultures (ideal mixing), and the absence of cells or virus influx from outside. The basic model is a nonlinear system of five ordinary differential equations. For this variant, it is possible to characterise global behaviour, using a conservation law. Analytic results are supplemented by computational studies. The second variant of the model includes age-of-infection structure of infected cells, which is described by a transport-type partial differential equation for infected cells. The conclusions are: (i) If virus mortality is included, the virus becomes eventually extinct and subpopulations of uninfected and resistant cells are established. (ii) If virus mortality is not included, the dynamics may lead to extinction of uninfected cells. (iii) Switching off the interferon defense results in a decrease of the sum total of uninfected and resistant cells. (iv) Infection-age structure of infected cells may result in stabilisation or destabilisation of the system, depending on detailed assumptions. Our work seems to constitute the first comprehensive mathematical analysis of the cell-virus-interferon system based on biologically plausible hypotheses.

  5. Viral Hepatitis

    MedlinePlus

    ... Public Home » For Veterans and the Public Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... the Public Veterans and Public Home How is Hepatitis C Treated? Find the facts about the newest ...

  6. Combination therapy including CpG oligodeoxynucleotides and entecavir induces early viral response and enhanced inhibition of viral replication in a woodchuck model of chronic hepadnaviral infection.

    PubMed

    Meng, Zhongji; Zhang, Xiaoyong; Pei, Rongjuan; Zhang, Ejuan; Kemper, Thekla; Vollmer, Jörg; Davis, Heather L; Glebe, Dieter; Gerlich, Wolfram; Roggendorf, Michael; Lu, Mengji

    2016-01-01

    CpG oligodeoxynucleotides (ODNs) stimulate immune cells via TLR9 and are potentially useful immunomodulators for the treatment of chronic viral infections. In the present study, different classes of CpGs were tested for their capacities for innate immune activation and antiviral activities in the woodchuck model. A class P CpG ODN was found to stimulate interferon (IFN) production in woodchuck peripheral blood mononuclear cells (PBMCs) in vitro, and following subcutaneous administration in vivo, it was observed to induce IFN and MxA expression in woodchuck PBMCs. Combination treatment with CpG ODN and entecavir (ETV) led to effective suppression of the woodchuck hepatitis virus (WHV) load in the woodchucks, with early viral responses and inhibition of replication. The woodchuck hepatitis surface antigen (WHsAg) serum concentrations were strongly decreased by CpG and ETV together but not by either agent alone, indicating synergistic effects. However, viral control post-treatment was still transient, similar to that observed with ETV alone. Significantly elevated levels of serum aspartate aminotransferase (AST) but not of alanine aminotransferase (ALT) in some of the woodchucks receiving CpG ODN were noted, but these increases were resolved before the completion of treatment and were not associated with an elevated serum bilirubin level or coagulation disorders, suggesting the absence of a significant safety concern. PMID:26585244

  7. Fine Mapping of Loci on BTA2 and BTA26 Associated with Bovine Viral Diarrhea Persistent Infection and Linked with Bovine Respiratory Disease in Cattle

    PubMed Central

    Zanella, Ricardo; Casas, Eduardo; Snowder, Gary; Neibergs, Holly L.

    2011-01-01

    Bovine respiratory disease (BRD) is considered to be the most costly infectious disease in the cattle industry. Bovine viral diarrhea virus (BVDV) is one of the pathogens involved with the BRD complex of disease. BVDV infection also negatively impacts cow reproduction and calf performance. Loci associated with persistently infected animals (BVD-PI) and linked with BRD have previously been identified near 14 Mb on bovine chromosome 2 (BTA2) and 15.3 Mb on bovine chromosome 26 (BTA26). The objective of this study was to refine the loci associated with BVD-PI and linked with BRD. Association testing for BVD-PI was performed on a population of 65 BVD-PI calves, 51 of their dams, and 60 unaffected calves (controls) with 142 single nucleotide polymorphisms (SNPs) on BTA2 and 173 SNPs on BTA26. Comparisons were made between BVD-PI calves and controls calves and the dams of BVD-PI calves and controls calves. For the linkage analysis of BRD, the same markers were used to genotype two half-sib families consisting of the sires and 72 BRD positive and 148 BRD negative offspring. Using an allelic chi-square test, 11 loci on BTA2 and 8 loci on BTA26 were associated with the dams of the BVD-PI calves (P < 0.05) and 4 loci on BTA2 and 11 loci on BTA26 were associated with BVD-PI calves. This demonstrates that although some of the loci on BTA2 and BTA26 are jointly involved in the fetal and dam response to BVD-PI infection, there are loci that are solely associated with the maternal or fetal susceptibility to disease. One locus on BTA2 and two loci on BTA26 were found to be linked (P < 0.05) with BRD. The regions linked with BRD were also associated with BVD-PI demonstrating that both the broad (BRD) and narrow (BVD-PI) definition of disease identified shared genomic regions as important in disease susceptibility. These results further refined the loci associated with BVD-PI and linked with BRD. PMID:22303376

  8. Precise numerical modeling of next generation multimode fiber based links

    NASA Astrophysics Data System (ADS)

    Maksymiuk, L.; Stepniak, G.

    2015-12-01

    In order to numerically model modern multimode fiber based links we are required to take into account modal and chromatic dispersion, profile dispersion and spectral dependent coupling. In this paper we propose a complete numerical model which not only is precise but also versatile. Additionally to the detailed mathematical description of the model we provide also a bunch of numerical calculations performed with the use of the model.

  9. Statistical modelling of the formulation variables in non-viral gene delivery systems.

    PubMed

    Birchall, J C; Waterworth, C A; Luscombe, C; Parkins, D A; Gumbleton, M

    2001-06-01

    Traditionally, optimisation of a gene delivery formulation utilises a study design that involves altering only one formulation variable at any one time whilst keeping the other variables constant. As gene delivery formulations become more complex, e.g. to include multiple cellular and sub-cellular targeting elements, there will be an increasing requirement to generate and analyse data more efficiently and allow examination of the interaction between variables. This study aims to demonstrate the utility of multifactorial design, specifically a Central Composite Design, in modelling the responses size, zeta potential and in vitro transfection efficiency of some prototypic non-viral gene delivery vectors. i.e. cationic liposome-pDNA complexes, and extending the application of the design strategy to more complex vectors, i.e. tri-component lipid:polycation:DNA (LPD). The modelled predictions of how the above responses change as a function of formulation show consistency with an extensive literature base of data obtained using more traditional approaches, and highlight the robustness and utility of the Central Composite Design in examining key formulation variables in non-viral gene delivery systems. The approach should be further developed to maximise the predictive impact of data across the full range of pharmaceutical sciences. PMID:11697203

  10. Link Prediction in Weighted Networks: A Weighted Mutual Information Model

    PubMed Central

    Zhu, Boyao; Xia, Yongxiang

    2016-01-01

    The link-prediction problem is an open issue in data mining and knowledge discovery, which attracts researchers from disparate scientific communities. A wealth of methods have been proposed to deal with this problem. Among these approaches, most are applied in unweighted networks, with only a few taking the weights of links into consideration. In this paper, we present a weighted model for undirected and weighted networks based on the mutual information of local network structures, where link weights are applied to further enhance the distinguishable extent of candidate links. Empirical experiments are conducted on four weighted networks, and results show that the proposed method can provide more accurate predictions than not only traditional unweighted indices but also typical weighted indices. Furthermore, some in-depth discussions on the effects of weak ties in link prediction as well as the potential to predict link weights are also given. This work may shed light on the design of algorithms for link prediction in weighted networks. PMID:26849659

  11. Link Prediction in Weighted Networks: A Weighted Mutual Information Model.

    PubMed

    Zhu, Boyao; Xia, Yongxiang

    2016-01-01

    The link-prediction problem is an open issue in data mining and knowledge discovery, which attracts researchers from disparate scientific communities. A wealth of methods have been proposed to deal with this problem. Among these approaches, most are applied in unweighted networks, with only a few taking the weights of links into consideration. In this paper, we present a weighted model for undirected and weighted networks based on the mutual information of local network structures, where link weights are applied to further enhance the distinguishable extent of candidate links. Empirical experiments are conducted on four weighted networks, and results show that the proposed method can provide more accurate predictions than not only traditional unweighted indices but also typical weighted indices. Furthermore, some in-depth discussions on the effects of weak ties in link prediction as well as the potential to predict link weights are also given. This work may shed light on the design of algorithms for link prediction in weighted networks. PMID:26849659

  12. Linking Output from regional Climat Models with Cryosphere Models

    NASA Astrophysics Data System (ADS)

    Winter, S.

    2003-04-01

    This study has the objective of linking the results of a low-resolution regional climate model (RCM) with high-resolution cryosphere models in order to determine the manner in which Alpine snow, ice and permafrost is likely to respond to enhanced atmospheric warming resulting from an increase in anthropogenic greenhouse gases. There are several constraints that need to be overcome prior to applying solutions to this problem. Firstly, as a result of the long response time of glaciers and alpine permafrost to climate change, long-term simulations of at least 30 years are required. Secondly, the smallest possible spatial resolution of current RCM still remains quite coarse (~ 50 km) because of the complex mathematical equations to be resolved in the RCM, the limited computer performance and the above mentioned long simulation period. On the other hand, cryosphere models used in the present study require gridded input climate variables with a typical mesh width of 50 m. The proposed solution consists in combining climate change data based on RCM scenarios with meteorological data of high elevation Alpine stations measured during a reference period. A RCM control run matching this reference period is required in order to quantify the expected change for each climate parameter. This approach allows breaking down the initial downscaling problem into two separate steps. First, the quantified change derived from RCM-control and scenario simulations is used to predict change for meteorological stations. Second, data sets of predicted change and meteorological measures of these stations are summed and then regionalized for the study area based on advanced algorithms and GIS techniques. Selecting a case study area close to one or more meteorological stations should minimize the associated regionalization error. A pilot study for a small area at Piz Corvatsch in the Eastern Swiss Alps has been designed. The A2 scenario of the IPCC (Intergovernmental Panel on Climate Change

  13. Link community detection using generative model and nonnegative matrix factorization.

    PubMed

    He, Dongxiao; Jin, Di; Baquero, Carlos; Liu, Dayou

    2014-01-01

    Discovery of communities in complex networks is a fundamental data analysis problem with applications in various domains. While most of the existing approaches have focused on discovering communities of nodes, recent studies have shown the advantages and uses of link community discovery in networks. Generative models provide a promising class of techniques for the identification of modular structures in networks, but most generative models mainly focus on the detection of node communities rather than link communities. In this work, we propose a generative model, which is based on the importance of each node when forming links in each community, to describe the structure of link communities. We proceed to fit the model parameters by taking it as an optimization problem, and solve it using nonnegative matrix factorization. Thereafter, in order to automatically determine the number of communities, we extend the above method by introducing a strategy of iterative bipartition. This extended method not only finds the number of communities all by itself, but also obtains high efficiency, and thus it is more suitable to deal with large and unexplored real networks. We test this approach on both synthetic benchmarks and real-world networks including an application on a large biological network, and compare it with two highly related methods. Results demonstrate the superior performance of our approach over competing methods for the detection of link communities. PMID:24489803

  14. Link Community Detection Using Generative Model and Nonnegative Matrix Factorization

    PubMed Central

    He, Dongxiao; Jin, Di; Baquero, Carlos; Liu, Dayou

    2014-01-01

    Discovery of communities in complex networks is a fundamental data analysis problem with applications in various domains. While most of the existing approaches have focused on discovering communities of nodes, recent studies have shown the advantages and uses of link community discovery in networks. Generative models provide a promising class of techniques for the identification of modular structures in networks, but most generative models mainly focus on the detection of node communities rather than link communities. In this work, we propose a generative model, which is based on the importance of each node when forming links in each community, to describe the structure of link communities. We proceed to fit the model parameters by taking it as an optimization problem, and solve it using nonnegative matrix factorization. Thereafter, in order to automatically determine the number of communities, we extend the above method by introducing a strategy of iterative bipartition. This extended method not only finds the number of communities all by itself, but also obtains high efficiency, and thus it is more suitable to deal with large and unexplored real networks. We test this approach on both synthetic benchmarks and real-world networks including an application on a large biological network, and compare it with two highly related methods. Results demonstrate the superior performance of our approach over competing methods for the detection of link communities. PMID:24489803

  15. Linking knowledge and action through mental models of sustainable agriculture.

    PubMed

    Hoffman, Matthew; Lubell, Mark; Hillis, Vicken

    2014-09-01

    Linking knowledge to action requires understanding how decision-makers conceptualize sustainability. This paper empirically analyzes farmer "mental models" of sustainability from three winegrape-growing regions of California where local extension programs have focused on sustainable agriculture. The mental models are represented as networks where sustainability concepts are nodes, and links are established when a farmer mentions two concepts in their stated definition of sustainability. The results suggest that winegrape grower mental models of sustainability are hierarchically structured, relatively similar across regions, and strongly linked to participation in extension programs and adoption of sustainable farm practices. We discuss the implications of our findings for the debate over the meaning of sustainability, and the role of local extension programs in managing knowledge systems. PMID:25157158

  16. Linking Goal-Oriented Requirements and Model-Driven Development

    NASA Astrophysics Data System (ADS)

    Pastor, Oscar; Giachetti, Giovanni

    In the context of Goal-Oriented Requirement Engineering (GORE) there are interesting modeling approaches for the analysis of complex scenarios that are oriented to obtain and represent the relevant requirements for the development of software products. However, the way to use these GORE models in an automated Model-Driven Development (MDD) process is not clear, and, in general terms, the translation of these models into the final software products is still manually performed. Therefore, in this chapter, we show an approach to automatically link GORE models and MDD processes, which has been elaborated by considering the experience obtained from linking the i * framework with an industrially applied MDD approach. The linking approach proposed is formulated by means of a generic process that is based on current modeling standards and technologies in order to facilitate its application for different MDD and GORE approaches. Special attention is paid to how this process generates appropriate model transformation mechanisms to automatically obtain MDD conceptual models from GORE models, and how it can be used to specify validation mechanisms to assure the correct model transformations.

  17. Link performance model for filter bank based multicarrier systems

    NASA Astrophysics Data System (ADS)

    Petrov, Dmitry; Oborina, Alexandra; Giupponi, Lorenza; Stitz, Tobias Hidalgo

    2014-12-01

    This paper presents a complete link level abstraction model for link quality estimation on the system level of filter bank multicarrier (FBMC)-based networks. The application of mean mutual information per coded bit (MMIB) approach is validated for the FBMC systems. The considered quality measure of the resource element for the FBMC transmission is the received signal-to-noise-plus-distortion ratio (SNDR). Simulation results of the proposed link abstraction model show that the proposed approach is capable of estimating the block error rate (BLER) accurately, even when the signal is propagated through the channels with deep and frequent fades, as it is the case for the 3GPP Hilly Terrain (3GPP-HT) and Enhanced Typical Urban (ETU) models. The FBMC-related results of link level simulations are compared with cyclic prefix orthogonal frequency division multiplexing (CP-OFDM) analogs. Simulation results are also validated through the comparison to reference publicly available results. Finally, the steps of link level abstraction algorithm for FBMC are formulated and its application for system level simulation of a professional mobile radio (PMR) network is discussed.

  18. Novel ATPase activity of the polyprotein intermediate, Viral Protein genome-linked-Nuclear Inclusion-a protease, of Pepper vein banding potyvirus

    SciTech Connect

    Mathur, Chhavi; Savithri, Handanahal S.

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer Pepper vein banding potyvirus VPg harbors Walker motifs. Black-Right-Pointing-Pointer VPg exhibits ATPase activity in the presence of NIa-Pro. Black-Right-Pointing-Pointer Plausible structural and functional interplay between VPg and NIa-Pro. Black-Right-Pointing-Pointer Functional relevance of prolonged presence of VPg-Pro during infection. -- Abstract: Potyviruses temporally regulate their protein function by polyprotein processing. Previous studies have shown that VPg (Viral Protein genome-linked) of Pepper vein banding virus interacts with the NIa-Pro (Nuclear Inclusion-a protease) domain, and modulates the kinetics of the protease. In the present study, we report for the first time that VPg harbors the Walker motifs A and B, and the presence of NIa-Pro, especially in cis (cleavage site (E191A) VPg-Pro mutant), is essential for manifestation of the ATPase activity. Mutation of Lys47 (Walker motif A) and Asp88:Glu89 (Walker motif B) to alanine in E191A VPg-Pro lead to reduced ATPase activity, confirming that this activity was inherent to VPg. We propose that potyviral VPg, established as an intrinsically disordered domain, undergoes plausible structural alterations upon interaction with globular NIa-Pro which induces the ATPase activity.

  19. Synthesis and characterization of new 5-linked pinoresinol lignin models.

    PubMed

    Yue, Fengxia; Lu, Fachuang; Sun, Runcang; Ralph, John

    2012-12-14

    Pinoresinol structures, featuring a β-β'-linkage between lignin monomer units, are important in softwood lignins and in dicots and monocots, particularly those that are downregulated in syringyl-specific genes. Although readily detected by NMR spectroscopy, pinoresinol structures largely escaped detection by β-ether-cleaving degradation analyses presumably due to the presence of the linkages at the 5 positions, in 5-5'- or 5-O-4'-structures. In this study, which is aimed at helping better understand 5-linked pinoresinol structures by providing the required data for NMR characterization, new lignin model compounds were synthesized through biomimetic peroxidase-mediated oxidative coupling reactions between pre-formed (free-phenolic) coniferyl alcohol 5-5'- or 5-O-4'-linked dimers and a coniferyl alcohol monomer. It was found that such dimers containing free-phenolic coniferyl alcohol moieties can cross-couple with the coniferyl alcohol producing pinoresinol-containing trimers (and higher oligomers) in addition to other homo- and cross-coupled products. Eight new lignin model compounds were obtained and characterized by NMR spectroscopy, and one tentatively identified cross-coupled β-O-4'-product was formed from a coniferyl alcohol 5-O-4'-linked dimer. It was demonstrated that the 5-5'- and 5-O-4'-linked pinoresinol structures could be readily differentiated by using heteronuclear multiple-bond correlation (HMBC) NMR spectroscopy. With appropriate modification (etherification or acetylation) to the newly obtained model compounds, it would be possible to identify the 5-5'- or 5-O-4'-linked pinoresinol structures in softwood lignins by 2D HMBC NMR spectroscopic methods. Identification of the cross-coupled dibenzodioxocin from a coniferyl alcohol 5-5'-linked moiety suggested that thioacidolysis or derivatization followed by reductive cleavage (DFRC) could be used to detect and identify whether the coniferyl alcohol itself undergoes 5-5'-cross-linking during

  20. A model to study viral and cytokine involvement in Sjögren's syndrome.

    PubMed

    Clark, D A; Lamey, P J; Jarrett, R F; Onions, D E

    1994-01-01

    To investigate mechanisms that may be important in the pathogenesis of Sjögren's syndrome (SS) we developed a protocol for the growth of salivary gland epithelial cells in culture. We examined the effect that viral infection has on the cellular location of the autoantigen La. Autoantibodies to La are common in SS and it has been proposed that viral infection may result in cell membrane expression of La. Co-expression of MHC class II molecules in infected cells could lead to the presentation of La peptides to the immune system. Advenovirus infection of salivary gland epithelial cells resulted in an altered nuclear staining of La. Treatment with interferon-gamma resulted in the expression of La in the cell cytoplasm and HLA-DR molecules at the cell surface. These findings suggest that a cytokine-driven mechanism may generate an autoimmune response to La in SS. Using the polymerase chain reaction (PCR) we tested salivary gland epithelial cell cultures for the presence of human herpesvirus-6 (HHV-6) and Epstein-Barr virus (EBV). Only HHV-6 was detected in 2 of 10 salivary gland epithelial cell cultures although the presence of HHV-6 was not associated with SS. Primary salivary gland cultures may prove useful as an in vitro model to study mechanisms of autoimmunity in SS. PMID:7999958

  1. Application of a patient-derived xenograft model in cytolytic viral activation therapy for nasopharyngeal carcinoma

    PubMed Central

    Hsu, Cheng-Lung; Kuo, Yung-Chia; Huang, Yenlin; Huang, Yin-Cheng; Lui, Kar-Wai; Chang, Kai-Ping; Lin, Tung-Liang; Fan, Hsien-Chi; Lin, An-Chi; Hsieh, Chia-Hsun; Lee, Li-Yu; Wang, Hung-Ming; Li, Hsin-Pai; Chang, Yu-Sun

    2015-01-01

    Nasopharyngeal carcinoma (NPC) is an Epstein Barr virus (EBV)-related malignancy in which the tumor microenvironment plays a pivotal role in tumor progression. Here, we developed two patient-derived xenograft (PDX) mouse lines from engrafted NPC metastatic tumors. Positive staining for EBV-encoded small RNAs confirmed that these tumors harbored EBV, and gene expression profile analyses further showed that the PDX was highly similar to the primary parent tumor. In vivo drug screening using the PDX system demonstrated that gemcitabine had the best antitumor effect among the tested drugs. The donor of this PDX also showed excellent responsiveness to gemcitabine treatment. The combination of gemcitabine and valproic acid exerted synergistic antitumor effects. Further addition of ganciclovir to this two-drug combination regimen enhanced cytolytic viral activation, yielding the best antitumor response among tested regimens. Treatment with this three-drug combination regimen decreased plasma EBV-DNA load, tumor viral concentration, and the number of viable tumor cells to a greater extent than the two-drug gemcitabine and valproic acid combination. These results highlight the value of PDX models in the development of EBV-targeted strategies to treat NPC. PMID:26416517

  2. Phase Diagram of the Bose Hubbard Model with Weak Links

    NASA Astrophysics Data System (ADS)

    Hettiarachchilage, Kalani; Rousseau, Valy; Tam, Ka-Ming; Moreno, Juana; Jarrell, Mark; Sheehy, Daniel

    2012-02-01

    We study the ground state phase diagram of strongly interacting ultracold Bose gas in a one-dimensional optical lattice with a tunable weak link, by means of Quantum Monte Carlo simulation. This model contains an on-site repulsive interaction (U) and two different near-neighbor hopping terms, J and t, for the weak link and the remainder of the chain, respectively. We show that by reducing the strength of J, a novel intermediate phase develops which is compressible and non-superfluid. This novel phase is identified as a Normal Bose Liquid (NBL) which does not appear in the phase diagram of the homogeneous bosonic Hubbard model. Further, we find a linear variation of the phase boundary of Normal Bose Liquid (NBL) to SuperFluid (SF) as a function of the strength of the weak link. These results may provide a new path to design advanced atomtronic devices in the future.

  3. Modeling Viral Infectious Diseases and Development of Antiviral Therapies Using Human Induced Pluripotent Stem Cell-Derived Systems

    PubMed Central

    Trevisan, Marta; Sinigaglia, Alessandro; Desole, Giovanna; Berto, Alessandro; Pacenti, Monia; Palù, Giorgio; Barzon, Luisa

    2015-01-01

    The recent biotechnology breakthrough of cell reprogramming and generation of induced pluripotent stem cells (iPSCs), which has revolutionized the approaches to study the mechanisms of human diseases and to test new drugs, can be exploited to generate patient-specific models for the investigation of host–pathogen interactions and to develop new antimicrobial and antiviral therapies. Applications of iPSC technology to the study of viral infections in humans have included in vitro modeling of viral infections of neural, liver, and cardiac cells; modeling of human genetic susceptibility to severe viral infectious diseases, such as encephalitis and severe influenza; genetic engineering and genome editing of patient-specific iPSC-derived cells to confer antiviral resistance. PMID:26184286

  4. Studying Links between Hormones and Negative Affect: Models and Measures.

    ERIC Educational Resources Information Center

    Brooks-Gunn, Jeanne; And Others

    1994-01-01

    Considers eight models for the study of pubertal change that explore possible links between hormones and negative affective experiences, such as depression and aggression. Notes that hormonal effects, though small, have demonstrated stability and have interacted with psychological and social factors, implicating hormonal changes in the development…

  5. A Model Linking the Learning Organization and Performance Job Satisfaction

    ERIC Educational Resources Information Center

    Dirani, Khalil M.

    2006-01-01

    The underlying theories of learning and performance are quite complex. This paper proposes a model that links the learning organization theory as a process with job satisfaction as a performance theory outcome. The literature reviewed considered three process levels of learning within the learning organization and three outcome levels of job…

  6. Linking Academic Entitlement and Student Incivility Using Latent Means Modeling

    ERIC Educational Resources Information Center

    Kopp, Jason P.; Finney, Sara J.

    2013-01-01

    Academic entitlement has been theoretically linked with uncivil student behavior; however, this relationship has not been tested. To address this gap in the literature, the authors used latent means modeling to estimate the relationship between the Academic Entitlement Questionnaire and uncivil student behavior. The authors gathered scores on the…

  7. Concepts in viral pathogenesis II

    SciTech Connect

    Notkins, A.L.; Oldstone, M.B.A.

    1986-01-01

    This paper contains papers divided among 10 sections. The section titles are: Viral Structure and Function; Viral Constructs; Oncogenes, Transfection, and Differentiation; Viral Tropism and Entry into Cells; Immune Recognition of Viruses; Evolving Concepts in Viral Pathogenesis Illustrated by Selected Plant and Animal Models; Evolving Concepts in Viral Pathogenesis Illustrated by Selected Diseases in Humans; New Trends in Diagnosis and Epidemiology; and Vaccines and Antiviral Therapy.

  8. An individual-based model of rabbit viral haemorrhagic disease on European wild rabbits (Oryctolagus cuniculus)

    USGS Publications Warehouse

    Fa, John E.; Sharples, Colin M.; Bell, Diana J.; DeAngelis, Donald L.

    2001-01-01

    We developed an individual-based model of Rabbit Viral Hemorrhagic Disease (RVHD) for European wild rabbits (Oryctolagus cuniculus L.), representing up to 1000 rabbits in four hectares. Model output for productivity and recruitment matched published values. The disease was density-dependent and virulence affected outcome. Strains that caused death after several days produced greater overall mortality than strains in which rabbits either died or recovered very quickly. Disease effect also depended on time of year. We also elaborated a larger scale model representing 25 km2 and 100,000+ rabbits, split into a number of grid-squares. This was a more traditional model that did not represent individual rabbits, but employed a system of dynamic equations for each grid-square. Disease spread depended on probability of transmission between neighboring grid-squares. Potential recovery from a major population crash caused by the disease relied on disease virulence and frequency of recurrence. The model's dependence on probability of disease transmission between grid-squares suggests the way that the model represents the spatial distribution of the population affects simulation. Although data on RVHD in Europe are lacking, our models provide a basis for describing the disease in realistic detail and for assessing influence of various social and spatial factors on spread.

  9. A murine model of coxsackievirus A16 infection for anti-viral evaluation.

    PubMed

    Liu, Qingwei; Shi, Jinping; Huang, Xulin; Liu, Fei; Cai, Yicun; Lan, Ke; Huang, Zhong

    2014-05-01

    Coxsackievirus A16 (CA16) is one of the main causative agents of hand, foot and mouth disease (HFMD), which is a common infectious disease in children. CA16 infection may lead to severe nervous system damage and even death in humans. However, study of the pathogenesis of CA16 infection and development of vaccines and anti-viral agents are hindered partly by the lack of an appropriate small animal model. In the present study, we developed and characterized a murine model of CA16 infection. We show that neonatal mice are susceptible to CA16 infection via intraperitoneal inoculation. One-day-old mice infected with 2×10(6)TCID50 of CA16/SZ05 strain consistently exhibited clinical signs, including reduced mobility, and limb weakness and paralysis. About 57% of the mice died within 14days after infection. Significant damage in the brainstem, limb muscles and intestines of the infected mice in the moribund state was observed by histological examination, and the presence of CA16 in neurons of the brainstem was demonstrated by immunohistochemical staining with a CA16-specific polyclonal antibody, strongly suggesting the involvement of the central nervous system in CA16 infection. Analysis of virus titers in various organs/tissues collected at 3, 6 and 9days post-infection, showed that skeletal muscle was the major site of virus replication at the early stage of infection, while the virus mainly accumulated in the brain at the late stage. In addition, susceptibility of mice to CA16 infection was found to be age dependent. Moreover, different CA16 strains could exhibit varied virulence in vivo. Importantly, we demonstrated that post-exposure treatment with an anti-CA16 monoclonal antibody fully protected mice against lethal CA16 infection. Collectively, these results indicate the successful development of a CA16 infection mouse model for anti-viral evaluation. PMID:24583030

  10. Assessing changes in vascular permeability in a hamster model of viral hemorrhagic fever

    PubMed Central

    2010-01-01

    Background A number of RNA viruses cause viral hemorrhagic fever (VHF), in which proinflammatory mediators released from infected cells induce increased permeability of the endothelial lining of blood vessels, leading to loss of plasma volume, hypotension, multi-organ failure, shock and death. The optimal treatment of VHF should therefore include both the use of antiviral drugs to inhibit viral replication and measures to prevent or correct changes in vascular function. Although rodent models have been used to evaluate treatments for increased vascular permeability (VP) in bacterial sepsis, such studies have not been performed for VHF. Results Here, we use an established model of Pichinde virus infection of hamsters to demonstrate how changes in VP can be detected by intravenous infusion of Evans blue dye (EBD), and compare those measurements to changes in hematocrit, serum albumin concentration and serum levels of proinflammatory mediators. We show that EBD injected into sick animals in the late stage of infection is rapidly sequestered in the viscera, while in healthy animals it remains within the plasma, causing the skin to turn a marked blue color. This test could be used in live animals to detect increased VP and to assess the ability of antiviral drugs and vasoactive compounds to prevent its onset. Finally, we describe a multiplexed assay to measure levels of serum factors during the course of Pichinde arenavirus infection and demonstrate that viremia and subsequent increase in white blood cell counts precede the elaboration of inflammatory mediators, which is followed by increased VP and death. Conclusions This level of model characterization is essential to the evaluation of novel interventions designed to control the effects of virus-induced hypercytokinemia on host vascular function in VHF, which could lead to improved survival. PMID:20846417

  11. Single photon time transfer link model for GNSS satellites

    NASA Astrophysics Data System (ADS)

    Vacek, Michael; Michalek, Vojtech; Peca, Marek; Prochazka, Ivan; Blazej, Josef

    2015-05-01

    The importance of optical time transfer serving as a complement to traditional microwave links, has been attested for GNSSes and for scientific missions. Single photon time transfer (SPTT) is a process, allowing to compare (subtract) time readings of two distant clocks. Such a comparison may be then used to synchronize less accurate clock to a better reference, to perform clock characterization and calibration, to calculate mean time out of ensemble of several clocks, displaced in space. The single-photon time transfer is well established in field of space geodesy, being supported by passive retro-reflectors within space segment of five known GNSSes. A truly two-way, active terminals work aboard of Jason-2 (T2L2) - multiphoton operation, GNSS Beidou (Compass) - SPTT, and are going to be launched within recent ACES project (ELT) - SPTT, and GNSS GLONASS - multiphoton operation. However, there is still missing comprehensive theoretical model of two-way (using satellite receiver and retroreflector) SPTT link incorporating all crucial parameters of receiver (both ground and space segment receivers), transmitter, atmosphere effects on uplink and downlink path, influence of retroreflector. The input to calculation of SPTT link performance will be among others: link budget (distance, power, apertures, beam divergence, attenuation, scattering), propagating medium (atmosphere scintillation, beam wander, etc.), mutual Tx/Rx velocity, wavelength. The SPTT model will be evaluated without the properties of real components. These will be added in the further development. The ground-to-space SPTT link performance of typical scenarios are modeled. This work is a part of the ESA study "Comparison of optical time-transfer links."

  12. Principles of selective inactivation of a viral genome. Comparative kinetic study of modification of the viral RNA and model protein with oligoaziridines.

    PubMed

    Tsvetkova, E A; Nepomnyaschaya, N M

    2001-08-01

    Comparative kinetic analysis of inactivation of bacteriophage MS2 infectivity and aminoalkylation of a model protein (trypsin inhibitor) with oligoaziridines was performed in order to evaluate the selectivity of viral RNA modification with oligocationic reagents. The transition from ethyleneimine monomer to di-, tri-, and tetramer leads to a sharp increase in the rate constant of infectivity inactivation, whereas the rate constant of protein modification changes insignificantly. The selectivity coefficient of the phage RNA aminoalkylation relative to trypsin inhibitor modification increases in this series by more than an order of magnitude. This effect is probably associated with the strengthening of the reagent binding to the nucleic acid, which implies a reaction mechanism that involves the formation of a reactive intermediate. The latter might be an electrostatic complex of the oligocationic reagent and RNA, the only polyanion in the virion. A pronounced decrease in the rate constant of infectivity inactivation in the presence of multiply charged anions (in phosphate buffer) and a biogenic polyamine (spermine) favors this hypothesis. Increasing the reaction temperature increases the rate constant of infectivity inactivation and decreases selectivity of the viral RNA modification. PMID:11566057

  13. Tailored delivery of analgesic ziconotide across a blood brain barrier model using viral nanocontainers

    PubMed Central

    Anand, Prachi; O’Neil, Alison; Lin, Emily; Douglas, Trevor; Holford, Mandë

    2015-01-01

    The blood brain barrier (BBB) is often an insurmountable obstacle for a large number of candidate drugs, including peptides, antibiotics, and chemotherapeutic agents. Devising an adroit delivery method to cross the BBB is essential to unlocking widespread application of peptide therapeutics. Presented here is an engineered nanocontainer for delivering peptidic drugs across the BBB encapsulating the analgesic marine snail peptide ziconotide (Prialt®). We developed a bi-functional viral nanocontainer based on the Salmonella typhimurium bacteriophage P22 capsid, genetically incorporating ziconotide in the interior cavity, and chemically attaching cell penetrating HIV-Tat peptide on the exterior of the capsid. Virus like particles (VLPs) of P22 containing ziconotide were successfully transported in several BBB models of rat and human brain microvascular endothelial cells (BMVEC) using a recyclable noncytotoxic endocytic pathway. This work demonstrates proof in principle for developing a possible alternative to intrathecal injection of ziconotide using a tunable VLP drug delivery nanocontainer to cross the BBB. PMID:26234920

  14. Complex dynamic behavior in a viral model with delayed immune response

    NASA Astrophysics Data System (ADS)

    Wang, Kaifa; Wang, Wendi; Pang, Haiyan; Liu, Xianning

    2007-02-01

    The rich dynamics of a viral infection model is studied under the assumption that the immune response is retarded. It is shown that if the basic reproductive ratio of the virus is less than one, the infection-free equilibrium is globally asymptotically stable. Analytical and numerical results show that if the basic reproductive ratio of the virus is greater than one, the combined effect of the strength of the lytic component, the time delay of the immune response and the birth rate of susceptible host cells is to create a rich dynamics, which includes the occurrence of stable periodic solutions and chaotic dynamical behavior. The route from periodic oscillations to chaos is investigated. These results can be used to explain irregular real time series data on the immune state of patients.

  15. Tailored delivery of analgesic ziconotide across a blood brain barrier model using viral nanocontainers

    NASA Astrophysics Data System (ADS)

    Anand, Prachi; O'Neil, Alison; Lin, Emily; Douglas, Trevor; Holford, Mandë

    2015-08-01

    The blood brain barrier (BBB) is often an insurmountable obstacle for a large number of candidate drugs, including peptides, antibiotics, and chemotherapeutic agents. Devising an adroit delivery method to cross the BBB is essential to unlocking widespread application of peptide therapeutics. Presented here is an engineered nanocontainer for delivering peptidic drugs across the BBB encapsulating the analgesic marine snail peptide ziconotide (Prialt®). We developed a bi-functional viral nanocontainer based on the Salmonella typhimurium bacteriophage P22 capsid, genetically incorporating ziconotide in the interior cavity, and chemically attaching cell penetrating HIV-Tat peptide on the exterior of the capsid. Virus like particles (VLPs) of P22 containing ziconotide were successfully transported in several BBB models of rat and human brain microvascular endothelial cells (BMVEC) using a recyclable noncytotoxic endocytic pathway. This work demonstrates proof in principle for developing a possible alternative to intrathecal injection of ziconotide using a tunable VLP drug delivery nanocontainer to cross the BBB.

  16. Tailored delivery of analgesic ziconotide across a blood brain barrier model using viral nanocontainers.

    PubMed

    Anand, Prachi; O'Neil, Alison; Lin, Emily; Douglas, Trevor; Holford, Mandë

    2015-01-01

    The blood brain barrier (BBB) is often an insurmountable obstacle for a large number of candidate drugs, including peptides, antibiotics, and chemotherapeutic agents. Devising an adroit delivery method to cross the BBB is essential to unlocking widespread application of peptide therapeutics. Presented here is an engineered nanocontainer for delivering peptidic drugs across the BBB encapsulating the analgesic marine snail peptide ziconotide (Prialt®). We developed a bi-functional viral nanocontainer based on the Salmonella typhimurium bacteriophage P22 capsid, genetically incorporating ziconotide in the interior cavity, and chemically attaching cell penetrating HIV-Tat peptide on the exterior of the capsid. Virus like particles (VLPs) of P22 containing ziconotide were successfully transported in several BBB models of rat and human brain microvascular endothelial cells (BMVEC) using a recyclable noncytotoxic endocytic pathway. This work demonstrates proof in principle for developing a possible alternative to intrathecal injection of ziconotide using a tunable VLP drug delivery nanocontainer to cross the BBB. PMID:26234920

  17. Viral Phylodynamics

    PubMed Central

    Volz, Erik M.; Koelle, Katia; Bedford, Trevor

    2013-01-01

    Viral phylodynamics is defined as the study of how epidemiological, immunological, and evolutionary processes act and potentially interact to shape viral phylogenies. Since the coining of the term in 2004, research on viral phylodynamics has focused on transmission dynamics in an effort to shed light on how these dynamics impact viral genetic variation. Transmission dynamics can be considered at the level of cells within an infected host, individual hosts within a population, or entire populations of hosts. Many viruses, especially RNA viruses, rapidly accumulate genetic variation because of short generation times and high mutation rates. Patterns of viral genetic variation are therefore heavily influenced by how quickly transmission occurs and by which entities transmit to one another. Patterns of viral genetic variation will also be affected by selection acting on viral phenotypes. Although viruses can differ with respect to many phenotypes, phylodynamic studies have to date tended to focus on a limited number of viral phenotypes. These include virulence phenotypes, phenotypes associated with viral transmissibility, cell or tissue tropism phenotypes, and antigenic phenotypes that can facilitate escape from host immunity. Due to the impact that transmission dynamics and selection can have on viral genetic variation, viral phylogenies can therefore be used to investigate important epidemiological, immunological, and evolutionary processes, such as epidemic spread [2], spatio-temporal dynamics including metapopulation dynamics [3], zoonotic transmission, tissue tropism [4], and antigenic drift [5]. The quantitative investigation of these processes through the consideration of viral phylogenies is the central aim of viral phylodynamics. PMID:23555203

  18. BTA2 and BTA26 are linked with bovine respiratory disease and associated with persistent infection of bovine viral diarrhea virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine viral diarrhea virus is a pathogen associated with bovine respiratory disease (BRD). BRD causes 28% of all cattle deaths and an annual U.S. loss over $692 million. The objective of this study was to refine the linkage of BRD and association of bovine viral diarrhea-persistent infection (BVD-P...

  19. Fine mapping of loci on BTA2 and BTA26 associated with bovine viral diarrhea persistent infection and linked with bovine respiratory disease in cattle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine respiratory disease (BRD) is considered to be the most costly infectious disease in the cattle industry. Bovine viral diarrhea virus (BVDV) is one of the pathogens involved with the BRD complex of disease. Bovine viral diarrhea virus infection also negatively impacts cow reproduction and calf...

  20. Viral persistence, latent reservoir, and blips: a review on HIV-1 dynamics and modeling during HAART and related treatment implications

    SciTech Connect

    Rong, Libin; Perelson, Alan

    2008-01-01

    HIV-1 eradication from infected individuals has not been achieved with the use of highly active antiretroviral therapy (HAART) for a prolonged period of time. The cellular reservoir for HIV-1 in resting memory CD4{sup +} T cells remains a major obstacle to viral elimination. The reservoir does not decay significantly over long periods of time as is able to release replication competent HIV-1 upon cell activation. Residual ongoing viral replication may likely occur in many patients because low levels of virus can be detected in plasma by sensitive assays and transient episodes of viremia, or HIV-1 blips, are often observed in patients even with successful viral suppression for many years. Here we review our current knowledge of the factors contributing to viral persistence, the latent reservoir, and blips, and mathematical models developed to explore them and their relationships. We show how mathematical modeling can help improve our understanding of HIV-1 dynamics in patients on HAART and the quantitative events underlying HIV-1 latency, reservoir stability, low-level viremic persistence, and emergence of intermittent viral blips. We also discuss treatment implications related to these studies.

  1. Bench-to-bedside review: Rare and common viral infections in the intensive care unit – linking pathophysiology to clinical presentation

    PubMed Central

    Stollenwerk, Nicholas; Harper, Richart W; Sandrock, Christian E

    2008-01-01

    Viral infections are common causes of respiratory tract disease in the outpatient setting but much less common in the intensive care unit. However, a finite number of viral agents cause respiratory tract disease in the intensive care unit. Some viruses, such as influenza, respiratory syncytial virus (RSV), cytomegalovirus (CMV), and varicella-zoster virus (VZV), are relatively common. Others, such as adenovirus, severe acute respiratory syndrome (SARS)-coronavirus, Hantavirus, and the viral hemorrhagic fevers (VHFs), are rare but have an immense public health impact. Recognizing these viral etiologies becomes paramount in treatment, infection control, and public health measures. Therefore, a basic understanding of the pathogenesis of viral entry, replication, and host response is important for clinical diagnosis and initiating therapeutic options. This review discusses the basic pathophysiology leading to clinical presentations in a few common and rare, but important, viruses found in the intensive care unit: influenza, RSV, SARS, VZV, adenovirus, CMV, VHF, and Hantavirus. PMID:18671826

  2. Linking Gap Model with MODIS Biophysical Products for Biomass Estimation

    NASA Astrophysics Data System (ADS)

    Wang, D.; Sun, G.; Cai, Y.; Guo, Z.; Fu, A.; Ni, W.; Liu, D.

    With the development of earth observation technology and data processing technology biophysical data from remote sensing means such as MODIS LAI and NPP are accessible now However it is still difficult for direct measurement of biomass from remote sensors One possibility for overcoming this problem is using ecological models to link the vegetation parameters currently available from remote sensing to biomass In this paper a combined work is done for estimating forest biomass A calibrated gap model ZELIG was run to simulate the forest development in a temperate forested area in NE China The output relationship between age and biomass was linked to registered MODIS LAI NPP and land cover type images of the same area From the above work forest age or biomass was estimated from existing remote sensed data Obviously there is a lot of work to be done such as optimal combination of biophysical parameters to improve the linkage between MODIS product and ecological modeling

  3. Modelling the spread of Bovine Viral Diarrhoea Virus (BVDV) in a managed metapopulation of cattle herds.

    PubMed

    Courcoul, Aurélie; Ezanno, Pauline

    2010-04-21

    In numerous epidemiological models developed within a metapopulation framework, it is assumed that a single infected individual introduced into a patch infects the whole patch and that the proportion of infected individuals into infected patches is consistent over time and among patches. If this approach is relevant for rapidly spreading pathogens, it is less appropriate for moderately spreading pathogens, like the Bovine Viral Diarrhoea Virus (BVDV), characterized by a variability in within-patch prevalence. Our objective is to study the respective influence of neighbouring relationships and animal movements on the spread of BVDV in a managed metapopulation of 100 cattle herds. Infection dynamics is represented by two coupled stochastic compartmental models in discrete-time: a within-herd and a between-herd models. Animal movements are mechanistically modelled. They largely influence the BVDV persistence, the prevalence in infected herds and the epidemic size. Neighbouring relationships only influence epidemic size. Whatever the neighbouring relationships, the infection does not persist in the metapopulation without animal movement between herds. The proposed model can be easily adapted for different herd contact structures. PMID:19875250

  4. UAS Modeling of the Communication Links Study Results

    NASA Technical Reports Server (NTRS)

    Birr, Richard B.; Girgis, Nancy; Murray, Jennifer

    2011-01-01

    The Federal Aviation Administration (FAA) is the authority that grants access into, and operations within, the National Airspace System (NAS) for all aircraft, including Unmanned Aircraft Systems (UAS). The safe operation of UAS in the NAS must be assured if the full potential of UAS is to be realized and supported by the public and Congress. This report analyzed the communication systems that are needed for the safe operations of UAS in the NAS. Safe operations can be defined as the availability of the required links to carry the information to control the UAS and the return links to allow controllers to know where the UAS is at any given moment as well as how it is performing. This report is the end result of work performed jointly between the FAA and National Aeronautics and Space Administration (NASA)/Kennedy Space Center (NASA KSC). The work was done in support of the Radio Technical Commission for Aeronautics (RTCA) Special Committee 203 (SC-203) Control and Communications Working Group. The RTCA is a federal advisory committee to the FAA. Though the work was not under the direction of the working group, a large part of the specific values used in the simulations came from the working group. Specifically, all of the radio links were modeled based on the formulation completed by the working group. This report analyzed three scenarios from RTCA SC-203 that represent how a UAS would operate in the NAS. Each scenario was created using the Satellite Tool Kit (STK) modeling and simulation tool. The flight paths of the UAS were generated and the UAS dynamics were likewise modeled. Then each communication asset such as transmitters, receivers, and antennas were modeled and placed on the appropriate UAS, satellite, or Control Station (CS). After that, the radio links were analyzed for signal strength and antenna blockage, and the overall link performance was analyzed in detail. The goal was to obtain 99.9% availability on all of the radio communication links. In order

  5. X-Linked Inhibitor of Apoptosis Protein-Mediated Attenuation of Apoptosis, Using a Novel Cardiac-Enhanced Adeno-Associated Viral Vector

    PubMed Central

    Piacentino III, Valentino; Milano, Carmelo A.; Bolanos, Michael; Schroder, Jacob; Messina, Emily; Cockrell, Adam S.; Jones, Edward; Krol, Ava; Bursac, Nenad; Mao, Lan; Devi, Gayathri R.; Samulski, R. Jude

    2012-01-01

    Abstract Successful amelioration of cardiac dysfunction and heart failure through gene therapy approaches will require a transgene effective at attenuating myocardial injury, and subsequent remodeling, using an efficient and safe delivery vehicle. Our laboratory has established a well-curated, high-quality repository of human myocardial tissues that we use as a discovery engine to identify putative therapeutic transgene targets, as well as to better understand the molecular basis of human heart failure. By using this rare resource we were able to examine age- and sex-matched left ventricular samples from (1) end-stage failing human hearts and (2) nonfailing human hearts and were able to identify the X-linked inhibitor of apoptosis protein (XIAP) as a novel target for treating cardiac dysfunction. We demonstrate that XIAP is diminished in failing human hearts, indicating that this potent inhibitor of apoptosis may be central in protecting the human heart from cellular injury culminating in heart failure. Efforts to ameliorate heart failure through delivery of XIAP compelled the design of a novel adeno-associated viral (AAV) vector, termed SASTG, that achieves highly efficient transduction in mouse heart and in cultured neonatal rat cardiomyocytes. Increased XIAP expression achieved with the SASTG vector inhibits caspase-3/7 activity in neonatal cardiomyocytes after induction of apoptosis through three common cardiac stresses: protein kinase C-γ inhibition, hypoxia, or β-adrenergic receptor agonist. These studies demonstrate the potential benefit of XIAP to correct heart failure after highly efficient delivery to the heart with the rationally designed SASTG AAV vector. PMID:22339372

  6. Viral pneumonia

    MedlinePlus

    ... Names Pneumonia - viral; "Walking pneumonia" - viral Images Lungs Respiratory system References Lee FE, Treanor J. Viral infections. In: Mason RJ, VC Broaddus, Martin TR, et al, eds. Murray and Nadel’s Textbook of Respiratory Medicine . 5th ed. Philadelphia, PA: Saunders Elsevier; 2010: ...

  7. A model of the spread of the bovine viral-diarrhoea virus within a dairy herd.

    PubMed

    Viet, Anne-France; Fourichon, Christine; Seegers, Henri; Jacob, Christine; Guihenneuc-Jouyaux, Chantal

    2004-05-14

    Wet BVDSim (a stochastic simulation model) was developed to study the dynamics of the spread of the bovine viral-diarrhoea virus (BVDV) within a dairy herd. This model took into account herd-management factors (common in several countries), which influence BVDV spread. BVDSim was designed as a discrete-entity and discrete-event simulation model. It relied on two processes defined at the individual-animal level, with interactions. The first process was a semi-Markov process and modelled the herd structure and dynamics (demography, herd management). The second process was a Markov process and modelled horizontal and vertical virus transmission. Because the horizontal transmission occurs by contacts (nose-to-nose) and indirectly, transmission varied with the separation of animals into subgroups. Vertical transmission resulted in birth of persistently infected (PI) calves. Other possible consequences of a BVDV infection during the pregnancy period were considered (pregnancy loss, immunity of calves). The outcomes of infection were modelled according to the stage of pregnancy at time of infection. BVDV pregnancy loss was followed either by culling or by a new artificial insemination depending on the modelled farmer's decision. Consistency of the herd dynamics in the absence of any BVDV infection was verified. To explore the model behaviour, the virus spread was simulated over 10 years after the introduction of a near-calving PI heifer into a susceptible 38 cow herd. Different dynamics of the virus spread were simulated, from early clearance to persistence of the virus 10 years after its introduction. Sensitivity of the model to the uncertainty on transmission coefficient was analysed. Qualitative validation consisted in comparing the bulk-milk ELISA results over time in a sample of herds detected with a new infection with the ones derived from simulations. PMID:15158572

  8. Next Generation Respiratory Viral Vaccine System: Advanced and Emerging Bioengineered Human Lung Epithelia Model (HLEM) Organoid Technology

    NASA Technical Reports Server (NTRS)

    Goodwin, Thomas J.; Schneider, Sandra L.; MacIntosh, Victor; Gibbons, Thomas F.

    2010-01-01

    Acute respiratory infections, including pneumonia and influenza, are the S t" leading cause of United States and worldwide deaths. Newly emerging pathogens signaled the need for an advanced generation of vaccine technology.. Human bronchial-tracheal epithelial tissue was bioengineered to detect, identify, host and study the pathogenesis of acute respiratory viral disease. The 3-dimensional (3D) human lung epithelio-mesechymal tissue-like assemblies (HLEM TLAs) share characteristics with human respiratory epithelium: tight junctions, desmosomes, microvilli, functional markers villin, keratins and production of tissue mucin. Respiratory Syntial Virus (RSV) studies demonstrate viral growth kinetics and membrane bound glycoproteins up to day 20 post infection in the human lung-orgainoid infected cell system. Peak replication of RSV occurred on day 10 at 7 log10 particles forming units per ml/day. HLEM is an advanced virus vaccine model and biosentinel system for emergent viral infectious diseases to support DoD global surveillance and military readiness.

  9. Modeling hepatitis C virus kinetics: the relationship between the infected cell loss rate and the final slope of viral decay

    PubMed Central

    Dahari, Harel; Shudo, Emi; Cotler, Scott J.; Layden, Thomas J.; Perelson, Alan S.

    2010-01-01

    Background Patients infected with hepatitis C virus (HCV) who respond to treatment with interferon-α plus ribavirin exhibit biphasic or triphasic viral load declines. While the rapid first phase is indicative of the effectiveness of therapy in blocking viral production, ε, the slope of the final phase, λ, i.e., the second phase in biphasic declines and the third phase in triphasic declines, depends on the infected-cell loss rate, δ. Further, in standard models λ is approximately εδ, when the viral-clearance rate c>>δ as has been previously estimated. Methods The relationship among ε, δ, λ and the baseline fraction of HCV-infected hepatocytes, π, was investigated in a model that includes proliferation of hepatocytes. Results We find that λ is not proportional to ε but rather obeys complex relationship that can lead to dramatic increases in estimates of δ as ε increases. In particular, when ε<99%, λ moderately underestimates δ in patients with a small π, whereas δ may be up to 10-fold larger than λ in patients with a large π. Interestingly, when ε>99%, δ~λ, regardless of π. Conclusions Our results indicate that under therapy achieving <2 log reduction in viral load (ε<99%), previously estimated δ values may represent only a minimal estimate of the infected-cell loss rate. Moreover, combining interferon-α with new antiviral agents to achieve ε>99% should allow for a more accurate estimate of δ in HCV-RNA kinetic studies. This may be important when using viral kinetics to estimate the impact of the immune response on viral elimination and the attainment of sustained virological response. PMID:19474480

  10. HIV-1 progression links with viral genetic variability and subtype, and patient's HLA type: analysis of a Nairobi-Kenyan cohort.

    PubMed

    Abidi, Syed Hani; Shahid, Aniqa; Lakhani, Laila S; Shah, Reena; Okinda, Nancy; Ojwang, Peter; Abbas, Farhat; Rowland-Jones, Sarah; Ali, Syed

    2014-02-01

    In a Nairobi-Kenyan cohort of 50 HIV-1 positive patients, we analysed the prevalence of HIV-1 subtypes and human leucocyte antigen (HLA) alleles. From this cohort, 33 patients were selected for the analysis of HIV-1 infection progression markers (i.e. CD4 cell counts and viral loads) and their association with HIV-1 genetic variability and subtype, and patient's HLA type. HIV-1 gag genetic variability, analysed using bioinformatics tools, showed an inverse relationship with CD4 cell count whereas with viral load that relationship was direct. Certain HLA types and viral subtypes were also found to associate with patients' viral load. Associations between disease parameters and the genetic makeup of the host and virus may be crucial in determining the outcome of HIV-1 infection. PMID:24142198

  11. Improving nonlinear modeling capabilities of functional link adaptive filters.

    PubMed

    Comminiello, Danilo; Scarpiniti, Michele; Scardapane, Simone; Parisi, Raffaele; Uncini, Aurelio

    2015-09-01

    The functional link adaptive filter (FLAF) represents an effective solution for online nonlinear modeling problems. In this paper, we take into account a FLAF-based architecture, which separates the adaptation of linear and nonlinear elements, and we focus on the nonlinear branch to improve the modeling performance. In particular, we propose a new model that involves an adaptive combination of filters downstream of the nonlinear expansion. Such combination leads to a cooperative behavior of the whole architecture, thus yielding a performance improvement, particularly in the presence of strong nonlinearities. An advanced architecture is also proposed involving the adaptive combination of multiple filters on the nonlinear branch. The proposed models are assessed in different nonlinear modeling problems, in which their effectiveness and capabilities are shown. PMID:26057613

  12. Human neural precursor cells promote neurologic recovery in a viral model of multiple sclerosis.

    PubMed

    Chen, Lu; Coleman, Ronald; Leang, Ronika; Tran, Ha; Kopf, Alexandra; Walsh, Craig M; Sears-Kraxberger, Ilse; Steward, Oswald; Macklin, Wendy B; Loring, Jeanne F; Lane, Thomas E

    2014-06-01

    Using a viral model of the demyelinating disease multiple sclerosis (MS), we show that intraspinal transplantation of human embryonic stem cell-derived neural precursor cells (hNPCs) results in sustained clinical recovery, although hNPCs were not detectable beyond day 8 posttransplantation. Improved motor skills were associated with a reduction in neuroinflammation, decreased demyelination, and enhanced remyelination. Evidence indicates that the reduced neuroinflammation is correlated with an increased number of CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs) within the spinal cords. Coculture of hNPCs with activated T cells resulted in reduced T cell proliferation and increased Treg numbers. The hNPCs acted, in part, through secretion of TGF-β1 and TGF-β2. These findings indicate that the transient presence of hNPCs transplanted in an animal model of MS has powerful immunomodulatory effects and mediates recovery. Further investigation of the restorative effects of hNPC transplantation may aid in the development of clinically relevant MS treatments. PMID:24936469

  13. The Effects of Simulated Weightlessness on Susceptibility to Viral and Bacterial Infections Using a Murine Model

    NASA Technical Reports Server (NTRS)

    Gould, C. L.

    1985-01-01

    Certain immunological responses may be compromised as a result of changes in environmental conditions, such as the physiological adaptation to and from the weightlessness which occurs during space flight and recovery. A murine antiorthostatic model was developed to simulate weightlessness. Using this model, the proposed study will determine if differences in susceptibility to viral and bacterial infections exist among mice suspended in an antiorthostatic orientation to simulate weightlessness, mice suspended in an orthostatic orientation to provide a stressful situation without the condition of weightlessness simulation, and non-suspended control mice. Inbred mouse strains which are resistant to the diabetogenic effects of the D variant of encephalomyocarditis virus (EMC-D) and the lethal effects of Salmonella typhimurium will be evaluated. Glucose tolerance tests will be performed on all EMC-D-infected and non-infected control groups. The incidence of EMC-D-induced diabetes and the percentage survival of S. typhimurium-infected animals will be determined in each group. An additional study will determine the effects of simulated weightlessness on murine responses to exogenous interferon.

  14. Evidence for differential viral oncolytic efficacy in an in vitro model of epithelial ovarian cancer metastasis

    PubMed Central

    Tong, Jessica G; Valdes, Yudith Ramos; Barrett, John W; Bell, John C; Stojdl, David; McFadden, Grant; McCart, J Andrea; DiMattia, Gabriel E; Shepherd, Trevor G

    2015-01-01

    Epithelial ovarian cancer is unique among most carcinomas in that metastasis occurs by direct dissemination of malignant cells traversing throughout the intraperitoneal fluid. Accordingly, we test new therapeutic strategies using an in vitro three-dimensional spheroid suspension culture model that mimics key steps of this metastatic process. In the present study, we sought to uncover the differential oncolytic efficacy among three different viruses—Myxoma virus, double-deleted vaccinia virus, and Maraba virus—using three ovarian cancer cell lines in our metastasis model system. Herein, we demonstrate that Maraba virus effectively infects, replicates, and kills epithelial ovarian cancer (EOC) cells in proliferating adherent cells and with slightly slower kinetics in tumor spheroids. Myxoma virus and vaccinia viruses infect and kill adherent cells to a much lesser extent than Maraba virus, and their oncolytic potential is almost completely attenuated in spheroids. Myxoma virus and vaccinia are able to infect and spread throughout spheroids, but are blocked in the final stages of the lytic cycle, and oncolytic-mediated cell killing is reactivated upon spheroid reattachment. Alternatively, Maraba virus has a remarkably reduced ability to initially enter spheroid cells, yet rapidly infects and spreads throughout spheroids generating significant cell killing effects. We show that low-density lipoprotein receptor expression in ovarian cancer spheroids is reduced and this controls efficient Maraba virus binding and entry into infected cells. Taken together, these results are the first to implicate the potential impact of differential viral oncolytic properties at key steps of ovarian cancer metastasis. PMID:27119108

  15. Using viral-mediated gene delivery to model Parkinson's disease: do nonhuman primate investigations expand our understanding?

    PubMed

    Fiandaca, Massimo S; Federoff, Howard J

    2014-06-01

    In this review, we consider the use of nonhuman primate (NHP) models of Parkinson's disease (PD) produced using viral-mediated gene delivery and information they provide in comparison to other model systems in rodents and NHPs. To date, rodent and NHP PD models have found it difficult to fully recapitulate the human disorder and, therefore, provide little actual insight into disease progression. The viral-mediated gene delivery method for α-synuclein has been shown to produce a parkinsonian rodent and NHP. This novel viral-mediated gene transfer model in the NHP appears to provide a significant advance beyond neurotoxicant models, by more closely mimicking the more chronic time course of developed behavioral deterioration and neuropathology. Although we agree that the use of these novel methods inducing parkinsonian NHPs may provide relevant treatment insights, beyond those of more standard PD models, we remain cautious as to the preclinical models' ability to predict outcomes in human trials. In specific cases of certain novel medical therapeutics, therefore, we also consider the phase 0 clinical trial as offering an alternative to the currently non-predictive preclinical models, including those in the NHP. PMID:23524194

  16. Defining Scenarios: Linking Integrated Models, Regional Concerns, and Stakeholders

    NASA Astrophysics Data System (ADS)

    Hartmann, H. C.; Stewart, S.; Liu, Y.; Mahmoud, M.

    2007-05-01

    Scenarios are important tools for long-term planning, and there is great interest in using integrated models in scenario studies. However, scenario definition and assessment are creative, as well as scientific, efforts. Using facilitated creative processes, we have worked with stakeholders to define regionally significant scenarios that encompass a broad range of hydroclimatic, socioeconomic, and institutional dimensions. The regional scenarios subsequently inform the definition of local scenarios that work with context-specific integrated models that, individually, can address only a subset of overall regional complexity. Based on concerns of stakeholders in the semi-arid US Southwest, we prioritized three dimensions that are especially important, yet highly uncertain, for long-term planning: hydroclimatic conditions (increased variability, persistent drought), development patterns (urban consolidation, distributed rural development), and the nature of public institutions (stressed, proactive). Linking across real-world decision contexts and integrated modeling efforts poses challenges of creatively connecting the conceptual models held by both the research and stakeholder communities.

  17. Groundwater Pollution Source Identification using Linked ANN-Optimization Model

    NASA Astrophysics Data System (ADS)

    Ayaz, Md; Srivastava, Rajesh; Jain, Ashu

    2014-05-01

    Groundwater is the principal source of drinking water in several parts of the world. Contamination of groundwater has become a serious health and environmental problem today. Human activities including industrial and agricultural activities are generally responsible for this contamination. Identification of groundwater pollution source is a major step in groundwater pollution remediation. Complete knowledge of pollution source in terms of its source characteristics is essential to adopt an effective remediation strategy. Groundwater pollution source is said to be identified completely when the source characteristics - location, strength and release period - are known. Identification of unknown groundwater pollution source is an ill-posed inverse problem. It becomes more difficult for real field conditions, when the lag time between the first reading at observation well and the time at which the source becomes active is not known. We developed a linked ANN-Optimization model for complete identification of an unknown groundwater pollution source. The model comprises two parts- an optimization model and an ANN model. Decision variables of linked ANN-Optimization model contain source location and release period of pollution source. An objective function is formulated using the spatial and temporal data of observed and simulated concentrations, and then minimized to identify the pollution source parameters. In the formulation of the objective function, we require the lag time which is not known. An ANN model with one hidden layer is trained using Levenberg-Marquardt algorithm to find the lag time. Different combinations of source locations and release periods are used as inputs and lag time is obtained as the output. Performance of the proposed model is evaluated for two and three dimensional case with error-free and erroneous data. Erroneous data was generated by adding uniformly distributed random error (error level 0-10%) to the analytically computed concentration

  18. Optimization model for UV-Riboflavin corneal cross-linking

    NASA Astrophysics Data System (ADS)

    Schumacher, S.; Wernli, J.; Scherrer, S.; Bueehler, M.; Seiler, T.; Mrochen, M.

    2011-03-01

    Nowadays UV-cross-linking is an established method for the treatment of keraectasia. Currently a standardized protocol is used for the cross-linking treatment. We will now present a theoretical model which predicts the number of induced crosslinks in the corneal tissue, in dependence of the Riboflavin concentration, the radiation intensity, the pre-treatment time and the treatment time. The model is developed by merging the difussion equation, the equation for the light distribution in dependence on the absorbers in the tissue and a rate equation for the polymerization process. A higher concentration of Riboflavin solution as well as a higher irradiation intensity will increase the number of induced crosslinks. However, performed stress-strain experiments which support the model showed that higher Riboflavin concentrations (> 0.125%) do not result in a further increase in stability of the corneal tissue. This is caused by the inhomogeneous distribution of induced crosslinks throughout the cornea due to the uneven absorption of the UV-light. The new model offers the possibility to optimize the treatment individually for every patient depending on their corneal thickness in terms of efficiency, saftey and treatment time.

  19. Modeling of Long-Range Atmospheric Lasercom Links Between Static and Mobile Platforms

    SciTech Connect

    Scharlemann, E T; Breitfeller, E F; Henderson, J R; Kallman, J S; Morris, J R; Ruggiero, A J

    2003-07-29

    We describe modeling and simulation of long-range terrestrial laser communications links between static and mobile platforms. Atmospheric turbulence modeling, along with pointing, tracking and acquisition models are combined to provide an overall capability to estimate communications link performance.

  20. Solanaceae—A Model for Linking Genomics With Biodiversity

    PubMed Central

    Bohs, Lynn; Nee, Michael; Spooner, David M.

    2004-01-01

    Recent progress in understanding the phylogeny of the economically important plant family Solanaceae makes this an ideal time to develop models for linking the new data on plant genomics with the huge diversity of naturally occurring species in the family. Phylogenetics provides the framework with which to investigate these linkages but, critically, good species-level descriptive resources for the Solanaceae community are currently missing. Phylogeny in the family as a whole is briefly reviewed, and the new NSF Planetary Biodiversity Inventories project ‘PBI: Solanum—a worldwide treatment’ is described. The aims of this project are to provide species-level information across the global scope of the genus Solanum and to make this available over the Internet. The project is in its infancy, but will make available nomenclatural information, descriptions, keys and illustrative material for all of the approximately 1500 species of Solanum. With this project, the opportunity of linking valid, up-to-date taxonomic information about wild species of Solanum with the genomic information being generated about the economically important species of the genus (potato, tomato and eggplant) can be realized. The phylogenetic framework in which the PBI project is set is also of enormous potential benefit to other workers on Solanum. The community of biologists working with Solanaceae has a unique opportunity to effectively link genomics and taxonomy for better understanding of this important family, taking plant biology to a new level for the next century. PMID:18629162

  1. Linking the Weather Generator with Regional Climate Model

    NASA Astrophysics Data System (ADS)

    Dubrovsky, Martin; Farda, Ales; Skalak, Petr; Huth, Radan

    2013-04-01

    One of the downscaling approaches, which transform the raw outputs from the climate models (GCMs or RCMs) into data with more realistic structure, is based on linking the stochastic weather generator with the climate model output. The present contribution, in which the parametric daily surface weather generator (WG) M&Rfi is linked to the RCM output, follows two aims: (1) Validation of the new simulations of the present climate (1961-1990) made by the ALADIN-Climate Regional Climate Model at 25 km resolution. The WG parameters are derived from the RCM-simulated surface weather series and compared to those derived from weather series observed in 125 Czech meteorological stations. The set of WG parameters will include statistics of the surface temperature and precipitation series (including probability of wet day occurrence). (2) Presenting a methodology for linking the WG with RCM output. This methodology, which is based on merging information from observations and RCM, may be interpreted as a downscaling procedure, whose product is a gridded WG capable of producing realistic synthetic multivariate weather series for weather-ungauged locations. In this procedure, WG is calibrated with RCM-simulated multi-variate weather series in the first step, and the grid specific WG parameters are then de-biased by spatially interpolated correction factors based on comparison of WG parameters calibrated with gridded RCM weather series and spatially scarcer observations. The quality of the weather series produced by the resultant gridded WG will be assessed in terms of selected climatic characteristics (focusing on characteristics related to variability and extremes of surface temperature and precipitation). Acknowledgements: The present experiment is made within the frame of projects ALARO-Climate (project P209/11/2405 sponsored by the Czech Science Foundation), WG4VALUE (project LD12029 sponsored by the Ministry of Education, Youth and Sports of CR) and VALUE (COST ES 1102

  2. A note on some common diffraction link loss models

    NASA Astrophysics Data System (ADS)

    Pogorzelski, R. J.

    1982-12-01

    A tropospheric propagation path obstructed by transverse obstacles is considered. The obstacles are modeled as perfectly absorbing half planes. Propagation loss relative to the unobstructed path is calculated by means of the method of Epstein and Peterson and the method of Deygout. These results are compared with those predicted by spectral diffraction theory. The comparison is made entirely outside the transition regions surrounding the shadow boundaries, permitting simplification of the spectral theory to the familiar geometrical theory of diffraction. The comparisons are used to explain the apparent superiority of the Deygout method over that of Epstein and Peterson in predicting the link loss.

  3. Does Viral Tropism Play a Role in Heterosexual Transmission of HIV? Findings in the SIV–Rhesus Macaque Model

    PubMed Central

    MILLER, CHRISTOPHER J.

    2009-01-01

    Substantial effort is being directed toward generating vaccines that can prevent the heterosexual transmission of HIV-1. If “Selection” for specific variants during sexual intercourse occurs, then vaccines should be designed to prevent transmission of these specific viruses. Using the SIV–rhesus macaque model to test the hypothesis that specific HIV genotypes are more efficient at producing infection by sexual transmission, it was possible to demonstrate that the genotypic determinants that permit SIV or SHIV to produce systemic infection differ depending on the route of virus inoculation. This finding supports the conclusion that there is selection for viral genotypes during sexual transmission of HIV. However, the ability of a virus to grow in rhesus macaque monocyte-derived macrophages in vitro does not predict the outcome of intravaginal inoculation with that virus. We did find that after intravenous inoculation all the vaginally transmitting viruses produced plasma antigenemia and high levels of plasma viral RNA. In contrast, although the nontransmitting viruses infect rhesus macaques after intravenous inoculation, the infection that occurs after intravenous inoculation is characterized by a lack of viral antigen in plasma and low levels of plasma viral RNA. On the basis of these results, it is clear that viruses which are adapted to replicate to high levels in vivo are transmitted by vaginal inoculation. This principle may also apply to the transmission of HIV in humans. PMID:9581889

  4. Evidence for a Functional Link between Uncoating of the Human Immunodeficiency Virus Type 1 Core and Nuclear Import of the Viral Preintegration Complex

    PubMed Central

    Dismuke, David J.; Aiken, Christopher

    2006-01-01

    Human immunodeficiency virus type 1 (HIV-1) particles begin their replication upon fusion with the plasma membrane of target cells and release of the viral core into the host cell cytoplasm. Soon thereafter, the viral capsid, which is composed of a polymer of the CA protein, disassociates from the internal ribonucleoprotein complex. While this disassembly process remains poorly understood, the available evidence indicates that proper uncoating of the core is a key step in infection. Defects in uncoating most often lead to a failure of the virus to undergo reverse transcription, resulting in an inability to form a functional viral preintegration complex (PIC). In a previous study, we reported that an HIV-1 mutant containing two substitutions in CA (Q63A/67A) was unusual in that it was poorly infectious yet synthesized normal levels of viral DNA. Here we report that this mutant is impaired for nuclear entry. Quantitative analysis of viral DNA synthesis from infected cells by Southern blotting and real-time PCR revealed that the Q63A/Q67A mutant is impaired in the synthesis of one-long terminal repeat (1-LTR) and 2-LTR circles. Isolation of PICs from acutely infected cells revealed that the Q63A/Q67A mutant produces protein-DNA complexes similar to wild-type in yield and overall composition, but these PICs contained elevated levels of CA and were impaired for integration in vitro. These results demonstrate that mutations in CA can have deleterious effects on both nuclear targeting and integration, suggesting that these steps in the HIV-1 life cycle are dependent on proper uncoating of the viral core. PMID:16571788

  5. The Viral Polymerase Inhibitor 7-Deaza-2'-C-Methyladenosine Is a Potent Inhibitor of In Vitro Zika Virus Replication and Delays Disease Progression in a Robust Mouse Infection Model.

    PubMed

    Zmurko, Joanna; Marques, Rafael E; Schols, Dominique; Verbeken, Erik; Kaptein, Suzanne J F; Neyts, Johan

    2016-05-01

    Zika virus (ZIKV) is an emerging flavivirus typically causing a dengue-like febrile illness, but neurological complications, such as microcephaly in newborns, have potentially been linked to this viral infection. We established a panel of in vitro assays to allow the identification of ZIKV inhibitors and demonstrate that the viral polymerase inhibitor 7-deaza-2'-C-methyladenosine (7DMA) efficiently inhibits replication. Infection of AG129 (IFN-α/β and IFN-γ receptor knock-out) mice with ZIKV resulted in acute neutrophilic encephalitis with viral antigens accumulating in neurons of the brain and spinal cord. Additionally, high levels of viral RNA were detected in the spleen, liver and kidney, and levels of IFN-γ and IL-18 were systematically increased in serum of ZIKV-infected mice. Interestingly, the virus was also detected in testicles of infected mice. In line with its in vitro anti-ZIKV activity, 7DMA reduced viremia and delayed virus-induced morbidity and mortality in infected mice, which also validates this small animal model to assess the in vivo efficacy of novel ZIKV inhibitors. Since AG129 mice can generate an antibody response, and have been used in dengue vaccine studies, the model can also be used to assess the efficacy of ZIKV vaccines.  . PMID:27163257

  6. The Viral Polymerase Inhibitor 7-Deaza-2’-C-Methyladenosine Is a Potent Inhibitor of In Vitro Zika Virus Replication and Delays Disease Progression in a Robust Mouse Infection Model

    PubMed Central

    Zmurko, Joanna; Marques, Rafael E.; Schols, Dominique; Verbeken, Erik; Kaptein, Suzanne J.F.; Neyts, Johan

    2016-01-01

    Zika virus (ZIKV) is an emerging flavivirus typically causing a dengue-like febrile illness, but neurological complications, such as microcephaly in newborns, have potentially been linked to this viral infection. We established a panel of in vitro assays to allow the identification of ZIKV inhibitors and demonstrate that the viral polymerase inhibitor 7-deaza-2’-C-methyladenosine (7DMA) efficiently inhibits replication. Infection of AG129 (IFN-α/β and IFN-γ receptor knock-out) mice with ZIKV resulted in acute neutrophilic encephalitis with viral antigens accumulating in neurons of the brain and spinal cord. Additionally, high levels of viral RNA were detected in the spleen, liver and kidney, and levels of IFN-γ and IL-18 were systematically increased in serum of ZIKV-infected mice. Interestingly, the virus was also detected in testicles of infected mice. In line with its in vitro anti-ZIKV activity, 7DMA reduced viremia and delayed virus-induced morbidity and mortality in infected mice, which also validates this small animal model to assess the in vivo efficacy of novel ZIKV inhibitors. Since AG129 mice can generate an antibody response, and have been used in dengue vaccine studies, the model can also be used to assess the efficacy of ZIKV vaccines.   PMID:27163257

  7. Viral meningitis.

    PubMed

    Chadwick, David R

    2005-01-01

    Viruses probably account for most cases of acute meningitis. Viral meningitis is often assumed to be a largely benign disease. For the commonest pathogens causing meningitis, enteroviruses, this is usually the case; however, for many of the other pathogens causing viral meningitis, and for common pathogens in the immunocompromised or infants, viral meningitis is frequently associated with substantial neurological complications and a significant mortality. Diagnostic methods for rapid and accurate identification of pathogens have improved over recent years, permitting more precise and earlier diagnoses. There have been fewer developments in therapies for viral meningitis, and there remain no effective therapies for most pathogens, emphasising the importance of prevention and early diagnosis. This review focuses on the presentation, diagnosis and management of viral meningitis and also covers the prevention of meningitis for pathogens where effective vaccines are available. PMID:16474042

  8. Model of Atmospheric Links on Optical Communications from High Altitude

    NASA Technical Reports Server (NTRS)

    Subich, Christopher

    2004-01-01

    Optical communication links have the potential to solve many of the problems of current radio and microwave links to satellites and high-altitude aircraft. The higher frequency involved in optical systems allows for significantly greater signal bandwidth, and thus information transfer rate, in excess of 10 Gbps, and the highly directional nature of laser-based signals eliminates the need for frequency-division multiplexing seen in radio and microwave links today. The atmosphere, however, distorts an optical signal differently than a microwave signal. While the ionosphere is one of the most significant sources of noise and distortion in a microwave or radio signal, the lower atmosphere affects an optical signal more significantly. Refractive index fluctuations, primarily caused by changes in atmospheric temperature and density, distort the incoming signal in both deterministic and nondeterministic ways. Additionally, suspended particles, such as those in haze or rain, further corrupt the transmitted signal. To model many of the atmospheric effects on the propagating beam, we use simulations based on the beam-propagation method. This method, developed both for simulation of signals in waveguides and propagation in atmospheric turbulence, separates the propagation into a diffraction and refraction problem. The diffraction step is an exact solution, within the limits of numerical precision, to the problem of propagation in free space, and the refraction step models the refractive index variances over a segment of the propagation path. By applying refraction for a segment of the propagation path, then diffracting over that same segment, this method forms a good approximation to true propagation through the atmospheric medium. Iterating over small segments of the total propagation path gives a good approximation to the problem of propagation over the entire path. Parameters in this model, such as initial beam profile and atmospheric constants, are easily modified in a

  9. Integrative modelling reveals mechanisms linking productivity and plant species richness.

    PubMed

    Grace, James B; Anderson, T Michael; Seabloom, Eric W; Borer, Elizabeth T; Adler, Peter B; Harpole, W Stanley; Hautier, Yann; Hillebrand, Helmut; Lind, Eric M; Pärtel, Meelis; Bakker, Jonathan D; Buckley, Yvonne M; Crawley, Michael J; Damschen, Ellen I; Davies, Kendi F; Fay, Philip A; Firn, Jennifer; Gruner, Daniel S; Hector, Andy; Knops, Johannes M H; MacDougall, Andrew S; Melbourne, Brett A; Morgan, John W; Orrock, John L; Prober, Suzanne M; Smith, Melinda D

    2016-01-21

    How ecosystem productivity and species richness are interrelated is one of the most debated subjects in the history of ecology. Decades of intensive study have yet to discern the actual mechanisms behind observed global patterns. Here, by integrating the predictions from multiple theories into a single model and using data from 1,126 grassland plots spanning five continents, we detect the clear signals of numerous underlying mechanisms linking productivity and richness. We find that an integrative model has substantially higher explanatory power than traditional bivariate analyses. In addition, the specific results unveil several surprising findings that conflict with classical models. These include the isolation of a strong and consistent enhancement of productivity by richness, an effect in striking contrast with superficial data patterns. Also revealed is a consistent importance of competition across the full range of productivity values, in direct conflict with some (but not all) proposed models. The promotion of local richness by macroecological gradients in climatic favourability, generally seen as a competing hypothesis, is also found to be important in our analysis. The results demonstrate that an integrative modelling approach leads to a major advance in our ability to discern the underlying processes operating in ecological systems. PMID:26760203

  10. Integrative modelling reveals mechanisms linking productivity and plant species richness

    NASA Astrophysics Data System (ADS)

    Grace, James B.; Anderson, T. Michael; Seabloom, Eric W.; Borer, Elizabeth T.; Adler, Peter B.; Harpole, W. Stanley; Hautier, Yann; Hillebrand, Helmut; Lind, Eric M.; Pärtel, Meelis; Bakker, Jonathan D.; Buckley, Yvonne M.; Crawley, Michael J.; Damschen, Ellen I.; Davies, Kendi F.; Fay, Philip A.; Firn, Jennifer; Gruner, Daniel S.; Hector, Andy; Knops, Johannes M. H.; MacDougall, Andrew S.; Melbourne, Brett A.; Morgan, John W.; Orrock, John L.; Prober, Suzanne M.; Smith, Melinda D.

    2016-01-01

    How ecosystem productivity and species richness are interrelated is one of the most debated subjects in the history of ecology. Decades of intensive study have yet to discern the actual mechanisms behind observed global patterns. Here, by integrating the predictions from multiple theories into a single model and using data from 1,126 grassland plots spanning five continents, we detect the clear signals of numerous underlying mechanisms linking productivity and richness. We find that an integrative model has substantially higher explanatory power than traditional bivariate analyses. In addition, the specific results unveil several surprising findings that conflict with classical models. These include the isolation of a strong and consistent enhancement of productivity by richness, an effect in striking contrast with superficial data patterns. Also revealed is a consistent importance of competition across the full range of productivity values, in direct conflict with some (but not all) proposed models. The promotion of local richness by macroecological gradients in climatic favourability, generally seen as a competing hypothesis, is also found to be important in our analysis. The results demonstrate that an integrative modelling approach leads to a major advance in our ability to discern the underlying processes operating in ecological systems.

  11. Bovine viral diarrhea virus cyclically impairs long bone trabecular modeling in experimental persistently infected fetuses.

    PubMed

    Webb, B T; Norrdin, R W; Smirnova, N P; Van Campen, H; Weiner, C M; Antoniazzi, A Q; Bielefeldt-Ohmann, H; Hansen, T R

    2012-11-01

    Persistent infection (PI) with bovine viral diarrhea virus (BVDV) has been associated with osteopetrosis and other long bone lesions, most commonly characterized as transverse zones of unmodeled metaphyseal trabeculae in fetuses and calves. This study was undertaken to characterize the morphogenesis of fetal long bone lesions. Forty-six BVDV-naïve pregnant Hereford heifers of approximately 18 months of age were inoculated with noncytopathic BVDV type 2 containing media or media alone on day 75 of gestation to produce PI and control fetuses, respectively, which were collected via cesarean section on days 82, 89, 97, 192, and 245 of gestation. Radiographic and histomorphometric abnormalities were first detected on day 192, at which age PI fetal long bone metaphyses contained focal densities (4 of 7 fetuses) and multiple alternating transverse radiodense bands (3 of 7 fetuses). Day 245 fetuses were similarly affected. Histomorphometric analysis of proximal tibial metaphyses from day 192 fetuses revealed transverse zones with increased calcified cartilage core (Cg.V/BV, %) and trabecular bone (BV/TV, %) volumes in regions corresponding to radiodense bands (P < .05). Numbers of tartrate resistant acid phosphatase positive osteoclasts (N.Oc/BS, #/mm(2)) and bone perimeter occupied (Oc.S/BS, %) were both decreased (P < .05). Mineralizing surface (MS/BS, %), a measure of tissue level bone formation activity, was reduced in PI fetuses (P < .05). It is concluded that PI with BVDV induces cyclic abnormal trabecular modeling, which is secondary to reduced numbers of osteoclasts. The factors responsible for these temporal changes are unknown but may be related to the time required for osteoclast differentiation from precursor cells. PMID:22362966

  12. Viral Glycoprotein Complex Formation, Essential Function and Immunogenicity in the Guinea Pig Model for Cytomegalovirus

    PubMed Central

    Maddux, Sarah; Choi, K. Yeon; McGregor, Alistair

    2015-01-01

    Development of a cytomegalovirus (CMV) vaccine is a major public health priority due to the risk of congenital infection. A key component of a vaccine is thought to be an effective neutralizing antibody response against the viral glycoproteins necessary for cell entry. Species specificity of human CMV (HCMV) precludes direct studies in an animal model. The guinea pig is the only small animal model for congenital cytomegalovirus infection. Analysis of the guinea pig CMV (GPCMV) genome indicates that it potentially encodes homologs to the HCMV glycoproteins (including gB, gH, gL, gM, gN and gO) that form various cell entry complexes on the outside of the virus: gCI (gB); gCII (gH/gL/gO); gCIII (gM/gN). The gB homolog (GP55) has been investigated as a candidate subunit vaccine but little is known about the other homolog proteins. GPCMV glycoproteins were investigated by transient expression studies which indicated that homolog glycoproteins to gN and gM, or gH, gL and gO were able to co-localize in cells and generate respective homolog complexes which could be verified by immunoprecipitation assays. ELISA studies demonstrated that the individual complexes were highly immunogenic in guinea pigs. The gO (GP74) homolog protein has 13 conserved N-glycosylation sites found in HCMV gO. In transient expression studies, only the glycosylated protein is detected but in virus infected cells both N-glycosylated and non-glycosylated gO protein were detected. In protein interaction studies, a mutant gO that lacked N-glycosylation sites had no impact on the ability of the protein to interact with gH/gL which indicated a potential alternative function associated with these sites. Knockout GPCMV BAC mutagenesis of the respective glycoprotein genes (GP55 for gB, GP75 for gH, GP115 for gL, GP100 for gM, GP73 for gN and GP74 for gO) in separate reactions was lethal for virus regeneration on fibroblast cells which demonstrated the essential nature of the GPCMV glycoproteins. The gene

  13. Viral Glycoprotein Complex Formation, Essential Function and Immunogenicity in the Guinea Pig Model for Cytomegalovirus.

    PubMed

    Coleman, Stewart; Hornig, Julia; Maddux, Sarah; Choi, K Yeon; McGregor, Alistair

    2015-01-01

    Development of a cytomegalovirus (CMV) vaccine is a major public health priority due to the risk of congenital infection. A key component of a vaccine is thought to be an effective neutralizing antibody response against the viral glycoproteins necessary for cell entry. Species specificity of human CMV (HCMV) precludes direct studies in an animal model. The guinea pig is the only small animal model for congenital cytomegalovirus infection. Analysis of the guinea pig CMV (GPCMV) genome indicates that it potentially encodes homologs to the HCMV glycoproteins (including gB, gH, gL, gM, gN and gO) that form various cell entry complexes on the outside of the virus: gCI (gB); gCII (gH/gL/gO); gCIII (gM/gN). The gB homolog (GP55) has been investigated as a candidate subunit vaccine but little is known about the other homolog proteins. GPCMV glycoproteins were investigated by transient expression studies which indicated that homolog glycoproteins to gN and gM, or gH, gL and gO were able to co-localize in cells and generate respective homolog complexes which could be verified by immunoprecipitation assays. ELISA studies demonstrated that the individual complexes were highly immunogenic in guinea pigs. The gO (GP74) homolog protein has 13 conserved N-glycosylation sites found in HCMV gO. In transient expression studies, only the glycosylated protein is detected but in virus infected cells both N-glycosylated and non-glycosylated gO protein were detected. In protein interaction studies, a mutant gO that lacked N-glycosylation sites had no impact on the ability of the protein to interact with gH/gL which indicated a potential alternative function associated with these sites. Knockout GPCMV BAC mutagenesis of the respective glycoprotein genes (GP55 for gB, GP75 for gH, GP115 for gL, GP100 for gM, GP73 for gN and GP74 for gO) in separate reactions was lethal for virus regeneration on fibroblast cells which demonstrated the essential nature of the GPCMV glycoproteins. The gene

  14. The Linked Dual Representation model of vocal perception and production

    PubMed Central

    Hutchins, Sean; Moreno, Sylvain

    2013-01-01

    The voice is one of the most important media for communication, yet there is a wide range of abilities in both the perception and production of the voice. In this article, we review this range of abilities, focusing on pitch accuracy as a particularly informative case, and look at the factors underlying these abilities. Several classes of models have been posited describing the relationship between vocal perception and production, and we review the evidence for and against each class of model. We look at how the voice is different from other musical instruments and review evidence about both the association and the dissociation between vocal perception and production abilities. Finally, we introduce the Linked Dual Representation (LDR) model, a new approach which can account for the broad patterns in prior findings, including trends in the data which might seem to be countervailing. We discuss how this model interacts with higher-order cognition and examine its predictions about several aspects of vocal perception and production. PMID:24204360

  15. Linking geophysics and soil function modelling - biomass production

    NASA Astrophysics Data System (ADS)

    Krüger, J.; Franko, U.; Werban, U.; Fank, J.

    2012-04-01

    The iSOIL project aims at reliable mapping of soil properties and soil functions with various methods including geophysical, spectroscopic and monitoring techniques. The general procedure contains three steps (i) geophysical monitoring, (ii) generation of soil property maps and (iii) process modelling. The objective of this work is to demonstrate the mentioned procedure with a focus on process modelling. It deals with the dynamics of soil water and the direct influence on crop biomass production. The new module PLUS extends CANDY to simulate crop biomass production based on environmental influences. A soil function modelling with an adapted model parameterisation based on data of ground penetration radar (GPR) and conductivity (EM38) was realized. This study shows an approach to handle heterogeneity of soil properties with geophysical data used for biomass production modelling. The Austrian field site Wagna is characterised by highly heterogenic soil with fluvioglacial gravel sediments. The variation of thickness of topsoil above a sandy subsoil with gravels strongly influences the soil water balance. EM38, mounted on a mobile platform, enables to rapidly scan large areas whereas GPR requires a greater logistical effort. However, GPR can detect exact soil horizon depth between topsoil and subsoil, the combination of both results in a detailed large scale soil map. The combined plot-specific GPR and field site EM38 measurements extends the soil input data and improves the model performance of CANDY PLUS for plant biomass production (Krüger et al. 2011). The example demonstrates how geophysics provides a surplus of data for agroecosystem modelling which identifies and contributes alternative options for agricultural management decisions. iSOIL - "Interactions between soil related sciences - Linking geophysics, soil science and digital soil mapping" is a Collaborative Project (Grant Agreement number 211386) co-funded by the Research DG of the European Commission

  16. Gene Therapy Studies in a Canine Model of X-Linked Severe Combined Immunodeficiency

    PubMed Central

    De Ravin, Suk See; Malech, Harry L.; Sorrentino, Brian P.; Burtner, Christopher; Kiem, Hans-Peter

    2015-01-01

    Abstract Since the occurrence of T cell leukemias in the original human γ-retroviral gene therapy trials for X-linked severe combined immunodeficiency (XSCID), considerable effort has been devoted to developing safer vectors. This review summarizes gene therapy studies performed in a canine model of XSCID to evaluate the efficacy of γ-retroviral, lentiviral, and foamy viral vectors for treating XSCID and a novel method of vector delivery. These studies demonstrate that durable T cell reconstitution and thymopoiesis with no evidence of any serious adverse events and, in contrast to the human XSCID patients, sustained marking in myeloid cells and B cells with reconstitution of normal humoral immune function can be achieved for up to 5 years without any pretreatment conditioning. The presence of sustained levels of gene-marked T cells, B cells, and more importantly myeloid cells for almost 5 years is highly suggestive of transduction of either multipotent hematopoietic stem cells or very primitive committed progenitors. PMID:25603151

  17. Linking genome-scale metabolic modeling and genome annotation

    PubMed Central

    Blais, Edik M.; Chavali, Arvind K.; Papin, Jason A.

    2014-01-01

    Summary Genome-scale metabolic network reconstructions, assembled from annotated genomes, serve as a platform for integrating data from heterogeneous sources and generating hypotheses for further experimental validation. Implementing constraint-based modeling techniques such as Flux Balance Analysis (FBA) on network reconstructions allow for interrogating metabolism at a systems-level, which aids in identifying and rectifying gaps in knowledge. With genome sequences for various organisms from prokaryotes to eukaryotes becoming increasingly available, a significant bottleneck lies in the structural and functional annotation of these sequences. Using topologically-based and biologically-inspired metabolic network refinement, we can better characterize enzymatic functions present in an organism and link annotation of these functions to candidate transcripts, both steps that can be experimentally validated. PMID:23417799

  18. Approaches for genetic purity testing of live recombinant viral vaccines using a human adenovirus:rabies model.

    PubMed Central

    Lutze-Wallace, C; Sapp, T; Nadin-Davis, S A; Wandeler, A

    1992-01-01

    A two part purity testing regimen for genetically engineered live viral vaccines is described using a human adenovirus 5: rabies glycoprotein gene recombinant as a model vaccine. Initially, restriction endonuclease analysis of the recombinant viral genome verified the integrity of the recombinant construct and identified the vector genome. The second stage employed the polymerase chain reaction to facilitate a more detailed study of the target rabies glycoprotein cassette. The size of the target region was predicted from known nucleic acid sequence information and compared to that obtained after electrophoresis with molecular weight standards. Digestion of the polymerase chain reaction product with a second restriction endonuclease cleaved the target into a number of small fragments. Resolution of the fragments by gel electrophoresis allowed analysis of the target region alone, verifying its identity and integrity. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. Fig. 5. PMID:1477804

  19. Measles virus-induced immune suppression in the cotton rat (Sigmodon hispidus) model depends on viral glycoproteins.

    PubMed Central

    Niewiesk, S; Eisenhuth, I; Fooks, A; Clegg, J C; Schnorr, J J; Schneider-Schaulies, S; ter Meulen, V

    1997-01-01

    Immune suppression during measles accounts for most of the morbidity and mortality associated with the virus infection. Experimental study of this phenomenon has been hampered by the lack of a suitable animal model. We have used the cotton rat to demonstrate that mitogen-induced proliferation of spleen cells from measles virus-infected animals is impaired. Proliferation inhibition is seen in all lymphocyte subsets and is not dependent on viral replication. Cells which express the viral glycoproteins (hemagglutinin and fusion protein) transiently by transfection induce proliferation inhibition after intraperitoneal inoculation, whereas application of a recombinant measles virus in which measles virus glycoproteins are replaced with the vesicular stomatitis virus G protein does not have an antiproliferative effect. Therefore, in vivo expression of measles virus glycoproteins is sufficient and necessary to induce inhibition of lymphocyte proliferation. PMID:9311794

  20. Viral cystatin evolution and three-dimensional structure modelling: A case of directional selection acting on a viral protein involved in a host-parasitoid interaction

    PubMed Central

    Serbielle, Céline; Chowdhury, Shafinaz; Pichon, Samuel; Dupas, Stéphane; Lesobre, Jérôme; Purisima, Enrico O; Drezen, Jean-Michel; Huguet, Elisabeth

    2008-01-01

    Background In pathogens, certain genes encoding proteins that directly interact with host defences coevolve with their host and are subject to positive selection. In the lepidopteran host-wasp parasitoid system, one of the most original strategies developed by the wasps to defeat host defences is the injection of a symbiotic polydnavirus at the same time as the wasp eggs. The virus is essential for wasp parasitism success since viral gene expression alters the immune system and development of the host. As a wasp mutualist symbiont, the virus is expected to exhibit a reduction in genome complexity and evolve under wasp phyletic constraints. However, as a lepidopteran host pathogenic symbiont, the virus is likely undergoing strong selective pressures for the acquisition of new functions by gene acquisition or duplication. To understand the constraints imposed by this particular system on virus evolution, we studied a polydnavirus gene family encoding cyteine protease inhibitors of the cystatin superfamily. Results We show that cystatins are the first bracovirus genes proven to be subject to strong positive selection within a host-parasitoid system. A generated three-dimensional model of Cotesia congregata bracovirus cystatin 1 provides a powerful framework to position positively selected residues and reveal that they are concentrated in the vicinity of actives sites which interact with cysteine proteases directly. In addition, phylogenetic analyses reveal two different cystatin forms which evolved under different selective constraints and are characterized by independent adaptive duplication events. Conclusion Positive selection acts to maintain cystatin gene duplications and induces directional divergence presumably to ensure the presence of efficient and adapted cystatin forms. Directional selection has acted on key cystatin active sites, suggesting that cystatins coevolve with their host target. We can strongly suggest that cystatins constitute major virulence

  1. Effects of linking a soil-water-balance model with a groundwater-flow model

    USGS Publications Warehouse

    Stanton, Jennifer S.; Ryter, Derek W.; Peterson, Steven M.

    2013-01-01

    A previously published regional groundwater-flow model in north-central Nebraska was sequentially linked with the recently developed soil-water-balance (SWB) model to analyze effects to groundwater-flow model parameters and calibration results. The linked models provided a more detailed spatial and temporal distribution of simulated recharge based on hydrologic processes, improvement of simulated groundwater-level changes and base flows at specific sites in agricultural areas, and a physically based assessment of the relative magnitude of recharge for grassland, nonirrigated cropland, and irrigated cropland areas. Root-mean-squared (RMS) differences between the simulated and estimated or measured target values for the previously published model and linked models were relatively similar and did not improve for all types of calibration targets. However, without any adjustment to the SWB-generated recharge, the RMS difference between simulated and estimated base-flow target values for the groundwater-flow model was slightly smaller than for the previously published model, possibly indicating that the volume of recharge simulated by the SWB code was closer to actual hydrogeologic conditions than the previously published model provided. Groundwater-level and base-flow hydrographs showed that temporal patterns of simulated groundwater levels and base flows were more accurate for the linked models than for the previously published model at several sites, particularly in agricultural areas.

  2. Viral arthritis

    MedlinePlus

    Infectious arthritis - viral ... Arthritis may be a symptom of many virus-related illnesses. It usually disappears on its own without ... the rubella vaccine, only a few people develop arthritis. No risk factors are known.

  3. Viral Infections

    MedlinePlus

    ... much smaller than bacteria. Viruses cause familiar infectious diseases such as the common cold, flu and warts. ... can help prevent you from getting many viral diseases. NIH: National Institute of Allergy and Infectious Diseases

  4. Viral Gastroenteritis

    MedlinePlus

    ... stomach, small intestine, and large intestine. Several different viruses can cause viral gastroenteritis, which is highly contagious ... and last for 1 to 3 days. Some viruses cause symptoms that last longer. [ Top ] What are ...

  5. Viral pneumonia

    MedlinePlus

    More serious infections can result in respiratory failure, liver failure, and heart failure. Sometimes, bacterial infections occur during or just after viral pneumonia, which may lead to more serious forms ...

  6. Pharyngitis - viral

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/001392.htm Pharyngitis - viral To use the sharing features on this page, please enable JavaScript. Pharyngitis , or sore throat, is swelling, discomfort, pain, or ...

  7. Linking Geomechanical Models with Observations of Microseismicity during CCS Operations

    NASA Astrophysics Data System (ADS)

    Verdon, J.; Kendall, J.; White, D.

    2012-12-01

    During CO2 injection for the purposes of carbon capture and storage (CCS), injection-induced fracturing of the overburden represents a key risk to storage integrity. Fractures in a caprock provide a pathway along which buoyant CO2 can rise and escape the storage zone. Therefore the ability to link field-scale geomechanical models with field geophysical observations is of paramount importance to guarantee secure CO2 storage. Accurate location of microseismic events identifies where brittle failure has occurred on fracture planes. This is a manifestation of the deformation induced by CO2 injection. As the pore pressure is increased during injection, effective stress is decreased, leading to inflation of the reservoir and deformation of surrounding rocks, which creates microseismicity. The deformation induced by injection can be simulated using finite-element mechanical models. Such a model can be used to predict when and where microseismicity is expected to occur. However, typical elements in a field scale mechanical models have decameter scales, while the rupture size for microseismic events are typically of the order of 1 square meter. This means that mapping modeled stress changes to predictions of microseismic activity can be challenging. Where larger scale faults have been identified, they can be included explicitly in the geomechanical model. Where movement is simulated along these discrete features, it can be assumed that microseismicity will occur. However, microseismic events typically occur on fracture networks that are too small to be simulated explicitly in a field-scale model. Therefore, the likelihood of microseismicity occurring must be estimated within a finite element that does not contain explicitly modeled discontinuities. This can be done in a number of ways, including the utilization of measures such as closeness on the stress state to predetermined failure criteria, either for planes with a defined orientation (the Mohr-Coulomb criteria) for

  8. Linking geophysics and soil function modelling - two examples

    NASA Astrophysics Data System (ADS)

    Krüger, J.; Franko, U.; Werban, U.; Dietrich, P.; Behrens, T.; Schmidt, K.; Fank, J.; Kroulik, M.

    2011-12-01

    iSOIL - "Interactions between soil related sciences - Linking geophysics, soil science and digital soil mapping" is a Collaborative Project (Grant Agreement number 211386) co-funded by the Research DG of the European Commission within the RTD activities of the FP7 Thematic Priority Environment. The iSOIL project aims at reliable mapping of soil properties and soil functions with various methods including geophysical, spectroscopic and monitoring techniques. The general procedure contains three steps (i) geophysical monitoring, (ii) generation of soil property maps and (iii) process modelling. The objective of this work is to demonstrate the methodological procedure on two different examples. Example A focuses on the turnover conditions for soil organic matter (SOM) since many soil functions in a direct or indirect way depend on SOM and SOM depletion is amongst the worst soil threats. Example B deals with the dynamics of soil water and the direct influence on crop biomass production. The applied CANDY model (Franko et al. 1995) was developed to describe dynamics of soil organic matter and mineral nitrogen as well as soil water and temperature. The new module PLUS extends CANDY to simulate crop biomass production based on environmental influences (Krüger et al. 2011). The methodological procedure of example A illustrates a model application for a field site in the Czech Republic using generated soil maps from combined geophysical data. Modelling requires a complete set of soil parameters. Combining measured soil properties and data of geophysical measurements (electrical conductivity and gamma spectrometry) is the basis for digital soil mapping which provided data about clay, silt and sand as well as SOC content. With these data pedotransfer functions produce detailed soil input data (e.g. bulk and particle density, field capacity, wilting point, saturated conductivity) for the rooted soil profile. CANDY calculated different indicators for SOM and gave hints about

  9. Viral evolution

    PubMed Central

    Nasir, Arshan; Kim, Kyung Mo; Caetano-Anollés, Gustavo

    2012-01-01

    Explaining the origin of viruses remains an important challenge for evolutionary biology. Previous explanatory frameworks described viruses as founders of cellular life, as parasitic reductive products of ancient cellular organisms or as escapees of modern genomes. Each of these frameworks endow viruses with distinct molecular, cellular, dynamic and emergent properties that carry broad and important implications for many disciplines, including biology, ecology and epidemiology. In a recent genome-wide structural phylogenomic analysis, we have shown that large-to-medium-sized viruses coevolved with cellular ancestors and have chosen the evolutionary reductive route. Here we interpret these results and provide a parsimonious hypothesis for the origin of viruses that is supported by molecular data and objective evolutionary bioinformatic approaches. Results suggest two important phases in the evolution of viruses: (1) origin from primordial cells and coexistence with cellular ancestors, and (2) prolonged pressure of genome reduction and relatively late adaptation to the parasitic lifestyle once virions and diversified cellular life took over the planet. Under this evolutionary model, new viral lineages can evolve from existing cellular parasites and enhance the diversity of the world’s virosphere. PMID:23550145

  10. Optimizing Viral Discovery in Bats

    PubMed Central

    Young, Cristin C. W.; Olival, Kevin J.

    2016-01-01

    Viral discovery studies in bats have increased dramatically over the past decade, yet a rigorous synthesis of the published data is lacking. We extract and analyze data from 93 studies published between 2007–2013 to examine factors that increase success of viral discovery in bats, and specific trends and patterns of infection across host taxa and viral families. Over the study period, 248 novel viruses from 24 viral families have been described. Using generalized linear models, at a study level we show the number of host species and viral families tested best explained number of viruses detected. We demonstrate that prevalence varies significantly across viral family, specimen type, and host taxonomy, and calculate mean PCR prevalence by viral family and specimen type across all studies. Using a logistic model, we additionally identify factors most likely to increase viral detection at an individual level for the entire dataset and by viral families with sufficient sample sizes. Our analysis highlights major taxonomic gaps in recent bat viral discovery efforts and identifies ways to improve future viral pathogen detection through the design of more efficient and targeted sample collection and screening approaches. PMID:26867024

  11. Optimizing Viral Discovery in Bats.

    PubMed

    Young, Cristin C W; Olival, Kevin J

    2016-01-01

    Viral discovery studies in bats have increased dramatically over the past decade, yet a rigorous synthesis of the published data is lacking. We extract and analyze data from 93 studies published between 2007-2013 to examine factors that increase success of viral discovery in bats, and specific trends and patterns of infection across host taxa and viral families. Over the study period, 248 novel viruses from 24 viral families have been described. Using generalized linear models, at a study level we show the number of host species and viral families tested best explained number of viruses detected. We demonstrate that prevalence varies significantly across viral family, specimen type, and host taxonomy, and calculate mean PCR prevalence by viral family and specimen type across all studies. Using a logistic model, we additionally identify factors most likely to increase viral detection at an individual level for the entire dataset and by viral families with sufficient sample sizes. Our analysis highlights major taxonomic gaps in recent bat viral discovery efforts and identifies ways to improve future viral pathogen detection through the design of more efficient and targeted sample collection and screening approaches. PMID:26867024

  12. Dose-dependent protective effect of nicotine in a murine model of viral myocarditis induced by coxsackievirus B3

    PubMed Central

    Li-Sha, Ge; Jing-Lin, Zhao; Guang-Yi, Chen; Li, Liu; De-Pu, Zhou; Yue-Chun, Li

    2015-01-01

    The alpha 7 nicotinic acetylcholine receptor (alpha7 nAChR) was recently described as an anti-inflammatory target in various inflammatory diseases. The aim of this study was to investigate the dose-related effects of nicotine, an alpha7 nAChR agonist, in murine model of viral myocarditis. BALB/C mice were infected by an intraperitoneally injection with coxsackievirus B3. Nicotine was administered at doses of 0.1, 0.2 or 0.4 mg/kg three times per day for 7 or 14 consecutive days. The effects of nicotine on survival, myocardial histopathological changes, cardiac function, and cytokine levels were studied. The survival rate on day 14 increased in a dose-dependent fashion and was markedly higher in the 0.2 and 0.4 mg/kg nicotine groups than in the infected untreated group. Treatment with high-dose nicotine reduced the myocardial inflammation and improved the impaired left ventricular function in infected mice. The mRNA expressions and protein levels of TNF-α, IL-1β, IL-6, and IL-17A were significantly downregulated in dose-dependent manners in the nicotine treatment groups compared to the infected untreated group. Nicotine dose-dependently reduced the severity of viral myocarditis through inhibiting the production of proinflammatory cytokines. The findings suggest that alpha7 nAChR agonists may be a promising new strategy for patients with viral myocarditis. PMID:26507386

  13. Modeling to link regional myocardial work, metabolism and blood flows

    PubMed Central

    Bassingthwaighte, James B.; Beard, Daniel A; Carlson, Brian E.; Dash, Ranjan K.; Vinnakota, Kalyan

    2012-01-01

    Given the mono-functional, highly coordinated processes of cardiac excitation and contraction, the observations that regional myocardial blood flows, rMBF, are broadly heterogeneous has provoked much attention, but a clear explanation has not emerged. In isolated and in vivo heart studies the total coronary flow is found to be proportional to the rate-pressure product (systolic mean blood pressure times heart rate), a measure of external cardiac work. The same relationship might be expected on a local basis: more work requires more flow. The validity of this expectation has never been demonstrated experimentally. In this article we review the concepts linking cellular excitation and contractile work to cellular energetics and ATP demand, substrate utilization, oxygen demand, vasoregulation, and local blood flow. Mathematical models of these processes are now rather well developed. We propose that the construction of an integrated model encompassing the biophysics, biochemistry and physiology of cardiomyocyte contraction, then combined with a detailed three-dimensional structuring of the fiber bundle and sheet arrangements of the heart as a whole will frame an hypothesis that can be quantitatively evaluated to settle the prime issue: Does local work drive local flow in a predictable fashion that explains the heterogeneity? While in one sense one can feel content that work drives flow is irrefutable, there are no cardiac contractile models that demonstrate the required heterogeneity in local strain-stress-work; quite the contrary, cardiac contraction models have tended toward trying to show that work should be uniform. The object of this review is to argue that uniformity of work does not occur, and is impossible in any case, and that further experimentation and analysis are necessary to test the hypothesis. PMID:22915334

  14. Rate-equation modelling and ensemble approach to extraction of parameters for viral infection-induced cell apoptosis and necrosis.

    PubMed

    Domanskyi, Sergii; Schilling, Joshua E; Gorshkov, Vyacheslav; Libert, Sergiy; Privman, Vladimir

    2016-09-01

    We develop a theoretical approach that uses physiochemical kinetics modelling to describe cell population dynamics upon progression of viral infection in cell culture, which results in cell apoptosis (programmed cell death) and necrosis (direct cell death). Several model parameters necessary for computer simulation were determined by reviewing and analyzing available published experimental data. By comparing experimental data to computer modelling results, we identify the parameters that are the most sensitive to the measured system properties and allow for the best data fitting. Our model allows extraction of parameters from experimental data and also has predictive power. Using the model we describe interesting time-dependent quantities that were not directly measured in the experiment and identify correlations among the fitted parameter values. Numerical simulation of viral infection progression is done by a rate-equation approach resulting in a system of "stiff" equations, which are solved by using a novel variant of the stochastic ensemble modelling approach. The latter was originally developed for coupled chemical reactions. PMID:27608985

  15. Network modeling links breast cancer susceptibility and centrosome dysfunction.

    PubMed

    Pujana, Miguel Angel; Han, Jing-Dong J; Starita, Lea M; Stevens, Kristen N; Tewari, Muneesh; Ahn, Jin Sook; Rennert, Gad; Moreno, Víctor; Kirchhoff, Tomas; Gold, Bert; Assmann, Volker; Elshamy, Wael M; Rual, Jean-François; Levine, Douglas; Rozek, Laura S; Gelman, Rebecca S; Gunsalus, Kristin C; Greenberg, Roger A; Sobhian, Bijan; Bertin, Nicolas; Venkatesan, Kavitha; Ayivi-Guedehoussou, Nono; Solé, Xavier; Hernández, Pilar; Lázaro, Conxi; Nathanson, Katherine L; Weber, Barbara L; Cusick, Michael E; Hill, David E; Offit, Kenneth; Livingston, David M; Gruber, Stephen B; Parvin, Jeffrey D; Vidal, Marc

    2007-11-01

    Many cancer-associated genes remain to be identified to clarify the underlying molecular mechanisms of cancer susceptibility and progression. Better understanding is also required of how mutations in cancer genes affect their products in the context of complex cellular networks. Here we have used a network modeling strategy to identify genes potentially associated with higher risk of breast cancer. Starting with four known genes encoding tumor suppressors of breast cancer, we combined gene expression profiling with functional genomic and proteomic (or 'omic') data from various species to generate a network containing 118 genes linked by 866 potential functional associations. This network shows higher connectivity than expected by chance, suggesting that its components function in biologically related pathways. One of the components of the network is HMMR, encoding a centrosome subunit, for which we demonstrate previously unknown functional associations with the breast cancer-associated gene BRCA1. Two case-control studies of incident breast cancer indicate that the HMMR locus is associated with higher risk of breast cancer in humans. Our network modeling strategy should be useful for the discovery of additional cancer-associated genes. PMID:17922014

  16. Implementation of a vibrationally linked chemical reaction model for DSMC

    NASA Technical Reports Server (NTRS)

    Carlson, A. B.; Bird, Graeme A.

    1994-01-01

    A new procedure closely linking dissociation and exchange reactions in air to the vibrational levels of the diatomic molecules has been implemented in both one- and two-dimensional versions of Direct Simulation Monte Carlo (DSMC) programs. The previous modeling of chemical reactions with DSMC was based on the continuum reaction rates for the various possible reactions. The new method is more closely related to the actual physics of dissociation and is more appropriate to the particle nature of DSMC. Two cases are presented: the relaxation to equilibrium of undissociated air initially at 10,000 K, and the axisymmetric calculation of shuttle forebody heating during reentry at 92.35 km and 7500 m/s. Although reaction rates are not used in determining the dissociations or exchange reactions, the new method produces rates which agree astonishingly well with the published rates derived from experiment. The results for gas properties and surface properties also agree well with the results produced by earlier DSMC models, equilibrium air calculations, and experiment.

  17. Th17-biased RORγt Transgenic Mice Become Susceptible to a Viral Model for Multiple Sclerosis

    PubMed Central

    Martinez, Nicholas E.; Sato, Fumitaka; Kawai, Eiichiro; Omura, Seiichi; Yoh, Keigyou; Takahashi, Satoru; Tsunoda, Ikuo

    2014-01-01

    In a viral model for multiple sclerosis (MS), Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), both immune-mediated tissue damage (immunopathology) and virus persistence have been shown to cause pathology. T helper (Th) 17 cells are a Th cell subset, whose differentiation requires the transcription factor retinoic acid-related orphan receptor (ROR) γt, secrete pro-inflammatory cytokines, including IL-17, and can antagonize Th1 cells. Although Th17 cells have been shown to play a pathogenic role in immune-mediated diseases or a protective role in bacterial and fungal infections, their role in viral infections is unclear. Using newly established Th17-biased RORγt Tg mice, we tested whether Th17 cells could play a pathogenic or protective role in TMEV-IDD by contributing to immunopathology and/or by modulating anti-viral Th1 immune responses. While TMEV-infected wild-type littermate C57BL/6 mice are resistant to TMEV-IDD, RORγt Tg mice developed inflammatory demyelinating lesions with virus persistence in the spinal cord. TMEV-infected RORγt Tg mice had higher levels of IL-17, lower levels of interferon-γ, and fewer CD8+ T cells, without alteration in overall levels of anti-viral lymphoproliferative and antibody responses, compared with TMEV-infected wild-type mice. This suggests that a Th17-biased “gain-of-function” mutation could increase susceptibility to virus-mediated demyelinating diseases. PMID:25046854

  18. A communications model for an ISAS to NASA span link

    NASA Technical Reports Server (NTRS)

    Green, James L.; Mcguire, Robert E.; Lopez-Swafford, Brian

    1987-01-01

    The authors propose that an initial computer-to-computer communication link use the public packet switched networks (PPSN) Venus-P in Japan and TELENET in the U.S. When the traffic warrants it, this link would then be upgraded to a dedicated leased line that directly connects into the Space Physics Analysis Network (SPAN). The proposed system of hardware and software will easily support migration to such a dedicated link. It therefore provides a cost effective approach to the network problem. Once a dedicated line becomes operation it is suggested that the public networks link and continue to coexist, providing a backup capability.

  19. Institutional Animal Care and Use Committee Considerations Regarding the Use of Virus-Induced Carcinogenesis and Oncolytic Viral Models.

    PubMed

    Lewis, Stephanie D; Hickman-Davis, Judy M; Bergdall, Valerie K

    2016-03-31

    The use of virus-induced carcinogenesis and oncologic experimental animal models is essential in understanding the mechanisms of cancer development to advance prevention, diagnosis, and treatment methods. The Institutional Animal Care and Use Committee (IACUC) is responsible for both the complex philosophical and practical considerations associated with animal models of cancer. Animal models of cancer carry their own unique issues that require special consideration from the IACUC. Many of the considerations to be discussed apply to cancer models in general; specific issues related to viral carcinogenesis or oncolytic viruses will be specifically discussed as they arise. Responsible animal use integrates good science, humane care, and regulatory compliance. To meet those standards, the IACUC, in conjunction with the research investigator and attending veterinarian, must address a wide range of issues, including animal model selection, cancer model selection, humane end point considerations, experimental considerations, postapproval monitoring, reporting requirements, and animal management and personnel safety considerations. PMID:27034398

  20. Viral arthritis.

    PubMed

    Marks, Michael; Marks, Jonathan L

    2016-04-01

    Acute-onset arthritis is a common clinical problem facing both the general clinician and the rheumatologist. A viral aetiology is though to be responsible for approximately 1% of all cases of acute arthritis with a wide range of causal agents recognised. The epidemiology of acute viral arthritis continues to evolve, with some aetiologies, such as rubella, becoming less common due to vaccination, while some vector-borne viruses have become more widespread. A travel history therefore forms an important part of the assessment of patients presenting with an acute arthritis. Worldwide, parvovirus B19, hepatitis B and C, HIV and the alphaviruses are among the most important causes of virally mediated arthritis. Targeted serological testing may be of value in establishing a diagnosis, and clinicians must also be aware that low-titre autoantibodies, such as rheumatoid factor and antinuclear antibody, can occur in the context of acute viral arthritis. A careful consideration of epidemiological, clinical and serological features is therefore required to guide clinicians in making diagnostic and treatment decisions. While most virally mediated arthritides are self-limiting some warrant the initiation of specific antiviral therapy. PMID:27037381

  1. Local degree blocking model for link prediction in complex networks.

    PubMed

    Liu, Zhen; Dong, Weike; Fu, Yan

    2015-01-01

    Recovering and reconstructing networks by accurately identifying missing and unreliable links is a vital task in the domain of network analysis and mining. In this article, by studying a specific local structure, namely, a degree block having a node and its all immediate neighbors, we find it contains important statistical features of link formation for complex networks. We therefore propose a parameter-free local blocking (LB) predictor to quantitatively detect link formation in given networks via local link density calculations. The promising experimental results performed on six real-world networks suggest that the new index can outperform other traditional local similarity-based methods on most of tested networks. After further analyzing the scores' correlations between LB and two other methods, we find that LB index simultaneously captures the features of both PA index and short-path-based index, which empirically verifies that LB index is a multiple-mechanism-driven link predictor. PMID:25637926

  2. A cell-based model system links chromothripsis with hyperploidy

    PubMed Central

    Mardin, Balca R; Drainas, Alexandros P; Waszak, Sebastian M; Weischenfeldt, Joachim; Isokane, Mayumi; Stütz, Adrian M; Raeder, Benjamin; Efthymiopoulos, Theocharis; Buccitelli, Christopher; Segura-Wang, Maia; Northcott, Paul; Pfister, Stefan M; Lichter, Peter; Ellenberg, Jan; Korbel, Jan O

    2015-01-01

    A remarkable observation emerging from recent cancer genome analyses is the identification of chromothripsis as a one-off genomic catastrophe, resulting in massive somatic DNA structural rearrangements (SRs). Largely due to lack of suitable model systems, the mechanistic basis of chromothripsis has remained elusive. We developed an integrative method termed “complex alterations after selection and transformation (CAST),” enabling efficient in vitro generation of complex DNA rearrangements including chromothripsis, using cell perturbations coupled with a strong selection barrier followed by massively parallel sequencing. We employed this methodology to characterize catastrophic SR formation processes, their temporal sequence, and their impact on gene expression and cell division. Our in vitro system uncovered a propensity of chromothripsis to occur in cells with damaged telomeres, and in particular in hyperploid cells. Analysis of primary medulloblastoma cancer genomes verified the link between hyperploidy and chromothripsis in vivo. CAST provides the foundation for mechanistic dissection of complex DNA rearrangement processes. PMID:26415501

  3. No exacerbation but impaired anti-viral mechanisms in a rhinovirus-chronic allergic asthma mouse model.

    PubMed

    Rochlitzer, Sabine; Hoymann, Heinz-Gerd; Müller, Meike; Braun, Armin

    2014-01-01

    Severe asthma and viral-induced asthma exacerbations represent a high unmet medical need as no therapy is currently available for these patients. HRV (human rhinovirus) is prominently associated with asthma exacerbations in humans. The aim of the present study was to establish a mouse model of severe asthma with additional rhinovirus infection to investigate the interplay between chronic allergic airway inflammation and acute respiratory viral infection. Balb/c mice were sensitized with HDM (house dust mite) extract (25 μg in 50 μl of saline) by i.n. (intranasal) delivery to the lung over 7 weeks. HRV1B (HRV serotype 1B) inoculation was performed i.n. on the last 3 days. Therapeutic treatment with FP (fluticasone propionate) was performed to assess steroid efficacy. Lung resistance was measured invasively to assess AHR (airway hyper-responsiveness). BAL (bronchoalveolar lavage) differential cell count, cytokines, lung histology and the proliferative and cytokine response of MLN (mediastinal lymph node) cells upon in vitro restimulation were analysed. Chronic HDM application induced a strong Th2-skewed eosinophilic airway inflammation and AHR, which was not exacerbated by superimposed HRV1B infection. Therapeutic steroid intervention in the chronic HDM model reduced BAL eosinophil cell counts, cytokine levels and AHR, while neutrophil numbers were unaffected. Steroid efficacy against inflammatory readouts was maintained during additional HRV1B infection. Animals with chronic allergic airway inflammation exhibited a diminished immune response towards superimposed HRV1B infection compared with HRV1B alone, as induction of the anti-viral and pro-inflammatory cytokines IFN (interferon)-α, IFN-γ and IL (interleukin)-12 were suppressed. Although superimposed HRV1B infection did not provoke asthma exacerbation in this severe model, a deficient anti-viral immune response to HRV1B was present under chronic allergic airway inflammatory conditions. Thus, this model is

  4. Link Analysis

    NASA Astrophysics Data System (ADS)

    Donoho, Steve

    Link analysis is a collection of techniques that operate on data that can be represented as nodes and links. This chapter surveys a variety of techniques including subgraph matching, finding cliques and K-plexes, maximizing spread of influence, visualization, finding hubs and authorities, and combining with traditional techniques (classification, clustering, etc). It also surveys applications including social network analysis, viral marketing, Internet search, fraud detection, and crime prevention.

  5. Linking the M&Rfi Weather Generator with Agrometeorological Models

    NASA Astrophysics Data System (ADS)

    Dubrovsky, Martin; Trnka, Miroslav

    2015-04-01

    Realistic meteorological inputs (representing the present and/or future climates) for the agrometeorological model simulations are often produced by stochastic weather generators (WGs). This contribution presents some methodological issues and results obtained in our recent experiments. We also address selected questions raised in the synopsis of this session. The input meteorological time series for our experiments are produced by the parametric single site weather generator (WG) Marfi, which is calibrated from the available observational data (or interpolated from surrounding stations). To produce meteorological series representing the future climate, the WG parameters are modified by climate change scenarios, which are prepared by the pattern scaling method: the standardised scenarios derived from Global or Regional Climate Models are multiplied by the change in global mean temperature (ΔTG) determined by the simple climate model MAGICC. The presentation will address following questions: (i) The dependence of the quality of the synthetic weather series and impact results on the WG settings. An emphasis will be put on an effect of conditioning the daily WG on monthly WG (presently being one of our hot topics), which aims at improvement of the reproduction of the low-frequency weather variability. Comparison of results obtained with various WG settings is made in terms of climatic and agroclimatic indices (including extreme temperature and precipitation characteristics and drought indices). (ii) Our methodology accounts for the uncertainties coming from various sources. We will show how the climate change impact results are affected by 1. uncertainty in climate modelling, 2. uncertainty in ΔTG, and 3. uncertainty related to the complexity of the climate change scenario (focusing on an effect of inclusion of changes in variability into the climate change scenarios). Acknowledgements: This study was funded by project "Building up a multidisciplinary scientific

  6. Viral potassium channels as a robust model system for studies of membrane-protein interaction.

    PubMed

    Braun, Christian J; Lachnit, Christine; Becker, Patrick; Henkes, Leonhard M; Arrigoni, Cristina; Kast, Stefan M; Moroni, Anna; Thiel, Gerhard; Schroeder, Indra

    2014-04-01

    The viral channel KcvNTS belongs to the smallest K(+) channels known so far. A monomer of a functional homotetramer contains only 82 amino acids. As a consequence of the small size the protein is almost fully submerged into the membrane. This suggests that the channel is presumably sensitive to its lipid environment. Here we perform a comparative analysis for the function of the channel protein embedded in three different membrane environments. 1. Single-channel currents of KcvNTS were recorded with the patch clamp method on the plasma membrane of HEK293 cells. 2. They were also measured after reconstitution of recombinant channel protein into classical planar lipid bilayers and 3. into horizontal bilayers derived from giant unilamellar vesicles (GUVs). The recombinant channel protein was either expressed and purified from Pichia pastoris or from a cell-free expression system; for the latter a new approach with nanolipoprotein particles was used. The data show that single-channel activity can be recorded under all experimental conditions. The main functional features of the channel like a large single-channel conductance (80pS), high open-probability (>50%) and the approximate duration of open and closed dwell times are maintained in all experimental systems. An apparent difference between the approaches was only observed with respect to the unitary conductance, which was ca. 35% lower in HEK293 cells than in the other systems. The reason for this might be explained by the fact that the channel is tagged by GFP when expressed in HEK293 cells. Collectively the data demonstrate that the small viral channel exhibits a robust function in different experimental systems. This justifies an extrapolation of functional data from these systems to the potential performance of the channel in the virus/host interaction. This article is part of a Special Issue entitled: Viral Membrane Proteins-Channels for Cellular Networking. PMID:23791706

  7. Herpes simplex virus-1 infection of colonic explants as a model of viral-induced activation of Crohn's disease.

    PubMed

    Silva, Manuel A; Menezes, José; Dionne, Serge; Levy, Emile; Amre, Devendra K; Seidman, Ernest G

    2012-05-01

    The exogenous triggers responsible for Crohn's disease (CD) relapses are not often identified. Cytomegalovirus and other members of the herpesvirus family have been implicated in precipitating relapses. However, the role of viral infections in the immunopathogenesis of CD remains poorly understood. We describe an ex-vivo model of primary viral infection of CD tissue with Herpes Simplex Virus type I (HSV-1). IL-6 and CD68 served as markers for CD inflammation, type I IFNs for viral infection. Colonic explants obtained from CD resections were infected via the luminal or the submucosal compartments with HSV-1 or mock virus solution, at varying concentrations for up to 20 h. Serial tissue sections were assayed for expression of HSV-1 specific antigens, CD-68, IL-6 and DC-SIGN. Culture supernatants were tested for IL-6 and type I IFN production. Positive immunostaining for HSV-1 specific antigens was consistently detectable using 11×10(6)PFU from 13 h onwards, mainly on cells located in the submucosa, and in the perivascular area. CD68 was up-regulated in lamina propria macrophages from mildly and non-inflamed CD tissue after HSV-1 infection. IL-6+ cells in the infected tissues were mainly submucosal DC-SIGN+ dendritic cells. IL-6 and IFN-β levels were higher in the supernatants from HSV-1-infected explants compared to controls after 20 h of culture (p<0.01). These data show increased expression of inflammatory markers during the initial stages of HSV-1 primary infection using CD colonic explants. This in vitro model appears promising to study the immunoregulatory changes induced by microbial infection in reactivation of CD. PMID:22398063

  8. Exposure to electronic cigarettes impairs pulmonary anti-bacterial and anti-viral defenses in a mouse model.

    PubMed

    Sussan, Thomas E; Gajghate, Sachin; Thimmulappa, Rajesh K; Ma, Jinfang; Kim, Jung-Hyun; Sudini, Kuladeep; Consolini, Nicola; Cormier, Stephania A; Lomnicki, Slawo; Hasan, Farhana; Pekosz, Andrew; Biswal, Shyam

    2015-01-01

    Electronic cigarettes (E-cigs) have experienced sharp increases in popularity over the past five years due to many factors, including aggressive marketing, increased restrictions on conventional cigarettes, and a perception that E-cigs are healthy alternatives to cigarettes. Despite this perception, studies on health effects in humans are extremely limited and in vivo animal models have not been generated. Presently, we determined that E-cig vapor contains 7 x 10(11) free radicals per puff. To determine whether E-cig exposure impacts pulmonary responses in mice, we developed an inhalation chamber for E-cig exposure. Mice that were exposed to E-cig vapor contained serum cotinine concentrations that are comparable to human E-cig users. E-cig exposure for 2 weeks produced a significant increase in oxidative stress and moderate macrophage-mediated inflammation. Since, COPD patients are susceptible to bacterial and viral infections, we tested effects of E-cigs on immune response. Mice that were exposed to E-cig vapor showed significantly impaired pulmonary bacterial clearance, compared to air-exposed mice, following an intranasal infection with Streptococcus pneumonia. This defective bacterial clearance was partially due to reduced phagocytosis by alveolar macrophages from E-cig exposed mice. In response to Influenza A virus infection, E-cig exposed mice displayed increased lung viral titers and enhanced virus-induced illness and mortality. In summary, this study reports a murine model of E-cig exposure and demonstrates that E-cig exposure elicits impaired pulmonary anti-microbial defenses. Hence, E-cig exposure as an alternative to cigarette smoking must be rigorously tested in users for their effects on immune response and susceptibility to bacterial and viral infections. PMID:25651083

  9. Exposure to Electronic Cigarettes Impairs Pulmonary Anti-Bacterial and Anti-Viral Defenses in a Mouse Model

    PubMed Central

    Sussan, Thomas E.; Gajghate, Sachin; Thimmulappa, Rajesh K.; Ma, Jinfang; Kim, Jung-Hyun; Sudini, Kuladeep; Consolini, Nicola; Cormier, Stephania A.; Lomnicki, Slawo; Hasan, Farhana; Pekosz, Andrew; Biswal, Shyam

    2015-01-01

    Electronic cigarettes (E-cigs) have experienced sharp increases in popularity over the past five years due to many factors, including aggressive marketing, increased restrictions on conventional cigarettes, and a perception that E-cigs are healthy alternatives to cigarettes. Despite this perception, studies on health effects in humans are extremely limited and in vivo animal models have not been generated. Presently, we determined that E-cig vapor contains 7x1011 free radicals per puff. To determine whether E-cig exposure impacts pulmonary responses in mice, we developed an inhalation chamber for E-cig exposure. Mice that were exposed to E-cig vapor contained serum cotinine concentrations that are comparable to human E-cig users. E-cig exposure for 2 weeks produced a significant increase in oxidative stress and moderate macrophage-mediated inflammation. Since, COPD patients are susceptible to bacterial and viral infections, we tested effects of E-cigs on immune response. Mice that were exposed to E-cig vapor showed significantly impaired pulmonary bacterial clearance, compared to air-exposed mice, following an intranasal infection with Streptococcus pneumonia. This defective bacterial clearance was partially due to reduced phagocytosis by alveolar macrophages from E-cig exposed mice. In response to Influenza A virus infection, E-cig exposed mice displayed increased lung viral titers and enhanced virus-induced illness and mortality. In summary, this study reports a murine model of E-cig exposure and demonstrates that E-cig exposure elicits impaired pulmonary anti-microbial defenses. Hence, E-cig exposure as an alternative to cigarette smoking must be rigorously tested in users for their effects on immune response and susceptibility to bacterial and viral infections. PMID:25651083

  10. Super High Frequency (SHF) Link Analysis Model (SLAM) for nonsatellite applications

    NASA Astrophysics Data System (ADS)

    James, R. R.; Rockway, J. W.

    1990-06-01

    A point-to-point link analysis model has been developed for the Super High Frequency (SHF) band. It was developed to evaluate ship-to-ship and ship-to-air links. The SHF Link Analysis Model (SLAM) evaluates a communication link and determines system margin. The link margin is determined after a user defines the transmitter subsystem, the receiver subsystem, the specified level of system performance, and the propagation channel. The propagation channel incorporates the Engineer's Refractive Effects Prediction System (EREPS) and includes the effects of the evaporation duct. A rain model developed by NASA is also included in the channel. SLAM provides a detailed discussion of the link equation, the propagation effects, the rain model, and the antenna characteristics. In addition, a detailed explanation of the operation of the SLAM computer program is given. Two communication links are evaluated and these examples are used to demonstrate the computer program's capabilities.

  11. Improving Power System Modeling. A Tool to Link Capacity Expansion and Production Cost Models

    SciTech Connect

    Diakov, Victor; Cole, Wesley; Sullivan, Patrick; Brinkman, Gregory; Margolis, Robert

    2015-11-01

    Capacity expansion models (CEM) provide a high-level long-term view at the prospects of the evolving power system. In simulating the possibilities of long-term capacity expansion, it is important to maintain the viability of power system operation in the short-term (daily, hourly and sub-hourly) scales. Production-cost models (PCM) simulate routine power system operation on these shorter time scales using detailed load, transmission and generation fleet data by minimizing production costs and following reliability requirements. When based on CEM 'predictions' about generating unit retirements and buildup, PCM provide more detailed simulation for the short-term system operation and, consequently, may confirm the validity of capacity expansion predictions. Further, production cost model simulations of a system that is based on capacity expansion model solution are 'evolutionary' sound: the generator mix is the result of logical sequence of unit retirement and buildup resulting from policy and incentives. The above has motivated us to bridge CEM with PCM by building a capacity expansion - to - production cost model Linking Tool (CEPCoLT). The Linking Tool is built to onset capacity expansion model prescriptions onto production cost model inputs. NREL's ReEDS and Energy Examplar's PLEXOS are the capacity expansion and the production cost models, respectively. Via the Linking Tool, PLEXOS provides details of operation for the regionally-defined ReEDS scenarios.

  12. Viral Hepatitis

    MedlinePlus

    ... with hepatitis? How does a pregnant woman pass hepatitis B virus to her baby? If I have hepatitis B, what does my baby need so that she ... Can I breastfeed my baby if I have hepatitis B? More information on viral hepatitis What is hepatitis? ...

  13. VIRAL GASTROENTERITIS

    EPA Science Inventory

    Two virus types have been clearly shown to have epidemiologic importance in viral gastroenteritis, i.e., rotavirus and Norwalk virus. Four other virus types have been associated with gastroenteritis but their epidemiologic importance is not yet known, i.e., enteric adenovirus, ca...

  14. Protein kinase R reveals an evolutionary model for defeating viral mimicry

    PubMed Central

    Elde, Nels C.; Child, Stephanie J.; Geballe, Adam P.; Malik, Harmit S.

    2008-01-01

    Distinguishing self from non-self is a fundamental biological challenge. Many pathogens exploit the challenge of self discrimination by employing mimicry to subvert key cellular processes including the cell cycle, apoptosis, and cytoskeletal dynamics1-5. Other mimics interfere with immunity6, 7. Poxviruses encode K3L, a mimic of eIF2α, which is the substrate of Protein Kinase R (PKR), an important component of innate immunity in vertebrates8, 9. The PKR-K3L interaction exemplifies the conundrum imposed by viral mimicry. To be effective, PKR must recognize a conserved substrate (eIF2α) while avoiding rapidly evolving substrate mimics like K3L. Using the PKR-K3L system and a combination of phylogenetic and functional analyses, we uncover evolutionary strategies by which host proteins can overcome mimicry. We find that PKR has evolved under dramatic episodes of positive selection in primates. The ability of PKR to evade viral mimics is partly due to positive selection at sites most intimately involved in eIF2α recognition. We also find that adaptive changes on multiple surfaces of PKR produce combinations of substitutions that increase the odds of defeating mimicry. Thus, while it can appear that pathogens gain insurmountable advantages by mimicking cellular components, host factors like PKR can compete in molecular ‘arms races’ with mimics because of remarkable evolutionary flexibility at protein interaction interfaces challenged by mimicry. PMID:19043403

  15. Stampidine prevents mortality in an experimental mouse model of viral hemorrhagic fever caused by lassa virus

    PubMed Central

    Uckun, Fatih M; Petkevich, Alexander S; Vassilev, Alexei O; Tibbles, Heather E; Titov, Leonid

    2004-01-01

    Background The potential use of microorganisms as agents of biological warfare (BW) is a growing concern. Lassa virus, a member of the Arenavirus class of Hemorrhagic fever (HF) viruses has emerged as a worldwide concern among public health officials. The purpose of the present study was to further elucidate the antiviral activity spectrum of stampidine, a novel nucleoside analog with potent anti-viral activity against the immunodeficiency viruses HIV-1, HIV-2, and FIV, by examining its effects on survival of mice challenged with Lassa virus. Methods We examined the therapeutic effect of Stampidine in CBA mice inoculated with intracerebral injections of the Josiah strain of Lassa virus. Mice were treated either with vehicle or nontoxic doses of stampidine administered intraperitoneally 24 hours prior to, 1 hour prior to, and 24 hours, 48 hours, 72 hours, and 96 hours after virus inoculation. Results The probability of survival following the Lassa challenge was significantly improved for stampidine treated mice (Kaplan Meier, Chi-squared = 11.7, df = 2, Log-Rank p-value = 0.003). Conclusion Therefore, stampidine shows clinical potential as a new agent for treatment of viral hemorrhagic fevers caused by Lassa virus. PMID:14720304

  16. Linking Student Retention Model with Institutional Planning: The Benefits and Limitations of a Student Matrix Model.

    ERIC Educational Resources Information Center

    Schartman, Laura; Rhee, Byung-Shik

    This study explored the possibility of linking the Luna (1999) student flow matrix model with institutional planning at a comprehensive state institution, investigating how student flow environments were associated with student characteristics such as race, gender, citizenship, class level, entry type, and cumulative grade point average. The study…

  17. Reactivation of latently infected HIV-1 viral reservoirs and correction of aberrant alternative splicing in the LMNA gene via AMPK activation: Common mechanism of action linking HIV-1 latency and Hutchinson-Gilford progeria syndrome.

    PubMed

    Finley, Jahahreeh

    2015-09-01

    AMPK, a master regulator of cellular metabolism which has been shown to activate PKC-theta (θ) and is essential for T cell activation, may modulate the splicing activities of SRp55 as well as enhance a p32-mediated inhibition of ASF/SF2-induced alternative splicing, potentially correcting aberrant alternative splicing in the LMNA gene and reactivating latent viral HIV-1 reservoirs. Moreover, similar epigenetic modifications and cell cycle regulators also characterize the analogous stages of premature senescence in progeroid cells and latency in HIV-1 infected T cells. AMPK-activating compounds including metformin and resveratrol may thus embody a novel treatment paradigm linking the pathophysiology of HGPS with that of HIV-1 latency. PMID:26115946

  18. Viral epidemics in a cell culture: novel high resolution data and their interpretation by a percolation theory based model.

    PubMed

    Gönci, Balázs; Németh, Valéria; Balogh, Emeric; Szabó, Bálint; Dénes, Ádám; Környei, Zsuzsanna; Vicsek, Tamás

    2010-01-01

    Because of its relevance to everyday life, the spreading of viral infections has been of central interest in a variety of scientific communities involved in fighting, preventing and theoretically interpreting epidemic processes. Recent large scale observations have resulted in major discoveries concerning the overall features of the spreading process in systems with highly mobile susceptible units, but virtually no data are available about observations of infection spreading for a very large number of immobile units. Here we present the first detailed quantitative documentation of percolation-type viral epidemics in a highly reproducible in vitro system consisting of tens of thousands of virtually motionless cells. We use a confluent astroglial monolayer in a Petri dish and induce productive infection in a limited number of cells with a genetically modified herpesvirus strain. This approach allows extreme high resolution tracking of the spatio-temporal development of the epidemic. We show that a simple model is capable of reproducing the basic features of our observations, i.e., the observed behaviour is likely to be applicable to many different kinds of systems. Statistical physics inspired approaches to our data, such as fractal dimension of the infected clusters as well as their size distribution, seem to fit into a percolation theory based interpretation. We suggest that our observations may be used to model epidemics in more complex systems, which are difficult to study in isolation. PMID:21187920

  19. UAS Modeling of the Communication Links Study Results

    NASA Technical Reports Server (NTRS)

    Birr, Richard; Murray, Jennifer; Girgis, nancy

    2011-01-01

    There were many links calculated for this and the other scenarios. The rain was analyzed for 99.9% availability with rain rated of none, 20 mm/hr and 90 mm/hr at a height of 5 km out to 25 NM. This was done for each scenario for LOS and for BLOS links for Scenario 5 and 6. Scenario 1 was a LOS-only scenario. Use of two 3 dB Antennas on both ends. The CS2 was unable to maintain a control RF Link during the flight. The largest access gap periods between object top and bottom UA antennae were caused by terrain (ridges and hills). The CS Antenna was changed to High Gain Directional Antenna, all three CS maintained lock on vehicle. There were RF dropouts between the top and bottom UA antennae caused by aircraft obstructions (fuselage, wings, wheel assembles, etc.). Note that for this study antenna locations were placed on top and bottom center of the UA body. Future study should include actual UA antenna locations on the aircraft providing manufactures are willing to provide information. The importance of CS location(s) was demonstrated for primary or backup CS. With a second backup CS placed in a suitable location the UA was able to maintain an overall RF link. The actual location of both backup CSs required the antenna location to be place 150 ft above ground in order to establish a RF link between the UA and CS.

  20. Noncytopathic bovine viral diarrhea virus 2 impairs virus control in a mouse model.

    PubMed

    Seong, Giyong; Lee, Jin-Sol; Lee, Kyung-Hyun; Shin, Seung-Uk; Yoon, Ji Young; Choi, Kyoung-Seong

    2016-02-01

    Bovine viral diarrhea virus (BVDV) is an economically important pathogen that causes development of mild to severe clinical signs in wild and domesticated ruminants. We previously showed that mice could be infected by BVDV. In the present study, we infected mice intraperitoneally with non-cytopathic (ncp) BVDV1 or ncp BVDV2, harvested the blood and organs of the infected mice at days 4, 7, 10 and 14 postinfection (pi), and performed immunohistochemical analyses to confirm BVDV infection. Viral antigens were detected in the spleens of all infected mice from days 4 through 14 and were also found in the mesenteric lymph nodes, gut-associated lymphoid tissue (GALT), heart, kidney, intestine, and bronchus-associated lymphoid tissue (BALT) of some infected mice. In ncp BVDV2-infected mice, flow cytometric analysis revealed markedly fewer CD4(+) and CD8(+) T lymphocytes and lower expression of costimulatory molecules CD80 (B7-1) and CD86 (B7-2) and major histocompatibility complex (MHC) class II (I-A/I-E) than those in ncp BVDV1-infected mice. Production of the cytokines interleukin (IL)-6 and monocyte chemotactic protein (MCP)-1 was higher in the plasma of ncp BVDV2-infected mice than that in that of ncp BVDV1-infected mice. Our results demonstrate that ncp BVDV1 and ncp BVDV2 interact differently with the host innate immune response in vivo. These findings highlight an important distinction between ncp BVDV1 and ncp BVDV2 and suggest that ncp BVDV2 impairs the host's ability to control the infection and enhances virus dissemination. PMID:26586332

  1. A novel animal model linking adiposity to altered circadian rhythms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Researchers have provided evidence for a link between obesity and altered circadian rhythms (e.g., shift work, disrupted sleep), but the mechanism for this association is still unknown. Adipocytes possess an intrinsic circadian clock, and circadian rhythms in adipocytokines and adipose tissue metab...

  2. Viral Diseases in Zebrafish: What Is Known and Unknown

    PubMed Central

    Crim, Marcus J.; Riley, Lela K.

    2013-01-01

    Naturally occurring viral infections have the potential to introduce confounding variability that leads to invalid and misinterpreted data. Whereas the viral diseases of research rodents are well characterized and closely monitored, no naturally occurring viral infections have been characterized for the laboratory zebrafish (Danio rerio), an increasingly important biomedical research model. Despite the ignorance about naturally occurring zebrafish viruses, zebrafish models are rapidly expanding in areas of biomedical research where the confounding effects of unknown infectious agents present a serious concern. In addition, many zebrafish research colonies remain linked to the ornamental (pet) zebrafish trade, which can contribute to the introduction of new pathogens into research colonies, whereas mice used for research are purpose bred, with no introduction of new mice from the pet industry. Identification, characterization, and monitoring of naturally occurring viruses in zebrafish are crucial to the improvement of zebrafish health, the reduction of unwanted variability, and the continued development of the zebrafish as a model organism. This article addresses the importance of identifying and characterizing the viral diseases of zebrafish as the scope of zebrafish models expands into new research areas and also briefly addresses zebrafish susceptibility to experimental viral infection and the utility of the zebrafish as an infection and immunology model. PMID:23382345

  3. Modeling and Simulation of a Slider Crank Mechanism with a Flexible Extensible Link

    NASA Astrophysics Data System (ADS)

    Dupac, M.; Noroozi, S.

    In this paper the modelling of a slider-crank mechanism with an extensible flexible link is presented and its dynamical behaviour analyzed. The link flexibility is modelled using extensible rigid links and rotational springs. The equations of motion with and without slider clearance are written. Accurate simulation of the extensible mechanism is performed to study its possible performance and behaviour under the combined effect of different parameters. A dynamic analysis is carried out in order to understand its behaviour under motion reconfiguration.

  4. Viral Exanthem

    MedlinePlus

    ... References/Trusted Links Related diseases: Chickenpox (Varicella) Hand-Foot-and-Mouth Disease Roseola (Sixth Disease) Scarlet Fever View all diseases Community: Discussion Forum Skinmatters Blog ...

  5. A mathematical model of hepatitis c virus dynamics in patients with high baseline viral loads or advanced liver disease

    PubMed Central

    Dahari, Harel; Layden-Almer, Jennifer E.; Kallwitz, Eric; Ribeiro, Ruy M.; Cotler, Scott J.; Layden, Thomas J.; Perelson, Alan S.

    2010-01-01

    Background & Aims Patients with baseline hepatitis C virus-RNA levels (bHCV-RNA) >6 log IU/ml or cirrhosis have a reduced probability of a sustained-virological response (SVR). We examined the relationship between bHCV-RNA, cirrhosis and SVR using a mathematical model that includes the critical-drug efficacy (εc; the efficacy required for a drug to clear HCV), the infection-rate constant (β) and the percentage of HCV-infected hepatocytes (π). Methods The relationship between baseline factors and SVR was evaluated in 1,000 in silico HCV-infected patients, generated by randomly assignment of realistic host and viral kinetic parameters. Model predictions were compared with clinical data from 170 non-cirrhotic and 75 cirrhotic patients. Results The ranges chosen for β and the viral production rate (p) resulted in bHCV-RNA levels that were in agreement with the distribution observed in US patients. Using these β and p values, higher bHCV-RNA levels led to higher εc, resulting in lower SVR rates. Alternatively, higher β values resulted in lower bHCV-RNA levels but higher π and εc, predicting lower rates of SVR. Cirrhotic patients had lower bHCV-RNA levels than non-cirrhotic patients (p=0.013) and more had bHCV-RNA levels <6 log IU/ml (p<0.001). Even cirrhotic patients with lower bHCV-RNA levels had lower SVR rates. An increase in β could explain the results observed in cirrhotic patients. Conclusions Our model predicts that higher bHCV-RNA levels lead to higher εc, reducing the chance of achieving SVR; cirrhotic patients have lower SVR rates because of large π values, caused by increased rates of hepatocyte infection. PMID:19208338

  6. CXCR4 Signaling Regulates Remyelination by Endogenous Oligodendrocyte Progenitor Cells in a Viral Model of Demyelination

    PubMed Central

    CARBAJAL, KEVIN S.; MIRANDA, JUAN L.; TSUKAMOTO, MICHELLE R.; LANE, THOMAS E.

    2016-01-01

    Following intracranial infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV), susceptible mice will develop widespread myelin destruction that results in pathological and clinical outcomes similar to those seen in humans with the demyelinating disease Multiple Sclerosis (MS). Partial remyelination and clinical recovery occurs during the chronic phase following control of viral replication yet the signaling mechanisms regulating these events remain enigmatic. Here we report the kinetics of proliferation and maturation of oligodendrocyte progenitor cells (OPCs) within the spinal cord following JHMV-induced demyelination and that CXCR4 signaling contributes to the maturation state of OPCs. Following treatment with AMD3100, a specific inhibitor of CXCR4, mice recovering from widespread demyelination exhibit a significant (P < 0.01) increase in the number of OPCs and fewer (P < 0.05) mature oligodendrocytes compared with HBSS-treated animals. These results suggest that CXCR4 signaling is required for OPCs to mature and contribute to remyelination in response to JHMV-induced demyelination. To assess if this effect is reversible and has potential therapeutic benefit, we pulsed mice with AMD3100 and then allowed them to recover. This treatment strategy resulted in increased numbers of mature oligodendrocytes, enhanced remyelination, and improved clinical outcome. These findings highlight the possibility to manipulate OPCs in order to increase the pool of remyelination-competent cells that can participate in recovery. PMID:21830237

  7. Myocardial uptake of antimyosin monoclonal antibody in a murine model of viral myocarditis

    SciTech Connect

    Matsumori, A.; Ohkusa, T.; Matoba, Y.; Okada, I.; Yamada, T.; Kawai, C.; Tamaki, N.; Watanabe, Y.; Yonekura, Y.; Endo, K.

    1989-02-01

    The myocardial uptake of 125I- and 131I-antimyosin monoclonal antibody Fab in experimental myocarditis in BALB/c mice induced by encephalomyocarditis virus was studied. The biodistribution of 125I-antimyosin demonstrated that the highest ratio of radioactivity appears in the heart of infected mice on day 14 (the ratio of percent dose per gram for the organ to percent dose per milliliter for blood; 9.75 +/- 2.79 vs. 1.27 +/- 0.78 at 24 hours in inoculated mice vs. control mice). There was no statistically significant difference between the mean activity ratios of tissues other than the heart in control and inoculated mice. The uptake ratio for the heart increased significantly 3 days after virus inoculation and reached a maximum on day 14 when myocardial lesions were most extensive and prominent. The uptake ratio decreased significantly, but it still remained high compared with controls on day 28 when cellular infiltration had decreased and fibrosis was evident. The scintigraphic images obtained with 131I-antimyosin monoclonal antibody clearly demonstrated that visualization of the heart in experimental myocarditis was possible 24 hours after administration of radiotracer, and localized activity was still observed in the 48-hour image. We conclude that antimyosin monoclonal antibodies localize selectively in the heart from the acute to subacute stage of viral myocarditis. These findings indicate that antimyosin scintigraphy is a reliable noninvasive method for the evaluation of patients suspected of having myocarditis.

  8. Covalent cross-links in polyampholytic chitosan fibers enhances bone regeneration in a rabbit model.

    PubMed

    Ghosh, Paulomi; Rameshbabu, Arun Prabhu; Das, Dipankar; Francis, Nimmy K; Pawar, Harpreet Singh; Subramanian, Bhuvaneshwaran; Pal, Sagar; Dhara, Santanu

    2015-01-01

    Chitosan fibers were prepared in citric acid bath, pH 7.4 and NaOH solution at pH 13, to form ionotropically cross-linked and uncross-linked fibers, respectively. The fibers formed in citric acid bath were further cross-linked via carbodiimide chemistry; wherein the pendant carboxyl moieties of citric acid were used for new amide bond formation. Moreover, upon covalent cross-linking in the ionically gelled citrate-chitosan fibers, incomplete conversion of the ion pairs to amide linkages took place resulting in the formation of a dual network structure. The dual cross-linked fibers displayed improved mechanical property, higher stability against enzymatic degradation, hydrophobicity and superior bio-mineralization compared to the uncross-linked and native citrate cross-linked fibers. Additionally, upon cyclic loading, the ion pairs in the dual cross-linked fibers dissociated by dissipating energy and reformed during the relaxation period. The twin property of elasticity and energy dissipation mechanism makes the dual cross-linked fiber unique under dynamic mechanical conditions. The differences in the physico-chemical characteristics were reflected in protein adsorption, which in turn influenced the cellular activities on the fibers. Compared to the uncross-linked and ionotropically cross-linked fibers, the dual cross-linked fibers demonstrated higher proliferation and osteogenic differentiation of the MSCs in vitro as well as better osseous tissue regeneration in a rabbit model. PMID:25483844

  9. Evaluation of a mouse model for the West Nile virus group for the purpose of determining viral pathotypes.

    PubMed

    Bingham, John; Payne, Jean; Harper, Jennifer; Frazer, Leah; Eastwood, Sarah; Wilson, Susanne; Lowther, Sue; Lunt, Ross; Warner, Simone; Carr, Mary; Hall, Roy A; Durr, Peter A

    2014-06-01

    West Nile virus (WNV; family Flaviviridae; genus Flavivirus) group members are an important cause of viral meningoencephalitis in some areas of the world. They exhibit marked variation in pathogenicity, with some viral lineages (such as those from North America) causing high prevalence of severe neurological disease, whilst others (such as Australian Kunjin virus) rarely cause disease. The aim of this study was to characterize WNV disease in a mouse model and to elucidate the pathogenetic features that distinguish disease variation. Tenfold dilutions of five WNV strains (New York 1999, MRM16 and three horse isolates of WNV-Kunjin: Boort and two isolates from the 2011 Australian outbreak) were inoculated into mice by the intraperitoneal route. All isolates induced meningoencephalitis in different proportions of infected mice. WNVNY99 was the most pathogenic, the three horse isolates were of intermediate pathogenicity and WNVKUNV-MRM16 was the least, causing mostly asymptomatic disease with seroconversion. Infectivity, but not pathogenicity, was related to challenge dose. Using cluster analysis of the recorded clinical signs, histopathological lesions and antigen distribution scores, the cases could be classified into groups corresponding to disease severity. Metrics that were important in determining pathotype included neurological signs (paralysis and seizures), meningoencephalitis, brain antigen scores and replication in extra-neural tissues. Whereas all mice infected with WNVNY99 had extra-neural antigen, those infected with the WNV-Kunjin viruses only occasionally had antigen outside the nervous system. We conclude that the mouse model could be a useful tool for the assessment of pathotype for WNVs. PMID:24694397

  10. Viral surveillance and discovery

    PubMed Central

    Lipkin, Walter Ian; Firth, Cadhla

    2014-01-01

    The field of virus discovery has burgeoned with the advent of high throughput sequencing platforms and bioinformatics programs that enable rapid identification and molecular characterization of known and novel agents, investments in global microbial surveillance that include wildlife and domestic animals as well as humans, and recognition that viruses may be implicated in chronic as well as acute diseases. Here we review methods for viral surveillance and discovery, strategies and pitfalls in linking discoveries to disease, and identify opportunities for improvements in sequencing instrumentation and analysis, the use of social media and medical informatics that will further advance clinical medicine and public health. PMID:23602435

  11. Circuit-level simulation of transistor lasers and its application to modelling of microwave photonic links

    NASA Astrophysics Data System (ADS)

    Iezekiel, Stavros; Christou, Andreas

    2015-03-01

    Equivalent circuit models of a transistor laser are used to investigate the suitability of this relatively new device for analog microwave photonic links. The three-terminal nature of the device enables transistor-based circuit design techniques to be applied to optoelectronic transmitter design. To this end, we investigate the application of balanced microwave amplifier topologies in order to enable low-noise links to be realized with reduced intermodulation distortion and improved RF impedance matching compared to conventional microwave photonic links.

  12. Visualization of the Interaction between the Precursors of VPg, the Viral Protein Linked to the Genome of Turnip Mosaic Virus, and the Translation Eukaryotic Initiation Factor iso 4E In Planta▿

    PubMed Central

    Beauchemin, Chantal; Boutet, Nathalie; Laliberté, Jean-François

    2007-01-01

    The RNA genome of Turnip mosaic virus is covalently linked at its 5′ end to a viral protein known as VPg. This protein binds to the translation eukaryotic initiation factor iso 4E [eIF(iso)4E]. This interaction has been shown to be important for virus infection, although its exact biological function(s) has not been elucidated. In this study, we investigated the subcellular site of the VPg-eIF(iso)4E interaction using bimolecular fluorescence complementation (BiFC). As a first step, eIF(iso)4E, 6K-VPg-Pro, and VPg-Pro were expressed as full-length green fluorescent protein (GFP) fusions in Nicotiana benthamiana, and their subcellular localizations were visualized by confocal microscopy. eIF(iso)4E was predominantly associated with the endoplasmic reticulum (ER), and VPg-Pro was observed in the nucleus and possibly the nucleolus, while 6K-VPg-Pro-GFP induced the formation of cytoplasmic vesicles budding from the ER. In BiFC experiments, reconstituted green fluorescence was observed throughout the nucleus, with a preferential accumulation in subnuclear structures when the GFP split fragments were fused to VPg-Pro and eIF(iso)4E. On the other hand, the interaction of 6K-VPg-Pro with eIF(iso)4E was observed in cytoplasmic vesicles embedded in the ER. These data suggest that the association of VPg with the translation factor might be needed for two different functions, depending of the VPg precursor involved in the interaction. VPg-Pro interaction with eIF(iso)4E may be involved in perturbing normal cellular functions, while 6K-VPg-Pro interaction with the translation factor may be needed for viral RNA translation and/or replication. PMID:17079311

  13. Comparison of Effects of Ivabradine versus Carvedilol in Murine Model with the Coxsackievirus B3-Induced Viral Myocarditis

    PubMed Central

    Yue-Chun, Li; Teng, Zhang; Na-Dan, Zhou; Li-Sha, Ge; Qin, Luo; Xue-Qiang, Guan; Jia-Feng, Lin

    2012-01-01

    Background Elevated heart rate is associated with increased cardiovascular morbidity. The selective If current inhibitor ivabradine reduces heart rate without affecting cardiac contractility, and has been shown to be cardioprotective in the failing heart. Ivabradine also exerts some of its beneficial effects by decreasing cardiac proinflammatory cytokines and inhibiting peroxidants and collagen accumulation in atherosclerosis or congestive heart failure. However, the effects of ivabradine in the setting of acute viral myocarditis and on the cytokines, oxidative stress and cardiomyocyte apoptosis have not been investigated. Methodology/Principal Findings The study was designed to compare the effects of ivabradine and carvedilol in acute viral myocarditis. In a coxsackievirus B3 murine myocarditis model (Balb/c), effects of ivabradine and carvedilol (a nonselective β-adrenoceptor antagonist) on myocardial histopathological changes, cardiac function, plasma noradrenaline, cytokine levels, cardiomyocyte apoptosis, malondialdehyde and superoxide dismutase contents were studied. Both ivabradine and carvedilol similarly and significantly reduced heart rate, attenuated myocardial lesions and improved the impairment of left ventricular function. In addition, ivabradine treatment as well as carvedilol treatment showed significant effects on altered myocardial cytokines with a decrease in the amount of plasma noradrenaline. The increased myocardial MCP-1, IL-6, and TNF-α. in the infected mice was significantly attenuated in the ivabradine treatment group. Only carvedilol had significant anti-oxidative and anti-apoptoic effects in coxsackievirus B3-infected mice. Conclusions/Significance These results show that the protective effects of heart rate reduction with ivabradine and carvedilol observed in the acute phase of coxsackievirus B3 murine myocarditis may be due not only to the heart rate reduction itself but also to the downregulation of inflammatory cytokines. PMID

  14. Modeling and control of a hydraulically actuated flexible-prismatic link robot

    SciTech Connect

    Love, L.; Kress, R.; Jansen, J.

    1996-12-01

    Most of the research related to flexible link manipulators to date has focused on single link, fixed length, single plane of vibration test beds. In addition, actuation has been predominantly based upon electromagnetic motors. Ironically, these elements are rarely found in the existing industrial long reach systems. This manuscript describes a new hydraulically actuated, long reach manipulator with a flexible prismatic link at Oak Ridge National Laboratory (ORNL). Focus is directed towards both modeling and control of hydraulic actuators as well as flexible links that have variable natural frequencies.

  15. Tools and Algorithms to Link Horizontal Hydrologic and Vertical Hydrodynamic Models and Provide a Stochastic Modeling Framework

    NASA Astrophysics Data System (ADS)

    Salah, Ahmad M.; Nelson, E. James; Williams, Gustavious P.

    2010-04-01

    We present algorithms and tools we developed to automatically link an overland flow model to a hydrodynamic water quality model with different spatial and temporal discretizations. These tools run the linked models which provide a stochastic simulation frame. We also briefly present the tools and algorithms we developed to facilitate and analyze stochastic simulations of the linked models. We demonstrate the algorithms by linking the Gridded Surface Subsurface Hydrologic Analysis (GSSHA) model for overland flow with the CE-QUAL-W2 model for water quality and reservoir hydrodynamics. GSSHA uses a two-dimensional horizontal grid while CE-QUAL-W2 uses a two-dimensional vertical grid. We implemented the algorithms and tools in the Watershed Modeling System (WMS) which allows modelers to easily create and use models. The algorithms are general and could be used for other models. Our tools create and analyze stochastic simulations to help understand uncertainty in the model application. While a number of examples of linked models exist, the ability to perform automatic, unassisted linking is a step forward and provides the framework to easily implement stochastic modeling studies.

  16. Theory and Practice: An Integrative Model Linking Class and Field

    ERIC Educational Resources Information Center

    Lesser, Joan Granucci; Cooper, Marlene

    2006-01-01

    Social work has evolved over the years taking on the challenges of the times. The profession now espouses a breadth of theoretical approaches and treatment modalities. We have developed a model to help graduate social work students master the skill of integrating theory and social work practice. The Integrative Model has five components: (l) The…

  17. Response of the Italian agile frog (Rana latastei) to a Ranavirus, frog virus 3: a model for viral emergence in naïve populations.

    PubMed

    Pearman, Peter B; Garner, Trenton W J; Straub, Monika; Greber, Urs F

    2004-10-01

    Ranavirus (family Iridoviridae) is a genus of pathogens of poikilotherms, and some ranaviruses may play a role in widespread mortality of amphibians. Ecology of viral transmission in amphibians is poorly known but can be addressed through experimentation in the laboratory. In this study, we use the Ranavirus frog virus 3 (FV3) as an experimental model for pathogen emergence in naive populations of tadpoles. We simulated emerging disease by exposing tadpoles of the Italian agile frog (Rana latastei), to the North American Ranavirus FV3. We demonstrated that mortality occurred due to viral exposure, exposure of tadpoles to decreasing concentrations of FV3 in the laboratory produced dose-dependent survival rates, and cannibalism of virus-carrying carcasses increased mortality due to FV3. These experiments suggest the potential for ecological mechanisms to affect the level of exposure of tadpoles to Ranavirus and to impact transmission of viral pathogens in aquatic systems. PMID:15650083

  18. EVALUATION OF MURINE NOROVIRUS, FELINE CALICIVIRUS, POLIOVIRUS, AND MS2 AS SURROGATES FOR HUMAN NOROVIRUS IN a Model of Viral Persistence in SURFACE Water AND GROUNDWATER

    EPA Science Inventory

    Human noroviruses (NoV) are a significant cause of non bacterial gastroenteritis worldwide with contaminated drinking water a potential transmission route. The absence of a cell culture infectivity model for NoV necessitates the use of molecular methods and/or viral surrogate mod...

  19. Defining Nursing Information System Requirements: A Linked Model

    PubMed Central

    Gassert, Carole A.

    1989-01-01

    There is increasing opportunity for nurses to make decisions about information systems. The purpose of this study was: to develop a model that provides nurses with a guiding framework for deriving nursing information system requirements needed to select, evaluate, enhance or design nursing information systems (NISs); and to test the model's completeness and usefulness. Five model elements were identified from the nursing informatics literature. Structured analysis was then used to identify sub-elements and to produce a graphic model. The Model for Defining Nursing Information System Requirements (MDNISR) was tested by surveying a purposive sample of 75 registered nurses who had made decisions about NISs in hospital settings. Findings support MDNISR as a complete and useful tool for defining requirements for nursing information systems.

  20. Linking Hydrology and Atmospheric Sciences in Continental Water Dynamics Modeling

    NASA Astrophysics Data System (ADS)

    David, C. H.; Gochis, D. J.; Maidment, D. R.; Wilhelmi, O.

    2006-12-01

    Atmospheric observation and model output datasets as well as hydrologic datasets are increasingly becoming available on a continental scale. Although the availability of these datasets could allow large-scale water dynamics modeling, the different objects and semantics used in atmospheric science and hydrology set barriers to their interoperability. Recent work has demonstrated the feasibility for modeling terrestrial water dynamics for the continental United States of America. Continental water dynamics defines the interaction of the hydrosphere, the land surface and subsurface at spatial scales ranging from point to continent. The improved version of the National Hydrographic Dataset (NHDPlus, an integrated suite of geospatial datasets stored in a vector and raster GIS format) was used as hydrologic and elevation data input to the Noah community Land Surface Model, developed at NCAR. Noah was successfully run on a watershed in the Ohio River Basin with NHDPlus inputs. The use of NHDPlus as input data for Noah is a crucial improvement for community modeling efforts allowing users to by-pass much of the time consumed in Digital Elevation Model and hydrological network processing. Furthermore, the community Noah land surface model, in its hydrologically-enhanced configuration, is capable of providing flow inputs for a river dynamics model. Continued enhancement of Noah will, as a consequence, be beneficial to the atmospheric science community as well as to the hydrologic community. Ongoing research foci include using a diversity of weather drivers as an input to Noah, and investigation of how to use land surface model outputs for river forecasting, using both the ArcHydro and OpenMI frameworks.

  1. Viral infection, inflammation and schizophrenia

    PubMed Central

    Kneeland, Rachel E.; Fatemi, S. Hossein

    2012-01-01

    Schizophrenia is a severe neurodevelopmental disorder with genetic and environmental etiologies. Prenatal viral/bacterial infections and inflammation play major roles in the genesis of schizophrenia. In this review, we describe a viral model of schizophrenia tested in mice whereby the offspring of mice prenatally infected with influenza at E7, E9, E16, and E18 show significant gene, protein, and brain structural abnormalities postnatally. Similarly, we describe data on rodents exposed to bacterial infection or injected with a synthetic viral mimic (PolyI:C) also demonstrating brain structural and behavioral abnormalities. Moreover, human serologic data has been indispensible in supporting the viral theory of schizophrenia. Individuals born seropositive for bacterial and viral agents are at a significantly elevated risk of developing schizophrenia. While the specific mechanisms of prenatal viral/bacterial infections and brain disorder are unclear, recent findings suggest that the maternal inflammatory response may be associated with fetal brain injury. Preventive and therapeutic treatment options are also proposed. This review presents data related to epidemiology, human serology, and experimental animal models which support the viral model of schizophrenia. PMID:22349576

  2. A model integration framework for linking SWAT and MODFLOW

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Hydrological response and transport phenomena are driven by atmospheric, surface and subsurface processes. These complex processes occur at different spatiotemporal scales requiring comprehensive modeling to assess the impact of anthropogenic activity on hydrology and fate and transport of chemical ...

  3. Cooperative modeling: linking science, communication, and ground water planning.

    PubMed

    Tidwell, Vincent C; van den Brink, Cors

    2008-01-01

    Equitable allocation of ground water resources is a growing challenge due to both the increasing demand for water and the competing values placed on its use. While scientists can contribute to a technically defensible basis for water resource planning, this framework must be cast in a broader societal and environmental context. Given the complexity and often contentious nature of resource allocation, success requires a process for inclusive and transparent sharing of ideas complemented by tools to structure, quantify, and visualize the collective understanding and data, providing an informed basis of dialogue, exploration, and decision making. Ideally, a process that promotes shared learning leading to cooperative and adaptive planning decisions. While variously named, mediated modeling, group modeling, cooperative modeling, shared vision planning, or computer-mediated collaborative decision making are similar approaches aimed at meeting these objectives. In this paper, we frame "cooperative modeling" in the context of ground water planning and illustrate the process with two brief examples. PMID:18194321

  4. Linking Time and Space Scales in Distributed Hydrological Modelling - a case study for the VIC model

    NASA Astrophysics Data System (ADS)

    Melsen, Lieke; Teuling, Adriaan; Torfs, Paul; Zappa, Massimiliano; Mizukami, Naoki; Clark, Martyn; Uijlenhoet, Remko

    2015-04-01

    One of the famous paradoxes of the Greek philosopher Zeno of Elea (~450 BC) is the one with the arrow: If one shoots an arrow, and cuts its motion into such small time steps that at every step the arrow is standing still, the arrow is motionless, because a concatenation of non-moving parts does not create motion. Nowadays, this reasoning can be refuted easily, because we know that motion is a change in space over time, which thus by definition depends on both time and space. If one disregards time by cutting it into infinite small steps, motion is also excluded. This example shows that time and space are linked and therefore hard to evaluate separately. As hydrologists we want to understand and predict the motion of water, which means we have to look both in space and in time. In hydrological models we can account for space by using spatially explicit models. With increasing computational power and increased data availability from e.g. satellites, it has become easier to apply models at a higher spatial resolution. Increasing the resolution of hydrological models is also labelled as one of the 'Grand Challenges' in hydrology by Wood et al. (2011) and Bierkens et al. (2014), who call for global modelling at hyperresolution (~1 km and smaller). A literature survey on 242 peer-viewed articles in which the Variable Infiltration Capacity (VIC) model was used, showed that the spatial resolution at which the model is applied has decreased over the past 17 years: From 0.5 to 2 degrees when the model was just developed, to 1/8 and even 1/32 degree nowadays. On the other hand the literature survey showed that the time step at which the model is calibrated and/or validated remained the same over the last 17 years; mainly daily or monthly. Klemeš (1983) stresses the fact that space and time scales are connected, and therefore downscaling the spatial scale would also imply downscaling of the temporal scale. Is it worth the effort of downscaling your model from 1 degree to 1

  5. A Simple Model Linking Galaxy and Dark Matter Evolution

    NASA Astrophysics Data System (ADS)

    Birrer, Simon; Lilly, Simon; Amara, Adam; Paranjape, Aseem; Refregier, Alexandre

    2014-09-01

    We construct a simple phenomenological model for the evolving galaxy population by incorporating predefined baryonic prescriptions into a dark matter hierarchical merger tree. The model is based on the simple gas-regulator model introduced by Lilly et al., coupled with the empirical quenching rules of Peng et al. The simplest model already does quite well in reproducing, without re-adjusting the input parameters, many observables, including the main sequence sSFR-mass relation, the faint end slope of the galaxy mass function, and the shape of the star forming and passive mass functions. Similar to observations and/or the recent phenomenological model of Behroozi et al., which was based on epoch-dependent abundance-matching, our model also qualitatively reproduces the evolution of the main sequence sSFR(z) and SFRD(z) star formation rate density relations, the Ms - Mh stellar-to-halo mass relation, and the SFR - Mh relation. Quantitatively the evolution of sSFR(z) and SFRD(z) is not steep enough, the Ms - Mh relation is not quite peaked enough, and, surprisingly, the ratio of quenched to star forming galaxies around M* is not quite high enough. We show that these deficiencies can simultaneously be solved by ad hoc allowing galaxies to re-ingest some of the gas previously expelled in winds, provided that this is done in a mass-dependent and epoch-dependent way. These allow the model galaxies to reduce an inherent tendency to saturate their star formation efficiency, which emphasizes how efficient galaxies around M* are in converting baryons into stars and highlights the fact that quenching occurs at the point when galaxies are rapidly approaching the maximum possible efficiency of converting baryons into stars.

  6. A simple model linking galaxy and dark matter evolution

    SciTech Connect

    Birrer, Simon; Lilly, Simon; Amara, Adam; Paranjape, Aseem; Refregier, Alexandre E-mail: simon.lilly@phys.ethz.ch

    2014-09-20

    We construct a simple phenomenological model for the evolving galaxy population by incorporating predefined baryonic prescriptions into a dark matter hierarchical merger tree. The model is based on the simple gas-regulator model introduced by Lilly et al., coupled with the empirical quenching rules of Peng et al. The simplest model already does quite well in reproducing, without re-adjusting the input parameters, many observables, including the main sequence sSFR-mass relation, the faint end slope of the galaxy mass function, and the shape of the star forming and passive mass functions. Similar to observations and/or the recent phenomenological model of Behroozi et al., which was based on epoch-dependent abundance-matching, our model also qualitatively reproduces the evolution of the main sequence sSFR(z) and SFRD(z) star formation rate density relations, the M{sub s} – M{sub h} stellar-to-halo mass relation, and the SFR – M{sub h} relation. Quantitatively the evolution of sSFR(z) and SFRD(z) is not steep enough, the M{sub s} – M{sub h} relation is not quite peaked enough, and, surprisingly, the ratio of quenched to star forming galaxies around M* is not quite high enough. We show that these deficiencies can simultaneously be solved by ad hoc allowing galaxies to re-ingest some of the gas previously expelled in winds, provided that this is done in a mass-dependent and epoch-dependent way. These allow the model galaxies to reduce an inherent tendency to saturate their star formation efficiency, which emphasizes how efficient galaxies around M* are in converting baryons into stars and highlights the fact that quenching occurs at the point when galaxies are rapidly approaching the maximum possible efficiency of converting baryons into stars.

  7. Linking Essential Tremor to the Cerebellum-Animal Model Evidence.

    PubMed

    Handforth, Adrian

    2016-06-01

    In this review, we hope to stimulate interest in animal models as opportunities to understand tremor mechanisms within the cerebellar system. We begin by considering the harmaline model of essential tremor (ET), which has ET-like anatomy and pharmacology. Harmaline induces the inferior olive (IO) to burst fire rhythmically, recruiting rhythmic activity in Purkinje cells (PCs) and deep cerebellar nuclei (DCN). This model has fostered the IO hypothesis of ET, which postulates that factors that promote excess IO, and hence PC complex spike synchrony, also promote tremor. In contrast, the PC hypothesis postulates that partial PC cell loss underlies tremor of ET. We describe models in which chronic partial PC loss is associated with tremor, such as the Weaver mouse, and others with PC loss that do not show tremor, such as the Purkinje cell degeneration mouse. We postulate that partial PC loss with tremor is associated with terminal axonal sprouting. We then discuss tremor that occurs with large lesions of the cerebellum in primates. This tremor has variable frequency and is an ataxic tremor not related to ET. Another tremor type that is not likely related to ET is tremor in mice with mutations that cause prolonged synaptic GABA action. This tremor is probably due to mistiming within cerebellar circuitry. In the final section, we catalog tremor models involving neurotransmitter and ion channel perturbations. Some appear to be related to the IO hypothesis of ET, while in others tremor may be ataxic or due to mistiming. In summary, we offer a tentative framework for classifying animal action tremor, such that various models may be considered potentially relevant to ET, subscribing to IO or PC hypotheses, or not likely relevant, as with mistiming or ataxic tremor. Considerable further research is needed to elucidate the mechanisms of tremor in animal models. PMID:26660708

  8. Proportional exponentiated link transformed hazards (ELTH) models for discrete time survival data with application

    PubMed Central

    Joeng, Hee-Koung; Chen, Ming-Hui; Kang, Sangwook

    2015-01-01

    Discrete survival data are routinely encountered in many fields of study including behavior science, economics, epidemiology, medicine, and social science. In this paper, we develop a class of proportional exponentiated link transformed hazards (ELTH) models. We carry out a detailed examination of the role of links in fitting discrete survival data and estimating regression coefficients. Several interesting results are established regarding the choice of links and baseline hazards. We also characterize the conditions for improper survival functions and the conditions for existence of the maximum likelihood estimates under the proposed ELTH models. An extensive simulation study is conducted to examine the empirical performance of the parameter estimates under the Cox proportional hazards model by treating discrete survival times as continuous survival times, and the model comparison criteria, AIC and BIC, in determining links and baseline hazards. A SEER breast cancer dataset is analyzed in details to further demonstrate the proposed methodology. PMID:25772374

  9. A brain slice culture model of viral encephalitis reveals an innate CNS cytokine response profile and the therapeutic potential of caspase inhibition

    PubMed Central

    Dionne, Kalen R.; Leser, J. Smith; Lorenzen, Kristi A.; Beckham, J. David; Tyler, Kenneth L.

    2011-01-01

    Viral encephalitis is a significant cause of human morbidity and mortality in large part due to suboptimal diagnosis and treatment. Murine reovirus infection serves as a classic experimental model of viral encephalitis. Infection of neonatal mice with T3 reoviruses results in lethal encephalitis associated with neuronal infection, apoptosis, and CNS tissue injury. We have developed an ex vivo brain slice culture (BSC) system that recapitulates the basic pathological features and kinetics of viral replication seen in vivo. We utilize the BSC model to identify an innate, brain-tissue specific inflammatory cytokine response to reoviral infection, which is characterized by the release of IL6, CXCL10, RANTES, and murine IL8 analog (KC). Additionally, we demonstrate the potential utility of this system as a pharmaceutical screening platform by inhibiting reovirus-induced apoptosis and CNS tissue injury with the pan-caspase inhibitor, Q-VD-OPh. Cultured brain slices not only serve to model events occurring during viral encephalitis, but can also be utilized to investigate aspects of pathogenesis and therapy that are not experimentally accessible in vivo. PMID:21241693

  10. Characterizing cognitive aging in humans with links to animal models

    PubMed Central

    Alexander, Gene E.; Ryan, Lee; Bowers, Dawn; Foster, Thomas C.; Bizon, Jennifer L.; Geldmacher, David S.; Glisky, Elizabeth L.

    2012-01-01

    With the population of older adults expected to grow rapidly over the next two decades, it has become increasingly important to advance research efforts to elucidate the mechanisms associated with cognitive aging, with the ultimate goal of developing effective interventions and prevention therapies. Although there has been a vast research literature on the use of cognitive tests to evaluate the effects of aging and age-related neurodegenerative disease, the need for a set of standardized measures to characterize the cognitive profiles specific to healthy aging has been widely recognized. Here we present a review of selected methods and approaches that have been applied in human research studies to evaluate the effects of aging on cognition, including executive function, memory, processing speed, language, and visuospatial function. The effects of healthy aging on each of these cognitive domains are discussed with examples from cognitive/experimental and clinical/neuropsychological approaches. Further, we consider those measures that have clear conceptual and methodological links to tasks currently in use for non-human animal studies of aging, as well as those that have the potential for translation to animal aging research. Having a complementary set of measures to assess the cognitive profiles of healthy aging across species provides a unique opportunity to enhance research efforts for cross-sectional, longitudinal, and intervention studies of cognitive aging. Taking a cross-species, translational approach will help to advance cognitive aging research, leading to a greater understanding of associated neurobiological mechanisms with the potential for developing effective interventions and prevention therapies for age-related cognitive decline. PMID:22988439