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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

    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 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

  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. 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

  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. 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.

  9. 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.

  10. 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

  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. 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

  20. 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

  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 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

  3. 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

  4. 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…

  5. 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

  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. 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

  20. 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

  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. 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.

  6. 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

  7. 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

  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. 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.

  13. 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.

  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. 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.

  16. 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 ...

  17. 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.

  18. 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

  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. 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

  2. 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

  3. 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.

  4. 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

  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. 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

  10. 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

  11. 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

  12. 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

  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. 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

  15. 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.

  16. 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.

  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. 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

  1. 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.

  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. 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

  13. 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

  14. 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.

  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. 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

  4. 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

  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 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

  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

    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

  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

    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.

  10. 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

  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

    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

  13. 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

  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 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 ...

  3. 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.

  4. 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

  5. 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 ...

  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. 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

  13. 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.

  14. 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

  15. 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

  16. 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

  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. 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.

  4. 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

  5. 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

  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. 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

  8. 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

  9. 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

  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 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...

  13. 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? ...

  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. 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…

  16. 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.

  17. 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.

  18. 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

  19. 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...

  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. 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 ...

  2. 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

  3. 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

  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

    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.

  6. 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.

  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. 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

  10. 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

  11. Linking plate reconstructions with deforming lithosphere to geodynamic models

    NASA Astrophysics Data System (ADS)

    Müller, R. D.; Gurnis, M.; Flament, N.; Seton, M.; Spasojevic, S.; Williams, S.; Zahirovic, S.

    2011-12-01

    While global computational models are rapidly advancing in terms of their capabilities, there is an increasing need for assimilating observations into these models and/or ground-truthing model outputs. The open-source and platform independent GPlates software fills this gap. It was originally conceived as a tool to interactively visualize and manipulate classical rigid plate reconstructions and represent them as time-dependent topological networks of editable plate boundaries. The user can export time-dependent plate velocity meshes that can be used either to define initial surface boundary conditions for geodynamic models or alternatively impose plate motions throughout a geodynamic model run. However, tectonic plates are not rigid, and neglecting plate deformation, especially that of the edges of overriding plates, can result in significant misplacing of plate boundaries through time. A new, substantially re-engineered version of GPlates is now being developed that allows an embedding of deforming plates into topological plate boundary networks. We use geophysical and geological data to define the limit between rigid and deforming areas, and the deformation history of non-rigid blocks. The velocity field predicted by these reconstructions can then be used as a time-dependent surface boundary condition in regional or global 3-D geodynamic models, or alternatively as an initial boundary condition for a particular plate configuration at a given time. For time-dependent models with imposed plate motions (e.g. using CitcomS) we incorporate the continental lithosphere by embedding compositionally distinct crust and continental lithosphere within the thermal lithosphere. We define three isostatic columns of different thickness and buoyancy based on the tectonothermal age of the continents: Archean, Proterozoic and Phanerozoic. In the fourth isostatic column, the oceans, the thickness of the thermal lithosphere is assimilated using a half-space cooling model. We also

  12. Modeling photosynthesis of discontinuous plant canopies by linking Geometric Optical Radiative Transfer model with biochemical processes

    NASA Astrophysics Data System (ADS)

    Xin, Q.; Gong, P.; Li, W.

    2015-02-01

    Modeling vegetation photosynthesis is essential for understanding carbon exchanges between terrestrial ecosystems and the atmosphere. The radiative transfer process within plant canopies is one of the key drivers that regulate canopy photosynthesis. Most vegetation cover consists of discrete plant crowns, of which the physical observation departs from the underlying assumption of a homogenous and uniform medium in classic radiative transfer theory. Here we advance the Geometric Optical Radiative Transfer (GORT) model to simulate photosynthesis activities for discontinuous plant canopies. We separate radiation absorption into two components that are absorbed by sunlit and shaded leaves, and derive analytical solutions by integrating over the canopy layer. To model leaf-level and canopy-level photosynthesis, leaf light absorption is then linked to the biochemical process of gas diffusion through leaf stomata. The canopy gap probability derived from GORT differs from classic radiative transfer theory, especially when the leaf area index is high, due to leaf clumping effects. Tree characteristics such as tree density, crown shape, and canopy length affect leaf clumping and regulate radiation interception. Modeled gross primary production (GPP) for two deciduous forest stands could explain more than 80% of the variance of flux tower measurements at both near hourly and daily time scales. We also demonstrate that the ambient CO2 concentration influences daytime vegetation photosynthesis, which needs to be considered in state-of-the-art biogeochemical models. The proposed model is complementary to classic radiative transfer theory and shows promise in modeling the radiative transfer process and photosynthetic activities over discontinuous forest canopies.

  13. Links between fluid mechanics and quantum mechanics: a model for information in economics?

    PubMed

    Haven, Emmanuel

    2016-05-28

    This paper tallies the links between fluid mechanics and quantum mechanics, and attempts to show whether those links can aid in beginning to build a formal template which is usable in economics models where time is (a)symmetric and memory is absent or present. An objective of this paper is to contemplate whether those formalisms can allow us to model information in economics in a novel way. PMID:27091173

  14. Viral diseases and pathogenesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    It includes classification of viral infection. It describes common ways of virus entry, replication, and transmission. It introduces the routes of viral invasion and molecular basis for viral pathogenesis....

  15. Loss of HCN1 enhances disease progression in mouse models of CNG channel-linked retinitis pigmentosa and achromatopsia.

    PubMed

    Schön, Christian; Asteriti, Sabrina; Koch, Susanne; Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Herms, Jochen; Seeliger, Mathias W; Cangiano, Lorenzo; Biel, Martin; Michalakis, Stylianos

    2016-03-15

    Most inherited blinding diseases are characterized by compromised retinal function and progressive degeneration of photoreceptors. However, the factors that affect the life span of photoreceptors in such degenerative retinal diseases are rather poorly understood. Here, we explore the role of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) in this context. HCN1 is known to adjust retinal function under mesopic conditions, and although it is expressed at high levels in rod and cone photoreceptor inner segments, no association with any retinal disorder has yet been found. We investigated the effects of an additional genetic deletion of HCN1 on the function and survival of photoreceptors in a mouse model of CNGB1-linked retinitis pigmentosa (RP). We found that the absence of HCN1 in Cngb1 knockout (KO) mice exacerbated photoreceptor degeneration. The deleterious effect was reduced by expression of HCN1 using a viral vector. Moreover, pharmacological inhibition of HCN1 also enhanced rod degeneration in Cngb1 KO mice. Patch-clamp recordings revealed that the membrane potentials of Cngb1 KO and Cngb1/Hcn1 double-KO rods were both significantly depolarized. We also found evidence for altered calcium homeostasis and increased activation of the protease calpain in Cngb1/Hcn1 double-KO mice. Finally, the deletion of HCN1 also exacerbated degeneration of cone photoreceptors in a mouse model of CNGA3-linked achromatopsia. Our results identify HCN1 as a major modifier of photoreceptor degeneration and suggest that pharmacological inhibition of HCN channels may enhance disease progression in RP and achromatopsia patients. PMID:26740549

  16. Shuttle Communications and Tracking Systems Modeling and TDRSS Link Simulations Studies

    NASA Technical Reports Server (NTRS)

    Chie, C. M.; Dessouky, K.; Lindsey, W. C.; Tsang, C. S.; Su, Y. T.

    1985-01-01

    An analytical simulation package (LinCsim) which allows the analytical verification of data transmission performance through TDRSS satellites was modified. The work involved the modeling of the user transponder, TDRS, TDRS ground terminal, and link dynamics for forward and return links based on the TDRSS performance specifications (4) and the critical design reviews. The scope of this effort has recently been expanded to include the effects of radio frequency interference (RFI) on the bit error rate (BER) performance of the S-band return links. The RFI environment and the modified TDRSS satellite and ground station hardware are being modeled in accordance with their description in the applicable documents.

  17. Linking Models: Reasoning from Patterns to Tables and Equations

    ERIC Educational Resources Information Center

    Switzer, J. Matt

    2013-01-01

    Patterns are commonly used in middle years mathematics classrooms to teach students about functions and modelling with tables, graphs, and equations. Grade 6 students are expected to, "continue and create sequences involving whole numbers, fractions and decimals," and "describe the rule used to create the sequence." (Australian…

  18. Functional regulation of PVBV Nuclear Inclusion protein-a protease activity upon interaction with Viral Protein genome-linked and phosphorylation

    SciTech Connect

    Mathur, C.; Jimsheena, V.K.; Banerjee, S.; Makinen, K.; Gowda, L.R.; Savithri, H.S.

    2012-01-20

    Regulation of NIa-Pro is crucial for polyprotein processing and hence, for successful infection of potyviruses. We have examined two novel mechanisms that could regulate NIa-Pro activity. Firstly, the influence of VPg domain on the proteolytic activity of NIa-Pro was investigated. It was shown that the turnover number of the protease increases when these two domains interact (cis: two-fold; trans: seven-fold) with each other. Secondly, the protease activity of NIa-Pro could also be modulated by phosphorylation at Ser129. A mutation of this residue either to aspartate (phosphorylation-mimic) or alanine (phosphorylation-deficient) drastically reduces the protease activity. Based on these observations and molecular modeling studies, we propose that interaction with VPg as well as phosphorylation of Ser129 could relay a signal through Trp143 present at the protein surface to the active site pocket by subtle conformational changes, thus modulating protease activity of NIa-Pro.

  19. An integrative model linking feedback environment and organizational citizenship behavior.

    PubMed

    Peng, Jei-Chen; Chiu, Su-Fen

    2010-01-01

    Past empirical evidence has suggested that a positive supervisor feedback environment may enhance employees' organizational citizenship behavior (OCB). In this study, we aim to extend previous research by proposing and testing an integrative model that examines the mediating processes underlying the relationship between supervisor feedback environment and employee OCB. Data were collected from 259 subordinate-supervisor dyads across a variety of organizations in Taiwan. We used structural equation modeling to test our hypotheses. The results demonstrated that supervisor feedback environment influenced employees' OCB indirectly through (1) both positive affective-cognition and positive attitude (i.e., person-organization fit and organizational commitment), and (2) both negative affective-cognition and negative attitude (i.e., role stressors and job burnout). Theoretical and practical implications are discussed. PMID:21166326

  20. Linking agent-based models and stochastic models of financial markets.

    PubMed

    Feng, Ling; Li, Baowen; Podobnik, Boris; Preis, Tobias; Stanley, H Eugene

    2012-05-29

    It is well-known that financial asset returns exhibit fat-tailed distributions and long-term memory. These empirical features are the main objectives of modeling efforts using (i) stochastic processes to quantitatively reproduce these features and (ii) agent-based simulations to understand the underlying microscopic interactions. After reviewing selected empirical and theoretical evidence documenting the behavior of traders, we construct an agent-based model to quantitatively demonstrate that "fat" tails in return distributions arise when traders share similar technical trading strategies and decisions. Extending our behavioral model to a stochastic model, we derive and explain a set of quantitative scaling relations of long-term memory from the empirical behavior of individual market participants. Our analysis provides a behavioral interpretation of the long-term memory of absolute and squared price returns: They are directly linked to the way investors evaluate their investments by applying technical strategies at different investment horizons, and this quantitative relationship is in agreement with empirical findings. Our approach provides a possible behavioral explanation for stochastic models for financial systems in general and provides a method to parameterize such models from market data rather than from statistical fitting. PMID:22586086

  1. Linking agent-based models and stochastic models of financial markets

    PubMed Central

    Feng, Ling; Li, Baowen; Podobnik, Boris; Preis, Tobias; Stanley, H. Eugene

    2012-01-01

    It is well-known that financial asset returns exhibit fat-tailed distributions and long-term memory. These empirical features are the main objectives of modeling efforts using (i) stochastic processes to quantitatively reproduce these features and (ii) agent-based simulations to understand the underlying microscopic interactions. After reviewing selected empirical and theoretical evidence documenting the behavior of traders, we construct an agent-based model to quantitatively demonstrate that “fat” tails in return distributions arise when traders share similar technical trading strategies and decisions. Extending our behavioral model to a stochastic model, we derive and explain a set of quantitative scaling relations of long-term memory from the empirical behavior of individual market participants. Our analysis provides a behavioral interpretation of the long-term memory of absolute and squared price returns: They are directly linked to the way investors evaluate their investments by applying technical strategies at different investment horizons, and this quantitative relationship is in agreement with empirical findings. Our approach provides a possible behavioral explanation for stochastic models for financial systems in general and provides a method to parameterize such models from market data rather than from statistical fitting. PMID:22586086

  2. Microbial Life in Soil - Linking Biophysical Models with Observations

    NASA Astrophysics Data System (ADS)

    Or, D.; Tecon, R.; Ebrahimi, A.; Kleyer, H.; Ilie, O.; Wang, G.

    2014-12-01

    Microbial life in soil occurs within fragmented aquatic habitats in complex pore spaces where motility is restricted to short hydration windows (e.g., following rainfall). The limited range of self-dispersion and physical confinement promote spatial association among trophically interdepended microbial species. Competition and preferences for different nutrient resources and byproducts and their diffusion require high level of spatial organization to sustain the functioning of multispecies communities. We report mechanistic modeling studies of competing multispecies microbial communities grown on hydrated surfaces and within artificial soil aggregates (represented by 3-D pore network). Results show how trophic dependencies and cell-level interactions within patchy diffusion fields promote spatial self-organization of motile microbial cells. The spontaneously forming patterns of segregated, yet coexisting species were robust to spatial heterogeneities and to temporal perturbations (hydration dynamics), and respond primarily to the type of trophic dependencies. Such spatially self-organized consortia may reflect ecological templates that optimize substrate utilization and could form the basic architecture for more permanent surface-attached microbial colonies. Hydration dynamics affect structure and spatial arrangement of aerobic and anaerobic microbial communities and their biogeochemical functions. Experiments with well-characterized artificial soil microbial assemblies grown on porous surfaces provide access to community dynamics during wetting and drying cycles detected through genetic fingerprinting. Experiments for visual observations of spatial associations of tagged bacterial species with known trophic dependencies on model porous surfaces are underway. Biophysical modeling provide a means for predicting hydration-mediated critical separation distances for activation of spatial self-organization. The study provides new modeling and observational tools that

  3. Microbial Life in Soil - Linking Biophysical Models with Observations

    NASA Astrophysics Data System (ADS)

    Or, Dani; Tecon, Robin; Ebrahimi, Ali; Kleyer, Hannah; Ilie, Olga; Wang, Gang

    2015-04-01

    Microbial life in soil occurs within fragmented aquatic habitats formed in complex pore spaces where motility is restricted to short hydration windows (e.g., following rainfall). The limited range of self-dispersion and physical confinement promote spatial association among trophically interdepended microbial species. Competition and preferences for different nutrient resources and byproducts and their diffusion require high level of spatial organization to sustain the functioning of multispecies communities. We report mechanistic modeling studies of competing multispecies microbial communities grown on hydrated surfaces and within artificial soil aggregates (represented by 3-D pore network). Results show how trophic dependencies and cell-level interactions within patchy diffusion fields promote spatial self-organization of motile microbial cells. The spontaneously forming patterns of segregated, yet coexisting species were robust to spatial heterogeneities and to temporal perturbations (hydration dynamics), and respond primarily to the type of trophic dependencies. Such spatially self-organized consortia may reflect ecological templates that optimize substrate utilization and could form the basic architecture for more permanent surface-attached microbial colonies. Hydration dynamics affect structure and spatial arrangement of aerobic and anaerobic microbial communities and their biogeochemical functions. Experiments with well-characterized artificial soil microbial assemblies grown on porous surfaces provide access to community dynamics during wetting and drying cycles detected through genetic fingerprinting. Experiments for visual observations of spatial associations of tagged bacterial species with known trophic dependencies on model porous surfaces are underway. Biophysical modeling provide a means for predicting hydration-mediated critical separation distances for activation of spatial self-organization. The study provides new modeling and observational tools

  4. Cross Linking and Degradation Mechanisms in Model Sealant Candidates

    NASA Technical Reports Server (NTRS)

    Paciorek, K. L.; Kaufman, J.; Ito, T. I.; Nakahara, J. H.; Kratzer, R. H.

    1977-01-01

    Model compounds were investigated as to which type of heterocyclic ring is the most advantageous for curing sealants based on perfluoroalkylether chains. The relative thermal, thermal oxidative, hydrolytic, and fuel stability of potential crosslinks were determined. Specifically substituted materials were synthesized and evaluation of their stabilities in air, inert atmosphere, water, and Jet-A fuel at 235 and 325 C was made. Three heterocyclic ring systems were considered, namely, triazine, 1,2,4- and 1,3,4-oxadiazoles.

  5. Modeling Prairie Pothole Lakes: Linking Satellite Observation and Calibration (Invited)

    NASA Astrophysics Data System (ADS)

    Schwartz, F. W.; Liu, G.; Zhang, B.; Yu, Z.

    2009-12-01

    This paper examines the response of a complex lake wetland system to variations in climate. The focus is on the lakes and wetlands of the Missouri Coteau, which is part of the larger Prairie Pothole Region of the Central Plains of North America. Information on lake size was enumerated from satellite images, and yielded power law relationships for different hydrological conditions. More traditional lake-stage data were made available to us from the USGS Cottonwood Lake Study Site in North Dakota. A Probabilistic Hydrologic Model (PHM) was developed to simulate lake complexes comprised of tens-of-thousands or more individual closed-basin lakes and wetlands. What is new about this model is a calibration scheme that utilizes remotely-sensed data on lake area as well as stage data for individual lakes. Some ¼ million individual data points are used within a Genetic Algorithm to calibrate the model by comparing the simulated results with observed lake area-frequency power law relationships derived from Landsat images and water depths from seven individual lakes and wetlands. The simulated lake behaviors show good agreement with the observations under average, dry, and wet climatic conditions. The calibrated model is used to examine the impact of climate variability on a large lake complex in ND, in particular, the “Dust Bowl Drought” 1930s. This most famous drought of the 20th Century devastated the agricultural economy of the Great Plains with health and social impacts lingering for years afterwards. Interestingly, the drought of 1930s is unremarkable in relation to others of greater intensity and frequency before AD 1200 in the Great Plains. Major droughts and deluges have the ability to create marked variability of the power law function (e.g. up to one and a half orders of magnitude variability from the extreme Dust Bowl Drought to the extreme 1993-2001 deluge). This new probabilistic modeling approach provides a novel tool to examine the response of the

  6. Linking continuous and discrete intervertebral disc models through homogenisation.

    PubMed

    Karajan, N; Röhrle, O; Ehlers, W; Schmitt, S

    2013-06-01

    At present, there are two main numerical approaches that are frequently used to simulate the mechanical behaviour of the human spine. Researchers with a continuum-mechanical background often utilise the finite-element method (FEM), where the involved biological soft and hard tissues are modelled on a macroscopic (continuum) level. In contrast, groups associated with the science of human movement usually apply discrete multi-body systems (MBS). Herein, the bones are modelled as rigid bodies, which are connected by Hill-type muscles and non-linear rheological spring-dashpot models to represent tendons and cartilaginous connective tissue like intervertebral discs (IVD). A possibility to benefit from both numerical methods is to couple them and use each approach, where it is most appropriate. Herein, the basic idea is to utilise MBS in simulations of the overall body and apply the FEM only to selected regions of interest. In turn, the FEM is used as homogenisation tool, which delivers more accurate non-linear relationships describing the behaviour of the IVD in the multi-body dynamics model. The goal of this contribution is to present an approach to couple both numerical methods without the necessity to apply a gluing algorithm in the context of a co-simulation. Instead, several pre-computations of the intervertebral disc are performed offline to generate an approximation of the homogenised finite-element (FE) result. In particular, the discrete degrees of freedom (DOF) of the MBS, that is, three displacements and three rotations, are applied to the FE model of the IVD, and the resulting homogenised forces and moments are recorded. Moreover, a polynomial function is presented with the discrete DOF of the MBS as variables and the discrete forces an moments as function values. For the sake of a simple verification, the coupling method is applied to a simplified motion segment of the spine. Herein, two stiff cylindrical vertebrae with an interjacent homogeneous

  7. Viral hepatitis: A new HCV cell culture model for the next clinical challenges.

    PubMed

    Colpitts, Che C; Baumert, Thomas F

    2015-11-01

    Despite advances in hepatitis C treatment, substantial clinical hurdles remain to achieve universal cure and global control of infection. Saeed et al. identified SEC14L2 as a host factor permitting replication of clinical HCV isolates in cell culture, providing a novel system to model infection of patient-derived viruses. PMID:26441247

  8. Zika in the Brain: New Models Shed Light on Viral Infection.

    PubMed

    Hickman, Heather D; Pierson, Theodore C

    2016-08-01

    The current Zika virus (ZIKV) outbreak is associated with high numbers of human congenital birth defects, yet it has been unclear how ZIKV infection during pregnancy causes these abnormalities. Three new mouse models now show that ZIKV crosses the placenta and replicates in the brains of fetal mice. PMID:27345865

  9. Promoting remyelination: utilizing a viral model of demyelination to assess cell-based therapies

    PubMed Central

    Marro, Brett S; Blanc, Caroline A; Loring, Jeanne F; Cahalan, Michael D; Lane, Thomas E

    2014-01-01

    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS. While a broad range of therapeutics effectively reduce the incidence of focal white matter inflammation and plaque formation for patients with relapse-remitting forms of MS, a challenge within the field is to develop therapies that allow for axonal protection and remyelination. In the last decade, growing interest has focused on utilizing neural precursor cells (NPCs) to promote remyelination. To understand how NPCs function in chronic demyelinating environments, several excellent pre-clinical mouse models have been developed. One well accepted model is infection of susceptible mice with neurotropic variants of mouse hepatitis virus (MHV) that undergo chronic demyelination exhibiting clinical and histopathologic similarities to MS patients. Combined with the possibility that an environmental agent such as a virus could trigger MS, the MHV model of demyelination presents a relevant mouse model to assess the therapeutic potential of NPCs transplanted into an environment in which inflammatory-mediated demyelination is established. PMID:25245576

  10. LINKING THE CMAQ AND HYSPLIT MODELING SYSTEM INTERFACE PROGRAM AND EXAMPLE APPLICATION

    EPA Science Inventory

    A new software tool has been developed to link the Eulerian-based Community Multiscale Air Quality (CMAQ) modeling system with the Lagrangian-based HYSPLIT (HYbrid Single-Particle Lagrangian Integrated Trajectory) model. Both models require many of the same hourly meteorological...

  11. A Dual-Process Model of the Alcohol-Behavior Link for Social Drinking

    ERIC Educational Resources Information Center

    Moss, Antony C.; Albery, Ian P.

    2009-01-01

    A dual-process model of the alcohol-behavior link is presented, synthesizing 2 of the major social-cognitive approaches: expectancy and myopia theories. Substantial evidence has accrued to support both of these models, and recent neurocognitive models of the effects of alcohol on thought and behavior have provided evidence to support both as well.…

  12. Viral Parkinsonism

    PubMed Central

    Jang, Haeman; Boltz, David A.; Webster, Robert G.; Smeyne, Richard Jay

    2015-01-01

    Parkinson's disease is a debilitating neurological disorder characterized that affects 1-2% of the adult population over 55 years of age. For the vast majority of cases, the etiology of this disorder is unknown, although it is generally accepted that there is a genetic susceptibility to any number of environmental agents. One such agent may be viruses. It has been shown that numerous viruses can enter the nervous system, i.e. they are neurotropic, and induce a number of encephalopathies. One of the secondary consequences of these encephalopathies can be parkinsonism, that is both transient as well as permanent. One of the most highlighted and controversial cases of viral parkinsonism is that which followed the 1918 influenza outbreak and the subsequent induction of von Economo's encephalopathy. In this review, we discuss the neurological sequelae of infection by influenza virus as well as that of other viruses known to induce parkinsonism including Coxsackie, Japanese encephalitis B, St. Louis, West Nile and HIV viruses. PMID:18760350

  13. Model analysis of the link between interest rates and crashes

    NASA Astrophysics Data System (ADS)

    Broga, Kristijonas M.; Viegas, Eduardo; Jensen, Henrik Jeldtoft

    2016-09-01

    We analyse the effect of distinct levels of interest rates on the stability of the financial network under our modelling framework. We demonstrate that banking failures are likely to emerge early on under sustained high interest rates, and at much later stage-with higher probability-under a sustained low interest rate scenario. Moreover, we demonstrate that those bank failures are of a different nature: high interest rates tend to result in significantly more bankruptcies associated to credit losses whereas lack of liquidity tends to be the primary cause of failures under lower rates.

  14. Linking seasonal climate forecasts with crop models in Iberian Peninsula

    NASA Astrophysics Data System (ADS)

    Capa, Mirian; Ines, Amor; Baethgen, Walter; Rodriguez-Fonseca, Belen; Han, Eunjin; Ruiz-Ramos, Margarita

    2015-04-01

    Translating seasonal climate forecasts into agricultural production forecasts could help to establish early warning systems and to design crop management adaptation strategies that take advantage of favorable conditions or reduce the effect of adverse conditions. In this study, we use seasonal rainfall forecasts and crop models to improve predictability of wheat yield in the Iberian Peninsula (IP). Additionally, we estimate economic margins and production risks associated with extreme scenarios of seasonal rainfall forecast. This study evaluates two methods for disaggregating seasonal climate forecasts into daily weather data: 1) a stochastic weather generator (CondWG), and 2) a forecast tercile resampler (FResampler). Both methods were used to generate 100 (with FResampler) and 110 (with CondWG) weather series/sequences for three scenarios of seasonal rainfall forecasts. Simulated wheat yield is computed with the crop model CERES-wheat (Ritchie and Otter, 1985), which is included in Decision Support System for Agrotechnology Transfer (DSSAT v.4.5, Hoogenboom et al., 2010). Simulations were run at two locations in northeastern Spain where the crop model was calibrated and validated with independent field data. Once simulated yields were obtained, an assessment of farmer's gross margin for different seasonal climate forecasts was accomplished to estimate production risks under different climate scenarios. This methodology allows farmers to assess the benefits and risks of a seasonal weather forecast in IP prior to the crop growing season. The results of this study may have important implications on both, public (agricultural planning) and private (decision support to farmers, insurance companies) sectors. Acknowledgements Research by M. Capa-Morocho has been partly supported by a PICATA predoctoral fellowship of the Moncloa Campus of International Excellence (UCM-UPM) and MULCLIVAR project (CGL2012-38923-C02-02) References Hoogenboom, G. et al., 2010. The Decision

  15. Modelling Optimal Control of Cholera in Communities Linked by Migration.

    PubMed

    Njagarah, J B H; Nyabadza, F

    2015-01-01

    A mathematical model for the dynamics of cholera transmission with permissible controls between two connected communities is developed and analysed. The dynamics of the disease in the adjacent communities are assumed to be similar, with the main differences only reflected in the transmission and disease related parameters. This assumption is based on the fact that adjacent communities often have different living conditions and movement is inclined toward the community with better living conditions. Community specific reproduction numbers are given assuming movement of those susceptible, infected, and recovered, between communities. We carry out sensitivity analysis of the model parameters using the Latin Hypercube Sampling scheme to ascertain the degree of effect the parameters and controls have on progression of the infection. Using principles from optimal control theory, a temporal relationship between the distribution of controls and severity of the infection is ascertained. Our results indicate that implementation of controls such as proper hygiene, sanitation, and vaccination across both affected communities is likely to annihilate the infection within half the time it would take through self-limitation. In addition, although an infection may still break out in the presence of controls, it may be up to 8 times less devastating when compared with the case when no controls are in place. PMID:26246850

  16. Modelling Optimal Control of Cholera in Communities Linked by Migration

    PubMed Central

    Njagarah, J. B. H.; Nyabadza, F.

    2015-01-01

    A mathematical model for the dynamics of cholera transmission with permissible controls between two connected communities is developed and analysed. The dynamics of the disease in the adjacent communities are assumed to be similar, with the main differences only reflected in the transmission and disease related parameters. This assumption is based on the fact that adjacent communities often have different living conditions and movement is inclined toward the community with better living conditions. Community specific reproduction numbers are given assuming movement of those susceptible, infected, and recovered, between communities. We carry out sensitivity analysis of the model parameters using the Latin Hypercube Sampling scheme to ascertain the degree of effect the parameters and controls have on progression of the infection. Using principles from optimal control theory, a temporal relationship between the distribution of controls and severity of the infection is ascertained. Our results indicate that implementation of controls such as proper hygiene, sanitation, and vaccination across both affected communities is likely to annihilate the infection within half the time it would take through self-limitation. In addition, although an infection may still break out in the presence of controls, it may be up to 8 times less devastating when compared with the case when no controls are in place. PMID:26246850

  17. Upregulation of the cannabinoid CB2 receptor in environmental and viral inflammation-driven rat models of Parkinson's disease.

    PubMed

    Concannon, Ruth M; Okine, Bright N; Finn, David P; Dowd, Eilís

    2016-09-01

    In recent years, it has become evident that Parkinson's disease is associated with a self-sustaining cycle of neuroinflammation and neurodegeneration, with dying neurons activating microglia, which, once activated, can release several factors that kill further neurons. One emerging pharmacological target that has the potential to break this cycle is the microglial CB2 receptor which, when activated, can suppress microglial activity and reduce their neurotoxicity. However, very little is known about CB2 receptor expression in animal models of Parkinson's disease which is essential for valid preclinical assessment of the anti-Parkinsonian efficacy of drugs targeting the CB2 receptor. Therefore, the aim of this study was to investigate and compare the changes that occur in CB2 receptor expression in environmental and inflammation-driven models of Parkinson's disease. To do so, male Sprague Dawley rats were given unilateral, intra-striatal injections of the Parkinson's disease-associated agricultural pesticide, rotenone, or the viral-like inflammagen, polyinosinic:polycytidylic acid (Poly (I:C)). Animals underwent behavioural testing for motor dysfunction on days 7, 14 and 28 post-surgery, and were sacrificed on days 1, 4, 14 and 28. Changes in the endocannabinoid system and neuroinflamamtion were investigated by qRT-PCR, liquid chromatography-mass spectrometry and immunohistochemistry. After injection of rotenone or Poly (I:C) into the rat striatum, we found that expression of the CB2 receptor was significantly elevated in both models, and that this increase correlated significantly with an increase in microglial activation in the rotenone model. Interestingly, the increase in CB2 receptor expression in the inflammation-driven Poly (I:C) model was significantly more pronounced than that in the neurotoxic rotenone model. Thus, this study has shown that CB2 receptor expression is dysregulated in animal models of Parkinson's disease, and has also revealed significant

  18. Conditions for Viral Influence Spreading through Multiplex Correlated Social Networks

    NASA Astrophysics Data System (ADS)

    Hu, Yanqing; Havlin, Shlomo; Makse, Hernán A.

    2014-04-01

    A fundamental problem in network science is to predict how certain individuals are able to initiate new networks to spring up "new ideas." Frequently, these changes in trends are triggered by a few innovators who rapidly impose their ideas through "viral" influence spreading, producing cascades of followers and fragmenting an old network to create a new one. Typical examples include the rise of scientific ideas or abrupt changes in social media, like the rise of Facebook to the detriment of Myspace. How this process arises in practice has not been conclusively demonstrated. Here, we show that a condition for sustaining a viral spreading process is the existence of a multiplex-correlated graph with hidden "influence links." Analytical solutions predict percolation-phase transitions, either abrupt or continuous, where networks are disintegrated through viral cascades of followers, as in empirical data. Our modeling predicts the strict conditions to sustain a large viral spreading via a scaling form of the local correlation function between multilayers, which we also confirm empirically. Ultimately, the theory predicts the conditions for viral cascading in a large class of multiplex networks ranging from social to financial systems and markets.

  19. Horizontal gene transfer in eukaryotes: The weak-link model

    PubMed Central

    Huang, Jinling

    2013-01-01

    The significance of horizontal gene transfer (HGT) in eukaryotic evolution remains controversial. Although many eukaryotic genes are of bacterial origin, they are often interpreted as being derived from mitochondria or plastids. Because of their fixed gene pool and gene loss, however, mitochondria and plastids alone cannot adequately explain the presence of all, or even the majority, of bacterial genes in eukaryotes. Available data indicate that no insurmountable barrier to HGT exists, even in complex multicellular eukaryotes. In addition, the discovery of both recent and ancient HGT events in all major eukaryotic groups suggests that HGT has been a regular occurrence throughout the history of eukaryotic evolution. A model of HGT is proposed that suggests both unicellular and early developmental stages as likely entry points for foreign genes into multicellular eukaryotes. PMID:24037739

  20. Adeno-Associated Viral-Mediated LARGE Gene Therapy Rescues the Muscular Dystrophic Phenotype in Mouse Models of Dystroglycanopathy

    PubMed Central

    Yu, Miao; He, Yonglin; Wang, Kejian; Zhang, Peng; Zhang, Shengle

    2013-01-01

    Abstract Dystroglycanopathies are a group of congenital muscular dystrophies (CMD) often caused by mutations in genes encoding glycosyltransferases that lead to hypoglycosylation of α-dystroglycan (α-DG) and reduce its extracellular matrix-binding activity. Overexpressing LARGE (formerly known as like-glycosyltransferase) generates an extracellular matrix-binding carbohydrate epitope in cells with CMD-causing mutations in not only LARGE but also other glycosyltransferases, including POMT1, POMGnT1, and fukutin, creating the possibilities of a one-for-all gene therapy. To determine the feasibility of LARGE gene therapy, a serotype 9 adeno-associated viral vector for overexpressing LARGE (AAV9-LARGE) was injected intracardially into newborns of two mouse models of CMD: the natural LARGE mutant Largemyd mice and protein O-mannose N-acetylglucosaminyltransferase 1 (POMGnT1) knockout mice. AAV9-LARGE virus treatment yielded partial restoration of α-DG glycosylation and ligand-binding activity. The muscular dystrophy phenotype in skeletal muscles was ameliorated as revealed by significantly reduced fibrosis, necrosis, and numbers of centrally located nuclei with improved motor function. These results indicate that LARGE overexpression in vivo by AAV9-mediated gene therapy is effective at restoring functional glycosylation of α-DG and rescuing the muscular dystrophy phenotype in deficiency of not only LARGE but also POMGnT1, providing evidence that in vivo LARGE gene therapy may be broadly useful in dystroglycanopathies. PMID:23379513

  1. Porous Hyaluronic Acid Hydrogels for Localized Non-Viral DNA Delivery in a Diabetic Wound Healing Model

    PubMed Central

    Tokatlian, Talar; Cam, Cynthia; Segura, Tatiana

    2015-01-01

    The treatment of impaired wounds requires the use of biomaterials that can provide mechanical and biological queues to the surrounding environment to promote angiogenesis, granulation tissue formation, and wound closure. Porous hydrogels have previously been shown to promote angiogenesis even in the absence of pro-angiogenic factors. We hypothesized that the added delivery of non-viral DNA encoding for pro-angiogenic growth factors could further enhance this effect. Here, 100 and 60 μm porous and non-porous (n-pore) hyaluronic acid-MMP hydrogels with encapsulated reporter (pGFPluc) or pro-angiogenic (pVEGF) plasmids were used to investigate scaffold-mediated gene delivery for local gene therapy in a diabetic wound healing mouse model. Porous hydrogels allowed for significantly faster wound closure compared to n-pore hydrogels, which did not degrade and essentially provided a mechanical barrier to closure. Interestingly, the delivery of pDNA/PEI polyplexes positively promoted granulation tissue formation even when the DNA did not encode for an angiogenic protein. And although transfected cells were present throughout the granulation tissue surrounding all hydrogels at 2 weeks, pVEGF delivery did not further enhance the angiogenic response. Despite this, the presence of transfected cells shows promise for the use of polyplex-loaded porous hydrogels for local gene delivery in the treatment of diabetic wounds. PMID:25694196

  2. Adeno-associated viral-mediated LARGE gene therapy rescues the muscular dystrophic phenotype in mouse models of dystroglycanopathy.

    PubMed

    Yu, Miao; He, Yonglin; Wang, Kejian; Zhang, Peng; Zhang, Shengle; Hu, Huaiyu

    2013-03-01

    Dystroglycanopathies are a group of congenital muscular dystrophies (CMD) often caused by mutations in genes encoding glycosyltransferases that lead to hypoglycosylation of α-dystroglycan (α-DG) and reduce its extracellular matrix-binding activity. Overexpressing LARGE (formerly known as like-glycosyltransferase) generates an extracellular matrix-binding carbohydrate epitope in cells with CMD-causing mutations in not only LARGE but also other glycosyltransferases, including POMT1, POMGnT1, and fukutin, creating the possibilities of a one-for-all gene therapy. To determine the feasibility of LARGE gene therapy, a serotype 9 adeno-associated viral vector for overexpressing LARGE (AAV9-LARGE) was injected intracardially into newborns of two mouse models of CMD: the natural LARGE mutant Large(myd) mice and protein O-mannose N-acetylglucosaminyltransferase 1 (POMGnT1) knockout mice. AAV9-LARGE virus treatment yielded partial restoration of α-DG glycosylation and ligand-binding activity. The muscular dystrophy phenotype in skeletal muscles was ameliorated as revealed by significantly reduced fibrosis, necrosis, and numbers of centrally located nuclei with improved motor function. These results indicate that LARGE overexpression in vivo by AAV9-mediated gene therapy is effective at restoring functional glycosylation of α-DG and rescuing the muscular dystrophy phenotype in deficiency of not only LARGE but also POMGnT1, providing evidence that in vivo LARGE gene therapy may be broadly useful in dystroglycanopathies. PMID:23379513

  3. Linking Air Quality and Watershed Models for Environmental Assessments: Analysis of the Effects of Model-Specific Precipitation Estimates on Calculated Water Flux

    EPA Science Inventory

    Directly linking air quality and watershed models could provide an effective method for estimating spatially-explicit inputs of atmospheric contaminants to watershed biogeochemical models. However, to adequately link air and watershed models for wet deposition estimates, each mod...

  4. Mathematical Model of Viral Kinetics In Vitro Estimates the Number of E2-CD81 Complexes Necessary for Hepatitis C Virus Entry

    PubMed Central

    Padmanabhan, Pranesh; Dixit, Narendra M.

    2011-01-01

    Interaction between the hepatitis C virus (HCV) envelope protein E2 and the host receptor CD81 is essential for HCV entry into target cells. The number of E2-CD81 complexes necessary for HCV entry has remained difficult to estimate experimentally. Using the recently developed cell culture systems that allow persistent HCV infection in vitro, the dependence of HCV entry and kinetics on CD81 expression has been measured. We reasoned that analysis of the latter experiments using a mathematical model of viral kinetics may yield estimates of the number of E2-CD81 complexes necessary for HCV entry. Here, we constructed a mathematical model of HCV viral kinetics in vitro, in which we accounted explicitly for the dependence of HCV entry on CD81 expression. Model predictions of viral kinetics are in quantitative agreement with experimental observations. Specifically, our model predicts triphasic viral kinetics in vitro, where the first phase is characterized by cell proliferation, the second by the infection of susceptible cells and the third by the growth of cells refractory to infection. By fitting model predictions to the above data, we were able to estimate the threshold number of E2-CD81 complexes necessary for HCV entry into human hepatoma-derived cells. We found that depending on the E2-CD81 binding affinity, between 1 and 13 E2-CD81 complexes are necessary for HCV entry. With this estimate, our model captured data from independent experiments that employed different HCV clones and cells with distinct CD81 expression levels, indicating that the estimate is robust. Our study thus quantifies the molecular requirements of HCV entry and suggests guidelines for intervention strategies that target the E2-CD81 interaction. Further, our model presents a framework for quantitative analyses of cell culture studies now extensively employed to investigate HCV infection. PMID:22174670

  5. Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy

    PubMed Central

    Blanchard, Miran; Shim, Kevin G.; Grams, Michael P.; Rajani, Karishma; Diaz, Rosa M.; Furutani, Keith M.; Thompson, Jill; Olivier, Kenneth R.; Park, Sean S.; Markovic, Svetomir N.; Pandha, Hardev; Melcher, Alan; Harrington, Kevin; Zaidi, Shane; Vile, Richard

    2016-01-01

    Purpose The oligometastatic state is an intermediate state between a malignancy that can be completely eradicated with conventional modalities and one in which a palliative approach is undertaken. Clinically, high rates of local tumor control are possible with stereotactic ablative radiation therapy (SABR), using precisely targeted, high-dose, low-fraction radiation therapy. However, in oligometastatic melanoma, virtually all patients develop progression systemically at sites not initially treated with ablative radiation therapy that cannot be managed with conventional chemotherapy and immunotherapy. We have demonstrated in mice that intravenous administration of vesicular stomatitis virus (VSV) expressing defined tumor-associated antigens (TAAs) generates systemic immune responses capable of clearing established tumors. Therefore, in the present preclinical study, we tested whether the combination of systemic VSV-mediated antigen delivery and SABR would be effective against oligometastatic disease. Methods and Materials We generated a model of oligometastatic melanoma in C57BL/6 immunocompetent mice and then used a combination of SABR and systemically administered VSV-TAA viral immunotherapy to treat both local and systemic disease. Results Our data showed that SABR generates excellent control or cure of local, clinically detectable, and accessible tumor through direct cell ablation. Also, the immunotherapeutic activity of systemically administered VSV-TAA generated T-cell responses that cleared subclinical metastatic tumors. We also showed that SABR induced weak T-cell-mediated tumor responses, which, particularly if boosted by VSV−TAA, might contribute to control of local and systemic disease. In addition, VSV−TAA therapy alone had significant effects on control of both local and metastatic tumors. Conclusions We have shown in the present preliminary murine study using a single tumor model that this approach represents an effective, complementary combination

  6. Simulating the link between ENSO and summer drought in Southern Africa using regional climate models

    NASA Astrophysics Data System (ADS)

    Meque, Arlindo; Abiodun, Babatunde J.

    2015-04-01

    This study evaluates the capability of regional climate models (RCMs) in simulating the link between El Niño Southern Oscillation (ENSO) and Southern African droughts. It uses the Standardized Precipitation-Evapotranspiration Index (SPEI, computed using rainfall and temperature data) to identify 3-month drought over Southern Africa, and compares the observed and simulated correlation between ENSO and SPEI. The observation data are from the Climate Research Unit, while the simulation data are from ten RCMs (ARPEGE, CCLM, HIRHAM, RACMO, REMO, PRECIS, RegCM3, RCA, WRF, and CRCM) that participated in the regional climate downscaling experiment (CORDEX) project. The study analysed the rainy season (December-February) data for 19 years (1989-2008). The results show a strong link between ENSO and droughts (SPEI) over Southern Africa. The link is owing to the influence of ENSO on both rainfall and temperature fields, but the correlation between ENSO and temperature is stronger than the correlation between ENSO and rainfall. Hence, using only rainfall to monitor droughts in Southern Africa may underestimate the influence of ENSO on the droughts. Only few CORDEX RCMs simulate the influence of ENSO on Southern African drought as observed. In this regard, the ARPEGE model shows the best simulation, while CRCM shows the worst. The different in the performance may be due to their lateral boundary conditions. The RCA-simulated link between ENSO and Southern African droughts is sensitive to the global dataset used as the lateral boundary conditions. In some cases, using RCA to downscale global circulation models (GCM) simulations adds value to the simulated link between ENSO and the droughts, but in other cases the downscaling adds no value to the link. The added value of RCA to the simulated link decreases as the capability of the GCM to simulate the link increases. This study suggests that downscaling GCM simulations with RCMs over Southern Africa may improve or depreciate the

  7. Breaking a virus: Identifying molecular level failure modes of a viral capsid by multiscale modeling

    NASA Astrophysics Data System (ADS)

    Krishnamani, V.; Globisch, C.; Peter, C.; Deserno, M.

    2016-07-01

    We use coarse-grained (CG) simulations to study the deformation of empty Cowpea Chlorotic Mottle Virus (CCMV) capsids under uniaxial compression, from the initial elastic response up to capsid breakage. Our CG model is based on the MARTINI force field and has been amended by a stabilizing elastic network, acting only within individual proteins, that was tuned to capture the fluctuation spectrum of capsid protein dimers, obtained from all atom simulations. We have previously shown that this model predicts force-compression curves that match AFM indentation experiments on empty CCMV capsids. Here we investigate details of the actual breaking events when the CCMV capsid finally fails. We present a symmetry classification of all relevant protein contacts and show that they differ significantly in terms of stability. Specifically, we show that interfaces which break readily are precisely those which are believed to form last during assembly, even though some of them might share the same contacts as other non-breaking interfaces. In particular, the interfaces that form pentamers of dimers never break, while the virtually identical interfaces within hexamers of dimers readily do. Since these units differ in the large-scale geometry and, most noticeably, the cone-angle at the center of the 5- or 6-fold vertex, we propose that the hexameric unit fails because it is pre-stressed. This not only suggests that hexamers of dimers form less frequently during the early stages of assembly; it also offers a natural explanation for the well-known β-barrel motif at the hexameric center as a post-aggregation stabilization mechanism. Finally, we identify those amino acid contacts within all key protein interfaces that are most persistent during compressive deformation of the capsid, thereby providing potential targets for mutation studies aiming to elucidate the key contacts upon which overall stability rests.

  8. Modelling soil nitrogen: the MAGIC model with nitrogen retention linked to carbon turnover using decomposer dynamics.

    PubMed

    Oulehle, F; Cosby, B J; Wright, R F; Hruška, J; Kopáček, J; Krám, P; Evans, C D; Moldan, F

    2012-06-01

    We present a new formulation of the acidification model MAGIC that uses decomposer dynamics to link nitrogen (N) cycling to carbon (C) turnover in soils. The new model is evaluated by application to 15-30 years of water chemistry data at three coniferous-forested sites in the Czech Republic where deposition of sulphur (S) and N have decreased by >80% and 40%, respectively. Sulphate concentrations in waters have declined commensurately with S deposition, but nitrate concentrations have shown much larger decreases relative to N deposition. This behaviour is inconsistent with most conceptual models of N saturation, and with earlier versions of MAGIC which assume N retention to be a first-order function of N deposition and/or controlled by the soil C/N ratio. In comparison with earlier versions, the new formulation more correctly simulates observed short-term changes in nitrate leaching, as well as long-term retention of N in soils. The model suggests that, despite recent deposition reductions and recovery, progressive N saturation will lead to increased future nitrate leaching, ecosystem eutrophication and re-acidification. PMID:22459669

  9. Convective rain cell modelling from radar data and their linking with a hydrological model

    NASA Astrophysics Data System (ADS)

    Morin, E.; Yakir, H.

    2009-04-01

    The technology of weather radar systems enables a detailed view of rainstorms over watersheds with high spatial and temporal resolution that was never available before. Nevertheless, the utilization of radar rainfall data in hydrological models has not brought a significant improvement in understanding rainfall-runoff processes, and in prediction capability of watershed responses. There is a need to develop new ways to exploit essential information about spatio-temporal rain structures, and gain greater insights into rainfall and subsequent watershed response behavior. The current study suggests an innovative approach to the above challenge. We emphasize as a key issue the structure in which the data are represented in the hydrological models. Whereas in the standard approach, radar data are utilized in a grid structure, we propose to represent the rainfall data in a model-structure that takes into account the known behavior and properties of the rain system. The spatial and temporal characteristics of the rain system are thus explicitly represented and are linked directly to hydrological responses. The basic distinction between the grid and the currently suggested data model-structures is the presence of a-priori knowledge about the represented system incorporated into the model. The above approach was applied in the analysis of a large flood event in a semi-arid catchment in southern Israel. A model representing the spatio-temporal structure of the derived rain cells was developed and fitted to the radar data. The hydrological model was then fed by the rain cell information rather than the gridded radar data. Using this direct linkage between rain cell features and hydrological features the main controls of the generated flood were determined.

  10. An information-theoretic model for link prediction in complex networks

    NASA Astrophysics Data System (ADS)

    Zhu, Boyao; Xia, Yongxiang

    2015-09-01

    Various structural features of networks have been applied to develop link prediction methods. However, because different features highlight different aspects of network structural properties, it is very difficult to benefit from all of the features that might be available. In this paper, we investigate the role of network topology in predicting missing links from the perspective of information theory. In this way, the contributions of different structural features to link prediction are measured in terms of their values of information. Then, an information-theoretic model is proposed that is applicable to multiple structural features. Furthermore, we design a novel link prediction index, called Neighbor Set Information (NSI), based on the information-theoretic model. According to our experimental results, the NSI index performs well in real-world networks, compared with other typical proximity indices.

  11. An information-theoretic model for link prediction in complex networks

    PubMed Central

    Zhu, Boyao; Xia, Yongxiang

    2015-01-01

    Various structural features of networks have been applied to develop link prediction methods. However, because different features highlight different aspects of network structural properties, it is very difficult to benefit from all of the features that might be available. In this paper, we investigate the role of network topology in predicting missing links from the perspective of information theory. In this way, the contributions of different structural features to link prediction are measured in terms of their values of information. Then, an information-theoretic model is proposed that is applicable to multiple structural features. Furthermore, we design a novel link prediction index, called Neighbor Set Information (NSI), based on the information-theoretic model. According to our experimental results, the NSI index performs well in real-world networks, compared with other typical proximity indices. PMID:26335758

  12. A Drosophila XPD model links cell cycle coordination with neuro-development and suggests links to cancer

    PubMed Central

    Stettler, Karin; Li, Xiaoming; Sandrock, Björn; Braga-Lagache, Sophie; Heller, Manfred; Dümbgen, Lutz; Suter, Beat

    2015-01-01

    XPD functions in transcription, DNA repair and in cell cycle control. Mutations in human XPD (also known as ERCC2) mainly cause three clinical phenotypes: xeroderma pigmentosum (XP), Cockayne syndrome (XP/CS) and trichothiodystrophy (TTD), and only XP patients have a high predisposition to developing cancer. Hence, we developed a fly model to obtain novel insights into the defects caused by individual hypomorphic alleles identified in human XP-D patients. This model revealed that the mutations that displayed the greatest in vivo UV sensitivity in Drosophila did not correlate with those that led to tumor formation in humans. Immunoprecipitations followed by targeted quantitative MS/MS analysis showed how different xpd mutations affected the formation or stability of different transcription factor IIH (TFIIH) subcomplexes. The XP mutants most clearly linked to high cancer risk, Xpd R683W and R601L, showed a reduced interaction with the core TFIIH and also an abnormal interaction with the Cdk-activating kinase (CAK) complex. Interestingly, these two XP alleles additionally displayed high levels of chromatin loss and free centrosomes during the rapid nuclear division phase of the Drosophila embryo. Finally, the xpd mutations showing defects in the coordination of cell cycle timing during the Drosophila embryonic divisions correlated with those human mutations that cause the neurodevelopmental abnormalities and developmental growth defects observed in XP/CS and TTD patients. PMID:25431422

  13. A methodology for linking 2D overland flow models with the sewer network model SWMM 5.1 based on dynamic link libraries.

    PubMed

    Leandro, Jorge; Martins, Ricardo

    2016-01-01

    Pluvial flooding in urban areas is characterized by a gradually varying inundation process caused by surcharge of the sewer manholes. Therefore urban flood models need to simulate the interaction between the sewer network and the overland flow in order to accurately predict the flood inundation extents. In this work we present a methodology for linking 2D overland flow models with the storm sewer model SWMM 5. SWMM 5 is a well-known free open-source code originally developed in 1971. The latest major release saw its structure re-written in C ++ allowing it to be compiled as a command line executable or through a series of calls made to function inside a dynamic link library (DLL). The methodology developed herein is written inside the same DLL in C + +, and is able to simulate the bi-directional interaction between both models during simulation. Validation is done in a real case study with an existing urban flood coupled model. The novelty herein is that the new methodology can be added to SWMM without the need for editing SWMM's original code. Furthermore, it is directly applicable to other coupled overland flow models aiming to use SWMM 5 as the sewer network model. PMID:27332848

  14. Characterization of Chikungunya Virus Induced Host Response in a Mouse Model of Viral Myositis

    PubMed Central

    Dhanwani, Rekha; Khan, Mohsin; Lomash, Vinay; Rao, Putcha Venkata Lakshmana; Ly, Hinh; Parida, Manmohan

    2014-01-01

    While a number of studies have documented the persistent presence of chikungunya virus (CHIKV) in muscle tissue with primary fibroblast as the preferable cell target, little is known regarding the alterations that take place in muscle tissue in response to CHIKV infection. Hence, in the present study a permissive mouse model of CHIKV infection was established and characterized in order to understand the pathophysiology of the disease. The two dimensional electrophoresis of muscle proteome performed for differential analysis indicated a drastic reprogramming of the proteins from various classes like stress, inflammation, cytoskeletal, energy and lipid metabolism. The roles of the affected proteins were explained in relation to virus induced myopathy which was further supported by the histopathological and behavioural experiments proving the lack of hind limb coordination and other loco-motor abnormalities in the infected mice. Also, the level of various pro-inflammatory mediators like IL-6, MCP-1, Rantes and TNF-α was significantly elevated in muscles of infected mice. Altogether this comprehensive study of characterizing CHIKV induced mouse myopathy provides many potential targets for further evaluation and biomarker study. PMID:24667237

  15. Computer modeling and analysis of thermal link performance for an optical refrigerator

    NASA Astrophysics Data System (ADS)

    Byram, Kevin; Mar, David; Parker, John; Von der Porten, Steven; Hankinson, John; Lee, Chris; Mayeda, Kai; Haskell, Richard C.; Yang, Qimin; Greenfield, Scott R.; Epstein, Richard I.

    2008-02-01

    We have used the thermal modeling tool in COMSOL Multiphysics to investigate factors that affect the thermal performance of the optical refrigerator. Assuming an ideal cooling element and a non-absorptive dielectric trapping mirror, the three dominant heating factors are blackbody radiation from the surrounding environment, conductive heat transfer through mechanical supports, and the absorption of fluoresced photons transmitted through the thermal link. Laboratory experimentation coupled with computer modeling using Code V optical software have resulted in link designs capable of reducing the transmission to 0.04% of the fluoresced photons emitted toward the thermal link. The ideal thermal link will have minimal surface area, provide complete optical isolation for the load, and possess high thermal conductivity. Modeling results imply that a 1cm 3 load can be chilled to 102 K with currently available cooling efficiencies using a 100 W pump laser on a YB:ZBLANP system, and using an ideal link that has minimal surface area and no optical transmission. We review the simulated steady-state cooling temperatures reached by the heat load for several link designs and system configurations as a comparative measure of how well particular configurations perform.

  16. A Simple Forecasting Model Linking Macroeconomic Policy to Industrial Employment Demand.

    ERIC Educational Resources Information Center

    Malley, James R.; Hady, Thomas F.

    A study detailed further a model linking monetary and fiscal policy to industrial employment in metropolitan and nonmetropolitan areas of four United States regions. The model was used to simulate the impacts on area and regional employment of three events in the economy: changing real gross national product (GNP) via monetary policy, holding the…

  17. Reproduction of links between circulation types and precipitation in Central Europe in regional climate model simulations

    NASA Astrophysics Data System (ADS)

    Plavcová, Eva; Kyselý, Jan; Štěpánek, Petr

    2014-05-01

    The study evaluates relationships between large-scale atmospheric circulation (represented by circulation indices and circulation types derived from gridded mean sea level pressure) and daily precipitation amounts over three regions in the Czech Republic (Central Europe) with different precipitation regimes. We examine how ENSEMBLES regional climate model (RCM) simulations driven by re-analysis reproduce the observed links and capture differences in the links between the regions (lowlands vs. highlands) and seasons. We study the links of circulation to (i) mean precipitation over the regions, (ii) probability of wet days, and (iii) probability of extreme daily precipitation (exceeding threshold defined by a high quantile of precipitation distribution in a given season). Relatively strong links between atmospheric circulation and the precipitation characteristics are found in the observed data. The links are generally more pronounced for highland than lowland regions. More wet days and higher precipitation amounts are found for cyclonic and stronger flows, and for westerly and north-easterly flows. The RCMs are generally able to capture basic features of the links; nevertheless, they have difficulties to reproduce some more specific features and differences in the links between the regions. The results also suggest that good performance in some precipitation characteristics may be due to compensating errors rather than model's perfection. Reference: Plavcová E., Kyselý J., Štěpánek P., 2014: Links between circulation types and precipitation in Central Europe in the observed data and regional climate model simulations. International Journal of Climatology, doi 10.1002/joc.3882.

  18. Structural basis of viral RNA-dependent RNA polymerase catalysis and translocation.

    PubMed

    Shu, Bo; Gong, Peng

    2016-07-12

    Viral RNA-dependent RNA polymerases (RdRPs) play essential roles in viral genome replication and transcription. We previously reported several structural states of the poliovirus RdRP nucleotide addition cycle (NAC) that revealed a unique palm domain-based active site closure mechanism and proposed a six-state NAC model including a hypothetical state representing translocation intermediates. Using the RdRP from another human enterovirus, enterovirus 71, here we report seven RdRP elongation complex structures derived from a crystal lattice that allows three NAC events. These structures suggested a key order of events in initial NTP binding and NTP-induced active site closure and revealed a bona fide translocation intermediate featuring asymmetric movement of the template-product duplex. Our work provides essential missing links in understanding NTP recognition and translocation mechanisms in viral RdRPs and emphasizes the uniqueness of the viral RdRPs compared with other processive polymerases. PMID:27339134

  19. Viral infection and aging as cofactors for the development of pulmonary fibrosis

    PubMed Central

    Naik, Payal K; Moore, Bethany B

    2011-01-01

    Idiopathic pulmonary fibrosis (IPF) is a disease of unknown origin and progression that primarily affects older adults. Accumulating clinical and experimental evidence suggests that viral infections may play a role, either as agents that predispose the lung to fibrosis or exacerbate existing fibrosis. In particular, herpesviruses have been linked with IPF. This article summarizes the evidence for and against viral cofactors in IPF pathogenesis. In addition, we review mechanistic studies in animal models that highlight the fibrotic potential of viral infection, and explore the different mechanisms that might be responsible. We also review early evidence to suggest that the aged lung may be particularly susceptible to viral-induced fibrosis and make recommendations for future research directions. PMID:21128751

  20. Combination of reverse transcription real-time polymerase chain reaction and antigen capture enzyme-linked immunosorbent assay for the detection of animals persistently infected with Bovine viral diarrhea virus.

    PubMed

    Yan, Lifang; Zhang, Shuping; Pace, Lanny; Wilson, Floyd; Wan, Henry; Zhang, Michael

    2011-01-01

    Bovine viral diarrhea virus (BVDV) is an economically important pathogen of cattle. A successful control program requires early detection and removal of persistently infected (PI) animals. The objective of the current study was to develop, validate, and apply a cost-effective testing scheme for the detection of BVDV PI animals in exposed herds. Pooled samples were screened by using a real-time reverse transcription polymerase chain reaction (real-time RT-PCR), and individual positives were identified with an antigen capture enzyme-linked immunosorbent assay (ACE). The detection limits of the optimized real-time RT-PCR were 10 and 100 RNA copies per reaction for BVDV-1 and BVDV-2, respectively. The semiquantitative results of real-time RT-PCR and ACE or real-time RT-PCR and immunohistochemistry were moderately correlated. The threshold cycle of real-time RT-PCR performed on pooled samples was significantly correlated with the pool size (R(2)  =  0.993). The least-cost pool sizes were 50 at a prevalence of 0.25-0.5% and 25 at a prevalence of 0.75-2.0%. By using the combined real-time RT-PCR and ACE procedure, 111 of 27,932 samples (0.4%) tested positive for BVDV. At this prevalence, cost reduction associated with the application of real-time RT-PCR and ACE ranged from 61% to 94%, compared with testing individual samples by ACE, immunohistochemistry, or real-time RT-PCR. Real-time RT-PCR screening also indicated that 92.94% of PI animals were infected with BVDV-1, 3.53% with BVDV-2, and 3.53% with both BVDV-1 and BVDV-2. Analysis of the 5'-untranslated region of 22 isolates revealed the predominance of BVDV-1b followed by BVDV-2a. PMID:21217023

  1. Cumulative t-link threshold models for the genetic analysis of calving ease scores

    PubMed Central

    Kizilkaya, Kadir; Carnier, Paolo; Albera, Andrea; Bittante, Giovanni; Tempelman, Robert J

    2003-01-01

    In this study, a hierarchical threshold mixed model based on a cumulative t-link specification for the analysis of ordinal data or more, specifically, calving ease scores, was developed. The validation of this model and the Markov chain Monte Carlo (MCMC) algorithm was carried out on simulated data from normally and t4 (i.e. a t-distribution with four degrees of freedom) distributed populations using the deviance information criterion (DIC) and a pseudo Bayes factor (PBF) measure to validate recently proposed model choice criteria. The simulation study indicated that although inference on the degrees of freedom parameter is possible, MCMC mixing was problematic. Nevertheless, the DIC and PBF were validated to be satisfactory measures of model fit to data. A sire and maternal grandsire cumulative t-link model was applied to a calving ease dataset from 8847 Italian Piemontese first parity dams. The cumulative t-link model was shown to lead to posterior means of direct and maternal heritabilities (0.40 ± 0.06, 0.11 ± 0.04) and a direct maternal genetic correlation (-0.58 ± 0.15) that were not different from the corresponding posterior means of the heritabilities (0.42 ± 0.07, 0.14 ± 0.04) and the genetic correlation (-0.55 ± 0.14) inferred under the conventional cumulative probit link threshold model. Furthermore, the correlation (> 0.99) between posterior means of sire progeny merit from the two models suggested no meaningful rerankings. Nevertheless, the cumulative t-link model was decisively chosen as the better fitting model for this calving ease data using DIC and PBF. PMID:12939202

  2. Links between the spatial structure of weather generator and hydrological modeling

    NASA Astrophysics Data System (ADS)

    Li, Zhi; Lü, Zhemin; Li, Jingjing; Shi, Xiaoping

    2015-12-01

    Impacts of the spatial structure of weather generators on hydrological modeling have been largely qualitatively discussed; however, their links have been rarely quantified. The precipitation occurrence and amount were respectively generated with Markov chain and the mixed exponential distribution for single sites, and then the procedures were extended to multi-site simulation according to Wilks (1998). In the multi-site model, precipitation amounts were respectively generated with untapered or tapered mixed exponential scale parameters. The generated precipitation series were used as inputs of Soil and Water Assessment Tool (SWAT) to interpret the links between the spatial structure of weather generators and hydrological modeling. The single-site and multi-site model using untapered scale parameters gave similar averages for monthly and annual streamflow; however, the untapered multi-site model was superior to simulating hydrological variability. The single-site model underestimated the maxima and variances while overestimated the minima of streamflow; therefore, the use of single-site models for hydrological variability simulation should be cautious. The multi-site model using tapered scale parameters greatly overestimated the averages, extremes, and variances of streamflow. The Wilks model for multi-site precipitation simulation using tapered scale parameters is not appropriate for hydrological modeling, and the untapered version is thus recommended. Overall, the spatial structure of weather generators has significant impacts on hydrological modeling, especially for hydrological variability simulation; therefore, the links between them should be paid great attentions.

  3. Synthesizing within-host and population-level selective pressures on viral populations: the impact of adaptive immunity on viral immune escape

    PubMed Central

    Volkov, Igor; Pepin, Kim M.; Lloyd-Smith, James O.; Banavar, Jayanth R.; Grenfell, Bryan T.

    2010-01-01

    The evolution of viruses to escape prevailing host immunity involves selection at multiple integrative scales, from within-host viral and immune kinetics to the host population level. In order to understand how viral immune escape occurs, we develop an analytical framework that links the dynamical nature of immunity and viral variation across these scales. Our epidemiological model incorporates within-host viral evolutionary dynamics for a virus that causes acute infections (e.g. influenza and norovirus) with changes in host immunity in response to genetic changes in the virus population. We use a deterministic description of the within-host replication dynamics of the virus, the pool of susceptible host cells and the host adaptive immune response. We find that viral immune escape is most effective at intermediate values of immune strength. At very low levels of immunity, selection is too weak to drive immune escape in recovered hosts, while very high levels of immunity impose such strong selection that viral subpopulations go extinct before acquiring enough genetic diversity to escape host immunity. This result echoes the predictions of simpler models, but our formulation allows us to dissect the combination of within-host and transmission-level processes that drive immune escape. PMID:20335194

  4. Impacts of Humanized Mouse Models on the Investigation of HIV-1 Infection: Illuminating the Roles of Viral Accessory Proteins in Vivo

    PubMed Central

    Yamada, Eri; Yoshikawa, Rokusuke; Nakano, Yusuke; Misawa, Naoko; Koyanagi, Yoshio; Sato, Kei

    2015-01-01

    Human immunodeficiency virus type 1 (HIV-1) encodes four accessory genes: vif, vpu, vpr, and nef. Recent investigations using in vitro cell culture systems have shed light on the roles of these HIV-1 accessory proteins, Vif, Vpr, Vpu, and Nef, in counteracting, modulating, and evading various cellular factors that are responsible for anti-HIV-1 intrinsic immunity. However, since humans are the exclusive target for HIV-1 infection, conventional animal models are incapable of mimicking the dynamics of HIV-1 infection in vivo. Moreover, the effects of HIV-1 accessory proteins on viral infection in vivo remain unclear. To elucidate the roles of HIV-1 accessory proteins in the dynamics of viral infection in vivo, humanized mouse models, in which the mice are xenotransplanted with human hematopoietic stem cells, has been utilized. This review describes the current knowledge of the roles of HIV-1 accessory proteins in viral infection, replication, and pathogenicity in vivo, which are revealed by the studies using humanized mouse models. PMID:25807049

  5. Cognitive vulnerability to depression: A comparison of the weakest link, keystone and additive models

    PubMed Central

    Reilly, Laura C.; Ciesla, Jeffrey A.; Felton, Julia W.; Weitlauf, Amy S.; Anderson, Nicholas L.

    2014-01-01

    Multiple theories of cognitive vulnerability to depression have been proposed, each focusing on different aspects of negative cognition and utilising different measures of risk. Various methods of integrating such multiple indices of risk have been examined in the literature, and each demonstrates some promise. Yet little is known about the interrelations among these methods, or their incremental validity in predicting changes in depression. The present study compared three integrative models of cognitive vulnerability: the additive, weakest link, and keystone models. Support was found for each model as predictive of depression over time, but only the weakest link model demonstrated incremental utility in predicting changes in depression over the other models. We also explore the correlation between these models and each model’s unique contribution to predicting onset of depressive symptoms. PMID:21851251

  6. Selection and mutation in X-linked recessive diseases epidemiological model.

    PubMed

    Verrilli, Francesca; Kebriaei, Hamed; Glielmo, Luigi; Corless, Martin; Del Vecchio, Carmen

    2015-08-01

    To describe the epidemiology of X-linked recessive diseases we developed a discrete time, structured, non linear mathematical model. The model allows for de novo mutations (i.e. affected sibling born to unaffected parents) and selection (i.e., distinct fitness rates depending on individual's health conditions). Applying Lyapunov direct method we found the domain of attraction of model's equilibrium point and studied the convergence properties of the degenerate equilibrium where only affected individuals survive. PMID:26737169

  7. [Viral superantigens].

    PubMed

    Us, Dürdal

    2016-07-01

    , expression of endogenous SAgs leads to thymic deletion of responding T cells (bearing Vβ6-9+ TCR) due to self-tolerance induction during the fetal life, and protects the host against future exogenous MMTV infections. The SAg of rabies virus is the N protein found in nucleocapsid structure and stimulates Vβ8+TCR-bearing T cells. The SAg-induced polyclonal activation of T cells leads to turn-off the specific immune response, to enhance the immunopathogenesis and facilitates viral transmission from the initial site of infection (the muscle tissue) to the nerve endings. In case of EBV-associated SAg that activates Vβ13+TCR-bearing T cells, it was detected that the SAg activity was not encoded by EBV itself, but instead was due to the transactivation of HERV-K18 by EBV latent membrane proteins, whose env gene encodes the SAg (Sutkowski, et al. 2001). It has been denoted that EBV-induced SAg expression plays a role in the long-term persistence and latency of virus in memory B cells, in the development of autoimmune diseases and in the oncogenesis mechanisms. The proteins which are identified as SAgs of HIV are Nef and gp120. It is believed that, the massive activation of CD4+ T cells (selectively with Vβ-12+, Vβ-5.3+ and Vβ-18+ TCRs) in early stages of infection and clonal deletion, anergy and apoptosis of bystander T cells in the late stages may be due to SAg property of Nef protein, as well as the other mechanisms. However there are some studies indicating that Nef does not act as a SAg (Lapatschek, et al. 2001). HIV gp120 glycoprotein is a B-cell SAg that binds to VH3-expressing B cell receptors and causes polyclonal B cell activation. In addition, binding of gp120 to IgE on the surface of basophiles and mast cells causes activation of those cells, secretion of high level proinflammatory mediators leading to allergic reactions and tissue damage. In a recent study, the depletion (anergy or deletion) of T cell populations bearing Vβ12+, Vβ13+ and Vβ17+ TCR have been

  8. Investigation of a dual fetal infection model with bovine viral diarrhoea viruses (BVDV)-1 and BVDV-2.

    PubMed

    Makoschey, B; Janssen, M G J

    2011-10-01

    Two studies were performed in pregnant heifers to determine whether inoculation with two bovine viral diarrhoea viruses (BVDV), one BVDV-1 and one BVDV-2, inoculated separately into either nostril, results in fetal infection with both viruses. Dual transplacental infection of the fetus with BVDV-1 and BVDV-2 was observed in one case, but not consistently. PMID:21597952

  9. Bovine respiratory disease model based on dual infections with infection with bovine viral diarrhea virus and bovine corona virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine respiratory disease complex (BRDC) is the leading cause of economic loss in the U.S. cattle industry. BRDC likely results from simultaneous or sequential infections with multiple pathogens including both viruses and bacteria. Bovine viral diarrhea virus (BVDV) and bovine corona virus (BoCV...

  10. An approximate closed-form link loss model for non-line-of-sight ultraviolet communication in noncoplanar geometry.

    PubMed

    Wang, Leijie; Xu, Zhengyuan; Sadler, Brian M

    2011-04-01

    Non-line-of-sight UV communication link path loss models have been explored for both coplanar and noncoplanar geometries, and these typically require numerical evaluation. In this Letter, we propose a closed-form and easily applied model to describe link behavior, applicable to noncoplanar geometry. The model is compared with a recently reported analytical model and shows good agreement. PMID:21479037

  11. Antiviral Activity of Bacillus sp. Isolated from the Marine Sponge Petromica citrina against Bovine Viral Diarrhea Virus, a Surrogate Model of the Hepatitis C Virus

    PubMed Central

    Bastos, Juliana Cristina Santiago; Kohn, Luciana Konecny; Fantinatti-Garboggini, Fabiana; Padilla, Marina Aiello; Flores, Eduardo Furtado; da Silva, Bárbara Pereira; de Menezes, Cláudia Beatriz Afonso; Arns, Clarice Weis

    2013-01-01

    The Hepatitis C virus causes chronic infections in humans, which can develop to liver cirrhosis and hepatocellular carcinoma. The Bovine viral diarrhea virus is used as a surrogate model for antiviral assays for the HCV. From marine invertebrates and microorganisms isolated from them, extracts were prepared for assessment of their possible antiviral activity. Of the 128 tested, 2 were considered active and 1 was considered promising. The best result was obtained from the extracts produced from the Bacillus sp. isolated from the sponge Petromica citrina. The extracts 555 (500 µg/mL, SI>18) and 584 (150 µg/mL, SI 27) showed a percentage of protection of 98% against BVDV, and the extract 616, 90% of protection. All of them showed activity during the viral adsorption. Thus, various substances are active on these studied organisms and may lead to the development of drugs which ensure an alternative therapy for the treatment of hepatitis C. PMID:23628828

  12. Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors.

    PubMed

    Mecha, M; Feliú, A; Iñigo, P M; Mestre, L; Carrillo-Salinas, F J; Guaza, C

    2013-11-01

    Inflammation in the central nervous system (CNS) is a complex process that involves a multitude of molecules and effectors, and it requires the transmigration of blood leukocytes across the blood-brain barrier (BBB) and the activation of resident immune cells. Cannabidiol (CBD), a non-psychotropic cannabinoid constituent of Cannabis sativa, has potent anti-inflammatory and immunosuppressive properties. Yet, how this compound modifies the deleterious effects of inflammation in TMEV-induced demyelinating disease (TMEV-IDD) remains unknown. Using this viral model of multiple sclerosis (MS), we demonstrate that CBD decreases the transmigration of blood leukocytes by downregulating the expression of vascular cell adhesion molecule-1 (VCAM-1), chemokines (CCL2 and CCL5) and the proinflammatory cytokine IL-1β, as well as by attenuating the activation of microglia. Moreover, CBD administration at the time of viral infection exerts long-lasting effects, ameliorating motor deficits in the chronic phase of the disease in conjunction with reduced microglial activation and pro-inflammatory cytokine production. Adenosine A2A receptors participate in some of the anti-inflammatory effects of CBD, as the A2A antagonist ZM241385 partially blocks the protective effects of CBD in the initial stages of inflammation. Together, our findings highlight the anti-inflammatory effects of CBD in this viral model of MS and demonstrate the significant therapeutic potential of this compound for the treatment of pathologies with an inflammatory component. PMID:23851307

  13. Viral Skin Diseases.

    PubMed

    Ramdass, Priya; Mullick, Sahil; Farber, Harold F

    2015-12-01

    In the vast world of skin diseases, viral skin disorders account for a significant percentage. Most viral skin diseases present with an exanthem (skin rash) and, oftentimes, an accompanying enanthem (lesions involving the mucosal membrane). In this article, the various viral skin diseases are explored, including viral childhood exanthems (measles, rubella, erythema infectiosum, and roseola), herpes viruses (herpes simplex virus, varicella zoster virus, Kaposi sarcoma herpes virus, viral zoonotic infections [orf, monkeypox, ebola, smallpox]), and several other viral skin diseases, such as human papilloma virus, hand, foot, and mouth disease, molluscum contagiosum, and Gianotti-Crosti syndrome. PMID:26612372

  14. Bayesian inference in an item response theory model with a generalized student t link function

    NASA Astrophysics Data System (ADS)

    Azevedo, Caio L. N.; Migon, Helio S.

    2012-10-01

    In this paper we introduce a new item response theory (IRT) model with a generalized Student t-link function with unknown degrees of freedom (df), named generalized t-link (GtL) IRT model. In this model we consider only the difficulty parameter in the item response function. GtL is an alternative to the two parameter logit and probit models, since the degrees of freedom (df) play a similar role to the discrimination parameter. However, the behavior of the curves of the GtL is different from those of the two parameter models and the usual Student t link, since in GtL the curve obtained from different df's can cross the probit curves in more than one latent trait level. The GtL model has similar proprieties to the generalized linear mixed models, such as the existence of sufficient statistics and easy parameter interpretation. Also, many techniques of parameter estimation, model fit assessment and residual analysis developed for that models can be used for the GtL model. We develop fully Bayesian estimation and model fit assessment tools through a Metropolis-Hastings step within Gibbs sampling algorithm. We consider a prior sensitivity choice concerning the degrees of freedom. The simulation study indicates that the algorithm recovers all parameters properly. In addition, some Bayesian model fit assessment tools are considered. Finally, a real data set is analyzed using our approach and other usual models. The results indicate that our model fits the data better than the two parameter models.

  15. Linking Education and Industry in Preparing Students for Nontraditional Jobs. Project Model. Final Report.

    ERIC Educational Resources Information Center

    Smith, Armenia

    The Ysleta Schools Vocational Equity Project was implemented to develop and test methods to link education and industry in preparing students for nontraditional jobs. Both factual and attitudinal data were collected from educators, students, employers, and employees to accomplish the following project objectives: identify successful role models to…

  16. Experimental validation of an analytical model for nonlinear propagation in uncompensated optical links.

    PubMed

    Torrengo, E; Cigliutti, R; Bosco, G; Carena, A; Curri, V; Poggiolini, P; Nespola, A; Zeolla, D; Forghieri, F

    2011-12-12

    Link design for optical communication systems requires accurate modeling of nonlinear propagation in fibers. This topic has been widely analyzed in last decades with partial successes in special conditions, but without a comprehensive solution. Since the introduction of coherent detection with electronic signal processing the scenario completely changed because this category of systems shows better performances in links without in-line dispersion management. This change to uncompensated transmission allowed to modify the approach in the study of nonlinear fiber propagation and in recent years a series of promising analytical models have been proposed. In this paper, we present an experimental validation over different fiber types of an analytical model for nonlinear propagation over uncompensated optical transmission links. Considering an ultra-dense WDM system, we transmitted ten 120-Gb/s PM-QPSK signals over a multi-span system probing different fiber types: SSMF, PSCF and NZDSF. A good matching was found in all cases showing the potential of the analytical model for accurate performance estimation that could lead to powerful tools for link design. PMID:22274104

  17. The Gender-Linked Language Effect: An Empirical Test of a General Process Model

    ERIC Educational Resources Information Center

    Mulac, Anthony; Giles, Howard; Bradac, James J.; Palomares, Nicholas A.

    2013-01-01

    The gender-linked language effect (GLLE) is a phenomenon in which transcripts of female communicators are rated higher on Socio-Intellectual Status and Aesthetic Quality and male communicators are rated higher on Dynamism. This study proposed and tested a new general process model explanation for the GLLE, a central mediating element of which…

  18. PILOT STUDY LINKING AIR AND WATER MODELS FOR MERCURY IN THE EVERGLADES

    EPA Science Inventory

    A major goal of the Everglades Pilot Study is to demonstrate the technical feasibility of linking atmospheric and aquatic system models to calculate an atmospherically-driven total maximum daily load (TMDL) for mercury, given the current state of knowledge of mercury cycling in t...

  19. Multiscale Modeling for Linking Growth, Microstructure, and Properties of Inorganic Microporous Films

    NASA Technical Reports Server (NTRS)

    Vlachos, Dion G.

    2002-01-01

    The focus of this presentation is on multiscale modeling in order to link processing, microstructure, and properties of materials. Overview of problems we study includes: Growth mechanisms in chemical and physical vapor epitaxy; thin films of zeolites for separation and sensing; thin Pd films for hydrogen separation and pattern formation by self-regulation routes.

  20. The Chain-Link Fence Model: A Framework for Creating Security Procedures

    ERIC Educational Resources Information Center

    Houghton, Robert F.

    2013-01-01

    A long standing problem in information technology security is how to help reduce the security footprint. Many specific proposals exist to address specific problems in information technology security. Most information technology solutions need to be repeatable throughout the course of an information systems lifecycle. The Chain-Link Fence Model is…

  1. Exploring Alternative Characteristic Curve Approaches to Linking Parameter Estimates from the Generalized Partial Credit Model.

    ERIC Educational Resources Information Center

    Roberts, James S.; Bao, Han; Huang, Chun-Wei; Gagne, Phill

    Characteristic curve approaches for linking parameters from the generalized partial credit model were examined for cases in which common (anchor) items are calibrated separately in two groups. Three of these approaches are simple extensions of the test characteristic curve (TCC), item characteristic curve (ICC), and operating characteristic curve…

  2. Entangled polymer dynamics in equilibrium and flow modeled through slip links.

    PubMed

    Schieber, Jay D; Andreev, Marat

    2014-01-01

    The idea that the dynamics of concentrated, high-molecular weight polymers are largely governed by entanglements is now widely accepted and typically understood through the tube model. Here we review alternative approaches, slip-link models, that share some similarities to and offer some advantages over tube models. Although slip links were proposed at the same time as tubes, only recently have detailed, quantitative mathematical models arisen based on this picture. In this review, we focus on these models, with most discussion limited to mathematically well-defined objects that conform to state-of-the-art beyond-equilibrium thermodynamics. These models are connected to each other through successive coarse graining, using nonequilibrium thermodynamics along the way, and with a minimal parameter set. In particular, the most detailed level of description has four parameters, three of which can be determined directly from atomistic simulations. Once the remaining parameter is determined for any system, all parameters for all members of the hierarchy are determined. We show how, using this hierarchy of slip-link models combined with atomistic simulations, we can make predictions about the nonlinear rheology of monodisperse homopolymer melts, polydisperse melts, or blends of different architectures. Mathematical details are given elsewhere, so these are limited here, and physical ideas are emphasized. We conclude with an outlook on remaining challenges that might be tackled successfully using this approach, including complex flow fields and polymer blends. PMID:24655135

  3. Linking Parameters Estimated with the Generalized Graded Unfolding Model: A Comparison of the Accuracy of Characteristic Curve Methods

    ERIC Educational Resources Information Center

    Anderson Koenig, Judith; Roberts, James S.

    2007-01-01

    Methods for linking item response theory (IRT) parameters are developed for attitude questionnaire responses calibrated with the generalized graded unfolding model (GGUM). One class of IRT linking methods derives the linking coefficients by comparing characteristic curves, and three of these methods---test characteristic curve (TCC), item…

  4. Rainfall retrieval in urban areas using commercial microwave links from mobile networks: A modelling feasibility study

    NASA Astrophysics Data System (ADS)

    Zohidov, Bahtiyor; Andrieu, Hervé; Servières, Myriam; Normand, Nicolas

    2014-05-01

    Rainfall is usually measured by networks of rain gauges and weather radars. Many cities worldwide are not supplied with these devices; however, they are generally equipped with mobile telecommunication networks. Mobile networks use atmospheric Hyper-Frequency (HF) links whose transmitted signal power is attenuated by rainfall. Measuring that signal attenuation along each link could allow the measurement of path-averaged rainfall [Leijnse et al 2007, Overeem et al 2013, Messer et al 2006, Guili et al 1991, Zinevich et al 2008, Cuccoli et al 2011]. As HF links are concentrated in cities, these networks could constitute a self-sufficient approach to monitoring rainfall in urban areas. We adopt a simulation approach in order to study the feasibility of mapping rainfall fields at the city scale by means of existing HF links. Our domain of study is the central part of the city of Nantes, France, where the density of cellular networks is greatest. As a basis, we use a data set consisting of hundreds of weather radar images recorded by the Météo-France C band weather radar at high spatial (250m x 250m) and temporal (5 minute) resolutions located about 10 km north of the center of Nantes. We convert these images into rainfall maps using the Z-R relation and consider them as reference rainfall fields. The simulation is performed as follows. First, we simulate the measurement of total attenuation along each HF link using a rain-attenuation model based on Mie theory and a known drop size distribution in a continental temperate climate. This procedure is applied for 256 real radio links operating at different frequencies (18, 23, 38 GHz) with lengths ranging from 0.4 to 16 km. This helps us to substitute the attenuation data for the signal power received from microwave links. Error sources affecting measurement accuracy are introduced as a zero-mean Gaussian distributed random variable with variance of 10% of total attenuation. The retrieval of the rainfield is performed by a

  5. Monogenic mouse models of autism spectrum disorders: Common mechanisms and missing links.

    PubMed

    Hulbert, S W; Jiang, Y-H

    2016-05-01

    Autism spectrum disorders (ASDs) present unique challenges in the fields of genetics and neurobiology because of the clinical and molecular heterogeneity underlying these disorders. Genetic mutations found in ASD patients provide opportunities to dissect the molecular and circuit mechanisms underlying autistic behaviors using animal models. Ongoing studies of genetically modified models have offered critical insight into possible common mechanisms arising from different mutations, but links between molecular abnormalities and behavioral phenotypes remain elusive. The challenges encountered in modeling autism in mice demand a new analytic paradigm that integrates behavioral assessment with circuit-level analysis in genetically modified models with strong construct validity. PMID:26733386

  6. Expression and In Silico Analysis of the Recombinant Bovine Papillomavirus E6 Protein as a Model for Viral Oncoproteins Studies

    PubMed Central

    Mazzuchelli-de-Souza, J.; Carvalho, R. F.; Ruiz, R. M.; Melo, T. C.; Araldi, R. P.; Carvalho, E.; Thompson, C. E.; Sircili, M. P.; Beçak, W.; Stocco, R. C.

    2013-01-01

    Bovine papillomaviruses (BPVs) are recognized as the causal agents of economical relevant diseases in cattle, associated with the development of tumors in skin and mucosa. The oncogenesis process is mainly associated with different viral oncoprotein expressions, which are involved in cell transformation. The expression and characterization of recombinant viral oncoproteins represent an attractive strategy to obtain biotechnological products as antibodies and potential vaccines, Thus, the aim of this work was to clone and express the BPV-1 and BPV-2 E6 recombinant proteins and perform in silico analysis in order to develop a strategy for the systematic study of other papillomaviruses oncoproteins. The results demonstrated that BPV-1 and BPV-2 E6 recombinant proteins were expressed and purified from bacterial system as well as its in silico analysis was performed in order to explore and predict biological characteristics of these proteins. PMID:23878806

  7. Relationship between CD4+ T-cell counts/HIV-1 RNA plasma viral load and AIDS defining events among persons followed in the ACTG Longitudinal Linked Randomized Trials (ALLRT) study

    PubMed Central

    Smurzynski, Marlene; Wu, Kunling; Benson, Constance A.; Bosch, Ronald J.; Collier, Ann C.; Koletar, Susan L.

    2010-01-01

    Background AIDS-defining events (ADEs) decreased in the era of highly active antiretroviral therapy but still lead to hospitalizations and deaths. Understanding factors related to ADEs is important to mitigate events. Methods We examined the relationship between demographics, behaviors, co-morbidities, laboratory, clinical measurements and ADEs diagnosed among subjects randomized to antiretroviral treatments (ART)/strategies and followed prospectively. Logistic regression models using generalized estimating equations generated odds ratios (ORs) focusing on the relationship between current CD4+ T-cell count (CD4)/HIV-1 RNA viral load (VL) and ADEs in the subsequent 16-week study period. Results Among the 2,948 subjects in the analysis, overall incidence of ADEs was 1.53 per 100 person-years. Multivariate regression models adjusted for demographics, BMI and ADE history. A 6-level time-varying variable examined VL (>100,000 copies/mL, ≤ 100,000) at CD4 levels (0–50, 51–200, >200 cells/μl); reference level was CD4>200/VL≤100,000. Among ART-naives, odds of having an ADE in the subsequent 16-week interval were greater among subjects with lower CD4 counts; this relationship was modified by VL level (CD4≤50/VL>100,000: OR 37.2; CD4≤50/VL≤100,000: OR 30.5; CD4 51–200/VL>100,000: OR 13.0; CD4 51–200/VL≤100,000: OR 4.5; all p-values <0.001). Similar results were seen among ART-experienced subjects. Conclusions Recent CD4 and VL values are closely associated with development of ADEs even after examining a multitude of potential factors. PMID:20622677

  8. Experimental scleral cross-linking increases glaucoma damage in a mouse model

    PubMed Central

    Kimball, Elizabeth C.; Nguyen, Cathy; Steinhart, Matthew R.; Nguyen, Thao D.; Pease, Mary E.; Oglesby, Ericka N.; Oveson, Brian C.; Quigley, Harry A.

    2014-01-01

    The purpose of this study was to assess the effect of a scleral cross-linking agent on susceptibility to glaucoma damage in a mouse model. CD1 mice underwent 3 subconjunctival injections of 0.5 M glyceraldehyde (GA) in 1 week, then had elevated intraocular pressure (IOP) induced by bead injection. Degree of cross-linking was measured by enzyme-linked immunosorbent assay (ELISA), scleral permeability was measured by fluorescence recovery after photobleaching (FRAP), and the mechanical effects of GA exposure were measured by inflation testing. Control mice had buffer injection or no injection in 2 separate glaucoma experiments. IOP was monitored by Tonolab and retinal ganglion cell (RGC) loss was measured by histological axon counting. To rule out undesirable effects of GA, we performed electroretinography and detailed histology of the retina. GA exposure had no detectable effects on RGC number, retinal structure or function either histologically or electrophysiologically. GA increased cross-linking of sclera by 37% in an ELISA assay, decreased scleral permeability (FRAP, p = 0.001), and produced a steeper pressure—strain behavior by in vitro inflation testing. In two experimental glaucoma experiments, GA-treated eyes had greater RGC axon loss from elevated IOP than either buffer-injected or control eyes, controlling for level of IOP exposure over time (p = 0.01, and 0.049, multivariable regression analyses). This is the first report that experimental alteration of the sclera, by cross-linking, increases susceptibility to RGC damage in mice. PMID:25285424

  9. Dynamic modelling and link mechanism design of four-legged mobile robot

    NASA Astrophysics Data System (ADS)

    Park, Sung-Ho

    In order to apply the advanced biological phenomena to the leg design of mobile robots, the structural and locomotive characteristics of several selected animals and insects are studied, and the four-legged mobile robot which can cover all existing leg arrangements and locomotion patterns is modeled by a rigid multibody system consisting of links and joints. The model is simulated to prove that the given structure or locomotive conditions satisfy the requirement of minimum energy expenditure. According to the first simulation, there exist ideal forward and backward stroke distances for each pair leg. Therefore, the walking volume and link lengths of existing legged mobile robots should be modified. Also, for other structural and locomotive characteristics which have been used by living creatures, the model is simulated to determine whether or not the actual or possible biological phenomena can be applied to the leg mechanism design of mobile robot.

  10. Linear DNA-linked colloidal chains: a model to visualize polymer dynamics

    NASA Astrophysics Data System (ADS)

    Biswal, Sibani; Byrom, Julie; Du, Daniel

    2012-02-01

    We present the development of synthetic materials consisting of chains of DNA-linked paramagnetic colloids that have rigidity and length specificity. These chains have demonstrated capability for folding and self-assembly. This is classic bead-spring-bead model can be a model system to visualize polymer dynamics. Here, I will describe the formation mechanism and stability of these DNA-linked magnetic particle chains. I will also describe a model that describes the total energy landscape that describes the inter-particle interactions and provides a workable theory toward the optimization of experimental parameters in synthesizing more stable and reliable colloidal assemblies. In addition to stability, we will also present the use of a colloidal worm-like chain (WLC) model system to describe chain dynamics. We measure bending rigidity by monitoring the thermal fluctuations of the chains. We show that the persistence length of the chains can be tuned from 1 to 50 mm (L/LP = 0.002 - 0.1), by changing the length of the DNA used to link adjacent particles from 75 to 15 bases. We also will show that the bending relaxation dynamics of these chains, which match well with theoretical predictions, further supporting the validity of using these colloidal chains as models for semiflexible polymer systems in both equilibrium and dynamic studies.

  11. Efficient estimation and prediction for the Bayesian binary spatial model with flexible link functions.

    PubMed

    Roy, Vivekananda; Evangelou, Evangelos; Zhu, Zhengyuan

    2016-03-01

    Spatial generalized linear mixed models (SGLMMs) are popular models for spatial data with a non-Gaussian response. Binomial SGLMMs with logit or probit link functions are often used to model spatially dependent binomial random variables. It is known that for independent binomial data, the robit regression model provides a more robust (against extreme observations) alternative to the more popular logistic and probit models. In this article, we introduce a Bayesian spatial robit model for spatially dependent binomial data. Since constructing a meaningful prior on the link function parameter as well as the spatial correlation parameters in SGLMMs is difficult, we propose an empirical Bayes (EB) approach for the estimation of these parameters as well as for the prediction of the random effects. The EB methodology is implemented by efficient importance sampling methods based on Markov chain Monte Carlo (MCMC) algorithms. Our simulation study shows that the robit model is robust against model misspecification, and our EB method results in estimates with less bias than full Bayesian (FB) analysis. The methodology is applied to a Celastrus Orbiculatus data, and a Rhizoctonia root data. For the former, which is known to contain outlying observations, the robit model is shown to do better for predicting the spatial distribution of an invasive species. For the latter, our approach is doing as well as the classical models for predicting the disease severity for a root disease, as the probit link is shown to be appropriate. Though this article is written for Binomial SGLMMs for brevity, the EB methodology is more general and can be applied to other types of SGLMMs. In the accompanying R package geoBayes, implementations for other SGLMMs such as Poisson and Gamma SGLMMs are provided. PMID:26331903

  12. Computational modeling of mechanical response of dual cross-linked polymer grafted nanoparticle networks

    NASA Astrophysics Data System (ADS)

    v S, Balaji; Yashin, Victor; Salib, Isaac; Kowalewski, Tomasz; Matyjaszewski, Krzystof; Balazs, Anna; Anna Balazs Collaboration; Krzystof Matyjaszewski Collaboration

    2013-03-01

    We develop a hybrid computational model for the behavior of a network of cross-linked polymer-grafted nanoparticles (PGNs). The individual nanoparticles are composed of a rigid core and a corona of grafted polymers that encompass reactive end groups. With the overlap of the coronas on adjacent particles, the reactive end groups can form permanent or labile bonds, which lead to the formation of a ``dual cross-linked'' network. To capture these multi-scale interactions, our approach integrates the essential structural features of the polymer grafted nanoparticles, the interactions between the overlapping coronas, and the kinetics of bond formation and rupture between the reactive groups on the chain ends. We investigate the mechanical response of the dual-cross linked network to an applied tensile deformation. We find that the response depends on the bond energies of the labile bonds, the fraction of permanent bonds in the network, and thickness of the corona. This model provides a powerful tool for the computational design of dual cross-linked PGN's by predicting how the structural features of the system affect the mechanical performance.

  13. Neuroinvasion and Inflammation in Viral Central Nervous System Infections

    PubMed Central

    Schroten, Horst

    2016-01-01

    Neurotropic viruses can cause devastating central nervous system (CNS) infections, especially in young children and the elderly. The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) have been described as relevant sites of entry for specific viruses as well as for leukocytes, which are recruited during the proinflammatory response in the course of CNS infection. In this review, we illustrate examples of established brain barrier models, in which the specific reaction patterns of different viral families can be analyzed. Furthermore, we highlight the pathogen specific array of cytokines and chemokines involved in immunological responses in viral CNS infections. We discuss in detail the link between specific cytokines and chemokines and leukocyte migration profiles. The thorough understanding of the complex and interrelated inflammatory mechanisms as well as identifying universal mediators promoting CNS inflammation is essential for the development of new diagnostic and treatment strategies. PMID:27313404

  14. A linked hydrodynamic and water quality model for the Salton Sea

    USGS Publications Warehouse

    Chung, E.G.; Schladow, S.G.; Perez-Losada, J.; Robertson, D.M.

    2008-01-01

    A linked hydrodynamic and water quality model was developed and applied to the Salton Sea. The hydrodynamic component is based on the one-dimensional numerical model, DLM. The water quality model is based on a new conceptual model for nutrient cycling in the Sea, and simulates temperature, total suspended sediment concentration, nutrient concentrations, including PO4-3, NO3-1 and NH4+1, DO concentration and chlorophyll a concentration as functions of depth and time. Existing water temperature data from 1997 were used to verify that the model could accurately represent the onset and breakup of thermal stratification. 1999 is the only year with a near-complete dataset for water quality variables for the Salton Sea. The linked hydrodynamic and water quality model was run for 1999, and by adjustment of rate coefficients and other water quality parameters, a good match with the data was obtained. In this article, the model is fully described and the model results for reductions in external phosphorus load on chlorophyll a distribution are presented. ?? 2008 Springer Science+Business Media B.V.

  15. Characterizing Class-Specific Exposure-Viral Load Suppression Response of HIV Antiretrovirals Using A Model-Based Meta-Analysis.

    PubMed

    Xu, Y; Li, Y F; Zhang, D; Dockendorf, M; Tetteh, E; Rizk, M L; Grobler, J A; Lai, M-T; Gobburu, J; Ankrom, W

    2016-08-01

    We applied model-based meta-analysis of viral suppression as a function of drug exposure and in vitro potency for short-term monotherapy in human immunodeficiency virus type 1 (HIV-1)-infected treatment-naïve patients to set pharmacokinetic targets for development of nonnucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (InSTIs). We developed class-specific models relating viral load kinetics from monotherapy studies to potency normalized steady-state trough plasma concentrations. These models were integrated with a literature assessment of doses which demonstrated to have long-term efficacy in combination therapy, in order to set steady-state trough concentration targets of 6.17- and 2.15-fold above potency for NNRTIs and InSTIs, respectively. Both the models developed and the pharmacokinetic targets derived can be used to guide compound selection during preclinical development and to predict the dose-response of new antiretrovirals to inform early clinical trial design. PMID:27171172

  16. Influence of atmospheric turbulence on OAM-based FSO system with use of realistic link model

    NASA Astrophysics Data System (ADS)

    Li, Ming; Yu, Zhongyuan; Cvijetic, Milorad

    2016-04-01

    We study the influence of atmospheric turbulence on OAM-based free-space optical (FSO) communication by using the Pump turbulence spectrum model which accurately characterizes the realistic FSO link. A comprehensive comparison is made between the Pump and Kolmogorov spectrum models with respect to the turbulence impact. The calculated results show that obtained turbulence-induced crosstalk is lower, which means that a higher channel capacity is projected when the realistic Pump spectrum is used instead of the Kolmogorov spectrum. We believe that our results prove that performance of practical OAM-based FSO is better than one predicted by using the original Kolmogorov turbulence model.

  17. Link functions in multi-locus genetic models: implications for testing, prediction, and interpretation.

    PubMed

    Clayton, David

    2012-05-01

    "Complex" diseases are, by definition, influenced by multiple causes, both genetic and environmental, and statistical work on the joint action of multiple risk factors has, for more than 40 years, been dominated by the generalized linear model (GLM). In genetics, models for dichotomous traits have traditionally been approached via the model of an underlying, normally distributed, liability. This corresponds to the GLM with binomial errors and a probit link function. Elsewhere in epidemiology, however, the logistic regression model, a GLM with logit link function, has been the tool of choice, largely because of its convenient properties in case-control studies. The choice of link function has usually been dictated by mathematical convenience, but it has some important implications in (a) the choice of association test statistic in the presence of existing strong risk factors, (b) the ability to predict disease from genotype given its heritability, and (c) the definition, and interpretation of epistasis (or epistacy). These issues are reviewed, and a new association test proposed. PMID:22508388

  18. Towards Controlling the Glycoform: A Model Framework Linking Extracellular Metabolites to Antibody Glycosylation

    PubMed Central

    Jedrzejewski, Philip M.; del Val, Ioscani Jimenez; Constantinou, Antony; Dell, Anne; Haslam, Stuart M.; Polizzi, Karen M.; Kontoravdi, Cleo

    2014-01-01

    Glycoproteins represent the largest group of the growing number of biologically-derived medicines. The associated glycan structures and their distribution are known to have a large impact on pharmacokinetics. A modelling framework was developed to provide a link from the extracellular environment and its effect on intracellular metabolites to the distribution of glycans on the constant region of an antibody product. The main focus of this work is the mechanistic in silico reconstruction of the nucleotide sugar donor (NSD) metabolic network by means of 34 species mass balances and the saturation kinetics rates of the 60 metabolic reactions involved. NSDs are the co-substrates of the glycosylation process in the Golgi apparatus and their simulated dynamic intracellular concentration profiles were linked to an existing model describing the distribution of N-linked glycan structures of the antibody constant region. The modelling framework also describes the growth dynamics of the cell population by means of modified Monod kinetics. Simulation results match well to experimental data from a murine hybridoma cell line. The result is a modelling platform which is able to describe the product glycoform based on extracellular conditions. It represents a first step towards the in silico prediction of the glycoform of a biotherapeutic and provides a platform for the optimisation of bioprocess conditions with respect to product quality. PMID:24637934

  19. Hepatitis C Viral Kinetics in Special Populations

    PubMed Central

    Dahari, Harel; Layden-Almer, Jennifer E.; Perelson, Alan S.; Layden, Thomas J.

    2008-01-01

    Mathematical models of hepatitis C viral (HCV) kinetics provide a means of estimating the antiviral effectiveness of therapy, the rate of virion clearance and the rate of loss of HCV-infected cells. They have also proved useful in evaluating the extrahepatic contribution to HCV plasma viremia and they have suggested mechanisms of action for both interferon-α and ribavirin. Viral kinetic models can explain the observed HCV RNA profiles under treatment, e.g., flat partial response, biphasic and triphasic viral decay and viral rebound. Current therapy with (pegylated) interferon-α and ribavirin has a poorer success in patients having insulin resistance, hepatic fibrosis, African American ethnicity, HCV/HIV-coinfection, HCV genotype-1 and high baseline viral load. The use of mathematical modeling and statistical analysis of experimental data have been useful in understanding some of these treatment obstacles. PMID:19148305

  20. Space Station communications and tracking systems modeling and RF link simulation

    NASA Technical Reports Server (NTRS)

    Tsang, Chit-Sang; Chie, Chak M.; Lindsey, William C.

    1986-01-01

    In this final report, the effort spent on Space Station Communications and Tracking System Modeling and RF Link Simulation is described in detail. The effort is mainly divided into three parts: frequency division multiple access (FDMA) system simulation modeling and software implementation; a study on design and evaluation of a functional computerized RF link simulation/analysis system for Space Station; and a study on design and evaluation of simulation system architecture. This report documents the results of these studies. In addition, a separate User's Manual on Space Communications Simulation System (SCSS) (Version 1) documents the software developed for the Space Station FDMA communications system simulation. The final report, SCSS user's manual, and the software located in the NASA JSC system analysis division's VAX 750 computer together serve as the deliverables from LinCom for this project effort.

  1. Simulink models for performance analysis of high speed DQPSK modulated optical link

    NASA Astrophysics Data System (ADS)

    Sharan, Lucky; Rupanshi, Chaubey, V. K.

    2016-03-01

    This paper attempts to present the design approach for development of simulation models to study and analyze the transmission of 10 Gbps DQPSK signal over a single channel Peer to Peer link using Matlab Simulink. The simulation model considers the different optical components used in link design with their behavior represented initially by theoretical interpretation, including the transmitter topology, Mach Zehnder Modulator(MZM) module and, the propagation model for optical fibers etc. thus allowing scope for direct realization in experimental configurations. It provides the flexibility to incorporate the various photonic components as either user-defined or fixed and, can also be enhanced or removed from the model as per the design requirements. We describe the detailed operation and need of every component model and its representation in Simulink blocksets. Moreover the developed model can be extended in future to support Dense Wavelength Division Multiplexing (DWDM) system, thereby allowing high speed transmission with N × 40 Gbps systems. The various compensation techniques and their influence on system performance can be easily investigated by using such models.

  2. Promoting professional nursing practice: linking a professional practice model to performance expectations.

    PubMed

    Murphy, Marcia; Hinch, Barbara; Llewellyn, Jane; Dillon, Paula J; Carlson, Elizabeth

    2011-03-01

    Professional practice models (PPMs) provide the conceptual framework for establishing professional nursing practice. Integrating a PPM requires complex organizational change. One strategy for integrating a PPM is to directly link the PPM with performance expectations to ensure that underlying beliefs are integrated into everyday practice. This article describes the development, implementation, and successful outcomes of a clinical advancement system that was aligned with a PPM. PMID:21320662

  3. Modeling and tachometer feedback in the control of an experimental single link flexible structure

    NASA Technical Reports Server (NTRS)

    Garcia, Ephrahim; Inman, Daniel J.

    1990-01-01

    In this work a formulation for the modeling of a single link flexible structure will be introduced that includes the effects of dynamic interaction between the actuator and structure. These effects are the rotational modal participation factors for the structure's vibratory motion that occurs at the slewing axis. It will be shown, both theoretically and experimentally, that this dynamic interaction can be advantageous for vibration suppression of the flexible modes of the system during slewing positioning maneuvers.

  4. Clinical trial simulation to evaluate power to compare the antiviral effectiveness of two hepatitis C protease inhibitors using nonlinear mixed effect models: a viral kinetic approach

    PubMed Central

    2013-01-01

    Background Models of hepatitis C virus (HCV) kinetics are increasingly used to estimate and to compare in vivo drug’s antiviral effectiveness of new potent anti-HCV agents. Viral kinetic parameters can be estimated using non-linear mixed effect models (NLMEM). Here we aimed to evaluate the performance of this approach to precisely estimate the parameters and to evaluate the type I errors and the power of the Wald test to compare the antiviral effectiveness between two treatment groups when data are sparse and/or a large proportion of viral load (VL) are below the limit of detection (BLD). Methods We performed a clinical trial simulation assuming two treatment groups with different levels of antiviral effectiveness. We evaluated the precision and the accuracy of parameter estimates obtained on 500 replication of this trial using the stochastic approximation expectation-approximation algorithm which appropriately handles BLD data. Next we evaluated the type I error and the power of the Wald test to assess a difference of antiviral effectiveness between the two groups. Standard error of the parameters and Wald test property were evaluated according to the number of patients, the number of samples per patient and the expected difference in antiviral effectiveness. Results NLMEM provided precise and accurate estimates for both the fixed effects and the inter-individual variance parameters even with sparse data and large proportion of BLD data. However Wald test with small number of patients and lack of information due to BLD resulted in an inflation of the type I error as compared to the results obtained when no limit of detection of VL was considered. The corrected power of the test was very high and largely outperformed what can be obtained with empirical comparison of the mean VL decline using Wilcoxon test. Conclusion This simulation study shows the benefit of viral kinetic models analyzed with NLMEM over empirical approaches used in most clinical studies. When

  5. Joint longitudinal hurdle and time-to-event models: an application related to viral load and duration of the first treatment regimen in patients with HIV initiating therapy.

    PubMed

    Brilleman, Samuel L; Crowther, Michael J; May, Margaret T; Gompels, Mark; Abrams, Keith R

    2016-09-10

    Shared parameter joint models provide a framework under which a longitudinal response and a time to event can be modelled simultaneously. A common assumption in shared parameter joint models has been to assume that the longitudinal response is normally distributed. In this paper, we instead propose a joint model that incorporates a two-part 'hurdle' model for the longitudinal response, motivated in part by longitudinal response data that is subject to a detection limit. The first part of the hurdle model estimates the probability that the longitudinal response is observed above the detection limit, whilst the second part of the hurdle model estimates the mean of the response conditional on having exceeded the detection limit. The time-to-event outcome is modelled using a parametric proportional hazards model, assuming a Weibull baseline hazard. We propose a novel association structure whereby the current hazard of the event is assumed to be associated with the current combined (expected) outcome from the two parts of the hurdle model. We estimate our joint model under a Bayesian framework and provide code for fitting the model using the Bayesian software Stan. We use our model to estimate the association between HIV RNA viral load, which is subject to a lower detection limit, and the hazard of stopping or modifying treatment in patients with HIV initiating antiretroviral therapy. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27027882

  6. Modelling the multidimensional niche by linking functional traits to competitive performance.

    PubMed

    Maynard, Daniel S; Leonard, Kenneth E; Drake, John M; Hall, David W; Crowther, Thomas W; Bradford, Mark A

    2015-07-22

    Linking competitive outcomes to environmental conditions is necessary for understanding species' distributions and responses to environmental change. Despite this importance, generalizable approaches for predicting competitive outcomes across abiotic gradients are lacking, driven largely by the highly complex and context-dependent nature of biotic interactions. Here, we present and empirically test a novel niche model that uses functional traits to model the niche space of organisms and predict competitive outcomes of co-occurring populations across multiple resource gradients. The model makes no assumptions about the underlying mode of competition and instead applies to those settings where relative competitive ability across environments correlates with a quantifiable performance metric. To test the model, a series of controlled microcosm experiments were conducted using genetically related strains of a widespread microbe. The model identified trait microevolution and performance differences among strains, with the predicted competitive ability of each organism mapped across a two-dimensional carbon and nitrogen resource space. Areas of coexistence and competitive dominance between strains were identified,and the predicted competitive outcomes were validated in approximately 95% of the pairings. By linking trait variation to competitive ability, our work demonstrates a generalizable approach for predicting and modelling competitive outcomes across changing environmental contexts. PMID:26136444

  7. A NEW GHOST-NODE METHOD FOR LINKING DIFFERENT MODELS WITH VARIED GRID REFINEMENT

    SciTech Connect

    J. dickinson; S.C. James; S. Mehl; M.C. Hill; S. Leake; G.A. Zyvoloski

    2005-10-18

    A flexible, robust method for linking grids of locally refined models that may be constructed using different types of numerical methods is needed to address a variety of hydrologic problems. This work outlines and tests a new ghost-node model-linking method based on the iterative method of Mehl and Hill (2002, 2004). It is applicable to steady-state solutions for ground-water flow. Tests are presented for a homogeneous two-dimensional system that facilitates clear analysis of typical problems. The coupled grids are simulated using the finite-difference and finite-element models MODFLOW and FEHM. Results indicate that when the grids are matched spatially so that nodes and control volume boundaries are aligned, the new coupling technique has approximately twice the error as coupling using two MODFLOW models. When the grids are non-matching; model accuracy is slightly increased over matching grid cases. Overall, results indicate that the ghost-node technique is a viable means to accurately couple distinct models.

  8. NEW GHOST-NODE METHOD FOR LINKING DIFFERENT MODELS WITH VARIED GRID REFINEMENT

    SciTech Connect

    S.C. James; J.E. Dickinson; S.W. Mehl; M.C. Hill; S.A. Leake; G.A. zyvoloski; A. Eddebbarh

    2006-02-15

    A flexible, robust method for linking grids of locally refined models constructed with different numerical methods is needed to address a variety of hydrologic problems. This work outlines and tests a new ghost-node model-linking method for a refined ''child'' model that is contained within a larger and coarser ''parent'' model that is based on the iterative method of Mehl and Hill (2002, 2004). The method is applicable to steady-state solutions for ground-water flow. Tests are presented for a homogeneous two-dimensional system that has either matching grids (parent cells border an integer number of child cells; Figure 2a) or non-matching grids (parent cells border a non-integer number of child cells; Figure 2b). The coupled grids are simulated using the finite-difference and finite-element models MODFLOW and FEHM, respectively. The simulations require no alteration of the MODFLOW or FEHM models and are executed using a batch file on Windows operating systems. Results indicate that when the grids are matched spatially so that nodes and child cell boundaries are aligned, the new coupling technique has error nearly equal to that when coupling two MODFLOW models (Mehl and Hill, 2002). When the grids are non-matching, model accuracy is slightly increased over matching-grid cases. Overall, results indicate that the ghost-node technique is a viable means to accurately couple distinct models because the overall error is less than if only the regional model was used to simulate flow in the child model's domain.

  9. New Ghost-node method for linking different models with varied grid refinement.

    SciTech Connect

    Mehl, Steffen W.; Hill, Mary Catherine.; James, Scott Carlton; Leake, Stanley A.; Zyvoloski, George A.; Dickinson, Jesse E.; Eddebbarh, Al A.

    2006-01-01

    A flexible, robust method for linking grids of locally refined models constructed with different numerical methods is needed to address a variety of hydrologic problems. This work outlines and tests a new ghost-node model-linking method for a refined 'child' model that is contained within a larger and coarser 'parent' model that is based on the iterative method of Mehl and Hill (2002, 2004). The method is applicable to steady-state solutions for ground-water flow. Tests are presented for a homogeneous two-dimensional system that has either matching grids (parent cells border an integer number of child cells; Figure 2a) or non-matching grids (parent cells border a non-integer number of child cells; Figure 2b). The coupled grids are simulated using the finite-difference and finite-element models MODFLOW and FEHM, respectively. The simulations require no alteration of the MODFLOW or FEHM models and are executed using a batch file on Windows operating systems. Results indicate that when the grids are matched spatially so that nodes and child cell boundaries are aligned, the new coupling technique has error nearly equal to that when coupling two MODFLOW models (Mehl and Hill, 2002). When the grids are non-matching, model accuracy is slightly increased over matching-grid cases. Overall, results indicate that the ghost-node technique is a viable means to accurately couple distinct models because the overall error is less than if only the regional model was used to simulate flow in the child model's domain.

  10. New ghost-node method for linking different models with varied grid refinement

    USGS Publications Warehouse

    James, S.C.; Dickinson, J.E.; Mehl, S.W.; Hill, M.C.; Leake, S.A.; Zyvoloski, G.A.; Eddebbarh, A.-A.

    2006-01-01

    A flexible, robust method for linking grids of locally refined ground-water flow models constructed with different numerical methods is needed to address a variety of hydrologic problems. This work outlines and tests a new ghost-node model-linking method for a refined "child" model that is contained within a larger and coarser "parent" model that is based on the iterative method of Steffen W. Mehl and Mary C. Hill (2002, Advances in Water Res., 25, p. 497-511; 2004, Advances in Water Res., 27, p. 899-912). The method is applicable to steady-state solutions for ground-water flow. Tests are presented for a homogeneous two-dimensional system that has matching grids (parent cells border an integer number of child cells) or nonmatching grids. The coupled grids are simulated by using the finite-difference and finite-element models MODFLOW and FEHM, respectively. The simulations require no alteration of the MODFLOW or FEHM models and are executed using a batch file on Windows operating systems. Results indicate that when the grids are matched spatially so that nodes and child-cell boundaries are aligned, the new coupling technique has error nearly equal to that when coupling two MODFLOW models. When the grids are nonmatching, model accuracy is slightly increased compared to that for matching-grid cases. Overall, results indicate that the ghost-node technique is a viable means to couple distinct models because the overall head and flow errors relative to the analytical solution are less than if only the regional coarse-grid model was used to simulate flow in the child model's domain.

  11. Influence of gender constancy and social power on sex-linked modeling.

    PubMed

    Bussey, K; Bandura, A

    1984-12-01

    Competing predictions derived from cognitive-developmental theory and social learning theory concerning sex-linked modeling were tested. In cognitive-developmental theory, gender constancy is considered a necessary prerequisite for the emulation of same-sex models, whereas according to social learning theory, sex-role development is promoted through a vast system of social influences with modeling serving as a major conveyor of sex role information. In accord with social learning theory, even children at a lower level of gender conception emulated same-sex models in preference to opposite-sex ones. Level of gender constancy was associated with higher emulation of both male and female models rather than operating as a selective determinant of modeling. This finding corroborates modeling as a basic mechanism in the sex-typing process. In a second experiment we explored the limits of same-sex modeling by pitting social power against the force of collective modeling of different patterns of behavior by male and female models. Social power over activities and rewarding resources produced cross-sex modeling in boys, but not in girls. This unexpected pattern of cross-sex modeling is explained by the differential sex-typing pressures that exist for boys and girls and socialization experiences that heighten the attractiveness of social power for boys. PMID:6527216

  12. A Refined Model for the TSG-6 Link Module in Complex with Hyaluronan

    PubMed Central

    Higman, Victoria A.; Briggs, David C.; Mahoney, David J.; Blundell, Charles D.; Sattelle, Benedict M.; Dyer, Douglas P.; Green, Dixy E.; DeAngelis, Paul L.; Almond, Andrew; Milner, Caroline M.; Day, Anthony J.

    2014-01-01

    Tumor necrosis factor-stimulated gene-6 (TSG-6) is an inflammation-associated hyaluronan (HA)-binding protein that contributes to remodeling of HA-rich extracellular matrices during inflammatory processes and ovulation. The HA-binding domain of TSG-6 consists solely of a Link module, making it a prototypical member of the superfamily of proteins that interacts with this high molecular weight polysaccharide composed of repeating disaccharides of d-glucuronic acid and N-acetyl-d-glucosamine (GlcNAc). Previously we modeled a complex of the TSG-6 Link module in association with an HA octasaccharide based on the structure of the domain in its HA-bound conformation. Here we have generated a refined model for a HA/Link module complex using novel restraints identified from NMR spectroscopy of the protein in the presence of 10 distinct HA oligosaccharides (from 4- to 8-mers); the model was then tested using unique sugar reagents, i.e. chondroitin/HA hybrid oligomers and an octasaccharide in which a single sugar ring was 13C-labeled. The HA chain was found to make more extensive contacts with the TSG-6 surface than thought previously, such that a d-glucuronic acid ring makes stacking and ionic interactions with a histidine and lysine, respectively. Importantly, this causes the HA to bend around two faces of the Link module (resembling the way that HA binds to CD44), potentially providing a mechanism for how TSG-6 can reorganize HA during inflammation. However, the HA-binding site defined here may not play a role in TSG-6-mediated transfer of heavy chains from inter-α-inhibitor onto HA, a process known to be essential for ovulation. PMID:24403066

  13. A local-world heterogeneous model of wireless sensor networks with node and link diversity

    NASA Astrophysics Data System (ADS)

    Li, Shudong; Li, Lixiang; Yang, Yixian

    2011-03-01

    In this paper, we present a novel local-world model of wireless sensor networks (WSN) with two kinds of nodes: sensor nodes and sink nodes, which is different from other models with identical nodes and links. The model balances energy consumption by limiting the connectivity of sink nodes to prolong the life of the network. How the proportion of sink nodes, different energy distribution and the local-world scale would affect the topological structure and network performance are investigated. We find that, using mean-field theory, the degree distribution is obtained as an integral with respect to the proportion of sink nodes and energy distribution. We also show that, the model exhibits a mixed connectivity correlation which is greatly distinct from general networks. Moreover, from the perspective of the efficiency and the average hops for data processing, we find some suitable range of the proportion p of sink nodes would make the network model have optimal performance for data processing.

  14. Successes and Challenges in Linking Observations and Modeling of Marine and Terrestrial Cryospheric Processes

    NASA Astrophysics Data System (ADS)

    Herzfeld, U. C.; Hunke, E. C.; Trantow, T.; Greve, R.; McDonald, B.; Wallin, B.

    2014-12-01

    Understanding of the state of the cryosphere and its relationship to other components of the Earth system requires both models of geophysical processes and observations of geophysical properties and processes, however linking observations and models is far from trivial. This paper looks at examples from sea ice and land ice model-observation linkages to examine some approaches, challenges and solutions. In a sea-ice example, ice deformation is analyzed as a key process that indicates fundamental changes in the Arctic sea ice cover. Simulation results from the Los Alamos Sea-Ice Model CICE, which is also the sea-ice component of the Community Earth System Model (CESM), are compared to parameters indicative of deformation as derived from mathematical analysis of remote sensing data. Data include altimeter, micro-ASAR and image data from manned and unmanned aircraft campaigns (NASA OIB and Characterization of Arctic Sea Ice Experiment, CASIE). The key problem to linking data and model results is the derivation of matching parameters on both the model and observation side.For terrestrial glaciology, we include an example of a surge process in a glacier system and and example of a dynamic ice sheet model for Greenland. To investigate the surge of the Bering Bagley Glacier System, we use numerical forward modeling experiments and, on the data analysis side, a connectionist approach to analyze crevasse provinces. In the Greenland ice sheet example, we look at the influence of ice surface and bed topography, as derived from remote sensing data, on on results from a dynamic ice sheet model.

  15. A link-segment model of upright human posture for analysis of head-trunk coordination

    NASA Technical Reports Server (NTRS)

    Nicholas, S. C.; Doxey-Gasway, D. D.; Paloski, W. H.

    1998-01-01

    Sensory-motor control of upright human posture may be organized in a top-down fashion such that certain head-trunk coordination strategies are employed to optimize visual and/or vestibular sensory inputs. Previous quantitative models of the biomechanics of human posture control have examined the simple case of ankle sway strategy, in which an inverted pendulum model is used, and the somewhat more complicated case of hip sway strategy, in which multisegment, articulated models are used. While these models can be used to quantify the gross dynamics of posture control, they are not sufficiently detailed to analyze head-trunk coordination strategies that may be crucial to understanding its underlying mechanisms. In this paper, we present a biomechanical model of upright human posture that extends an existing four mass, sagittal plane, link-segment model to a five mass model including an independent head link. The new model was developed to analyze segmental body movements during dynamic posturography experiments in order to study head-trunk coordination strategies and their influence on sensory inputs to balance control. It was designed specifically to analyze data collected on the EquiTest (NeuroCom International, Clackamas, OR) computerized dynamic posturography system, where the task of maintaining postural equilibrium may be challenged under conditions in which the visual surround, support surface, or both are in motion. The performance of the model was tested by comparing its estimated ground reaction forces to those measured directly by support surface force transducers. We conclude that this model will be a valuable analytical tool in the search for mechanisms of balance control.

  16. Identification of Unknown Groundwater Pollution Source Using Linked ANN-Optimization Model

    NASA Astrophysics Data System (ADS)

    Ayaz, M.; Srivastava, R.

    2011-12-01

    Identification of groundwater pollution sources is a major step in groundwater pollution remediation, particularly for assigning fractions of the remediation cost to different polluters. Identification of unknown groundwater pollution source is an inverse problem which is generally ill-posed. A pollution source is said to be identified completely when its source characteristics (location, strength and release period) are known. In practice, the lag time between the first reading at observation well and the time at which the source becomes active is not known. For such cases, pollution source identification problem becomes more difficult. We propose a linked ANN-Optimization model for complete identification of unknown groundwater pollution sources. Spatial and temporal data of observed and simulated concentration is used to formulate the objective function. An optimization model is then used to minimize the objective function. We define the lag time as the time from the start of the pollutant release to the peak of the breakthrough curve observed at a monitoring well. Lag time for a particular monitoring well is then dependent only on the source location and release period. An ANN model is trained for different source locations and release periods as input data to determine the lag time for breakthrough curve. In the proposed model, the ANN model is linked externally with the optimization model to identify the pollution sources. The main advantage of the proposed model is to identify the unique solution for pollution sources when lag time is not known. The performance of the model is evaluated for a one dimensional case with error-free and erroneous data. The measurement errors incorporated in the data vary from 0% to 10% of the analytically computed values. The results indicate that the proposed linked ANN-Optimization model is able to predict the source parameters quite well for the error-free data. For the observations subjected to random measurement errors, the

  17. Effect of preexisting anti-herpes immunity on the efficacy of herpes simplex viral therapy in a murine intraperitoneal tumor model.

    PubMed

    Lambright, E S; Kang, E H; Force, S; Lanuti, M; Caparrelli, D; Kaiser, L R; Albelda, S M; Molnar-Kimber, K L

    2000-10-01

    HSV-1716, a replicating nonneurovirulent herpes simplex virus type 1, has shown efficacy in treating multiple types of human tumors in immunodeficient mice. Since the majority of the human population has been previously exposed to herpes simplex virus, the efficacy of HSV-based oncolytic therapy was investigated in an immunocompetent animal tumor model. EJ-6-2-Bam-6a, a tumor cell line derived from h-ras-transformed murine fibroblast, exhibit a diffuse growth pattern in the peritoneal cavity of BALB/c mice and replicate HSV-1716 to titers observed in human tumors. An established intraperitoneal (ip) tumor model of EJ-6-2-Bam-6a in naive and HSV-immunized mice was used to evaluate the efficacy of single or multiple ip administrations of HSV-1716 (4 x 10(6) pfu/treatment) or of carrier cells, which are irradiated, ex vivo virally infected EJ-6-2-Bam-6a cells that can amplify the viral load in situ. All treated groups significantly prolonged survival versus media control with an approximately 40% long-term survival rate (cure) in the multiply treated, HSV-naive animals. Prior immunization of the mice with HSV did not significantly decrease the median survival of the single or multiply treated HSV-1716 or the carrier cell-treated groups. These studies support the development of replication-selective herpes virus mutants for use in localized intraperitoneal malignancies. PMID:11020355

  18. Evidence of TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism.

    PubMed

    Domingo, Aloysius; Amar, David; Grütz, Karen; Lee, Lillian V; Rosales, Raymond; Brüggemann, Norbert; Jamora, Roland Dominic; Cutiongco-Dela Paz, Eva; Rolfs, Arndt; Dressler, Dirk; Walter, Uwe; Krainc, Dimitri; Lohmann, Katja; Shamir, Ron; Klein, Christine; Westenberger, Ana

    2016-08-01

    The molecular dysfunction in X-linked dystonia-parkinsonism is not completely understood. Thus far, only noncoding alterations have been found in genetic analyses, located in or nearby the TATA-box binding protein-associated factor 1 (TAF1) gene. Given that this gene is ubiquitously expressed and is a critical component of the cellular transcription machinery, we sought to study differential gene expression in peripheral models by performing microarray-based expression profiling in blood and fibroblasts, and comparing gene expression in affected individuals vs. ethnically matched controls. Validation was performed via quantitative polymerase chain reaction in discovery and independent replication sets. We observed consistent downregulation of common TAF1 transcripts in samples from affected individuals in gene-level and high-throughput experiments. This signal was accompanied by a downstream effect in the microarray, reflected by the dysregulation of 307 genes in the disease group. Gene Ontology and network analyses revealed enrichment of genes involved in RNA polymerase II-dependent transcription, a pathway relevant to TAF1 function. Thus, the results converge on TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism, and provide evidence of altered expression of a canonical gene in this disease. Furthermore, our study illustrates a link between the previously described genetic alterations and TAF1 dysfunction at the transcriptome level. PMID:26879577

  19. Primary hemocyte culture of Penaeus monodon as an in vitro model for white spot syndrome virus titration, viral and immune related gene expression and cytotoxicity assays.

    PubMed

    Jose, Seena; Mohandas, A; Philip, Rosamma; Bright Singh, I S

    2010-11-01

    Immortal cell lines have not yet been reported from Penaeus monodon, which delimits the prospects of investigating the associated viral pathogens especially white spot syndrome virus (WSSV). In this context, a method of developing primary hemocyte culture from this crustacean has been standardized by employing modified double strength Leibovitz-15 (L-15) growth medium supplemented with 2% glucose, MEM vitamins (1×), tryptose phosphate broth (2.95 gl⁻¹), 20% FBS, N-phenylthiourea (0.2 mM), 0.06 μg ml⁻¹ chloramphenicol, 100 μg ml⁻¹ streptomycin and 100 IU ml⁻¹ penicillin and hemolymph drawn from shrimp grown under a bio-secured recirculating aquaculture system (RAS). In this medium the hemocytes remained viable up to 8 days. 5-Bromo-2'-deoxyuridine (BrdU) labeling assay revealed its incorporation in 22 ± 7% of cells at 24h. Susceptibility of the cells to WSSV was confirmed by immunofluorescence assay using a monoclonal antibody against 28 kDa envelope protein of WSSV. A convenient method for determining virus titer as MTT(50)/ml was standardized employing the primary hemocyte culture. Expression of viral genes and cellular immune genes were also investigated. The cell culture could be demonstrated for determining toxicity of a management chemical (benzalkonium chloride) by determining its IC(50). The primary hemocyte culture could serve as a model for WSSV titration and viral and cellular immune related gene expression and also for investigations on cytotoxicity of aquaculture drugs and chemicals. PMID:20807537

  20. Women and work in rural Taiwan: building a contextual model linking employment and health.

    PubMed

    Gallin, R S

    1989-12-01

    This paper is based on ethnographic research in a rural Taiwanese village in which married women with children are a major source of labor for local industry. Responsibility for job and home exposes these women to repeated stressors that can increase their susceptibility to illness. Existing explanatory models linking employment and women's health, however, do not explain adequately the women's response to their wage labor and the consequences of the social aspects of their work on their health. This paper describes women's work and its meaning, and discusses the way in which micro phenomena such as meanings and health states are linked to macro phenomena such as national political-economic processes and the world capitalist system. PMID:2689508

  1. Contrasting life strategies of viruses that infect photo- and heterotrophic bacteria, as revealed by viral tagging.

    PubMed

    Deng, Li; Gregory, Ann; Yilmaz, Suzan; Poulos, Bonnie T; Hugenholtz, Philip; Sullivan, Matthew B

    2012-01-01

    Ocean viruses are ubiquitous and abundant and play important roles in global biogeochemical cycles by means of their mortality, horizontal gene transfer, and manipulation of host metabolism. However, the obstacles involved in linking viruses to their hosts in a high-throughput manner bottlenecks our ability to understand virus-host interactions in complex communities. We have developed a method called viral tagging (VT), which combines mixtures of host cells and fluorescent viruses with flow cytometry. We investigated multiple viruses which infect each of two model marine bacteria that represent the slow-growing, photoautotrophic genus Synechococcus (Cyanobacteria) and the fast-growing, heterotrophic genus Pseudoalteromonas (Gammaproteobacteria). Overall, viral tagging results for viral infection were consistent with plaque and liquid infection assays for cyanobacterial myo-, podo- and siphoviruses and some (myo- and podoviruses) but not all (four siphoviruses) heterotrophic bacterial viruses. Virus-tagged Pseudoalteromonas organisms were proportional to the added viruses under varied infection conditions (virus-bacterium ratios), while no more than 50% of the Synechococcus organisms were virus tagged even at viral abundances that exceeded (5 to 10×) that of their hosts. Further, we found that host growth phase minimally impacts the fraction of virus-tagged Synechococcus organisms while greatly affecting phage adsorption to Pseudoalteromonas. Together these findings suggest that at least two contrasting viral life strategies exist in the oceans and that they likely reflect adaptation to their host microbes. Looking forward to the point at which the virus-tagging signature is well understood (e.g., for Synechococcus), application to natural communities should begin to provide population genomic data at the proper scale for predictively modeling two of the most abundant biological entities on Earth. Viral study suffers from an inability to link viruses to hosts en

  2. Links between circulation indices and precipitation in the Mediterranean in an ensemble of regional climate models

    NASA Astrophysics Data System (ADS)

    Beranová, Romana; Kyselý, Jan

    2016-02-01

    Spatial and temporal variability of precipitation in the Mediterranean is related to atmospheric circulation patterns such as the North Atlantic Oscillation (NAO), the Mediterranean Oscillation (MO) and the Western Mediterranean Oscillation (WeMO). This study examines ability of an ensemble of 12 regional climate model (RCM) simulations to reproduce observed links between these circulation indices and precipitation, as well as how these links may change in the late twenty-first century. We focus on the winter season and differences in precipitation amounts on the highest and lowest 25 % of days according to a given index. The relationships are evaluated against the E-OBS data set for 1961-1990. The observed pattern of differences in precipitation between positive and negative phases is generally similar for MO and NAO, which relates to the high correlation between these indices. Most regional climate models (RCMs) simulate links between the circulation indices and precipitation over most of the Mediterranean area reasonably well, especially for the MO and WeMO indices. The RCM with the largest deficiencies in reproducing the links is HadRM for all indices. The spatial patterns of differences in daily precipitation under positive and negative phases of the circulation indices for the future scenario (2070-2099) are similar to those for the control climate for all indices. This suggests that NAO, MO and WeMO are likely to play similar roles in affecting precipitation in the Mediterranean also in the future. However, increased NAO and decreased WeMO index, projected in most examined RCMs for the late twenty-first century in winter, may affect overall precipitation patterns.

  3. Kinematic modeling of mobile robot with rocker-bogie link structure

    NASA Astrophysics Data System (ADS)

    Gang, Taig-Gi; Yi, Soo-Yeong

    2005-12-01

    A method for kinematic modeling of a mobile robot with rocker-bogie link mechanism was described. By using the well-known concept of the instantaneous coordinates, it derives the kinematic model for the full six degree of freedom motion including the x, y, and z motions and the pitch, roll, and yaw rotations. The kinematic model here implies both of the forward and the inverse kinematic equations. The forward kinematic equation with the wheel Jacobian matrices can be used to obtain the robot position and orientation from the measured wheel velocities and the rocker-bogie joint angles. On the contrary, the inverse kinematic equation implies a resulting robot motions consisting of body velocity and turning rate from the individual wheel velocities. Through the computer simulation, the kinematic model of the mobile robot was verified.

  4. Global sensitivity analysis, probabilistic calibration, and predictive assessment for the data assimilation linked ecosystem carbon model

    NASA Astrophysics Data System (ADS)

    Safta, C.; Ricciuto, D. M.; Sargsyan, K.; Debusschere, B.; Najm, H. N.; Williams, M.; Thornton, P. E.

    2015-07-01

    In this paper we propose a probabilistic framework for an uncertainty quantification (UQ) study of a carbon cycle model and focus on the comparison between steady-state and transient simulation setups. A global sensitivity analysis (GSA) study indicates the parameters and parameter couplings that are important at different times of the year for quantities of interest (QoIs) obtained with the data assimilation linked ecosystem carbon (DALEC) model. We then employ a Bayesian approach and a statistical model error term to calibrate the parameters of DALEC using net ecosystem exchange (NEE) observations at the Harvard Forest site. The calibration results are employed in the second part of the paper to assess the predictive skill of the model via posterior predictive checks.

  5. Full Scale Rotor Aeroacoustic Predictions and the Link to Model Scale Rotor Data

    NASA Technical Reports Server (NTRS)

    Boyd, D. Douglas, Jr.; Burley, Casey L.; Conner, David A.

    2004-01-01

    The NASA Aeroacoustic Prediction System (NAPS) is used to establish a link between model-scale and full-scale rotor predictions and is partially validated against measured wind tunnel and flight aeroacoustic data. The prediction approach of NAPS couples a comprehensive rotorcraft analysis with acoustic source noise and propagation codes. The comprehensive analysis selected for this study is CAMRAD-II, which provides the performance/trim/wake solution for a given rotor or flight condition. The post-trim capabilities of CAMRAD-II are used to compute high-resolution sectional airloads for the acoustic tone noise analysis, WOPMOD. The tone noise is propagated to observers on the ground with the propagation code, RNM (Rotor Noise Model). Aeroacoustic predictions are made with NAPS for an isolated rotor and compared to results of the second Harmonic Aeroacoustic Rotor Test (HART-II) program, which tested a 40% dynamically and Mach-scaled BO-105 main rotor at the DNW. The NAPS is validated with comparisons for three rotor conditions: a baseline condition and two Higher Harmonic Control (HHC) conditions. To establish a link between model and full-scale rotor predictions, a full-scale BO-105 main rotor input deck for NAPS is created from the 40% scale rotor input deck. The full-scale isolated rotor predictions are then compared to the model predictions. The comparisons include aerodynamic loading, acoustic levels, and acoustic pressure time histories for each of the three conditions. With this link established, full-scale predictions are made for a range of descent flight conditions and compared with measured trends from the recent Rotorcraft Operational Noise Abatement Procedures (RONAP) flight test conducted by DLR and ONERA. Additionally, the effectiveness of two HHC conditions from the HART-II program is demonstrated for the full-scale rotor in flight.

  6. Latent constructs model explaining the attachment-linked variation in autobiographical remembering.

    PubMed

    Öner, Sezin; Gülgöz, Sami

    2016-01-01

    In the current study, we proposed a latent constructs model to characterise the qualitative aspects of autobiographical remembering and investigated the structural relations in the model that may vary across individuals. Primarily, we focused on the memories of romantic relationships and argued that attachment anxiety and avoidance would be reflected in the ways that individuals encode, rehearse, or remember autobiographical memories in close relationships. Participants reported two positive and two negative relationship-specific memories and rated the characteristics for each memory. As predicted, the basic memory model yielded appropriate fit, indicating that event characteristics (EC) predicted the frequency of rehearsal (RC) and phenomenology at retrieval (PC). When attachment variables were integrated, the model showed that rehearsal mediated the link between anxiety and PC, especially for negative memories. On the other hand, for avoidance EC was the key factor mediating the link between avoidance and RC, as well as PC. Findings were discussed with respect to autobiographical memory functions emphasising a systematically, integrated framework. PMID:25716295

  7. Linked Hydrologic-Hydrodynamic Model Framework to Forecast Impacts of Rivers on Beach Water Quality

    NASA Astrophysics Data System (ADS)

    Anderson, E. J.; Fry, L. M.; Kramer, E.; Ritzenthaler, A.

    2014-12-01

    The goal of NOAA's beach quality forecasting program is to use a multi-faceted approach to aid in detection and prediction of bacteria in recreational waters. In particular, our focus has been on the connection between tributary loads and bacteria concentrations at nearby beaches. While there is a clear link between stormwater runoff and beach water quality, quantifying the contribution of river loadings to nearshore bacterial concentrations is complicated due to multiple processes that drive bacterial concentrations in rivers as well as those processes affecting the fate and transport of bacteria upon exiting the rivers. In order to forecast potential impacts of rivers on beach water quality, we developed a linked hydrologic-hydrodynamic water quality framework that simulates accumulation and washoff of bacteria from the landscape, and then predicts the fate and transport of washed off bacteria from the watershed to the coastal zone. The framework includes a watershed model (IHACRES) to predict fecal indicator bacteria (FIB) loadings to the coastal environment (accumulation, wash-off, die-off) as a function of effective rainfall. These loadings are input into a coastal hydrodynamic model (FVCOM), including a bacteria transport model (Lagrangian particle), to simulate 3D bacteria transport within the coastal environment. This modeling system provides predictive tools to assist local managers in decision-making to reduce human health threats.

  8. The Role of Viral Introductions in Sustaining Community-Based HIV Epidemics in Rural Uganda: Evidence from Spatial Clustering, Phylogenetics, and Egocentric Transmission Models

    PubMed Central

    Grabowski, Mary K.; Lessler, Justin; Redd, Andrew D.; Kagaayi, Joseph; Laeyendecker, Oliver; Ndyanabo, Anthony; Nelson, Martha I.; Cummings, Derek A. T.; Bwanika, John Baptiste; Mueller, Amy C.; Reynolds, Steven J.; Munshaw, Supriya; Ray, Stuart C.; Lutalo, Tom; Manucci, Jordyn; Tobian, Aaron A. R.; Chang, Larry W.; Beyrer, Chris; Jennings, Jacky M.; Nalugoda, Fred; Serwadda, David; Wawer, Maria J.; Quinn, Thomas C.; Gray, Ronald H.

    2014-01-01

    Background It is often assumed that local sexual networks play a dominant role in HIV spread in sub-Saharan Africa. The aim of this study was to determine the extent to which continued HIV transmission in rural communities—home to two-thirds of the African population—is driven by intra-community sexual networks versus viral introductions from outside of communities. Methods and Findings We analyzed the spatial dynamics of HIV transmission in rural Rakai District, Uganda, using data from a cohort of 14,594 individuals within 46 communities. We applied spatial clustering statistics, viral phylogenetics, and probabilistic transmission models to quantify the relative contribution of viral introductions into communities versus community- and household-based transmission to HIV incidence. Individuals living in households with HIV-incident (n = 189) or HIV-prevalent (n = 1,597) persons were 3.2 (95% CI: 2.7–3.7) times more likely to be HIV infected themselves compared to the population in general, but spatial clustering outside of households was relatively weak and was confined to distances <500 m. Phylogenetic analyses of gag and env genes suggest that chains of transmission frequently cross community boundaries. A total of 95 phylogenetic clusters were identified, of which 44% (42/95) were two individuals sharing a household. Among the remaining clusters, 72% (38/53) crossed community boundaries. Using the locations of self-reported sexual partners, we estimate that 39% (95% CI: 34%–42%) of new viral transmissions occur within stable household partnerships, and that among those infected by extra-household sexual partners, 62% (95% CI: 55%–70%) are infected by sexual partners from outside their community. These results rely on the representativeness of the sample and the quality of self-reported partnership data and may not reflect HIV transmission patterns outside of Rakai. Conclusions Our findings suggest that HIV introductions into communities are

  9. Mathematical model of the Tat-Rev regulation of HIV-1 replication in an activated cell predicts the existence of oscillatory dynamics in the synthesis of viral components

    PubMed Central

    2014-01-01

    Background The life cycle of human immunodeficiency virus type-1 (HIV-1) makes possible the realization of regulatory strategies that can lead to complex dynamical behavior of the system. We analyze the strategy which is based on two feedback mechanisms, one mediating a positive regulation of the virus replication by Tat protein via the antitermination of the genomic RNAs transcription on TAR (transactivation responsive) element of the proviral DNA and the second mechanism providing a negative regulation of the splicing of the full-length (9 kb) RNAs and incompletely spliced (4 kb) RNAs via their transport from the nucleus to the cytoplasm. Although the existence of these two regulatory feedback loops has been considered in other mathematical models, none of them examined the conditions for the emergence of complex oscillatory patterns in the intracellular dynamics of viral components. Results We developed a mechanistic mathematical model for the Tat-Rev mediated regulation of HIV-1 replication, which considers the activation of proviral DNA transcription, the Tat-specific antitermination of transcription on TAR-element, resulting in the synthesis of the full-length 9 kb RNA, the splicing of the 9 kb RNA down to the 4 kb RNA and the 4 kb RNA to 2 kb RNA, the transport of 2 kb mRNAs from the nucleus to the cytoplasm by the intracellular mechanisms, the multiple binding of the Rev protein to RRE (Rev Response Element) sites on 9 kb and 4 kb RNA resulting in their export to the cytoplasm and the synthesis of Tat and Rev proteins in the cytoplasm followed by their transport into the nucleus. The degradation of all viral proteins and RNAs both in the cytoplasm and the nucleus is described. The model parameters values were derived from the published literature data. The model was used to examine the dynamics of the synthesis of the viral proteins Tat and Rev, the mRNAs under the intracellular conditions specific for activated HIV-1 infected macrophages. In addition, we

  10. A linked simulation-optimization model for solving the unknown groundwater pollution source identification problems.

    PubMed

    Ayvaz, M Tamer

    2010-09-20

    This study proposes a linked simulation-optimization model for solving the unknown groundwater pollution source identification problems. In the proposed model, MODFLOW and MT3DMS packages are used to simulate the flow and transport processes in the groundwater system. These models are then integrated with an optimization model which is based on the heuristic harmony search (HS) algorithm. In the proposed simulation-optimization model, the locations and release histories of the pollution sources are treated as the explicit decision variables and determined through the optimization model. Also, an implicit solution procedure is proposed to determine the optimum number of pollution sources which is an advantage of this model. The performance of the proposed model is evaluated on two hypothetical examples for simple and complex aquifer geometries, measurement error conditions, and different HS solution parameter sets. Identified results indicated that the proposed simulation-optimization model is an effective way and may be used to solve the inverse pollution source identification problems. PMID:20633952

  11. Non-random patterns in viral diversity

    PubMed Central

    Anthony, Simon J.; Islam, Ariful; Johnson, Christine; Navarrete-Macias, Isamara; Liang, Eliza; Jain, Komal; Hitchens, Peta L.; Che, Xiaoyu; Soloyvov, Alexander; Hicks, Allison L.; Ojeda-Flores, Rafael; Zambrana-Torrelio, Carlos; Ulrich, Werner; Rostal, Melinda K.; Petrosov, Alexandra; Garcia, Joel; Haider, Najmul; Wolfe, Nathan; Goldstein, Tracey; Morse, Stephen S.; Rahman, Mahmudur; Epstein, Jonathan H.; Mazet, Jonna K.; Daszak, Peter; Lipkin, W. Ian

    2015-01-01

    It is currently unclear whether changes in viral communities will ever be predictable. Here we investigate whether viral communities in wildlife are inherently structured (inferring predictability) by looking at whether communities are assembled through deterministic (often predictable) or stochastic (not predictable) processes. We sample macaque faeces across nine sites in Bangladesh and use consensus PCR and sequencing to discover 184 viruses from 14 viral families. We then use network modelling and statistical null-hypothesis testing to show the presence of non-random deterministic patterns at different scales, between sites and within individuals. We show that the effects of determinism are not absolute however, as stochastic patterns are also observed. In showing that determinism is an important process in viral community assembly we conclude that it should be possible to forecast changes to some portion of a viral community, however there will always be some portion for which prediction will be unlikely. PMID:26391192

  12. Combination fluconazole/paroxetine treatment is neuroprotective despite ongoing neuroinflammation and viral replication in an SIV model of HIV neurological disease

    PubMed Central

    Meulendyke, Kelly A.; Queen, Suzanne E.; Engle, Elizabeth L.; Shirk, Erin N.; Liu, Jiayang; Steiner, Joseph P.; Nath, Avindra; Tarwater, Patrick M.; Graham, David R.; Mankowski, Joseph L.; Zink, M. Christine

    2014-01-01

    Effective combined antiretroviral therapy (cART) in HIV infected patients has made HIV a treatable condition; however, debilitating HIV-associated neurocognitive disorders (HAND) can still affect up to 50% of HIV infected individuals even under cART. While cART has greatly reduced the prevalence of the most severe form of HAND, milder forms have increased in prevalence, leaving a the total proportion of HIV-infected individuals suffering from HAND relatively unchanged. In this study an in vitro drug screen identified fluconazole and paroxetine as protective compounds against HIV gp120 and Tat neurotoxicity. Using an accelerated, consistent SIV/macaque model of HIV-associated CNS disease, we tested the in vivo neuroprotective capabilities of combination fluconazole/paroxetine (FluPar) treatment. FluPar treatment protected macaques from SIV-induced neurodegeneration, as measured by neurofilament light chain in the CSF, APP accumulation in the axons, and CaMKIIα in the frontal cortex, but did not significantly reduce markers of neuroinflammation or plasma or CNS viral loads. Since HIV and SIV neurodegeneration is often attributed to accompanying neuroinflammation, this study provides proof of concept that neuroprotection can be achieved even in the face of ongoing neuroinflammation and viral replication. PMID:25227932

  13. Bovine viral diarrhea virus NS3 serine proteinase: polyprotein cleavage sites, cofactor requirements, and molecular model of an enzyme essential for pestivirus replication.

    PubMed Central

    Xu, J; Mendez, E; Caron, P R; Lin, C; Murcko, M A; Collett, M S; Rice, C M

    1997-01-01

    Members of the Flaviviridae encode a serine proteinase termed NS3 that is responsible for processing at several sites in the viral polyproteins. In this report, we show that the NS3 proteinase of the pestivirus bovine viral diarrhea virus (BVDV) (NADL strain) is required for processing at nonstructural (NS) protein sites 3/4A, 4A/4B, 4B/5A, and 5A/5B but not for cleavage at the junction between NS2 and NS3. Cleavage sites of the proteinase were determined by amino-terminal sequence analysis of the NS4A, NS4B, NS5A, and NS5B proteins. A conserved leucine residue is found at the P1 position of all four cleavage sites, followed by either serine (3/4A, 4B/5A, and 5A/5B sites) or alanine (4A/4B site) at the P1' position. Consistent with this cleavage site preference, a structural model of the pestivirus NS3 proteinase predicts a highly hydrophobic P1 specificity pocket. trans-Processing experiments implicate the 64-residue NS4A protein as an NS3 proteinase cofactor required for cleavage at the 4B/5A and 5A/5B sites. Finally, using a full-length functional BVDV cDNA clone, we demonstrate that a catalytically active NS3 serine proteinase is essential for pestivirus replication. PMID:9188600

  14. Application of cross-linked and hydrolyzed arabinoxylans in baking of model rye bread.

    PubMed

    Buksa, Krzysztof; Nowotna, Anna; Ziobro, Rafał

    2016-02-01

    The role of water extractable arabinoxylan with varying molar mass and structure (cross-linked vs. hydrolyzed) in the structure formation of rye bread was examined using a model bread. Instead of the normal flour, the dough contained starch, arabinoxylan and protein, which were isolated from rye wholemeal. It was observed that the applied mixes of these constituents result in a product closely resembling typical rye bread, even if arabinoxylan was modified (by cross-linking or hydrolysis). The levels of arabinoxylan required for bread preparation depended on its modification and mix composition. At 3% protein, the maximum applicable level of poorly soluble cross-linked arabinoxylan was 3%, as higher amounts of this preparation resulted in an extensively viscous dough and diminished bread volume. On the other hand highly soluble, hydrolyzed arabinoxylan could be used at a higher level (6%) together with larger amounts of rye protein (3% or 6%). Further addition of arabinoxylan leads to excessive water absorption, resulting in a decreased viscosity of the dough during baking and insufficient gas retention. PMID:26304439

  15. An atomistic model for cross-linked HNBR elastomers used in seals

    NASA Astrophysics Data System (ADS)

    Molinari, Nicola; Sutton, Adrian; Stevens, John; Mostofi, Arash

    2015-03-01

    Hydrogenated nitrile butadiene rubber (HNBR) is one of the most common elastomeric materials used for seals in the oil and gas industry. These seals sometimes suffer ``explosive decompression,'' a costly problem in which gases permeate a seal at the elevated temperatures and pressures pertaining in oil and gas wells, leading to rupture when the seal is brought back to the surface. The experimental evidence that HNBR and its unsaturated parent NBR have markedly different swelling properties suggests that cross-linking may occur during hydrogenation of NBR to produce HNBR. We have developed a code compatible with the LAMMPS molecular dynamics package to generate fully atomistic HNBR configurations by hydrogenating initial NBR structures. This can be done with any desired degree of cross-linking. The code uses a model of atomic interactions based on the OPLS-AA force-field. We present calculations of the dependence of a number of bulk properties on the degree of cross-linking. Using our atomistic representations of HNBR and NBR, we hope to develop a better molecular understanding of the mechanisms that result in explosive decompression.

  16. LERC-SLAM - THE NASA LEWIS RESEARCH CENTER SATELLITE LINK ATTENUATION MODEL PROGRAM (MACINTOSH VERSION)

    NASA Technical Reports Server (NTRS)

    Manning, R. M.

    1994-01-01

    The frequency and intensity of rain attenuation affecting the communication between a satellite and an earth terminal is an important consideration in planning satellite links. The NASA Lewis Research Center Satellite Link Attenuation Model Program (LeRC-SLAM) provides a static and dynamic statistical assessment of the impact of rain attenuation on a communications link established between an earth terminal and a geosynchronous satellite. The program is designed for use in the specification, design and assessment of satellite links for any terminal location in the continental United States. The basis for LeRC-SLAM is the ACTS Rain Attenuation Prediction Model, which uses a log-normal cumulative probability distribution to describe the random process of rain attenuation on satellite links. The derivation of the statistics for the rainrate process at the specified terminal location relies on long term rainfall records compiled by the U.S. Weather Service during time periods of up to 55 years in length. The theory of extreme value statistics is also utilized. The user provides 1) the longitudinal position of the satellite in geosynchronous orbit, 2) the geographical position of the earth terminal in terms of latitude and longitude, 3) the height above sea level of the terminal site, 4) the yearly average rainfall at the terminal site, and 5) the operating frequency of the communications link (within 1 to 1000 GHz, inclusive). Based on the yearly average rainfall at the terminal location, LeRC-SLAM calculates the relevant rain statistics for the site using an internal data base. The program then generates rain attenuation data for the satellite link. This data includes a description of the static (i.e., yearly) attenuation process, an evaluation of the cumulative probability distribution for attenuation effects, and an evaluation of the probability of fades below selected fade depths. In addition, LeRC-SLAM calculates the elevation and azimuth angles of the terminal

  17. LERC-SLAM - THE NASA LEWIS RESEARCH CENTER SATELLITE LINK ATTENUATION MODEL PROGRAM (IBM PC VERSION)

    NASA Technical Reports Server (NTRS)

    Manning, R. M.

    1994-01-01

    The frequency and intensity of rain attenuation affecting the communication between a satellite and an earth terminal is an important consideration in planning satellite links. The NASA Lewis Research Center Satellite Link Attenuation Model Program (LeRC-SLAM) provides a static and dynamic statistical assessment of the impact of rain attenuation on a communications link established between an earth terminal and a geosynchronous satellite. The program is designed for use in the specification, design and assessment of satellite links for any terminal location in the continental United States. The basis for LeRC-SLAM is the ACTS Rain Attenuation Prediction Model, which uses a log-normal cumulative probability distribution to describe the random process of rain attenuation on satellite links. The derivation of the statistics for the rainrate process at the specified terminal location relies on long term rainfall records compiled by the U.S. Weather Service during time periods of up to 55 years in length. The theory of extreme value statistics is also utilized. The user provides 1) the longitudinal position of the satellite in geosynchronous orbit, 2) the geographical position of the earth terminal in terms of latitude and longitude, 3) the height above sea level of the terminal site, 4) the yearly average rainfall at the terminal site, and 5) the operating frequency of the communications link (within 1 to 1000 GHz, inclusive). Based on the yearly average rainfall at the terminal location, LeRC-SLAM calculates the relevant rain statistics for the site using an internal data base. The program then generates rain attenuation data for the satellite link. This data includes a description of the static (i.e., yearly) attenuation process, an evaluation of the cumulative probability distribution for attenuation effects, and an evaluation of the probability of fades below selected fade depths. In addition, LeRC-SLAM calculates the elevation and azimuth angles of the terminal

  18. Probing the Lipid-Protein Interface Using Model Transmembrane Peptides with a Covalently Linked Acyl Chain

    PubMed Central

    Nyholm, Thomas K.M.; van Duyl, Bianca; Rijkers, Dirk T.S.; Liskamp, Rob M.J.; Killian, J. Antoinette

    2011-01-01

    The aim of this study was to gain insight into how interactions between proteins and lipids in membranes are sensed at the protein-lipid interface. As a probe to analyze this interface, we used deuterium-labeled acyl chains that were covalently linked to a model transmembrane peptide. First, a perdeuterated palmitoyl chain was coupled to the Trp-flanked peptide WALP23 (Ac-CGWW(LA)8LWWA-NH2), and the deuterium NMR spectrum was analyzed in di-C18:1-phosphatidylcholine (PC) bilayers. We found that the chain order of this peptide-linked chain is rather similar to that of a noncovalently coupled perdeuterated palmitoyl chain, except that it exhibits a slightly lower order. Similar results were obtained when site-specific deuterium labels were used and when the palmitoyl chain was attached to the more-hydrophobic model peptide WLP23 (Ac-CGWWL17WWA-NH2) or to the Lys-flanked peptide KALP23 (Ac-CGKK(LA)8LKKA-NH2). The experiments showed that the order of both the peptide-linked chains and the noncovalently coupled palmitoyl chains in the phospholipid bilayer increases in the order KALP23 < WALP23 < WLP23. Furthermore, changes in the bulk lipid bilayer thickness caused by varying the lipid composition from di-C14:1-PC to di-C18:1-PC or by including cholesterol were sensed rather similarly by the covalently coupled chain and the noncovalently coupled palmitoyl chains. The results indicate that the properties of lipids adjacent to transmembrane peptides mostly reflect the properties of the surrounding lipid bilayer, and hence that (at least for the single-span model peptides used in this study) annular lipids do not play a highly specific role in protein-lipid interactions. PMID:22004750

  19. LINKING ETA MODEL WITH THE COMMUNITY MULTISCALE AIR QUALITY (CMAQ) MODELING SYSTEM: OZONE BOUNDARY CONDITIONS

    EPA Science Inventory

    A prototype surface ozone concentration forecasting model system for the Eastern U.S. has been developed. The model system is consisting of a regional meteorological and a regional air quality model. It demonstrated a strong prediction dependence on its ozone boundary conditions....

  20. The Repeated Insertion Model for Rankings: Missing Link between Two Subset Choice Models

    ERIC Educational Resources Information Center

    Doignon, Jean-Paul; Pekec, Aleksandar; Regenwetter, Michel

    2004-01-01

    Several probabilistic models for subset choice have been proposed in the literature, for example, to explain approval voting data. We show that Marley et al.'s latent scale model is subsumed by Falmagne and Regenwetter's size-independent model, in the sense that every choice probability distribution generated by the former can also be explained by…

  1. Excitonic Coupling and Femtosecond Relaxation of Zinc Porphyrin Oligomers Linked with Triazole Bridge: Dynamics and Modeling.

    PubMed

    Bukreev, Alexey; Mikhailov, Konstantin; Shelaev, Ivan; Gostev, Fedor; Polevaya, Yuliya; Tyurin, Vladimir; Beletskaya, Irina; Umansky, Stanislav; Nadtochenko, Victor

    2016-03-31

    The synthesis of new zinc porphyrin oligomers linked by a triazole bridge was carried out via "click" reaction. A split in the porphyrin oligomer B-band was observed. It was considered as evidence of exciton-excitonic coupling. The relaxation of excited states in Q-band porphyrin oligomers was studied by the femtosecond laser spectroscopy technique with a 20 fs pump pulse. The transient oscillations of two B-band excitonic peaks have a π-radian shift. For explanation of the coherent oscillation, a theoretical model was developed. The model considered the combination of the exciton-excitonic coupling between porphyrin rings in dimer and weak exciton-vibronic coupling in one porphyrin ring. By varying the values of the structural parameters of porphyrins (the strength values of this couplings and measure of symmetry breaking), we obtained correspondence between the experimental data (phase shift and amplitudes of the spectrum oscillations) and the predictions of the model developed here. PMID:26935579

  2. Two Allergen Model Reveals Complex Relationship Between IgE Cross-Linking and Degranulation

    PubMed Central

    Handlogten, Michael W.; Deak, Peter E.; Bilgicer, Basar

    2014-01-01

    Summary Allergy is an immune response to complex mixtures of multiple allergens yet current models use a single synthetic allergen. Multiple allergens were modeled using two well-defined tetravalent allergens each specific for a distinct IgE thus enabling a systematic approach to evaluate the effect of each allergen and percent of allergen specific IgE on mast cell degranulation. We found the overall degranulation response caused by two allergens is additive for low allergen concentrations or low percent specific IgE, does not change for moderate allergen concentrations with moderate to high percent specific IgE, and is reduced for high allergen concentrations with moderate to high percent specific IgE. These results provide further evidence that supra-optimal IgE cross-linking decreases the degranulation response and establishes the two allergen model as a relevant experimental system to elucidate mast cell degranulation mechanisms. PMID:25308278

  3. Modeling framework to link climate, hydrology and flood hazards: An application to Sacramento, California

    NASA Astrophysics Data System (ADS)

    Kim, B.; David, C. H.; Druffel-Rodriguez, R.; Sanders, B. F.; Famiglietti, J. S.

    2013-12-01

    The City of Sacramento and the broader delta region may be the most flood vulnerable urbanized area in the United States. Management of flood risk here and elsewhere requires an understanding of flooding hazards, which is in turn linked to California hydrology, climate, development and flood control infrastructure. A modeling framework is presented here to make predictions of flooding hazards (e.g., depth and velocity) at the household scale (personalized flood risk information), and to study how these predictions could change under different climate change, land-use change, and infrastructure adaptation scenarios. The framework couples a statewide hydrologic model (RAPID) that predicts runoff and streamflow to a city-scale hydrodynamic model (BreZo) capable of predicting levee-breach flows and overland flows into urbanized lowlands. Application of the framework to the Sacramento area is presented here, with a focus on data needs, computational demands, results and hazard communication strategies, for selected flooding scenarios.

  4. Link between hopping models and percolation scaling laws for charge transport in mixtures of small molecules

    NASA Astrophysics Data System (ADS)

    Ha, Dong-Gwang; Kim, Jang-Joo; Baldo, Marc A.

    2016-04-01

    Mixed host compositions that combine charge transport materials with luminescent dyes offer superior control over exciton formation and charge transport in organic light emitting devices (OLEDs). Two approaches are typically used to optimize the fraction of charge transport materials in a mixed host composition: either an empirical percolative model, or a hopping transport model. We show that these two commonly-employed models are linked by an analytic expression which relates the localization length to the percolation threshold and critical exponent. The relation is confirmed both numerically and experimentally through measurements of the relative conductivity of Tris(4-carbazoyl-9-ylphenyl)amine (TCTA) :1,3-bis(3,5-dipyrid-3-yl-phenyl)benzene (BmPyPb) mixtures with different concentrations, where the TCTA plays a role as hole conductor and the BmPyPb as hole insulator. The analytic relation may allow the rational design of mixed layers of small molecules for high-performance OLEDs.

  5. Linking Slow Dynamics and Local Structure in Simple Models of Glass-Forming Liquids

    NASA Astrophysics Data System (ADS)

    Coslovich, D.; Pastore, G.

    2008-07-01

    Establishing a relation between the dynamical features of supercooled liquids, their structural properties and the nature of intermolecular interactions is a key issue in the description of the glass transition. To investigate this point we perform molecular dynamics simulations for three model glass-forming liquids with different types of local order. Our results show that the roughness of the energy landscape, estimated from the amplitude of average energy barriers, and the localization of unstable modes provide useful means to rationalize the link between structure and dynamics in glass-forming liquids.

  6. Modeling channel interference in an orbital angular momentum-multiplexed laser link

    NASA Astrophysics Data System (ADS)

    Anguita, Jaime A.; Neifeld, Mark A.; Vasic, Bane V.

    2009-08-01

    We study the effects of optical turbulence on the energy crosstalk among constituent orbital angular momentum (OAM) states in a vortex-based multi-channel laser communication link and determine channel interference in terms of turbulence strength and OAM state separation. We characterize the channel interference as a function of C2n and transmit OAM state, and propose probability models to predict the random fluctuations in the received signals for such architecture. Simulations indicate that turbulence-induced channel interference is mutually correlated across receive channels.

  7. Linking nutrient loading and oxygen in the coastal ocean: A new global scale model

    NASA Astrophysics Data System (ADS)

    Reed, Daniel C.; Harrison, John A.

    2016-03-01

    Recent decades have witnessed an exponential spread of low-oxygen regions in the coastal ocean due at least in-part to enhanced terrestrial nutrient inputs. As oxygen deprivation is a major stressor on marine ecosystems, there is a great need to quantitatively link shifts in nutrient loading with changes in oxygen concentrations. To this end, we have developed and here describe, evaluate, and apply the Coastal Ocean Oxygen Linked to Benthic Exchange And Nutrient Supply (COOLBEANS) model, a first-of-its-kind, spatially explicit (with 152 coastal segments) model, global model of coastal oxygen and nutrient dynamics. In COOLBEANS, benthic oxygen demand (BOD) is calculated using empirical models for aerobic respiration, iron reduction, and sulfate reduction, while oxygen supply is represented by a simple parameterization of exchange between surface and bottom waters. A nutrient cycling component translates shifts in riverine nutrient inputs into changes in organic matter delivery to sediments and, ultimately, oxygen uptake. Modeled BOD reproduces observations reasonably well (Nash-Sutcliffe efficiency = 0.71), and estimates of exchange between surface and bottom waters correlate with stratification. The model examines sensitivity of bottom water oxygen to changes in nutrient inputs and vertical exchange between surface and bottom waters, highlighting the importance of this vertical exchange in defining the susceptibility of a system to oxygen depletion. These sensitivities along with estimated maximum hypoxic areas that are supported by present day nutrient loads are consistent with existing hypoxic regions. Sensitivities are put into context by applying historic changes in nitrogen loading observed in the Gulf of Mexico to the global coastal ocean, demonstrating that such loads would drive many systems anoxic or even sulfidic.

  8. A model integration approach linking signalling and gene-regulatory logic with kinetic metabolic models.

    PubMed

    Ryll, A; Bucher, J; Bonin, A; Bongard, S; Gonçalves, E; Saez-Rodriguez, J; Niklas, J; Klamt, S

    2014-10-01

    Systems biology has to increasingly cope with large- and multi-scale biological systems. Many successful in silico representations and simulations of various cellular modules proved mathematical modelling to be an important tool in gaining a solid understanding of biological phenomena. However, models spanning different functional layers (e.g. metabolism, signalling and gene regulation) are still scarce. Consequently, model integration methods capable of fusing different types of biological networks and various model formalisms become a key methodology to increase the scope of cellular processes covered by mathematical models. Here we propose a new integration approach to couple logical models of signalling or/and gene-regulatory networks with kinetic models of metabolic processes. The procedure ends up with an integrated dynamic model of both layers relying on differential equations. The feasibility of the approach is shown in an illustrative case study integrating a kinetic model of central metabolic pathways in hepatocytes with a Boolean logical network depicting the hormonally induced signal transduction and gene regulation events involved. In silico simulations demonstrate the integrated model to qualitatively describe the physiological switch-like behaviour of hepatocytes in response to nutritionally regulated changes in extracellular glucagon and insulin levels. A simulated failure mode scenario addressing insulin resistance furthermore illustrates the pharmacological potential of a model covering interactions between signalling, gene regulation and metabolism. PMID:25063553

  9. Exosomes in Viral Disease.

    PubMed

    Anderson, Monique R; Kashanchi, Fatah; Jacobson, Steven

    2016-07-01

    Viruses have evolved many mechanisms by which to evade and subvert the immune system to ensure survival and persistence. However, for each method undertaken by the immune system for pathogen removal, there is a counteracting mechanism utilized by pathogens. The new and emerging role of microvesicles in immune intercellular communication and function is no different. Viruses across many different families have evolved to insert viral components in exosomes, a subtype of microvesicle, with many varying downstream effects. When assessed cumulatively, viral antigens in exosomes increase persistence through cloaking viral genomes, decoying the immune system, and even by increasing viral infection in uninfected cells. Exosomes therefore represent a source of viral antigen that can be used as a biomarker for disease and targeted for therapy in the control and eradication of these disorders. With the rise in the persistence of new and reemerging viruses like Ebola and Zika, exploring the role of exosomes become more important than ever. PMID:27324390

  10. Ensuring Congruency in Multiscale Modeling: Towards Linking Agent Based and Continuum Biomechanical Models of Arterial Adaptation

    PubMed Central

    Hayenga, Heather N.; Thorne, Bryan C.; Peirce, Shayn M.; Humphrey, Jay D.

    2011-01-01

    There is a need to develop multiscale models of vascular adaptations to understand tissue level manifestations of cellular level mechanisms. Continuum based biomechanical models are well suited for relating blood pressures and flows to stress-mediated changes in geometry and properties, but less so for describing underlying mechanobiological processes. Discrete stochastic agent based models are well suited for representing biological processes at a cellular level, but not for describing tissue level mechanical changes. We present here a conceptually new approach to facilitate the coupling of continuum and agent based models. Because of ubiquitous limitations in both the tissue- and cell-level data from which one derives constitutive relations for continuum models and rule-sets for agent based models, we suggest that model verification should enforce congruency across scales. That is, multiscale model parameters initially determined from data sets representing different scales should be refined, when possible, to ensure that common outputs are consistent. Potential advantages of this approach are illustrated by comparing simulated aortic responses to a sustained increase in blood pressure predicted by continuum and agent based models both before and after instituting a genetic algorithm to refine 16 objectively bounded model parameters. We show that congruency-based parameter refinement not only yielded increased consistency across scales, it also yielded predictions that are closer to in vivo observations. PMID:21809144

  11. Predictive statistical models linking antecedent meteorological conditions and waterway bacterial contamination in urban waterways.

    PubMed

    Farnham, David J; Lall, Upmanu

    2015-06-01

    Although the relationships between meteorological conditions and waterway bacterial contamination are being better understood, statistical models capable of fully leveraging these links have not been developed for highly urbanized settings. We present a hierarchical Bayesian regression model for predicting transient fecal indicator bacteria contamination episodes in urban waterways. Canals, creeks, and rivers of the New York City harbor system are used to examine the model. The model configuration facilitates the hierarchical structure of the underlying system with weekly observations nested within sampling sites, which in turn were nested inside of the harbor network. Models are compared using cross-validation and a variety of Bayesian and classical model fit statistics. The uncertainty of predicted enterococci concentration values is reflected by sampling from the posterior predictive distribution. Issuing predictions with the uncertainty reasonably reflected allows a water manager or a monitoring agency to issue warnings that better reflect the underlying risk of exposure. A model using only antecedent meteorological conditions is shown to correctly classify safe and unsafe levels of enterococci with good accuracy. The hierarchical Bayesian regression approach is most valuable where transient fecal indicator bacteria contamination is problematic and drainage network data are scarce. PMID:25813489

  12. A generalized linear mixed model for longitudinal binary data with a marginal logit link function

    PubMed Central

    Parzen, Michael; Ghosh, Souparno; Lipsitz, Stuart; Sinha, Debajyoti; Fitzmaurice, Garrett M.; Mallick, Bani K.; Ibrahim, Joseph G.

    2010-01-01

    Summary Longitudinal studies of a binary outcome are common in the health, social, and behavioral sciences. In general, a feature of random effects logistic regression models for longitudinal binary data is that the marginal functional form, when integrated over the distribution of the random effects, is no longer of logistic form. Recently, Wang and Louis (2003) proposed a random intercept model in the clustered binary data setting where the marginal model has a logistic form. An acknowledged limitation of their model is that it allows only a single random effect that varies from cluster to cluster. In this paper, we propose a modification of their model to handle longitudinal data, allowing separate, but correlated, random intercepts at each measurement occasion. The proposed model allows for a flexible correlation structure among the random intercepts, where the correlations can be interpreted in terms of Kendall’s τ. For example, the marginal correlations among the repeated binary outcomes can decline with increasing time separation, while the model retains the property of having matching conditional and marginal logit link functions. Finally, the proposed method is used to analyze data from a longitudinal study designed to monitor cardiac abnormalities in children born to HIV-infected women. PMID:21532998

  13. Transgenic Expression of Viral Capsid Proteins Predisposes to Axonal Injury in a Murine Model of Multiple Sclerosis

    PubMed Central

    Denic, Aleksandar; Zoecklein, Laurie; Kerkvliet, Jason; Papke, Louisa; Edukulla, Ramakrishna; Warrington, Arthur; Bieber, Allan; Pease, Larry R.; David, Chella S.; Rodriguez, Moses

    2010-01-01

    We used transgenic expression of capsid antigens to Theiler's murine encephalomyelitis virus (TMEV) to study the influence of VP1, VP2, or VP2121-130 to either protection or pathogenesis to chronic spinal cord demyelination, axonal loss and functional deficits during the acute and chronic phases of infection. We used both mice that are normally susceptible (FVB) and mice normally resistant (FVB.Db) to demyelination. Transgenic expression of VP2121-130 epitope in resistant FVB.Db mice caused spinal cord pathology and virus persistence because the VP2121-130 epitope is the dominant peptide recognized by Db, which is critical for virus clearance. In contrast, all three FVB TMEV transgenic mice showed more demyelination, inflammation, and axonal loss as compared to wild type FVB mice even though virus load was not increased. Motor function measured by rotarod showed weak correlation with total number of midthoracic axons, but a strong correlation with large caliber axons (>10μm2). This study supports the hypothesis that expression of viral capsid proteins as self influences the extent of axonal pathology following Theiler's virus-induced demyelination. The findings provide insight into the role of axonal injury in the development of functional deficits that may have relevance to human demyelinating disease. PMID:21314744

  14. Optimization of in situ hybridization for detection of viral genomes in cultured cells on 96-microwell plates: a cytomegalovirus model.

    PubMed Central

    Mougin, C; Bassignot, A; Coaquette, A; Bourgeois, A; Lab, M

    1991-01-01

    In situ hybridization (ISH) for identification of infectious replicative cytomegalovirus (CMV) in cell culture microplates (96 microwells) infected by clinical specimens was tested by using a biotin-labeled DNA probe and an avidin-alkaline phosphatase conjugate. A total of 395 specimens were examined by using ISH and a monoclonal antibody (MAb) specific for an early antigen of CMV. Of 47 specimens that gave a positive signal for CMV by ISH, 33 were confirmed virus positive by MAb staining. Of 141 blood samples tested, 4.96% were positive by ISH, and 0.7% were positive by the MAb technique. ISH shows 40% more sensitivity than MAb staining. This technique should be widely applicable for the specific identification of viral isolates (e.g., herpesvirus, myxovirus, paramyxovirus, and enterovirus) in cell culture 96-microwell microplates, thereby making it feasible to screen a larger number of samples than is possible with classical methods using conventional culture tubes, shell vials, or 24-well plates. Images PMID:1662228

  15. Actinobacteria from Termite Mounds Show Antiviral Activity against Bovine Viral Diarrhea Virus, a Surrogate Model for Hepatitis C Virus

    PubMed Central

    Padilla, Marina Aiello; Rodrigues, Rodney Alexandre Ferreira; Bastos, Juliana Cristina Santiago; Martini, Matheus Cavalheiro; Barnabé, Ana Caroline de Souza; Kohn, Luciana Konecny; Uetanabaro, Ana Paula Trovatti; Bomfim, Getúlio Freitas; Afonso, Rafael Sanches; Fantinatti-Garboggini, Fabiana; Arns, Clarice Weis

    2015-01-01

    Extracts from termite-associated bacteria were evaluated for in vitro antiviral activity against bovine viral diarrhea virus (BVDV). Two bacterial strains were identified as active, with percentages of inhibition (IP) equal to 98%. Both strains were subjected to functional analysis via the addition of virus and extract at different time points in cell culture; the results showed that they were effective as posttreatments. Moreover, we performed MTT colorimetric assays to identify the CC50, IC50, and SI values of these strains, and strain CDPA27 was considered the most promising. In parallel, the isolates were identified as Streptomyces through 16S rRNA gene sequencing analysis. Specifically, CDPA27 was identified as S. chartreusis. The CDPA27 extract was fractionated on a C18-E SPE cartridge, and the fractions were reevaluated. A 100% methanol fraction was identified to contain the compound(s) responsible for antiviral activity, which had an SI of 262.41. GC-MS analysis showed that this activity was likely associated with the compound(s) that had a peak retention time of 5 min. Taken together, the results of the present study provide new information for antiviral research using natural sources, demonstrate the antiviral potential of Streptomyces chartreusis compounds isolated from termite mounds against BVDV, and lay the foundation for further studies on the treatment of HCV infection. PMID:26579205

  16. Curative haploidentical BMT in a murine model of X-linked chronic granulomatous disease.

    PubMed

    Takeuchi, Yasuo; Takeuchi, Emiko; Ishida, Takashi; Onodera, Masafumi; Nakauchi, Hiromitsu; Otsu, Makoto

    2015-07-01

    Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by defective microbial killing in phagocytes. Long-term prognosis for CGD patients is generally poor, highlighting the need to develop minimally toxic, curative therapeutic approaches. We here describe the establishment of a mouse model in which X-linked CGD can be cured by allogeneic bone marrow transplantation. Using a combination of non-myeloablative-dose total body irradiation and a single injection of anti-CD40 ligand monoclonal antibody, transplantation of whole bone marrow cells achieved long-lasting mixed chimerism in X-linked CGD mice in a haploidentical transplantation setting. Stable mixed chimerism was maintained for up to 1 year even at a low range (<20 % donor cells), indicating induction of donor-specific tolerance. The regimen induced mild myelosuppression without severe acute complications. Stable chimerism was therapeutic, as it suppressed cutaneous granuloma formation in an in vivo test suited for evaluation of treatment efficacy in murine CGD models. These results warrant future development of a simplified allogeneic hematopoietic cell transplantation regimen that would benefit CGD patients by allowing the use of haploidentical donor grafts without serious concerns of severe treatment-related toxicity. PMID:25921405

  17. Condensation transitions in a model for a directed network with weighted links

    NASA Astrophysics Data System (ADS)

    Angel, A. G.; Hanney, T.; Evans, M. R.

    2006-01-01

    An exactly solvable model for the rewiring dynamics of weighted, directed networks is introduced. Simulations indicate that the model exhibits two types of condensation: (i) a phase in which, for each node, a finite fraction of its total out-strength condenses onto a single link; (ii) a phase in which a finite fraction of the total weight in the system is directed into a single node. A virtue of the model is that its dynamics can be mapped onto those of a zero-range process with many species of interacting particles—an exactly solvable model of particles hopping between the sites of a lattice. This mapping, which is described in detail, guides the analysis of the steady state of the network model and leads to theoretical predictions for the conditions under which the different types of condensation may be observed. A further advantage of the mapping is that, by exploiting what is known about exactly solvable generalizations of the zero-range process, one can infer a number of generalizations of the network model and dynamics which remain exactly solvable.

  18. Linking Statistically- and Physically-Based Models for Improved Streamflow Simulation in Gaged and Ungaged Areas

    NASA Astrophysics Data System (ADS)

    Lafontaine, J.; Hay, L.; Archfield, S. A.; Farmer, W. H.; Kiang, J. E.

    2014-12-01

    The U.S. Geological Survey (USGS) has developed a National Hydrologic Model (NHM) to support coordinated, comprehensive and consistent hydrologic model development, and facilitate the application of hydrologic simulations within the continental US. The portion of the NHM located within the Gulf Coastal Plains and Ozarks Landscape Conservation Cooperative (GCPO LCC) is being used to test the feasibility of improving streamflow simulations in gaged and ungaged watersheds by linking statistically- and physically-based hydrologic models. The GCPO LCC covers part or all of 12 states and 5 sub-geographies, totaling approximately 726,000 km2, and is centered on the lower Mississippi Alluvial Valley. A total of 346 USGS streamgages in the GCPO LCC region were selected to evaluate the performance of this new calibration methodology for the period 1980 to 2013. Initially, the physically-based models are calibrated to measured streamflow data to provide a baseline for comparison. An enhanced calibration procedure then is used to calibrate the physically-based models in the gaged and ungaged areas of the GCPO LCC using statistically-based estimates of streamflow. For this application, the calibration procedure is adjusted to address the limitations of the statistically generated time series to reproduce measured streamflow in gaged basins, primarily by incorporating error and bias estimates. As part of this effort, estimates of uncertainty in the model simulations are also computed for the gaged and ungaged watersheds.

  19. Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus

    PubMed Central

    Crampton, Steve P.; Morawski, Peter A.; Bolland, Silvia

    2014-01-01

    Systemic lupus erythematosus (SLE) represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS) and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease. PMID:25147296

  20. A computer model for unconscious spread of anxiety-linked inhibition in cognitive networks.

    PubMed

    Blum, G S

    1989-01-01

    Unconscious inhibitory processes, triggered by a potential anxiety reaction, are reviewed in the context of an emerging rapprochement between psychodynamic and cognitive approaches in experimental psychology. Conditions underlying spread of inhibitory action to other cognitive networks are first explored in three tachistoscopic experiments utilizing words posthypnotically tied to a potential anxiety, pleasure, or neutral reaction. Response times of subjects, instructed to ignore those words while naming pictures or solving anagrams as quickly as possible, reveal a highly differentiated pattern of circumstances governing likelihood of inhibitory spread from anxiety-linked words to target stimuli. Next a computer model is constructed to simulate cognitive processes from onset of display to eventual response, and the model is then tested for its fit to the empirical data. Finally, an illustrative study shows that a subset of computer-generated predictions for spread of inhibitory action is verifiable experimentally. PMID:2920005

  1. Individual-based modeling of fish: Linking to physical models and water quality.

    SciTech Connect

    Rose, K.A.

    1997-08-01

    The individual-based modeling approach for the simulating fish population and community dynamics is gaining popularity. Individual-based modeling has been used in many other fields, such as forest succession and astronomy. The popularity of the individual-based approach is partly a result of the lack of success of the more aggregate modeling approaches traditionally used for simulating fish population and community dynamics. Also, recent recognition that it is often the atypical individual that survives has fostered interest in the individual-based approach. Two general types of individual-based models are distribution and configuration. Distribution models follow the probability distributions of individual characteristics, such as length and age. Configuration models explicitly simulate each individual; the sum over individuals being the population. DeAngelis et al (1992) showed that, when distribution and configuration models were formulated from the same common pool of information, both approaches generated similar predictions. The distribution approach was more compact and general, while the configuration approach was more flexible. Simple biological changes, such as making growth rate dependent on previous days growth rates, were easy to implement in the configuration version but prevented simple analytical solution of the distribution version.

  2. Channel modelling for free-space optical inter-HAP links using adaptive ARQ transmission

    NASA Astrophysics Data System (ADS)

    Parthasarathy, S.; Giggenbach, D.; Kirstädter, A.

    2014-10-01

    Free-space optical (FSO) communication systems have seen significant developments in recent years due to growing need for very high data rates and tap-proof communication. The operation of an FSO link is suited to diverse variety of applications such as satellites, High Altitude Platforms (HAPs), Unmanned Aerial Vehicles (UAVs), aircrafts, ground stations and other areas involving both civil and military situations. FSO communication systems face challenges due to different effects of the atmospheric channel. FSO channel primarily suffers from scintillation effects due to Index of Refraction Turbulence (IRT). In addition, acquisition and pointing becomes more difficult because of the high directivity of the transmitted beam: Miss-pointing of the transmitted beam and tracking errors at the receiver generate additional fading of the optical signal. High Altitude Platforms (HAPs) are quasi-stationary vehicles operating in the stratosphere. The slowly varying but precisely determined time-of-flight of the Inter-HAP channel adds to its characteristics. To propose a suitable ARQ scheme, proper theoretical understanding of the optical atmospheric propagation and modeling of a specific scenario FSO channel is required. In this paper, a bi-directional symmetrical Inter-HAP link has been selected and modeled. The Inter-HAP channel model is then investigated via simulations in terms of optical scintillation induced by IRT and in presence of pointing error. The performance characteristic of the model is then quantified in terms of fading statistics from which the Packet Error Probability (PEP) is calculated. Based on the PEP characteristics, we propose suitable ARQ schemes.

  3. Remyelination Is Correlated with Regulatory T Cell Induction Following Human Embryoid Body-Derived Neural Precursor Cell Transplantation in a Viral Model of Multiple Sclerosis.

    PubMed

    Plaisted, Warren C; Zavala, Angel; Hingco, Edna; Tran, Ha; Coleman, Ronald; Lane, Thomas E; Loring, Jeanne F; Walsh, Craig M

    2016-01-01

    We have recently described sustained clinical recovery associated with dampened neuroinflammation and remyelination following transplantation of neural precursor cells (NPCs) derived from human embryonic stem cells (hESCs) in a viral model of the human demyelinating disease multiple sclerosis. The hNPCs used in that study were derived by a novel direct differentiation method (direct differentiation, DD-NPCs) that resulted in a unique gene expression pattern when compared to hNPCs derived by conventional methods. Since the therapeutic potential of human NPCs may differ greatly depending on the method of derivation and culture, we wanted to determine whether NPCs differentiated using conventional methods would be similarly effective in improving clinical outcome under neuroinflammatory demyelinating conditions. For the current study, we utilized hNPCs differentiated from a human induced pluripotent cell line via an embryoid body intermediate stage (EB-NPCs). Intraspinal transplantation of EB-NPCs into mice infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) resulted in decreased accumulation of CD4+ T cells in the central nervous system that was concomitant with reduced demyelination at the site of injection. Dampened neuroinflammation and remyelination was correlated with a transient increase in CD4+FOXP3+ regulatory T cells (Tregs) concentrated within the peripheral lymphatics. However, compared to our earlier study, pathological improvements were modest and did not result in significant clinical recovery. We conclude that the genetic signature of NPCs is critical to their effectiveness in this model of viral-induced neurologic disease. These comparisons will be useful for understanding what factors are critical for the sustained clinical improvement. PMID:27310015

  4. Remyelination Is Correlated with Regulatory T Cell Induction Following Human Embryoid Body-Derived Neural Precursor Cell Transplantation in a Viral Model of Multiple Sclerosis

    PubMed Central

    Plaisted, Warren C.; Zavala, Angel; Hingco, Edna; Tran, Ha; Coleman, Ronald; Lane, Thomas E.; Loring, Jeanne F.; Walsh, Craig M.

    2016-01-01

    We have recently described sustained clinical recovery associated with dampened neuroinflammation and remyelination following transplantation of neural precursor cells (NPCs) derived from human embryonic stem cells (hESCs) in a viral model of the human demyelinating disease multiple sclerosis. The hNPCs used in that study were derived by a novel direct differentiation method (direct differentiation, DD-NPCs) that resulted in a unique gene expression pattern when compared to hNPCs derived by conventional methods. Since the therapeutic potential of human NPCs may differ greatly depending on the method of derivation and culture, we wanted to determine whether NPCs differentiated using conventional methods would be similarly effective in improving clinical outcome under neuroinflammatory demyelinating conditions. For the current study, we utilized hNPCs differentiated from a human induced pluripotent cell line via an embryoid body intermediate stage (EB-NPCs). Intraspinal transplantation of EB-NPCs into mice infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) resulted in decreased accumulation of CD4+ T cells in the central nervous system that was concomitant with reduced demyelination at the site of injection. Dampened neuroinflammation and remyelination was correlated with a transient increase in CD4+FOXP3+ regulatory T cells (Tregs) concentrated within the peripheral lymphatics. However, compared to our earlier study, pathological improvements were modest and did not result in significant clinical recovery. We conclude that the genetic signature of NPCs is critical to their effectiveness in this model of viral-induced neurologic disease. These comparisons will be useful for understanding what factors are critical for the sustained clinical improvement. PMID:27310015

  5. On linking an Earth system model to the equilibrium carbon representation of an economically optimizing land use model

    SciTech Connect

    Bond-Lamberty, Benjamin; Calvin, Katherine V.; Jones, Andrew D.; Mao, Jiafu; Patel, Pralit L.; Shi, Xiaoying; Thomson, Allison M.; Thornton, Peter E.; Zhou, Yuyu

    2014-01-01

    Human activities are significantly altering biogeochemical cycles at the global scale, posing a significant problem for earth system models (ESMs), which may incorporate static land-use change inputs but do not actively simulate policy or economic forces. One option to address this problem is a to couple an ESM with an economically oriented integrated assessment model. Here we have implemented and tested a coupling mechanism between the carbon cycles of an ESM (CLM) and an integrated assessment (GCAM) model, examining the best proxy variables to share between the models, and quantifying our ability to distinguish climate- and land-use-driven flux changes. CLM’s net primary production and heterotrophic respiration outputs were found to be the most robust proxy variables by which to manipulate GCAM’s assumptions of long-term ecosystem steady state carbon, with short-term forest production strongly correlated with long-term biomass changes in climate-change model runs. By leveraging the fact that carbon-cycle effects of anthropogenic land-use change are short-term and spatially limited relative to widely distributed climate effects, we were able to distinguish these effects successfully in the model coupling, passing only the latter to GCAM. By allowing climate effects from a full earth system model to dynamically modulate the economic and policy decisions of an integrated assessment model, this work provides a foundation for linking these models in a robust and flexible framework capable of examining two-way interactions between human and earth system processes.

  6. Stabilizing PID controllers for a single-link biomechanical model with position, velocity, and force feedback.

    PubMed

    Iqbal, Kamran; Roy, Anindo

    2004-12-01

    In this paper we address the problem of PID stabilization of a single-link inverted pendulum-based biomechanical model with force feedback, two levels of position and velocity feedback, and with delays in all the feedback loops. The novelty of the proposed model lies in its physiological relevance, whereby both small and medium latency sensory feedbacks from muscle spindle (MS), and force feedback from Golgi tendon organ (GTO) are included in the formulation. The biomechanical model also includes active and passive viscoelastic feedback from Hill-type muscle model and a second-order low-pass function for muscle activation. The central nervous system (CNS) regulation of postural movement is represented by a proportional-integral-derivative (PID) controller. Padé approximation of delay terms is employed to arrive at an overall rational transfer function of the biomechanical model. The Hermite-Biehler theorem is then used to derive stability results, leading to the existence of stabilizing PID controllers. An algorithm for selection of stabilizing feedback gains is developed using the linear matrix inequality (LMI) approach. PMID:15796343

  7. Evaluating a model linking assessed parent factors to four domains of youth risky driving.

    PubMed

    Schmidt, Sarah; Morrongiello, Barbara A; Colwell, Scott R

    2014-08-01

    Motor vehicle collisions are the leading cause of death in youth aged 15-19. Research has consistently shown that driver education programs do not result in safer youth driving. Indeed, the biggest predictor of collisions involving youth is parental history of collisions. The current study examined how parental modeling of and teaching about risky driving behaviors related to youth practices within four domains of risky driving (aggressive, substance use, distracted, moving violations), and evaluated whether the Prototype-Willingness Model explains links from parent to teen driving practices. Participants (N=432) were undergraduate students (mean age 18 years, age range 17-22 years) who had obtained their G2 driver's license within the past year; the G2 driver's license allows youth to drive alone on all municipal roads, with some restrictions on their blood alcohol level and the number of passengers they can carry. Results revealed that parental modeling was more predictive than parental teaching for all domains of risky driving examined. Youth whose parents modeled risky driving behaviors were found to be more likely to have engaged in those risky driving behaviors in the past, as well as to be more willing to engage in the behaviors in the future. The Prototype-Willingness Model was not a good fit to explain these relations. Findings from this study highlight the role parents play in the development of youth risky driving practices. PMID:24797085

  8. Development of conceptual ecological models linking management of the Missouri River to pallid sturgeon population dynamics

    USGS Publications Warehouse

    Jacobson, Robert B.; Parsley, Michael J.; Annis, Mandy L.; Colvin, Michael E.; Welker, Timothy L.; James, Daniel A.

    2015-01-01

    This report documents the process of developing and refining conceptual ecological models (CEMs) for linking river management to pallid sturgeon (Scaphirhynchus albus) population dynamics in the Missouri River. The refined CEMs are being used in the Missouri River Pallid Sturgeon Effects Analysis to organize, document, and formalize an understanding of pallid sturgeon population responses to past and future management alternatives. The general form of the CEMs, represented by a population-level model and component life-stage models, was determined in workshops held in the summer of 2013. Subsequently, the Missouri River Pallid Sturgeon Effects Analysis team designed a general hierarchical structure for the component models, refined the graphical structure, and reconciled variation among the components and between models developed for the upper river (Upper Missouri & Yellowstone Rivers) and the lower river (Missouri River downstream from Gavins Point Dam). Importance scores attributed to the relations between primary biotic characteristics and survival were used to define a candidate set of working dominant hypotheses about pallid sturgeon population dynamics. These CEMs are intended to guide research and adaptive-management actions to benefit pallid sturgeon populations in the Missouri River.

  9. A dynamical systems analysis of the data assimilation linked ecosystem carbon (DALEC) models

    NASA Astrophysics Data System (ADS)

    Chuter, Anna M.; Aston, Philip J.; Skeldon, Anne C.; Roulstone, Ian

    2015-03-01

    Changes in our climate and environment make it ever more important to understand the processes involved in Earth systems, such as the carbon cycle. There are many models that attempt to describe and predict the behaviour of carbon stocks and stores but, despite their complexity, significant uncertainties remain. We consider the qualitative behaviour of one of the simplest carbon cycle models, the Data Assimilation Linked Ecosystem Carbon (DALEC) model, which is a simple vegetation model of processes involved in the carbon cycle of forests, and consider in detail the dynamical structure of the model. Our analysis shows that the dynamics of both evergreen and deciduous forests in DALEC are dependent on a few key parameters and it is possible to find a limit point where there is stable sustainable behaviour on one side but unsustainable conditions on the other side. The fact that typical parameter values reside close to this limit point highlights the difficulty of predicting even the correct trend without sufficient data and has implications for the use of data assimilation methods.

  10. Viruses and viral proteins

    PubMed Central

    Verdaguer, Nuria; Ferrero, Diego; Murthy, Mathur R. N.

    2014-01-01

    For more than 30 years X-ray crystallography has been by far the most powerful approach for determining the structures of viruses and viral proteins at atomic resolution. The information provided by these structures, which covers many important aspects of the viral life cycle such as cell-receptor recognition, viral entry, nucleic acid transfer and genome replication, has extensively enriched our vision of the virus world. Many of the structures available correspond to potential targets for antiviral drugs against important human pathogens. This article provides an overview of the current knowledge of different structural aspects of the above-mentioned processes. PMID:25485129

  11. Linking Formal and Informal Science Education: A Successful Model using Libraries, Volunteers and NASA Resources

    NASA Astrophysics Data System (ADS)

    Race, M. S.; Lafayette Library; Learning Center Foundation (Lllcf)

    2011-12-01

    In these times of budget cuts, tight school schedules, and limited opportunities for student field trips and teacher professional development, it is especially difficult to expose elementary and middle school students to the latest STEM information-particularly in the space sciences. Using our library as a facilitator and catalyst, we built a volunteer-based, multi-faceted, curriculum-linked program for students and teachers in local middle schools (Grade 8) and showcased new astronomical and planetary science information using mainly NASA resources and volunteer effort. The project began with the idea of bringing free NASA photo exhibits (FETTU) to the Lafayette and Antioch Libraries for public display. Subsequently, the effort expanded by adding layers of activities that brought space and science information to teachers, students and the pubic at 5 libraries and schools in the 2 cities, one of which serves a diverse, underserved community. Overall, the effort (supported by a pilot grant from the Bechtel Foundation) included school and library based teacher workshops with resource materials; travelling space museum visits with hands-on activities (Chabot-to-Go); separate powerpoint presentations for students and adults at the library; and concurrent ancillary space-related themes for young children's programs at the library. This pilot project, based largely on the use of free government resources and online materials, demonstrated that volunteer-based, standards-linked STEM efforts can enhance curriculum at the middle school, with libraries serving a special role. Using this model, we subsequently also obtained a small NASA-Space Grant award to bring star parties and hand-on science activities to three libraries this Fall, linking with numerous Grade 5 teachers and students in two additional underserved areas of our county. It's not necessary to reinvent the wheel, you just collect the pieces and build on what you already have.

  12. Linking Murine and Human Plasmodium falciparum Challenge Models in a Translational Path for Antimalarial Drug Development

    PubMed Central

    McCarthy, James S.; Marquart, Louise; Sekuloski, Silvana; Trenholme, Katharine; Elliott, Suzanne; Griffin, Paul; Rockett, Rebecca; O'Rourke, Peter; Sloots, Theo; Angulo-Barturen, Iñigo; Ferrer, Santiago; Jiménez-Díaz, María Belén; Martínez, María-Santos; Duparc, Stephan; Leroy, Didier; Wells, Timothy N. C.; Baker, Mark

    2016-01-01

    Effective progression of candidate antimalarials is dependent on optimal dosing in clinical studies, which is determined by a sound understanding of pharmacokinetics and pharmacodynamics (PK/PD). Recently, two important translational models for antimalarials have been developed: the NOD/SCID/IL2Rγ−/− (NSG) model, whereby mice are engrafted with noninfected and Plasmodium falciparum-infected human erythrocytes, and the induced blood-stage malaria (IBSM) model in human volunteers. The antimalarial mefloquine was used to directly measure the PK/PD in both models, which were compared to previously published trial data for malaria patients. The clinical part was a single-center, controlled study using a blood-stage Plasmodium falciparum challenge inoculum in volunteers to characterize the effectiveness of mefloquine against early malaria. The study was conducted in three cohorts (n = 8 each) using different doses of mefloquine. The characteristic delay in onset of action of about 24 h was seen in both NSG and IBSM systems. In vivo 50% inhibitory concentrations (IC50s) were estimated at 2.0 μg/ml and 1.8 μg/ml in the NSG and IBSM models, respectively, aligning with 1.8 μg/ml reported previously for patients. In the IBSM model, the parasite reduction ratios were 157 and 195 for the 10- and 15-mg/kg doses, within the range of previously reported clinical data for patients but significantly lower than observed in the mouse model. Linking mouse and human challenge models to clinical trial data can accelerate the accrual of critical data on antimalarial drug activity. Such data can guide large clinical trials required for development of urgently needed novel antimalarial combinations. (This trial was registered at the Australian New Zealand Clinical Trials Registry [http://anzctr.org.au] under registration number ACTRN12612000323820.) PMID:27044554

  13. Linking Murine and Human Plasmodium falciparum Challenge Models in a Translational Path for Antimalarial Drug Development.

    PubMed

    McCarthy, James S; Marquart, Louise; Sekuloski, Silvana; Trenholme, Katharine; Elliott, Suzanne; Griffin, Paul; Rockett, Rebecca; O'Rourke, Peter; Sloots, Theo; Angulo-Barturen, Iñigo; Ferrer, Santiago; Jiménez-Díaz, María Belén; Martínez, María-Santos; Hooft van Huijsduijnen, Rob; Duparc, Stephan; Leroy, Didier; Wells, Timothy N C; Baker, Mark; Möhrle, Jörg J

    2016-06-01

    Effective progression of candidate antimalarials is dependent on optimal dosing in clinical studies, which is determined by a sound understanding of pharmacokinetics and pharmacodynamics (PK/PD). Recently, two important translational models for antimalarials have been developed: the NOD/SCID/IL2Rγ(-/-) (NSG) model, whereby mice are engrafted with noninfected and Plasmodium falciparum-infected human erythrocytes, and the induced blood-stage malaria (IBSM) model in human volunteers. The antimalarial mefloquine was used to directly measure the PK/PD in both models, which were compared to previously published trial data for malaria patients. The clinical part was a single-center, controlled study using a blood-stage Plasmodium falciparum challenge inoculum in volunteers to characterize the effectiveness of mefloquine against early malaria. The study was conducted in three cohorts (n = 8 each) using different doses of mefloquine. The characteristic delay in onset of action of about 24 h was seen in both NSG and IBSM systems. In vivo 50% inhibitory concentrations (IC50s) were estimated at 2.0 μg/ml and 1.8 μg/ml in the NSG and IBSM models, respectively, aligning with 1.8 μg/ml reported previously for patients. In the IBSM model, the parasite reduction ratios were 157 and 195 for the 10- and 15-mg/kg doses, within the range of previously reported clinical data for patients but significantly lower than observed in the mouse model. Linking mouse and human challenge models to clinical trial data can accelerate the accrual of critical data on antimalarial drug activity. Such data can guide large clinical trials required for development of urgently needed novel antimalarial combinations. (This trial was registered at the Australian New Zealand Clinical Trials Registry [http://anzctr.org.au] under registration number ACTRN12612000323820.). PMID:27044554

  14. Underestimation of boreal soil carbon stocks by mathematical soil carbon models linked to soil nutrient status

    NASA Astrophysics Data System (ADS)

    Ťupek, Boris; Ortiz, Carina A.; Hashimoto, Shoji; Stendahl, Johan; Dahlgren, Jonas; Karltun, Erik; Lehtonen, Aleksi

    2016-08-01

    Inaccurate estimate of the largest terrestrial carbon pool, soil organic carbon (SOC) stock, is the major source of uncertainty in simulating feedback of climate warming on ecosystem-atmosphere carbon dioxide exchange by process-based ecosystem and soil carbon models. Although the models need to simplify complex environmental processes of soil carbon sequestration, in a large mosaic of environments a missing key driver could lead to a modeling bias in predictions of SOC stock change.We aimed to evaluate SOC stock estimates of process-based models (Yasso07, Q, and CENTURY soil sub-model v4) against a massive Swedish forest soil inventory data set (3230 samples) organized by a recursive partitioning method into distinct soil groups with underlying SOC stock development linked to physicochemical conditions.For two-thirds of measurements all models predicted accurate SOC stock levels regardless of the detail of input data, e.g., whether they ignored or included soil properties. However, in fertile sites with high N deposition, high cation exchange capacity, or moderately increased soil water content, Yasso07 and Q models underestimated SOC stocks. In comparison to Yasso07 and Q, accounting for the site-specific soil characteristics (e. g. clay content and topsoil mineral N) by CENTURY improved SOC stock estimates for sites with high clay content, but not for sites with high N deposition.Our analysis suggested that the soils with poorly predicted SOC stocks, as characterized by the high nutrient status and well-sorted parent material, indeed have had other predominant drivers of SOC stabilization lacking in the models, presumably the mycorrhizal organic uptake and organo-mineral stabilization processes. Our results imply that the role of soil nutrient status as regulator of organic matter mineralization has to be re-evaluated, since correct SOC stocks are decisive for predicting future SOC change and soil CO2 efflux.

  15. LINKING AIR TOXIC CONCENTRATIONS FROM CMAQ TO THE HAPEM5 EXPOSURE MODEL AT NEIGHORHOOD SCALES FOR THE PHILADELPHIA AREA

    EPA Science Inventory

    This paper provides a preliminary demonstration of the EPA neighborhood scale modeling paradigm for air toxics by linking concentration from the Community Multi-scale Air Quality (CMAQ) modeling system to the fifth version of the Hazardous Pollutant Exposure Model (HAPEM5). For ...

  16. Persisting Viral Sequences Shape Microbial CRISPR-based Immunity

    PubMed Central

    Weinberger, Ariel D.; Sun, Christine L.; Pluciński, Mateusz M.; Denef, Vincent J.; Thomas, Brian C.; Horvath, Philippe; Barrangou, Rodolphe; Gilmore, Michael S.; Getz, Wayne M.; Banfield, Jillian F.

    2012-01-01

    Well-studied innate immune systems exist throughout bacteria and archaea, but a more recently discovered genomic locus may offer prokaryotes surprising immunological adaptability. Mediated by a cassette-like genomic locus termed Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), the microbial adaptive immune system differs from its eukaryotic immune analogues by incorporating new immunities unidirectionally. CRISPR thus stores genomically recoverable timelines of virus-host coevolution in natural organisms refractory to laboratory cultivation. Here we combined a population genetic mathematical model of CRISPR-virus coevolution with six years of metagenomic sequencing to link the recoverable genomic dynamics of CRISPR loci to the unknown population dynamics of virus and host in natural communities. Metagenomic reconstructions in an acid-mine drainage system document CRISPR loci conserving ancestral immune elements to the base-pair across thousands of microbial generations. This ‘trailer-end conservation’ occurs despite rapid viral mutation and despite rapid prokaryotic genomic deletion. The trailer-ends of many reconstructed CRISPR loci are also largely identical across a population. ‘Trailer-end clonality’ occurs despite predictions of host immunological diversity due to negative frequency dependent selection (kill the winner dynamics). Statistical clustering and model simulations explain this lack of diversity by capturing rapid selective sweeps by highly immune CRISPR lineages. Potentially explaining ‘trailer-end conservation,’ we record the first example of a viral bloom overwhelming a CRISPR system. The polyclonal viruses bloom even though they share sequences previously targeted by host CRISPR loci. Simulations show how increasing random genomic deletions in CRISPR loci purges immunological controls on long-lived viral sequences, allowing polyclonal viruses to bloom and depressing host fitness. Our results thus link documented

  17. Modeling the Biodegradation of Bacterial Community Assembly Linked Antibiotics in River Sediment Using a Deterministic-Stochastic Combined Model.

    PubMed

    Zhang, Wenlong; Li, Yi; Wang, Chao; Wang, Peifang; Hou, Jun; Yu, Zhongbo; Niu, Lihua; Wang, Linqiong; Wang, Jing

    2016-08-16

    To understand the interaction between bacterial community assembly and the assembly linked antibiotics biodegradation, a unique model framework containing a Monod kinetic, a logistic kinetic, and a stochastic item was established to describe the biodegradation of bacterial community assembly linked sulfamethoxazole (SMX) in river sediment. According to the modeling results, both deterministic and stochastic processes driving bacterial population variations played important roles in controlling SMX biodegradation, and the relative importance depended on the in situ concentration of SMX. A threshold concentration of SMX, which was biodegraded in the experimental river sediment depending on different processes, was obtained (i.e., 20 μg/kg). The higher introduced concentration of SMX (>20 μg/kg) was found to promote the acclimation of antibiotic degradation bacteria in microbial community through niche differentiation, which resulted in the specific microbial metabolization of SMX. In contrast, the lower introduced concentration of SMX (<20 μg/kg) was not able to lead to a significant increase of deterministic processes and resulted in the biodegradation of SMX through co-metabolism by the coexisting microorganisms. The developed model can be considered a useful tool for improving the technologies of water environmental protection and remediation. PMID:27428250

  18. Cross-linked hyaluronate hydrogel prevents adhesion formation and reformation in mouse uterine horn model.

    PubMed

    Sawada, T; Tsukada, K; Hasegawa, K; Ohashi, Y; Udagawa, Y; Gomel, V

    2001-02-01

    The aim of this study was to evaluate the efficacy of cross-linked hyaluronate hydrogel (HA gel) as an adjuvant for postoperative adhesion prevention, in a mouse uterine horn model. In experiment 1 uterine horns were abrased with iodine. HA gel was applied to the injured surface before closure in the treatment group. In experiment 2, after injuring the uterine horns, three stitches were placed at equal distances around the uterine horns to appose the injured medial surfaces of the two horns during healing. HA gel was inserted between the uterine horns in the treatment group. In experiment 3 prevention of adhesion reformation was assessed. After lysis of adhesions that were induced as in experiment 2, HA gel was introduced between the serosal surfaces of apposing uterine horns. Untreated animals served as controls in each experiment. Statistical analysis was carried out using Student's t-test. The adhesion score was significantly lower in the HA gel group on the 14th day compared with controls in all the experiments: in experiment 1, 0.3 +/- 0.4 versus 1.7 +/- 1.2; in experiment 2, 0.9 +/- 1.0 versus 2.6 +/- 0.5; and in experiment 3, 1.5 +/- 0.9 versus 2.2 +/- 0.6 respectively. Cross-linked HA gel significantly reduced de-novo adhesions (P< 0.03) and adhesion reformation (P < 0.03). PMID:11157833

  19. VIRAL INFECTIONS DURING PREGNANCY

    PubMed Central

    Silasi, Michelle; Cardenas, Ingrid; Racicot, Karen; Kwon, Ja-Young; Aldo, Paula; Mor, Gil

    2015-01-01

    Viral infections during pregnancy have long been considered benign conditions with a few notable exceptions, such as herpes virus. The recent Ebola outbreak and other viral epidemics and pandemics show how pregnant women suffer worse outcomes (such as preterm labor and adverse fetal outcomes) than the general population and non-pregnant women. New knowledge about the ways the maternal-fetal interface and placenta interact with the maternal immune system may explain these findings. Once thought to be “immunosuppressed”, the pregnant woman actually undergoes an immunological transformation, where the immune system is necessary to promote and support the pregnancy and growing fetus. When this protection is breached, as in a viral infection, this security is weakened and infection with other microorganisms can then propagate and lead to outcomes, such as preterm labor. In this manuscript, we review the major viral infections relevant to pregnancy, and offer potential mechanisms for the associated adverse pregnancy outcomes. PMID:25582523

  20. HIV and Viral Hepatitis

    MedlinePlus

    ... prevalent among blacks as among whites. Viral Hepatitis Transmission People can be infected with the three most ... risk for HAV. • • New data suggest that sexual transmission of HCV among MSM with HIV occurs more ...

  1. Viral quasispecies complexity measures.

    PubMed

    Gregori, Josep; Perales, Celia; Rodriguez-Frias, Francisco; Esteban, Juan I; Quer, Josep; Domingo, Esteban

    2016-06-01

    Mutant spectrum dynamics (changes in the related mutants that compose viral populations) has a decisive impact on virus behavior. The several platforms of next generation sequencing (NGS) to study viral quasispecies offer a magnifying glass to study viral quasispecies complexity. Several parameters are available to quantify the complexity of mutant spectra, but they have limitations. Here we critically evaluate the information provided by several population diversity indices, and we propose the introduction of some new ones used in ecology. In particular we make a distinction between incidence, abundance and function measures of viral quasispecies composition. We suggest a multidimensional approach (complementary information contributed by adequately chosen indices), propose some guidelines, and illustrate the use of indices with a simple example. We apply the indices to three clinical samples of hepatitis C virus that display different population heterogeneity. Areas of virus biology in which population complexity plays a role are discussed. PMID:27060566

  2. Mathematical modeling of cross-linking monomer elution from resin-based dental composites.

    PubMed

    Manojlovic, Dragica; Radisic, Marina; Lausevic, Mila; Zivkovic, Slavoljub; Miletic, Vesna

    2013-01-01

    Elution of potentially toxic substances, including monomers, from resin-based dental composites may affect the biocompatibility of these materials in clinical conditions. In addition to the amounts of eluted monomers, mathematical modeling of elution kinetics reveals composite restorations as potential chronic sources of leachable monomers. The aim of this work was to experimentally quantify elution of main cross-linking monomers from four commercial composites and offer a mathematical model of elution kinetics. Composite samples (n = 7 per group) of Filtek Supreme XT (3M ESPE), Tetric EvoCeram (Ivoclar Vivadent), Admira (Voco), and Filtek Z250 (3M ESPE) were prepared in 2-mm thick Teflon moulds and cured with halogen or light-emitting diode light. Monomer elution in ethanol and water was analyzed using high-performance liquid chromatography up to 28 days postimmersion. The mathematical model was expressed as a sum of two exponential regression functions representing the first-order kinetics law. Elution kinetics in all cases followed the same mathematical model though differences in rate constants as well as the extent of monomer elution were material-, LCU-, medium-dependent. The proposed mechanisms of elution indicate fast elution from surface and subsurface layers and up to 100 times slower monomer extraction from the bulk polymer. PMID:22997145

  3. Bone fracture toughness and strength correlate with collagen cross-link maturity in a dose-controlled lathyrism mouse model

    PubMed Central

    McNerny, Erin M. B.; Gong, Bo; Morris, Michael D.; Kohn, David H.

    2014-01-01

    Collagen cross-linking is altered in many diseases of bone, and enzymatic collagen cross-links are important to bone quality as evidenced by losses of strength following lysyl oxidase inhibition (lathyrism). We hypothesized that cross-links also contribute directly to bone fracture toughness. A mouse model of lathyrism using subcutaneous injection of up to 500mg/kg β-aminopropionitrile (BAPN) was developed and characterized (60 animals across 4 dosage groups). Three weeks of 150 or 350 mg/kg BAPN treatment in young growing mice significantly reduced cortical bone fracture toughness, strength, and pyridinoline cross-link content. Ratios reflecting relative cross-link maturity were positive regressors of fracture toughness (HP/[DHLNL+HLNL] r2=0.208, p<0.05; [HP+LP]/[DHNL+HLNL] r2=0.196, p<0.1), whereas quantities of mature pyridinoline cross-links were significant positive regressors of tissue strength (lysyl pyridinoline r2=0.159, p=0.014; hydroxylysyl pyridinoline r2=0.112, p<0.05). Immature and pyrrole cross-links, which were not significantly reduced by BAPN, did not correlate with mechanical properties. The effect of BAPN treatment on mechanical properties was dose specific, with the greatest impact found at the intermediate (350mg/kg) dose. Calcein labeling was used to define locations of new bone formation, allowing for the identification of regions of normally cross-linked (preexisting) and BAPN treated (newly formed, cross-link-deficient) bone. Raman spectroscopy revealed spatial differences due to relative tissue age and effects of cross-link inhibition. Newly deposited tissues had lower mineral/matrix, carbonate/phosphate and Amide I cross-link (matrix maturity) ratios compared to preexisting tissues. BAPN treatment did not affect mineral measures, but significantly increased the cross-link (matrix maturity) ratio compared to newly formed control tissue. Our study reveals that spatially localized effects of short term BAPN cross-link inhibition can alter

  4. Entangled Cross-Linked Fibres for an Application as Core Material for Sandwich Structures - Part II: Analytical Model

    NASA Astrophysics Data System (ADS)

    Mezeix, L.; Poquillon, D.; Bouvet, C.

    2016-02-01

    Entangled cross-linked carbon, aramid and glass fibres were recently produced by epoxy spraying for an application as core material for sandwich panel. The Young's moduli in compression and tension have been previously measured and briefly summarized in this paper. To optimize the core structure, modelling of these properties has been achieved in the present paper. The cross-link fibres have a random orientation and the stiffness of the epoxy joint is modelled by a torsion spring. A parallel model is chosen for homogenisation. It was found that the experimentally estimated stiffness of these materials fits fairly well with the modelled ones.

  5. Longitudinal follow-up and characterization of a robust rat model for Parkinson's disease based on overexpression of alpha-synuclein with adeno-associated viral vectors.

    PubMed

    Van der Perren, Anke; Toelen, Jaan; Casteels, Cindy; Macchi, Francesca; Van Rompuy, Anne-Sophie; Sarre, Sophie; Casadei, Nicolas; Nuber, Silke; Himmelreich, Uwe; Osorio Garcia, Maria Isabel; Michotte, Yvette; D'Hooge, Rudi; Bormans, Guy; Van Laere, Koen; Gijsbers, Rik; Van den Haute, Chris; Debyser, Zeger; Baekelandt, Veerle

    2015-03-01

    Testing of new therapeutic strategies for Parkinson's disease (PD) is currently hampered by the lack of relevant and reproducible animal models. Here, we developed a robust rat model for PD by injection of adeno-associated viral vectors (rAAV2/7) encoding α-synuclein into the substantia nigra, resulting in reproducible nigrostriatal pathology and behavioral deficits in a 4-week time period. Progressive dopaminergic dysfunction was corroborated by histopathologic and biochemical analysis, motor behavior testing and in vivo microdialysis. L-DOPA treatment was found to reverse the behavioral phenotype. Non-invasive positron emission tomography imaging and magnetic resonance spectroscopy allowed longitudinal monitoring of neurodegeneration. In addition, insoluble α-synuclein aggregates were formed in this model. This α-synuclein rat model shows improved face and predictive validity, and therefore offers the possibility to reliably test novel therapeutics. Furthermore, it will be of great value for further research into the molecular pathogenesis of PD and the importance of α-synuclein aggregation in the disease process. PMID:25599874

  6. Interactions between airway epithelial cells and dendritic cells during viral infections using an in vitro co-culture model

    EPA Science Inventory

    Rationale: Historically, single cell culture models have been limited in pathological and physiological relevance. A co-culture model of dendritic cells (DCs) and differentiated human airway epithelial cells was developed to examine potential interactions between these two cell t...

  7. Viral miRNAs.

    PubMed

    Plaisance-Bonstaff, Karlie; Renne, Rolf

    2011-01-01

    Since 2004, more than 200 microRNAs (miRNAs) have been discovered in double-stranded DNA viruses, mainly herpesviruses and polyomaviruses (Nucleic Acids Res 32:D109-D111, 2004). miRNAs are short 22  ±  3 nt RNA molecules that posttranscriptionally regulate gene expression by binding to 3'-untranslated regions (3'UTR) of target mRNAs, thereby inducing translational silencing and/or transcript degradation (Nature 431:350-355, 2004; Cell 116:281-297, 2004). Since miRNAs require only limited complementarity for binding, miRNA targets are difficult to determine (Mol Cell 27:91-105, 2007). To date, targets have only been experimentally verified for relatively few viral miRNAs, which either target viral or host cellular gene expression: For example, SV40 and related polyomaviruses encode miRNAs which target viral large T antigen expression (Nature 435:682-686, 2005; J Virol 79:13094-13104, 2005; Virology 383:183-187, 2009; J Virol 82:9823-9828, 2008) and miRNAs of α-, β-, and γ-herpesviruses have been implicated in regulating the transition from latent to lytic gene expression, a key step in the herpesvirus life cycle. Viral miRNAs have also been shown to target various host cellular genes. Although this field is just beginning to unravel the multiple roles of viral miRNA in biology and pathogenesis, the current data strongly suggest that virally encoded miRNAs are able to regulate fundamental biological processes such as immune recognition, promotion of cell survival, angiogenesis, proliferation, and cell differentiation. This chapter aims to summarize our current knowledge of viral miRNAs, their targets and function, and the challenges lying ahead to decipher their role in viral biology, pathogenesis, and for γ-herepsvirus-encoded miRNAs, potentially tumorigenesis. PMID:21431678

  8. Modeling photosynthesis of discontinuous plant canopies by linking the Geometric Optical Radiative Transfer model with biochemical processes

    NASA Astrophysics Data System (ADS)

    Xin, Q.; Gong, P.; Li, W.

    2015-06-01

    Modeling vegetation photosynthesis is essential for understanding carbon exchanges between terrestrial ecosystems and the atmosphere. The radiative transfer process within plant canopies is one of the key drivers that regulate canopy photosynthesis. Most vegetation cover consists of discrete plant crowns, of which the physical observation departs from the underlying assumption of a homogenous and uniform medium in classic radiative transfer theory. Here we advance the Geometric Optical Radiative Transfer (GORT) model to simulate photosynthesis activities for discontinuous plant canopies. We separate radiation absorption into two components that are absorbed by sunlit and shaded leaves, and derive analytical solutions by integrating over the canopy layer. To model leaf-level and canopy-level photosynthesis, leaf light absorption is then linked to the biochemical process of gas diffusion through leaf stomata. The canopy gap probability derived from GORT differs from classic radiative transfer theory, especially when the leaf area index is high, due to leaf clumping effects. Tree characteristics such as tree density, crown shape, and canopy length affect leaf clumping and regulate radiation interception. Modeled gross primary production (GPP) for two deciduous forest stands could explain more than 80% of the variance of flux tower measurements at both near hourly and daily timescales. We demonstrate that ambient CO2 concentrations influence daytime vegetation photosynthesis, which needs to be considered in biogeochemical models. The proposed model is complementary to classic radiative transfer theory and shows promise in modeling the radiative transfer process and photosynthetic activities over discontinuous forest canopies.

  9. Sphingosine-1-phosphate receptor antagonism enhances proliferation and migration of engrafted neural progenitor cells in a model of viral-induced demyelination.

    PubMed

    Blanc, Caroline A; Grist, Jonathan J; Rosen, Hugh; Sears-Kraxberger, Ilse; Steward, Oswald; Lane, Thomas E

    2015-10-01

    The oral drug FTY720 affects sphingosine-1-phosphate (S1P) signaling on targeted cells that bear the S1P receptors S1P1, S1P3, S1P4, and S1P5. We examined the effect of FTY720 treatment on the biology of mouse neural progenitor cells (NPCs) after transplantation in a viral model of demyelination. Intracerebral infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) resulted in an acute encephalomyelitis, followed by demyelination similar in pathology to the human demyelinating disease, multiple sclerosis. We have previously reported that intraspinal transplantation of mouse NPCs into JHMV-infected animals resulted in selective colonization of demyelinated lesions, preferential differentiation into oligodendroglia accompanied by axonal preservation, and increased remyelination. Cultured NPCs expressed transcripts for S1P receptors S1P1, S1P2, S1P3, S1P4, and S1P5. FTY720 treatment of cultured NPCs resulted in increased mitogen-activated protein kinase phosphorylation and migration after exposure to the chemokine CXCL12. Administration of FTY720 to JHMV-infected mice resulted in enhanced migration and increased proliferation of transplanted NPCs after spinal cord engraftment. FTY720 treatment did not improve clinical disease, diminish neuroinflammation or the severity of demyelination, nor increase remyelination. These findings argue that FTY720 treatment selectively increases NPC proliferation and migration but does not either improve clinical outcome or enhance remyelination after transplantation into animals in which immune-mediated demyelination is initiated by the viral infection of the central nervous system. PMID:26435414

  10. Pathophysiology of white-nose syndrome in bats: a mechanistic model linking wing damage to mortality.

    PubMed

    Warnecke, Lisa; Turner, James M; Bollinger, Trent K; Misra, Vikram; Cryan, Paul M; Blehert, David S; Wibbelt, Gudrun; Willis, Craig K R

    2013-08-23

    White-nose syndrome is devastating North American bat populations but we lack basic information on disease mechanisms. Altered blood physiology owing to epidermal invasion by the fungal pathogen Geomyces destructans (Gd) has been hypothesized as a cause of disrupted torpor patterns of affected hibernating bats, leading to mortality. Here, we present data on blood electrolyte concentration, haematology and acid-base balance of hibernating little brown bats, Myotis lucifugus, following experimental inoculation with Gd. Compared with controls, infected bats showed electrolyte depletion (i.e. lower plasma sodium), changes in haematology (i.e. increased haematocrit and decreased glucose) and disrupted acid-base balance (i.e. lower CO2 partial pressure and bicarbonate). These findings indicate hypotonic dehydration, hypovolaemia and metabolic acidosis. We propose a mechanistic model linking tissue damage to altered homeostasis and morbidity/mortality. PMID:23720520

  11. Pathophysiology of white-nose syndrome in bats: a mechanistic model linking wing damage to mortality

    USGS Publications Warehouse

    Warnecke, Lisa; Turner, James M.; Bollinger, Trent K.; Misra, Vikram; Cryan, Paul M.; Blehert, David S.; Wibbelt, Gudrun; Willis, Craig K.R.

    2013-01-01

    White-nose syndrome is devastating North American bat populations but we lack basic information on disease mechanisms. Altered blood physiology owing to epidermal invasion by the fungal pathogen Geomyces destructans (Gd) has been hypothesized as a cause of disrupted torpor patterns of affected hibernating bats, leading to mortality. Here, we present data on blood electrolyte concentration, haematology and acid–base balance of hibernating little brown bats, Myotis lucifugus, following experimental inoculation with Gd. Compared with controls, infected bats showed electrolyte depletion (i.e. lower plasma sodium), changes in haematology (i.e. increased haematocrit and decreased glucose) and disrupted acid–base balance (i.e. lower CO2 partial pressure and bicarbonate). These findings indicate hypotonic dehydration, hypovolaemia and metabolic acidosis. We propose a mechanistic model linking tissue damage to altered homeostasis and morbidity/mortality.

  12. Immigration and viral hepatitis.

    PubMed

    Sharma, Suraj; Carballo, Manuel; Feld, Jordan J; Janssen, Harry L A

    2015-08-01

    WHO estimates reveal that the global prevalence of viral hepatitis may be as high as 500 million, with an annual mortality rate of up to 1.3 million individuals. The majority of this global burden of disease is borne by nations of the developing world with high rates of vertical and iatrogenic transmission of HBV and HCV, as well as poor access to healthcare. In 2013, 3.2% of the global population (231 million individuals) migrated into a new host nation. Migrants predominantly originate from the developing countries of the south, into the developed economies of North America and Western Europe. This mass migration of individuals from areas of high-prevalence of viral hepatitis poses a unique challenge to the healthcare systems of the host nations. Due to a lack of universal standards for screening, vaccination and treatment of viral hepatitis, the burden of chronic liver disease and hepatocellular carcinoma continues to increase among migrant populations globally. Efforts to increase case identification and treatment among migrants have largely been limited to small outreach programs in urban centers, such that the majority of migrants with viral hepatitis continue to remain unaware of their infection. This review summarizes the data on prevalence of viral hepatitis and burden of chronic liver disease among migrants, current standards for screening and treatment of immigrants and refugees, and efforts to improve the identification and treatment of viral hepatitis among migrants. PMID:25962882

  13. Static and dynamic properties of model elastomer with various cross-linking densities: A molecular dynamics study

    NASA Astrophysics Data System (ADS)

    Liu, Jun; Cao, Dapeng; Zhang, Liqun

    2009-07-01

    The effects of the cross-linking density on the static and dynamic properties of polymer networks are examined by using a molecular dynamics simulation based on a simple elastomer model. Simulation results indicate that the introduced cross-linking junctions show almost no effect on the static structure factor. The glass transition temperature Tg increases slightly with the cross-linking density. By analyzing the mean square displacement of the monomers, the chain diffusion, and the incoherent intermediate dynamic structure factor ϕqs(t) at the chain and segmental length scales, it is found that the mobilities of the monomers and chains are retarded and the relaxation behavior is hindered by the cross linking of polymers. Furthermore, the spatial localization of the monomers is also observed at a long time period for a highly cross-linked system. For the cross-linked system, the time-temperature superposition principle is valid at the segmental length scale but breaks down at the chain length scale. The effect of the cross-linking density on the terminal relaxation is investigated by the end-to-end vector correlation, which is well fitted to the Kohlrauch-William-Watts (KWW) or modified KWW functions. The characteristic relaxation time shows an approximately linear relationship with the cross-linking density. It is demonstrated that the relaxation behavior tends to broaden, attributed to the stronger intermolecular coupling or cooperativity induced by the cross linking, suggesting that the system with a higher cross-linking degree becomes more fragile. For the dynamic properties, the bond orientation and the end-to-end distance along the deformed direction, which is an indicator of the entropic change, and the nonbonded energy are examined during the deformation and relaxation processes, respectively. The results explore the molecular mechanism accounting for the residual stress in the stress relaxation of cross-linked elastomer networks.

  14. Static and dynamic properties of model elastomer with various cross-linking densities: a molecular dynamics study.

    PubMed

    Liu, Jun; Cao, Dapeng; Zhang, Liqun

    2009-07-21

    The effects of the cross-linking density on the static and dynamic properties of polymer networks are examined by using a molecular dynamics simulation based on a simple elastomer model. Simulation results indicate that the introduced cross-linking junctions show almost no effect on the static structure factor. The glass transition temperature T(g) increases slightly with the cross-linking density. By analyzing the mean square displacement of the monomers, the chain diffusion, and the incoherent intermediate dynamic structure factor phi(q)(s)(t) at the chain and segmental length scales, it is found that the mobilities of the monomers and chains are retarded and the relaxation behavior is hindered by the cross linking of polymers. Furthermore, the spatial localization of the monomers is also observed at a long time period for a highly cross-linked system. For the cross-linked system, the time-temperature superposition principle is valid at the segmental length scale but breaks down at the chain length scale. The effect of the cross-linking density on the terminal relaxation is investigated by the end-to-end vector correlation, which is well fitted to the Kohlrauch-William-Watts (KWW) or modified KWW functions. The characteristic relaxation time shows an approximately linear relationship with the cross-linking density. It is demonstrated that the relaxation behavior tends to broaden, attributed to the stronger intermolecular coupling or cooperativity induced by the cross linking, suggesting that the system with a higher cross-linking degree becomes more fragile. For the dynamic properties, the bond orientation and the end-to-end distance along the deformed direction, which is an indicator of the entropic change, and the nonbonded energy are examined during the deformation and relaxation processes, respectively. The results explore the molecular mechanism accounting for the residual stress in the stress relaxation of cross-linked elastomer networks. PMID:19624229

  15. Linking landscape characteristics to local grizzly bear abundance using multiple detection methods in a hierarchical model

    USGS Publications Warehouse

    Graves, T.A.; Kendall, K.C.; Royle, J. Andrew; Stetz, J.B.; Macleod, A.C.

    2011-01-01

    Few studies link habitat to grizzly bear Ursus arctos abundance and these have not accounted for the variation in detection or spatial autocorrelation. We collected and genotyped bear hair in and around Glacier National Park in northwestern Montana during the summer of 2000. We developed a hierarchical Markov chain Monte Carlo model that extends the existing occupancy and count models by accounting for (1) spatially explicit variables that we hypothesized might influence abundance; (2) separate sub-models of detection probability for two distinct sampling methods (hair traps and rub trees) targeting different segments of the population; (3) covariates to explain variation in each sub-model of detection; (4) a conditional autoregressive term to account for spatial autocorrelation; (5) weights to identify most important variables. Road density and per cent mesic habitat best explained variation in female grizzly bear abundance; spatial autocorrelation was not supported. More female bears were predicted in places with lower road density and with more mesic habitat. Detection rates of females increased with rub tree sampling effort. Road density best explained variation in male grizzly bear abundance and spatial autocorrelation was supported. More male bears were predicted in areas of low road density. Detection rates of males increased with rub tree and hair trap sampling effort and decreased over the sampling period. We provide a new method to (1) incorporate multiple detection methods into hierarchical models of abundance; (2) determine whether spatial autocorrelation should be included in final models. Our results suggest that the influence of landscape variables is consistent between habitat selection and abundance in this system. ?? 2011 The Authors. Animal Conservation ?? 2011 The Zoological Society of London.

  16. Viral suppressors of RNA-based viral immunity: Host targets

    PubMed Central

    Wu, Qingfa; Wang, Xianbing

    2010-01-01

    Discovery of diverse plant and animal viral proteins as suppressors of RNA silencing has provided strong support for an RNA-based viral immunity (RVI), which is now known to specifically destroy viral RNAs by RNA interference in fungi, plants and invertebrates. Here we review several recent studies that have revealed new mechanistic insights into plant and insect viral suppressors of RVI or suggested a role for RNA silencing suppression during mammalian viral infection. PMID:20638637

  17. Link between hopping models and percolation scaling laws for charge transport in mixtures of small molecules

    DOE PAGESBeta

    Ha, Dong -Gwang; Kim, Jang -Joo; Baldo, Marc A.

    2016-04-29

    Mixed host compositions that combine charge transport materials with luminescent dyes offer superior control over exciton formation and charge transport in organic light emitting devices (OLEDs). Two approaches are typically used to optimize the fraction of charge transport materials in a mixed host composition: either an empirical percolative model, or a hopping transport model. We show that these two commonly-employed models are linked by an analytic expression which relates the localization length to the percolation threshold and critical exponent. The relation is confirmed both numerically and experimentally through measurements of the relative conductivity of Tris(4-carbazoyl-9-ylphenyl) amine (TCTA) :1,3-bis(3,5-dipyrid-3-yl-phenyl) benzene (BmPyPb)more » mixtures with different concentrations, where the TCTA plays a role as hole conductor and the BmPyPb as hole insulator. Furthermore, the analytic relation may allow the rational design of mixed layers of small molecules for high-performance OLEDs.« less

  18. Linking genes to communities and ecosystems: Daphnia as an ecogenomic model.

    PubMed

    Miner, Brooks E; De Meester, Luc; Pfrender, Michael E; Lampert, Winfried; Hairston, Nelson G

    2012-05-22

    How do genetic variation and evolutionary change in critical species affect the composition and functioning of populations, communities and ecosystems? Illuminating the links in the causal chain from genes up to ecosystems is a particularly exciting prospect now that the feedbacks between ecological and evolutionary changes are known to be bidirectional. Yet to fully explore phenomena that span multiple levels of the biological hierarchy requires model organisms and systems that feature a comprehensive triad of strong ecological interactions in nature, experimental tractability in diverse contexts and accessibility to modern genomic tools. The water flea Daphnia satisfies these criteria, and genomic approaches capitalizing on the pivotal role Daphnia plays in the functioning of pelagic freshwater food webs will enable investigations of eco-evolutionary dynamics in unprecedented detail. Because its ecology is profoundly influenced by both genetic polymorphism and phenotypic plasticity, Daphnia represents a model system with tremendous potential for developing a mechanistic understanding of the relationship between traits at the genetic, organismal and population levels, and consequences for community and ecosystem dynamics. Here, we highlight the combination of traits and ecological interactions that make Daphnia a definitive model system, focusing on the additional power and capabilities enabled by recent molecular and genomic advances. PMID:22298849

  19. Linking genes to communities and ecosystems: Daphnia as an ecogenomic model

    PubMed Central

    Miner, Brooks E.; De Meester, Luc; Pfrender, Michael E.; Lampert, Winfried; Hairston, Nelson G.

    2012-01-01

    How do genetic variation and evolutionary change in critical species affect the composition and functioning of populations, communities and ecosystems? Illuminating the links in the causal chain from genes up to ecosystems is a particularly exciting prospect now that the feedbacks between ecological and evolutionary changes are known to be bidirectional. Yet to fully explore phenomena that span multiple levels of the biological hierarchy requires model organisms and systems that feature a comprehensive triad of strong ecological interactions in nature, experimental tractability in diverse contexts and accessibility to modern genomic tools. The water flea Daphnia satisfies these criteria, and genomic approaches capitalizing on the pivotal role Daphnia plays in the functioning of pelagic freshwater food webs will enable investigations of eco-evolutionary dynamics in unprecedented detail. Because its ecology is profoundly influenced by both genetic polymorphism and phenotypic plasticity, Daphnia represents a model system with tremendous potential for developing a mechanistic understanding of the relationship between traits at the genetic, organismal and population levels, and consequences for community and ecosystem dynamics. Here, we highlight the combination of traits and ecological interactions that make Daphnia a definitive model system, focusing on the additional power and capabilities enabled by recent molecular and genomic advances. PMID:22298849

  20. Modeling dynamic interactions and coherence between marine zooplankton and fishes linked to environmental variability

    NASA Astrophysics Data System (ADS)

    Liu, Hui; Fogarty, Michael J.; Hare, Jonathan A.; Hsieh, Chih-hao; Glaser, Sarah M.; Ye, Hao; Deyle, Ethan; Sugihara, George

    2014-03-01

    The dynamics of marine fishes are closely related to lower trophic levels and the environment. Quantitatively understanding ecosystem dynamics linking environmental variability and prey resources to exploited fishes is crucial for ecosystem-based management of marine living resources. However, standard statistical models typically grounded in the concept of linear system may fail to capture the complexity of ecological processes. We have attempted to model ecosystem dynamics using a flexible, nonparametric class of nonlinear forecasting models. We analyzed annual time series of four environmental indices, 22 marine copepod taxa, and four ecologically and commercially important fish species during 1977 to 2009 on Georges Bank, a highly productive and intensively studied area of the northeast U.S. continental shelf ecosystem. We examined the underlying dynamic features of environmental indices and copepods, quantified the dynamic interactions and coherence with fishes, and explored the potential control mechanisms of ecosystem dynamics from a nonlinear perspective. We found: (1) the dynamics of marine copepods and environmental indices exhibiting clear nonlinearity; (2) little evidence of complex dynamics across taxonomic levels of copepods; (3) strong dynamic interactions and coherence between copepods and fishes; and (4) the bottom-up forcing of fishes and top-down control of copepods coexisting as target trophic levels vary. These findings highlight the nonlinear interactions among ecosystem components and the importance of marine zooplankton to fish populations which point to two forcing mechanisms likely interactively regulating the ecosystem dynamics on Georges Bank under a changing environment.

  1. Linking riparian dynamics and groundwater: an ecohydrologic approach to modeling groundwater and riparian vegetation.

    PubMed

    Baird, Kathryn J; Stromberg, Juliet C; Maddock, Thomas

    2005-10-01

    The growing use of global freshwater supplies is increasing the need for improved modeling of the linkage between groundwater and riparian vegetation. Traditional groundwater models such as MODFLOW have been used to predict changes in regional groundwater levels, and thus riparian vegetation potential attributable to anthropogenic water use. This article describes an approach that improves on these modeling techniques through several innovations. First, evapotranspiration from riparian/wetland systems is modeled in a manner that more realistically reflects plant ecophysiology and vegetation complexity. In the authors' model programs (RIP-ET and PRE-RIP-ET), the single, monotonically increasing evapotranspiration flux curve in traditional groundwater models is replaced with a set of ecophysiologically based curves, one for each plant functional group present. For each group, the curve simulates transpiration declines that occur both as water levels decline below rooting depths and as waters rise to levels that produce anoxic soil conditions. Accuracy is further improved by more effective spatial handling of vegetation distribution, which allows modeling of surface elevation and depth to water for multiple vegetation types within each large model cell. The use of RIP-ET in groundwater models can improve the accuracy of basin scale estimates of riparian evapotranspiration rates, riparian vegetation water requirements, and water budgets. Two case studies are used to demonstrate that RIP-ET produces significantly different evapotranspiration estimates than the traditional method. When combined with vegetation mapping and a supporting program (RIP-GIS), RIP-ET also enables predictions of riparian vegetation response to water use and development scenarios. The RIP-GIS program links the head distribution from MODFLOW with surface digital elevation models, producing moderate- to high-resolution depth-to-groundwater maps. Together with information on plant rooting depths

  2. Linking environmental variability to village-scale malaria transmission using a simple immunity model

    PubMed Central

    2013-01-01

    constituting a mechanistic link between spatial and temporal environmental variability and village-scale malaria transmission. Incorporating acquired immunity into the model has allowed simulation of prevalence in the two villages, and isolation of the effects of acquired immunity in dampening the difference in prevalence between the two villages. Without these effects, the difference in prevalence between the two villages would have been significantly larger in response to the large differences in mosquito populations and the associated biting rates. PMID:23919581

  3. The use of statistical channel models, full-field propagation codes, and field data to predict link availability

    NASA Astrophysics Data System (ADS)

    Michael, Steven; Parenti, Ronald R.; Moores, John D.; Wilcox, William, Jr.; Yarnall, Timothy M.; Volpicelli, Alicia M.; Taylor, John A.

    2009-08-01

    The free-space communications community has only recently recognized the complexity of atmospheric channel interactions, which are highly dependent on the turbulence profile, beam propagation geometry, and transceiver design. The search for models that accurately describe link performance and overall availability is currently an active field of research. This paper describes a method for defining link availability based on statistical channel models, which can be derived from measured signal fluctuations during periods of stable atmospheric conditions. Measurements made during an extended communication link experiment conducted during the summer of 2008 indicate that the intervals of channel stability, which impact the length of link outages, can vary in duration from a few minutes to several hours. This work was sponsored by the Department of Defense, RRCO DDR&E, under Air Force Contract FA8721-05-C-0002. Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the United States Government.

  4. Structural organization of poliovirus RNA replication is mediated by viral proteins of the P2 genomic region.

    PubMed Central

    Bienz, K; Egger, D; Troxler, M; Pasamontes, L

    1990-01-01

    Transcriptionally active replication complexes bound to smooth membrane vesicles were isolated from poliovirus-infected cells. In electron microscopic, negatively stained preparations, the replication complex appeared as an irregularly shaped, oblong structure attached to several virus-induced vesicles of a rosettelike arrangement. Electron microscopic immunocytochemistry of such preparations demonstrated that the poliovirus replication complex contains the proteins coded by the P2 genomic region (P2 proteins) in a membrane-associated form. In addition, the P2 proteins are also associated with viral RNA, and they can be cross-linked to viral RNA by UV irradiation. Guanidine hydrochloride prevented the P2 proteins from becoming membrane bound but did not change their association with viral RNA. The findings allow the conclusion that the protein 2C or 2C-containing precursor(s) is responsible for the attachment of the viral RNA to the vesicular membrane and for the spatial organization of the replication complex necessary for its proper functioning in viral transcription. A model for the structure of the viral replication complex and for the function of the 2C-containing P2 protein(s) and the vesicular membranes is proposed. Images PMID:2154600

  5. The Union Health Center: a working model of clinical care linked to preventive occupational health services.

    PubMed

    Herbert, R; Plattus, B; Kellogg, L; Luo, J; Marcus, M; Mascolo, A; Landrigan, P J

    1997-03-01

    As health care provision in the United States shifts to primary care settings, it is vital that new models of occupational health services be developed that link clinical care to prevention. The model program described in this paper was developed at the Union Health Center (UHC), a comprehensive health care center supported by the International Ladies Garment Workers Union (now the Union of Needletrades, Industrial and Textile Employees) serving a population of approximately 50,000 primarily minority, female garment workers in New York City. The objective of this paper is to describe a model occupational medicine program in a union-based comprehensive health center linking accessible clinical care with primary and secondary disease prevention efforts. To assess the presence of symptoms suggestive of occupational disease, a health status questionnaire was administered to female workers attending the UHC for routine health maintenance. Based on the results of this survey, an occupational medicine clinic was developed that integrated direct clinical care with worker and employer education and workplace hazard abatement. To assess the success of this new approach, selected cases of sentinel health events were tracked and a chart review was conducted after 3 years of clinic operation. Prior to initiation of the occupational medicine clinic, 64% (648) of the workers surveyed reported symptoms indicative of occupational illnesses. However, only 42 (4%) reported having been told by a physician that they had an occupational illness and only 4 (.4%) reported having field a workers' compensation claim for an occupational disease. In the occupational medicine clinic established at the UHC, a health and safety specialist acts as a case manager, coordinating worker and employer education as well as workplace hazard abatement focused on disease prevention, ensuring that every case of occupational disease is treated as a potential sentinel health event. As examples of the success

  6. Studying the immune response to human viral infections using zebrafish

    PubMed Central

    Goody, Michelle F.; Sullivan, Con; Kim, Carol H.

    2014-01-01

    Humans and viruses have a long co-evolutionary history. Viral illnesses have and will continue to shape human history: from smallpox, to influenza, to HIV, and beyond. Animal models of human viral illnesses are needed in order to generate safe and effective antiviral medicines, adjuvant therapies, and vaccines. These animal models must support the replication of human viruses, recapitulate aspects of human viral illnesses, and respond with conserved immune signaling cascades. The zebrafish is perhaps the simplest, most commonly used laboratory model organism in which innate and/or adaptive immunity can be studied. Herein, we will discuss the current zebrafish models of human viral illnesses and the insights they have provided. We will highlight advantages of early life stage zebrafish and the importance of innate immunity in human viral illnesses. We will also discuss viral characteristics to consider before infecting zebrafish with human viruses as well as predict other human viruses that may be able to infect zebrafish. PMID:24718256

  7. View and review on viral oncology research

    PubMed Central

    2010-01-01

    To date, almost one and a half million cases of cancer are diagnosed every year in the US and nearly 560,000 Americans are expected to die of cancer in the current year, more than 1,500 people a day (data from the American Cancer Society at http://www.cancer.org/). According to the World Health Organization (WHO), roughly 20% of all cancers worldwide results from chronic infections; in particular, up to 15% of human cancers is characterized by a viral aetiology with higher incidence in Developing Countries. The link between viruses and cancer was one of the pivotal discoveries in cancer research during the past Century. Indeed, the infectious nature of specific tumors has important implications in terms of their prevention, diagnosis, and therapy. In the 21st Century, the research on viral oncology field continues to be vigorous, with new significant and original studies on viral oncogenesis and translational research from basic virology to treatment of cancer. This review will cover different viral oncology aspects, starting from the history of viral oncology and moving to the peculiar features of oncogenic RNA and DNA viruses, with a special focus on human pathogens. PMID:20497566

  8. Linking near- and far-field hydrodynamic models for simulation of desalination plant brine discharges.

    PubMed

    Botelho, D A; Barry, M E; Collecutt, G C; Brook, J; Wiltshire, D

    2013-01-01

    A desalination plant is proposed to be the major water supply to the Olympic Dam Expansion Mining project. Located in the Upper Spencer Gulf, South Australia, the site was chosen due to the existence of strong currents and their likely advantages in terms of mixing and dilution of discharged return water. A high-resolution hydrodynamic model (Estuary, Lake and Coastal Ocean Model, ELCOM) was constructed and, through a rigorous review process, was shown to reproduce the intricate details of the Spencer Gulf dynamics, including those characterising the discharge site. Notwithstanding this, it was found that deploying typically adopted 'direct insertion' techniques to simulate the brine discharge within the hydrodynamic model was problematic. Specifically, it was found that in this study the direct insertion technique delivered highly conservative brine dilution predictions in and around the proposed site, and that these were grid and time-step dependent. To improve the predictive capability, a strategy to link validated computational fluid dynamics (CFD) predictions to hydrodynamic simulations was devised. In this strategy, environmental conditions from ELCOM were used to produce boundary conditions for execution of a suite of CFD simulations. In turn, the CFD simulations provided the brine dilutions and flow rates to be applied in ELCOM. In order to conserve mass in a system-wide sense, artificial salt sinks were introduced to the ELCOM model such that salt quantities were conserved. As a result of this process, ELCOM predictions were naturally very similar to CFD predictions near the diffuser, whilst at the same time they produced an area of influence (further afield) comparable to direct insertion methods. It was concluded that the linkage of the models, in comparison to direct insertion methods, constituted a more realistic and defensible alternative to predict the far-field dispersion of outfall discharges, particularly with regards to the estimation of brine

  9. Viral fitness: definitions, measurement, and current insights

    USGS Publications Warehouse

    Wargo, Andrew R.; Kurath, Gael

    2012-01-01

    Viral fitness is an active area of research, with recent work involving an expanded number of human, non-human vertebrate, invertebrate, plant, and bacterial viruses. Many publications deal with RNA viruses associated with major disease emergence events, such as HIV-1, influenza virus, and Dengue virus. Study topics include drug resistance, immune escape, viral emergence, host jumps, mutation effects, quasispecies diversity, and mathematical models of viral fitness. Important recent trends include increasing use of in vivo systems to assess vertebrate virus fitness, and a broadening of research beyond replicative fitness to also investigate transmission fitness and epidemiologic fitness. This is essential for a more integrated understanding of overall viral fitness, with implications for disease management in the future.

  10. Tectonic plates, difficulties for pupils to link models and scientific data.

    NASA Astrophysics Data System (ADS)

    David-Ameline, Jacques

    2014-05-01

    In a secondary school in the west of France, I teach Biology and Geology to young pupils from 12 to 15 years old. This poster deals with the difficulties that pupils have to link the scientific data concerning the plate tectonics and the models. I choose to reproduce for pupils some situations that faced some first scientific people as they discovered arguments for the plate tectonics. For example, they have to discover the thickness of the plates by studying the speed of the seismic waves regarding the deepness. That means that they have to construct a curve starting with a table and then to analyze it. The first step is linked to math lessons and is quite easy for them. But the second one needs to mix the curve with its signification. This point is particularly hard and as we correct it, it appears like one moment of « pure science » because they seem to discover something none did before, with the power of their brain ! The second work on this subject is to study the representations of the subduction at an oceanic trench and of the mid-ocean ridge. They first look for drawing explaining what happens for the plates in those places and then they look for proofs that permitted to create those drawings. They really need help to make the difference between scientific data (pictures, curves...) and other drawings similar to the one they choose. For this subject working with documents is not easy because pupils have to ask themselves « what kind of document is it ?» before going further into their thinking. Nevertheless, they often succeed in those works because the teacher helps them a little. Those subjects open their eyes on what science is for a geological theme. It's also a good method to make them having fun doing science and to make them being seduced by making science.

  11. The role of ecological models in linking ecological risk assessment to ecosystem services in agroecosystems.

    PubMed

    Galic, Nika; Schmolke, Amelie; Forbes, Valery; Baveco, Hans; van den Brink, Paul J

    2012-01-15

    Agricultural practices are essential for sustaining the human population, but at the same time they can directly disrupt ecosystem functioning. Ecological risk assessment (ERA) aims to estimate possible adverse effects of human activities on ecosystems and their parts. Current ERA practices, however, incorporate very little ecology and base the risk estimates on the results of standard tests with several standard species. The main obstacles for a more ecologically relevant ERA are the lack of clear protection goals and the inherent complexity of ecosystems that is hard to approach empirically. In this paper, we argue that the ecosystem services framework offers an opportunity to define clear and ecologically relevant protection goals. At the same time, ecological models provide the tools to address ecological complexity to the degree needed to link measurement endpoints and ecosystem services, and to quantify service provision and possible adverse effects from human activities. We focus on the ecosystem services relevant for agroecosystem functioning, including pollination, biocontrol and eutrophication effects and present modeling studies relevant for quantification of each of the services. The challenges of the ecosystem services approach are discussed as well as the limitations of ecological models in the context of ERA. A broad, multi-stakeholder dialog is necessary to aid the definition of protection goals in terms of services delivered by ecosystems and their parts. The need to capture spatio-temporal dynamics and possible interactions among service providers pose challenges for ecological models as a basis for decision making. However, we argue that both fields are advancing quickly and can prove very valuable in achieving more ecologically relevant ERA. PMID:21802704

  12. A model linking clinical workforce skill mix planning to health and health care dynamics

    PubMed Central

    2010-01-01

    Background In an attempt to devise a simpler computable tool to assist workforce planners in determining what might be an appropriate mix of health service skills, our discussion led us to consider the implications of skill mixing and workforce composition beyond the 'stock and flow' approach of much workforce planning activity. Methods Taking a dynamic systems approach, we were able to address the interactions, delays and feedbacks that influence the balance between the major components of health and health care. Results We linked clinical workforce requirements to clinical workforce workload, taking into account the requisite facilities, technologies, other material resources and their funding to support clinical care microsystems; gave recognition to productivity and quality issues; took cognisance of policies, governance and power concerns in the establishment and operation of the health care system; and, going back to the individual, gave due attention to personal behaviour and biology within the socio-political family environment. Conclusion We have produced the broad endogenous systems model of health and health care which will enable human resource planners to operate within real world variables. We are now considering the development of simple, computable national versions of this model. PMID:20433720

  13. Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model.

    PubMed

    Bestas, Burcu; Moreno, Pedro M D; Blomberg, K Emelie M; Mohammad, Dara K; Saleh, Amer F; Sutlu, Tolga; Nordin, Joel Z; Guterstam, Peter; Gustafsson, Manuela O; Kharazi, Shabnam; Piątosa, Barbara; Roberts, Thomas C; Behlke, Mark A; Wood, Matthew J A; Gait, Michael J; Lundin, Karin E; El Andaloussi, Samir; Månsson, Robert; Berglöf, Anna; Wengel, Jesper; Smith, C I Edvard

    2014-09-01

    X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTK transcripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2'-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro-B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA. PMID:25105368

  14. Linking Fine-Scale Observations and Model Output with Imagery at Multiple Scales

    NASA Astrophysics Data System (ADS)

    Sadler, J.; Walthall, C. L.

    2014-12-01

    The development and implementation of a system for seasonal worldwide agricultural yield estimates is underway with the international Group on Earth Observations GeoGLAM project. GeoGLAM includes a research component to continually improve and validate its algorithms. There is a history of field measurement campaigns going back decades to draw upon for ways of linking surface measurements and model results with satellite observations. Ground-based, in-situ measurements collected by interdisciplinary teams include yields, model inputs and factors affecting scene radiation. Data that is comparable across space and time with careful attention to calibration is essential for the development and validation of agricultural applications of remote sensing. Data management to ensure stewardship, availability and accessibility of the data are best accomplished when considered an integral part of the research. The expense and logistical challenges of field measurement campaigns can be cost-prohibitive and because of short funding cycles for research, access to consistent, stable study sites can be lost. The use of a dedicated staff for baseline data needed by multiple investigators, and conducting measurement campaigns using existing measurement networks such as the USDA Long Term Agroecosystem Research network can fulfill these needs and ensure long-term access to study sites.

  15. Ecological-network models link diversity, structure and function in the plankton food-web

    PubMed Central

    D’Alelio, Domenico; Libralato, Simone; Wyatt, Timothy; Ribera d’Alcalà, Maurizio

    2016-01-01

    A planktonic food-web model including sixty-three functional nodes (representing auto- mixo- and heterotrophs) was developed to integrate most trophic diversity present in the plankton. The model was implemented in two variants - which we named ‘green’ and ‘blue’ - characterized by opposite amounts of phytoplankton biomass and representing, respectively, bloom and non-bloom states of the system. Taxonomically disaggregated food-webs described herein allowed to shed light on how components of the plankton community changed their trophic behavior in the two different conditions, and modified the overall functioning of the plankton food web. The green and blue food-webs showed distinct organizations in terms of trophic roles of the nodes and carbon fluxes between them. Such re-organization stemmed from switches in selective grazing by both metazoan and protozoan consumers. Switches in food-web structure resulted in relatively small differences in the efficiency of material transfer towards higher trophic levels. For instance, from green to blue states, a seven-fold decrease in phytoplankton biomass translated into only a two-fold decrease in potential planktivorous fish biomass. By linking diversity, structure and function in the plankton food-web, we discuss the role of internal mechanisms, relying on species-specific functionalities, in driving the ‘adaptive’ responses of plankton communities to perturbations. PMID:26883643

  16. Ecological-network models link diversity, structure and function in the plankton food-web.

    PubMed

    D'Alelio, Domenico; Libralato, Simone; Wyatt, Timothy; Ribera d'Alcalà, Maurizio

    2016-01-01

    A planktonic food-web model including sixty-three functional nodes (representing auto- mixo- and heterotrophs) was developed to integrate most trophic diversity present in the plankton. The model was implemented in two variants - which we named 'green' and 'blue' - characterized by opposite amounts of phytoplankton biomass and representing, respectively, bloom and non-bloom states of the system. Taxonomically disaggregated food-webs described herein allowed to shed light on how components of the plankton community changed their trophic behavior in the two different conditions, and modified the overall functioning of the plankton food web. The green and blue food-webs showed distinct organizations in terms of trophic roles of the nodes and carbon fluxes between them. Such re-organization stemmed from switches in selective grazing by both metazoan and protozoan consumers. Switches in food-web structure resulted in relatively small differences in the efficiency of material transfer towards higher trophic levels. For instance, from green to blue states, a seven-fold decrease in phytoplankton biomass translated into only a two-fold decrease in potential planktivorous fish biomass. By linking diversity, structure and function in the plankton food-web, we discuss the role of internal mechanisms, relying on species-specific functionalities, in driving the 'adaptive' responses of plankton communities to perturbations. PMID:26883643

  17. ON THE TRANSITIONAL DISK CLASS: LINKING OBSERVATIONS OF T TAURI STARS AND PHYSICAL DISK MODELS

    SciTech Connect

    Espaillat, C.; Andrews, S.; Qi, C.; Wilner, D.; Ingleby, L.; Calvet, N.; Hernandez, J.; Furlan, E.; D'Alessio, P.; Muzerolle, J. E-mail: sandrews@cfa.harvard.edu E-mail: dwilner@cfa.harvard.edu E-mail: ncalvet@umich.edu E-mail: Elise.Furlan@jpl.nasa.gov E-mail: muzerol@stsci.edu

    2012-03-10

    Two decades ago 'transitional disks' (TDs) described spectral energy distributions (SEDs) of T Tauri stars with small near-IR excesses, but significant mid- and far-IR excesses. Many inferred this indicated dust-free holes in disks possibly cleared by planets. Recently, this term has been applied disparately to objects whose Spitzer SEDs diverge from the expectations for a typical full disk (FD). Here, we use irradiated accretion disk models to fit the SEDs of 15 such disks in NGC 2068 and IC 348. One group has a 'dip' in infrared emission while the others' continuum emission decreases steadily at all wavelengths. We find that the former have an inner disk hole or gap at intermediate radii in the disk and we call these objects 'transitional disks' and 'pre-transitional disks' (PTDs), respectively. For the latter group, we can fit these SEDs with FD models and find that millimeter data are necessary to break the degeneracy between dust settling and disk mass. We suggest that the term 'transitional' only be applied to objects that display evidence for a radical change in the disk's radial structure. Using this definition, we find that TDs and PTDs tend to have lower mass accretion rates than FDs and that TDs have lower accretion rates than PTDs. These reduced accretion rates onto the star could be linked to forming planets. Future observations of TDs and PTDs will allow us to better quantify the signatures of planet formation in young disks.

  18. Playing the role of weak clique property in link prediction: A friend recommendation model

    NASA Astrophysics Data System (ADS)

    Ma, Chuang; Zhou, Tao; Zhang, Hai-Feng

    2016-07-01

    An important fact in studying link prediction is that the structural properties of networks have significant impacts on the performance of algorithms. Therefore, how to improve the performance of link prediction with the aid of structural properties of networks is an essential problem. By analyzing many real networks, we find a typical structural property: nodes are preferentially linked to the nodes with the weak clique structure (abbreviated as PWCS to simplify descriptions). Based on this PWCS phenomenon, we propose a local friend recommendation (FR) index to facilitate link prediction. Our experiments show that the performance of FR index is better than some famous local similarity indices, such as Common Neighbor (CN) index, Adamic-Adar (AA) index and Resource Allocation (RA) index. We then explain why PWCS can give rise to the better performance of FR index in link prediction. Finally, a mixed friend recommendation index (labelled MFR) is proposed by utilizing the PWCS phenomenon, which further improves the accuracy of link prediction.

  19. Accelerating Influenza Research: Vaccines, Antivirals, Immunomodulators and Monoclonal Antibodies. The Manufacture of a New Wild-Type H3N2 Virus for the Human Viral Challenge Model

    PubMed Central

    Fullen, Daniel J.; Noulin, Nicolas; Catchpole, Andrew; Fathi, Hosnieh; Murray, Edward J.; Mann, Alex; Eze, Kingsley; Balaratnam, Ganesh; Borley, Daryl W.; Gilbert, Anthony; Lambkin-Williams, Rob

    2016-01-01

    Background Influenza and its associated diseases are a major cause of morbidity and mortality. The United States Advisory Committee on Immunization Practices recommends influenza vaccination for everyone over 6 months of age. The failure of the flu vaccine in 2014–2015 demonstrates the need for a model that allows the rapid development of novel antivirals, universal/intra-seasonal vaccines, immunomodulators, monoclonal antibodies and other novel treatments. To this end we manufactured a new H3N2 influenza virus in compliance with Good Manufacturing Practice for use in the Human Viral Challenge Model. Methods and Strain Selection We chose an H3N2 influenza subtype, rather than H1N1, given that this strain has the most substantial impact in terms of morbidity or mortality annually as described by the Centre for Disease Control. We first subjected the virus batch to rigorous adventitious agent testing, confirmed the virus to be wild-type by Sanger sequencing and determined the virus titres appropriate for human use via the established ferret model. We built on our previous experience with other H3N2 and H1N1 viruses to develop this unique model. Human Challenge and Conclusions We conducted an initial safety and characterisation study in healthy adult volunteers, utilising our unique clinical quarantine facility in London, UK. In this study we demonstrated this new influenza (H3N2) challenge virus to be both safe and pathogenic with an appropriate level of disease in volunteers. Furthermore, by inoculating volunteers with a range of different inoculum titres, we established the minimum infectious titre required to achieve reproducible disease whilst ensuring a sensitive model that can be translated to design of subsequent field based studies. Trial Registration ClinicalTrials.gov NCT02525055 PMID:26761707

  20. The Role of VP1 Amino Acid Residue 145 of Enterovirus 71 in Viral Fitness and Pathogenesis in a Cynomolgus Monkey Model

    PubMed Central

    Kataoka, Chikako; Suzuki, Tadaki; Kotani, Osamu; Iwata-Yoshikawa, Naoko; Nagata, Noriyo; Ami, Yasushi; Wakita, Takaji; Nishimura, Yorihiro; Shimizu, Hiroyuki

    2015-01-01

    Enterovirus 71 (EV71), a major causative agent of hand, foot, and mouth disease, occasionally causes severe neurological symptoms. We identified P-selectin glycoprotein ligand-1 (PSGL-1) as an EV71 receptor and found that an amino acid residue 145 in the capsid protein VP1 (VP1-145) defined PSGL-1-binding (PB) and PSGL-1-nonbinding (non-PB) phenotypes of EV71. However, the role of PSGL-1-dependent EV71 replication in neuropathogenesis remains poorly understood. In this study, we investigated viral replication, genetic stability, and the pathogenicity of PB and non-PB strains of EV71 in a cynomolgus monkey model. Monkeys were intravenously inoculated with cDNA-derived PB and non-PB strains of EV71, EV71-02363-EG and EV71-02363-KE strains, respectively, with two amino acid differences at VP1-98 and VP1-145. Mild neurological symptoms, transient lymphocytopenia, and inflammatory cytokine responses, were found predominantly in the 02363-KE-inoculated monkeys. During the early stage of infection, viruses were frequently detected in clinical samples from 02363-KE-inoculated monkeys but rarely in samples from 02363-EG-inoculated monkeys. Histopathological analysis of central nervous system (CNS) tissues at 10 days postinfection revealed that 02363-KE induced neuropathogenesis more efficiently than that induced by 02363-EG. After inoculation with 02363-EG, almost all EV71 variants detected in clinical samples, CNS, and non-CNS tissues, possessed a G to E amino acid substitution at VP1-145, suggesting a strong in vivo selection of VP1-145E variants and CNS spread presumably in a PSGL-1-independent manner. EV71 variants with VP1-145G were identified only in peripheral blood mononuclear cells in two out of four 02363-EG-inoculated monkeys. Thus, VP1-145E variants are mainly responsible for the development of viremia and neuropathogenesis in a non-human primate model, further suggesting the in vivo involvement of amino acid polymorphism at VP1-145 in cell-specific viral

  1. The beginning of a beautiful friendship: Cross-linking/mass spectrometry and modelling of proteins and multi-protein complexes

    PubMed Central

    Rappsilber, Juri

    2011-01-01

    After more than a decade of method development, cross-linking in combination with mass spectrometry and bioinformatics is finally coming of age. This technology now provides improved opportunities for modelling by mapping structural details of functional complexes in solution. The structure of proteins or protein complexes is ascertained by identifying amino acid pairs that are positioned in close proximity to each other. The validity of this technique has recently been benchmarked for large multi-protein complexes, by comparing cross-link data with that from a crystal structure of RNA polymerase II. Here, the specific nature of this cross-linking data will be discussed to assess the technical challenges and opportunities for model building. We believe that once remaining technological challenges of cross-linking/mass spectrometry have been addressed and cross-linking/mass spectrometry data has been incorporated into modelling algorithms it will quickly become an indispensable companion of protein and protein complex modelling and a corner-stone of integrated structural biology. PMID:21029779

  2. Myeloid Leukemias and Virally Induced Lymphomas in Miniature Inbred Swine: Development of a Large Animal Tumor Model.

    PubMed

    Duran-Struuck, Raimon; Matar, Abraham J; Huang, Christene A

    2015-01-01

    The lack of a large animal transplantable tumor model has limited the study of novel therapeutic strategies for the treatment of liquid cancers. Swine as a species provide a natural option based on their similarities with humans and their already extensive use in biomedical research. Specifically, the Massachusetts General Hospital miniature swine herd retains unique genetic characteristics that facilitate the study of hematopoietic cell and solid organ transplantation. Spontaneously arising liquid cancers in these swine, specifically myeloid leukemias and B cell lymphomas, closely resemble human malignancies. The ability to establish aggressive tumor cell lines in vitro from these naturally occurring malignancies makes a transplantable tumor model a close reality. Here, we discuss our experience with myeloid and lymphoid tumors in major histocompatibility characterized miniature swine and future approaches regarding the development of a large animal transplantable tumor model. PMID:26635868

  3. Myeloid Leukemias and Virally Induced Lymphomas in Miniature Inbred Swine: Development of a Large Animal Tumor Model

    PubMed Central

    Duran-Struuck, Raimon; Matar, Abraham J.; Huang, Christene A.

    2015-01-01

    The lack of a large animal transplantable tumor model has limited the study of novel therapeutic strategies for the treatment of liquid cancers. Swine as a species provide a natural option based on their similarities with humans and their already extensive use in biomedical research. Specifically, the Massachusetts General Hospital miniature swine herd retains unique genetic characteristics that facilitate the study of hematopoietic cell and solid organ transplantation. Spontaneously arising liquid cancers in these swine, specifically myeloid leukemias and B cell lymphomas, closely resemble human malignancies. The ability to establish aggressive tumor cell lines in vitro from these naturally occurring malignancies makes a transplantable tumor model a close reality. Here, we discuss our experience with myeloid and lymphoid tumors in major histocompatibility characterized miniature swine and future approaches regarding the development of a large animal transplantable tumor model. PMID:26635868

  4. Viral hepatitis: Indian scenario.

    PubMed

    Satsangi, Sandeep; Chawla, Yogesh K

    2016-07-01

    Viral hepatitis is a cause for major health care burden in India and is now equated as a threat comparable to the "big three" communicable diseases - HIV/AIDS, malaria and tuberculosis. Hepatitis A virus and Hepatitis E virus are predominantly enterically transmitted pathogens and are responsible to cause both sporadic infections and epidemics of acute viral hepatitis. Hepatitis B virus and Hepatitis C virus are predominantly spread via parenteral route and are notorious to cause chronic hepatitis which can lead to grave complications including cirrhosis of liver and hepatocellular carcinoma. Around 400 million people all over the world suffer from chronic hepatitis and the Asia-Pacific region constitutes the epicentre of this epidemic. The present article would aim to cover the basic virologic aspects of these viruses and highlight the present scenario of viral hepatitis in India. PMID:27546957

  5. Linking land use change to recreational fishery valuation with a spatially explicit behavior model: A case study from Tampa Bay, FL USA

    EPA Science Inventory

    Drawing a link between habitat change and production and delivery of ecosystem services is a priority in coastal estuarine ecosystems. This link is needed to fully understand how human communities can influence ecosystem sustainability. Mechanistic modeling tools are highly fun...

  6. Linking GIS-based models to value ecosystem services in an Alpine region.

    PubMed

    Grêt-Regamey, Adrienne; Bebi, Peter; Bishop, Ian D; Schmid, Willy A

    2008-11-01

    Planning frequently fails to include the valuation of public goods and services. This can have long-term negative economic consequences for a region. This is especially the case in mountainous regions such as the Alps, which depend on tourism and where land-use changes can negatively impact key ecosystem services and hence the economy. In this study, we develop a semi-automatic procedure to value ecosystem goods and services. Several existing process-based models linked to economic valuation methods are integrated into a geographic information system (GIS) platform. The model requires the input of a digital elevation model, a land-cover map, and a spatially explicit temperature dataset. These datasets are available for most regions in Europe. We illustrate the approach by valuing four ecosystem services: avalanche protection, timber production, scenic beauty, and habitat, which are supplied by the "Landschaft Davos", an administrative district in the Swiss Alps. We compare the impacts of a human development scenario and a climate scenario on the value of these ecosystem services. Urban expansion and tourist infrastructure developments have a negative impact on scenic beauty and habitats. These impacts outweigh the benefits of the developments in the long-term. Forest expansion, predictable under a climate change scenario, favours natural avalanche protection and habitats. In general, such non-marketed benefits provided by the case-study region more than compensate for the costs of forest maintenance. Finally, we discuss the advantages and disadvantages of the approach. Despite its limitations, we show how this approach could well help decision-makers balance the impacts of different planning options on the economic accounting of a region, and guide them in selecting sustainable and economically feasible development strategies. PMID:17825979

  7. Linking Human Diseases to Animal Models Using Ontology-Based Phenotype Annotation

    PubMed Central

    Mungall, Christopher J.; Ashburner, Michael; Westerfield, Monte; Lewis, Suzanna E.

    2009-01-01

    Scientists and clinicians who study genetic alterations and disease have traditionally described phenotypes in natural language. The considerable variation in these free-text descriptions has posed a hindrance to the important task of identifying candidate genes and models for human diseases and indicates the need for a computationally tractable method to mine data resources for mutant phenotypes. In this study, we tested the hypothesis that ontological annotation of disease phenotypes will facilitate the discovery of new genotype-phenotype relationships within and across species. To describe phenotypes using ontologies, we used an Entity-Quality (EQ) methodology, wherein the affected entity (E) and how it is affected (Q) are recorded using terms from a variety of ontologies. Using this EQ method, we annotated the phenotypes of 11 gene-linked human diseases described in Online Mendelian Inheritance in Man (OMIM). These human annotations were loaded into our Ontology-Based Database (OBD) along with other ontology-based phenotype descriptions of mutants from various model organism databases. Phenotypes recorded with this EQ method can be computationally compared based on the hierarchy of terms in the ontologies and the frequency of annotation. We utilized four similarity metrics to compare phenotypes and developed an ontology of homologous and analogous anatomical structures to compare phenotypes between species. Using these tools, we demonstrate that we can identify, through the similarity of the recorded phenotypes, other alleles of the same gene, other members of a signaling pathway, and orthologous genes and pathway members across species. We conclude that EQ-based annotation of phenotypes, in conjunction with a cross-species ontology, and a variety of similarity metrics can identify biologically meaningful similarities between genes by comparing phenotypes alone. This annotation and search method provides a novel and efficient means to identify gene candidates

  8. [Viral hepatitis in travellers].

    PubMed

    Abreu, Cândida

    2007-01-01

    Considering the geographical asymmetric distribution of viral hepatitis A, B and E, having a much higher prevalence in the less developed world, travellers from developed countries are exposed to a considerable and often underestimated risk of hepatitis infection. In fact a significant percentage of viral hepatitis occurring in developed countries is travel related. This results from globalization and increased mobility from tourism, international work, humanitarian and religious missions or other travel related activities. Several studies published in Europe and North America shown that more than 50% of reported cases of hepatitis A are travel related. On the other hand frequent outbreaks of hepatitis A and E in specific geographic areas raise the risk of infection in these restricted zones and that should be clearly identified. Selected aspects related with the distribution of hepatitis A, B and E are reviewed, particularly the situation in Portugal according to the published studies, as well as relevant clinical manifestations and differential diagnosis of viral hepatitis. Basic prevention rules considering enteric transmitted hepatitis (hepatitis A and hepatitis E) and parenteral transmitted (hepatitis B) are reviewed as well as hepatitis A and B immunoprophylaxis. Common clinical situations and daily practice "pre travel" advice issues are discussed according to WHO/CDC recommendations and the Portuguese National Vaccination Program. Implications from near future availability of a hepatitis E vaccine, a currently in phase 2 trial, are highlighted. Potential indications for travellers to endemic countries like India, Nepal and some regions of China, where up to 30% of sporadic cases of acute viral hepatitis are caused by hepatitis E virus, are considered. Continued epidemiological surveillance for viral hepatitis is essential to recognize and control possible outbreaks, but also to identify new viral hepatitis agents that may emerge as important global health

  9. Effects of Shenqi Fuzheng injection on Fas/FasL protein expression levels in the cardiomyocytes of a mouse model of viral myocarditis

    PubMed Central

    WU, TIANMIN; CHEN, JINSHUI; FAN, LIUFANG; XIE, WENYAN; XU, CHANGSHENG; WANG, HUAJUN

    2016-01-01

    The aim of the present study was to examine the effects of Shenqi Fuzheng injection (SFI) on Fas and FasL protein expression levels in the cardiomyocytes of mice with viral myocarditis (VMC) and to explore the underlying anti-apoptotic mechanisms. A total of 120 male BALB/c mice were randomly divided into five groups as follows: Blank control group, model group, ribavirin group, low-dose SFI group and high-dose SFI group. The VMC model was established by the injection of coxsackievirus group B type 3 and saline, ribavirin or SFI was administered 30 min later. Cardiac samples were harvested from mice in each group on days 3, 10 and 30. Apoptosis of cardiac cells was examined using terminal deoxynucleotidyl transferase dUTP nick-end labeling, and Fas and FasL protein expression levels were detected using immunohistochemistry. Myocardial apoptosis and Fas/FasL protein expression levels were significantly increased in the model group, as compared with the blank group (P<0.01), whereas the apoptotic index (AI) and Fas/FasL protein expression levels of cardiac cells in the high-dose SFI group were significantly decreased compared with those in the model group on day 10 (acute phase; P<0.01). The AI and Fas/FasL protein expression levels of cardiac cells in the low- and high-dose SFI groups were also significantly decreased on day 30 (chronic phase; P<0.01); however, no differences between the high- and low-dose groups were detected. In conclusion, SFI relieves VMC via the downregulation of Fas and FasL protein expression and the inhibition of cell apoptosis. PMID:27168814

  10. The hydrological calibration and validation of a complexly-linked watershed reservoir model for the Occoquan watershed, Virginia

    NASA Astrophysics Data System (ADS)

    Xu, Zhongyan; Godrej, Adil N.; Grizzard, Thomas J.

    2007-10-01

    SummaryRunoff models such as HSPF and reservoir models such as CE-QUAL-W2 are used to model water quality in watersheds. Most often, the models are independently calibrated to observed data. While this approach can achieve good calibration, it does not replicate the physically-linked nature of the system. When models are linked by using the model output from an upstream model as input to a downstream model, the physical reality of a continuous watershed, where the overland and waterbody portions are parts of the whole, is better represented. There are some additional challenges in the calibration of such linked models, because the aim is to simulate the entire system as a whole, rather than piecemeal. When public entities are charged with model development, one of the driving forces is to use public-domain models. This paper describes the use of two such models, HSPF and CE-QUAL-W2, in the linked modeling of the Occoquan watershed located in northern Virginia, USA. The description of the process is provided, and results from the hydrological calibration and validation are shown. The Occoquan model consists of six HSPF and two CE-QUAL-W2 models, linked in a complex way, to simulate two major reservoirs and the associated drainage areas. The overall linked model was calibrated for a three-year period and validated for a two-year period. The results show that a successful calibration can be achieved using the linked approach, with moderate additional effort. Overall flow balances based on the three-year calibration period at four stream stations showed agreement ranging from -3.95% to +3.21%. Flow balances for the two reservoirs, compared via the daily water surface elevations, also showed good agreement ( R2 values of 0.937 for Lake Manassas and 0.926 for Occoquan Reservoir), when missing (un-monitored) flows were included. Validation of the models ranged from poor to fair for the watershed models and excellent for the waterbody models, thus indicating that the

  11. Failure of Viral Shells

    NASA Astrophysics Data System (ADS)

    Klug, William S.; Bruinsma, Robijn F.; Michel, Jean-Philippe; Knobler, Charles M.; Ivanovska, Irena L.; Schmidt, Christoph F.; Wuite, Gijs J. L.

    2006-12-01

    We report a combined theoretical and experimental study of the structural failure of viral shells under mechanical stress. We find that discontinuities in the force-indentation curve associated with failure should appear when the so-called Föppl von Kármán (FvK) number exceeds a critical value. A nanoindentation study of a viral shell subject to a soft-mode instability, where the stiffness of the shell decreases with increasing pH, confirms the predicted onset of failure as a function of the FvK number.

  12. Linking an economic model for European agriculture with a mechanistic model to estimate nitrogen losses from cropland soil in Europe

    NASA Astrophysics Data System (ADS)

    Leip, A.; Marchi, G.; Koeble, R.; Kempen, M.; Britz, W.; Li, C.

    2007-07-01

    For the comprehensive assessment of the policy impact on greenhouse gas emissions from agricultural soils both socio-economic aspects and the environmental heterogeneity of the landscape are important factors that must be considered. We developed a modelling framework that links the large-scale economic model for agriculture CAPRI with the bio-geochemistry model DNDC to simulate greenhouse gas fluxes, carbon stock changes and the nitrogen budget of agricultural soils in Europe. The framework allows the ex-ante simulation of agricultural or agri-environmental policy impacts on wide range of environmental problems such as climate change (greenhouse gas emissions), air pollution and groundwater pollution. Those environmental impacts can be analysed in the context of economic and social indicators as calculated by the economic model. The methodology consists in four steps (i) the definition of appropriate calculation units that can be considered as homogeneous in terms of economic behaviour and environmental response; (ii) downscaling of regional agricultural statistics and farm management information from a CAPRI simulation run into the spatial calculation units; (iii) setting up of environmental model scenarios and model runs; and finally (iv) aggregating results for interpretation. We show first results of the nitrogen budget in cropland for the area of fourteen countries of the European Union. These results, in terms of estimated nitrogen fluxes, must still be considered as illustrative as needs for improvements in input data (e.g. the soil map) and management data (yield estimates) have been identified and will be the focus of future work. Nevertheless, we highlight inter-dependencies between farmer's choices of land uses and the environmental impact of different cultivation systems.

  13. A modeling approach to estimate the solar disinfection of viral indicator organisms in waste stabilization ponds and surface waters.

    PubMed

    Kohn, Tamar; Mattle, Michael J; Minella, Marco; Vione, Davide

    2016-01-01

    Sunlight is known to be a pertinent factor governing the infectivity of waterborne viruses in the environment. Sunlight inactivates viruses via endogenous inactivation (promoted by absorption of solar light in the UVB range by the virus) and exogenous processes (promoted by adsorption of sunlight by external chromophores, which subsequently generate inactivating reactive species). The extent of inactivation is still difficult to predict, as it depends on multiple parameters including virus characteristics, solution composition, season and geographical location. In this work, we adapted a model typically used to estimate the photodegradation of organic pollutants, APEX, to explore the fate of two commonly used surrogates of human viruses (coliphages MS2 and ϕX174) in waste stabilization pond and natural surface water. Based on experimental data obtained in previous work, we modeled virus inactivation as a function of water depth and composition, as well as season and latitude, and we apportioned the contributions of the different inactivation processes to total inactivation. Model results showed that ϕX174 is inactivated more readily than MS2, except at latitudes >60°. ϕX174 inactivation varies greatly with both season (20-fold) and latitude (10-fold between 0 and 60°), and is dominated by endogenous inactivation under all solution conditions considered. In contrast, exogenous processes contribute significantly to MS2 inactivation. Because exogenous inactivation can be promoted by longer wavelengths, which are less affected by changes in season and latitude, MS2 exhibits smaller fluctuations in inactivation throughout the year (10-fold) and across the globe (3-fold between 0 and 60°) compared to ϕX174. While a full model validation is currently not possible due to the lack of sufficient field data, our estimated inactivation rates corresponded well to those reported in field studies. Overall, this study constitutes a step toward estimating microbial water

  14. Vibro-acoustic modelling of aircraft double-walls with structural links using Statistical Energy Analysis

    NASA Astrophysics Data System (ADS)

    Campolina, Bruno L.

    The prediction of aircraft interior noise involves the vibroacoustic modelling of the fuselage with noise control treatments. This structure is composed of a stiffened metallic or composite panel, lined with a thermal and acoustic insulation layer (glass wool), and structurally connected via vibration isolators to a commercial lining panel (trim). The goal of this work aims at tailoring the noise control treatments taking design constraints such as weight and space optimization into account. For this purpose, a representative aircraft double-wall is modelled using the Statistical Energy Analysis (SEA) method. Laboratory excitations such as diffuse acoustic field and point force are addressed and trends are derived for applications under in-flight conditions, considering turbulent boundary layer excitation. The effect of the porous layer compression is firstly addressed. In aeronautical applications, compression can result from the installation of equipment and cables. It is studied analytically and experimentally, using a single panel and a fibrous uniformly compressed over 100% of its surface. When compression increases, a degradation of the transmission loss up to 5 dB for a 50% compression of the porous thickness is observed mainly in the mid-frequency range (around 800 Hz). However, for realistic cases, the effect should be reduced since the compression rate is lower and compression occurs locally. Then the transmission through structural connections between panels is addressed using a four-pole approach that links the force-velocity pair at each side of the connection. The modelling integrates experimental dynamic stiffness of isolators, derived using an adapted test rig. The structural transmission is then experimentally validated and included in the double-wall SEA model as an equivalent coupling loss factor (CLF) between panels. The tested structures being flat, only axial transmission is addressed. Finally, the dominant sound transmission paths are

  15. Predictive oncology: multidisciplinary, multi-scale in-silico modeling linking phenotype, morphology and growth

    PubMed Central

    Sanga, Sandeep; Frieboes, Hermann B.; Zheng, Xiaoming; Gatenby, Robert; Bearer, Elaine L.; Cristini, Vittorio

    2007-01-01

    Empirical evidence and theoretical studies suggest that the phenotype, i.e., cellular- and molecular-scale dynamics, including proliferation rate and adhesiveness due to microenvironmental factors and gene expression that govern tumor growth and invasiveness, also determine gross tumor-scale morphology. It has been difficult to quantify the relative effect of these links on disease progression and prognosis using conventional clinical and experimental methods and observables. As a result, successful individualized treatment of highly malignant and invasive cancers, such as glioblastoma, via surgical resection and chemotherapy cannot be offered and outcomes are generally poor. What is needed is a deterministic, quantifiable method to enable understanding of the connections between phenotype and tumor morphology. Here, we critically review advantages and disadvantages of recent computational modeling efforts (e.g., continuum, discrete, and cellular automata models) that have pursued this understanding. Based on this assessment, we propose and discuss a multi-scale, i.e., from the molecular to the gross tumor scale, mathematical and computational “first-principle” approach based on mass conservation and other physical laws, such as employed in reaction-diffusion systems. Model variables describe known characteristics of tumor behavior, and parameters and functional relationships across scales are informed from in vitro, in vivo and ex vivo biology. We demonstrate that this methodology, once coupled to tumor imaging and tumor biopsy or cell culture data, should enable prediction of tumor growth and therapy outcome through quantification of the relation between the underlying dynamics and morphological characteristics. In particular, morphologic stability analysis of this mathematical model reveals that tumor cell patterning at the tumor-host interface is regulated by cell proliferation, adhesion and other phenotypic characteristics: histopathology information of

  16. A model linking biology, behavior and psychiatric diagnoses in perpetrators of domestic violence.

    PubMed

    George, David T; Phillips, Monte J; Doty, Linda; Umhau, John C; Rawlings, Robert R

    2006-01-01

    Research indicates that perpetrators of domestic violence have abnormalities in central serotonin and testosterone metabolism, an increased sensitivity to anxiogenic stimuli, and an impaired neuro-connection between their cortex and the amygdala. Clinical evaluations show that perpetrators of domestic violence also have a distinguishing set of behaviors and diagnoses related to anxiety, depression, intermittent explosive disorder, and borderline personality disorder. In this paper we propose a model to understand how the biological abnormalities can potentially explain the behaviors and diagnoses exhibited by the perpetrators. Changes in the perpetrator's neurotransmitters lead to a heightened sensitivity to environmental stimuli, anxiety, and conditioned fear. Lack of cortical input to the amygdala impairs the perpetrator's ability to extinguish anxiety and/or conditioned fear and gives rise to either innate behaviors (e.g., fight, flight, and shut down) or learned fear avoidant behaviors designed to avoid anxiety (e.g., alcohol consumption, self-injurious acts, and obsessive behaviors). Linking conditioned fear and fear avoidance to the behaviors and psychiatric diagnoses will serve to change the way the medical community perceives and treats perpetrators of domestic violence. PMID:16580153

  17. Gene Therapy Model of X-linked Severe Combined Immunodeficiency Using a Modified Foamy Virus Vector

    PubMed Central

    Horino, Satoshi; Uchiyama, Toru; So, Takanori; Nagashima, Hiroyuki; Sun, Shu-lan; Sato, Miki; Asao, Atsuko; Haji, Yoichi; Sasahara, Yoji; Candotti, Fabio; Tsuchiya, Shigeru; Kure, Shigeo; Sugamura, Kazuo; Ishii, Naoto

    2013-01-01

    X-linked severe combined immunodeficiency (SCID-X1) is an inherited genetic immunodeficiency associated with mutations in the common cytokine receptor γ chain (γc) gene, and characterized by a complete defect of T and natural killer (NK) cells. Gene therapy for SCID-X1 using conventional retroviral (RV) vectors carrying the γc gene results in the successful reconstitution of T cell immunity. However, the high incidence of vector-mediated T cell leukemia, caused by vector insertion near or within cancer-related genes has been a serious problem. In this study, we established a gene therapy model of mouse SCID-X1 using a modified foamy virus (FV) vector expressing human γc. Analysis of vector integration in a human T cell line demonstrated that the FV vector integration sites were significantly less likely to be located within or near transcriptional start sites than RV vector integration sites. To evaluate the therapeutic efficacy, bone marrow cells from γc-knockout (γc-KO) mice were infected with the FV vector and transplanted into γc-KO mice. Transplantation of the FV-treated cells resulted in the successful reconstitution of functionally active T and B cells. These data suggest that FV vectors can be effective and may be safer than conventional RV vectors for gene therapy for SCID-X1. PMID:23990961

  18. Solvent/Detergent Virally Inactivated Serum Eye Drops Restore Healthy Ocular Epithelium in a Rabbit Model of Dry-Eye Syndrome

    PubMed Central

    Tseng, Ching-Li; Chen, Zhi-Yu; Renn, Ting-Yi; Hsiao, Shun-Hung; Burnouf, Thierry

    2016-01-01

    Application of autologous serum eye drops (SEDs) is a recognized means to treat severe dry-eye syndrome (DES). Due to the inconvenience and difficulty of preparing SEDs from some patients, producing SEDs from allogeneic blood donations is gaining popularity. A major safety concern associated with allogeneic blood is virus transmission. We therefore herein evaluated the possibility of applying a solvent/detergent (S/D) treatment to inactivate viruses and studied the impacts of such treatment of SEDs to resolve DES in a rabbit model. Sera prepared from the blood of five rabbits were pooled and divided into two sub-pools. One was untreated (SEDs), while the other was virally-inactivated with 1% Tri-n-butyl phosphate/1% Triton X-45 at 31°C for 1 h (S/D-SEDs). DES was induced in rabbits using 0.1% benzalkonium chloride (BAC). Rabbits were divided into five groups of two rabbits each. One group was untreated (control), three were treated twice daily for 3 weeks using PBS, SEDs, or S/D-SEDs, and the last received an additional 0.1% BAC (as the negative control). The DES condition was determined by measuring aqueous tear secretion (Schirmer’s test), corneal fluorescein staining, a corneal histologic examination, TUNEL stain apoptosis, and corneal inflammatory marker (tumor necrosis factor-α, interleukin (IL)-1β, IL-8, and IL-6) expressions. We first confirmed that SEDs and S/D-SEDs had similar protein profiles and transforming growth factor (TGF)-β contents. Animal experiments showed that tear secretion did not significantly differ between the SED and S/D-SED groups but was significantly higher than in the PBS group. Eye fluorescein staining revealed dramatic improvements in epithelial defects in groups treated with SEDs or S/D-SEDs, and hematoxylin/eosin staining revealed microscopic epithelial layers similar to those of the untreated controls. Inflammatory markers and TUNEL studies showed that healthy epithelium had been restored in groups treated with SEDs or S

  19. Solvent/Detergent Virally Inactivated Serum Eye Drops Restore Healthy Ocular Epithelium in a Rabbit Model of Dry-Eye Syndrome.

    PubMed

    Tseng, Ching-Li; Chen, Zhi-Yu; Renn, Ting-Yi; Hsiao, Shun-Hung; Burnouf, Thierry

    2016-01-01

    Application of autologous serum eye drops (SEDs) is a recognized means to treat severe dry-eye syndrome (DES). Due to the inconvenience and difficulty of preparing SEDs from some patients, producing SEDs from allogeneic blood donations is gaining popularity. A major safety concern associated with allogeneic blood is virus transmission. We therefore herein evaluated the possibility of applying a solvent/detergent (S/D) treatment to inactivate viruses and studied the impacts of such treatment of SEDs to resolve DES in a rabbit model. Sera prepared from the blood of five rabbits were pooled and divided into two sub-pools. One was untreated (SEDs), while the other was virally-inactivated with 1% Tri-n-butyl phosphate/1% Triton X-45 at 31°C for 1 h (S/D-SEDs). DES was induced in rabbits using 0.1% benzalkonium chloride (BAC). Rabbits were divided into five groups of two rabbits each. One group was untreated (control), three were treated twice daily for 3 weeks using PBS, SEDs, or S/D-SEDs, and the last received an additional 0.1% BAC (as the negative control). The DES condition was determined by measuring aqueous tear secretion (Schirmer's test), corneal fluorescein staining, a corneal histologic examination, TUNEL stain apoptosis, and corneal inflammatory marker (tumor necrosis factor-α, interleukin (IL)-1β, IL-8, and IL-6) expressions. We first confirmed that SEDs and S/D-SEDs had similar protein profiles and transforming growth factor (TGF)-β contents. Animal experiments showed that tear secretion did not significantly differ between the SED and S/D-SED groups but was significantly higher than in the PBS group. Eye fluorescein staining revealed dramatic improvements in epithelial defects in groups treated with SEDs or S/D-SEDs, and hematoxylin/eosin staining revealed microscopic epithelial layers similar to those of the untreated controls. Inflammatory markers and TUNEL studies showed that healthy epithelium had been restored in groups treated with SEDs or S

  20. An affine continuum mechanical model for cross-linked F-actin networks with compliant linker proteins.

    PubMed

    Holzapfel, Gerhard A; Unterberger, Michael J; Ogden, Ray W

    2014-10-01

    Cross-linked actin networks are important building blocks of the cytoskeleton. In order to gain deeper insight into the interpretation of experimental data on actin networks, adequate models are required. In this paper we introduce an affine constitutive network model for cross-linked F-actin networks based on nonlinear continuum mechanics, and specialize it in order to reproduce the experimental behavior of in vitro reconstituted model networks. The model is based on the elastic properties of single filaments embedded in an isotropic matrix such that the overall properties of the composite are described by a free-energy function. In particular, we are able to obtain the experimentally determined shear and normal stress responses of cross-linked actin networks typically observed in rheometer tests. In the present study an extensive analysis is performed by applying the proposed model network to a simple shear deformation. The single filament model is then extended by incorporating the compliance of cross-linker proteins and further extended by including viscoelasticity. All that is needed for the finite element implementation is the constitutive model for the filaments, the linkers and the matrix, and the associated elasticity tensor in either the Lagrangian or Eulerian formulation. The model facilitates parameter studies of experimental setups such as micropipette aspiration experiments and we present such studies to illustrate the efficacy of this modeling approach. PMID:25043658

  1. Viral diseases of the rabbit.

    PubMed

    Krogstad, Aric P; Simpson, Janet E; Korte, Scott W

    2005-01-01

    Viral disease in the rabbit is encountered infrequently by the clinical practitioner; however, several viral diseases were reported to occur in this species. Viral diseases that are described in the rabbit primarily may affect the integument, gastrointestinal tract or, central nervous system or maybe multi-systemic in nature. Rabbit viral diseases range from oral papillomatosis, with benign clinical signs, to rabbit hemorrhagic disease and myxomatosis, which may result in significant clinical disease and mortality. The wild rabbit may serve as a reservoir for disease transmission for many of these viral agents. In general, treatment of viral disease in the rabbit is supportive in nature. PMID:15585192

  2. Efficient Source of Cells in Proximal Oviduct for Testing Non-Viral Expression Constructs in the Chicken Bioreactor Model and for Other in Vitro Studies.

    PubMed

    Stadnicka, Katarzyna; Bodnar, Magdalena; Marszałek, Andrzej; Bajek, Anna; Drewa, Tomasz; Płucienniczak, Grazyna; Chojnacka-Puchta, Luiza; Cecuda-Adamczewska, Violetta; Dunisławska, Aleksandra; Bednarczyk, Marek

    2016-01-01

    This work shows the usefulness of chicken oviduct epithelial cells (COEC) in evaluating the efficacy of non-viral expression vectors carrying human therapeutic genes. Secondly, an efficient source of progenitor COEC for in vitro studies is described. Within the distal part of the oviduct, weak to moderate expression of a trans membrane glycoprotein (CD44) was observed. Single cells presenting only weak expression of CD44 were found in magnum sections. in vitro cultured oviduct cells originating from the distal oviduct were suitable for subculturing and showed a stable proliferation potential up to the 2nd passage. However, the pavimentous epithelial-like morphology of COEC was progressively lost over time and mainly a fibroblast-like monolayer was established in consecutive passages. Moreover, various commercial transfection agents including FuGENE6 and XtremeGENE9 DNA were used to optimize delivery of human interferon alfa-2a, (IFNα2a) a therapeutic protein gene under an ovalbumin promoter. The transfection efficiency of adherent COEC was estimated for up to 40% at a ratio of 6:1 of transfectant to pOVA5EIFN + GFP plasmid. Expression of IFNα2a was confirmed by western blotting in transformed COEC. In conclusion, the population of epithelial progenitor cells sourced from the distal oviduct can significantly contribute to in vitro culture of COEC, representing an efficient model to develop the production of avian bioreactors and other in vitro studies related to oviduct tissue. PMID:27172711

  3. Two-photon imaging of remyelination of spinal cord axons by engrafted neura