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Induction of GADD34 Is Necessary for dsRNA-Dependent Interferon-β Production and Participates in the Control of Chikungunya Virus Infection  [PDF]
Giovanna Clavarino equal contributor,Nuno Cláudio equal contributor,Thérèse Couderc equal contributor,Alexandre Dalet,Delphine Judith,Voahirana Camosseto,Enrico K. Schmidt,Till Wenger,Marc Lecuit,Evelina Gatti ? ,Philippe Pierre ?
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002708
Abstract: Nucleic acid sensing by cells is a key feature of antiviral responses, which generally result in type-I Interferon production and tissue protection. However, detection of double-stranded RNAs in virus-infected cells promotes two concomitant and apparently conflicting events. The dsRNA-dependent protein kinase (PKR) phosphorylates translation initiation factor 2-alpha (eIF2α) and inhibits protein synthesis, whereas cytosolic DExD/H box RNA helicases induce expression of type I-IFN and other cytokines. We demonstrate that the phosphatase-1 cofactor, growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a), an important component of the unfolded protein response (UPR), is absolutely required for type I-IFN and IL-6 production by mouse embryonic fibroblasts (MEFs) in response to dsRNA. GADD34 expression in MEFs is dependent on PKR activation, linking cytosolic microbial sensing with the ATF4 branch of the UPR. The importance of this link for anti-viral immunity is underlined by the extreme susceptibility of GADD34-deficient fibroblasts and neonate mice to Chikungunya virus infection.
Chromosome Visualization Tool: A Whole Genome Viewer  [PDF]
Ethalinda K. S. Cannon,Steven B. Cannon
International Journal of Plant Genomics , 2011, DOI: 10.1155/2011/373875
Abstract: CViT (chromosome visualization tool) is a Perl utility for quickly generating images of features on a whole genome at once. It reads GFF3-formated data representing chromosomes (linkage groups or pseudomolecules) and sets of features on those chromosomes. It can display features on any chromosomal unit system, including genetic (centimorgan), cytological (centiMcClintock), and DNA unit (base-pair) coordinates. CViT has been used to track sequencing progress (status of genome sequencing, location and number of gaps), to visualize BLAST hits on a whole genome view, to associate maps with one another, to locate regions of repeat densities to display syntenic regions, and to visualize centromeres and knobs on chromosomes. 1. Introduction Visualizing features on a whole genome (all chromosomes together) can be informative for many reasons: for identifying genome-wide patterns such as gene or repeat densities, for viewing internal duplications or synteny, for assessing clustering of genes or repeats or other features, for comparing chromosomal structures such as centromeres and pericentromeric regions, or for looking for associations between different types of genomic features. Several very capable genome browsers enable visualization of single chromosomes or regions, but few visualization tools have been developed for whole-genome-at-a-time views. We present CViT (chromosome visualization tool), for viewing a wide range of genomic features on an arbitrary set of linear regions—typically, all of the chromosomes or linkage groups for a genome. CViT is a set of Perl scripts that generate a PNG (portable network graphics) image of features on chromosomes. It can be executed as a standalone Unix command line utility or wrapped in a web page for either static display or as part of an interactive online tool. The characteristics of the output images are highly configurable. A package containing the CViT code itself along with documentation, examples, supporting scripts, and sample web implementations can be freely downloaded from SourceForge at http://sourceforge.net/projects/cvit/. CViT was initially developed to support the Medicago truncatula sequencing project [1] where it was used to display the assembled bacterial artificial chromosomes (BACs) and the status of the sequencing for each BAC. CViT was also wrapped in web pages to create interactive tools: to display BLAST [2] hits on the whole genome (see http://www.medicagohapmap.org/advanced_search_page.php?seq) and to search where BACs of interest are anchored on the pseudomolecules. For other projects, it
A Mouse Model for Chikungunya: Young Age and Inefficient Type-I Interferon Signaling Are Risk Factors for Severe Disease  [PDF]
Thérèse Couderc equal contributor,Fabrice Chrétien equal contributor,Clémentine Schilte equal contributor,Olivier Disson,Madly Brigitte,Florence Guivel-Benhassine,Yasmina Touret,Georges Barau,Nadège Cayet,Isabelle Schuffenecker,Philippe Desprès,Fernando Arenzana-Seisdedos,Alain Michault,Matthew L Albert equal contributor,Marc Lecuit equal contributor
PLOS Pathogens , 2008, DOI: 10.1371/journal.ppat.0040029
Abstract: Chikungunya virus (CHIKV) is a re-emerging arbovirus responsible for a massive outbreak currently afflicting the Indian Ocean region and India. Infection from CHIKV typically induces a mild disease in humans, characterized by fever, myalgia, arthralgia, and rash. Cases of severe CHIKV infection involving the central nervous system (CNS) have recently been described in neonates as well as in adults with underlying conditions. The pathophysiology of CHIKV infection and the basis for disease severity are unknown. To address these critical issues, we have developed an animal model of CHIKV infection. We show here that whereas wild type (WT) adult mice are resistant to CHIKV infection, WT mouse neonates are susceptible and neonatal disease severity is age-dependent. Adult mice with a partially (IFN-α/βR+/?) or totally (IFN-α/βR?/?) abrogated type-I IFN pathway develop a mild or severe infection, respectively. In mice with a mild infection, after a burst of viral replication in the liver, CHIKV primarily targets muscle, joint, and skin fibroblasts, a cell and tissue tropism similar to that observed in biopsy samples of CHIKV-infected humans. In case of severe infections, CHIKV also disseminates to other tissues including the CNS, where it specifically targets the choroid plexuses and the leptomeninges. Together, these data indicate that CHIKV-associated symptoms match viral tissue and cell tropisms, and demonstrate that the fibroblast is a predominant target cell of CHIKV. These data also identify the neonatal phase and inefficient type-I IFN signaling as risk factors for severe CHIKV-associated disease. The development of a permissive small animal model will expedite the testing of future vaccines and therapeutic candidates.
Whole-Genome Sequencing Analysis from the Chikungunya Virus Caribbean Outbreak Reveals Novel Evolutionary Genomic Elements  [PDF]
Kenneth A. Stapleford?,Gonzalo Moratorio?,Rasmus Henningsson?,Rubing Chen?,Séverine Matheus?,Antoine Enfissi?,Daphna Weissglas-Volkov?,Ofer Isakov?,Hervé Blanc?,Bryan C. Mounce
PLOS Neglected Tropical Diseases , 2016, DOI: 10.1371/journal.pntd.0004402
Abstract: Background Chikungunya virus (CHIKV), an alphavirus and member of the Togaviridae family, is capable of causing severe febrile disease in humans. In December of 2013 the Asian Lineage of CHIKV spread from the Old World to the Americas, spreading rapidly throughout the New World. Given this new emergence in na?ve populations we studied the viral genetic diversity present in infected individuals to understand how CHIKV may have evolved during this continuing outbreak. Methodology/Principle Findings We used deep-sequencing technologies coupled with well-established bioinformatics pipelines to characterize the minority variants and diversity present in CHIKV infected individuals from Guadeloupe and Martinique, two islands in the center of the epidemic. We observed changes in the consensus sequence as well as a diverse range of minority variants present at various levels in the population. Furthermore, we found that overall diversity was dramatically reduced after single passages in cell lines. Finally, we constructed an infectious clone from this outbreak and identified a novel 3’ untranslated region (UTR) structure, not previously found in nature, that led to increased replication in insect cells. Conclusions/Significance Here we preformed an intrahost quasispecies analysis of the new CHIKV outbreak in the Caribbean. We identified novel variants present in infected individuals, as well as a new 3’UTR structure, suggesting that CHIKV has rapidly evolved in a short period of time once it entered this na?ve population. These studies highlight the need to continue viral diversity surveillance over time as this epidemic evolves in order to understand the evolutionary potential of CHIKV.
Novel Chikungunya Vaccine Candidate with an IRES-Based Attenuation and Host Range Alteration Mechanism  [PDF]
Kenneth Plante,Eryu Wang,Charalambos D. Partidos,James Weger,Rodion Gorchakov,Konstantin Tsetsarkin,Erin M. Borland,Ann M. Powers,Robert Seymour,Dan T. Stinchcomb,Jorge E. Osorio,Ilya Frolov,Scott C. Weaver
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002142
Abstract: Chikungunya virus (CHIKV) is a reemerging mosquito-borne pathogen that has recently caused devastating urban epidemics of severe and sometimes chronic arthralgia. As with most other mosquito-borne viral diseases, control relies on reducing mosquito populations and their contact with people, which has been ineffective in most locations. Therefore, vaccines remain the best strategy to prevent most vector-borne diseases. Ideally, vaccines for diseases of resource-limited countries should combine low cost and single dose efficacy, yet induce rapid and long-lived immunity with negligible risk of serious adverse reactions. To develop such a vaccine to protect against chikungunya fever, we employed a rational attenuation mechanism that also prevents the infection of mosquito vectors. The internal ribosome entry site (IRES) from encephalomyocarditis virus replaced the subgenomic promoter in a cDNA CHIKV clone, thus altering the levels and host-specific mechanism of structural protein gene expression. Testing in both normal outbred and interferon response-defective mice indicated that the new vaccine candidate is highly attenuated, immunogenic and efficacious after a single dose. Furthermore, it is incapable of replicating in mosquito cells or infecting mosquitoes in vivo. This IRES-based attenuation platform technology may be useful for the predictable attenuation of any alphavirus.
Imaging zebrafish neural circuitry from whole brain to synapse  [PDF]
Louis C. Leung,Gordon X. Wang,Philippe Mourrain
Frontiers in Neural Circuits , 2013, DOI: 10.3389/fncir.2013.00076
Abstract: Recent advances in imaging tools are inspiring zebrafish researchers to tackle ever more ambitious questions in the neurosciences. Behaviorally fundamental conserved neural networks can now be potentially studied using zebrafish from a brain-wide scale to molecular resolution. In this perspective, we offer a roadmap by which a zebrafish researcher can navigate the course from collecting neural activities across the brain associated with a behavior, to unraveling molecular identities and testing the functional relevance of active neurons. In doing so, important insights will be gained as to how neural networks generate behaviors and assimilate changes in synaptic connectivity.
Whole plant based treatment of hypercholesterolemia with Crataegus laevigata in a zebrafish model  [cached]
Littleton Robert M,Miller Matthew,Hove Jay R
BMC Complementary and Alternative Medicine , 2012, DOI: 10.1186/1472-6882-12-105
Abstract: Background Consumers are increasingly turning to plant-based complementary and alternative medicines to treat hypercholesterolemia. Many of these treatments are untested and their efficacy is unknown. This multitude of potential remedies necessitates a model system amenable to testing large numbers of organisms that maintains similarity to humans in both mode of drug administration and overall physiology. Here we develop the larval zebrafish (4–30 days post fertilization) as a vertebrate model of dietary plant-based treatment of hypercholesterolemia and test the effects of Crataegus laevigata in this model. Methods Larval zebrafish were fed high cholesterol diets infused with fluorescent sterols and phytomedicines. Plants were ground with mortar and pestle into a fine powder before addition to food. Fluorescent sterols were utilized to optically quantify relative difference in intravascular cholesterol levels between groups of fish. We utilized the Zeiss 7-Live Duo high-speed confocal platform in order to both quantify intravascular sterol fluorescence and to capture video of the heart beat for determination of cardiac output. Results In this investigation we developed and utilized a larval zebrafish model to investigate dietary plant-based intervention of the pathophysiology of hypercholesterolemia. We found BODIPY-cholesterol effectively labels diet-introduced intravascular cholesterol levels (P < 0.05, Student’s t-test). We also established that zebrafish cardiac output declines as cholesterol dose increases (difference between 0.1% and 8% (w/w) high cholesterol diet-treated cardiac output significant at P < 0.05, 1-way ANOVA). Using this model, we found hawthorn leaves and flowers significantly reduce intravascular cholesterol levels (P < 0.05, 1-way ANOVA) and interact with cholesterol to impact cardiac output in hypercholesterolemic fish (2-way ANOVA, P < 0.05 for interaction effect). Conclusions The results of this study demonstrate that the larval zebrafish has the potential to become a powerful model to test plant based dietary intervention of hypercholesterolemia. Using this model we have shown that hawthorn leaves and flowers have the potential to affect cardiac output as well as intravascular cholesterol levels. Further, our observation that hawthorn leaves and flowers interact with cholesterol to impact cardiac output indicates that the physiological effects of hawthorn may depend on diet.
Soedarto Soekiman
Bulletin of Health Research , 2012,
Abstract: Colonies of Aedes aegypti (Surabaya strain) and Aedes albopictus (Malang strain) were studied to compare their susceptibility to oral infection with dengue type 3 and Chikungunya viruses. Growth curves of dengue type 3 and Chikungunya viruses in these mosquitoes indicated that both mosquito species were susceptible to oral infection with these viruses. Electron microscopic observation of the salivary glands of A. aegypti and A. albopictus infected with Chikungunya virus showed that this organ plays an important role in producing and maintaining high virus titers in these mosquitoes. The results suggest that both Aedes species are potentially important vectors on the transmission of dengue and Chikungunya infection in Indonesia.
Induction of Cytopathogenicity in Human Glioblastoma Cells by Chikungunya Virus  [PDF]
Rachy Abraham, Prashant Mudaliar, Aiswaria Padmanabhan, Easwaran Sreekumar
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0075854
Abstract: Chikungunya virus (CHIKV), an arthritogenic old-world alphavirus, has been implicated in the central nervous system (CNS) infection in infants and elderly patients. Astrocytes are the major immune cells of the brain parenchyma that mediate inflammation. In the present study we found that a local isolate of CHIKV infect and activate U-87 MG cells, a glioblastoma cell line of human astrocyte origin. The infection kinetics were similar in infected U-87 MG cells and the human embryo kidney (HEK293) cells as indicated by immunofluorescence and plaque assays, 24h post-infection (p.i.). In infected U-87 MG cells, apoptosis was detectable from 48h p.i. evidenced by DNA fragmentation, PARP cleavage, loss of mitochondrial membrane potential, nuclear condensation and visible cytopathic effects in a dose and time-dependent manner. XBP1 mRNA splicing and eIF2α phosphorylation studies indicated the occurrence of endoplasmic reticulum stress in infected cells. In U-87 MG cells stably expressing a green fluorescent protein-tagged light chain-3 (GFP-LC3) protein, CHIKV infection showed increased autophagy response. The infection led to an enhanced expression of the mRNA transcripts of the pro-inflammatory cytokines IL-1β, TNF-α, IL-6 and CXCL9 within 24h p.i. Significant up-regulation of the proteins of RIG-I like receptor (RLR) pathway, such as RIG-I and TRAF-6, was observed indicating the activation of the cytoplasmic-cellular innate immune response. The overall results show that the U-87 MG cell line is a potential in vitro model for in depth study of these molecular pathways in response to CHIKV infection. The responses in these cells of CNS origin, which are inherently defective in Type I interferon response, could be analogous to that occurring in infants and very old patients who also have a compromised interferon-response. The results also point to the intriguing possibility of using this virus for studies to develop oncolytic virus therapy approaches against glioblastoma, a highly aggressive malignancy.
A Review Of Chikungunya  [cached]
Bincy Thomas,A.R.Tekade,Pande V.V
Pharmaceutical Reviews , 2007,
Abstract: Vaccines and new drugs against chikungunya are urgently needed. Chikungunya is generally not fatal.However, in 2005-2007, many deaths have been associated with chikungunya worldwide and still it is continuing. Currently there is no vaccine and fully satisfied drugs to treat all symptoms of chikungunya.Treatment are just symptomatic and in many cases improper use of NSAIDS leads to more complications. Every year 1000s are getting infected and many are dying. So it is high time to turn health organisation’s concentration to find a solution for this health issue.IntroductionThe word chikungunya meaning "that which bends up", which is derived from its arthritic symptoms. It is the hottest topic of discussion among public today, so is necessary to know the causes, symptoms, treatment and preventive measures of this viral fever. Usually chikungunya virus or CHIKV is spread by mosquito bites from Aedes aegypti mosquitoes, Aedes albopictus (Tiger mosquito), Aedes luteocephalus, or A. taylori.. There is no reported case of human-human transmission of CHIKV. The outbreak of infection and studies about it reveals that people living near to forest and water stores are more prone to this viral desease, since these areas provide better environment for mosquito breeding.High fever and arthritic pain, especially severe pain on extremes is characteristic of chikungunya fever. In allopathic, treatment is based on the symptoms and no preventive drugs are available. Siddha system claims some medicines for both treatment and prevention, but is not scientifically proven. By taking proper precaution against mosquito bites by using insecticides, repellents and other measures, transmission of CHIKV can be prevented to greater extent.
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